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PMC4911217_01

Female

The proband 1 is a 24-year-old female with history of episodic loss of coordination, dysarthria, and visual disturbance resembling cataplexy. She was asymptomatic until 5 years when an episode of slurred speech and "wobbly" legs without falling to the ground associated with fever was noted. This first episode resolved spontaneously after a few minutes and without sequelae. Following this, she had very frequent, brief (30 s-2 min) episodes occurring often with playing sports like basketball and cross-country running and associated with the excitement of returning to the basketball court, starting or finishing a cross-country race. During the spells, she could not handle the basketball or felt her knees become weak and her legs "rubbery" causing her to slow down or fall. She also reported spells when sitting in class feeling stressed. She did not take naps and reported no excessive sleepiness. Because of the resemblance of the spells to cataplexy, at age 12, the patient was prescribed clomipramine, 25 mg every night at bedtime. She responded well to treatment without side effects and with abatement of spells and improved sports performance. At age 16, she took herself off clomipramine (75 mg/day) because of depression and emotional lability. History of feeling tired and sleepiness in class prompted a polysomnogram followed by a Multiple Sleep Latency Test (MSLT), while off clomipramine, to investigate the possibility of narcolepsy. Her polysomnogram was essentially normal, and she was given a presumptive clinical diagnosis of isolated cataplexy. Her brain MRI at 12 years age was normal except for a small right subcortical frontal area of gliosis of uncertain significance, essentially unchanged on a follow-up brain MRI 13 months later. At age 21, she presented again with renewed difficulty competing in track events after a relative stability during her first 3 years of college. She was asked to do a strenuous exercise in the office, and a spell was elicited. She had difficulty extending her legs, developed a head tremor, bilateral dysmetria in the arms and legs, tremulous voice, needed to sit down, and was without nystagmus. She was diagnosed with episodic ataxia and started on acetazolamide with a decrease in the frequency of spells, but this was discontinued because of depression. She was then evaluated by the genetics team and serum creatine phosphokinase (CPK), and acylcarnitine and amino acids along with urine organic acids were performed that returned within normal limits. She has a significant family history of similar episodes on her maternal side, which appears to be inherited in a dominant fashion. Other family members had a similar age of onset as well as a decrease in severity and frequency of episodes over time. In all affected members of this family, the precipitating factors for these episodes appeared to be rapid-onset muscle contractions. The patient and her family members reported an increase in the frequency of these episodes related to the menstrual cycle (for females), inter-current illnesses, particularly with fever, and at times of emotional stress. Caffeine and alcohol also exacerbated the episodes. Additional triggers included cold weather and postural change. Headache, tinnitus, hearing loss, vertigo, and scotomas were not reported (Table 1).

cataplexy, episodic ataxia, hypertonia, kcna1, whole exome sequencing

PMC8059039_01

Female

A 47-year-old woman presented with intermittent cough, shortness of breath, fever, and body temperature up to 38.5 C, accompanied by right eyelid swelling around June 17, 2017, which worsened day by day. Weight loss was about 9 kg. On July 5, 2017, she visited a local hospital and received both eyes and head computed tomography (CT) scan, no obvious abnormalities were found. Chest CT showed pulmonary infection with a high possibility of fungal infection, and a small amount of pleural effusion in the left lung. She received antibiotics about 10 days, but the symptoms appreciated no improvement. Later, the patient had aggravated the above symptoms and developed high fever with the highest body temperature of 39.4 C. As a result, the patient was transferred to our hospital with "pulmonary infection" on July 17, 2017. Physical examination included a high body temperature of 39 C, right eyelid swelling and a painless enlarged lymph node about 2 cm x 2 cm in size was in the left axilla. The auscultation of the lungs had coarse respiratory sounds with the moist rale. No hepatosplenomegaly and edema in lower limbs. Laboratory data revealed decreased leucocyte (1.50 x 10-9/L) and hemoglobin (88 g/L), raised aspartate transaminase (AST) (61 U/L), and lactate dehydrogenase (LDH) (724 U/L). Galactomannan (GM) test was positive and plasma (1,3)-beta-D-glucan (G) test was negative. Coagulation function, kidney function, ferritin, and erythrocyte sedimentation rate were all normal. An infectious origin was ruled out by sputum culture and acid-fast staining, and blood culture. HIV, hepatitis, and syphilis test panels were negative. Her autoimmune workup was negative. Reexamination of chest CT showed interstitial exudation in both lungs, mass lesions, and left pleural effusion, still considering fungal infection (Figure 1(a)). Bronchoscopy showed acute inflammatory changes in the bronchial mucosa. The above clinical findings indicated suspected aspergillosis pneumonia. After symptomatic treatment with antibacterial, fungal, and leucocyte-elevating, her systemic symptoms such as fever, cough, and eyelid swelling improved, and leucocyte increased. Reexamination of orbital and chest CT showed no abnormalities in the orbit, but interstitial exudation of both lungs and left pleural effusion were more than the previous CT scan. On August 4, 2017, positron emission tomography (PET)-CT images showed multiple spherical lesions and ground glass-like increased images in the lungs, with significant lower lobe, and mostly hypermetabolic activity; left pleural and right interlobular effusion. Biopsy of hypermetabolic nodules in the chest wall revealed difficulty in differentiating inflammation and tumor, and PCR was negative for tuberculosis in paraffin-embedded tissue. Anti-infective treatment was continued and the patient was discharged 1 week later due to improvement in symptoms. However, fever returned after a brief respite and did not improve. She revisited our hospital on August 28, 2017. Reexamination of chest CT exhibited a reduced volume of multiple lesions of both lungs, and the interstitial exudation was slightly absorbed compared to before. A blood reexamination revealed re-decrease of leucocyte, higher levels of AST and LDH than in the first admission, and raised blood beta2 microglobulin (2549 ng/Ml). A of biopsy of the lung tissue was performed and revealed a high number of inflammatory cells infiltration in the pleural. Anti-infective treatment was ineffective, and her fever was unremitting, along with right thigh redness, swolling, heat, and painful (Figure 2(a) and (b)). On September 1, 2017, vascular ultrasound of the right lower limb showed intermuscular venous thrombosis, enlarged inguinal lymph nodes (multiple), and subcutaneous soft tissue edema with interstitial effusion on the lateral thigh. The patient underwent surgical decompression of fascial compartment and pathological biopsy of neoplasm (subcutaneous neoplasm, muscle interstitial neoplasm) of the right limb on September 4, 2017. Histopathological examination demonstrated focal rimming of individual adipocytes by infiltrating small to medium-sized atypical T lymphocytes with irregular and hyperchromatic nuclei. Immunohistochemistry exhibited positivity for CD3, CD8, granzyme B (GB), CD43, and T-cell intracellular antigen-1 (TIA-1), and negativity for CD4, CD56, CK, and CD79, Ki67 staining positive was 50% (Figure 3(a)-(d)), which led to a pathological diagnosis of SPTCL. A monoclonal rearrangement of TCR-beta gene was confirmed by polymerase chain reaction (PCR). Bone marrow aspiration suggested proliferative anemia and infection, and bone marrow biopsy had no lymphoma cells infiltration. A final diagnosis of SPTCL (IIB phase, IPI scores of 2) was made. She was treated on September 15, 2017 with etoposide, vincristine, cyclophosphamide, doxorubicin, and prednisone (EPOCH) chemotherapy. After two cycles of chemotherapy, the patient's clinical symptoms were not significantly improved, she still had intermittent fever and shortness of breath, the enlarged lymph node in the left axillary did not noticeably shrunk, and the swelling of right thigh was not significantly reduced. Considering obvious systemic symptoms of the patients and chidamide is effective in PTCL, an attempt was made to add chidamide (30 mg BIW oral) to the chemotherapy from the third cycle. Fortunately, the patient responded well with resolution of all systemic manifestations of disease within four cycles of combined chemotherapy with chidamide, the patient had normal body temperature, significant improvement in cough and shortness of breath, and complete resolution of enlarged lymph node of left axillary and swelling of right thigh. Additionally, the chest CT showed that the lung lesions were significantly diminished (Figure 1(b)), and the right thigh magnetic resonance imaging (MRI) showed no obvious abnormal signal in subcutaneous and layers of muscle group (Figure 4). The efficacy was evaluated as CR, and patient was recommended to undergo HSCT as consolidation for long-term disease control, but the patient declined HSCT treatment, so she continued to underwent two cycles of EPOCH chemotherapy combined with chidamide. CR was evaluated again after six cycles of combined treatment, followed by chidamide monotherapy for maintenance. The last follow-up date was on January 16, 2020, and remission has been maintained. Written informed consent was obtained from the patient's legally authorized representative for publication of this case report and accompanying images.

chidamide, histone deacetylase inhibitor, long-term remission, subcutaneous panniculitis-like t-cell lymphoma

PMC6611383_01

Female

The case is a female, Filipino child born at 37 weeks' age of gestation. Her skeletal dysplasia was identified on fetal anomaly scanning during pregnancy and was diagnosed with achondroplasia after birth. She was the third and youngest child to a 36-year-old mother and a 37-year-old father. She has a healthy and neurotypical older sister and brother. The parents were not consanguineous and have no known genetic abnormalities in their family history. Her birth weight was 1,390 g (less than the third percentile, World Health Organization (WHO)), birth length was 40 cm (less than the third percentile, WHO), and head circumference was 32 cm (third to 15th percentile, WHO). Her physical features at birth were described as having proportionately small frontal bossing and dolichocephaly with infraorbital creases. She had a relatively small thoracic cage, which was proportionate to her size. There were no gross rhizomelia or acromelic shortening of limbs. She had bilateral simian creases, bilateral fifth digit midphalanx hypoplasia, and hypoplastic toenails. External genitalia were grossly female. Peri-natal care included 17-day confinement in the neonatal intensive care unit for hyperbilirubinemia and antibiotic treatment with amikacin and ampicillin for suspected sepsis. Newborn screening and otoacoustic emission tests were normal. She was breastfed for 2 months, after which she was started on formula milk. She has frequent respiratory infections but does not have a history of recurrent ear infections. She also had an exposure to tuberculosis, which was managed with isoniazid for 6 months. Bone aging reports were normal. At the age of 6 months, delays in motor, language, socio-emotional, and cognitive development were observed. Her fine motor skills included visually tracking, grasping a rattle, and holding her hands together but not yet regarding and reaching for objects. Her gross motor skills were almost of a newborn wherein she was not able to hold up or lift her head. Her language skills included vocalizations, turning to sounds and voices, and laughing but did not yet imitate speech sounds or babbled. Her personal-social skills included regarding faces and smiling responsively and spontaneously but not yet regarding her own hands or feeding herself. Anthropometric measurements were as follows: body weight was 4,100 g (less than the third percentile, WHO), body length was 53 cm (less than the third percentile, WHO), and head circumference was 42.5 cm (50th percentile, WHO). Physical examination revealed universal hypotonia, with a preference for the right hand. At the age of 17 months, she had improvements in her developmental skills with more motor imitations, vocalizations, and babbling and the ability to follow simple commands. Physical examination continued to show poor muscle tone, flat foot, and joint laxity. She had difficulty feeding as she choked on solid food and had frequent regurgitation. A gastroenterologist assessed her to have gastroesophageal reflux due to hypotonia. She was advised to have slower, smaller feeding to help in her digestion. The issues with reflux resolved by 30 months of age. In the next 2 years, the child continued receiving physical, occupational, and speech therapy. Table 2 presents her developmental skills acquisition. It is compared with the skills acquisition of other children with achondroplasia in a study by Ireland et al. By the age of 27 months, her parents began noticing her poor social skills such as fleeting eye contact, not turning to her name being called, and not pointing or requesting for her needs. Despite undergoing early intervention services, she continued to demonstrate delays in all developmental domains. A summary of her progress and developmental quotient using the Griffith Mental Development Scales is presented in Table 1 . At 39 months, she meets the DSM-5 criteria for autism spectrum disorder, manifested by her delays in communication and social skills. She also presented with repetitive and stereotypic behaviors such as a fascination of shadows and hand flapping and would demonstrate repetitive tapping of objects (i.e., pencil) and her hands against hard surfaces like the table. The Autism Diagnostic Observation Schedule (ADOS-2), Module 1, was administered at 39 months, and she received an additional diagnosis of autism spectrum disorder. The Autism Diagnostic Observation Schedule is a semi-structured standardized assessment of communication, reciprocal social interaction, play, and imaginative use of materials. Module 1 of the assessment was used, which consisted of 10 activities that focused on playful use of toys and other concrete materials. The child's communication score was 6 (cut-off = 4), and social interaction was 8 (cut-off = 7), which both reached the cut-off for autism. Management of her developmental delays and behavioral concerns continues to be targeted through speech and language therapies that focus on pre-language skills, pragmatics, and communication of her needs and wants. She also continues occupational therapy and physical therapy to address her motor skills, activities of daily living, and sensory processing concerns. She receives special education with focus on self-regulation and engagement, and behavior modifications to allow her to be involved in learning activities.

achondroplasia, autism spectrum disorder, developmental delays, neurodevelopmental disorders

PMC6837770_01

Female

A 34-year-old gravid female was referred to a tertiary hospital at 38+ weeks with a large cystic pelvi-abdominal (PA) mass detected on ultrasound. She had no known medical co-morbidities and one previous uneventful pregnancy culminating in a normal vaginal delivery (NVD) at full term. On presentation, the patient was asymptomatic and examination revealed only an increased symphysis-pubis fundal height (SFH) for expected gestation. Urine analysis showed proteinuria and blood tests revealed a minimally elevated cancer antigen-125 of 48 kU/L (normal range 0-35 kU/L) and a normal carcinoembryonic antigen level of 0.7 ng/mL (normal < 5.0 ng/mL). Transabdominal ultrasound showed a thick-walled cystic mass measuring approximately 25 cm x 14 cm x 15 cm with no internal vascularity. The mass was assumed to be ovarian in origin. A singleton intra-uterine pregnancy with foetal heartbeat was confirmed. A transvaginal ultrasound scan was not performed. The decision was made to induce labour based on the unclassified proteinuria and the clinical suspicion of possible underlying pre-eclampsia. During the induction of labour, foetal monitoring showed subtle signs of foetal distress, which warranted continuous monitoring, but despite in-patient care and continuous foetal monitoring, there was subsequent intra-uterine foetal demise and the patient delivered a stillborn baby via NVD. Following delivery, the patient's condition deteriorated in the ward, developing a persistent unexplained tachycardia of approximately 150 bpm, a blood pressure of 156/119 mmHg and a serum calcium level well above normal limits (4.25 mmol/L, normal limit is 2.62 mmol/L). Emergent cross-sectional imaging in the form of contrasted CT abdomen showed a large cystic mass with a thick, irregular enhancing wall and septations (Figure 1), which was inseparable from the uterine fundus (Figure 2). In addition, extensive left ovarian and pelvic vein thrombosis (Figure 3) and an enlarged, poorly enhancing left ovary were noted (Figure 4). Exploratory laparotomy revealed a large, friable, thick-walled, pedunculated fundal mass, left ovarian vein thrombosis, necrosis of the left ovary and broad ligament and offensive intra-uterine contents. The decision to proceed to total abdominal hysterectomy and left salpingo-oophorectomy was taken based on significant intra-operative bleeding, friable necrotic tissue and haemodynamic instability. Histopathological evaluation revealed a subserosal uterine leiomyoma with extensive hyaline degeneration and necrosis, left ovarian vein thrombosis, haemorrhagic infarction of the left ovary and endometrial and myometrial necrosis. No patient identifiable information has been presented. Informed verbal consent was obtained from the patient prior to publication.

leiomyoma, hypercalcaemia, ovarian vein thrombosis, pregnancy, intra-uterine foetal demise

PMC5449724_01

Male

An otherwise healthy 75-year-old man had a spontaneous collapse on a golf course, witnessed by other club members. He had no pulse and was not breathing and received cardiopulmonary resuscitation (CPR) from a bystander. After 15 minutes of CPR, a public automated external defibrillator (AED) was appropriately deployed, and he received one shock, following which he appeared to regain some consciousness. Due to the rural location, the fastest prehospital transport to the scene was by air ambulance. A crew of two Critical Care Paramedics (CCPs) arrived to find the patient placed in the recovery position, spontaneously ventilating, with a palpable pulse, adequate blood pressure, normal oxygen saturation readings, and normal blood glucose. A 12-lead ECG showed no acute abnormalities. The patient had a reduced Glasgow Coma Scale (GCS) and a unilateral fixed, dilated pupil. He exhibited trismus and occasional decorticate posturing. History from the patient's wife (via telephone) was that earlier in the morning he had slipped on some ice and fallen over, hitting his head, but had decided that he was well enough to play golf. Raised intracranial pressure was considered a possibility due to these signs. The patient was given high flow oxygen via a nonrebreathing mask and the airway was managed to good effect using basic manual techniques and a nasal pharyngeal airway. Determining the aetiology of cardiac arrest in the prehospital environment can be difficult, and some of the differential diagnoses in this case included traumatic brain injury, acute myocardial infarction, or cerebrovascular accident. The CCPs made a decision to convey the patient to a Major Trauma Centre that had neurosurgical and cardiology specialist expertise, rather than the nearest hospital. When he arrived at the Emergency Department, he was anaesthetised and underwent rapid sequence induction. A head CT was performed, and this was reported as normal. He then proceeded to undergo coronary angiography, which demonstrated an occlusion of two coronary arteries. He underwent percutaneous coronary intervention (PCI) via the right radial artery, with angioplasty and stenting of the right coronary artery, left main stem, and proximal left anterior descending coronary artery. During his inpatient stay, he informed medical staff that his left pupil has been permanently dilated since he was a boy, following a traumatic ocular injury whilst playing football (shown in Figure 1).

PMC10126506_01

Male

The participant was a 25-year-old, right-handed male, who has been playing the NBA2K basketball games for 5+ years, totaling over 4,000 h. The participant was seated in front of a 24'' monitor at roughly 15" distance from a Tobii 5L Eye Tracker (Tobii AB, Sweden). The monitor was connected to a PlayStation 4 (Sony Interactive Entertainment, San Mateo, CA) console. The video was captured through an Elgato HD60 S+ (Elgato Systems GmbH, Germany) capture card at native 60fps. Using corneal reflection (by illuminating the eye with infrared light and measuring the reflection from the cornea and the pupil), pupil diameter data was collected through Tobii 5L Eye Tracker sampling at 120 hz (For information on the accuracy and precision of Tobii 5L, please, see). EEG data were collected using a Neurosity Crown (Neurosity Inc., San Francisco, CA) EEG device (8 channels, 256 hz). The game was NBA2K 22 Basketball for the PlayStation 4, and the primary game mode was the Recreational Center, which is a 5-on-5 competitive game mode but is not ranked. The participant played 11 times in 1 day with breaks of 10-60 min in between. The recordings took place on 22 April 2022. To investigate the dynamic interactions over time, we chose three recordings (first, sixth, and eleventh), namely, Sessions 1, 2, and 3. Session 1 started at 14:51 (Pacific Time), Session 2 started at 19:12, and Session 3 started at 23:58. They all lasted about 30 min. Lighting was the same throughout and no stimulants were used. EEG signals were recorded from four brain locations: P03, P04, CP3, and CP4 via the Neurosity Crown. That EEG device was connected via Wi-Fi and using the LabStreamingLayer (LSL) functionality provided by Neurosity. The LSL stream was connected to CuriaRecorder (Curia LLC, Dublin, CA), which is a fork of the open-source Labrecorder app provided by LSL. The CuriaRecorder is designed to subscribe to and record LSL streams, keeping timestamping and jitter information. The raw data was stored and preprocessed into native XDF format, after which it was run through basic de-noising (i.e., data >4SD of the dataset is removed). Finally, the raw and preprocessed data was made available and a final processing pass was performed. The recording was cut into 15-s intervals. Calculations were performed on these 15-s intervals as single data points. This technique allows long recordings to show the trends over time while being broken into discrete 'bins' that calculate the data independently. For example, in order to collect data on eye movements, the utilized eye tracking device recorded at a sampling rate of 120 Hz. This resulted in a total of 1800 samples being collected within a 15-s processing window, representing the left pupil size in millimeters. The mean of these 1800 values was calculated and stored as the average for that 15-s window. Over the course of an 8-h data collection period, this design resulted in the storage of approximately 3.5 million values for the left pupil size alone. Given the large number of data points collected, and the potential for device noise and cumulative error over the prolonged data collection period, subsampling of the data was employed to "sparsify" the data and facilitate the identification of long-term trends while minimizing short-term variation in any given sample or bin. The subsampled data was extensively tested against the full sample data for both accuracy and various parameters, ranging from 5 to 60-s "chunks". It was determined that a 15-s processing window provided the desired benefits in processing without altering the shape of the data or the trends that emerged when compared to full sample recordings. The Tobii 5L Eye Tracker was connected via USB3 to the collection system and was using Curia-written LSL broadcasters that take the Tobii datastream from the API and also push it to LSL as a datastream. Using the same acquisition method (i.e., the CuriaRecorder), the Tobii LSL streams were recorded with accurate timestamps and jitter information. They were also stored in LSL native XDF format. The data were preprocessed for outliers, stored as raw and preprocessed data, and finally cut into the same 15-s subintervals for comparison between time points. Concerning extraction of outliers, the process for cleaning EEG data involves performing a 4-SD removal pass, followed by a 2 SD removal pass. The first step in the process is to calculate a rolling standard deviation of the data with a 1-s window. A threshold is then calculated by taking the 0.3 quantile of these values and multiplying it by 4, resulting in a threshold of 691 muV in this example. Any values (absolute values) exceeding this threshold, plus or minus 691 muV, are rejected and set to 0 for subsequent calculations. For an example channel with 380,000 samples, 866 samples were rejected for exceeding the threshold. The second pass is a standard z-score and 2 SD removal for each channel once the first pass is complete. For pupil data, an exponentially weighted smoothing algorithm is applied to the pupil and gaze values to compensate for the potential introduction of noise by the 120 Hz eye tracking device. This algorithm uses the pandas exponentially weighted mean (EWM) functionality, which is similar to a median filter. The smoothing factor used in this implementation is 0.3 (equivalent to moving the smoothing slider in "Tensorflow" for Python). The relevant code section is provided as Supplementary Material. Of note, in the present study, we employed two distinct methods to address noise (i.e., any undesired or extraneous signal that is not generated by the brain) and outlier (i.e., data points that deviate significantly from the rest of the data and may indicate errors in the recording or data processing) removal from EEG data. The fundamental difference between the two methods is that the 4-SD removal pass was solely directed towards noise reduction in the raw data, while the combined usage of 4-SD and 2-SD removal passes were primarily employed for removing outliers from preprocessed data. As stated above, the sampling frequency of the Tobii 5L eye tracker and Neurosity Crown EEG were 120 Hz and 256 Hz, respectively. In order to facilitate a comparison between the two datasets, it was necessary to establish a common sampling frequency. Utilizing the "scipy" resample function within the Python programming language, the eye tracking data, stored in a Pandas dataframe, was upsampled to 256 Hz to align with the EEG data. The decision to upsample the eye tracking data rather than downsample the EEG data was made based on the tradeoffs between frequency resolution and the potential loss of information. Therefore, the sampling frequency for both Neurosity Crown and Tobii 5L Eye Tracker was 256 Hz. Section 2.2-Section 2.5 summarize the main steps for the spectral decomposition and cross-correlations analysis (for a detailed explanation of the entire procedure, please see). We first segmented the previously pre-processed signals (see Section 2.1. for details) from each brain location and eye into 2-s time windows with a 1-s overlap across each session. Within each 2-s time window, we extracted the spectral power S(f) from each EEG/EYE signal using the 'pwelch' function in Matlab, based on the discrete Fourier transform (DFT) and the Welch's overlapped segment averaging estimator. For each time window, we obtained a spectral power value in bins of 0.5 Hz (fbin) for the range from near 0 Hz to the Nyquist frequency, fN, of 128 Hz (i.e., the half of the sampling frequency of 256 Hz), which renders the total number of spectral estimates, N, for each window of 2 s N = fN * (1/fbin) = 256; that means that N = 256 is the number of spectral power data points for each window of 2 s. To probe specific contributions from different frequency bands fi to the spectral power within each 2-s time window of the EEG/Eye signal, we considered seven frequency bands corresponding to the commonly utilized cortical rhythms: delta (0.5-3.5 Hz), theta (4-7.5 Hz), alpha (8-11.5 Hz), sigma (12-15.5 Hz), beta (16-19.5 Hz), gamma1 (20-33.5 Hz), and gamma2 (34-98.5 Hz). We calculated the average power across all frequency bins within each frequency: , where are all frequencies considered in each frequency band. Thus, we obtained seven time series of EEG/Eye band power with 1-s resolution for each Brain Location/Eye. Based on the exploratory nature of this research (e.g., investigating the linear relationship between two time series data sets), for each protocol session and each pair of Brain location-Eye (a total of eight different Brain Location/Eye combinations), we calculated the bivariate equal-time Pearson's cross-correlation for all pairs of time series representing EEG/Eye spectral power in the frequency bands fi, where i = 1, ... ,7. This led to 49 (7 x 7) cross-correlation values Ci,j for each pair of Brain Location-Eye, as shown in the cortico-ocular cross-correlation matrices (Figure 1). The cross-correlation values range from Ci,j = -1 (fully anti-correlated) to Ci,j = 1 (fully correlated), with Ci,j = 0 indicating the absence of a linear relationship between the power spectra of two EEG/EYE frequency bands. Cortico-ocular cross-correlation matrices represent pairwise coupling strength between the seven frequency bands fi of one brain location with the same bands derived from one Eye (i.e., eight distinct pairs: CP3-Eye Left, CP3-Eye Right, P03-Eye Left, P03-Eye Right, P04-Eye Left, P04-Eye Right, CP4-Eye Left, and CP4-Eye Right) during a given session (Figure 1A). Matrix elements indicate the coupling strength between the band-wise power of EEG signal in a given Brain Location and the pupil diameter dynamics in one Eye. To visualize the information provided by the cortico-ocular cross-correlation matrices, we mapped the matrices in Figure 1 into different networks for Session 1, Session 2, and Session 3. Each brain location and the Eye is represented by a semicircle/circle, where color nodes represent distinct frequency bands fi. Network links correspond to the values of cross-correlation matrix elements Ci,j in Figure 1. Link strength is marked by line color and width. To illustrate the differences in network organization, we used the following link strength classification: positive links [Ci,j > 0.17; dark red); weak positive links (0.12 < Ci,j < 0.17; light red); negative links (Ci,j < -0.17; dark blue)] and weak negative links (-0.17 < Ci,j < -0.12; light blue). Links corresponding to cross-correlation values -0.1< Cij < 0.1 (Figure 2) are not shown in the network maps. Note that this set of thresholds was arbitrarily selected to provide the best visualization for the main results of the study shown in the cross-correlation matrices (Figure 1). To visualize the hierarchical organization of cortico-ocular network interactions among Brain Locations and Eyes, all multiplex networks (Figure 2) are presented separately as sub-network maps for all pairs of Brain Location-Eye (Figures 3, 4). Each sub-network map corresponds to a pair for a given Brain Location-Eye and follows the same color code as in the original network. Due to space limitations, we only present the sub-networks for the right hemisphere: P04-Eye Left, P04-Eye Right, CP4-Eye Left, and CP4-Eye Right (Figures 3, 4). The results for the left hemisphere (P03-Eye Left, and P03-Eye Right, CP3-Eye Left, CP3-Eye Right) are shown in Supplementary Figures S1, S2. To examine the changes in the relationships between the frequency bins of each subnetwork pair across time, we used a multi-step process. It should first be noted that the correlation between sub-network pairs at each time point was based on 900 observations (i.e., one observation every 2 seconds for each 30-min session), which rendered statistical significance even for very small correlations. Thus, we examined the changes in standardized estimates of association (i.e., Cohen's q) across time. For all sub-networks examined, the correlation between frequency bin 1 for one node and frequency bin 7 for the second node of each pair changed considerably over time (see Supplementary Figure S3). For example, the correlation in the P04-Left Eye sub-network changed from 0.12 in Session 1 to -0.51 in Session 3.

eeg, brain waves, curia, esports, eye tracking, pupillometry, sport neuroscience

PMC4573207_01

Male

A 23-year-old male patient was admitted to our clinic due to progressive difficulties in swallowing and a constant weight loss of 23 kg, which had developed over the past three years. During meals, dysphagia was overcome by drinking water. Additional symptoms were retrosternal pain, regurgitations (Eckardt score of 10), and respiratory ailments. While the laboratory results did not show any abnormalities, a computed tomography (CT) scan of the chest revealed a massive extension of the esophagus starting proximally of the cardia up to cervical vertebral body 7. The consequence of this megaesophagus was a transversal widening of the mediastinum up to 6.7 x 5.2 cm in diameter accompanied by a consecutive slit-shaped cranial narrowing of the trachea (Fig. 1). Due to the twisted passage of the esophagus, a standard manometry was not feasible. Upper endoscopy did not show any pathological alterations in the mucous membrane of the esophagus, stomach or duodenum. Due to the age of the patient and his physical complaints we performed a laparoscopic Heller myotomy with anterior semi-fundoplication 180 according to Dor. Because of the profound tracheal stenosis, intubation was done with fiber optic equipment. Intraoperative findings revealed a distinctive thickening of the muscularis at the high-pressure zone of the LES. Surgical myotomy was performed by incision of muscle fibers with a length of 7.0 cm at the distal esophageal body and additional 2 cm at the proximal stomach. Due to the complicated intubation conditions, for safety reasons, the patient was transferred intubated and ventilated to the intensive care unit. Peri- and post-operative courses were uneventful. The patient was extubated one hour after surgery without complications. After the transfer to the patient ward, he was gradually accustomed to normal diet. He initially complained about occasional heartburn, which was successfully treated with proton-pump inhibitors. Five months after surgery, the technical postoperative findings appeared normal. The physical examination did not reveal any pathology. Body weight remained stable and retrosternal pain and regurgitations disappeared, resulting in an Eckardt score of 1. The patient tolerated normal diet very well. Conventional postoperative esophageal manometry showed a resting pressure of 5.6 mmHg. The barium swallow test detected a residually altered morphology represented by diminished motility and disturbed contractions. In addition, the barium remained for an extended time within the esophageal body and complete emptying of the stomach was only possible by drinking copious amounts of water (Fig. 2). The performed tracheal X-ray imaging did not present a tracheal compression any longer. Overall, the patient was gratefully satisfied with the early postoperative result. Three and a half years after surgery, the structured interview demonstrated good results. Besides minor difficulties and pain in swallowing during meals, the patient presented in a very good clinical condition with an Eckardt score of 2. The initially reported symptoms of dysphagia, regurgitation, and respiratory ailments were absent.

achalasia, megaesophagus, tracheal compression

PMC3643046_01

Female

A 55-year-old Caucasian woman was diagnosed with type 2 DM 15 years prior to presentation. Her DM remained uncontrolled with fasting blood glucose (BG) values ranging between 300 mg/dl and 400 mg/dl, and as high as 500 mg/dl in the recent past as measured by her Ascensia Contour which reports plasma values. Her most recent hemoglobin A1C (A1C) was 8.0% and previously was 8.4%. Antidiabetic medications included metformin 500 mg TID, glimepiride 4 mg BID, and NovoLog 70/30 Mix FlexPen 50 units BID. The patient reported adherence to all drug therapies, no previous hypoglycemic symptoms or episodes, and received diet counseling at most appointments. Other medical conditions and medications included the following: obesity (body mass index [BMI] 40.3, 110 kg) treated with diet and exercise, insomnia treated with zolpidem 10 mg qHS prn, depression treated with bupropion XL 300 mg daily and alprazolam 0.5 mg TID, hypertension treated with valsartan/hydrocholorthiazide 160/25 mg daily, dyslipidemia treated with rosuvastatin 10 mg daily, and heartburn treated with lansoprazole 30 mg daily. Due to continued elevated BG values, sitagliptin was added to her current therapy; no other medication alterations were made at this time. As the patient's creatinine clearance (CrCl) was normal (serum creatinine [SCr] 0.7 to 0.8 mg/dl) sitagliptin was dosed at 100 mg daily, which she administered at 6 AM. At the patient's visit, 10 days later, she reported fasting, lunch-time, and afternoon BG values of 200 mg/dl, 100 mg/dl, and 200 mg/dl, respectively. She was particularly concerned about several low values around 50 mg/dl that consistently occurred at 10 AM with symptoms of diaphoresis, tachycardia, and ataxia. In response, glimepiride was discontinued, and her insulin was slowly self-titrated downward to 36 units BID. All other medications and doses were maintained. Two months following sitagliptin initiation her A1C had decreased to 6.7% and her morning BG values ranged between 108 and 130 mg/dl while evening values were always less than 170 mg/ dl. Periodically BG levels nadired in the upper 60s mg/dl with minimal hypoglycemic symptoms. Approximately one year after sitagliptin initiation, the patient's Medicare Part D plan required a prior authorization (PA). The patient was unable to pay full price for sitagliptin and was without the medication for three days. During this time all other medication doses remained the same and she experienced no symptoms of hypoglycemia or documented BG less than 70 mg/dl. While the insurance provider was contacted the patient was provided with samples of sitagliptin and again mild hypoglycemic events immediately presented. The PA was submitted with proof of efficacy (decline in A1C) and other medications previously and currently used. The PA was promptly rejected and an appeal was denied. During a follow-up phone conversation, a representative from the Medicare Part D provider explained sitagliptin would continue to be rejected because of the off-label combination with insulin regardless of the patient's disease state improvements. The clinician plans to provide the patient with sitagliptin samples until she is able to switch Medicare Part D plans in hopes of regaining sitagliptin coverage.

dpp-iv inhibitor, diabetes, drug-induced, hypoglycemia, off-label, sitagliptin

PMC4074854_01

Unknown

The other study reports the administration of a gluten-free casein-free modified KGD (1.5:1 lipid:non-lipid ratio; medium-chain and polyunsaturated FA) for 14-months to a 12-year-old child with ASD and seizures with substantial medical comorbidities associated with a family history of metabolic and immune disturbances. Due to the improvements in seizure activity, improved electroencephalogram, cognitive and social skills, language function, and complete resolution of stereotypies, anticonvulsant medication doses were reduced without worsening of seizures. Of note, the administration of the diet was accompanied by a wealth of medications, a significant weight loss, and transitioning to puberty, so it is difficult to assess the sole role of the diet with this clinical background. In mouse models of ASD [i.e., Rett syndrome, BTBR model, and succinate semialdehyde dehydrogenase (SSADH) deficiency ], the use of the KGD has improved behavioral abnormalities (increased sociability and decreased self-directed repetitive behavior) and/or decreased the number of seizures, normalized ataxia, and increased lifespan of mutant mice. However, while the KGD was originally designed to be administered under controlled caloric intake, most of the mouse studies have been performed under ad libitum conditions and/or for a relatively short period [see Ref. ]. Moreover, a ketogenic low-carbohydrate diet does not have a significant metabolic advantage over a non-ketogenic low-carbohydrate diet as judged by equal effects in body weight reduction and decreased insulin resistance; however, the former one was associated with higher inflammatory risk and increased perception of fatigue. Although the exact molecular mechanisms underlying the effect of the KGD are still under investigation, several scenarios are reported below to explore the potential therapeutic effects of the KGD in ASD. Peripheral blood mononucleated cell (PBMC) from children with high severity scores for ASD has shown impaired PDH activity. The KGD is recommended as an alternative source of the acetylCoA in patients with pathogenic mutations in PDH- or GLUT1-encoding genes leading to amelioration of some symptoms especially in those with milder phenotypes. Thus, the use of the KGD in ASD with PDH deficiencies might prove to be beneficial. Some patients with ASD have been reported to have defects in fatty acid beta-oxidation evidenced as long-chain acyl dehydrogenase deficiency and high concentrations of short or long acyl-carnitines in plasma. Carnitine biosynthesis has been recently identified as a risk factor for ASD. Thus in these cases, it is advisable to limit the use of a high-fat diet or improve its safety by switching to short or medium-chain FA, which do not utilize the carnitine system. The KGD might improve mitochondrial function by enhancing mitochondrial biogenesis in murine models. The medium-chain triglyceride diet has been shown to produce significant increases in citrate synthase and Complex I activity in SH-SY5Y neurons. However, the increases in mitochondrial mass would need to result in an OXPHOS outcome of >=30% [30% as the limit for minor diagnostic criteria of mitochondrial RC disorder ] for that particular tissue, given that each tissue has a different ATP threshold. Otherwise the increases in mass might not be sufficient to rescue the already impaired ATP production in ASD individuals. Moreover, given the presence of mitochondrial DNA (mtDNA) deletions in PBMC from ASD, the KGD-driven mitochondrial biogenesis may result in an enrichment of defective mitochondria due to the proliferating advantage of damaged or deleted mtDNA over wild-type. Conversely, treatment of cells containing large-scale mtDNA deletions from a patient with Kearns-Sayre syndrome with KB shifted the heteroplasmy between and within cells. The observation that KB can distinguish between normal and respiration-compromised cells suggests that the KB may be useful in treating patients with heteroplasmic mtDNA disorders. Children with ASD display an array of mitochondrial dysfunction (MD) of differing severity. Electron transport chain (ETC) deficiencies have been reported in ASD, primarily in Complex I and IV, but also affecting others such as Complex II, III, and IV. The prevalence of seizures (41%) has been observed to be significantly higher in individuals with ASD and MD than in the general ASD population (11%), raising the possibility that epileptic episodes observed in ASD might have a mitochondrial origin. Indeed, epilepsy is a recurrent feature of many inherited "classic" mitochondrial disorders, like myoclonic epilepsy with ragged red fibers, mitochondrial encephalopathy with lactic acidosis, and stroke-like episodes, and Leigh syndrome. In a small study on children with ETC defects (Table 1), the KGD has been proven to reduce epileptic attacks, with far better prognosis among children with Complex I deficits than Complex IV. These results are not surprising given that KGD generates more NADH/FADH2 than glucose (2 vs. 5). Recently, KGD-fed rats showed increased brain expression of insulin-like growth factor receptor (ILGFR) and neuronal GLUT3. The KGD might have a beneficial effect in some ASD cases considering that IGFR is important for brain health throughout life, and that IGFR and GLUT3 have both been implicated in ASD. Some energy-sensing molecules and metabolism regulators (including the mammalian target of rapamycin, mTOR) have been recently indicated as possible downstream targets of KGD and may be involved in neuroprotective effects associated to the diet. Defects in the mTOR pathway have been linked to ASD. Failure to inhibit mTOR pathway could lead to MD due to decreased mitophagy resulting in an accumulation of dysfunctional mitochondria as observed in a mouse model of ASD with phosphatase and tensin homolog on chromosome ten (Pten) gene haploinsuffciency. Indeed, inhibition of mTOR has been linked to a delay in the occurrence of the epileptic episodes and KGD-fed rats showed inhibition of the activation of the mTOR pathway in brain, thus representing an appropriate treatment to control seizures while enhancing the clearance of defective/damaged mitochondria. Ketone bodies (without glucose and at concentrations 10-times higher than physiological ones) inhibit mitochondrial reactive oxygen species (ROS) production in rat neurocortical neurons by increasing NADH oxidation following glutamate (Glu) excitotoxicity. It has been suggested that the production of NADPH via oxidation of succinate semialdehyde (SSA) into succinate in the Glu decarboxylase (GAD)/gamma-aminobutyric acid (GABA) pathway may buffer the redox changes likely to occur in stressful conditions. However, other mitochondrial NADPH sources are quantitatively more important than SSADH and fatty acid oxidation produces more mitochondrial ROS than pyruvate oxidation. Thus, the use of KGD could be beneficial in ASD given that higher rates of mitochondrial ROS production and compromised cellular antioxidant status have been reported in peripheral cells from children with ASD. The GABA shunt bypasses two steps of the tricarboxylic acid cycle - the alpha-ketoglutarate (KG) dehydrogenase complex and the succinylCoA synthase - for the conversion of KG into succinate (Figure 1). It involves three enzymes: a GAD, catalyzing the Glu decarboxylation to GABA, a GABA transaminase, converting GABA to SSA, and an SSADH, catalyzing the oxidation of SSA to succinate. This metabolic route (the GAD/GABA pathway) is conserved from bacteria, through yeast and plants, to vertebrates. In higher eukaryotes, SSA can be reduced to gamma-hydroxybutyric acid (GHB) by an alternative reaction catalyzed by a GHB dehydrogenase. It has been proposed that KGD may limit the availability of oxaloacetate to aspartate aminotransferase, an enzyme involved in brain Glu metabolism, resulting in increased Glu or Gln availability to produce GABA. The increased conversion of Glu to GABA would be potentially beneficial in ASD (Figure 1). Changes in GABA neurotransmission by KGD might explain the decrease in seizure frequencies and improved behavior observed in Rett syndrome. Studies in patients with ASD strongly suggest a dysfunction in the GABAergic system. However, changes in other components (including Gly, taurine, and GABA) cannot be excluded. In the case of SSADH deficiency (SSADH), the KGD may work through restitution of GABAergic neurotransmission, although the use of KGD in SSADHD has been strongly argued until more research is performed to test its potential detrimental effects in humans. Conversely, ketotic rodents fed on KGD showed no changes in whole brain (GABA) [between brackets = concentrations; ]; however, regional (GABA) changes cannot be ruled out, in addition to species-specific differences in the expression of GABA receptors subtypes. Considering that cerebrospinal fluid from children treated with KGD showed higher (GABA), it would be of interest to evaluate GABA and amino acid concentrations in different brain areas in animal models of ASD fed KGD. Dysfunction in the cholinergic system has been observed when PDH deficits are present because a block in this enzyme decreases (citrate), the precursor of acetylcholine via citrate lyase. Studies in humans and animal models of ASD suggested that dysfunction of the cholinergic system underlies ASD-related behavioral symptoms. Trials conducted on ASD individuals have shown beneficial effects of galantamine (an acetylcholinesterase inhibitor) in the management of aberrant behaviors in children and adolescents with ASD. Treatment of BTBR mice with the acetylcholinesterase inhibitor donepezil hydrochloride improved social preference, social interaction and decreased cognitive rigidity. Thus, a KGD has the potential to exhibit beneficial effects in individuals with both ASD and PDH deficiency because the metabolism of KB overcomes the decrease in (citrate) and that of (acetylcholine). Several side effects of KGD have been reported, among them: (a) limitation in protein, carbohydrate, and other nutrients intake can result in a lack of weight gain and growth inhibition, which could be detrimental in ASD because of a predisposition for being underweight and the presence of eating disorders. Thiamine, lipoic acid, and l-carnitine supplementation have been helpful in selected cases. (b) Dyslipidemia from KGD would need to be supervised in ASD patients with beta-oxidation deficits, including carnitine deficiency and, for older patients, the additional increased risk in heart disease and atherosclerosis. These patients should limit their fat intake or a modified KGD possibly with carnitine and/or coenzyme Q10 supplementation, should be used. (c) KGD has an increased risk of systemic ketosis, which may result in lower affinity of hemoglobin for oxygen, resulting in severe outcomes (e.g., coma and death) especially in anemic ASD patients. (d) Adverse events experienced by patients with RC complex deficits and epilepsy, which could be extrapolated to those with ASD, included symptomatic persistent hypoglycemia, persistent metabolic acidosis, aspiration pneumonia, and pneumonia followed by respiratory failure. (e) Initial fasting and prolonged caloric restriction can cause acute metabolic decompensation in ASD patients with metabolic disorders. To reduce the adverse effects of fasting, some studies have omitted the initial fasting period and substituted it with a gradual increase in calories. (g) Other side effects include constipation, slower growth, kidney stones, and gastroesophageal reflux, although most of them are treatable and/or preventable.

autism spectrum disorders, bioenergetics, dietary intervention, epilepsy, ketogenic diet, mitochondria, oxidative stress

PMC6394184_01

Female

A 23-year-old female patient presented in outpatient department with chief complaints of pain in neck, restricted neck movement, gait changes, and weakness in all the extremities for the past 3 months. She had no history of trauma, but the history of difficulty in speech and constitutional symptoms were present. The general physical examination was within normal limits. On clinical examination, cervical spine tenderness was present with paraspinal muscle spasm. There was no palpable swelling or sinus. Cervical lymph nodes were not palpably enlarged. The range of motion of neck was markedly reduced due to pain and spasm. Neurological examination revealed that a higher mental function and cranial nerves except hypoglossal nervewithin normal limits. The upper motor neuron signs were present in bilateral upper and lower limbs. Tonewas increased with clasp knife type of rigidity. Power was grossly 5/5 in all the limbs, with exaggerated deep tendon reflexes, and planters were upgoing. On hematological investigation, erythrocyte sedimentation rate (ESR) was 90 mm, rest hematological, and biochemical examinations were normal. HIV, HBsAg, anti-HCV, X-ray chest, and ultrasonography abdomen were normal. The patient had X-ray of cervical spine showing increased soft-tissue shadow [Figure 1] andmagnetic resonance imaging (MRI) of occipitocervical junction and cervical spine. An MRI was suggestive of destruction of atlas and axis vertebra with an abscess in the prevertebral region and cord having a mild compression from anterior aspect [Figure 2]. By clinical-radiological correlation, the patient was diagnosedwithpott's spine of C1-C2. She was started on antituberculosis therapy (ATT) Category 1 (Rifampicin 450 mg, Ethambutol 1000 mg, INH 300 mg, and Pyrazinamide 1500 mg), advised complete bed rest and initially kept on head halter traction for 6 weeks, at 6 weeks of patient was given four postcollar, and was mobilized. Patient improved clinically with no worsening of symptoms, but she noticed tongue deviation and hypotrophy of the right side of the tongue. She was followed up regularly in the outpatient department. Four postcollar was removed at 1 year, and ATT was given for 18 months. At followup of 4 years, flexion and extension X-ray of cervical spine shows no instability, on repeat MRI there are healed lesion of C1-C2 spine with no abscess [Figure 3]. Clinically, she has no neck pain, there is a terminal restriction of neck nodding movements, and on the protrusion of tongue there is deviation of tongue with hypotrophy on the right side [Figure 4]. She has some difficulty in speaking, apart from that patient is doing all her activities without any difficulty.

atlas, c1-c2 tuberculosis, axis, hypoglossal nerve, prevertebral fascia, tuberculosis

PMC6394184_02

Female

A 13-year-old female patient presented in the orthopedic department with chief complaints of pain in neck, difficulty in walking, and difficulty in deglutition for2 months. General physical examinations were within normal limits except posterior cervical lymphadenopathy. On further examination, she had cervical tenderness along with grossly normal power in all four limbs with exaggerated reflexes and planter upgoing. Blood investigations were done which showed raised ESR along with raised lymphocyte count and rest parameters were within normal limits. X-rays were done which showed destruction at C1-C2 level with increased prevertebral shadow. CT was done which also showed destructive lesion in C1 vertebra [Figure 5]. Clinicoradiologically diagnosis was made of tuberculosis, and the patient was started on ATT Category 1 and head halter traction was given for 3 months. ENT opinion was also taken regarding difficulty in deglutition but conservative treatment was planned. The patient was serially followed and at 1-year followup, she has no complaint in neck or difficulty in walking, but on the protrusion of tongue, there is deviation of tongue to the left side [Figure 6].

atlas, c1-c2 tuberculosis, axis, hypoglossal nerve, prevertebral fascia, tuberculosis

PMC9424730_01

Male

Mucopolysaccharidosis type I S (MPS IS) or Scheie syndrome (OMIM #607016) is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme alpha-L-iduronidase (EC 3.2.1.76), leading to storage of dermatan sulfate and heparan sulfate. MPS IS is caused by mutations in the IDUA gene, located on chromosome 4p16.3. In MPS IS patients, treatment with recombinant human alpha-L-iduronidase (laronidase) - the deficient enzyme - reduces lysosomal storage in the liver and improves some clinical manifestations whilst stabilizing others. Although the incidence of tuberculosis (TB) in Latvia is decreasing (23 cases per 100,000 in 2020), Latvia remains in the top six EU and European Economic Area countries with the highest TB case notifications and there is a high burden of multi-drug resistant (MDR) TB. BCG vaccination in Latvia is offered to all newborns between the 2nd and 5th day after birth; booster vaccinations are not given at an older age. Routine screening for TB is not performed; however, patients (including children) are tested if they show signs/symptoms or have been in contact with a TB patient. To date, there are no published reports of TB treatment in MPS IS patients receiving enzyme replacement therapy (ERT) and as such it is not known whether both conditions can be treated simultaneously. Here, we report the case of a 14-year-old male with MPS IS receiving ERT who was diagnosed with a latent TB infection (positive IGRA test) after contact with an MDR TB patient. The patient was born at 40 weeks' gestation to non-consanguineous parents and received his BCG vaccination post birth. Early psychomotor development was normal. During preschool years, he suffered from frequent upper respiratory tract infections, sinusitis, otitis media and bronchial asthma. At the age of 5 years, the patient developed knee pain and joint stiffness. At the age of seven years, he was diagnosed with polyarthritis and chronic uveitis and was initially treated for juvenile idiopathic arthritis. However, when an elevated level of mucopolysaccharide in his urine was detected, further diagnostic enzyme analysis revealed pathologically low alpha-L-iduronidase activity and two heterozygous disease-causing mutations in the IDUA gene were identified - the first one in exon 2 (c.208C>T p.Q70*) and the second one in intron 12 (c.1727+4C>T). A diagnosis of MPS type I was made, and he was put under the supervision of a multidisciplinary team. Consequently, ERT was started with intravenous laronidase 100 U/kg once a week. In response, the patient's joint mobility improved, and no joint pain was reported. However, he continued to endure mild bilateral carpal tunnel syndrome, extension contractures of the distal phalanges, restricted mobility of the wrists and rigid equinus deformity of both feet. The lattermost was corrected by reconstructive surgeries and bilateral Achilles tendon extension. The patient developed mild mitral regurgitation, but this did not require any treatment. His lung function (FVC, FEV1) also improved and fewer respiratory infections were noted. The patient wears spectacles. His most recent ophthalmologic evaluation in 2022 revealed disseminated point-like dystrophic changes in the cornea (corneal dystrophy) and hypermetropic astigmatism with amblyopia ex anopsia. He has never displayed a neurological or intellectual deficit and attends a mainstream school. In 2017, at the age of 10 years, the patient was in contact with a family member with MDR TB resistant to the first line of anti-tuberculosis drugs. He was subsequently tested for TB infection (Mantoux tuberculin skin test) and a skin induration of 14 mm was observed, but IGRA test was negative. A lung CT scan was conducted, and no pathologic changes were detected. A diagnosis of latent tuberculosis infection was made, but during this period, prophylaxis with second line anti-tuberculosis drugs was not recommended by the WHO, so the prophylaxis was not prescribed. No other family members were infected. In 2021, at the age of 14 years, the patient was in contact with a close neighbor with MDR TB (resistant to isoniazid, rifampicin and pyrazinamide; preserved sensitivity to moxifloxacin). All family members were tested again, and the patient showed a positive IGRA test. Lung and intrathoracic lymph node CT scans were conducted, and no TB process was detected. A diagnosis of latent TB infection was made and prophylactic treatment was started with peroral moxifloxacin 400 mg once a day for 6 months. Due to the high burden of MDR TB in Latvia and to ensure patient compliance, monitoring of TB drug treatment via Skype (DOT or directly observed therapy) is used with patients who cannot attend a medical institution each day to receive the prescribed medication. DOT was used in this case. The patient reported nausea and dizziness shortly after administration of moxifloxacin and vomiting once a week, which continued throughout the duration of the treatment. During the treatment, no abnormal liver function tests were observed, the corrected QT interval on ECG was normal, and the patient continued to receive ERT once a week. No complications were reported and no active TB disease has been detected to date.

enzyme replacement therapy (ert), laronidase, latent tuberculosis treatment, mucopolysaccharidosis type i, multi drug resistant tuberculosis (mdr-tb)

PMC6522775_01

Male

69-year-old, Chinese, male, with a history of ileus, was referred to the emergency department of our hospital because of worsening states in shortness of breath, cough and fever despite antibiotic therapy from another hospital. Upon admission, the patient had no other underlying diseases. 5 days before admission, he was diagnosed as upper respiratory tract infection in community clinic and accepted antibiotic therapy for 4 days. However, no improvement on his conditions were observed. On 11th in December 2014, his body temperature rose up to 39.5 C, then he presented to our hospital. After admission, a chest CT was performed which showed multiple dense consolidation located in right lung, predominantly in low lobe (Fig. 1A). His white blood cell (WBC) count was 6.30 x 10^9 cells/L, C-reactive protein was 6.8 mg/dL. Take all of these in consideration, we treated him with Piperacillin-sulbactam and levofloxacin. On 28th in December 2014, we performed bronchoalveolar lavage (BAL). Through bronchoscopy, we found that the wall of the air tube was edematous with a small amount of pus (Fig. 1B), the lavage was clear. Bronchoalveolar lavage fluid (BALF) cultures were negative for bacterial. Because there was only a small amount of pus in airways, bronchoscopic segmental lavage was not performed again. 2 weeks after treatment, a repeated chest CT showed the increased consolidation, while the patient's symptoms, including dyspnea, fever and pleuritic chest pain were improved. As a result, the patient was discharged on 28th in December 2014. Then he continued to receive antibiotic treatment for an additional week in clinic. However, the fever with highest temperature at 40.0 C occurred on 4th January 2015. He rehospitalized after 4 days, during which transbronchial lung biopsy (TBLB) was performed in the right lower lobe. Lung specimens showed chronic inflammatory cell infiltrated. Based on this, we empirically treated him with steroid. After steroid treatment, the patient was no longer feverish, other symptoms were also improved obviously. A chest CT performed after 1 week steroid treatment showed resolution of the radiographic abnormalities. In order to confirm the nature of the lesions, CT guided percutaneous transthoracic needle biopsy was performed. Lung biopsy showed lipid granulomas with fat-laden macrophages (Fig. 1D), consistent with the pathological features of lipoid pneumonia. After two months of missed diagnosis, the patient was diagnosed ELP at last. Oral systemic steroid was continued for 8 weeks with gradual tapering off. Chest CT showed dramatic improvement 1 year after steroid therapy. (Fig. 1C).

antibiotic, chest ct, exogenous lipid pneumonia, pathology, steroid

PMC6522775_02

Male

65-year old, male, with a history of daily ingestion of liquid paraffin for chronic constipation, was admitted following cough, sputum, chest pains and episodes of fever in June 2018. Two days before admission, he accidently inhaled liquid paraffin which used as laxative. Chest CT scan performed at our hospital showed necrotic consolidation, ground glass opacity (GGO) and bronchial wall thickening in the right middle lobe (Fig. 2A). Laboratory examination showed leukocytosis (18000/mm3) with increased C-reactive protein level. Then we treated him with broad spectrum antibiotic. Bronchoscopy was performed with BAL and TBLB on the second day after admission. Edematous changes was observed in the right middle and lower lobe with a lot of grayish purulent secretions were observed under bronchoscopy (Fig. 2B). The lavage was turbid, oily substances could be seen floating on the precipitated surface of the lavage solution. The pathological examinations reflected the acute inflammation and granuloma formation (Fig. 2D). The diagnosis of ELP was confirmed preliminarily based on medical history and radiological findings. Then we treated the patient with 30 mg prednisolone for 3 days, which significantly improved the patient's symptoms including fever, cough and sputum. Along with pharmacologic treatment, BAL was performed for several times to eliminate the non-soluble paraffin and inflammation. Two weeks after admission, we decided to discharge the patient because the symptoms and chest CT manifestations were thoroughly improved. A low dose chest CT was performed in outpatient clinic after 2 week of discharge. The CT scanning showed a remarkable decrease in necrotic consolidation and GGO in right middle lobe. Oral systemic steroid was prescribed for 6 weeks with gradual tapering off. 6 months after the treatment, chest CT showed dramatic Improvement (Fig. 2C), no recurrence has been observed in the patient so far.

antibiotic, chest ct, exogenous lipid pneumonia, pathology, steroid

PMC5355005_01

Male

A 45-year-old Caucasian, right-handed man presented to our emergency department (ED) with 3 to 4 weeks history of progressive gait disturbances and left lower extremity weakness. His pertinent medical history was negative for any recent history of head trauma, but was significant for a moderate traumatic brain injury (TBI) at the age of 9 years, where he fell off a tree and sustained a closed parietal skull fracture with no posttraumatic cognitive or neurologic deficits. He had no history of seizures, central nervous system infections, stroke, or brain tumor. His neurological exam at admission was significant for left hemiparesis (strikingly more pronounced on lower than upper extremity) and positive left pronator drift testing. A positive Babinski sign could be elicited on the left. He was initially seen in the ED where a magnetic resonance imaging (MRI) showed IE of the right parasagittal parietal bone containing portions of the right precentral gyrus and surrounding brain parenchyma (Fig. 1D). There were no bony deformities upon palpation of scalp. Noncontrasted computed Tomography (CT) demonstrated a well-circumscribed, 4.3 x 3.7 cm area of osteolysis in the right parasagittal parietal bone, with internal soft tissue attenuation (Fig. 1A-C), complete erosion of the inner table, and noncontiguous lytic changes of the outer table (Fig. 1B, C). MRI with and without gadolinium contrast administration demonstrated a right parasagittal dural defect with intradiploic herniation of the right precentral gyrus (Fig. 1D). There was no restricted diffusion to suggest acute infarction (Fig. 2A-D). After initial neurosurgical evaluation in the ED, the patient was admitted to the neurosurgical ward and started on dexamethasone 4 mg intravenously every 6 hours. His left lower extremity weakness responded positively to the initial steroids therapy, with partial but transient improvement on his leg weakness to antigravity strength and ambulatory with a rolling walker. He was reluctant to proceed with surgical intervention initially, and elected to continue hospital observation for a few days. Since no sustainable improvement on his strength was seen after 2 days of high-dose dexamethasone treatment, he decided to proceed with surgical intervention. Under general anesthesia, and using CT-guided intraoperative frameless stereotactic navigation, the area correspondent to the encephalocele was identified and marked. The calvarium was exposed through a bicoronal incision. The bone overlying the encephalocele appeared to be mottled and thin. Cortical brain matter was visualized directly underneath the most thinned portions of the right parietal bone. It appeared pale with no evidence of cortical vasculature, and the usual gyral anatomy had been lost. Starting from the areas of bone dehiscence, the craniectomy was then extended centrifugally until identification of the normal inner table surrounding the whole encephalocele. Once the margins of the encephalocele were completely identified and dissected, a large craniotomy incorporating the bone defect was completed using high-speed craniotome (Fig. 3). Despite an extensive stellate-shaped dural opening and encephalocele decompression, we were unsuccessful on reducing the encephalocele through the pial opening. The pial-arachnoid plane surrounding that area was very sclerotic and firmly adherent to the encephalocele pedicle. Due to the risk of vascular injury to an already friable but apparently still eloquent brain, we decided not to proceed with arachnoidal opening or resection of the encephalocele sac. An expansile duraplasty was completed using a pericranial autograft. The bone flap was replaced with a titanium mesh used for coverage over the craniectomy site. He tolerated the procedure well and was kept in intensive care unit for 24 hours without complications. Postoperative noncontrasted CT head revealed no ischemic changes on the surrounding parenchyma and adequate reduction of the encephalocele (Fig. 4A-C). He was transported to the neurosurgery ward in stable condition. He was discharged with mild improvement in left hemiparesis. On 2-month follow-up, his preoperative left leg weakness has greatly improved with near resolution of preoperative hemiparesis.

computed tomography, history, magnetic resonance imaging, parietal intradiploic encephalocele, traumatic brain injury

PMC7769658_01

Female

A 23-year-old Hispanic female at 19 weeks of gestation, with medical history significant for preeclampsia and mild intermittent asthma, presented to the Emergency Room complaining of fever, dry cough, and shortness of breath for a week. The patient also reported painful swelling in her hands and feet associated with morning stiffness. She had tried acetaminophen at home which did not relieve her symptoms. Initial examination was remarkable for tachycardia (103 beats/min), tachypnea (20 breaths/min), and fever (101.8 F). Her lung examination was clear with equal air entry bilaterally. Joint exam showed swelling, tenderness, and warmth of bilateral ankles, knees, proximal interphalangeal joints, and metacarpal phalangeal joints. Laboratory studies were significant for lymphopenia (white blood cell count of 2.6 x 10/microL) and anemia (hemoglobin of 10.5 g/dL). Chest X-ray on admission did not show abnormalities. Bilateral lower-extremity venous duplex studies did not show evidence of deep vein thromboses. Additionally, left knee arthrocentesis ruled out septic arthritis. She was started empirically on ceftriaxone and azithromycin for possible community-acquired pneumonia. Her symptoms did not improve. C-reactive protein (CRP) and erythrocyte sedimentation rate were elevated (13 mg/L and 59 mm/h, respectively). Low complement levels were noted (C3 of 36 mg/dL and C4 of <8 mg/dL). The ANA test was positive. On day 5 of admission, she became tachypneic and hypoxic, saturating 84% on room air despite noninvasive ventilation. She was upgraded to the Intensive Care Unit where she required a high-flow nasal cannula. Repeat chest X-ray showed new multifocal bilateral airspace opacities but no pleural effusions or pneumothorax (Figure 1). Extensive infectious workup for viral, bacterial, and parasitic causes was negative. Notably, sputum cultures, blood cultures, and cultures for SARS-CoV-2, HIV, CMV, EBV, parvovirus B-19, hepatitis, and West Nile virus were negative. Legionella and Streptococcus urine antigens, Mycoplasma pneumoniae, QuantiFERON for tuberculosis, Lyme, Ehrlichia, Anaplasma, PCR for influenza A (subtypes H1 and H3), adenovirus, parainfluenza, and rhinovirus were also negative. The patient was started empirically on IV methylprednisolone 60 mg daily for probable pneumonitis. This led to significant improvement of symptoms as her fever, tachypnea, hypoxia, cough, and arthralgias had resolved within 24 hours. On further investigation, she was found to have positive anti-dsDNA (1 : 160 titers) and anti-SSA antibodies. CT chest was not pursued, given the risk of radiation exposure in pregnancy. She never developed hemoptysis or significant drop in hemoglobin to favor of alveolar hemorrhage. The patient was diagnosed with new-onset SLE as per the EULAR/ACR 2019 criteria as she presented with fever, leukopenia, arthritis, pneumonitis, low complements, and positive serological lupus studies (ANA and anti-dsDNA). She was started on hydroxychloroquine 200 mg twice daily, and intravenous corticosteroids were switched to oral prednisone on the fourth day of IV methylprednisolone. This achieved adequate clinical and serological response as her CRP, hypocomplementemia, and pancytopenia significantly improved within 5 days.

PMC4984996_01

Female

A 31-year-old female with a history of secondary infertility of 1 year and 6 months was referred to our clinic. She had two spontaneous miscarriages at tenth week of gestation, the last being 2 years and 6 months back, both followed by dilatation and curettage. After her last abortion, she did not conceive for 2 years. Multiple cycles of ovulation induction with oral agents as well as injectable gonadotropins were done. All follicular studies showed consistently thin endometrium of 6-8 mm around the time of ovulation. Routine investigations such as hysterosalpingogram, blood sugar, tuberculosis polymerase chain reaction of the endometrium, and antiphospholipid antibodies were normal. On hysteroscopy done 1 year back, uterine cavity was normal. At our clinic, we started with follicular growth and endometrial thickness monitoring in natural cycle. Doppler for endometrial blood flow around the time of ovulation was suggestive of absent flow in zones 2, 3, and 4 of endometrium (Applebaum criteria). An attempt to improve the blood flow was made by starting Aspirin 75 mg, vitamin E, and Pentoxyfylline. However, repeat Doppler around the time of implantation did not show any improvement. In the next cycle, successful ovulation induction with gonodatropins was done, and trigger was given when the follicle was 18 mm, followed by intrauterine insemination. Luteal support was given with oral estrogen, progesterone, and vaginal Sildenafil citrate 25 mg (Alivher ; Akumentis Healthcare Ltd., Mumbai, India) twice a day in view of decreased endometrial blood flow in the previous cycle, which may be one of the causes of repeated abortions. Doppler for endometrial blood flow around the time of implantation (7-8 days after ovulation) showed good flow in all the zones. Serum beta-human chorionic gonadotropin test done 14 days later confirmed the pregnancy. Sildenafil citrate was stopped on confirmation of pregnancy. First trimester of pregnancy was uneventful. Ultrasound at 12 weeks for nuchal translucency, nasal bone, and dual marker test were normal. Patient was called for follow-up visits every 3 weeks. Ultrasound for congenital malformation at 20 weeks did not reveal any abnormality. Fetal weight at that time was 440 g, and amniotic fluid index (AFI) was 10. Repeat ultrasound at 24 weeks was suggestive of oligohydramnios (AFI 6) with a fetal weight of 490 g (less than fifth percentile). Color Doppler in umbilical arteries showed normal systolic/diastolic (S/D) ratio, pulsatility index, and resistive index. However, there was notching seen in the uterine artery Doppler study. Investigations such as complete blood count, blood sugars, liver function test, renal function test, urine routine, and microscopy were within normal limits. Her blood pressure was normal; there was no peripheral pitting edema or proteinuria and hence no evidence of preeclampsia. The couple was informed regarding the guarded prognosis of pregnancy, and written informed consent was obtained voluntarily. The patient was kept on bed rest and given vitamin supplements, intravenous amino acid infusions, and nitric oxide donor (L-arginine sachets). Ultrasound at 26 weeks showed an estimated fetal weight of 550 g and an AFI of 4.5. Color Doppler showed an increased S/D ratio in the umbilical arteries with brain-sparing effect in the middle cerebral artery (MCA) as shown in Figures 1 and 2. A repeat ultrasonography at 27 weeks showed reduction in diastolic flow in the umbilical arteries. Figure 3 shows the ultrasonography Doppler image with reduced blood flow at the myometrial placental junction at diagnosis of intrauterine growth restriction. In view of grave prognosis of the pregnancy and unavailability of any other established definitive treatment, the couple was counseled regarding the limited role and experimental nature of Sildenafil citrate in oligohydramnios and FGR. After detailed counseling, the couple opted for Sildenafil citrate 25 mg vaginally twice a day. Repeat ultrasound at 28 weeks showed an improvement in blood flow and an increase in AFI to 6.5 with a fetal weight of 680 g after starting sildenafil citrate as shown in Figure 4. The umbilical artery diastolic flow improved after 2 weeks of therapy, with no brain-sparing effect in MCA; however, the S/D ratio was >3. Furthermore, ultrasound at 30 weeks showed an AFI of 7.5 and a fetal weight of 1,000 g. The patient also experienced a subjective increase in perception of fetal movements. All medications were continued with weekly monitoring of fetal weight and AFI. Gradually at 31 weeks, there was further decrease in pulsatility index, and S/D ratio was <3, in both umbilical and MCAs as shown in Figures 5 and 6. The fetal well-being was continuously monitored using biophysical profile every 2 weeks. Sildenafil citrate therapy was stopped at 36 weeks. An elective cesarean section was done at 37th week for breech presentation, and a healthy female child of 2.3 kg was delivered. Baby cried immediately after birth, and Apgar score was 7/10 and 9/10 at 1 and 5 minutes, respectively. Placenta was examined after delivery; on gross examination, it was smaller in size (400 g) with areas of calcifications and increased thickness of membranes. On histopathological examination, there were areas of infarction. The maternal and neonatal courses were uneventful. We have followed up the child up to 14 months with normal mental and physical development.

fetal growth restriction, oligohydramnios, sildenafil citrate, thin endometrium

PMC6167885_01

Male

A 62-year-old Nepali, a professional health worker, presented in Grande International Hospital with red erythematous papules near around the previous site of renal transplantation(Fig. 1a). He had lived with diabetes and hypertension for 27 years and had a history of visiting the south-western and south-eastern region of the USA. The renal transplantation was done 6 months ago (6th October 2017). The previous diagnosis was made as cutaneous tuberculosis; in a local hospital, based on clinical presentations and unresolved lesion with a course of antimicrobial therapy (cloxacillin). Simultaneously, the patient had received a course of anti-tubercular therapy for two months. Paradoxically, the lesions continued to progress with pus discharges. A routine culture revealed no bacterial and fungal growth associated with the infection. On clinical examinations, few red erythematous papules with erosions and crusting seen over the site of prior the scar (Fig. 1b); no other systemic abnormality were found to be associated. Hence, the differential diagnosis of actinomycosis, deep mycosis, and rifampicin resistant cutaneous tuberculosis was made. On histopathological examination, multiple basophilic colonies surrounded by neutrophilic abscesses and granulation tissue with dense infiltration by acute and chronic inflammatory cells were observed. However, the serological marker: HIV, HBsAg, HCV (ELISA) were negative. The Renal function and Liver function were found normal. The level of tacrolimus was assessed 9.0mcg/dl. As of microbiological approaches, for the detection of an etiologies: right angaled branching, filamentous Acid Fast Bacilli (AFB) was observed on Ziehl-neelson staining (Fig. 2); chalky white adherent colonies were seen on aerobic culture after 72 h of incubation, which turns molar tooth appearance on further incubation (Figs. 3 and 4). Further, identification of the isolate, Nocardia asteroids, was done with standard microbiological culture methods as recommended by American Society for Microbiology, based on phenotypic characteristics, biochemical interpretations, and varied incubation temperature to grow the pathogen; since molecular analysis and sequencing was not accessible in our laboratory setting. Plus, antibiogram of the isolate was determined by modified Kirby-Bauer disk diffusion method on Blood agar against commercially prepared antibiotic disks (HiMedia Laboratories Pvt. Limited, India) in acquiescence with Clinical Laboratory Standards Institute (CLSI). Additionally, the CT scan of lungs and brain was done to rule out the possible disseminated nocardiosis; however, no abnormalities detected. In view of examination and investigations, a diagnosis of primary cutaneous nocardiosis was made on post-renal transplant patient. Subsequently, anti-tubercular therapy was discontinued, and the patient was treated with trimethoprime and sulfamethoxazole as per the drug susceptibility testing. The patient was treated with trimethoprime and sulfamethoxazole, BACTRIM-DS (PO x BD), 2 double strength oral tablets each containing 800 mg sulfamethoxazole and 160 mg trimethoprim for 3 months. He has now completed 2 months of treatment; has undergone progressive changes no relapse noted (Fig. 1c); transplant function observed in a good state. He is under regular follow up since then and we found him asymptomatic; however, with limited side effects due to prolonged antimicrobial therapy.

cutaneous nocardiosis, cutaneous tuberculosis, immunocompromised, nocardia asteroides, renal transplant, sulfamethoxazole and trimethoprim

PMC3558375_01

Male

These patients are more than one year old and present mainly with liver and/or renal disease. The illness may be complicated by cardiomyopathy and neurological problems such as porphyria-like episodes. Cirrhotic liver changes are generally already present. Newborn screening for HT1 is not widely available because of the rarity of HT1 in most areas. However together with early treatment with nitisinone and diet, it is the medical management of choice. Recent studies have shown confirmed this Newborn screening is best performed using succinylacetone (SA) as a primary marker because it is sensitive and specific. Blood spot tyrosine is neither specific nor sensitive. Although biochemical abnormalities may be identified shortly after birth, babies with HT1 are rarely symptomatic in the first days of life. Newborn screening enables treatment of children who are not yet clinically ill. However newborn babies diagnosed by screening have markedly raised AFP levels and mild abnormalities of coagulation. The most useful test is for succinylacetone that may be measured in plasma, dried blood spot as used in newborn screening (DBS) or urine. This is highly specific and sensitive. SA may not be detected in routine organic acids analyses in urine, particularly if the concentration of SA very low or the urine very dilute so specific assays may be needed. Testing is urgent if tyrosinaemia type 1 is suspected. Initial tests for HT1 should include the following: Blood/ plasma Blood gases Liver function tests: bilirubin, aspartate and alanine aminotransferase (AST, ALT), alkaline phosphatase, gamma glutamyl transpeptidase (gammaGT) albumin. Coagulation: Prothrombin time, partial thromboplastin time, fibrinogen, Urea and electrolytes, creatinine Calcium, phosphate Glucose and ammonia (in acute liver failure) Full blood count Aminoacids (quantitative) alpha-fetoprotein (AFP) Succinylacetone (if available. Note: plasma SA is protein bound and is a better test with which to monitor metabolic control than urine SA, although urine SA is more widely available at present. Urine Glucose Aminoacids Tubular re-absorption of phosphate (TRP) Calcium/creatinine ratio Albumin, protein, beta2-microglobulin Organic acids and succinylacetone (Note: Routine organic acid analysis may not be sufficiently sensitive) Interpretation: Initial tests may show evidence of liver disease, usually with a striking disorder of clotting. Plasma amino acids may show raised tyrosine as well as raised methionine, abnormalities that are consistent with any severe liver disease. AFP is usually markedly raised but it is not specific. Imaging for hepatic disease is important, particularly at presentation. All patients should have an ultrasound examination of the liver and kidneys initially and thereafter at regular intervals. If nodules are present in the liver further imaging, preferably by MRI, should be done. However there is no single ideal method. To some degree the method chosen will depend on the resources and facilities available. Ultrasound with high resolution transducers and colour-doppler remains the first modality of choice. It is rapid and safe allowing identification of the echogenicity of the parenchyma and nodular lesions as small as 2 mm in diameter. Colour-doppler can be used to assess the hepatic vessels and portal hypertension. However not all nodules may be detected and the technique is operator dependent. Multi detector CT scan is quick and enables multiplanar imaging with good spatial resolution of abnormalities in the liver. Contrast may improve the detail, enabling identification of malignant change. However, a risk-benefit analysis is mandatory to avoid radiation in children already at risk of malignancy so it requires repeated evaluation. Sedation is sometimes required MRI has emerged as the best technique to help in differentiating nodules in children with chronic liver disease, because of its ability to identify different tissues properties. After intravenous gadolinium injection dynamic sequences provide analysis of nodule vascularisation. Diffusion-weighted imaging may help to distinguish well-differentiated hepatocellular carcinomas from benign nodules, C Dionisi Vici and L Monti unpublished. However it requires some form of sedation in many children. Conclusion: All patients should have an ultrasound examination of the liver and kidneys. If nodules are present in the liver further imaging, preferably by MRI, should be done. Bone X-ray (for those with a definite tubulopathy): wrist or chest An outline flow diagram for the management of patients with tyrosinaemia type 1 is shown in Figure 2. As soon as the diagnosis is confirmed, or even suspected because of liver disease and appropriate investigations have been sent, start nitisinone (NTBC, Orfadin ,) in a dose of 1 mg/kg/d once a day as the half life is 54 hrs. A dose of 2 mg/kg/d should be given for 48 hours for those in acute severe liver failure. An alternative approach is to give all patients in liver failure nitisinone at a dose of 2 mg/kg/d from the start and allow the dose to fall with growth to 1 mg/kg/d before increasing it. Nitisinone can only be given orally (or by naso-gastric tube). It is imperative to do so quickly to prevent further liver and kidney damage and avoid potentially major complications such as haemorrhage. The risk of long term complications is also reduced. Details of potential side effects of nitisinone are listed in the appendix. The patient should also be started on a low tyrosine and low phenylalanine diet. If plasma tyrosine concentrations are raised a high energy diet with a phenylalanine and tyrosine free aminoacid supplement should be given (0.5-1.0 g/kg/d) but natural protein should be introduced early and certainly once plasma tyrosine concentrations are falling. If plasma tyrosine concentrations are initially normal or only slightly raised, natural protein should generally be introduced at the outset. Fructose and galactose from should be excluded until the diagnosis of galactosaemia and fructosaemia have been excluded. Patients, particularly younger ones, may be seriously ill and require intensive supportive measures including clotting factors albumin electrolytes, correction of acid-base status and aggressive treatment of infections. Children with a plasma bilirubin concentration of more than 100 mumol/l, plasma ammonia of more than 100 mumol/l or with severe acute liver failure at presentation should be discussed with a liver transplant centre at an early stage. The essential investigations to check the response and to monitor progress are liver function tests, AFP, coagulation studies, quantitative plasma aminoacids and quantitative blood or urine succinylacetone. The response to nitisinone is usually rapid. Coagulation usually improves within 48 hours and all patients should respond within a week. Succinylacetone in the urine and blood should no longer be detectable after the first 24 hours. The concentrations of plasma tyrosine and urine phenolic acids will increase as a result of the inhibition of the 4-hydroxyphenyl pyruvate dioxygenase although the increase in these should be blunted by the diet. AFP will fall more slowly, usually logarithmically. It there is not a steady fall, check the liver imaging carefully. It can take up to one year or even longer for the AFP to fall to the target value < 10 ng/l. Normally there is a marked improvement in the liver function and coagulation within less than one week but, if the liver function does not normalise or succinylacetone can still be detected in plasma and/or urine, then first check compliance and the dosing. If nitisinone is being given correctly, then the dose should be increased to 2 mg/kg/d, if not already receiving that dose. As the plasma concentrations in individuals are variable, if rapid assay of plasma nitisinone level is available it may be useful in detecting problems. Recovery from severe liver failure is possible but the time taken to do so is variable in severely ill patients. In such patients, management must be individualized during the early days of nitisinone treatment. If the patient deteriorates, as judged by coagulation, liver function (progressive jaundice or hyperammonaemia) or signs of encephalopathy, then orthotopic liver transplantation should be considered. Before the advent of nitisinone major complications of HT1 including cirrhosis, liver failure, hepatocellular carcinoma and porphyria-like syndrome were frequent. Even when being treated with nitisinone, there are still important risks of long term complications of HT1, most importantly hepatocellular carcinoma. All patients must be followed carefully. Nitisinone must be continued without interruption. Failure to do so may precipitate serious complications including acute liver failure, a neurological crisis or even hepatic malignant change. On the standard dose of 1 mg/kg/d, the plasma concentrations in individuals that suppress SA are variable. Adjustments of the dose based on plasma nitisinone concentrations may be indicated. However the target NTBC concentrations in plasma are uncertain and vary from 30-50 muM. Some prefer to maintain the concentration above 50 muM, G Mitchell personal communication. Others use a value greater than 40 muM [C De Laet and P Goyens personal communication]. However lower doses of nitisinone have been found to be effective. In one case the serum nitisinone concentration was only maintained above 30 mumol/l with apparently good metabolic control. Whatever the dose, complete suppression of succinylacetone concentrations is essential. Obese patients require a lower dose than that calculated from total body mass. For older children and adults the dose may be calculated using 35 mg/M2/day. Molecular genetic studies may be needed for counselling, prenatal diagnosis and family screening. One splice mutation is prevalent in French-Canadians and more than 40 mutations are now known. The patients should be monitored regularly. The frequency should take account of the age of the patient, the severity of the illness, the family's understanding and compliance. It is suggested that in the first year the patient is seen every month (or even every week) until the patient is stable and well controlled and the family confident. Thereafter the intervals can be lengthened. The tests that should be included in each visit are: Blood/ plasma Blood gases Liver function tests: bilirubin, aspartate and alanine aminotransferase (AST, ALT), alkaline phosphatase, gammaglutamyl transpeptidase (gammaGT), albumin. Coagulation: Prothrombin time, partial thromboplastin time, fibrinogen, Urea and electrolytes, creatinine, calcium, phosphate Full blood count Aminoacids (quantitative) alpha-fetoprotein (AFP) Succinylacetone (if available) Albumin Nitisinone (NTBC) If the patient is in acute liver failure plasma glucose and ammonia should be added. Recently, a simple method allowing the simultaneous determination of NTBC, succinylacetone, tyrosine, phenylalanine, and methionine on a dried blood has been developed with great practical advantages especially in paediatric patients. Urine Glucose Aminoacids Tubular re-absorption of phosphate (TRP) Calcium/creatinine ratio Urine acidification (by the locally preferred method) Albumin, Protein, beta2-microglobulin Organic acids and succinylacetone (note: A specific assay for succinylacetone may necessary to detect very low concentrations as routine organic acid assays may not be sufficiently sensitive). The following investigations should be done as with any patient on a strict diet at intervals of every 6 months to one year. Iron and ferritin, vitamins A,D,E, Folate & vitamin B12, Micronutrients (Se, Zn, Cu) The AFP should decline steadily and it should be close to the target (normal) value of 10 ng/l by one year but there is considerable variability so that some reach the target earlier and a few later. A slow decrease, failure to normalise or a slight rise should be regarded with suspicion and prompt a careful review of the imaging. The value of lectin reactive-AFP is unclear. If there is any doubt the patient should be referred for assessment by the liver transplant team. The low tyrosine low phenylalanine diet must also be continued indefinitely and should be carefully supervised. The target plasma concentrations of tyrosine and phenylalanine are unclear and long term follow-up studies are urgently needed. The increase in plasma concentrations are associated with increased CSF concentrations of tyrosine. The effects on the tryptophan-derived neurotransmitters is unknown. As a guide the aim should be to keep tyrosine concentrations between 200 - 400 mumol/l up to the age of about 12 years. This is not easy and some centres allow plasma tyrosine concentrations up to 500 mumol/l. After the age of 12 years it is common to allow the plasma tyrosine concentrations to rise modestly but the safety of this is not known and it needs to be kept under careful review. As it is difficult to measure the plasma aminoacids fasting they should be measured under the same conditions each time. To maintain these concentrations of tyrosine, a diet similar to that used in phenylketonuria but without tyrosine supplements is necessary. The quantity of natural protein will be restricted and given as exchanges. A phenylalanine and tyrosine free aminoacid supplement is necessary. Low phenylalanine concentrations may be damaging. If the plasma phenylalanine concentrations are persistently very low, some clinicians prescribe phenylalanine supplements but plasma phenylalanine concentrations show a marked diurnal variation and the precise timing of any supplements is unclear. Such phenylalanine supplements may increase plasma tyrosine concentrations. The diet should be monitored as any strict low protein diet. Whilst the eye complications are rare with tyrosine concentrations below 800 mumol/l (see below) there is increasing concern about the cognitive outcome. Many patients on nitisinone have learning difficulties and it is widely thought that this is associated with the increased tyrosine concentrations. Strict control of plasma tyrosine concentrations is to be encouraged. However a stricter diet is not easy and the evidence that stricter control of plasma tyrosine concentrations improves the outcome is not conclusive. The relevance of the concentrations of other large neutral aminoacids, notably tryptophan, is uncertain. The risk of developing HCC is not easily assessed but the later the diagnosis is made the greater the risk of hepatocellular carcinoma (see Table 18.1 in reference 1).Constant vigilance is needed in all patients. Hepatic imaging therefore must be done regularly at least every six months, particularly in the late diagnosed patients. If the liver is uniform ultrasound may be done every 6 months with MRI (or CT if no alternative) every year. However if there are any changes MRI (or CT if no alternative) should be done without delay. Occasionally nodules are present before nitisinone treatment but regress on repeated imaging following treatment. It may be permissible to do an MRI (or CT if no alternative) every two years in patients detected by newborn screening, started on treatment early and who are stable. If there are nodules cross sectional imaging (by MRI (or CT if no alternative)) should be done every 3-6 months. It is difficult to assess the potential risk of malignancy in liver nodules so that if a nodule has any characteristics suggestive of HCC or if it persists on repeat imaging (within 3-6 months) in a child with a good metabolic response to treatment, the patient should be discussed with a liver transplantation team. Imaging should also be done without delay if there is any rise or failure of the expected fall in AFP. Any changes need to be reviewed carefully. If there is a sudden change in a nodule, the development of a new nodule or a nodule is larger than 10 mm in diameter, HCC is likely and the patient should be referred for assessment for liver transplantation. Liver biopsy should be avoided because of the risk of seeding metastases. Renal imaging: The kidneys should be imaged using ultrasound when the liver is imaged in order to monitor kidney growth and changes in renal parenchyma. Psychometric evaluation is important but is of little predictive value before 4 years of age. The facilities for psychometric evaluation are generally in short supply. For most units realistically the first assessment should be before school entry and at intervals thereafter according to the apparent progress and the resources available. Neuropsychological studies may be more helpful that standard IQ tests. School reports can be useful to supplement the assessment. Eye complications do not appear to be common but periodic eye examination with a slit lamp may be indicated (for example annually). There does not appear to be a clear cut-off of plasma tyrosine concentrations either in man or experimental animals. It is not clear whether it is necessary in the asymptomatic child. One approach to minimise clinic appointments is to arrange for an initial eye examination looking for anomalies and then only refer if the child develops symptoms (or if compliance is not good with high plasma tyrosine concentrations). Bone mineral density should be checked as with any patient on a strict diet. It is particularly important in those with any severe or persisting renal tubular disease. Nitisinone and the diet must be continued indefinitely but some families will need intensive support to maintain the treatment. Although the quality of life after a successful liver transplant is usually good, there are serious risks including those of the surgery and lifelong immunosuppression. The indications for liver transplantation include acute liver failure and malignancy. Young babies may need emergency liver transplantation if they fail to respond to nitisinone. If the recommended medical treatment with nitisinone is not adhered to or is not available, the patient is at risk for acute and chronic complications of HT1. They may be considered for liver transplantation according to the classical criteria established before the availability of nitisinone. If the diagnosis of HCC without extrahepatic disease is proven or the diagnosis of HCC is suspected because of radiological or serological investigations, the patient should be evaluated by a liver transplantation team urgently. The safety of nitisinone in the treatment in pregnancy, and of the accompanying fetal and maternal hypertyrosinaemia, has not been firmly established. However, three patients on nitisinone have had babies who were normal on examination in the newborn period, unpublished case report. Early follow-up was also normal. In affected babies SA is detectable in amniotic fluid in pregnancy and both SA and AFP are raised in cord blood. This suggests that the tyrosine degradation pathway is active in utero. In one pregnancy both mother and baby had HT1, the nitisinone not only crossed the placenta freely but suppressed the disease in the fetus. If NTBC is proved to be completely safe it might be given to the mother to prevent damage in utero. This approach should be regarded as experimental and subject to a research protocol.

PMC4531579_01

Male

In December 2002, a 90-year-old man was diagnosed with pulmonary tuberculosis via an abnormal chest X-ray and an AFB smear that was done on his bronchial washing fluids. He was treated with antitubercular agents, including isoniazid (INH; 400 mg/day), rifampin (RFP; 600 mg/day), pyrazinamide (PZ; 1500 mg/day), and ethambutol (EMB; 800 mg/day). Thereafter, the findings on his chest X-ray gradually improved, but he complained of intermittent loose stool. 1 month later, his diarrhea took a turn for a worse: it was bloody and mucoid with a jelly-like appearance and he suffered from lower abdominal cramping pain. In February 2003, the patient was admitted to our hospital because of frequent bloody, mucoid, jelly-like diarrhea and lower abdominal pain. He had a poor oral intake of food and drink due to his continuing diarrhea, which occurred 4 to 5 times per day. The patient was afebrile and his vital signs were normal. His breathing sounds were still coarse on both lung fields and his bowel movements were very frequent. The abdomen was soft and flat, but tenderness was noted on LLQ area without rebound tenderness. His white blood cell count was 13,600/mm3 with 54.2% segmented neutrophils. The stool culture was negative for C.difficile toxin and salmonella-shigella. Sigmoidoscopy revealed multiple yellowish plaque lesions from the rectum to the sigmoid colon (Figure 2A), and mucosal biopsy from the sigmoid colon showed chronic inflammation with mucous exudates (Figure 3). There was the strong likelihood that the antitubercular agents were causing PMC, so we discontinued these agents. After oral metronidazole 250 mg three times a day and conservative therapy with intravenous fluid and electrolytes, the symptoms of the patient were ameliorated and then the patient was discharged. After 2 weeks, we restarted antitubercular agents with the 4 drugs regimen (HERZ) at the same initial doses. The patient again developed abdominal pain and diarrhea within only 3days after the retreatment with antitubercular agents. So the patient occasionally withheld the antitubercular agents by himself according to symptom, and when symptoms were relieved, he restarted taking the drugs. Only 3 weeks after discharge, he admitted with complains of mucoid, bloody diarrhea, severe abdominal pain and fever up to 38.4 C. His chest X-ray showed little change during this interval compared with the previous films (Figure 1). The white blood cell count was 20,200/mm3 with 78.7% segmented neutrophils. We stopped all medication including the anti-tubercular agents except the metronidazole. For 3 days, conservative management was done including fluid therapy and fasting, but he did not show improvement. So sigmoidoscopy was again done and it revealed diffuse white plaque and debris on the colon mucosa from the rectum to the sigmoid colon, with scattered whitish erosion (Figure 2B). Mucosal biopsy of the colon was compatible with a diagnosis of PMC on account of the ulceration with exudates of a pseudomembrane made up of inflammatory cells, fibrin, and necrotic debris. C. difficile toxin and stool culture were negative. 11 days after admission, the patient's symptoms were much resolved and follow-up sigomidoscopy demonstrated a much improved state of the colitis. 2 days later, the antitubercular agents were retried with regimen of 3drugs without the RFP (INH 400 mg, PZ 1500 mg, EMB 800 mg) and we observed the patient for another 10 days. The patient had no further recurrence of diarrhea, and he recovered his general condition; the follow-up sigmoidoscopy did not show any evidence of recurrent PMC (Figure 2C), and he was then discharged.

PMC4983335_01

Male

A 30-year-old right hand (RH) dominant Hispanic male with no past medical history presented to the ED after injuring his finger during a recreational football game. The patient attempted to catch the ball but jammed and dislocated the fourth digit of his RH at the middle phalangeal joint (MPJ). The patient presented with the following vital signs: blood pressure (BP) 126/83 mmHg, heart rate (HR) 90 beats/min, respiratory rate (RR) 18 breaths/min, SpO2 100% on room air (RA), and temperature 36.3 C. The patient underwent a hand radiograph that demonstrated a fracture dislocation of the proximal phalanx. The patient received an ultrasound-guided ulnar nerve block using a total of 5 mL of 1% lidocaine without epinephrine for pain control. After five minutes, adequate anesthesia was obtained as noted by the patient, and the reduction and splinting were successfully performed. The ED physician noted the reduction was easy to perform; the patient noted only minimal pain while performing the nerve block and was pain-free during the reduction and splinting of the digit. The patient had complete return of sensation to his hand prior to discharge. Vital signs at the time of discharge were blood pressure (BP) 120/80 mmHg, heart rate (HR) 80 beats/min, respiratory rate (RR) 20 breaths/min, and SpO2 100% on room air (RA). The patient was discharged with a prescription for Vicodin for pain control.

PMC4983335_03

Male

20-year-old RH dominant male presented to the ER with a left hand deformity that occurred while playing football. He reported pain on palpation of the metacarpophalangeal (MCP) joint of the left thumb with decreased sensation of the left thumb. The patient's vital signs were as follows: BP 127/62 mmHg, HR 74 beats/min, RR 18 breaths/min, SpO2 100% on RA, and temperature 36.8 C; pain was reported as 10/10. The patient's hand radiograph showed dorsal dislocation of the left thumb at the MCP joint without evidence of fracture (Figure 1). The patient underwent an in-plane ultrasound-guided radial and median peripheral nerve block using a total of 12 mL of 1% lidocaine with epinephrine and after two minutes the reduction procedure was performed. The patient tolerated the procedure well; the left MCP joint was successfully reduced and his finger was splinted. The patient had complete return of sensation to his hand, was able to flex, extend, abduct, and oppose his thumb, and noted that his pain was 0/10 prior to discharge. Vital signs at the time of discharge were BP 118/49, HR 80 beats/min, RR 20 breaths/min, and SpO2 100% on RA. He was given prescription for ibuprofen and Vicodin at the time of discharge.

PMC7587992_03

Male

The patient was a 63-year-old male with obesity, cold symptoms, and loss of taste and smell senses, which had started five days before the visit. He was admitted to the ED, and his vital signs were: T = 39.5 C, BP = 105/70 mmHg, PR = 104/min, RR = 24/min, SPO2 = 90% in room air, and BS = 122 mg/dL. He also had heroin addiction. He was diagnosed with COVID-19 infection based on PCR results. He had withdrawal signs and respiratory distress due to infection in the lower respiratory tract. Legal considerations: The patient had been a heroin addict for about 15 years. He had a high school diploma and was not willing to stay in hospital due to addiction; but his discharge could be a hazard to society, due to infection with COVID-19. Therefore, due to his unstable conditions and in order to prevent worsening of the COVID-19 outbreak, his admission to intensive care unit (ICU) was recommended. He received IV medications for addiction withdrawal in addition to routine COVID-19 treatments. His discharge was prohibited, and since he could not make his own medical decisions, the healthcare system informed the hospital authorities. Case3:

covid-19, forensic medicine, legal considerations, legal medicine, severe acute respiratory syndrome coronavirus 2

PMC9674505_01

Female

A 56-year-old Vietnamese woman presented to Blood Transfusion Hematology Hospital in February 2019 because of prolonged fever and fatigue. Her initial complete blood count (CBC) on admission was notable for severe anemia: hemoglobin (Hb) 60 g/L (120-175 g/L), mean corpuscular volume 72.9 fL (78-100), white blood cell count 9.65 G/L (4-10 G/L), neutrophils 55% (45%-75%), lymphocytes 20 % (20%-35%), monocytes 20% (4%-10%), platelet count 193 G/L (150-450 G/L). Human immunodeficiency virus (HIV) antibody, antinuclear antibody (ANA), Anti-double stranded DNA antibody (Anti ds-DNA), rheumatoid factor (RF), Coombs tests were negative. Other laboratory test results showed hypertriglyceridemia (565.49 mg/dL) (40-166 mg/dL), hyperferritinemia (3153.84 ng/ml) (10-280 ng/ml), increased soluble CD25 levels (3316.936U/ml) (Normal < 511.364 U/ml) and elevated lactate dehydrogenase (LDH) (592.34 U/L) (Normal < 248 U/L). Epstein-Barr virus (EBV) Detection by PCR (Polymerase Chain Reaction) result was positive. A lumbar puncture was performed which showed 14 white blood cell; 6 red blood cells; protein of 32.6 mg/dl (Normal < 45 mg/dL); glucose of 3.58 mmol/L (2.2-3.9 mmol/L) (serum glucose of 5.3 mmol/L) and Mycobacterium tuberculosis detection by PCR result was negative. Bone marrow aspirate cytology revealed red blood cell and platelet phagocytosis. Abdominopelvic CT scan and brain MRI were obtained showing hepatomegaly, splenomegaly and subacute bilateral pontine infarction (Fig. 1). Gastrointestinal and colorectal endoscopy were performed with unremarkable results. The diagnosis was established with Hemophagocytic syndrome probably secondary to Epstein-Barr virus (EBV) infection - Pontine infarction. The patient was treated with Aspirin (81mg/day) and Dexamethasone (5 mg/day). The fever was controlled and anemia improved partially over the next several weeks. She was continuously treated with Aspirin (81 mg/day) and Dexamethason (2 mg/day) after discharge from the hospital. In May 2019, the patient was admitted to University Medical Center - Ho Chi Minh city due to acute weakness at the left side and slurred speech. She presented an expressive language impairment, short-term and long-term memory deficit, left central facial palsy and quadriparesis. CBC showed anemia, mild thrombocytopenia: WBC count 13.39 G/L (4-10 G/L), Hb 96 g/L (120-175 g/L), Platelets 142 G/L (150-450 G/L). Brain MRI showed multifocal cerebral infarcts located at left frontal lobe and bilateral corona radiata (Fig. 1). However, magnetic resonance angiography (MRA) of the brain revealed normal intracranial vasculature. Holter monitor, echocardiography, carotid Doppler, lower extremity venous Doppler ultrasound results were unremarkable. Cerebrospinal fluid (CSF) examination showed 19 white blood cell; 2000 red blood cells; protein of 95.22 mg/dL (Normal < 45 mg/dL); glucose of 3.6 mmol/L (2.2-3.9 mmol/L) (serum glucose of 6 mmol/L (3.9-6.4 mmol/L)), Lactate 4.139 mmol/l (1.1-2.4 mmol/L). Other CSF studies including CFS culture looking for bacteria and fungi, Herpes Simplex virus (HSV) PCR test, GeneXpert for the detection of Mycobacterium tuberculosis were all negative. The patient was treated with Dexamethasone and Plavix (75 mg/day) and discharged 7 days after the admission. Ten days after discharge, the patient was readmitted with deteriorated neurological condition as noted by developing quadriplegia and a worsening level of consciousness. On examination at the time of admission, she was agitated and had visual hallucinations. Concurrently, she had developed low-grade fever without an identifiable source of infection. Laboratory tests showed anemia, thrombocytopenia: WBC count 9.01 G/L (4-10 G/L), Hb 78 g/L (120-175 g/L), Platelets 122 G/L (150-450 G/L) and elevated LDH (300 U/L) (Normal < 248 U/L). Brain MRI showed some recent small subcortical infarcts located at left frontal lobe when comparing with the brain MRI 2 weeks earlier. Intracranial high resolution vessel wall magnetic resonance imaging (HR-vwMRI) post-contrast T1W showed vessel wall thickening with moderate enhancement at the left PCA and bilateral MCA segments relevant to the cerebral infarction suggesting vasculitis (Fig. 2). Lumbar puncture was performed again and CSF examination showed: 13 white blood cell, neutrophils 10%, lymphocytes 90 %, 0 red blood cells; protein of 111.08 mg/dL (Normal < 45 mg/dL); glucose of 5.2 mmol/L (2.2-3.9 mmol/L) (serum glucose of 8.9 mmol/L (3.9-6.4 mmol/L)); lactate 4.139 mmol/L (1.1-2.4 mmol/L). CSF culture looking for bacteria and fungi, GeneXpert for the detection of Mycobacterium tuberculosis were all negative. An abdominal, pelvic and thoracic CT-Scan revealed splenomegaly, multiple bilateral small nodules of the lung, multiple liver lesions, multiple bilateral renal masses, gastric wall thickening and multiple nodules in the omentum (Fig. 3). Red blood cell and platelet phagocytosis was showed on bone marrow aspirate cytology. Gastrointestinal endoscopy was performed again showing mild congestive gastritis and Kaposi's sarcoma was doubted. The pathological findings of gastric tissue biopsy revealed large B cell lymphoma (Fig. 4). The patient was planned to start on chemotherapy but she developed septic shock from severe pneumonia and died 28 days after the definitive diagnosis.

diffuse large b-cell lymphoma, hemophagocytic lymphohistiocytosis, lymphoma-associated hemophagocytic syndrome, recurrent multi-territory infarcts

PMC9720303_01

Male

A 9-year-old male castrated domestic shorthair cat was presented to its local veterinarian for coughing and waxing and waning peripheral edema. Thoracic radiographs revealed pleural effusion. After three thoracocentesis events that each recovered between 300 and 420 cm3 of fluid, the cat was referred to the study institution. At presentation the cat weighed 4.4 kg and had a body condition score of 4/9. A moderate amount of peripheral edema was present in its inguinal region. The cat exhibited increased respiratory effort, and decreased breath sounds were appreciated ventrally. A grade II/VI left parasternal systolic heart murmur was ausculted. Pleural effusion was detected bilaterally via thoracic ultrasound, and bilateral thoracocentesis drained 362 cm3 of translucent fluid from the pleural space. The fluid was classified as a pure transudate (protein 3 kg/m3, total nucleated cell count 90/mm3) and contained a creatinine of 29 g/m3, glucose of 1.32 kg/m3, and potassium of 2.7 mol/m3. Complete blood count showed a moderate normocytic, normochromic, nonregenerative anemia (hematocrit 22.8%; RR: 30-50%). Serum biochemistry panel revealed azotemia [consistent with IRIS stage 2 chronic kidney disease (CKD)] characterized by a creatinine of 28 g/m3 (RR: 12-22 g/m3) and BUN of 540 g/m3 (RR: 180-330 g/m3). Urinalysis revealed a specific gravity of 1.031 with proteinuria (750 g/m3) and glucosuria (10,000 g/m3). Lactate dehydrogenase (LDH) evaluation was as follows: < 0.01 IU/cm3 in the effusion, 0.092 IU/cm3 in the urine, and 0.188 IU/cm3 in the blood. A NT-proBNP test (IDEXX, Westbrook, ME) was normal. Abdominal ultrasound showed bilaterally decreased renal corticomedullary distinction with cortical cysts and scant peritoneal effusion. Echocardiography revealed a mild myocardial irregularity and an impaired relaxation pattern of left ventricular diastolic filling (possibly age related or early heart disease). Renal scintigraphy was performed using 99mTc diethylenetriamine penta-acetic acid (Tc-DTPA) to investigate for presence of urothorax. In this case, 2.25 millicuries Tc-DTPA were administered intravenously and 60 s static images were acquired using a low-energy, all-purpose collimator at 5 min, 20 min, and hourly until 4 h following injection (Figures 1, 2). Initially, there was blushing of the renal silhouettes as the Tc-DTPA accumulated within the kidneys with immediate extension of radiopharmaceutical in the urinary bladder. Over the next 4 h, technetium progressively accumulated within the pleural space, demonstrating a communication between the urinary tract and pleural space. Multiphase contrast-enhanced CT of the thorax and abdomen was performed with multiple post-contrast sequences (Figures 3A-C). On venous phase images, both kidneys had a thin outline of subcapsular contrast media with mild extravasation of the contrast into the retroperitoneal space. On delayed phase images, there was progressive accumulation of contrast media in the retroperitoneal effusion as well as an increase in Hounsfield units (from 8 to 16) of the pleural effusion. The pleura was mildly thickened, consistent with pleuritis from chronic pleural effusion, and fluid could be seen on either side of the plica vena cava. There were multiple small contrast filling defects within the renal cortical tissue consistent with renal cortical cysts, and no ureteral abnormalities were detected. Subcutaneous edema was noted in the pelvic limbs and perineal region. Exploratory celiotomy revealed minimal translucent peritoneal effusion. No visible or palpable defects were identified in the substance of the diaphragm or at the caval foramen, esophageal hiatus, or aortic hiatus. The retroperitoneum appeared gelatinous bilaterally. After retroperitoneal incision, leakage of fluid was traced to circular defects in the cranial aspect of the renal capsules bilaterally. Retroperitoneal fat was adhered to the exposed renal parenchyma (Figure 4) and local retroperitoneal fibrosis was detected in these regions. Fluid was observed to be leaking from these defects and gentle probing revealed a lack of connection of the renal capsule surrounding the defects to the underlying renal parenchyma. Ultrafiltrate fluid was observed accumulating in this space before leaking into the retroperitoneal space. No ureteral or bladder leaks were identified. No reconstructive options were available, so the retroperitoneum was incised from the level of each kidney to the diaphragm to encourage drainage of fluid from the retroperitoneum into the peritoneum and thereby minimize tracking into the pleural space. Due to the subsequent instability of the renal attachments to the body wall, bilateral nephropexies were performed between the retroperitoneal sublumbar musculature and caudal pole of each kidney using 3-0 polypropylene in a cruciate pattern. The abdomen was closed in routine fashion. A biopsy of the right renal capsule adjacent to the capsular defect revealed minimal chronic lymphocytic and plasmacytic perinephritis. The cat received a packed red blood cell transfusion during the procedure and recovered from anesthesia without complications. The cat returned 11 days postoperatively for a recheck examination. No clinical signs of pleural effusion were exhibited, though a brief ultrasound scan revealed a moderate amount of pleural effusion and pockets of free peritoneal fluid. The cat presented again 16 days later with an increased respiratory effort and respiratory rate of 40 breaths per minute. A brief ultrasound exam revealed a moderate amount of pleural effusion and a scant amount of peritoneal effusion. Thoracocentesis was performed and 294 cm3 of clear fluid was removed. The cat continued to produce small amounts of pleural effusion, and intermittent peripheral edema was reported during periods of increased pleural effusion. The owner elected to place a pleural drainage catheter and port system ~2 months after the initial surgery. Pleural effusion was managed for 2 additional years, at which time the cat was euthanized due to progressive CKD (IRIS stage 4) and an associated decline in quality of life. Necropsy revealed bicavitary effusion with severe CKD changes (including interstitial fibrosis and lymphoplasmacytic nephritis), multifocal, nodular, pulmonary interstitial fibrosis without inflammation (suspect idiopathic feline pulmonary fibrosis), cardiac interstitial fibrosis (concentric ventricular myocardial hypertrophy), and parathyroid hyperplasia as well as bone marrow erythroid hypoplasia (suspect secondary to renal disease). The underlying cause of the bicavitary effusion was not grossly or histologically apparent.

tc-dtpa, feline, hydrothorax, perinephric pseudocyst, urothorax

PMC9474833_01

Unknown

The world s youngest nation, South Sudan, descended into civil war in December 2013, followed by another significant flare-up in 2016 after a failed peace process and has been reeling in the effects of the prolonged conflict ever since. The cumulative impact of the conflict and attendant humanitarian crisis has resulted in 8.3 million people in need of humanitarian assistance, 7.2 million people experiencing severe food insecurity, and 2.0 million internally displaced persons (IDP) in 2021. Severe recurrent flooding, acute food insecurity and famine, sub-national violence, mass displacement, disease outbreaks and the COVID-19 pandemic are among the top drivers of humanitarian needs among the communities. The provision of essential health services has been complicated by a health system that is under-developed, under-resourced, and highly dependent on the development and humanitarian partners with limited access to essential health services occasioned by the poor road system, insecurity, and natural disasters like floods. South Sudan has amongst the poorest health indicators owing to poor access to essential services and severe disruption of health service delivery during the decades of civil war. The maternal mortality rate at 1,150 per 100,000 live births is the highest in the world, while the under-5-year-old mortality rate at 98 per 1000 live births is among the highest globally. The routine immunization coverage for vaccine-preventable diseases was estimated at <50% in 2020 with lower coverages in the conflict-affected counties in Jonglei, Unity and Upper Nile, which predisposed the vulnerable population to multiple diseases outbreaks. Measles outbreaks were confirmed in 24 out of 47 counties, four UN Protection of Civilians (PoC) sites in 2019 and five counties in 2020. The use of mobile medical teams, usually self-sufficient, multidisciplinary medical teams with sufficient flexibility to deploy rapidly, is a common modality in humanitarian emergencies. Mobile clinics deliver preventive (i.e. immunization, screening, and health education) and curative (i.e. treatment of common morbidities and minor surgeries) services to communities that are unable to access health facilities. The mobile health services are operated with clear referral pathways for services that cannot be rendered by the mobile clinic. Mobile clinics are common and favored in humanitarian crises, although they are limited in coverage, expensive and logistically burdensome, and lack sustainability and continuity for chronic illnesses. The vulnerable populations in the humanitarian crisis face frequent disease outbreaks and breakdowns in essential services and require an emergency response to provide timely and essential services to prevent and reduce excess morbidity and mortality. With almost 80% of health services being delivered by health partners, the South Sudan health system can barely provide routine service delivery and respond to emergencies. Health service delivery is fragmented and faces enormous challenges due to limited access as only 44% of the population live within 5km of a health facility. The country experiences frequent humanitarian and public health emergencies that exacerbate the needs of vulnerable communities. The World Health Organization (WHO) South Sudan has a standby emergency mobile medical teams (eMMT) within its emergency program. The eMMT is deployed to verify, investigate, and respond to disease outbreaks and other public health emergencies. The WHO eMMT operates within the framework of the Health Cluster with the frontline Health Cluster partners fulfilling their mandate of providing basic health and essential services including surveillance and response to emergencies in fragile, conflict, and vulnerable settings. WHO provides overall technical backstopping for the health cluster response and strategy, and is a provider of last resort that fills in health response gaps in locations where the frontline partners are either lacking or are overwhelmed based by the scale of the acute crisis and scope of response needs. It is in these settings that the WHO eMMTs are deployed to augment the health cluster response. Here we describe the teams experiences, challenges, and usefulness in a complex humanitarian setting in South Sudan and share the lessons learned and recommendations for improving the intervention. WHO South Sudan established the eMMT in 2016. The intent was to have a readily deployable capacity to conduct assessments, investigations, and institute initial life-saving integrated services during acute emergencies. The eMMTs are WHO personnel engaged on short-term contracts to support response to acute emergencies. The eMMTs comprise epidemiologists, clinicians or doctors, nurses, laboratory specialists, nutritionists, health promotion experts, and public health officers or water, sanitation, and hygiene (WASH) experts. The teams are constituted to ensure they are self-sufficient during their field deployment. For each deployment, the team composition is tailored to the unique response needs of the emergency at hand. Each member of the team plays specific roles and responsibilities on the team. The epidemiologist is the team lead and provides technical leadership during outbreak investigations and rapid assessments, planning and coordination of mobile outreaches, training and vaccination campaigns, and data analysis and report writing. The clinicians and nurses are tasked to undertake clinical care of patients during the outreaches and vaccination activities while the laboratory personnel are charged with collecting, packaging and transporting samples collected from the field. The public health officer and WASH experts are involved in health promotion and messaging, while the nutritionist is tasked to spearhead the nutrition component of the intervention. All the team members support their respective areas during training organized for the local health workers or partners. There have been two to three eMMTs under WHO South Sudan during different emergencies depending on the response needs. The teams are based in Juba, state or county level. While the teams based in the states or counties are specific for those locations, the team based in Juba functions to support any location that lacks local capacity and requires support. The eMMTs are standby rapidly deployable within 24-48 hours of receiving an alert or a report from the counties, surveillance officers, implementing health partners, or community informers or leaders. The teams receive orientation on planning and preparing for deployments, conducting mobile medical outreaches, emergency vaccination campaigns and capacity building of local health workers upon joining the team. The teams also undergo trainer of trainers training for the Integrated Disease Surveillance and Response (IDSR) to ensure that they are adequately skilled to build local health workers' capacity to report, detect and investigate alerts or suspected outbreaks, and initiate an appropriate response. The eMMTs are resourced to undertake their mandates while on field deployments. The materials, tools and support provided are dependent on the intervention planned. The teams are usually equipped with the Ministry of Health (MoH) outpatient registers (used during outreaches), referral forms, and information, education and communication (IEC) materials. In addition, the teams are equipped with emergency health kits (containing essential drugs and supplies required during outreaches), laboratory sample collection kits, water sample collection and testing kits, and first aid supplies. The IDSR, case management and other training materials are also provided to the teams to train local health workers. The operation and logistics support are usually provided through WHO field teams who support securing accommodations and local transportation, while the United Nations Humanitarian Air Services (UNHAS) support transportation from the duty station to response sites. The eMMT interventions are mostly supported through emergency donor-funded projects focused on providing short-term humanitarian aid during acute emergencies. We deployed eMMTs to locations with acute emergencies where support is required to supplement the existing local capacities. We deployed the eMMTs to respond to acute emergencies such as infectious disease outbreaks, large-scale population displacements, natural disasters like floods, famine and malnutrition, and breakdown in basic health service delivery where there is no other health partner to fill the critical gap. The eMMTs were deployed to over 35 counties across the country during the period 2017-2020 (Figure 1). The Health Cluster, health preparedness and response coordination forum, agrees on the emergency response locations based on the needs assessments and partner presence. WHO mobilized the eMMTs to provide integrated health and nutrition services. The eMMTs were deployed to conflict-affected locations such as Kajo-Keji and Tambura from 2017 to 2020, and flood-affected locations such as Pibor, Akobo and Mayom in 2019 and 2020. During the deployments, the teams select sites for mobile outreaches in consultation with local health leaders and partners to avoid duplication, set up temporary outreach sites and provide services for two to five days. The sites were revisited as per the schedule prepared to ensure adequate coverage of all the locations in need of mobile services. The integrated health and nutrition services provided by the eMMT include preventive (i.e. routine vaccination, antenatal care, health education and promotion), curative (i.e. outpatient consultation, nursing care, minor surgeries, and referral for severe cases) and nutrition (i.e. screening and referral of severely malnourished cases for inpatient care) services. The outreach services were provided as per the clinical package of services by the Health Cluster and the Basic Package of Health and Nutrition Services by the South Sudan Ministry of Health. Secondly, the eMMTs are deployed to conduct alert verification and outbreak investigation. Alerts and suspected disease outbreaks are usually generated through the Early Warning, Alert and Response System (EWARS) and communicated to Public Health Emergency Operation Centre (PHEOC) leadership and WHO by PHEOC officers assigned to monitor alerts. The eMMTs are deployed to conduct outbreak investigations and collect patient and environmental samples for laboratory confirmation. In addition, the eMMT initiated health responses for the affected locations by supporting local health facilities, delivering essential commodities and supplies, and disseminating findings to PHEOC and partners to guide further action. The eMMTs have been deployed to investigate suspected outbreaks of cholera in Pibor and Kapoeta East Counties, yellow fever in Nzara County, and Rift Valley fever in Yirol East County, measles and COVID-19 in several counties. The deployment of eMMTs is done in coordination with the National PHEOC, which is charged with coordinating responses in the country. The eMMTs support the PHEOC through on-job training of the national and state Rapid Response Teams (RRT). The RRTs are the Ministry of Health officers who constitute a critical early detection and response arm of the PHEOC. Figure 2 depicts the working relationship between WHO eMMT, PHEOC, and the RRTs in their mandate to conduct early identification, confirmation of, and response to acute public health events. Thirdly, we have deployed the eMMTs to implement vaccination activities in locations affected by emergencies. The eMMTs have been deployed during confirmed outbreaks to implement reactive measles and cholera vaccination campaigns and pre-emptive Oral Cholera Vaccination (OCV) campaigns in flood-affected locations. The eMMTs implemented vaccination campaigns in several locations, including Kapoeta South and Pibor. The eMMTs utilized standard MoH vaccination registers, cold chain equipment and supplies, and collaborated with local health workers and partners during the campaigns. The eMMTs have also been deployed to provide training on IDSR, case management of common endemic diseases, infection prevention and control (IPC), and Clinical Management of Rape (CMR) for healthcare workers. The IDSR training that targeted surveillance officers and facility in-charges aims to enhance surveillance and reporting by health facilities and is conducted using the adapted IDSR training modules. The case management training targeted clinicians and nurses, while IPC training was meant for clinical cadres and public health officers. Both the case management and IPC training are based on the treatment and IPC guidelines by the MoH and WHO. All the training utilized customized PowerPoint presentations and case study exercises. Data on the outpatient consultation were extracted from the outpatient registers that are completed during mobile medical outreaches. We obtained the information on the number of health workers trained from the attendance sheet. Training and deployment reports were submitted using a standardized training and field report template utilized by the eMMT to document the interventions and achievements. In addition, we extracted the vaccination campaign data from the field reports and the Ministry of Health s daily tally sheet and summary sheet filled by the vaccinators and team supervisors during the vaccination exercise. The coverage of the vaccination campaigns was calculated using Microsoft Excel as a proportion of the targeted population.

rift valley fever, south sudan, vulnerable populations, cholera, disease outbreaks, emergency medical teams, measles, psychosocial care, public health emergencies, rapid response teams

PMC9474833_02

Unknown

The eMMT has implemented its intervention in 38 counties spread across nine states, with almost half (42%) of the counties located in Jonglei and Unity States (Figure 1). The interventions implemented ranged from disease outbreak investigations, and implementation of emergency pre-emptive and reactive vaccination campaigns to conducting mobile medical outreaches. Notably, eMMTs have investigated and confirmed rift valley fever outbreaks in 2018. The eMMT investigated measles outbreaks and implemented reactive vaccination campaigns in seven counties during the review period, including Maruwa and Labarab in Pibor, during the widespread measles outbreak in the country in 2019. Labarab and Maruwa are hard-to-reach locations in Pibor Administrative Area, where the eMMT implemented a reactive measles vaccination as the provider of last resort as no partner could access the area. Overall, 148,725 (72-125% coverage) under-5-year-old children were vaccinated in seven locations with confirmed measles outbreaks in 2019 and 2020. Some 355,790 (coverage 51-89% in round 1 and 50-78% in round 2) individuals were reached with oral cholera vaccines in four locations with active cholera outbreaks in 2018. Further, the eMMT implemented a pre-emptive oral cholera vaccination campaign in Bor South, a severe flood county in 2020, and vaccinated 63,280 (88.1%) people in round 1 and 64,137 (89.3%) people in round 2. In 2019 and 2020, the eMMT took the lead in training RRTs and other health workers as part of the country s preparedness activities for the Ebola Virus Disease (EVD) and COVID-19 pandemic and formed a critical component of the COVID-19 response team after the outbreak was confirmed in the country as members of contact tracers. A summary of some critical achievements is presented in Table 1. The implementation of the mobile medical team strategy has revealed a few important lessons that can be used to strengthen the future approaches for the intervention. First, there is a need for collaboration and coordination with the local administration and partners on the ground for adequate information on insecurity and access challenges critical for planning. Second, the team composition must be reconstituted and adapted based on the nature of the emergency being responded to, assuring adequate capacity within the team to attend the event. A different set of skills and experiences is required to respond to different emergencies adequately. Thirdly, to ensure the needs of the vulnerable populations are addressed comprehensively, it would be prudent to broaden the scope of the services offered by the eMMTs to include psychosocial and mental care. Mental health and psychosocial disorders, including post-traumatic stress syndrome and depression, are prevalent among conflict-affected populations. There is a high need for mental health services during and after conflicts. The effectiveness of delivering community mental health services through mobile health clinic approach has been demonstrated in rural Haiti. Further, there must be a proper referral linkage with local health facilities where the mobile outreaches are being conducted to attend to severe clinical cases requiring an inpatient or specialized service. Transportation and costs of referring these cases from outreach sites to the receiving facilities should be anticipated and planned. Fifth, there is a need for collaboration between eMMTs and local health workers, including community health workers during outreaches and outbreak investigations for on-the-job training and skills transfer with the view of promoting ownership and sustainability of interventions. Our operations and delivery of essential services have been affected by multiple factors ranging from insecurity to difficulties in delivering essential commodities and personnel on time to where they are required. Unpredictable security situations, inefficient and costly logistics, rugged terrain and poor road and transportation networks, frequent flooding, and lack of continuity of services the mobile teams offer are some of the key challenges faced. The frequent insecurity flare-ups, displacement of the targeted populations, flooding of airstrips, impassable roads, delays in delivery of essential medicines, vaccines, emergency responders, and funds required for planned activities and attacks on health facilities or health personnel have contributed to the mobile missions being postponed, terminated, or being unsuccessful. Many of the locations served by the mobile teams are hard-to-reach areas that caused the teams to trek for long hours through challenging terrains, mud, or flood water or be flown into the area to reach the vulnerable, isolated groups. Some locations lacked a partner or local authority to address the reported emergencies and required WHO to send in the mobile teams as the provider of the last resort. The lack of continuity of the services offered by the eMMTs is related to the absence of strategies to ensure the continued provision of vaccination services and the management of the chronic conditions initiated during the mobile outreach. The lack of predictability of the visit by the mobile teams may negatively affect the community s uptake of the services and the ability of the teams to offer certain services. The other notable challenges encountered include weak public health surveillance and poor mobile network coverage in the conflict-affected counties contributing to delays in receiving and responding to reports of public health events and inconsistent capture and reporting of data from the mobile clinics.

rift valley fever, south sudan, vulnerable populations, cholera, disease outbreaks, emergency medical teams, measles, psychosocial care, public health emergencies, rapid response teams

PMC3068585_02

Female

An 18-year-old girl presented with a progressive bulging mass 2 x 3 cm2 in size, mildly tender, and soft without any fluctuation in 3 weeks located in her rib inter-space 1-2 near the left border of the sternum. She was living in the urban area and was healthy otherwise, except for a history of unpasteurized cheese usage. Intermittent low-grade fever (at night) and sweating were the only complaints. CXR was normal and ultrasonography reported the mass as a lymphadenopathy. Brucella seroagglutination tests, Wright, and 2ME were requested. Laboratory data showed: WBC = 11,200: Neut = 78%, Lymph = 20%, Mono = 2%, Hb = 11.1, Wright = 1/640, 2ME = 1/80, ESR = 9. Other lab data were not remarkable. Biopsy of the lesion showed nonspecific inflammation of the lymph node. She was treated with Cap. Doxycycline (100 mg/BID/Po) and Tab. Rifampin (600 mg/day/Po). After 2 months, lymphadenopathy disappeared and no relapse was reported after 1 year follow-up. The third case was an 18-month-boy referred with a history of multiple, firm, and tender parasternal nodules (about 1.5 x 2 cm2 in size). He showed no constitutional symptoms. There was no clear history of using unpasteurized dairy products. Wright and Coomb's Wright and all workups were negative. Routine laboratory exams revealed normal results. As a diagnostic approach, excisional biopsy was performed. Grossly, the lesion was cartilaginous with no evidence of necrosis or tumoral involvement. Microscopic examination revealed chronic nonspecific inflammatory process. The smear and culture of biopsied material were negative for tuberculosis or other bacteria. Due to persistent signs and symptoms, follow-up was done by repeated serologic tests which showed four-fold rising in brucella titer (8 weeks later). Treatment was started by Tab. Trimethoprim-sulfamethoxazole (trimethoprim, 8 mg/kg/Po) and Tab. Rifampin (10 mg/kg/Po) and continued for 8 weeks. Good response to therapy was achieved.

brucellosis, chest wall involvement, manifestation

PMC4804557_01

Male

A forty-five-year-old black male patient from Apucarana,Parana, with one atypical lesion on the right side of his back was attended, in March 2009, in the LEPAC (Laboratorio de Ensino e Pesquisa em Analises Clinicas) of the Universidade Estadual de Maringa, for cutaneous leishmaniasis (CL) laboratory diagnosis. The patient reported that the lesion had been present for approximately one month (Fig. 1A). The lesion was a rounded plaque, with a erythematous violaceous center, descamative ulcerated edges, surrounded by an extensive area of lichenification, measuring 20 cm. Based on clinical appearance, the differential diagnosis of the lesion included chronic simple lichen, psoriasis, squamous cell carcinoma, chromomycosis, cutaneous tuberculosis, syphilis, paracoccidioidomycosis, and sarcoidosis. Before seeking for medical attention, the patient used topical antibiotics, but the lesion persisted without improvement. The performed tests showed a positive Montenegro skin test (MST) with an induration of 10 mm and indirect immunofluorescence (IIF) positive for anti-Leishmania IgG antibodies, reaching a titer of 80.Leishmania amastigotes were detected in the material obtained by scraping of the lesion stained by Giemsa (Fig. 1B) and cultured in blood base agar (BBA). The BBA grown parasites were sent to the Colecao de Leishmania of Instituto Oswaldo Cruz (CLIOC), Rio de Janeiro, Brazil, for identification and the strains were confirmed as L. (V.) braziliensis (MHOM/BR/2009/3476). The species identification was performed by multilocus enzyme electrophoresis (MLEE). To exclude the possibility of coexisting infections, fungi and HIV investigations were performed with negative results. The patient was treated with 120 ampoules of intramuscular meglumine antimoniate (approximately 15 mg/kg Sb5+ per day) in three cycles of 20 days each at the Pronto Atendimento Municipal of Apucarana municipality. Approximately 40 days after the end of treatment (August 2009) the lesion was still active and new laboratory tests were performed. The IIF test was positive with a titer of 160 and the direct parasite search was negative. About six months later (May 2010) the patient was submitted to another treatment with intravenous pentamidine (4 mg/kg per day) for seven days, which resulted in apparent healing of the lesion. In June 2010, the values of serum amylase (87 U/L) and creatinine (1.0 mg/dL) were normal. However, some months later, new papular lesions emerged, ulcerated and spread to the axillary region. In November 2010, the patient was admitted for treatment with amphotericin B desoxycholate (50 mg/day). The treatment was discontinued after three doses because the values of serum urea (88 mg/dL) and creatinine (3.1 mg/dL) were increased indicating renal failure. One additional course of pentamidine for 10 days was established (April 2011). There was a partial clinical resolution of lesions with the patient still presenting some residual lesions. In February 2012, about three years after the onset of the lesion and despite the multiple treatments, the lesion was not healing. The lesion was an ulcerated plaque with erythematous fibrous bottom and verrucous edges, surrounded by a lichenification area in the right scapular region and posterior region of the right arm (Fig. 1C). New laboratory tests were performed. The direct parasite search revealed the presence of characteristic amastigotes of Leishmania spp., the IIF showed titer 320, and the polymerase chain reaction (PCR) for kDNA minicircles of the subgenusLeishmania (Viannia) was positive. The patient was treated again with meglumine antimoniate by the intravenous route (3 ampoules per day) for approximately 40 days. Following this treatment, the lesion healed. Unfortunately, about a year after the end of the treatment, the patient died of a heart attack.

PMC4941090_01

Male

Table 1 shows the clinical characteristics of the patients. We did not collect data on the healthcare workers involved other than treatment and outcomes. The timeline of the outbreak is shown in Figure 1. The presumed index patient (Patient no. 1) was a 6-year-old immunocompromised boy who presented to an outpatient clinic with respiratory symptoms. Influenza was suspected, a nasopharyngeal swab was obtained and the decision for hospitalization was made later that evening when at home, the patient's fever and symptoms worsened. The patient was hospitalized on the pediatric hematology-oncology unit, but was inadvertently not placed in isolation immediately. Isolation was instituted upon confirmation of the diagnosis a day later.

PMC4941090_03

Male

Patient no. 2 was a 2-year-old boy, present on the inpatient pediatric hematology-oncology floor for over a month, receiving inpatient care for hepatoblastoma and associated complications. This patient was likely exposed to the 2009 influenza A (H1N1) virus by HCW no. 1, on day 4 of the outbreak, and became febrile on day 6. Staff and family noted increased fussiness and a runny nose prior to development of fever, but otherwise no new symptoms. Nasopharyngeal swabs were obtained within 24 hours of the onset of fever, and oseltamivir therapy and isolation precautions were initiated. The patient initially did well, was without fever after 48 hours, and isolation precautions were discontinued after 7 days (on day 13 of the outbreak). On day 13 of the outbreak, Patient no. 2 began a new cycle of chemotherapy and developed new fevers beginning on day 20 of the outbreak with no new symptoms noted other than nasal congestion on exam. Testing for respiratory viruses, including H1N1, was performed that same day, isolation and treatment with oseltamivir were reinitiated, and the patient gradually improved with resolution of fever after 4 days. In response to the outbreak, emphasis was placed on enhanced respiratory precautions. The nursing staff were cohorted and vaccinated with inactivated pandemic H1N1 vaccine. Other exposed patients, many of whom were immunocompromised, received oseltamivir prophylaxis. The prophylactic treatment was well tolerated, and no additional patients developed symptoms. Initially, the outbreak appeared to be successfully contained and Patient no. 2, who had recovered well, was taken out of isolation precautions after 7 days. Approximately 1 week after the discontinuation of isolation precautions (14 days following the initial positive test), Patient no. 2 underwent chemotherapy, developed fever, and a second nasopharyngeal swab tested positive for Influenza A (the 2009 pandemic H1N1 virus) by RT-PCR. Testing for other respiratory viruses was negative. A chest radiograph was normal. The patient remained hospitalized throughout this course of events. While it is possible that the second episode represented new nosocomial acquisition, given lack of evidence of ongoing transmission, reactivation is a more likely explanation of the patient's recurrent infection. A healthcare worker (HCW no. 4) caring for Patient no. 2 between episodes, while no isolation precautions were in place, subsequently developed H1N1 infection as well. Observations to determine HCW compliance with isolation precautions were undertaken during the period of the outbreak and increased over the course of a few days from 80% to 98%. However, observations were not undertaken routinely prior to the outbreak. Three of the four healthcare workers tested positive for H1N1 at onset of symptoms - one was treated presumptively and did not undergo testing. All four healthcare workers were treated with oseltamivir for 5 days and responded to treatment. They returned to work 1 week after treatment was initiated. A follow-up nasopharyngeal swab was not required or obtained, but all were free of symptoms at the time of returning to work. To determine whether these epidemiologically linked cases of influenza were initiated by a single source patient, we performed genetic analyses on viruses isolated from nasopharyngeal swabs taken from both patients and from the two healthcare workers who were tested. We first isolated influenza vRNA from each sample and determined its concentration using a quantitative reverse-transcription (QRT-) PCR assay. The concentration of viral vRNA ranged from 70 000 to 51 million copies/ml. Because of the relatively low concentration of vRNA in Patient no. 2's samples, we chose to focus our genetic analysis on two of the eight segments of the influenza virus RNA genome. The highly variable HA gene encodes the viral attachment protein and is the major target of virus-specific antibodies, which can drive diversification of virus sequences. 7 We reasoned that if the nosocomial outbreak was initiated by more than one virus, then sequence differences distinguishing the strains would be most apparent in HA. We also analyzed the basic polymerase subunit 2 (PB2) gene, which is more tightly conserved than HA, but encodes well-characterized pathogenicity determinants. 8 We were able to sequence full-length HA and PB2 genes directly from all available samples except for Patient no. 2's second sample; sequence data from this sample was, therefore, derived from an in vitro-expanded virus stock. The HA and PB2 segments of viruses isolated from all patients were completely identical to each other (Figure S1). blast database searches revealed no previously identified influenza viruses that matched these sequences exactly at the nucleotide level, but both the HA and PB2 genes in viruses isolated from these patients showed 99% identity to contemporaneous viruses isolated in Southeastern Wisconsin (http://www.ncbi.nlm.nih.gov/nuccore). To estimate the genetic distance of viruses in this outbreak from the contemporaneous virus population, we performed a phylogenetic analysis of HA and PB2 genes using the vaccine strain A/California/07/2009 (CA07; H1N1), isolated early in the pandemic, as an outgroup (Figure S2). Although the topologies of the HA and PB2 trees differed slightly, in both trees, the UW Hospital isolates clustered together, as expected for identical sequences. Indeed, the CA07 sequences, isolated in April 2009, clustered closely together with Southeastern Wisconsin isolates from September to December 2009, suggesting that all these viruses are closely related. Our results are consistent with the conclusion that Patient no. 1 had a community-acquired infection with 2009 influenza A (H1N1) virus and was the sole source of this nosocomial outbreak.

PMC7685367_01

Male

A 40-year-old man was referred to our clinic with a 23-year history of AS who presented with acute back pain after a slight fall 21 months ago. On examination, the patient presented with significant percussion tenderness over the T11-T12 spine, and although the neurological examination was negative, the activity of the whole spine was restricted. CT images showed "bamboo-like changes" in the spine, and the fresh three-column fracture of T12 was characterized by no marked displacement and reduction in vertebral body height (Figure 1A). He was treated conservatively, which included a brace, rest, physiotherapy, and a regimen of intramuscular methotrexate (10 mg/week), sulfasalazine (1000 mg twice daily), and oral NSAIDS (nimesulide 0.1 g twice daily). However, he did not take his medicines regularly and experienced a more stooped position. The symptoms gradually worsened. Six months after the initial trauma, the patient returned to the outpatient clinic and complained of persistent low back pain with no neurological signs. CT images revealed pseudarthrosis with marked sclerosis at T12, and the upper part of the T12 vertebral body was irregularly damaged, with lesions identified as ALs (Figure 1B). We recommended surgery, but the patient refused and continued conservative treatment. Nine months after the initial trauma, the patient returned again and presented with progressive thoracolumbar pain without neurological symptoms. CT showed that the lesion involved the intervertebral space and the lower part of the T11 vertebral body, with pseudarthrosis and obvious hyperplasia (Figure 1C). Considering the history of progressive back pain, no neurological deficits, and progressive kyphosis at pseudarthrosis, we recommended surgery, but the patient still refused. Twelve months after the initial trauma, the patient was admitted to our hospital after presenting with unbearable back pain, hypoesthesia in the perineal area, walking weakness, and increases in urinary frequency and urgency. CT demonstrated that the scope of the lesions had extended, and there was severe thoracolumbar kyphosis and spinal canal stenosis (Figure 1D). The patient reported no history of tumor or tuberculosis. On examination, his legs showed weakness and numbness and hypoesthesia of the skin in the perineal area. His key muscle strength was grade IV, the deep reflexes were weakened, and the Babinski sign was negative. Laboratory examination showed that the erythrocyte sedimentation rate and C-reactive protein were 24 mm/h and 148.4 mg/l, respectively. The HLA-B27 results were positive; antinuclear antibodies and tuberculosis screening test (T-SPOT. TB) were negative; and blood counts and other serum chemicals were normal. The patient agreed to under surgery. Debridement and interbody fusion via the posterior pedicle lateral approach were performed. Postoperative CT showed great positioning of pedicle screw fixation, obvious correction of kyphosis and adequate intervertebral bone grafting (Figure 1E). Histopathologic analysis showed degenerative fibrocartilage tissue calcification, necrotic intervertebral disc tissue, and fibrovascular hyperplasia, and focal accumulation of inflammatory cells (Figure 2). When discharged, the back pain was significantly relieved, and the patient could walk independently with a brace. During the 9-month follow-up, the symptoms were significantly improved. CT showed that there was no screw loosening or fracture, no loss of kyphosis correction, and good ALs segmental bone graft fusion (Figure 1F).

andersson lesions, ct, ankylosing spondylitis

PMC4591341_01

Male

In April 2012, a 54-year-old male patient presented to the outpatient department of the "Centre de Recherche Medicale de la Ngounie," Fougamou, Gabon. He complained of grotesque facial deformity (Fig 2), dysarthria, hypersalivation, and incapacity to eat properly. In July 2009, he had a persisting rhinitis and recurrent epistaxis, while he was still working as a gardener. Six months later, a nodule occurred on his right nostril. Within three months, the nodule spread to the nasal bridge, causing reddish and hyperthermic swellings. Physical examination revealed ligneous hard swellings of the whole face and left part of the neck. The upper and lower eyelids of both eyes were swollen, impairing his vision. No ulcerations of the skin or mucosa and no enlarged lymph nodes were noticed. Laboratory analyses revealed an anaemia (haemoglobin 8.1 g/dl) and an absolute (2290/mm3) and relative (29%) eosinophilia, no leucocytosis. Microfilaria of Loa Loa were detected in venous EDTA blood (Citrate-Saponin acid method) and stool samples revealed an infection with Ascaris lumbricoides and Trichuris trichiura. We found no serologic evidence for hepatitis A, hepatitis B, syphilis, or HIV infection. A rhinoentomophthoromycosis was suspected and a biopsy was taken (buccal region, 1 cm3) including the skin and indurated subcutaneous tissue. Histopathology revealed fungal hyphae suggestive for Conidiobolus sp. (Fig 3A, 3C and 3D) and the Splendore-Hoeppli phenomenon (Fig 3B). The histopathology did not show any evidence for tuberculosis, leprosy, or any malignancy. Fungal cultures showed no growth. DNA from clinical samples was extracted and amplified using fungus-specific primers. A BLAST search using the sequence of the 676bp amplicon yielded a 100% match with sequences of C. coronatus (HQ602777.1, AJ345094.1, and AY997041.1). Antifungal therapy (fluconazole 400 mg, terbinafine 250 mg, SID, po) was started in April 2012. After partial response during the first nine months of treatment, no further reductions were seen in the following three months. Dosages were therefore increased (to fluconazole 800mg, terbinafine 500mg, SID, po) and given for further six months. We observed no further improvement and stopped the treatment in September 2013 after 18 months in total. Helminth infections were treated with albendazole 400 mg (day 1, 3, and 9, po). Ferrous glycine sulfate (100 mg, BDS, po) was given for one month, and the haemoglobin level normalized (haemoglobin 13.7 g/dl). Serum transaminases (ASAT, ALAT) and creatinine were controlled every 30 days to monitor potential side effects. The laboratory parameters stayed within normal limits. Residual swellings remained after treatment. The patient is free of relapse after 14 months without antifungal therapy (Fig 2D). Where possible, we considered the recommended items proposed by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) group. Literature search was performed on January 13, 2013, and included literature published until December 31, 2013. An update was performed on January 18, 2015, to add all articles published between January 1 and December 31, 2014, plus the case that we reported here. We assessed the literature using the medpilot portal (www.medpilot.de), which accesses several electronic databases, including Current Contents, Catalogue of the U.S. National Library of Medicine (NLM), and MEDLINE (see website for complete list of databases). Search terms were "phycomycosis," "zygomycosis," "entomophthoromycosis," "entomophthora," "conidiobolus," "basidiobolus," "conidiobolomycosis," "basidiobolomycosis," "facial swelling," and "rhinoentomophthoromycosis" (S1 Table). Titles and abstracts were screened for eligibility criteria. All cases that were diagnosed by the authors of the papers as an infection of nasopharyngeal and/or facial structures due to entomophthorales were eligible. The case definition included (i) rhinitis and/or intermittent epistaxis and/or sinus pain and/or tissue augmentation of nasopharyngeal and/or facial structures and (ii) confirmation of an entomophthoralean fungi infection by histopathology, culture, or PCR. The reference lists of all eligible articles were screened for additional articles that were not detected using the search terms. All manuscripts were fully reviewed for initial symptoms, course of the disease, diagnostic tools, therapy, and outcome. All eligible cases were reviewed for year of publication, country, continent, climate zone, age, sex, duration of disease before diagnosis, symptoms (i.e., coryza, epistaxis, nasal obstruction, facial elephantiasis), tissue invasion (i.e., nasal mucosa, nasal bridge, cheek, upper and lower lip, eyelids, orbit, lymph nodes, viscera), diagnostics for confirmation (i.e., smear microscopy, culture, histology, presence of the Splendore-Hoeppli phenomenon), antifungal treatment (i.e., agent, duration of therapy), and outcome (i.e., residual swellings, cure, sequelae, or death during follow-up). Cure was defined as being disease free after treatment with complete resolution of all clinical symptoms. Residual swellings were considered when the patients were disease free after treatment but showed persisting tissue augmentation. Cases were classified into atypical, early, intermediate, and late disease. Atypical disease was defined as ulcerations of the skin and/or invasion of the orbit, central nervous system, visceral organs, bones, muscles, and/or lymph nodes within 11 months after onset of disease (Fig 4). Patients with atypical disease were younger (Table 1), more frequently immunosuppressed (29% vs. 0%, p<0.001), and more commonly female (76% versus 23%, p = 0.001). They had active tuberculosis more often (29% versus 3%, p<0.001), originated more likely from non-tropical regions (43% versus 3.1%, p<0.001), and had more frequent infections with C. incongruus (43% versus 0.8%, p<0.001) compared to patients with typical rhinoentomophthoromycosis (early, intermediate, and late disease). As atypical disease differs from early, intermediate, and late disease in several aspects, we assessed the homogeneity of patient's data only from early, intermediate, and late disease. These groups were comparable concerning age, distribution of all pathogens among the stages, and number of antifungal drugs (Table 1). Pooled data of early, intermediate, and late disease showed that duration of disease before diagnosis correlated inversely with cure (r = -0.34, p<0.001). Additionally, duration of disease before diagnosis correlated positively with residual swellings after treatment (r = 0.27, p = 0.02) and no response to treatment (r = 0.27, p = 0.03). Involvement of the lower lip (16%, n = 21) correlated negatively with cure (r = -0.34, p<0.001) and correlated positively with duration of disease before diagnosis (r = 0.38, p<0.001) and residual swellings after treatment (r = 0.32, p<0.001).

PMC3829233_01

Male

A 22-year-old male presented to our department with a 3-months history of generalized headache, hearing loss, tinnitus and blurred vision. Physical examination of the patient revealed decreased visual acuity (right eye 20/80 and left eye one meter finger count), bilateral papillaedema, bilateral hearing loss and bilateral upward plantar responses. Other neurological examinations including muscle strength, sensory and gait were normal. Brain magnetic resonance imaging (MRI) with and without contrast showed intense dural enhancement of cerebellar folia and cerebral convexity, moderate hydrocephalus and intraparenchymal signal changes in right cerebellar hemisphere (Figures 1 and 2). Lumbar punctures were done three times that had negative results for gram stain, culture, Wright, angiotensin-converting enzyme, Indian ink, cerebrospinal fluid (CSF) adenosine deaminase, polymerase chain reaction for tuberculosis, CSF cytology and human immunodeficiency virus (HIV) antibody. CSF pressure was extremely high (about 70 cm H2O). CSF analysis showed normal cellular counts but elevated protein level and decrease glucose level was significant. Complete blood count, biochemistry profiles were normal. Erythrocyte sedimentation rate was 11 and C-reactive protein result was negative. Serum HIV antibody, HBs antigen, HCV antibody were all negative. Tuberculin purified protein derivative (PPD) was performed that had negative result. Serum Wright, ANA, ds DNA, Antineutrophil cytoplasmic antibody (cANCA and pANCA) and antiphospholipid antibody were within normal limits, too. Paranasal sinus, chest, pelvic and abdominal CT-Scan with contrast all had normal results. Audiometric evaluation showed bilateral asymmetrical sensory neural hearing loss. A suboccipital craniotomy was performed and the posterior fossa dura, pia arachnoid and cerebellar hemispheres were subject to biopsy. Histological examination of biopsy material showed highly cellular neoplasm that is composed of cells with small to medium-sized, hyperchromatic nuclei and little apparent cytoplasm. Immunohistochemical stains performed on the biopsy material revealed positive reaction of tumor cells with neuron-specific enolase and glial fibrillary acidic protein and negative result with CD99. Synaptophysin shows weak positive reaction (Figure 3A-H).

children, headache, leptomeningeal metastasis, medulloblastoma

PMC9758706_01

Male

We report a case of a 41-year-old married, nonsmoker man who brought to the hospital with the major complaint of abdominal pain, accompanied by nausea and vomiting since ten days prior to admission. Three months earlier, he had experienced shortness of breath which exacerbated when lying on his right side (Trepopnea). The patient had productive cough and fever during the hospital stay. No chest pain, paroxysmal nocturnal dyspnea, and lower extremity edema were detected. Our patient tested negative for SARS-CoV-2 with Polymerase Chain Reaction (PCR). Electrocardiogram (ECG) was unremarkable. Ultrasound study at the time showed minimal free fluids in the abdominal cavity and dilated hypo peristaltic bowel loops in favor of partial bowel obstruction. In chest radiography, consolidation in the right lung and right side pleural effusion was detected. Thoracentesis was performed and about 120 ml of exudative pleural fluid was extracted. Bronchoscopy and biopsy confirmed the pulmonary TB diagnosis. The medication was started for the treatment of pulmonary TB, and the patient was discharged. The patient was relatively in good condition for two months when he developed abdominal pain, nausea, and vomiting. After ten days, he visited the hospital and admitted for better evaluation. He described his Abdominal pain as generalized, intermittent, and his vomit as massive, non projectile and bilous. He also had a positive history of constipation and obstipation. Initial vital signs were stable with a body temperature of 37oC, respiratory rate 18/min, pulse rate of 80/min, arterial blood pressure of 116/80 mmHg, and arterial oxygen saturation of 98%. We detected mild generalized abdominal tenderness without abdominal distention, guarding, or rebound tenderness in physical examination. The patient did not have any dyspnea in the course of hospitalization. Laboratory results reported mild anemia (hemoglobin was 12.7 gr/dl (normal range 13.5-17.5 gr/dl for men)), No leukocytosis (white blood cell count was 9.7x103 /mul (normal range 4.5-11x103/mul)), or thrombocytosis (platelet count was 377x103 /mul (normal range 150-450x103 /mul)). Renal function test showed slightly increased creatinine (1.55 mg/dl (normal range 0.7-1.2 mg/dl)) and normal blood urea nitrogen (16 (normal range 7-30 mg/dl)). He had mildly decreased estimated glomerular filtration rate(eGFR) (66.53 ml/min (normal range 90-120 ml/min)), Which was calculated by the Cockroft-Gault formula. Electrolyte levels were within the normal range. Liver enzymes were normal. Alkaline phosphatase was elevated (316 U/L (normal range 40-150 U/L)) and hypoalbuminemia was also detected (2.9 gr/dl (normal range 3.5-5 g/dl)). Chest X-ray showed right upper lobe pulmonary consolidation and infiltration (Figure 1) in favor of pneumonitis and possibly due to the previous TB infection. Abdominal radiography also demonstrated several air-fluid levels (Figure 2) suggestive of bowel obstruction. Ultrasound study reported several echogenic wall thickenings, largest 11x12 mm. Computed tomography scan revealed right-sided pleural effusion and subsegmental atelectasis in the right lower lobe of the lung (Figure 3). In the abdominal cavity, significant dilatation of jejunal and proximal ileal bowel loops associated with a transitional zone in mid ileal bowel loops in the pelvic cavity was detected, suggesting mechanical obstruction (Figure 4). In liver, several hypodense lesions were seen in the right and left lobe of the liver, suggestive for visceral TB (Figure 5). On the 2nd day of hospitalization, the patient was transferred to the operating room for exploratory laparotomy. During the surgical exploration of the abdominal cavity, severe adhesion was noted, and adhesiolysis was done. The cause of mechanical obstruction seemed to be an adhesion band about 20 cm prior to the ileocecal valve, which was released. Due to severe inflammation of the appendix, appendectomy was also performed with double ligation method. Another finding was TB-like lesions all along with the small bowel, colon, omentum, and liver surface. We sent excised tissues to the pathology laboratory for further evaluation. Pathology reports were consonant with the diagnosis of PTB as all the samples had caseating granuloma formation despite negative acid-fast staining. After the operation, anti TB medications (Ethambutol 500mg and Rifampicin 150 mg once daily) resumed. Three days later, after complete recovery, he was discharged with follow-up of a general surgeon, and infectious specialist.

abdominal tuberculosis, extrapulmonary tuberculosis, peritoneal tuberculosis, intestinal obstruction

PMC9558873_01

Female

We present a 61-year-old female from San Luis Potosi, Mexico, with type 2 DM, hypertension, and 2-year history of gallstone disease with no other comorbidities. Her surgical history was not significant. She presented at the Emergency Department of our hospital with a 2-day history of moderate-to-severe colicky RUQ abdominal pain that started an hour after eating a large, fatty meal for breakfast. It radiated to the mid-back and right shoulder and had no alleviating or aggravating factors. Also, she complained of nausea, vomiting, and food intolerance. The patient had previous self-limited episodes of RUQ abdominal pain. On general examination, she had a poor general status and was diaphoretic and dehydrated with unstable vital signs: a respiratory rate of 20 r/min, a heart rate of 127 bpm, an oxygen saturation of 92%, a blood pressure of 84/52 mmHg, and a body temperature of 38.1 C. The abdominal physical examination revealed tenderness to palpation in the epigastric region with a firm and painful palpable mass in the RUQ abdominal region. Laboratory tests showed an elevated white blood count (WBC) count of 15,670 mcl with 15,400 mcl (98.0%) neutrophils and 235 mcl (1.5%) of lymphocytes, 287,000 mcl platelets, lactate blood levels of 2.3 mmol/l, total bilirubin of 1.09 mg/dl, conjugated bilirubin of 0.45 mg/dl, unconjugated bilirubin of 0.64 mg/dl, creatinine of 0.89 mg/dl, urea of 53.6 mg/dl, prothrombin time of 14.2 seconds, partial thromboplastin time of 35 seconds, and C-reactive protein of 305 mg/L with no other alterations. Blood cultures were obtained prior the start of antibiotics. There was no ultrasound available, but an abdominal computed tomography (CT) scan was performed and showed an enlarged gallbladder with marked wall thickening. Also, a gallstone obstructing the gallbladder neck was shown (Figure 1). The patient was started with IV antibiotic therapy of ciprofloxacin and metronidazole. Preoperative resuscitation followed by an emergency open cholecystectomy was performed for source control. Surgical exploration revealed omentum and duodenum adherences to the enlarged gallbladder. The gallbladder was also necrotic without perforation. Retrograde gallbladder dissection with subtotal fenestrating cholecystectomy was performed because of the impossibility to identify the common hepatic bile duct, cystic duct, and cystic artery. Intraoperative drainage of the gallbladder was performed, obtaining 60 ml of purulent fluid. Cultures were collected from the content of gallbladder. Saratoga sump drainage was collocated on the liver bed for wound drainage. Because of the risk of bile duct injury along with the procedure and risk of biliary fistula, the patient was taken for an endoscopic retrograde cholangiopancreatography (ERCP), where an endoscopic biliary prosthesis was inserted. All blood and fluid cultures and Gram-stain yield negative. The patient recovered uneventfully without pain and fever and was discharged on the fifth postoperative day. The gallbladder specimen removed during cholecystectomy was sent for histopathologic examination to the Pathology Department of our hospital. The presence of a gallstone of 5.5 x 3 x 3 cm, a wall thickness of 4-10 mm, and a nodular cheesy-looking lesion of 9 mm were noted. The reported histopathologic diagnosis was AC with areas of caseous necrosis. Routine staining was performed and showed intracellular acid-fast bacilli (AFB). (Figure 2) The gallbladder specimen was sent for molecular testing, where M. tuberculosis was identified by polymerase chain reaction. A diagnosis of AC complicated with gallbladder empyema due to M. tuberculosis was performed and treatment was adjusted. An epidemiological report was sent to our Epidemiology Department and the authorities of the National Secretary of Health for follow-up and starting the antituberculous therapy. They started the shortened primary TB treatment which comprises an intensive therapy with isoniazid, rifampicin, pyrazinamide, and ethambutol for 2 months, followed by 4 months of continuation phase with isoniazid and rifampicin. The patient had completed the intensive phase and currently is in the second month of continuation phase. During follow-up, the patient has not presented any complications due the disease or the treatment.

mycobacterium tuberculosis, abdominal tuberculosis, acute cholecystitis, gallbladder disease, gallbladder empyema, tuberculosis

PMC5447517_01

Female

A 30-year-old woman with a bilateral hypomastia underwent subfascial TBA with texturized anatomic silicone implants (Natrelle 410 MF style, 295cc) (Fig. 1a-d). One year after surgery, the patient noticed a painful mass in the medial lower part of her right breast. At that time a breast seroma or capsular contracture was suspected. A breast ultrasound was performed and showed no sign of seroma. Magnetic resonance imaging (MRI) revealed a solid mass (6.1 x 3.1 x 4.1 cm) with low/intermediate signal intensity in T1 and high signal intensity in T2. The mass exhibited high contrast medium enhancement without signs of infiltration of the fatty tissue or the costal cartilage (Fig. 2a and b). After discussing the case with thoracic surgeons and radiologists, the decision was made to plan a wide resection.

breast augmentation, breast reconstruction, case report, chest reconstruction, complication, desmoid tumor, form-stable silicone implants, myocutaneous flap

PMC3169087_01

Male

A 45-year-old male patient was admitted to a local hospital with a history of high fever and myalgia, predominantly in the lower limbs and lumbar region for 1 week. After 11 days of the initial symptoms, the patient presented with petechiae and melena, followed by headache, reduced consciousness, and increasing jaundice within the past 48 hours. On admission, the patient presented with fever (axillary temperature, 38.2 C), tachycardia (heart rate, 106 beats/min), a blood pressure of 160 mmHg systolic and 90 mmHg diastolic, and a respiratory rate of 20/min. Laboratory data on admission are summarized in Table 1. In a 24-hour interval, clinical conditions deteriorated and the patient was placed on artificial ventilation. At this point a presumptive diagnosis of TMA was established based on the abrupt onset of thrombocytopenia, microangiopathic hemolytic anemia, elevated lactate dehydrogenase (LDH), neurologic abnormalities, and renal failure. Infusion of fresh-frozen plasma was introduced (10 mL/kg/day), until transference to a reference hospital was possible. Two days later, the patient was transferred to the intensive care unit of a university hospital where plasma exchange was available. On this admission the laboratory data (Table 1) showed an elevated level of LDH (2662 IU/L; normal range, <480 IU/L), low PLT count (11.0 x 109/L), a hemoglobin (Hb) level of 7.1 g/dL, a negative direct antiglobulin test, and negative RBC antibodies. Serum bilirubin (total and direct) was slightly elevated (1.83 and 0.77 g/dL; normal ranges, <1.0 and 0.7 g/dL, respectively), elevated serum creatinine (1.97 mg/dL), slightly prolonged prothrombin time (17 sec; control, 12.8 sec), and normal activated partial thromboplastin time (ratio, 1.01). Peripheral blood smear showed 5 to 10 schistocytes per high-power field and 14% erythroblasts of total RBCs. Flow cytometry assay was also performed to identify autoantibodies against PLTs, but the results were negative for both IgG and IgM. Other tests for antibodies against glycoprotein (GP) IIb-IIIa (Gi5), GPIa-IIa (Gi9), and GPIb-IX (anti-CD42) were also negative. The patient lived in an area where a dengue fever outbreak was occurring. In addition, he had a positive exposure to leptospirosis due to his occupation. Dengue serology tests were performed, including Dengue IgM capture enzyme-linked immunosorbent assay (PanBio, Queensland, Australia) and DV IgM- and IgG-specific tests (Dengue DuoCassette, PanBio), and all confirmed-positive IgM results, suggesting the acute dengue viral infection. Serologic tests for leptospirosis, hantavirus, and Brazilian spotted fever, performed in a reference public health laboratory, were negative as the differential diagnosis imposed by the epidemic of DV infection in the icterus-hemorrhagic fever syndrome (as shown by a positive tourniquet test) plus thrombocytopenia. We sought to determine whether TMA rather than icterus-hemorrhagic fever syndrome was the main underlying mechanism of the patient clinical evolution. The activity of ADAMTS13 and presence of autoantibodies against ADAMTS13 was then evaluated. The results obtained in blood samples collected at 2 weeks of the beginning of the fever showed that ADAMTS13 activity was below 5% of normal human plasma. Autoantibodies against ADAMTS13 were detected at a titer of 3 units/mL. Both ADAMTS13 activity and autoantibody inhibitors were determined by two different assays (FRETS-VWF73 and collagen-binding assay) as previously described. The anti-ADAMTS13 IgG bound specifically to both full-length ADAMTS13 and the variant deleted after the seventh TSP1 repeat (delCUB-CUB domain presents peptide sequences of complement subcomponents C1r/C1s; embryonic sea urchin protein EGF; and bone morphogenic protein-1), which were expressed in HEK293 cells. The antibody-antigen complexes were determined by immunoprecipitation, followed by Western blot with anti-V5 that recognizes the C-terminal V5-His tag (Fig. 1). The amount of ADAMTS13 or variant that could be pulled down with IgG from this DV-infected patient was similar to that with IgG from a TTP patient with acquired idiopathic TTP caused by known anti-ADAMTS13 IgG. Taken together, the clinical manifestations, response to the treatment, and the detection of anti-ADAMTS13 IgG autoantibody formation all suggest the diagnosis of TMA (probably TTP) concomitant to DV infection. We opted for a therapy for TTP by plasma exchange therapy (1.0 plasma volume, daily) due to severity of the case, initiated before laboratorial results confirming DV infection. The time course of clinical and laboratorial findings showed evidence of temporal clinical and laboratorial improvements (Fig. 2). After 11 plasma exchanges, the PLT count recovered to values of 123 x 109/L and LDH decreased to 660 IU/L when plasma exchange was discontinued. At 4-month follow-up, the patient exhibited a normal PLT count and a normal level of serum LDH. Plasma ADAMTS13 activity returned to 100% of normal human plasma and no anti-ADAMTS13 inhibitor was detected at this time. No recurrence of TMA was observed after 2-year follow-up.

PMC7292101_01

Male

A 32-year-old Asian male presented with a 1-month history of painless bilateral scrotal swelling. The patient was diagnosed with lung sarcoidosis (stage II) 2 years prior to presentation to our hospital and he took no regular medications. There was no family history of sarcoidosis. His height and weight were 171 cm and 87.4 kg, respectively. The physical examination revealed painless bilateral scrotal swelling and palpable 1- to 1.5-cm testicular masses. Initial blood tests, including complete blood count, electrolytes, renal function, and C-reactive protein levels, were within the normal limits, but slight liver dysfunction due to fatty liver was observed (AST 41 U/L, ALT 71 U/L, and gamma-GTP 72 U/L). Serum levels of testosterone, follicle-stimulating hormone, luteinizing hormone, and prolactin were within the normal range. Serum tumor markers, including AFP, beta-HCG, and LDH, were within the normal limits. The soluble IL-2 receptor level was mildly increased to 686 U/mL (normal range, 145-519 U/L) and the serum ACE level increased to 26 U/mL (normal range, 8.3-21.4 U/L). The rapid plasma reagin test and Treponema pallidum hemagglutination assay were negative. Tuberculosis skin tests and serology findings regarding hepatitis C and B were also negative. Ultrasonography revealed scattered hypoechoic mass lesions in both testes (Fig. 1). A nodular lesion with an internal cavity in the left upper lobe of the lung, hilar lymph nodes, and para-aortic lymph node swelling was noted on chest and abdominal CT (Fig. 2a,b). MRI demonstrated scattered T2 low-signal areas in both testes. There was an abnormal accumulation in both testes on gallium-67 scintigraphy. We suspected testicular sarcoidosis and testicular biopsy was performed. The lesions were identified by ultrasonography, and we incised the scrotum and the tunica albuginea of the testes. There were hard nodules with clear boundaries and the lesions were easily strippable. As the pathological diagnosis during the biopsy was suspected to be sarcoidosis without malignancy, we collected some nodules and finished the biopsy. Pathologically, noncaseating epithelial cells with multinucleated giant cells, and some normal spermatogonia and spermatocytes were observed in both testes, and we diagnosed the patient with testicular sarcoidosis without any tumor cells (Fig. 3). Semen examination was performed after the biopsy, demonstrating oligospermia (2 x 106/mL). As the patient wished to have children, we administered corticosteroids. He initially received 40 mg of oral prednisone/day, and the dose was reduced to a maintenance dose of 2.5 mg/day during the 7 months of treatment. On CT examination after treatment, the left lung nodule, hilar lymph node, and para-aortic lymph node had shrunk (Fig. 2c,d), and no abnormal accumulation in either testis was observed on gallium-67 scintigraphy. Mild improvement of the sperm count of 7 x 106/mL was noted by semen examination. We encouraged the patient to receive assisted reproductive treatments, such as intracytoplasmic sperm injection, as a treatment option for oligozoospermia, but he refused.

corticosteroid, genitourinary sarcoidosis, oligospermia, scrotal mass, testicular sarcoidosis

CT scans of the chest and abdomen. A nodular lesion with an internal cavity in the left upper lobe of the lung , hilar lymph nodes, and.

PMC7292101_01

Male

A 32-year-old Asian male presented with a 1-month history of painless bilateral scrotal swelling. The patient was diagnosed with lung sarcoidosis (stage II) 2 years prior to presentation to our hospital and he took no regular medications. There was no family history of sarcoidosis. His height and weight were 171 cm and 87.4 kg, respectively. The physical examination revealed painless bilateral scrotal swelling and palpable 1- to 1.5-cm testicular masses. Initial blood tests, including complete blood count, electrolytes, renal function, and C-reactive protein levels, were within the normal limits, but slight liver dysfunction due to fatty liver was observed (AST 41 U/L, ALT 71 U/L, and gamma-GTP 72 U/L). Serum levels of testosterone, follicle-stimulating hormone, luteinizing hormone, and prolactin were within the normal range. Serum tumor markers, including AFP, beta-HCG, and LDH, were within the normal limits. The soluble IL-2 receptor level was mildly increased to 686 U/mL (normal range, 145-519 U/L) and the serum ACE level increased to 26 U/mL (normal range, 8.3-21.4 U/L). The rapid plasma reagin test and Treponema pallidum hemagglutination assay were negative. Tuberculosis skin tests and serology findings regarding hepatitis C and B were also negative. Ultrasonography revealed scattered hypoechoic mass lesions in both testes (Fig. 1). A nodular lesion with an internal cavity in the left upper lobe of the lung, hilar lymph nodes, and para-aortic lymph node swelling was noted on chest and abdominal CT (Fig. 2a,b). MRI demonstrated scattered T2 low-signal areas in both testes. There was an abnormal accumulation in both testes on gallium-67 scintigraphy. We suspected testicular sarcoidosis and testicular biopsy was performed. The lesions were identified by ultrasonography, and we incised the scrotum and the tunica albuginea of the testes. There were hard nodules with clear boundaries and the lesions were easily strippable. As the pathological diagnosis during the biopsy was suspected to be sarcoidosis without malignancy, we collected some nodules and finished the biopsy. Pathologically, noncaseating epithelial cells with multinucleated giant cells, and some normal spermatogonia and spermatocytes were observed in both testes, and we diagnosed the patient with testicular sarcoidosis without any tumor cells (Fig. 3). Semen examination was performed after the biopsy, demonstrating oligospermia (2 x 106/mL). As the patient wished to have children, we administered corticosteroids. He initially received 40 mg of oral prednisone/day, and the dose was reduced to a maintenance dose of 2.5 mg/day during the 7 months of treatment. On CT examination after treatment, the left lung nodule, hilar lymph node, and para-aortic lymph node had shrunk (Fig. 2c,d), and no abnormal accumulation in either testis was observed on gallium-67 scintigraphy. Mild improvement of the sperm count of 7 x 106/mL was noted by semen examination. We encouraged the patient to receive assisted reproductive treatments, such as intracytoplasmic sperm injection, as a treatment option for oligozoospermia, but he refused.

corticosteroid, genitourinary sarcoidosis, oligospermia, scrotal mass, testicular sarcoidosis

CT scans of the chest and abdomen. A significant decrease in the size of the lung nodule , hilar lymph nodes, and.

PMC6195937_02

Male

A 67-year-old male was initially referred for CT scan of the chest, abdomen and pelvis for investigation of a systemic illness comprising anorexia, nocturnal night sweats and approximately 10 kg weight loss. He was previously in good health and lived independently with his family. No history of significant occupational exposure (e.g. asbestos) was present, but he may have been exposed to asbestos in farm outbuildings during his work as a farmer. The patient had a long-standing history of atrial fibrillation and atrial flutter. Approximately 12 months prior to presentation, he developed symptoms of pericarditis and was found to have a pericardial effusion on echocardiogram without definite solid components. He was treated clinically at that time and no pericardiocentesis was performed. Therefore, it was not possible retrospectively to determine whether there was any evidence of malignancy at the time of the echocardiogram.

PMC8295552_01

Male

The patient, a 3-year-old boy, was born at term through an uneventful delivery with normal birth parameters of consanguineous Chinese parents. He was the first child in a second pregnancy, after the first resulted in an induced abortion due to fetal death. The grandparents of the patients were cousins. The pedigree of the family was as follows (Figure 1A). The age at the first visit was 5 months. The first symptoms observed were motor and cognitive retardation. He could not attain head control, turn over, or actively grasp objects. He had normal eyesight and hearing. The second symptom, paroxysmal hypertonia, began as early as 1 month after birth. Initially, the symptoms were clenched fists with both hands and straightened limbs, which gradually progressed to flexion of both upper limbs, fisted hands, and straightened lower limbs. During the course, consciousness was clear and the symptoms lasted for a few seconds to a few minutes before spontaneous relief. Physical examination revealed microcephaly, white skin, yellow hair, slightly long face, high palatine arch, right hand penetration, small penis, and small hands and feet. His muscle force was grade three, and he had paroxysmal hypertonia, negative limb deep reflection, and bilateral symmetric flexor plantar reflex. Magnetic resonance imaging (MRI) showed ventricular broadening and left lateral fissure widening in 2017. 1 year later, MRI revealed symmetric hyperintensity in the bilateral basal ganglia on T2-weighted imaging, T2-FLAIR, and DWI sequences (Figure 1B). Video electroencephalogram showed a normal background and recorded paroxysmal limb rigidity with no epileptiform discharges. Liver and renal function, myocardial enzyme, and ceruloplasmin levels were normal, but metabolism screening showed mild ketonuria and hyperlactacidemia (2.55-3.36). G-banding karyotype analysis: 46, XY. Gesell Developmental Scale: Adaptability: DQ 26.7, DA 2.5, severe delay; Gross motor: DQ 23.7, DA 2.2, extremely severe delay; Fine motor: DQ 24.7, DA 2.3, extremely severe delay; Communication: DQ 49.5, DA 4.6, moderately delayed; personal-social skills: DQ 37.6, DA 3.5, severe delay. DNA was extracted from peripheral blood using the QIAamp DNA Blood Mini Kit (QIAGEN). A total of 3 mug of patient DNA was sheared to produce 200-300 base pair (bp) fragments. Whole-exome enrichment was performed using an Agilent SureSelect Target Enrichment system (Agilent Technologies). Coding exons and flanking intronic regions were enriched with the Agilent SureSelect Human All Exon V6 reagent (Agilent Technologies), according to the manufacturer's protocol. Captured libraries were loaded onto a HiSeq 2500 platform (Illumina). Base calling and assessments of sequence read quality were performed using Illumina Sequence Control Software (SCS; Illumina), which provided real-time analyses. Reads with average quality scores <25 were removed, and bases with quality scores <20 were trimmed. The mean read depth of each sample was 100 x. The reads were aligned to the human reference genome (UCSC GRCh37/hg19) using the Burrows-Wheeler Aligner (BWA v0.7.15) BWA-MEM algorithm. Reads with low mapping quality scores were removed. Presumed PCR duplicates were identified using Picard's MarkDuplicates and removed. Local alignment optimization and base quality recalibration were performed using the Genome Analysis Toolkit (GATK). Single-nucleotide variants (SNVs) and InDels were identified with Mutect2, respectively, and saved in a variant call format. Variants were functionally annotated and filtered with ANNOVAR (http://annovar.openbioinformatics.org/en/latest), which provided built-in public databases (OMIM, InterVar, ClinVar, HGMD, Cosmic70, dbSNP, 1000G, ESP, ExAC, and gnomAD), and the HGMD Professional database. We identified a de novo variant (c.116 G>A, p.S39N) in exon 2 of DNM1L, which has not been reported previously. Furthermore, gene variation was validated using Sanger sequencing (Figure 1C). The conservation of the identified amino acid across different species and the protein 3D modeling for the DNM1L-wild and identified missense variant were shown in Figures 1D-F. The pathogenicity score was checked using the following online tools (Table 1). Benzhexol (0.5 mg BID) and Medopar (31.25 mg QID) were used to reduce muscle tension, and a cocktail therapy (VitB1 10 mg TID, VitC 0.5 g BID, VitE 100 mg QD, CoQ 10 mg TID and L-carnitine 100 mg BID) was administered to treat the primary illness, but none provided significant clinical benefit. At the last follow-up, the patient was 3 years and 4 months of age. He was 85 cm tall and weighed 8 kg, with a head circumference of 46 cm. He was admitted to our hospital with symptoms including spastic tetraparesis, no postural control, paroxysmal hypermyotonia and tremor, and severe cognitive impairment but no seizures. He could only follow a voice and light, occasionally respond to communication, and make vowel sounds, but he could not cry or laugh out loud. We searched for reported cases in the PubMed database using the terms "DNM1L" and "mitochondrial." Thirty-five cases from 20 relevant references were retrieved; these included the first case reported by Waterham in 2007 and other cases reported from January 2015 to date. A total of 36 cases were analyzed together with the case reported by us. Fifteen males, 16 females, and two patients without reference to sex and three pedigrees (both male and female) were included. The median age of onset was 6 months (range, neonatal period: 9 years). Clinical manifestations included psychomotor retardation in 77.8% (28/36) of patients, limb paralysis in 66.7% (18/27), dystonia in 82.8% (24/29), and epilepsy in 59.4% (19/32). Other symptoms included ataxia in six cases, nystagmus in three cases, optic atrophy in six cases, dysarthria in four cases, microcephaly in four cases, pain insensitivity in two cases, and sensory and motor axonal neuropathy in two cases. On auxiliary examination, 83.3% (25/30) of the cases had abnormalities in brain MR images, including abnormal hyperintensity in the cortex (10 cases), basal ganglia/thalamus (10 cases), subcortical white matter (three cases), brain atrophy (12 cases), lactate peak (four cases), and thinning/absence of the corpus callosum (three cases). Seventy-five percent (15/20) of the cases showed abnormalities in EEG, such as epileptic discharge or a weak background. Hyperlactacidemia was identified in 60.7% (17/28) of the cases, and decreased respiratory chain enzyme activity was detected in 28.6% (4/14) of cases. Muscle biopsy was performed in 22 cases, ragged red fibers were observed in four cases, and long tangled or swollen mitochondria were observed in 12 cases. At the last follow-up, the 23 surviving patients had a median age of 7 years (2-27 years), whilst 12 had died with a median age at death of 1.5 years (from the neonatal period to 13 years). The median course of follow-up was 3.5 years (range, 7-24 years), and the median course of disease from illness to death was 1 year (range, 8-11.5 years). At the last follow-up, barring three families with optic atrophy as an isolated symptom, the rest had varying degrees of dyskinesia (four patients could walk with assistance, two could stand with assistance, one could sit alone, 11 could not control body position, and the rest were not mentioned), cognitive impairment, dystonia, or epileptic seizure. De novo variants were identified in 72.2% (26/36) of the cases, 13.9% (5/36) had heterozygous dominant variants, 11.1% (4/36) had compound heterozygous variants, and 2.8% (1/36) had homozygous variants. A total of 24 DNM1L variants were identified, including 21 missense variants, two deletion variants, and one duplication variant (Table 2). The clinical manifestations of the GTPase domain group were milder than those of the middle domain group (Figure 1G, Table 3). The prevalence of psychomotor retardation and epilepsy in the GTPase domain group was lower than that in the middle-domain group (Psychomotor retardation: GTPase domain group, 50.0% [6/12] vs. middle domain group, 91.3% [21/23]; epilepsy: GTPase domain group, 8.3% [1/12] vs. middle domain group, 89.5% [17/19]); these differences were statistically significant (P < 0.05). In the five patients with heterozygous variants, three pedigrees with variants in the GTPase domain presented with optic atrophy as the isolated symptom, which was the mildest phenotype, and the family pedigrees were shown together with the segregation of the DNM1L variants in the affected individuals. The variants of the two other patients were located in the middle domain; one patient had a c.1048G>A, p.G350R variant, and variant analysis by Sanger sequencing suggested a low level (6-8%) of maternal mosaicism. The patient presented with developmental delay, hypotonia, status epilepticus, and elevated serum lactate levels, and he died of status epilepticus at the age of 5. Another patient had two heterozygous DNM1L variants (c.1085G>A, p.Gly362Asp; c.1535T>C, p.lle512Thr) on the same allele (maternal allele). His mother with the variant (c.1535T>C, p.lle512Thr) was healthy, but the other variant (c.1085G>A, p.Gly362Asp) was not present in either parent. However, further analysis of the DNM1L gene using a next-generation sequencing approach revealed that the variant (c.1085G>A, p.Gly362Asp) was present in the mother's blood DNA at a very low level. Furthermore, the patient's half-brother had died at the age of 3 years. Therefore, these findings supported maternal germline mosaicism for a dominant variant (c.1085G>A, p.Gly362Asp). The patient manifested developmental delay prior to the onset of illness. At 5 years and 5 months of age, he presented with partial motor status epilepticus after a viral illness. 4 months later, he presented with spastic quadriplegia and hyperkinesis but poor voluntary movements, no postural control, and severe cognitive impairment. However, there was no statistically significant difference in the survival rate in the different domain groups (log-rank test, P = 0.39, Figure 1H). Auxiliary examination revealed that 83.3% (25/30) of the cases had abnormalities in brain MR images; 62.5% (5/8) of the GTPase domain group vs. 90.9% (20/22) of the middle domain group (P = 0.102), with no statistically significant difference. Seventy-five percent (15/20) of the cases showed abnormality in EEG; 20.0% (1/5) of the GTPase domain group vs. 92.9% (13/14) of the middle domain group (P = 0.006), with statistically significant differences.

dnm1l, drp1, dyskinesia, follow-up study, hypertonia, mitochondrial disease, psychomotor retardation

PMC8494488_01

Female

Here we describe the case of a 26-year-old female patient with an HIV-1 infection (PLWHA) initially revealed by a pulmonary tuberculosis correctly treated and cured, who was on a combined antiviral triple therapy based on efavirenz/ emtricitabine/tenofovir disoproxil (TDF/FTC/EFV) for three years, but which she stopped one year before the present hospitalization. She sought the emergency department for a one month complaint of melena with chronic liquid diarrhea at a rate of three stools a day, accompanied by fever and weight loss, but without rectal syndrome. On admission, the patient was conscious, presented with a Glasgow coma score of 15/15, was hemodynamically and respiratory stable, febrile with a body temperature of 38 C, heart rate of 100 per min, respiratory rate of 20 cycles per min, blood pressure of 110/40 mmHg, weighting 46 kg, in addition to an oral candidiasis with possible esophageal involvement. On the abdominal examination, the patient had pain on the right upper quadrant, epigastric tenderness associated with a homogeneous hepatomegaly (21 cm) and splenomegaly (14 cm) and the hernia orifices were free. The abdominal ultrasound showed multiple collections at the level of the segments I, IV, and V related to liver abscesses of which the largest lesion measured 5.8 by 4.2 cm with hepatomegaly associated with an anechoic peritoneal effusion of moderate abundance (Figure 1). The patient was treated empirically with ceftriaxone, metronidazole and gentamicin for the liver abscesses, fluconazole for oral and esophageal candidiasis, and a medication to slow down the intestinal transit. On the blood count, the patient had normochromic normocytic anemia, 5.8 g/dL of hemoglobin (11.5 - 16.5), lymphopenia, with 840/mm3 (1,000 - 4,000), normal leukocytes - 6,040/mm3, (3,600 - 11,000), normal neutrophils - 4,490/mm3 (1,800 - 7,500), and a normal platelet count of 166,000/mm3, (140,000 - 400,000), and the CD4 - positive T cell count was 27 cells/mm3. She had hepatitis flares and cholestasis with AST 162 IU/L (5N) (< 30), ALT 55 IU/L (N) (< 50), ALP 495 IU/L (5 N) (30-100), gammaGT 280 IU/L (6 N) (<45), CRP 117 mg/L (< 5 mg/L), normal renal function; negative serology to hydatid, amebiasis, hepatitis B virus (HBV), hepatitis C virus (HCV), syphilis and toxoplasmosis, while serology to CMV IgG was positive but negative to IgM, COVID-19 RT-PCR and IgG antibodies raised to SARS-CoV-2 were negative, and the patient also presented with negative sputum evaluated by the Xpert MTB/RIF (Genexpert Cepheid Inc, California, USA) and three Acid-Fast Bacilli (AFB) smear microscopy, three cultures of stool and parasitological stool examination were also negative, in addition to a blood culture. An ultrasound-guided puncture was performed which revealed the presence of a Salmonella enterica subsp. enterica in the purulent secretion that was only resistant to cefalotin, cefoxitin, gentamicin, amikacin, but was sensitive to amoxicilline (Figure 2). The Genexpert on the purulent secretion was negative. A wet smear was negative for Entamoeba histolytica trophozoite. Next, we stopped metronidazole and gentamicin and we continued the treatment with intravenous amoxicillin plus clavulanic acid 1 g tid for eight days; then we switched to oral amoxicillin 1 g tid during three weeks and the antiretroviral therapy was restarted. Ten days after the treatment, the patient improved clinically and the CRP decreased to 13 mg/L. A follow-up ultrasound showed that the size of the abscess had decreased and the patient had a favorable outcome.

PMC8348523_01

Female

A 29-year-old woman presented with fever and productive cough at our hospital. She had undergone thymectomy for thymoma 9 years ago and had comorbid myasthenia gravis, pure red cell aplasia, and autoimmune hepatitis. She was prescribed immunosuppressants including cyclosporine (200 mg/d) and prednisolone (5 mg/d). Radiotherapy was initiated for a recurrent thymoma lesion 2 weeks before her admission delivered to a total dose of 54 Gy in 27 fractions (Fig. 1). Her bone marrow was an area spared from radiation therapy. Pneumococcal pneumonia episode in the previous months were remarkable in her medical history. Her chest examination revealed bilateral coarse crackles and rhonchi. Laboratory examination revealed leukocytosis with a left shift and elevated C-reactive protein. Hypogammaglobulinemia, fungal antigens, and Mycobacterium tuberculosis infection were unremarkable on the interferon-gamma release assay and anti-HIV antibodies. Chest computed tomography (CT) revealed infiltrations and a granular shadow in the bilateral lobes (Fig. 2A). She was diagnosed with broncho-pneumonia and hospitalized. After admission, a 14-d course of piperacillin-tazobactam was initiated for broncho-pneumonia, and her symptoms and laboratory findings improved. However, after switching from piperacillin-tazobactam to an oral antimicrobial (levofloxacin), pneumonia reexercabted (Fig. 2B). Therefore, piperacillin-tazobactam treatment was resumed and pneumonia was under control again; however, drug fever and granulocytopenia caused by piperacillin-tazobactam was observed and hence cefepime was administered as an alternative. However, severe drug eruptions were observed 4 d after switching to cefepime, and drug eruption exacerbated even after a switch to meropenem. Therefore, antimicrobial treatment was discontinued. Antimicrobial therapy with cefepime, piperacillin-tazobactam, and meropenem were administered for 21 d. Drug eruption improved with no treatment after discontinuation of antimicrobial therapy. Immunodeficiency was suspected as the cause of recurrent lower respiratory tract infections because peripheral CD4-positive cells were reduced to 284 mu/L, and lymphocytopenia (<1,000/muL) occurred after radiation therapy for recurrent thymoma. Hypogammaglobulinemia was not observed; nonetheless, immunoglobulin was administered at 5,000 mg once daily for three consecutive days for severe infection. Furthermore, cyclosporine was gradually tapered to 100 mg/d after admission to control pneumonia. After discontinuation of antimicrobial therapy, fever recurred and the oxygen demand increased, and CT revealed new consolidation in her lower lobe of the left lung (Fig. 2C). For the third treatment cycle for pneumonia, a combination of vancomycin and doripenem, plus immunoglobulin, was initiated, because methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas fluorescens were detected in sputum cultures after hospitalization. Despite intensive treatment, no improvement in the oxygen demand and fever was observed. Since the patient had pneumonia refractory to broad-spectrum antimicrobial agents, pneumonia caused by agents other than bacterial was suspected as the cause of the respiratory failure and pneumonia findings on chest CT. Simultaneously, candidiasis was noted in the oral cavity (Fig. 3), and the decline in CD4-positive cells suggested T-cell immunodeficiency. Furthermore, based on elevated serum beta-D glucan levels and a positive PCR test for Pneumocystis jirovecii in sputum samples, P. jirovecii pneumonia was diagnosed as a cause of respiratory failure. Along with antimicrobial treatment, sulfamethoxazole (3,600 mg/d) and trimethoprim (720 mg/d) were initiated, and prednisolone was administered at 80 mg/d. Respiratory failure improved rapidly, and the infiltrative shadow on chest X-ray was obliterated. Prednisolone was tapered to a maintenance dose over 2 weeks, and anti-biotherapy and sulfamethoxazole/trimethoprim were administered for 3 weeks each and completed. During hospitalization, the peripheral lymphocyte count was elevated to almost 2,000/muL, and she was discharged on hospitalization day 99 without pneumonia recurrence after treatment for P. jirovecii pneumonia. Her clinical course after admission is described in Fig. 4. During her hospitalization, her gammaglobulin levels remained within the normal range, while her peripheral lymphocyte counts tended to slowly increase.

myasthenia gravis, oral candidiasis, pneumoniae, radiotherapy, t-cell immunodeficiency, thymoma

Chest computed tomographic images upon hospitalization. . Chest computed tomography revealed centrilobular granular and infiltrative shadows and thickening of the bronchial wall in bilateral lung fields.

PMC8348523_01

Female

A 29-year-old woman presented with fever and productive cough at our hospital. She had undergone thymectomy for thymoma 9 years ago and had comorbid myasthenia gravis, pure red cell aplasia, and autoimmune hepatitis. She was prescribed immunosuppressants including cyclosporine (200 mg/d) and prednisolone (5 mg/d). Radiotherapy was initiated for a recurrent thymoma lesion 2 weeks before her admission delivered to a total dose of 54 Gy in 27 fractions (Fig. 1). Her bone marrow was an area spared from radiation therapy. Pneumococcal pneumonia episode in the previous months were remarkable in her medical history. Her chest examination revealed bilateral coarse crackles and rhonchi. Laboratory examination revealed leukocytosis with a left shift and elevated C-reactive protein. Hypogammaglobulinemia, fungal antigens, and Mycobacterium tuberculosis infection were unremarkable on the interferon-gamma release assay and anti-HIV antibodies. Chest computed tomography (CT) revealed infiltrations and a granular shadow in the bilateral lobes (Fig. 2A). She was diagnosed with broncho-pneumonia and hospitalized. After admission, a 14-d course of piperacillin-tazobactam was initiated for broncho-pneumonia, and her symptoms and laboratory findings improved. However, after switching from piperacillin-tazobactam to an oral antimicrobial (levofloxacin), pneumonia reexercabted (Fig. 2B). Therefore, piperacillin-tazobactam treatment was resumed and pneumonia was under control again; however, drug fever and granulocytopenia caused by piperacillin-tazobactam was observed and hence cefepime was administered as an alternative. However, severe drug eruptions were observed 4 d after switching to cefepime, and drug eruption exacerbated even after a switch to meropenem. Therefore, antimicrobial treatment was discontinued. Antimicrobial therapy with cefepime, piperacillin-tazobactam, and meropenem were administered for 21 d. Drug eruption improved with no treatment after discontinuation of antimicrobial therapy. Immunodeficiency was suspected as the cause of recurrent lower respiratory tract infections because peripheral CD4-positive cells were reduced to 284 mu/L, and lymphocytopenia (<1,000/muL) occurred after radiation therapy for recurrent thymoma. Hypogammaglobulinemia was not observed; nonetheless, immunoglobulin was administered at 5,000 mg once daily for three consecutive days for severe infection. Furthermore, cyclosporine was gradually tapered to 100 mg/d after admission to control pneumonia. After discontinuation of antimicrobial therapy, fever recurred and the oxygen demand increased, and CT revealed new consolidation in her lower lobe of the left lung (Fig. 2C). For the third treatment cycle for pneumonia, a combination of vancomycin and doripenem, plus immunoglobulin, was initiated, because methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas fluorescens were detected in sputum cultures after hospitalization. Despite intensive treatment, no improvement in the oxygen demand and fever was observed. Since the patient had pneumonia refractory to broad-spectrum antimicrobial agents, pneumonia caused by agents other than bacterial was suspected as the cause of the respiratory failure and pneumonia findings on chest CT. Simultaneously, candidiasis was noted in the oral cavity (Fig. 3), and the decline in CD4-positive cells suggested T-cell immunodeficiency. Furthermore, based on elevated serum beta-D glucan levels and a positive PCR test for Pneumocystis jirovecii in sputum samples, P. jirovecii pneumonia was diagnosed as a cause of respiratory failure. Along with antimicrobial treatment, sulfamethoxazole (3,600 mg/d) and trimethoprim (720 mg/d) were initiated, and prednisolone was administered at 80 mg/d. Respiratory failure improved rapidly, and the infiltrative shadow on chest X-ray was obliterated. Prednisolone was tapered to a maintenance dose over 2 weeks, and anti-biotherapy and sulfamethoxazole/trimethoprim were administered for 3 weeks each and completed. During hospitalization, the peripheral lymphocyte count was elevated to almost 2,000/muL, and she was discharged on hospitalization day 99 without pneumonia recurrence after treatment for P. jirovecii pneumonia. Her clinical course after admission is described in Fig. 4. During her hospitalization, her gammaglobulin levels remained within the normal range, while her peripheral lymphocyte counts tended to slowly increase.

myasthenia gravis, oral candidiasis, pneumoniae, radiotherapy, t-cell immunodeficiency, thymoma

Chest computed tomographic images upon pneumonia exacerbation. . The centrilobular granular and infiltrative shadows were re-exacerbated and extensive infiltrative shadows were observed around the bronchi in the right upper lobe.

PMC8348523_01

Female

A 29-year-old woman presented with fever and productive cough at our hospital. She had undergone thymectomy for thymoma 9 years ago and had comorbid myasthenia gravis, pure red cell aplasia, and autoimmune hepatitis. She was prescribed immunosuppressants including cyclosporine (200 mg/d) and prednisolone (5 mg/d). Radiotherapy was initiated for a recurrent thymoma lesion 2 weeks before her admission delivered to a total dose of 54 Gy in 27 fractions (Fig. 1). Her bone marrow was an area spared from radiation therapy. Pneumococcal pneumonia episode in the previous months were remarkable in her medical history. Her chest examination revealed bilateral coarse crackles and rhonchi. Laboratory examination revealed leukocytosis with a left shift and elevated C-reactive protein. Hypogammaglobulinemia, fungal antigens, and Mycobacterium tuberculosis infection were unremarkable on the interferon-gamma release assay and anti-HIV antibodies. Chest computed tomography (CT) revealed infiltrations and a granular shadow in the bilateral lobes (Fig. 2A). She was diagnosed with broncho-pneumonia and hospitalized. After admission, a 14-d course of piperacillin-tazobactam was initiated for broncho-pneumonia, and her symptoms and laboratory findings improved. However, after switching from piperacillin-tazobactam to an oral antimicrobial (levofloxacin), pneumonia reexercabted (Fig. 2B). Therefore, piperacillin-tazobactam treatment was resumed and pneumonia was under control again; however, drug fever and granulocytopenia caused by piperacillin-tazobactam was observed and hence cefepime was administered as an alternative. However, severe drug eruptions were observed 4 d after switching to cefepime, and drug eruption exacerbated even after a switch to meropenem. Therefore, antimicrobial treatment was discontinued. Antimicrobial therapy with cefepime, piperacillin-tazobactam, and meropenem were administered for 21 d. Drug eruption improved with no treatment after discontinuation of antimicrobial therapy. Immunodeficiency was suspected as the cause of recurrent lower respiratory tract infections because peripheral CD4-positive cells were reduced to 284 mu/L, and lymphocytopenia (<1,000/muL) occurred after radiation therapy for recurrent thymoma. Hypogammaglobulinemia was not observed; nonetheless, immunoglobulin was administered at 5,000 mg once daily for three consecutive days for severe infection. Furthermore, cyclosporine was gradually tapered to 100 mg/d after admission to control pneumonia. After discontinuation of antimicrobial therapy, fever recurred and the oxygen demand increased, and CT revealed new consolidation in her lower lobe of the left lung (Fig. 2C). For the third treatment cycle for pneumonia, a combination of vancomycin and doripenem, plus immunoglobulin, was initiated, because methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas fluorescens were detected in sputum cultures after hospitalization. Despite intensive treatment, no improvement in the oxygen demand and fever was observed. Since the patient had pneumonia refractory to broad-spectrum antimicrobial agents, pneumonia caused by agents other than bacterial was suspected as the cause of the respiratory failure and pneumonia findings on chest CT. Simultaneously, candidiasis was noted in the oral cavity (Fig. 3), and the decline in CD4-positive cells suggested T-cell immunodeficiency. Furthermore, based on elevated serum beta-D glucan levels and a positive PCR test for Pneumocystis jirovecii in sputum samples, P. jirovecii pneumonia was diagnosed as a cause of respiratory failure. Along with antimicrobial treatment, sulfamethoxazole (3,600 mg/d) and trimethoprim (720 mg/d) were initiated, and prednisolone was administered at 80 mg/d. Respiratory failure improved rapidly, and the infiltrative shadow on chest X-ray was obliterated. Prednisolone was tapered to a maintenance dose over 2 weeks, and anti-biotherapy and sulfamethoxazole/trimethoprim were administered for 3 weeks each and completed. During hospitalization, the peripheral lymphocyte count was elevated to almost 2,000/muL, and she was discharged on hospitalization day 99 without pneumonia recurrence after treatment for P. jirovecii pneumonia. Her clinical course after admission is described in Fig. 4. During her hospitalization, her gammaglobulin levels remained within the normal range, while her peripheral lymphocyte counts tended to slowly increase.

myasthenia gravis, oral candidiasis, pneumoniae, radiotherapy, t-cell immunodeficiency, thymoma

Chest computed tomographic images on the third onset of pneumonia. . Consolidation of the right upper lobe improved, and a novel extensive infiltrative shadow was observed from the upper region to the basilar region of the left lower lobe.

PMC9585182_01

Male

A 66-year-old man, who presented with paroxysmal weakness of the left lower limb during activities for half a month, was admitted to a local hospital in December 2021 ( Figure 1 ). The patient reported one to two transient episodes per day with a duration of 2-10 min for each transient episode. The patient had a history of well-managed hypertension and a 1-year history of RA. This patient presented with pain in the major joints of the extremities without minor arthritis of the extremities and extra-articular manifestations, and he was treated with tripterygium glycoside tablets (three times per day, 25 mg a time) and triamcinolone tablets (8 mg/day). He stopped taking these medicines half a month before admission to the hospital because it was not responding to his joint pain. Magnetic resonance imaging (MRI) examination showed atypical enhancement of the pia meningeal, whereas stereoscopic meningeal biopsy only indicated non-specific inflammatory changes ( Figures 1 , 2A ). The patient was transferred to our hospital in January 2022 owing to a poor diagnosis ( Figure 1 ). On examination, the patient was in good general condition without headache, psychiatric behavior, cognitive dysfunction, speech dysfunction, seizures, movement disorder, consciousness disorder, and autonomic dysfunction. Neurological examination was rigorously normal except for a positive Babinski sign on the left lower limb. Musculoskeletal examination revealed only slight tenderness of large joints of extremities. Hyperintensity was observed in the leptomeninges of the right frontal and parietal lobes, and subtle hyperintensity was observed in the left frontal and parietal lobes as indicated in the diffusion-weighted image (DWI) ( Figure 3A ), contrast-enhanced T1-weighted sequences ( Figure 3B ), and contrast-enhanced fluid-attenuated inversion recovery (FLAIR) sequences ( Figure 3C ) after examination through brain MRI. No irregularity was observed in intracranial arteries through magnetic resonance angiography (MRA). The patient underwent 18F-FDG PET/CT scan, showing hypermetabolism of bilateral frontal-parietal meninges and adjacent cortex ( Figure 2B ). Electroencephalography (EEG) did not show any changes in brain activity. Cardiac color Doppler ultrasound, ECG, and CT examinations of the whole abdomen and lung were normal. A lumbar puncture examination was performed on the 3rd day after admission ( Figure 1 ). Cerebrospinal fluid (CSF) analysis showed increased protein content (0.477 g/L), high pressure (260 mm H2O), and elevated cell count (60 cells/mm3, with high levels of lymphocytes, Table 1 ). Notably, concentrations of lactic acid, glucose, and chloride were normal, whereas viral and fungal markers and culture results using CSF were negative. Analysis showed positive RF (96.3 IU/mL) and ACPA (>800 U/mL). In addition, C-reactive protein (CRP, 13.30 mg/L) was increased, while the erythrocyte sedimentation rate (ESR, 14 mm/h) was normal. Flow cytometry showed that the concentration of serum IL-6 (37.51 pg/mL) was significantly increased ( Table 1 ). Cell-based assay (CBA) showed the presence of NMDAR Abs IgG in CSF (titer 1:1, Figure 2D ), while the Abs were absent in serum ( Figure 2C ). Moreover, other autoimmune Abs (ANA, ENA, ANCA, anti-thyroid, anti-AMPAR1, anti-AMPAR2, anti-LG1, anti-CASPR2, anti-GABABR, anti-DPPX, anti-IgLON5, anti-GABAAR alpha1, anti-GABAAR beta3, anti-GlyRalpha1, anti-GluR5, anti-D2R, anti-Neurexin3alpha, and anti-GAD65) were not observed. Serum concentrations of C3, C4, IgA, IgG, and IgM were normal. Analysis showed negative results for infectious pathogens, such as herpesviruses, Mycobacterium tuberculosis, HIV, syphilis, and Lyme disease ( Figure 1 ). The patient underwent a composite evaluation, and a diagnosis of RM with positive NMDAR Abs was proposed. He received IVIg (0.4 g/kg.d) for 5 days from the 7th day after admission. Notably, the left lower limb weakness was alleviated after the second IVIg treatment. The patient received oral prednisone acetate (20 mg/day) and azathioprine (150 mg/day) to prevent the recurrence of RM ( Figure 1 ). Analysis of the lumbar puncture, some biochemical indexes, and MRI examination were conducted after 7 days of IVIg treatment. CSF analysis showed that the protein content (0.185 g/L) was restored to the normal level, and the pressure (185 mmH2O) and the cell count (20 cells/mm3) were decreased compared with pre-treatment values. CRP level (1.0 mg/L) was normal, and IL-6 level (9.62 pg/mL) was significantly lower than that before treatment. Serum RF (57.5 IU/mL) and ACPA (>800 U/mL) were positive ( Table 1 ). The titer of NMDAR Abs in CSF was 1:1, similar to that observed before treatment ( Table 1 ). Only subtle hyperintensity of the bilateral frontal and parietal lobes was observed in DWI ( Figure 3D ), contrast-enhanced T1-weighted sequences ( Figure 3E ), and contrast-enhanced FLAIR sequences ( Figure 3F ). The patient was generally in good condition, and RM did not relapse during the 1-month follow-up. The patient was instructed to reduce the prednisone dose to 5 mg per day by 5 mg every 2 weeks ( Figure 1 ). After 5 months, the patient was hospitalized for follow-up and was in good physical condition ( Figure 1 ). Indicators of abnormal levels included IL-6 in serum (14.79 pg/mL) and CSF (6.16 pg/mL), ACPA in serum (>800 U/mL) and CSF (2.8 U/mL), and NMDAR Abs in CSF (1:1), while other indicators were basically normal ( Table 1 ). Considering that the IL-6 and ACPA levels of the patient were still abnormal, he was suggested to increase the dosage of prednisone acetate tablet to 10 mg per day ( Figure 1 ).

ivig, nmdar antibody, case report, diagnosis and treatment, rheumatoid meningitis

PMC4737748_01

Female

A 2.5-year-old girl, previously healthy, was admitted to the hospital because of the respiratory tract infection and erythema multiforme. On physical examination, petechiae and polymorphic rash with changes, 0.5 to 10 cm in diameter on buttocks, legs and feet were found (Fig. 1). Laboratory tests revealed increased inflammatory markers: CRP - 1.3 mg/dl (Normal value < 1.0 mg/dl), leukocytosis - 11.7 x 103/ul, ESR - 16 mm/1 h and IgA - 164 mg/dl (Normal value: 15-154). Urinalysis and serum creatinine (0.3 mg/dl) were normal. The girl received amoxicillin with clavulanic acid (90 mg/kg/day) for 7 days. After 5 days of treatment, inflammatory markers resolved, but because of recurrent skin changes, another etiology of the infection was suspected. Laboratory tests excluded tuberculosis, streptococcal infection, yersiniosis, toxoplasmosis, lambliasis, borreliosis, EBV and HSV infections. Mycoplasma pneumoniae infection was confirmed by a positive serological test (Table 1). Indication for the X-ray was the positive titer of antibodies against M. pneumoniae. X-ray of the chest revealed right-sided pneumonia without any changes on auscultation of the lungs. Treatment with clarithromycin at a dose of 15 mg/kg/day was started and was continued for 21 days. After 3 weeks of treatment, skin changes disappeared and the chest X-ray image was normal.

henoch-schönlein purpura, mycoplasma pneumoniae, children

PMC5329816_01

Female

The patient is female, 27 years old, with her mother, aunt, and brother and cousin history of HS. She was sent to our hospital in April 2005, for "yellowish discoloration of the sclera and the skin for 3 years, aggravated for 2 months". Physical examination shows "mild yellowish discoloration of the sclera and the skin, soft abdomen, liver not palpable, spleen is palpable 3cm below the left costal margin. Auxiliary examinations: blood routine test: white blood cell count (WBC) 8.2*10E9/L, red blood cell count (RBC) 2.84*10E12/L, hemoglobin (Hb) 92g/L, mean corpuscular hemoglobin concentration (MCHC) 382g/L, platelet count (PLT) 327*10E9/L, proportion of reticulocyte 10.1%; blood smear shows the proportion of spherocytes is 18%; Erythrocyte osmotic fragility test: hemolysis begins at 0.56% salt solution (normal control at 0.42%), complete hemolysis at 0.41% salt solution (normal control at 0.22%); liver function tests: total bilirubin (TB) 163.3umol/L, indirect bilirubin (IB) 154.4umol/L, Lactate dehydrogenase (LDH) 402U/L. computed tomography of the abdomen shows splenomegaly (7 rib units); bone marrow routine test shows significantly active bone marrow proliferation (Figure 1), erythroid proliferation is active, spherocytes are commonly seen, counts for 15%, folic acid, vitamin B12, ferritin, glucose phosphate isomerase, glucose-6-phosphate dehydrogenase test and pyruvate kinase tests were normal, Coomb's test shows negative result; normal hemoglobin electrophoresis; expression of CD55 and CD59 on erythrocytes and granulocytes are not significantly below normal range. The clinical diagnosis is: HS. She was given partial embolization of the splenic artery, after which yellowish discoloration of the skin and sclera faded, hemoglobin and bilirubin level returned to normal and splenomegly relieved. Yellowish discoloration of the skin and sclera occurred again in September 200 7. Auxiliary examination shows: WBC 12.4*10E9/L, RBC 3.17*10E12/L, H 108g/L, PLT 425*10E9/L, proportion of reticulocyte 12%; liver function tests: TB 122.3umol/L, IB 108umol/L; upper abdomen CT shows splenomegly (7 rib units) and splenic embolization postoperative change; bone marrow test gives the same result as the previous one. She received a second partial splenic artery embolization. After the procedure, yellowish discoloration of the skin and sclera faded, hemoglobin and bilirubin level returned to normal and splenomegly relieved again. Her blood routine test in February 2008 shows a result of WBC 69.2*10E9/L the proportion of neutrophils is 74% RBC 3.93*10E12/L Hb 124g/L PLT 575*10E9/L proportion of late promyelocyte is 10%, the proportion of reticulocytes is 11% Physical examination shows her skin and sclera are mildly yellowish discolored, spleen is enlarged and being palpable 8cm below the left costal margin. Bone marrow test shows extremely active proliferation, Myeloid: erythroid ratio is 8:1, all stages of myeloid cells are increased, especially late promyelocytes, eosinophils and basophils are commonly seen, neutrophil alkaline phosphatase positive rate is 1%, score 2. Chromosome: 46, XX, t(9; 22)(q34; q11) (Figure 2); bone marrow gene test: M-bcr-abl/abl 92%, m-bcr-abl/abl(-). She was diagnosed of CML (chronic phase), and was given imatinib therapy for 1 month before recheck her blood routine test: WBC 7.4*10E9/L, RBC 3.8*10E12/L, Hb 121g/L, PLT 344*10E9/L. She didn't re-examine chromosome and fusion gene. Ethical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies and in accordance the tenets of the Helsinki Declaration, and has been approved by the authors' institutional review board or equivalent committee. Informed consent: Informed consent has been obtained from all individuals included in this study.

case report, chronic myelocytic leukemia, hereditary spherocytosis

PMC5330001_01

Male

We report a case of 20-year-old male, belonging to lower socioeconomic class, educated up to 2nd standard, presented with severe unilateral dystonic left sided neck movements [Figure 1]. Careful history exploration revealed he was taking risperidone 2 mg irregularly for 2 months and then olanzapine 5 mg for another 4 months. At 19 years, the patient presented with occasional anger outbursts, getting provoked on small matters and beating family members, running away from home, screaming episodes occasionally, fearfulness, sleep disturbance for 2 days; which was precipitated after fever. According to the mother, one friend might have threatened/made fun of him actually and after that patient stopped going out of house, and displayed above mentioned symptoms. This was interpreted as psychosis with persecutory ideas, and he was treated with risperidone 2 mg/day for 2 months and then with olanzapine 5 mg/day for 4 months. In last two follow-ups patient did not present himself, and mother reported unusual neck movements, which were taken as a part of his overall psychopathology and not taken seriously, slight intermittent neck movements reported were missed as part of adolescent behavior problems mimicking some hero in movies. As neck dystonia increased, the patient had a severe disability as patient had to keep his hands behind his head for the support. The movement would decrease when the patient was lying down and was absent during sleep. He stopped going outside or doing household work. Sitting comfortably or walking straight became impossible in waking hours. He even stopped taking food due to severe neck movements making chewing and swallowing difficult. His Abnormal Involuntary Movement Scale scoring was in severe rating. His birth and early developmental milestones were normal. During 2-10 years of age patient was inattentive and mildly hyperactive. Other siblings were educated with Master's degree, and patient was also sent to school, but due to inattention and restlessness, he did not pass 2nd standard after three attempts. He left the schooling. With average executive functioning and life skills, he worked as an unskilled laborer in the neighborhood shops as a helping hand. Nobody suspected him of having an intellectual disability. Between 11 and 18 years, he was found to be getting over familiar, cheerful, moody, and short tempered. Sometimes, the patient had inappropriate social judgment; for which his friends made fun of him, and teased him. On mental status assessment, patient was found to be having borderline intellectual functioning with standard intelligence quotient test. Routine investigations, thyroid function tests, electroencephalogram, fundus examination, cervical X-ray, magnetic resonance imaging brain were normal. After consulting neurophysician, Wilson's disease and other secondary causes of dystonia were ruled out. The patient was treated with clonazepam 1 mg total dissolved solid (TDS), tetrabenazine 25 mg TDS, trihexiphenidyl 2 mg bipolar disorder (BD). After 2 months, there was some improvement of around 30%. Baclofen 10 mg was added; increased up to 20 mg, trihexyphenidyl reduced to 2 mg. With little improvement after 4 months of treatment for dystonia, levodopa + carbidopa (100 + 25) was added by neurophysician and increased up to 1/2 tablet TDS and baclofen omitted. After 12 months of treatment, patient has improved around 90% with tetrabenazine 75 mg, levodopa + carbidopa (100 + 25) - 1/2 tablet BD, and clonazepam 1 mg BD. He has shown no psychotic or behavioral symptoms and is not on any antipsychotics.

antipsychotic agents, borderline intellectual functioning, tardive dyskinesia

PMC10172662_01

Male

A 67-years-old male patient was diagnosed with locally advanced non-small cell lung cancer (NSCLC) (clinical oncological staging: T3 N3 M0) with subcarinal lymph node metastasis causing esophageal compression. [18F]Fluorodeoxyglucose (FDG)-positron emission tomography (PET) confirmed an increased metabolic activity on the lower left lobe, site of the primary neoplastic tissue, and in correspondence with the metastatic lymph nodes at the level of the esophageal stenosis [standardized uptake value (SUV) max 10.2]. Considering the dysphagia reported by the patient, esophagogastroduodenoscopy (EGDS) was performed showing a 6 cm long intrinsic neoplastic stenosis in the caudal part of the esophagus. A fully covered metal esophageal stent was then positioned, leading to dysphagia resolution. After a multidisciplinary discussion with oncologist and radiotherapist, concomitant radiotherapy and chemotherapy (cCRT) was started. After the treatment, a restaging with computer tomography (CT)-scan and FDG-PET was performed, and a partial response (PR) was defined based on Response Evaluation Criteria in Solid Tumor (RECIST). After a 17-months follow-up without disease progression, the patient developed cough, chest pain and pneumonia. The patient underwent chest CT-scan, which detected the development of TEF and inhaled pneumonia. Urgent bronchoscopy was performed showing a roughly 3 cm x 1 cm TEF superior to the carina with the esophageal stent protruding into the tracheal lumen (Figure 1). A multidisciplinary discussion was made including bronchoscopists, otolaryngologists, plastic surgeons and anesthesiologists. Surgical correction was excluded due to high operative risk. However, given the patient's life expectancy after cCRT and the absence of disease progression after 17 months from treatments, an alternative procedure was proposed to allow the reconstruction of the tracheal laceration avoiding the progression of TEF secondary to a double stenting. The multidisciplinary team expressed consensus over a bronchoscopic repair of TEF with autologous fascia lata was decided, but without the removal of the esophageal stent due to the high risks on the esophagus such a procedure would have involved. General anesthesia was induced and spontaneous breathing mantained. A Dumon rigid bronchoscope was employed (Efer Medical, La Ciotat, Cedex, France). A 5 cm long incision was performed along the lateral aspect of the caudal part of the thigh and a fascia lata graft of roughly 7 cm x 3 cm and 6 mm in thickness with subcutaneous fat tissue was harvested to obtain sufficient graft thickness (Figure 1). Under bronchoscopic guidance TEF was identified and margins were freshened using a suction instrument. Synthetic biodegradable cyanoacrylate glue (Glubran 2;GEM) was injected on the edges of the tracheal laceration using a syringe via 5 Fr angioplasty catheter [Angiographic Catheter Tempo Vertebral (VERT) Ref. 451-514H0 Cordis ] to create an elastic film on the posterior wall of the trachea and facilitate graft adhesion to the surrounding tissue. The fascia lata graft was taken with endoscopic forcep and positioned in the tracheal lumen passing through the rigid bronchoscope. The whole defect was fully covered with subcutaneous fat facing the esophageal stent and fascial side facing the tracheal lumen. During graft placement, spontaneous breathing was suppressed in order to avoid fascia lata displacement. A silicone tracheal stent (NOVATECH Dumon stents, ST 18-16-18 L 15-20-15, Boston Medical Products, Inc., Westborough, MA, USA) was placed to maintain the fascia lata graft in place allowing to cover TEF site both cranially and caudally (Figure 2). Flexible bronchoscopy was performed at the end of surgery in order to check the adequate graft placement. Videofluoroscopy was performed 1 week after the procedure showing no signs of TEF patency (Figure 3). Oral feeding was progressively introduced after 2 days. No aspiration symptoms were referred. Videofluoroscopy and EGDS were performed after 7 months showing no signs of TEF patency. EGDS showed esophageal stent and fascia lata in place (Figure 3) with the patient maintaining oral feeding without any weight loss or aspiration symptoms or signs.

bronchoscope, fascia lata autograft, stent, tracheoesophageal fistula (tef), tracheoscopy

PMC9048595_01

Male

LM is a 26-year-old man with a medical history significant for ulcerative colitis, diagnosed at age 21. Despite treatment with oral and suppository mesalamine and hydrocortisone enemas, he was unable to remain in remission for longer than 8 weeks. At 23, he experimentally adopted a Mediterranean-style ketogenic diet [with an emphasis on intake of fatty seafood, extra virgin olive oil, and low-carbohydrate fibrous fruits and vegetables ] and entered a 6-month period of remission, following which he elected to discontinue all medications and has largely remained in remission. Since adopting a ketogenic diet two and a half years ago, LM has only experienced colitis flares on three occasions: twice when trying to reintroduce carbohydrates in the form of honey, fruit, and/or starchy vegetables, and once following acute mold exposure. As previously reported, in the first 6 months following carbohydrate restriction, LM's LDL-C increased from 95 mg/dl to 321 mg/dl, along with low TG and an increase in HDL-C from 48 to 109 mg/dl. This change occurred despite LM's self-reported prioritization of foods rich in unsaturated fats, restricted intake of saturated fat-rich foods, such as red meat and dairy, and moderate fiber intake of ~30 g/day. Of note, LM subsequently reduced intake of fiber in order to manage constipation, and current intake is ~15 g/day. When statin therapy was recommended to LM upon first presentation with hypercholesterolemia, he declined. While he expressed concern about his LDL-C levels, he also conveyed reluctance about consenting to potentially lifelong pharmacotherapy without first attempting to address his hypercholesterolemia with diet and lifestyle change. LM attempted on two occasions to reintroduce carbohydrates to lower his LDL-C. On both occasions, he experienced near-immediate gastrointestinal discomfort and blood in the stool within a week. Although he initially declined statins, he consented to trial ezetimibe but experienced gastrointestinal discomfort and discontinued treatment. To further investigate potential contributing dietary factors to his hypercholesterolemia within the context of his ketogenic diet, in August 2020, LM began measuring his dietary intake using a gram food scale and by keeping fastidious dietary records in the 7 days prior to scheduled lipid testing. Nutritional information extracted from these records, using data exported from the USDA Food Central database along with brand-specific nutrition information, is provided with photographs of representative meals in Supplemental Information . Lipid and metabolic panels over the years have been notable for elevated LDL-C-related markers, LDLp and apoB, and elevated Lp(a) ranging from 109 to 168 mg/dl. Despite his low LDL-C while consuming a mixed diet (95 mg/dl), Lp(a) was elevated in LM prior to starting a ketogenic diet and is also elevated in LM's father, who has a history of coronary artery disease manifesting in 99% left anterior descending stenosis at age 44, although the father presented with a profile in strong contrast to his son: unremarkable LDL-C (70-92 mg/dl), atherogenic dyslipidemia (HDL-C 33-39 mg/dl, TG 199-294 mg/dl, with a preponderance of sdLDL), and history of obesity. (NB: Subsequent to his event, the father adopted a CRD and has lost 50 lbs and reversed metabolic syndrome, while maintaining LDL-C <100 mg/dl on atorvastatin and ezetimibe). LM exhibits normal thyroid and testosterone, HbA1c (4.8-5.0%), and fasting insulin (<3 muIU/ml), low hsCRP (<1.0 mg/L), Pattern A phenotype, and an extremely low TG/HDL-C ratio (~0.3) characteristic of the LMHR phenotype. Whole exome sequencing performed by Veritas Genetics, and independent dyslipidemia and ASCVD genetic risk testing by GB Healthwatch, revealed no pathogenic or likely pathogenic variants that could account for LM's phenotype. Results of lipid panels conducted between August 2020 and October 2021, in conjunction with data extracted from LM's dietary records, are presented in Table 1 and Figure 1 . In August 2020, LDL-C was 521 mg/dl (HDL-C 113 mg/dl, TG 47 mg/dl). This time point corresponds to LM's BMI nadir of 18.8 kg/m2 and 83% unsaturated fat intake (17% saturated). In the following month, LM was recommended to reduce dietary cholesterol intake, eliminating liver, shellfish, and egg yolks from his diet (in substitution for lean chicken, fish, and egg whites). One month later, in September 2020, his LDL-C was re-measured at 545 mg/dl (HDL-C 94 mg/dl, TG 58 mg/dl). In January 2021, following a weight gain of 6 lbs and elevated intake of polyunsaturated fatty acid in the form of ~3 Tbsp toasted sesame oil daily, LDL-C was measured at 393 mg/dl (HDL-C 116 mg/dl, TG 40 mg/dl). Finally, testing in October 2021 following further weight gain of 4 lbs (BMI 20.2 kg/m2), and in the context of a diet far richer in saturated fat, LDL-C measured at 411 mg/dl (HDL-C 116 mg/dl, TG 39 mg/dl) ( Table 1 and Figure 1 ). After two and a half years of persistently elevated LDL-C levels, and a prior CAC of 0, LM was again counseled to initiate statin therapy. He considered, and a compromise was reached whereby he agreed to initiate pharmacotherapy if "it was first proven" that he was developing measurable atherosclerotic plaque. Given consideration of data available at the time in young people at elevated risk for ASCVD, and LM's significant exposure (LDL-C ~400-550 for ~2.5 years), a CCTA was ordered for calcified and non-calcified plaques. No plaque or stenosis was observed in any vessels CAD-RADS = 0 ( Figure 2 ).

hdl cholesterol, ldl cholesterol, carbohydrate restriction, coronary computed tomography angiography (ccta), ketogenic diet, lean mass hyper-responder, triglycerides

PMC2782168_01

Female

A 65-yr-old female presented with hoarseness that began 3 weeks ago. She had no previous history of trauma, pulmonary and bronchial tuberculosis. On admission, her vital signs were normal and blood pressure was equal on both arms. The laboratory workup showed a white blood cell count of 6,500/microL, normal erythrocyte sedimentation rate and C-reactive protein. Syphilis serology, rheumatoid factor, and antinuclear antibody tests were negative. Chest radiograph (CXR) demonstrated a superior mediastinal mass (Fig. 1). Because laryngoscopy showed a fixed right vocal cord, hoarseness was considered to be due to recurrent laryngeal nerve palsy. Computed tomography (CT) and magnetic resonance imaging (MRI) demonstrated a 7 cm sized proximal right subclavian artery aneurysm (Fig. 2, 3). Thoracic and subclavian aortography revealed a tortuous right subclavian arterial anatomy with a saccular aneurysm beginning near the subclavian origin (Fig. 4). The preoperative diagnosis was atherosclerotic right subclavian artery aneurysm. Repair of the aneurysm was performed through a median sternotomy. We dissected at the aneurysmal afferent loop and efferent loop. We made end-to-end anastomosis by Gore Tex (6 mm sized) graft interposition. In the operation field, we could not find the recurrent laryngeal nerve due to severe adhesions. After the debridement, a partially undetached aneurysm was left. Cultures from the wall of the aneurysm and thrombus were negative. Pathology was consistent with an atherosclerotic aneurysm filled with thrombus (Fig. 5). After one month follow-up, she still complains of hoarseness and laryngoscopic examination revealed right vocal cord palsy.

PMC8722817_01

Male

A 29-year-old male presented with progressively increasing right inguinal, cervical, and left axillary swellings over two and a half months, which measured 20 x 10 cm, 10 x 5 cm, and 7 x 5 cm respectively on clinical examination, along with mild fever. There was no history of night sweats or weight loss. He had consumed homeopathic therapy for 10 days, followed by therapy for tuberculosis for the last 1.5 months. On examination, the liver and spleen were non-palpable. Positron emission tomography (PET) scan revealed an FDG avid (SUV max 23.97) conglomerate nodal mass in the (i) left cervical regions (level II-V), (ii) left axillary region, (iii) retroperitoneal nodal mass extending from the pelvic region to the right external iliac region, and (iv) bilateral inguinal nodes; measuring up to 7.7 x 5.5 cm. Erosion of the left third rib and left pleural infiltration were also identified. The working diagnosis was lymphoma. The cervical lymph node's core biopsy histopathologic examination (HPE) showed multiple tissue cores infiltrated by medium to large-sized pleomorphic atypical cells with variable morphology admixed with small lymphocytes, histiocytes, and few plasma cells, neutrophils, occasional eosinophils and foamy macrophages. The cells demonstrated moderate atypia and ovoid folded to indented nuclei, fine chromatin, inconspicuous nucleoli and moderate cytoplasm. A fair number of the cells were large-sized with wreath-like nuclei and plasmacytoid appearance (Figures 1A, 1B, and 1C). Mitotic index was high (approximately 10-12/10HPF), including atypical mitosis. The differential diagnosis initially considered on HPE included anaplastic large cell lymphoma, diffuse large B cell lymphoma, metastatic carcinoma, myeloid sarcoma and blastic plasmacytoid dendritic cell neoplasm (BPDCN). On immunohistochemistry, the atypical cells were positive for LCA (weak) and negative for PanCK (AE1/AE3), CD20, CD3, CD5, CD8, CD30, ALK-1, CD43, CD2, CD7, CD68, SOX10 and PAX-5. CD4 staining in the atypical cells was diffuse and of strong intensity. At the same time, Ki-67 proliferative index revealed heterogeneous staining, being approximately 65-70% in the highest proliferative zone. LCA stained the remnant lymphocytes, CD20 and CD3 the B and T-lymphocytes among them, respectively, and CD68 the histiocytes. An unequivocal diagnosis could not be rendered at this moment and the possibilities proffered were BPDCN and myeloid sarcoma. The same was communicated to the attending clinician, and the case was discussed in the multidisciplinary tumor board. The moot point was the lack of handy markers such as CD123 and MPO (myeloperoxidase) on IHC, but fortunately, it was available on flow cytometry. A decision was taken to attempt flow cytometry on the material aspirated by fine-needle cytology from the suspicious lymph nodes. Thus, fine needle aspiration cytology was performed from the left cervical lymph node mass, and smears were also prepared while subjecting the material to flow cytometry. The cellular smears revealed singly scattered and a few cohesive clusters of pleomorphic neoplastic cells, which were medium to large-sized, with a round to oval irregularly folded subcentric to eccentric vesicular nuclei and moderate to abundant cytoplasm, vacuolated at places. Prominent nuclear grooves were discerned in some of the cells. Many multinucleated giant cells containing wreath-like nuclei were evident, accompanied by increased phagocytic activity and marked cytologic atypia, especially in the cells seen in the clusters (Figure 1D). Cytologic diagnosis suggested neoplasm of histiocytic origin. The histopathology slides were reviewed along with the IHC analysis. Careful and meticulous appraisal evinced nuclear grooves in the atypical cells and variable positivity of CD68 in the atypical cells, thus prompting the consideration of a histiocytic neoplasm, probably of Langerhans cell origin. Additional IHC was resorted to, which illustrated diffuse and strong positivity of the atypical cells for CD1a, S100, and langerin (CD207) and negativity for CD21 and CD23, thus confirming a Langerhans cell neoplasm (Figure 2, 3, and 4). Providing succor was also the flowcytometric finding of negativity of the atypical cells for CD123 and MPO. However, the dilemma flummoxing the pathologist now was whether the lesion was a Langerhans cell sarcoma or Langerhans cell histiocytosis. In conjunction with the cytopathologic observations and in view of the moderate atypia, high mitotic, and proliferative indices, a final diagnosis of Langerhans cell histiocytosis progressing to Langerhans cell sarcoma was rendered. Molecular analysis, especially for BRAF V600E mutation, was not feasible. Chemotherapy was instituted, and the patient was treated with a combined regimen comprising ifosfamide, carboplatin, and etoposide. After 3 cycles of chemotherapy, the PET-CT scan showed decreased metabolic activity of the retroperitoneal and right inguinofemoral lymph nodes; however, new lesions were detected in the left pleural and right thigh region. Biopsy of the pleural lesion was performed, HPE of which revealed similar histopathologic features as mentioned above and IHC positivity for CD1a, thus reiterating the diagnosis of LCS. The chemotherapy was continued and, until the last follow-up, after having completed 6 cycles of the chemotherapy regimen, a significant reduction in disease activity has been documented.

langerhans cell, histiocytosis, lymphoma, pleura, sarcoma

PMC3747430_01

Male

An 86-year-old man presented with a headache and blurred vision. His surgical history was significant for an uneventful left sided CEA with a Vascular Patch (Synovis VG-0106N) and utilizing a Pruitt-Inahara Shunt during the procedure. This surgery was performed 2 months ago for high grade left internal carotid stenosis (90%). Patient was having no other associated symptoms and had no clinical signs of infection. Computed tomography (CT) angiography of the head and neck was then performed, revealing a 1.2 x 2.0 cm pseudoaneurysm with a small amount of surrounding thrombus within the distal left cervical internal carotid artery just proximal to the petrous portion (Figure 1). The PA was found to be distal to the endarterectomized area of the carotid artery which means that the defect was likely caused by the balloon portion of the shunt. A short segment of high grade stenosis (80%) was also revealed in the postbulbar region of the proximal left internal carotid artery (Figure 2). Patient was then taken to the catheterization lab for endovascular exclusion of the PA. The right groin was prepped, and a 6 French catheter was placed in the femoral artery. An internal mammary catheter was used and then selectively cannulated the internal mammary to gain access to the left carotid artery where angiography was performed. A 0.035 wire was then passed through, and a 7 French 9 cm long sheath was passed into the left common carotid artery where a repeat angiography was performed. Then a 0.014 BMW wire was passed across those lesions, and the position was confirmed. A 6 x 50 mm long covered Viabahn stent (W. L. Gore & Associates Inc., Flagstaff, AZ) was successfully deployed across the PA, but there were still the tight stenosis and 90-degree bend of the graft anastomosis of the endarterectomy site. For the residual stenosis, a 7 x 10 stent (Nitinol Acculink) was successfully deployed and expanded using a 5 Balloon to 6 Atmospheres (Figure 3). After full expansion was noted, the balloon was withdrawn, and completion angiography was performed confirming complete obliteration of the PA (Figure 4). Patient recovered with no postoperative neurological symptoms and had no complications upon 3-year followup.

PMC10154059_01

Female

A 16-year-old girl came to our outpatient clinic complaining low back pain and clinically evident thoracolumbar joint deformity. Her medical history was nonetheless complex: she was born in a foreign country at 37 weeks with oligohydramnios, foetal hypoplasia, and dysmorphia, Neonatal echocardiogram showed a patent foramen ovale (PFO); on abdominal ultrasonography, the kidneys were of normal size with hydrocalicosis. The patient underwent genetic investigation and was found to have a 46 XX karyotype, thus initially excluding genetical abnormalities. At 1 year and 6 months, the patient began to walk with a walker; parents noticed initial clinical evidence of back irregularity, so an orthopaedic examination was performed, and a thoracolumbar junction hyperkyphosis secondary to L1 hemivertebrae with marked ligamentous laxity, Nonetheless, no further workup was undertaken, and the patient remained untreated. At age 3 years, she underwent a clinical check-up showing mental retardation, clinodactyly of 1 toe, syndactyly of 2nd and 3rd toes bilaterally. At age 13, the patient presented with primary amenorrhea, and hormonal tests were performed revealing hypothalamic-pituitary-ovarian axis dysfunction. At the age of 16 years, she was brought to our attention for back pain and clinically evident thoracolumbar joint deformity. The physical examination was unremarkable, without signs of neurological deterioration. Full spine X-rays showed severe kyphosis of the thoracolumbar junction (T11-L2 Cobb angle 95.2 ) with L1 hemivertebra and T12 morphological alteration; no coronal deformity was observed (Fig. 1). Further workup consisted in a full spine MRI and CT scan of the lumbosacral and thoracic spine; the CT highlighted a partial dimorphism of T12 and an anterior wedged L1 (Fig. 2). Magnetic resonance imaging of the abdomen showed aplasia of the uterus (Fig. 3) and upper two-thirds of the vagina, the presence of mullerian remnants, hypoplastic ovaries, hypoplastic right kidney with calyx changes. Following all these investigations, the diagnosis of Mayer-Rokitansky-Kuster-Hauser syndrome (MRKH) was made. In order to treat the severe sagittal deformity, a surgical correction with L1 corpectomy and circumferential fusion was proposed. However, due to the outbreak of Sars-Cov-2 pandemic, the surgery was delayed: indeed, during that time, the Regional Healthcare system was reorganized to face the emergency. Under the new system, our specialistic Orthopaedic Institute was tasked to accept and treat only orthopaedics emergencies (i.e. fractures) in patients who did not need post-operative intensive care, while surgeries with required postoperative ICU were shifted to other Institutions. Due to this unprecedented situation, the patient was lost to follow-up during preoperative investigations. The patient returned to our attention following sudden onset of weakness in her lower extremities. Clinical examination revealed neurological involvement of the lower extremities with paraparesis (Asia Score C). An MRI was performed, which demonstrated thoracic myelopathy caused by a T11-T12 disc herniation (Fig. 4); this occurrence is typically associated to wedge deformity of thoracolumbar vertebra.. The abrupt neurological deterioration led us to consider a different surgical strategy: thus, a two-stage intervention was planned, with an initial T11-T12 discectomy performed through a video-assisted left sided thoracotomy, followed by a scheduled L1 PVCR with TL fusion. During the first surgical stage a good cord decompression was achieved, and A T12-L1 discectomy was also performed to facilitate the next step. After the first step, halo-traction was positioned to gradually correct the severe deformity. The patient remained in Halo-Gravity traction for the first postoperative period, during which no complication of traction was recorded and good neurological recovery was achieved in approximately 1 week. After 3 weeks, when the patient's hemodynamic and clinical conditions had stabilized, we proceeded with the second step: posterior vertebral column resection (PVCR) of L1 with T12-L2 anterior fusion, and T8-L4 posterior fusion; Correction of the deformity was achieved alternating in situ bending of the rods and compression until we obtained a complete correction of the deformity (Fig. 5). In five days, the patient was able to walk with a brace; postoperative X-Rays (Fig. 6) showed optimal restoration of sagittal profile. The patient was discharged in the 7th postoperative days, fully able to walk. Correction of the hyperkyphosis was optimal: segmental (T11-L2) kyphosis corrected from 95.2 in preop to a post-operative value of 17.3 , with 81.8% correction (Fig. 7). At one-year clinical and radiological follow-up, the patient has had a full recovery, can go to school and swim, NRS is 0, Asia score is E.

congenital hyperkyphosis, mrkh, rokitansky syndrome, sars-cov2

PMC5292989_01

Female

A 30-year-old female patient presented to the surgery outpatient clinic of our institution with complaints of non-radiating epigastric pain accompanied by mildly painful epigastric swelling which had been gradually progressing for the past 4 months. There was a history of undocumented/unconfirmed episodes of pyrexia. There was no history of trauma, significant weight loss, chronic medical illness or family history of tuberculosis. On examination, a mildly fluctuant and tender midline epigastric swelling, 3x2.5 cm in size, was seen in the epigastric region. Overlying skin was unremarkable. Axillary examination was normal. The patient was sent for an abdominal ultrasound as a suspected case of an incompletely treated liver abscess. Ultrasound of the abdomen using curvilinear transducer (3-5 MHz) revealed no evidence of hepatomegaly or liver abscess or any other abdominal pathology. Examination of the epigastric region using a high-frequency transducer (7-9 MHz) revealed subcutaneous tissue thickening with an irregular hypoechoic collection measuring 9x9.8x10 mm in the lower plane. The hypoechoic collection showed linear echogenic bone fragments located on its posterior aspect (Figure 1). Osteomyelitis of the xiphisternum likely to be of tubercular etiology was considered at this stage. Simultaneously, blood samples were obtained and laboratory examination showed marginally raised total leucocyte count (13600/cumm) with lymphocytosis (42%) and raised erythrocyte sedimentation rate (85 mm at the end of the first hour using Wintrobe's method) and C-reactive protein levels. Patient was HIV-negative. Mantoux test was positive (20x20 mm) after 72 hours. Subsequently, Lateral chest radiographs focused at the distal sternum were obtained, demonstrating lytic destruction of the xiphisternum (Figure 2). Contrast enhanced Multidetector computed tomography (MDCT) of the thorax and abdomen was obtained to exclude mediastinal/abdominal extension of the disease. CT examination of the thorax revealed almost complete erosion of the xiphoid process of the sternum. The surrounding soft tissue revealed poorly-enhancing inflammatory changes in the form of stranding (Figure 3). The lung window view showed patchy fibrotic nodules in both lungs. Additionally, traction brochiolectasis was observed in the right upper lobe and left lower lobe suggesting an old infective etiology (Figure 4). There was no other focus of tubercular infection in the chest and abdomen on CT scan. Contrast-enhanced MRI demonstrated abscess formation in the soft tissue of the xiphisternal region (Figure 5A, 5B). MRI also helped to exclude concurrent spinal tuberculosis. Sonography-guided antigravity aspiration was carried out on two occasions which revealed scant blood mixed aspirate. The samples were subjected to microbiological and pathological analyses. Microscopic findings were suggestive of non-specific inflammation. The aspirate did not show pyogenic organisms on gram's staining or acid-fast bacilli on Ziehl-Neelsen staining. ADA levels were 367 IU/L in the tissue aspirate. Culture for pyogenic organisms was negative after 48 hours of incubation. Polymerase Chain Reaction (PCR) for Mycobacterium tuberculosis and Amplified Mycobacterium tuberculosis DNA test (AMT-DT) were also performed and were positive for tuberculosis. The sputum examination was negative for acid-fast bacilli. Enzyme-linked immunosorbant assay (ELISA) was negative for HIV I & II antibodies. The patient's immune status was normal with no other focus of infection either clinically or radiologically. Standard multidrug antitubercular chemotherapy (Isoniazide 5 mg/kg; Rifampicin 10 mg/kg; Pyrazinamide 25 mg/kg; Ethambutol 15 mg/kg; along with pyridoxine 20 mg) was administered to the patient. The constitutional symptoms and pain subsided over the next 12 weeks and the size of swelling gradually decreased over 6 months. The drug therapy was continued for a period of 12 months. The patient was asymptomatic when last seen in the outpatient department, which was 18 months post therapy. The patient was informed that data concerning her case would be submitted for publication, and therefore a written, informed consent was obtained.

magnetic resonance imaging, multidetector computed tomography, osteoarticular, tuberculosis, sternum, ultrasonography, xiphoid bone

CT thorax: coronal reformatted lung window view, shows traction bronchiolectasis along the horizontal fissure in the right lung and posterior basal segment of the left lung (white arrows) with multiple fibrotic nodules in bilateral lung parenchyma.

PMC8635719_01

Male

A 60-year-old previously healthy male farmer presented to the First Affiliated Hospital of Xi'an Jiaotong University with a 6-month history of intermittent fever. Five months ago, he was diagnosed with VL and treated with sodium antimony gluconate (SAG) (0.6 g/d) for 6 days. The patients' condition improved, and he was discharged from the hospital. However, he was readmitted to our hospital because of recrudesce fever. He had a history of working in coalmines and current hypertension treated with oral therapy. There was no complication related to hypertension. Medical, surgical, pharmacological and family histories were not significant. His body weight was 70 kg. Physical examination revealed splenomegaly, no superficial lymphadenopathy, and no edema of the lower limbs. Blood cultures as well as tests for bacteria, fungi, tuberculosis, parasites, and brucellosis agglutination were all negative. His laboratory findings included pancytopenia with a C-reactive protein (CRP) level of 82.8 mg/L and procalcitonin (PCT) level of 0.88 ng/mL. The patient's liver function and coagulation function were abnormal. Computed tomography of the abdomen confirmed the presence of splenomegaly. Examination of bone marrow aspirate revealed amastigotes, which is the typical sign of leishmaniasis. PACE-seq metagenomic next-generation sequencing (mNGS) (Hugobiotech, Beijing, China) detected 5,074 specific reads of Leishmania in the blood sample, also indicating leishmaniasis (Figure 1). The polymerase chain reaction (PCR) test of the bone marrow aspirate confirmed the diagnosis. He was thus diagnosed with recurrent VL. Because the patient experienced relapse after treatment with antimonials, he received L-AmB. The starting dose of L-AmB was 10 mg/day (~0.15 mg/kg). Then dose escalation of the L-AmB for the patient is presented in Figure 2. On the 17th day of the treatment protocol when the accumulated dose reached 500 mg (10 mg/kg), PCR of the bone marrow aspirate of Leishmania was negative. The patient's blood cell counts (red blood cells, white blood cells, and platelets) increased gradually, and his spleen size decreased gradually. During the treatment, patient's liver function remained normal. There was no recurrence of VL at the 1-year follow-up visit. The patient's temperature and L-AmB dose were presented in Figure 2, and his basic information was summarized in Table 1.

amphotericin b (amb), case series, liposomal amphotericin b (l-amb), the low-dose l-amb therapy, visceral leishmaniasis (vl)

PMC8635719_03

Female

A 56-year-old woman presented with fever. Her symptoms weren't improved after 1 week of anti-infective treatment in a local hospital. Similar to case 2, she also had picked Zanthoxylum seeds in Hancheng 1 years ago, and she had a history of mosquito bites. She was healthy in the past. Her body weight was 50 kg. Physical examination revealed splenomegaly, mild lower extremity edema, and multiple skin petechiae. Blood cultures as well as tests for bacteria, fungi, tuberculosis, parasites, and brucellosis agglutination were all negative. The patient's laboratory results revealed pancytopenia and elevated liver enzyme levels (aspartate aminotransferase, 121 U/L; alanine aminotransferase, 36 U/L). Her PCT, CRP, and creatinine levels were 5.67 ng/mL, 89.7 mg/L, and 641 mumol/L, respectively. Computed tomography of the abdomen revealed homogeneous splenomegaly. Her bone marrow smear was negative for Leishmania. Conversely, antibodies against Leishmania were detected in peripheral blood, and PCR was positive for Leishmania. The patient was diagnosed with VL combined with acute renal impairment. Continuous renal replacement therapy (CRRT) was administered on days 2, 4, and 6 after admission, and this treatment resulted in significantly diminished creatinine levels. To avoid the aggravation of pre-existing renal injury, the low-dose therapy of L-AmB was initiated with a starting dose of 5mg (~ 0.10 mg/kg) on days 9-10 after admission. The L-AmB administration protocol is presented in Figure 3. During therapy, an increase of plasma creatinine levels was observed, peaking at 178 mumol/L on day 4 of treatment. Her creatinine level subsequently declined to 148 mumol/L on day 8 in the absence of CRRT. Thus, slow dose escalation appeared to prevent the further deterioration of renal function. The patient's creatinine further declined during maintenance therapy. Routine blood testing revealed gradual increase of red blood cell, white blood cell, and platelet counts. Her spleen size was gradually decreased, and her kidney function was gradually improved by therapy. The patient's liver function also gradually returned to normal during treatment. No relapse was observed during the 3- and 6-month follow-up visit. In addition, we observed complete recovery of her renal function at 6 months after discharge (urea, 5.66 mmol/L; creatinine, 75 umol/L).

amphotericin b (amb), case series, liposomal amphotericin b (l-amb), the low-dose l-amb therapy, visceral leishmaniasis (vl)

PMC8635719_04

Male

A 46-year-old man presented with a 3-week history of fever and pancytopenia. He had worked in coalmines in Hebei Province, Henan Province, and Shanxi Province for more than 10 years. There was negative past medical and past surgical history. His body weight was 70 kg. Physical examination suggested sporadic hemorrhagic spots on his skin of chest and back, palpable right sided cervical lymphadenopathy, and splenomegaly. Blood cultures as well as tests for bacteria, fungi, tuberculosis, parasites, and brucellosis agglutination were all negative. The laboratory examination revealed pancytopenia, coagulation abnormalities, and elevated liver enzyme levels. The patient's PCT and CRP levels were 0.99 ng/mL and 73.4 mg/L, respectively. Bone marrow biopsy disclosed hypocellular marrow with trilineage hematopoiesis and macrophages with microorganisms. The aspirate prominently contained hemophagocytic macrophages. Additional investigations identified elevated ferritin and soluble interleukin-2 receptor (sCD25) levels and absent natural killer (NK)-cell activity, supportive of hemophagocytic lymphohistiocytosis (HLH). Antibodies against Leishmania in peripheral blood and PCR were positive, confirming the diagnosis of VL. He was received intravenous gammaglobulin. The L-AmB protocol followed that presented in Figure 3. The initial dose was 10 mg (~ 0.14 mg/kg), and the maintenance dose was 70 mg (~1.0 mg/kg). The total accumulative dosage was 910 mg (13 mg/kg), which was close to the WHO-recommended dosage. The patient's liver enzymes (AST and ALT) were mild abnormal before the treatment. He received the low-dose L-AmB therapy in addition to liver-protecting treatment. His liver function gradually recovered and kidney function remained normal during the treatment. No complications occurred during treatment excluding hypokalaemia, which was corrected via potassium supplementation. The patient's blood routine parameters gradually normalized and spleen size gradually decreased during therapy. No VL recurrence was observed at the 6-month follow-up visit.

amphotericin b (amb), case series, liposomal amphotericin b (l-amb), the low-dose l-amb therapy, visceral leishmaniasis (vl)

PMC9062449_01

Male

A 79 year old man had a history of ascending aortic replacement and omentopexy for tuberculous ascending aortic aneurysm rupture when he was 66 years old (Fig. 1A). He was treated for tuberculosis after surgery and had no recurrence. Thirteen years later, a pseudoaneurysm was identified on a computed tomography (CT) scan performed on routine follow up examination. Enhanced CT revealed a pseudoaneurysm arising from the side branch stump of the prosthesis (Fig. 1C and D). The pseudoaneurysm was mushroom shaped, measured 30 mm in protrusion, and had a lateral diameter of 26 mm. A thrombus was found at the tip of the pseudoaneurysm. Plain CT performed one year earlier showed no pseudoaneurysm formation (Fig. 1B). There were no findings suggestive of infection, such as fever or an increased inflammatory response. Considering his medical history, it was discerned that it would be difficult to perform repeat sternotomy, and deployment of a stent graft was considered. The ascending aortic prosthesis had a diameter of 30 mm, and the length from the proximal anastomosis to the orifice of the brachiocephalic artery was 52.6 mm on the greater curvature and 50.9 mm on the lesser curvature. The distance from the coronary artery ostia to the pseudoaneurysm was 40.6 mm. It was feasible to use the shortest thoracic endograft, although the lesser curvature was slightly shorter. The operation was performed under general anaesthesia. Following systemic heparinisation, the right inguinal region was incised, and an 8 Fr sheath was inserted via the right femoral artery (FA). Under fluoroscopy, the aortic valve was crossed with a 0.035 inch guide wire with the support of a pigtail catheter, which was subsequently exchanged for a pre-shaped Safari 2 guidewire with an extra small curve (Boston Scientific, Natick, MA, USA). A 5 Fr sheath was inserted via the right femoral vein (FV) and the left FA percutaneously. A temporary pacing catheter was inserted into the right ventricle from the right FV. A pigtail catheter was placed in the non-coronary cusp from left FA for injection of contrast. A stent graft with a diameter of 34 mm and a length of 52 mm (Valiant Navion CoveredSeal stent graft system, Medtronic, Minneapolis, MN, USA) was implanted into the ascending aorta under 180 beats/min of rapid ventricular pacing. Touch up balloon dilatation was not performed, and final angiography showed that the endograft was well positioned with no endoleaks. The rapid pacing time was 40 seconds, and the operation time was 65 minutes. A post-operative CT scan confirmed complete exclusion of the pseudoaneurysm (Fig. 1E and F).

ascending aortic replacement, graft side branch, pseudoaneurysm, redo surgery, thoracic endovascular aortic repair

PMC3335511_01

Female

The couple came to our attention due to the positive first trimester screen. The woman is a healthy 25-year-old, G1P0. The first trimester nuchal translucency screen at 13 weeks was positive, and the couple decided to proceed with chorionic villus sampling. To rule out common chromosomal aneuploidies, fluorescence in situ hybridization (FISH) studies were performed using specific probes targeting chromosome 13, 18, 21, X, and Y (AneuVysion kit, Abbott Molecular Inc.), and the results were normal. The followup G-banded chromosome study revealed a reciprocal translocation involving the short arm of one chromosome 11 and the short arm of one chromosome 12 - 46,XY,t(11;12)(p14;p13.2) (Figure 1(a)), which appeared to be balanced. To determine whether this translocation was familial, chromosome studies were performed on both parents and the results were normal. Subsequent prenatal ultrasounds showed signs of a significant cardiac defect as well as mild bilateral dilatation of the renal pelvis. Followup fetal echocardiogram confirmed the complex congenital heart defect:left ventricular hypoplasia, ventricular septal defect, and mild tricuspid insufficiency. Given the presence of the de novo reciprocal translocation, it was suspected that a cryptic imbalance may be present. Array CGH study was therefore performed using the CytoChip ISCA 8 x 60 K v2.0 Oligonucleotide array platform (BlueGnome) and showed that there is significant copy number loss (5.48 Mb in size) on the long arm of chromosome 16 (q23.2-q24.1) from nucleotide 79,945,820 to 85,430,304 (NCBI 36/HG 18) (Figure 1(b)). This deletion was confirmed by FISH studies using a BAC probe RP11-625B13 mapped to 16q23.3 (Figure 1(c)) and was not related to the translocation breakpoints. FISH analysis was also performed on parental blood samples which showed a normal result. Of note, this large deletion on chromosome 16 is not detectable on karyotype (Figure 1(a)). The Database of Genomic Variants (DGV, NCBI 36/HG 18) is a useful tool to exclude benign CNVs. DGV revealed that there are no reported benign CNVs encompassing this deleted region, suggesting that it is not likely to be a benign change. This de novo deletion encompasses multiple genes including FOXF1, and two other related genes FOXC2 and FOXL1 (Figure 1(d)). Deletion in FOXF1 is associated with a lethal condition named alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV, OMIM no. 265380). Alveolar capillary dysplasia is characterized by abnormal development of the capillary vasculature around the alveoli leading to persistent pulmonary hypertension in the early postnatal period. Affected infants are usually born without any prior suspicion of lung malformation. However, most babies deteriorate rapidly, and many die of respiratory failure within the newborn period even with significant respiratory support. Other features of ACD/MPV include abnormal development of the cardiovascular, gastrointestinal, genitourinary, and musculoskeletal systems. A recent array CGH study demonstrated that alveolar capillary dysplasia is caused by the genomic deletion of the FOX gene cluster. It also suggests that the cardiovascular malformation in this disorder is caused by the haploinsufficiency for the neighboring FOXC2 and FOXL1 genes, as a patient with a downstream deletion encompassing just FOXC2 and FOXL1 exhibited cardiac defects without any respiratory complications. Therefore, this deletion is considered pathogenic and would explain the fetal cardiac anomalies seen on prenatal ultrasounds and fetal echocardiogram. The prognosis for this pregnancy is extremely poor with the presence of the lethal condition ACD in addition to the fetal cardiac anomalies. The previousy identified reciprocal translocation t(11;12) and this large deletion are most likely de novo events which occurred together within a single germ cell. Therefore, the recurrence risk will be low for future pregnancies. The majority of apparently balanced structural rearrangements are not associated with an abnormal phenotype. After the identification of such rearrangements, it is important to test the parents and determine whether it is inherited or de novo. Inherited rearrangements have reduced clinical concerns and are likely to be benign. However, de novo apparently balanced rearrangements predispose to a higher risk of a cryptic genomic imbalance at the breakpoints or somewhere else, which may be causative for the clinical phenotypes in the patients. Therefore, prenatal array CGH should be recommended in such circumstances for better clinical management. A 2-year boy was referred to the genetics clinic for assessment of his recurrent thrombocytopenia, short stature, and dysmorphic features. He was found to have isolated thrombocytopenia during acute illnesses which would resolve spontaneously with resolution of the intercurrent illness. Platelet count was below normal when well. Hematologic investigations included a normal peripheral blood smear, bone marrow aspirate and biopsy, and a normal immune workup. His past medical history was significant for vesicoureteral reflux, hypospadias, bilateral cryptorchidism, laryngomalacia, eczema, and constipation. He has mild fine motor and speech delays as well as behavioural issues including poor socialization, aggressive behaviour, and decreased attention. On physical examination at 6 years of age his growth parameters were all below the 3rd percentile. He had coarse hair, hypertelorism, epicanthal folds, short palpebral fissures, a depressed nasal root with a bulbous nasal tip, small teeth, low-set ears which were posteriorly angulated as well as short 5th fingers bilaterally with clinodactyly of the 5th digit on the left hand. Review of the family history revealed a younger brother who was small for age but was proportionate. He was nondysmorphic and had no other clinical concerns. Considering that he has a normal karyotype and his parents are small in stature, no further cytogenetic investigations (e.g., array CGH) were performed. Cytogenetic investigations in the patient showed a chromosome abnormality with additional satellites on the distal long arm of one chromosome 21 (46,XY,21qs), which was confirmed by FISH studies using an Acro-p probe (Abbott Molecular Inc.) (Figure 2(a)). To determine whether this abnormality was familial, chromosome studies were performed on both parents, and the results were normal. Further FISH studies demonstrated a deletion of the 21q subtelomere region (Figure 2(b)) with a diminished signal for the RUNX1 locus (Figure 2(c)), suggesting that one of the deletion breakpoints is located within the RUNX1 locus. Due to the clinical significance of haploinsufficiency for the RUNX1 gene (as discussed below), further investigation was undertaken to determine if the gene was completely deleted. Surprisingly, array CGH analysis using the Cytosure Syndrome Plus V2 2 x 105 k Oligonucleotide array platform (OGT) not only confirmed the complete deletion of the RUNX1 gene but it also revealed a complex chromosomal rearrangement of chromosome 21 with interspersed duplications (x3) and deletions (x2) (Figure 2(d)). The first and most proximal copy number variation (CNV) is a gain which encompasses a region of 1.1 Mb from nucleotide 23,449,744 to 24,557,710. DGV revealed there are no reported benign CNVs fully encompassing this duplicated region. However, there are no known genes within this region (by UCSC genome browser), suggesting that this duplicated region is of no clinical significance. The second CNV is a loss which encompasses 1.81 Mb from nucleotide 34,965,815 to 36,781,907 and includes the gene RUNX1 (Figure 2(e)). No reported benign CNVs have been found encompassing this loss (by DGV). Besides RUNX1 which will be discussed later, there is another disease-associated OMIM gene CLDN14, which is associated with a type of autosomal recessive deafness. Since there is no concerns about the patient's hearing, haploinsufficiency of CLDN14 has unknown clinical significance. The third CNV is a gain encompassing 0.42 Mb from nucleotide 37,847,805 to 38,276,148. There is no reported benign CNVs fully encompassing this gain (by DGV), and there is only one RefSeq gene KCNJ6 located within it (by UCSC genome browser). Duplication of KCNJ6 is of unknown clinical significance. The fourth CNV is also a gain of 4.1 Mb in size from nucleotide 40,917,977 to 45,022,823. Similar to the other two gains, there is no reported benign CNVs fully encompassing this region (by DGV). UCSC genome browser revealed several disease-associated OMIM genes (TMPRSS3, CBS, CRYAA, CSTB, AIRE, and PFKL). Mutations and/or deletions of these genes are associated with various diseases. However, extra copies of them are of unknown clinical significance. The fifth and most distal CNV is a terminal loss encompassing 1.82 Mb from nucleotide 45,096,184 to 46,920,235. DGV showed no reported benign CNVs fully encompassing this loss, and UCSC genome browser revealed several disease-associated OMIM genes (as follows). Biallelic loss-of-function mutations in ITGB2, COL18A1, FTCD, and PCNT2 cause leukocyte adhesion deficiency (OMIM no. 116920), Knobloch syndrome type I (OMIM no. 267750), formiminotransferase deficiency (OMIM no. 229100), and type II icrocephalic osteodysplastic primordial dwarfism (OMIM no. 210720) respectively. Whether haploinsufficiency of these genes is associated with any clinical significance remains unknown. Mutations in COL6A1 and COL6A2 cause two autosomal dominant muscular diseases: Bethlem myopathy (OMIM no. 158810) and Ullrich congenital muscular dystrophy (OMIM no. 254090). Haploinsufficiency of the two genes could explain the 5th finger clinodactyly and the delay motor development observed in the patient. Of note, none of the gains encompass the Down syndrome critical regions. Besides, there is no probe between the fourth and the fifth CNVs and after the distal end of the fifth CNV. RUNX1, deleted in the second CNV, is a hematopoietic transcription factor frequently involved in somatic or acquired chromosome translocations associated with leukemia. The constitutional mutations and deletions of RUNX1 are known to be associated with familial platelet disorder with propensity to acute myelogenous leukemia (FPD/AML, OMIM no. 601399). FPD/AML is an autosomal dominant disorder which is characterized by the prolonged bleeding time, mild-to-moderate thrombocytopenia with normal platelet size and morphology, with or without abnormal platelet aggregation in response to arachidonic acid. Predisposition to the development of myeloid malignancies is another feature, with 20-50% progressing into AML and myelodysplasia. A lower cancer risk has been reported in individuals found to be haploinsufficient for RUNX1 while partial deletions or missense mutations have been associated with a higher risk for hematologic malignancy. By using the array CGH analysis, we confirmed that the patient was haploinsufficient for RUNX1 and thus has a decreased risk for AML and myelodysplasia. Furthermore, the complex rearrangement of chromosome 21 most likely represents de novo events. Therefore, the recurrence risk will be low for future pregnancies in this family. This patient is the firstborn child to a healthy unrelated couple. At the time of birth the father and the mother's ages were 30 and 29, respectively. No anomalies were seen on the prenatal ultrasound, and the newborn was healthy. By nine months, the weight and length were at the 3rd percentile, while the head circumference remained at the 50th percentile. Developmental delay (delay in sitting, standing, and walking) was evident in the first year. At 16 months, severe expressive language delay was noted but receptive language was within normal limits. At 14 months, he had five seizures associated with fever and some focal signs. The patient was first seen at the genetics clinic at 20 months. No precise diagnosis had been made despite many investigations. The karyotype showed a normal male chromosome complement. Subtelomere FISH studies (TelVysion kit, Abbott Molecular Inc.) also showed a normal result. Other studies included UPD7, multiple biochemical tests, CT, brain MRI, skeletal survey, and thyroid studies which were all normal. At seven years nine months, the patient's height and weight were less then the 3rd percentile and head circumference remained at the 50th percentile. Now at the age of nine, he speaks intelligibly and in sentences. There are no behavior problems, no further seizures, and no sleep problems. He remains small despite a good appetite. His physical features demonstrate a relative macrocephaly with a prominent forehead, sparse hair and eyebrows, prominent ears which are low set, and cup-shaped, deep set eyes with esotropia, astigmatism, and possible congenital anomaly of the left optic disc (Figure 3(a)). Once the technology was developed locally, array CGH was performed on the peripheral blood of the patient using the CytoChip ISCA 8 x 60 K v2.0 Oligonucleotide array platform (BlueGnome). The array analysis identified two chromosomal abnormalities. The first one is a copy number loss of a 10.5 Mb region on the long arm of chromosome 4 (q13.2-q21.1) from nucleotide 67,133,352 to 77,615,947 (Figure 3(b)). According to DGV, there are no reported benign CNVs fully encompassing this large deletion. The clinical significance of the deletion will be discussed later. The second one is copy number gain of a 1.9 Mb region on the long arm of chromosome 6 (q24.3) from nucleotide 146,155,718 to 148,055,364 (NCBI 36/HG 18) (Figure 3(c)). DGV showed no reported benign CNVs fully encompassing this duplication, and UCSC genome browser revealed that there are no disease-associated OMIM genes within this region. In order to validate the array result, FISH studies were performed using a BAC probe RP11-135D10 mapping to the deleted region 4q13.2, a BAC probe RP11-1077K2 mapping to the duplicated region 6q24.3, two control probes on 4q25 (RP11-483A2) and on 6p21.33 (RP11-346K8) (RPC1-11 Human BAC library-CIHR Genome Resource Facility). Metaphase FISH confirmed the deletion at 4q13.2 and the duplication at 6q24.3. Interestingly, the third copy of 6q24.3 was located at 4q13 (Figures 3(d) and 3(e)). To further investigate whether this complex rearrangement is de novo or inherited, FISH studies were performed on the parental samples using the above 4 probes. The mother's result revealed a normal hybridization pattern with all probes hybridizing at the expected locations and with the expected copy number. The father's result, however, identified an abnormal hybridization pattern involving one chromosome 4 and one chromosome 6. The segment 4q13.2-q21.1 and the segment 6q24.3 are involved in a reciprocal insertional translocation which appears to be balanced (Figures 4(a) and 4(b)). Therefore, the patient's father has a four-break balanced complex rearrangement t(4;6)(q13.2q21.1;q24.3q24.3) which is not evident on the routine G-banded chromosomes. During the paternal meiosis, the der(4)t(4;6) and normal chromosome 6 segregated together and resulted in the chromosomal imbalances in this patient. The patient's clinical presentation is most likely due to the deletion and duplication of many genes involved in the imbalanced regions (Figures 3(f) and 3(g)). However, there is a limited genotype-phenotype correlation in terms of each gene involved. The 10.5 Mb deletion on chromosome 4 contains 8 disease-associated OMIM genes (GNRHR, MUC7, ENAM, SLC4A4, GC, ALB, AFP, and SCARB2). Among these, ENAM mutations are associated with amelogenesis imperfecta, type 1B (OMIM no. 104500) which is an inherited defect of dental enamel formation with autosomal dominance as the likely mode of inheritance. However, this patient has a full set of primary teeth with normal tooth shape and enamel but delayed secondary teeth erupting. Currently, it is unclear whether haploinsufficiency of ENAM is responsible for the delay in secondary teeth erupting. The 1.9 Mb duplication on chromosome 6 does not contain any disease-associated OMIM genes (UCSC genome browser), and its clinical significance remains unknown. Through combining array CGH and FISH techniques, we successfully identified the genomic imbalances responsible for the patient's clinical manifestation and further a familial chromosomal rearrangement which changes the predicted outcome and clinical management in this family. The father now carries a significant risk of having another abnormal liveborn with either der(4)t(4;6) as in the patient or der(6)t(4;6) (Figure 4(c)). Therefore, prenatal diagnosis will be offered for any future pregnancies. The patient has two siblings who are both normal. Cytogenetic testing will be available to determine the carrier status when they become adults.

PMC9065283_01

Male

A 14-year-old boy (weight: 90 kg; height: 175 cm; BMI: 29.39 kg/m2) was admitted to our hospital on 22 June 2020 with symptoms of yellow eyes and diarrhea for more than 20 days. The child had been treated with a Chinese patent cold medicine (that included acetaminophen) for an upper respiratory tract infection 30 days prior. He had never taken the medicine before, and during treatment, a maculopapular rash developed on the trunk. The local hospital's laboratory studies on June 4 showed a total bilirubin (TBil) of 277 mumol/L, direct bilirubin (DBIL) of 150.2 mumol/L, alanine aminotransferase (ALT) of 580 U/L, and aspartic acid aminotransferase (AST) of 320 U/L. On June 14, he was treated with methylprednisolone 40 mg/d intravenously for 3 days, and the rash improved. Liver function was noted to be aggravated 1 week later, and he was treated with prednisone acetate 20 mg orally every day from 22 June 2020, but his condition did not improve. He was allergic to penicillin, and there was no history of any significant disease in his family. Moderate jaundice of the skin and sclera was noted, and no cardiopulmonary abnormalities were found. A liver biopsy was performed on June 24, and pathological examinations were consistent with DILI (G3 S1) (Figure 1A). Pathological sections were sent to Renji Hospital, School of Medicine, Shanghai Jiao Tong University, for consultation, and after review, the diagnosis was autoimmune hepatitis (acute-severe). Mycophenolate mofetil (MMF) 750 mg/d (250 mg t.i.d.) orally began on 3 July 2020, and after 4 days, his TBil, PT, and INR levels had increased to 250.30 mumol/L, 23.2 s, and 2.12, respectively. Based on the laboratory studies and his condition, he had progressed to subacute liver failure (SALF). He was placed on the liver transplant list, and a complete pre-liver transplantation workup was performed. Prednisone acetate was changed to methylprednisolone 30 mg q12 h ivgtt on 9 July 2020, and hepatic encephalopathy was diagnosed on July 10. MMF was discontinued on July 11, and he was given intravenous gamma globulin 20 g/d, but there was no improvement in his condition after 5 days of treatment. He was given treatment with a non-bioartificial liver (NBAL) starting on July 21, and after 5 treatments (from July 21 to August 3, once every 3-4 days) in combination with integrative medical treatments including liver protection, plasma infusion, and human albumin, his symptoms improved. On 7 August 2020, the patient experienced sudden chills, shivering, and hyperpyrexia. Sputum culture revealed Candida albicans, and chest computed tomography (CT) showed multiple nodules in the lungs (Figures 2A,B). The 1,3-beta-D glucan test (G test) and galactomannan antigen detection test (GM test) were negative. Due to poor coagulation, tracheoscopy was not performed. Pulmonary candidiasis was diagnosed, and the patient's fever persisted after a week of treatment with fluconazole 400 mg/d ivgtt. A repeat sputum culture on 14 August 2020 revealed Aspergillus niger, resulting in a diagnosis of invasive pulmonary aspergillosis (IPA). Fluconazole was changed to voriconazole (loading dose on 18 August 2020 of 400 mg q12 h ivgtt, and maintenance dose of 200 mg q12 h ivgtt was started on D2. The regimen was adjusted according to the clinical situation and therapeutic drug monitoring (TDM) results), and his condition improved. His chest CT showed resolution of the lung lesions after 85 days of treatment, and voriconazole was discontinued on 10 November 2020. On 31 May 2021, laboratory studies revealed TBil, 11.9 mumol/L; ALT, 52 U/L; AST, 40 U/L; ALP, 204 U/L; and gamma-GT, 93 U/L. A repeat liver biopsy after 24 weeks of treatment was consistent with autoimmune-like phenomenon liver failure (G3 S3) (Figures 1B,C). A diagnosis was made according to the Roussel Uclaf Causality Assessment Method (RUCAM), and a probable diagnosis of autoimmune hepatitis was made based on 2008 International Autoimmune Hepatitis Group's (IAIHG) criteria: (1) DILI, cholestatic, acute, and RUCAM score calculated as 10 (highly likely); (2) IAIHG score 4, combined with liver pathology, the diagnosis of the teenager is drug-induced liver injury with autoimmune-like phenomenon (AL-DILI), drug-induced autoimmune hepatitis (DI-AIH) is not excluded.

chinese patent medicine, invasive pulmonary fungal infections (ipfi), autoimmune-like phenomena, case report, drug-induced liver failure, voriconazole (vcz)

PMC9065283_02

Female

A 17-year-old girl (weight: 53 kg; height: 160 cm; BMI: 20.70 kg/m2) was admitted to our hospital on 6 July 2020 complaining of dysphoria, fatigue, vomiting, and yellow eyes which began 9 days before admission. She had been treated with a Chinese patent medicine, QubaiBabuqi tablets (4 tablets t.i.d. for more than 3 months) for vitiligo before the onset of the symptoms. Physical examination showed severe jaundice of the skin and sclera, and localized whitish patches on her face. No cardiopulmonary abnormalities were noted. Laboratory studies on July 7 revealed: TBil, 439.60 mumol/L; DBil, 325.70 mumol/L; ALT, 1174 U/L; AST, 505 U/L; gamma-GT, 131 U/L; ALP, 166 U/L; PT, 44.5 s; prothrombin time activity (PTA), 16.00%; INR, 4.84; and blood ammonia, 258 mumol/L. A diagnosis of drug-induced acute liver failure was considered. The patient developed hepatic encephalopathy and frequent vomiting on day 4, and she was placed on the liver transplant waiting list. She was treated with dexamethasone (10 mg q.d. i.v., gradually decreased after 3 days), liver protection, and NBAL (from July 7 to July 20, once every 3-4 days), and her liver function rapidly improved. After 10 days in a comatose state, she regained consciousness. She continued to have an intermittent low-grade fever on 24 July 2020, and no cough or other symptoms. Her TBil level had increased to 388 mumol/L, and the white blood cell (WBC) count was 12.13 x 109/L with 83.50% neutrophils. Her chest CT scan showed multiple nodules in both lungs on July 26 (Figures 3A,B), and IFI was diagnosed. A loading dose of caspofungin of 70 mg q.d. ivgtt was given on the first day, and then it was continued at a dose of 35 mg/d ivgtt for 23 days. However, a repeat chest CT showed an increase in the number of lung lesions and the presence of an air crescent sign (Figures 3C,D). Bronchoalveolar lavage fluid (BALF), G test, GM test, and next-generation sequencing (NGS) were all negative; however, based on her history and chest CT findings, a diagnosis of IPA was highly likely. Caspofungin was changed to voriconazole (loading dose on D1 of 6 mg/kg daily q12 h ivgtt, maintenance dose of 4 mg/kg q12 h orally was started on D2) on 19 August 2020, and her liver function gradually improved. A liver biopsy on 25 August 2020 was consistent with DILI (G 3-4 S 3-4) (Figures 4A,B). She was discharged on oral voriconazole (250 mg, q12 h), methylprednisolone (4 mg, q.d.), and other medications. A second liver biopsy after 10 weeks revealed an autoimmune-like phenomena hepatitis (G 1-2 S 2-3) (Figures 4C,D). A liver biopsy was performed, and ink staining, periodic acid-Schiff staining, hexamine silver staining, acid-fast staining, and NGS of liver tissue were negative. A diagnosis of DILI was made according to the RUCAM and 2008 IAIHG criteria: (1) DILI, hepatocellular damage-type, acute, RUCAM score calculated as 9 (highly likely); (2) IAIHG score 4, the diagnosis of DILI with autoimmune-like phenomena. In order to confirm the diagnosis and efficacy, we performed a third liver biopsy a year later (12 August 2021). The liver histopathology indicated chronic hepatitis (G 1 S 2) (Figures 4E,F), which was significantly improved compared with the previous two. No autoimmune-like phenomena were observed. Therefore, we have discontinued glucocorticoids on 18 August 2021. After 406 days of voriconazole treatment, the pulmonary nodules were completely absorbed. In both patients, serological studies for hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis E virus (HEV), and human immunodeficiency virus (HIV) were negative. Laboratory studies for cytomegalovirus nucleic acid (CMV-DNA), Epstein-Barr virus nucleic acid (EBV-DNA), and herpes simplex virus (HSV) IgM antibody were negative. Serum copper, ceruloplasmin, iron, and ferritin levels were normal. Tests of thyroid function and for genetic metabolic liver diseases were normal. Ultrasound scans of the hepatobiliary system did not reveal any abnormalities. MRI plain scan, enhanced MRI scan, magnetic resonance cholangiopancreatography (MRCP), and diffusion-weighted imaging (DWI) of the liver indicated a diffuse liver injury, and no bile duct dilatation was observed on MRCP. Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), anti-liver and kidney microsomal type 1 antibody (LKM1), anti-hepatocyte cytoplasmic type 1 antibody (LC1), anti-soluble liver antigen antibody (SLA) and immunoglobulin G (IgG), gamma-globulin, G test, GM test, blood cultures, and Cryptococcus capsular antigen tests were performed several times during the course of each patient's disease, and all tests were negative. In both patients, after voriconazole reached a steady state, that is, in the morning of the 4th day or after adjusting the dose for 5 days, in the morning of the 6th day, 30-60 min before fasting medication, the contralateral venous blood was collected to detect the concentration of voriconazole valley, and the therapeutic drug monitoring (TDM) of voriconazole was carried out. The regimen was adjusted according to the clinical situation and voriconazole TDM results (Table 1). The liver pathological examination results were read by two pathologists.

chinese patent medicine, invasive pulmonary fungal infections (ipfi), autoimmune-like phenomena, case report, drug-induced liver failure, voriconazole (vcz)

PMC7661936_01

Male

A previously healthy 8-month-old boy presented to an outside hospital with high fever and cough since weeks. Because of C-reactive protein test showing elevated level and unspecific infiltration detected on chest x-ray, the child had been administered antibiotic therapy, consisting of beta-lactams and glycopeptides. Beside reduced levels of hemoglobin (5.6-7.8 mmol/L; normal range: 6.3-7.8 mmol/L) and platelets (90-125 x 109/L; normal range: 206.000-445.000 x 109/L), laboratory results were otherwise unremarkable. Results of infectious work-up [blood, cerebral spinal fluid and urine cultures, as well as polymerase chain reaction (PCR) for respiratory viruses and pathogens for atypical pneumonia] remained negative. Because of the persisting fever, the child was transferred to three other hospitals, recently to a tertiary care hospital, where he was evaluated for immunodeficiency. Bronchoscopy with bronchoalveolar lavage was carried out under general anesthesia with endotracheal intubation because of declining general condition. Since respiratory functions had deteriorated dramatically, the child was transferred to our institution for ECMO-support (at 4 wk after first presentation). No definite diagnosis existed to that time. Medical history taking with the parents revealed an uneventful pregnancy and birth in Germany. The parents originated from the Balkan peninsula. The patient was the first child and the parents claimed to be healthy. The child was unconscious due to deep analgo-sedation (Glasgow coma score of 3/15). The vesical temperature was 40.3 C, heart rate was 142 bpm, blood pressure was 82/44 mmHg (under continuous infusion with epinephrine 2.0 mcg/kg/min), weight was 7.9 kg (15th percentile, World Health Organization scale), length was 70 cm (30th percentile, World Health Organization scale), SpO2 was 70%. The pressure-controlled ventilation maintained peak inspiratory pressure of 60 cm H2O, positive end-expiratory pressure of 12 cm H2O, FiO2 of 1.0, frequency of 40 pm, and Horovitz quotient of 30. The spleen was 5 cm and the liver 6 cm, palpable in midclavicular lines. Our first clinical impression was that of a systemic infection with severe acute respiratory failure and unexplained lymphoproliferation. Blood analysis revealed pancytopenia (hemoglobin: 4.3 mmol/L; leucocytes: 2.600 x 109/L; neutrophils: 800 x 109/L; platelets: 32.000 x 109/L), elevated levels of C-reactive protein (194 mg/L; normal range: <5 mg/L), ferritin (1,020 mug/L; normal range: 14-103 mug/L), triglycerides (3.58 mmol/L normal range: 0.4-1.6mmol/L), and soluble interleukin-2 receptor (30,247 U/mL; normal range: 158-623 U/mL). Analyses of arterial blood gases showed pH of 6.9, pCO2 of 93 mmHg, pO2 of 30 mmHg, and base-excess of -11.1 mmol/L. Initial imaging with x-ray showed a "white lung" (Figure 1A) and with ultrasound showed hepato- and splenomegaly. Further imaging work-up, with either computed tomography or magnetic resonance imaging, could not be performed because of the instable situation. Bone marrow biopsy showed a distinct hemophagocytosis upon cytologic evaluation (Figure 1B). The lymphocyte population consisted of CD3+ of 1,358 x 109/L, CD4+ of 1,119 x 109/L, CD8+ of 2,017 x 109/L, CD19+ of 487 x 109/L, and CD56+ of 2 x 109/L. Further immunological studies by fluorescence-activated cell sorting revealed normal fresh degranulation of natural killer cells (14.7%; normal: >10%), and normal expressions of perforin, CD27, SAP, and XIAP on d 7. Microscopy of the patient's hairs showed no anomaly of pigmentation, as would be found in children with Griscelli syndrome. The patient was further evaluated with cultures of blood, urine, tracheal secretion, and stool. Examinations for ova or parasites provided negative results. All serological and PCR tests for viruses (Epstein-Barr, human immunodeficiency, cytomegaly, hanta, adeno, influenza a/b, respiratory syncytial, herpes simplex, corona, metapneumonia, parvo B19, parainfluenza, rhino, and enterovirus) were negative. Also negative were results of testing for leishmania, legionella, aspergillus, Pneumocystis jirovecii, Hemophilus influenza b, and pneumococcus-PCR/immunoglobulins (IgG/IgM). All tumors markers alpha-fetoprotein (2.5 IU/mL), neuron-specific enolase (10 ng/mL), ss-hCG (0.2 mIU/mL), homovanillic acid (10 mg/g creatinine), and vanillylmandelic acid (18 mg/g creatinine) were unrevealing. A positive result from the interferon-gamma release assay (IGRA) was the first indication for possible TBC infection on d 12. However, microscopy for acid-fast bacilli (Ziehl-Neelsen stain) as well as PCR testing for TBC in the first bronchoalveolar lavage were both negative on d 6. Further along in the clinical course, PCR for TBC became positive and the bronchoalveolar lavage fluid culture returned positive results on d 40. The identified strain of M. tuberculosis was found to be sensitive to rifampicin, ethambutol, pyrazinamide, and isoniazid, retrospectively. After discontinuation of the ECMO therapy, further imaging was performed. Magnetic resonance imaging of the central nervous system showed a miliary TBC and a computed tomography scan of the thorax revealed a calcified, round lesion consistent with TBC (Figures 1C,D). Normal functional assays virtually excluded hereditary forms of HLH. A secondary form was therefore recommended to be considered, as was a complete diagnostic re-evaluation (infection, tumor, leukemia). The etoposide (VP-16, according to the HLH-04 protocol) was terminated after three doses administered according the HLH protocol. The child presented with severe hypoxia, and respiratory and metabolic acidosis, despite pressure-controlled ventilation and attempts of high frequency oscillation ventilation, both at high inspiratory oxygen level. The decision was therefore made to start veno-venous ECMO immediately after admission of the patient (see Figure 2). A 16F Avalon double-lumen cannula (Getinge AB, Gothenburg, Sweden) was inserted in the right internal jugular vein. A blood flow of 120 mL/kg/min was established, which was sufficient to achieve a PaO2 between 85 and 95 mmHg, and a PaCO2 between 40 and 50 mmHg. Ventilator parameters were reduced as much as possible (peak inspiratory pressure of 16 cm H2O, positive end-expiratory pressure of 6 cm H2O, and FiO2 of 0.4) to guarantee "lung protection" as well as a transcutaneous O2-saturation of >90%. After initiation of the ECMO catecholamine support with epinephrine and noradrenaline (maximum dosage of 0.18 mug/kg/min) was progressively weaned (until d 12). Because of the fulfillment of criteria for HLH therapy, the HLH-94 protocol was initiated. The boy was treated with dexamethasone at 10 mg/m2 (d 2 to d 12, and reduced/discontinued at d 24) and etoposide at 150 mg/m2 (three doses in total, given on d 2 through d 7 and being stopped upon normal results from the T cell degranulation assay on d 7). Additionally, intravenous immunoglobulin (0.5 g/kg body weight, given on d 2 through d 15) was administered. With the suspicion of TBC, on d 12 (positive IRGA) a 4-fold tuberculostatic therapy was started, consisting of rifampicin at 1 x 15 mg/kg body weight/d, ethambutol at 1 x 30 mg/kg body weight/d, pyrazinamide at 1 x 30 mg/kg body weight/d, and isoniazid 1 x 10 mg/kg body weight/d). At 10 d after the start of tuberculostatic therapy, there was improvement in the general condition (stable cardiorespiratory situation, rising tidal volumes). The C-reactive protein level declined from 194 mg/L to 5 mg/L on d 28, followed by the soluble interleukin-2 receptor from 30,247 U/mL to 931 U/mL on d 40. After full lung recovery, the ECMO support was able to be discontinued on d 28. The child was extubated on d 33. The boy survived this critical condition. After discharge on d 66, the child was re-evaluated on d 98, d 460, and d 745. During that time, the boy developed frontotemporal hygroma (left side > right side) with spontaneous resolution. Neurological assessment during the follow-up period revealed a mild retardation of development (speech and fine motor skills) and moderate aggressive behavior with beginning improvement.

ecmo, case report, extracorporeal membrane oxygenation, hemophagocytic lymphohistiocytosis, infant, lung failure, tuberculosis

PMC8378191_01

Male

On 26 November 2019, a 48-year-old, HIV-negative man presented to the Primary Health Care Facility in Johannesburg, South Africa, with symptoms suspicious of TB. His sputum was collected and sent for GeneXpert testing. This confirmed a diagnosis of rifampicin-sensitive TB. On 28 November 2019 he was referred to the Clinical HIV Research Unit for screening for an observational study called TB Sequel. The TB Sequel project's aim is: [T]o advance the understanding of the clinical, microbiologic, environmental and host immune factors affecting the long-term sequelae of pulmonary TB; to determine occurrence of reversible and irreversible costs and socioeconomic consequences for TB patients and health care systems; and to facilitate novel interventions to restore and preserve overall health, well-being and financial protection in patients with TB. At the screening visit, the patient complained of a 3 month history of cough, fatigue, night sweats, body weakness, loss of appetite, loss of weight, chest pain, shortness of breath, nausea and vomiting. He also complained of an intermittent fever since February 2019. He had no significant family history of malignancy. On examination, he was generally wasted but apyrexial and the rest of his vital signs were normal. He had cervical and axillary lymphadenopathy and a hepatomegaly (without splenomegaly). His chest examination revealed scattered lung crackles. He was managed by his Primary Health Care Facility according to the National Tuberculosis Management Guidelines and was thus started on treatment for rifampicin-sensitive TB, rifafour (rifampicin, isoniazid, pyrazinamide and ethambutol), pyridoxine and vitamin BCO on the same day. He was enrolled onto the TB Sequel study on 02 December 2019 and routine baseline investigations were performed. His chest X-ray showed bilateral infiltrates, left hilar lymphadenopathy and a right pleural effusion, with approximately 80% of his lungs affected. His baseline bloods, along with repeated blood results (see Table 1), showed abnormalities in the full blood count, specifically of the white blood cells. His blood results were suggestive of a lymphoproliferative disorder which required further workup. The patient was admitted to a tertiary public hospital in Johannesburg on 11 December 2019 for further investigation. His full blood count, differential count and peripheral smear upon admission showed a profound absolute lymphocytosis, comprising predominantly small mature forms, with occasional smudge cells and large granular lymphocytes. Approximately 3% of these were larger more primitive cells with features in keeping with prolymphocytes. No increase in blasts was noted. No other secondary causes for eosinophilia and thrombocytosis were discovered and both were regarded as reactive in nature. His lactate dehydrogenase (LDH) from 12 December 2019 was 262 U/L (reference range: 100-190 U/L). His renal function and liver function tests were normal. A bone marrow aspirate and trephine biopsy was performed on 12 December 2019 and referred to the National Health Laboratory Service for routine analysis. The report described a hypercellular bone marrow with extensive diffuse infiltration by small mature lymphocytes. Fluorescence in situ hybridisation (FISH) performed on the bone marrow aspirate sample confirmed that all screened cells were negative for (1) deletion of the tumour protein p53 (TP53) and ATM serine/threonine kinase (ATM) genes, (2) deletion of the long arm of chromosome 13 (13q14.3) and (3) trisomy of chromosome 12. Flow cytometry immunophenotyping performed on the bone marrow aspirate showed a population ('81%) of clonal (kappa light chain restricted) B-cells, which expressed the following markers: CD19+, CD5+/++, CD20++, CD23 dim/+, CD45+/++, CD22+, CD38 and possible dim FMC7. CD10 was not expressed. These morphological and immunophenotypical findings were in line with a diagnosis of CLL. A staging computed tomography (CT) scan was performed on 18 December 2019, which showed an extensive bilateral tree-in-bud pattern, and a right-sided pleural effusion, both are suggestive of active pulmonary TB. Signs of pulmonary artery hypertension as well as supraclavicular, mediastinal and intra-abdominal lymphadenopathy were also noted. Furthermore, a thrombus in the inferior vena cava (IVC) was seen, starting from the level of the renal veins and extending distally. Although a hepatomegaly was found on clinical examination, the CT scan confirmed a normal liver and spleen, with no focal lesions. An echocardiogram was performed on 19 December 2019, which was normal. Based on all of the above results, the patient was classified as stage I under the Rai classification and stage B using the Binet classification of CLL. He had both good (Rai I) and bad (male sex, Binet B, diffuse bone marrow appearance, CD38 expression and raised LDH) prognostic indicators, which would affect his management. The patient was initially anticoagulated and monitored by the tertiary public hospital's coagulation clinic for the IVC thrombus and subsequently referred to the oncology unit at Charlotte Maxeke Johannesburg Academic Hospital for further management of his CLL. As cure is rare in CLL, treatment is mainly symptomatic and the risk-benefit analysis of available treatments should be considered on a case-by-case basis. Ethical approval to conduct the study was obtained from the Human Research Ethics Committee (Medical) of the University of the Witwatersrand (Reference number: R14/49, Protocol No: M1911204) on 29 January 2020. Informed consent for publication of this case report was obtained from the patient.

chronic lymphocytic leukaemia, haematology, infectious diseases, leukaemia, tuberculosis

PMC6078583_01

Female

A 54-year-old nulliparous postmenopausal Indian woman presented to the gynecologic outpatient department of a tertiary referral center, being referred from a primary health clinic, with a complaint of discharge per vaginum for 2 months. It was serous in nature, non-foul smelling, and not associated with pruritus. It was not associated with bleeding or postcoital spotting. She was a known hypertensive on regular treatment, on oral amlodipine and clonidine, for 7 years. There was no history of loss of appetite; however, there was a history of weight loss. The patient did not have any other constitutional symptoms like cough or fever. The vitals were within normal limits. On per vaginum examination, the perineum appeared unremarkable. Palpation revealed no cystocoele or prolapse of the uterus. Per speculum examination (using a Graves speculum) showed a normal vagina with an ulcerated growth over the anterior lip of the cervix, obliterating the external os. A Papanicolaou smear was then taken using an Ayres spatula. On palpation, the same growth was felt, which bled on touch. However, a bimanual examination revealed a normal-sized uterus, and the fornices were free. The parametria also appeared free. A clinical diagnosis of carcinoma of cervix was made, considering the age. A pap smear taken was sent to the pathology laboratory attached to the tertiary referral center. Subsequently, a cervical biopsy was also done to rule out malignancy. On microscopy, the vaginal smear studied was partly air-dried and showed superficial, intermediate, and parabasal cells along with a few epithelioid cell clusters, numerous Langhans giant cells (Figures 1, 2), lymphocytes, plasma cells, and histiocytes against a background of focal patchy necrosis. A diagnosis of granulomatous cervicitis, probably TB was made and a biopsy requested for confirmation. The histological examination of the cervical biopsy showed tissue bits with ulcerated mucosa overlying tuberculous granulation tissue, which was composed of well-formed granulomas with epithelioid histiocytes, Langhans, and foreign body giant cells with focal necrosis. A modified Gabbett staining for acid fast bacilli showed numerous tubercle bacilli, especially within the giant cells (Figure 3). The chest x-ray showed fibrous areas, suggestive of old healed TB. The patient was subsequently given antituberculous treatment for 6 months (ethambutol 1 g; isoniazid 300 mg; pyrazinamide 1.5 g; and rifampicin 600 mg for 2 months and isoniazid 300 mg and rifampicin 600 mg for 4 months) following which she was asymptomatic. The follow-up pelvic examination showed a normal cervix on per speculum examination, and the ultrasound scan also showed a uterus of normal size with an endometrium of 1.5 mm thickness. However, 2 months after completing the treatment, she developed cough and breathlessness. The chest x-ray showed a minimal right-sided pleural effusion with underlying opacity, suggestive of an old healed TB or an active lesion. This was followed by a CT, which revealed a mass/consolidation in the right lower lobe. CT-guided fine-needle aspiration cytology from the lesion was planned to differentiate an active pulmonary TB from malignancy, but the patient went against medical advice and did not return for the follow-up.

PMC10330784_01

Female

A 63-year-old female housewife from Narayanganj district of Dhaka division in Bangladesh attended the outpatient department of a local private hospital on January 2022. Her main complaints were dysuria, fever with chills, lethargy and mild lower abdominal pain for 6 days. She had a history of hypertension and T2D for 4 years. She was on medication for hypertension [Bisoprolol Hemifumarate (5 mg)] and diabetes [Linagliptin plus Metformin Hydrochloride (2.5 mg plus 500 mg)]. On consultation, the patient was found febrile with a 101 F body temperature, and her pulse, respiratory rate, blood pressure and oxygen saturation were detected to be 109 pulses/min, 20 breaths/min, 128/84 mmHg, and 97% on room air, respectively. She did not have a recent history of a hospital visit, travel, contact with the pet, or ingesting raw food. The patient provided a blood sample for a laboratory investigation. An initial hematological assessment of the blood specimen demonstrated that the patient's hemoglobin was 10.3 g/dl and the erythrocyte sedimentation rate was 50 mm/h. In particular, the number of leukocytes was 13,000 cells/mm3, with 81% neutrophils, 26% lymphocytes, 3% eosinophils, and 2% monocytes. The platelet counts, as well as other blood cell variables, were normal. Blood biochemistry analysis showed random blood glucose raised at 10.3 mmol/L and C-reactive protein elevated at 85 mg/ml with normal hepatorenal function parameters. A COVID-19 screening test was done per the hospital requirements and a negative result was obtained. Preliminarily, it was suspected to be a case of UTI. Therefore, the patient was empirically treated with intravenous ceftriaxone (500 mg/8 h) for 7 days. However, she did not respond to the treatment and symptoms like increased frequency of painful and burning micturition, fever, and abdominal pain continued while she was admitted to the hospital (Table 1). Therefore, a clean catch midstream urine sample was obtained and sent to the laboratory for routine microscopic examination and microbiological investigation. The urine sample was turbid and revealed the presence of 20 to 30 pus cells per high-power field. The urine sample was inoculated onto 5% sheep blood agar, MacConkey's agar, and CHROMagar Orientation agar plates and incubated the plates at 37 C in an aerobic environment. After overnight incubation, a significant (>105 CFU/ml) growth of single-type colonies was observed on all culture plates. The bacteria produced 2-3mm, circular, raised, mucoid, pale pink color colonies on MacConkey agar, gray-white colonies on a blood agar plate with gamma hemolysis and metallic blue pigmented colonies on a CHROMagar Orientation plate. Based on the colony morphology on MacConkey and CHROMagar Orientation agar plates, we suspected it would be either Klebsiella or Enterobacter species. Gram staining revealed gram-negative bacilli. Further, biochemical characterization was carried out as described previously. The bacterium was finally identified as K. aerogenes based on its gram-negative morphology, motility, utilization of citrate, decarboxylation of Ornithine, reduction of nitrate and fermentation of glucose and lactose with the production of acid and gas (Table 2). The strain was further tested with the API 20E test (BioMerieux, France), and it confirmed the strain as Enterobacter aerogenes with 96% certainty. Antibiotic susceptibility testing followed the Kirby-Bauer disc diffusion method using 21 antibiotic disks representing 11 classes. The K. aerogenes (RD99) strain was resistant to most antibiotic classes tested, including aminoglycosides, beta-Lactams (penicillin), beta lactams (cephalosporins), amphenicol, fluoroquinolones, folate drugs, tetracyclines, phosphonic acid, and glycycline. However, the strain was susceptible to carbapenems and polymyxins (Table 3). The K. aerogenes (RD99) strain was further subjected to bacterial whole-genome sequencing (WGS) using an Illumina NextSeq 500 platform at icddr,b using an established protocol. The raw genome sequence data is publicly available at GenBank with accession number: JAQQRH000000000. The quality control, assembly of sequenced data into draft genomes and annotation were performed using established bioinformatic pipelines. The FastANI tool was used for taxonomy identification, and K. aerogenes was confirmed with a 98.81 Average Nucleotide Identity (ANI) value. The in-silico analysis predicted sequence types (ST) and clonal complex using the PubMLST database (https://pubmlst.org/kaerogenes/), capsule polysaccharides using the Kaptive database, and plasmid replicons using Plasmid Finder 2.1. The virulence genes were identified using Virulence Factor Database (VFDB). The resistance genes were identified by ABRicate tool v1.0.1 (https://github.com/tseemann/abricate) using Resfinder, and NCBI AMR Finder database. Mobile genetic elements using Mobile Element Finder v1.0.3, point mutations using PointFinder software, prophage using PHASTER, and integrons using IntegronFinder 2.0. Default parameters were applied for all software unless otherwise mentioned. We aligned six K. aerogenes isolates (including RD99), 15 publicly available Klebsiella species, and 5 Enterobacter species genomes with K. pneumoniae ATCC 25955 as reference genome using Snippy v4.4.0 and Gubbins v3.2 5. A phylogenetic tree was constructed using RaxML v8.2.12, employing the Generalized Time Reversible substitution model and the GAMMA distribution for rate heterogeneity. The tree was visualized using iTOL. The K. aerogenes strain (RD99) genome sequence is 5,490,860 bp with a GC content of 54.8%. It comprises 73 contigs, having 5,348 genes, of which 5,224 coding DNA sequences (CDSs) and 124 RNAs. In silico profiling revealed that RD99 is a K. aerogenes strain and belonged to ST4 and the CC1 clonal complex group. More than 60% (108/175) of the reference virulence genes were detected in the RD99 strain. It harbored the fimA-K operon, involved in adherence to human mucosal or epithelial surfaces, iutA, basG, ent, fep, and iro, which encodes aerobactin, acinetobactin, enterobactin and salmochelin siderophores, rcsAB, regulators of mucoid phenotype A. We also found SenB, an intrinsic gene encoding toxin (Table 4). A total of 10 prophage elements were detected, including 3 intact, 5 incomplete and 2 questionable phages and a Class 1 integron was identified. The strain RD99 harbored 17 antibiotic resistance genes that included aminoglycosides resistance genes aph(3')-Ib, aph(6)-Id, aac(3)-Ile, aac(6')-Ib-cr, beta-Lactams resistance genes, blaTEM - 1B, blaCTX - M-15, blaOXA - 1, blaampC, folate pathway antagonists resistance genes, dfrA14, sul2, plasmid-mediated fluoroquinolones resistance genes, oqxA, oqxB, amphenicol resistance gene catB3, fosfomycin resistance gene fosA, and tetracyclines resistance gene tet(D). The efflux pumps AcrAB-associated genes acrA and acrB were also detected in this strain that would mediate tigecycline resistance. The genes blaampC and fosA were located on the chromosome. Other resistance genes were located on plasmids, including blaTEM - 1B, blaCTX - M-15, and blaOXA - 1. We also identified the TN2 transposon element linked with the blaTEM - 1B gene. In addition, we identified amino acid substitutions at codon positions S83I in gyrA and S80I in parC. We also found mutations in ompK36 gene. No mutations were detected in ompK35 and ompK37 genes. In agreement with the phenotypic results, we did not detect any genes conferring resistance to polymyxins and carbapenem antibiotics. We identified five plasmid replicons in RD99 genome, which were Col440I, IncFIB(K), IncFII(K), IncN, IncR (Table 2). The strain RD99 demonstrated OL102 and KL186 antigens. We conveyed the results of the above analysis, particularly its phenotypic and genotypic features, to the physician. Based on this, the therapy course was changed to meropenem (500 mg/8 h) for 14 days. After 8 days of effective antibiotic treatment and appropriate management of diabetes, the patient became afebrile with no complaints of dysuria and abdominal pain. She was discharged from the hospital and advised to complete the course of antibiotics to avoid the recurrence of the infection. After 14th day the patient recovered completely and demonstrated a negative urine and blood culture. A monthly urine culture was advised for 3 months (one urine CS/month) to assess the efficacy of treatment and the recurrence of infection. All monthly follow-ups (for 3 months) of urine culture and sensitivity tests were negative, and the patient did not experience infection recurrence.

bangladesh, esbls (extended spectrum β-lactamases), klebsiella aerogenes, community-acquired urinary tract infection, extensive drug resistance (xdr), type 2 diabetes mellitus

PMC3934770_01

Female

On June 5, 2012, a 76-year-old female patient was transported to the Intensive Care Unit of Mehr General Hospital (Tehran, Iran) via ambulance. She had a 3-week history of progressive somnolence, confusion, agitation, symptoms of depersonalization, and visual hallucinations. Her disorder began 12 weeks prior to her current admission, with daily and repeated short, sharp, lancinating, electric shock-like pain involving the left lower division of the fifth cranial nerve. She was taken to a local hospital in another city, where she underwent neurological evaluation by magnetic resonance imaging (MRI) and electroencephalography (EEG), with normal results. The patient was instructed to take 200 mg carbamazepine 3 times a day, which partially relieved her pain episodes. Eight weeks later, and following attacks of nocturnal hallucinations, a neurologist prescribed 5 mg olanzapine to be taken each night. However, her mental and psychiatric state deteriorated, and she was transferred to Mehr General Hospital. On physical examination, the patient was afebrile. Scars from a coronary artery bypass surgery performed in 2008 were present on her anterior chest wall. Her lungs were clear, and no lymphadenopathy or organomegaly was detected. Neurological evaluation revealed an awake, agitated, confused woman with garbled and incoherent speech. She was easily distracted by irrelevant stimuli and could not sustain attention. No carotid bruit or stiff neck was detected. Cranial nerves were grossly normal, and no sensory or motor abnormalities were detected in the fifth cranial nerve. Corneal, orbicularis oculi, and sneeze reflexes were intact. Her motor power was 5/5 in all 4 extremities, her deep tendon reflexes were 2/4 in the arms and 1/4 in the legs, she had normal flexor plantar responses, and no abnormalities were seen in gait or coordination. Brain MRI, MR angiography, and MR venography were normal. EEG showed moderately diffuse slowing (fig. 1). A lumbar puncture was performed, and the results of the cerebrospinal fluid analysis are shown in table 1. To avoid any possible treatable diagnosis, intravenous phenytoin and acyclovir were started, but acyclovir was stopped 5 days later when the final diagnosis was achieved. Quetiapine was administered to keep the patient calm. Blood tests showed an elevated erythrocyte sedimentation rate (40 mm after 1 h; normal: <20 mm) with normal complete blood count, and low hemoglobin (10.6 mg/dl; normal: 12-16 mg/dl). Liver and kidney function tests and blood sugar levels were normal. Immunologic tests showed negative anti-Ro, anti-nuclear, and anti-neutrophil cytoplasmic antibodies. Serum protein electrophoresis and angiotensin-converting enzyme levels were normal. Broad serological screening assays for infectious conditions, including HIV, herpes simplex virus 1 and 2, hepatitis, Lyme disease, syphilis, and tuberculosis using the intermediate-strength purified protein derivative skin test, were negative. Tumor markers, including carbohydrate antigen (CA)-125, CA-19.9, CA-15.3, CA-242, carcinoembryonic antigen, serum alpha-fetoprotein, and anti-Ri and anti-Yo antibodies were not detected, but anti-Hu antibodies were present in the serum, as visualized by dot blot and indirect immunofluorescence techniques. To localize the suspected malignancy, the patient underwent computed tomography scans of the chest and abdomen, which disclosed a large mass in the left ovary (fig. 2). She underwent surgery, and a 20-cm ovarian intestinal-type mucinous tumor (fig. 3) was removed. After surgery, the patient recovered quickly. After 2 weeks, she was alert and oriented with normal speech. Her second EEG at this stage was normal (fig. 4). Two months after the operation, the patient was pain-free, and her carbamazepine and phenytoin were gradually discontinued. At her last follow-up visit in March 2013, the patient was well and free of symptoms.

anti-hu, ovarian tumor, paraneoplastic syndrome, trigeminal neuralgia

PMC9894099_01

Female

An 83-year-old woman presented to the emergency department with a seven-day history of productive cough with dark sputum, dyspnea on exertion, symmetrical leg swelling, and left pleuritic chest pain. She had a history of pulmonary tuberculosis (PT) at the age of 15 years, and at that time, she had undergone several procedures that she could not recall. She had not been treated with antimycobacterial antibiotics. She also had hypertension and an ischemic stroke with residual memory deficits. She had recently been submitted to an echocardiogram, which had shown a non-dilated left ventricle, septum hypertrophy, and good systolic function, with no valvular dysfunction. On physical examination, her oxygen saturation was 95% on room air and her heart rate was 105 beats per minute. Auscultation revealed diminished lung sounds on the left posterior hemithorax, where a long thoracic scar was observed. Fine crackles could also be heard throughout the lungs, and mild pitting edema was present on both feet. Her blood workup was relevant for elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) of 839 pg/mL (normal value: <125 pg/mL), and slightly elevated reactive C-reactive protein of 6.3 mg/dL. No changes in blood count, or kidney or liver function were present (Table 1). Her chest X-ray revealed an oval-shaped peripherally calcified mass on her left apex compatible with oleothorax (Figures 1, 2), and a linear calcified image (Figure 1) was seen on the internal right lateral thorax wall, consistent with calcified pleural plaques from TB pleurisy. The patient had been previously unaware of this finding and had no previous respiratory or thoracic symptoms. The patient was diagnosed with de novo acute heart failure, triggered by community-acquired bronchitis, and was treated with intravenous furosemide and amoxicillin-clavulanate, and soon discharged with the same medications in oral formulations.

chest x ray, elderly, lung mass, mycobacterium tuberculosis complex, oleothorax, radiographic interpretation, tuberculosis

PMC8406023_01

Male

A 27-year-old man was admitted to our emergency department complaining about cough, recurrent episodes of hemoptysis and B symptoms (weight loss and nocturnal sweating) that had persisted for several weeks and coming to a crescendo. Upon presentation, physical examination was strictly. The patient was free of medical issue, recent corticotherapy and addiction. He had been living in Belgium for six months and previously lived many years in Spain and Morocco. Basic investigations were subsequently performed in the emergency unit at day 0. The results of the laboratory tests disclosed that the eosinophil count was significantly high (1.46 x 103/mm3). C-Reactive Protein, white cells count and d-dimers were normal. A lung CT scan was performed and showed bilateral apical ground-glass opacities associated to an atypical condensation in the left upper lobe apical segment (Fig. 1). The patient was then hospitalized and underwent bronchoalveolar lavage (BAL) at day +1. Cultures, Ziehl-Neelsen staining for mycobacteria and PCR Mycobacterium tuberculosis were negative. In view of the persistent and worsening hemoptysis, patient underwent thoracoscopic wedge resection of the concerned left upper lobe at day +3. The thoracoscopic exploration was marked by a blackish indurated mass on the left upper lobe which was therefore resected. Pathologic examination revealed the presence of foci of pneumonia with numerous eosinophilic polynuclear cells (Fig. 2). The following days in our department were marked by complete resolution of symptoms without benefit of any treatment. A thorough etiological laboratory test was performed at day +5, such as auto-immune tests (anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies), complement system markers (C3, C4 and CH50), protein electrophoresis, HIV serology, lymphocytic count (CD4+/CD8+) and immunoglobulins (IgM, IgA and IgG). No abnormalities were found but lingered a persistent hypereosinophilia. Interferon-gamma release assays (IGRA) and direct examination on sputum smear were negative. Serum galactomannan optical density index was also negative. Anatomopathological examination showed features consistent with a bronchiolitis obliterans organizing pneumonitis and marked hypereosinophilia. No branching hyphae were observed. A PET-CT was performed at day +8 and displayed moderately hypermetabolic changes at the apex of the left lung (place of wedge resection) but no other hypermetabolic lesion. A corticosteroid therapy based on methylprenisolone 64mg was started at day +7. As the follow-up was completed and the patient relieved from his symptoms, he was discharged 10 days after admission while tapering off the oral corticotherapy. However, a few days later, microbiology culture of the lung sample revealed black colonies with a granular appearance whose microscopic characteristics were reminiscent of Aspergillus niger (Fig. 3) leading us to consider the diagnosis of IPA. PCR Aspergillus on the lung sample was positive with a low cycle threshold (17 cycles). Corticotherapy was immediately stopped and the patient went on oral Voriconazole 200mg twice daily, without loading dose, for 6 weeks. Compliance and tolerance were excellent. No adverse effect was encountered during those 6 weeks. However, a week after treatment withdrawal, the patient noticed the quick resurgence of the same symptoms that had initially brought him to the emergency room (especially hemoptysis and asthenia). By performing a chest scan, we highlighted the presence of a consolidation at the operative site. The patient therefore benefited from a treatment by itraconazole 200mg twice daily for another 6 weeks. The evolution was quickly spectacular and there have never been any new relapses to this day (2 years follow-up). The indoor environment analysis service was asked to inspect the patient's workplace and home but no Aspergillus was found.

aspergillus niger, invasive pulmonary aspergillosis, organizing pneumonia

Chest CT showing the condensation in the left upper lobe (red arrows). The bilateral ground glass opacities are not present on this section. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article. ).

PMC5435593_01

Female

A 24-year-old Asian woman at 32 weeks' gestation presented with a 2-day history of worsening dyspnea. She gave a history of sore throat, dry cough, fever, nausea, vomiting, myalgia, weakness and headache. Her examination revealed reduced air entry on both lower zones of the lung with crepitation on auscultation. The rest of the examination was unremarkable. Arterial blood gases (ABG) showed severe hypoxemia with po2 only 90 mmHg despite delivery of fio2 70% via NIV. She had an elevated C-reactive protein (CRP) 200 mg/L on admission. Her chest radiograph demonstrated bilateral opacities consistent with severe pneumonia (Fig. 2) in comparison with her normal chest radiograph taken 2 years prior to illness (Fig. 1). Her tracheal aspirate and urine culture were negative. There were also negative results for nasopharyngeal swab for H1N1. She also tested negative for dengue, infectious diseases such as tuberculosis, human immunodeficiency virus (HIV), hepatitis and syphilis. She was admitted to our ICU and was started on non-invasive ventilation (NIV) bi-level mode. Her condition gradually worsened within a day of admission. She was given intravenous rehydration and broad spectrum antibiotics, tazocin 4.5 g every 6 hours and levofloxacin 750 mg once daily and antiviral osetalmivir. She was planned for intubation if her dyspnea worsened, her respiratory rate increased to more than 35 breaths per minute, or there was a drop in consciousness level. The patient was started on a BiPAP, bi-level positive airway pressure (Philips-Respironics) after poor oxygenation with a high flow mask 15 liters oxygen. She was successfully weaned from NIV on day 3 of ventilation. She was discharged from the ICU to the general ward on day 5 and discharged home on day 13 of admission in good condition. Fig. 2 (a). Patchy air space opacification of the bilateral mid and lower zone with the presence of air bronchogram consistent with consolidation with associated bilateral pleural effusion on the day of admission to the ICU. Fig. (2b) shows worsening of the bronchogram on Day 2. Fig. (2c) shows resolving consolidation and pleural effusion on Day 4.

non-invasive ventilation, pneumonia, pregnancy

PMC5925102_01

Male

A 14-year-old male with a past medical history significant for a concussion and exercise-induced asthma presented to the Emergency Department (ED) via an ambulance after having sudden onset left-sided hemiparesis during basketball practice. Prior to this, the patient's mother had reported that he had been complaining of headaches, neck pain, and intermittent palpitations. He had been using ibuprofen with some relief of the symptoms. In the department, the patient was noted to have flaccid left-sided paralysis, with a left-sided facial droop (forehead sparing), and mild dysarthria. He was complaining of a 5/10 headache and nausea. The patient was otherwise alert and oriented. Within thirty minutes of neurological focal loss and shortly after arriving in the department, the patient's symptoms improved significantly. He was noted to have 4/5 strength in his left upper and lower extremities, with a mild sensory deficit and pronator drift of the left upper and lower extremities. He was seen by a pediatric neurologist at that time and had an NIHSS of 2. Two hours after initial resolution, while having the braces in his mouth removed, he had complete return of his previous symptoms. The patient was sent to MRI at that time which was suboptimal but showed diminished caliber of the right internal carotid artery (R ICA) and diminished flow through the right middle cerebral artery (R MCA) (Figure 1). The patient returned to the department and was noted to be disoriented. Shortly after, he had a generalized seizure that lasted two minutes and resolved after lorazepam administration. He was intubated, CT angiogram was performed at approximately 6 hours after waxing and waning symptoms and showed an R MCA occlusion (Figures 2 and 3), and interventional radiology was contacted at this time. Arterial puncture was performed at seven hours and thirty-seven minutes from initial presentation to the Emergency Department. Interventional neuroradiology was able to perform a mechanical thrombectomy of the R ICA and R MCA with successful clot retrieval (Figure 4). Specifically, eight hours and 24 minute after arrival, a second pass with a Trevo retriever 4 x 30 mm (Stryker) with intermediate catheter aspiration was performed with a Catalyst 6 (Stryker). Base catheter was a FlowGate (Stryker). The patient was extubated the following day. At that time, he had 4/5 strength in the left upper and lower extremities and a mild facial droop. After discharge, the patient participated in intensive physical therapy and occupational therapy with significant improvement in symptoms. At short-term follow-up, the patient had returned to school and was running track. Serial follow-up MRIs were obtained. At over 3 months postevent, brain MRI showed sequela of prior multifocal infarcts in the right cerebral hemisphere conforming to the R MCA vascular territory, with extensive multifocal encephalomalacia and gliosis. At over 6 months postevent, MRI showed stable sequela of multifocal infarcts in the R MCA territory. No new lesions within the brain were seen. Clinically, at over 6 months postevent, his only physical deficit from the AIS was decreased fine movement dexterity of his left fingers.

PMC3364042_01

Male

A 68-year-old male patient was referred by his general practitioner to the Gastroenterology Outpatient Department, Northampton General Hospital due to on and off symptoms of dyspepsia that started only months after the initiation of aspirin and dipyridamole for a recent lacunar stroke. He experienced occasional heartburn and vomiting for the last year and he also had a few episodes of haematemesis while trying to relieve the reflux symptoms. Shortly after this he had two episodes of melaena. Blood investigations were performed and his urea was raised, but he maintained a satisfactory haemoglobin. His general practitioner initiated an empirical treatment for dyspepsia consisting of the combination of a proton pump inhibitor (PPI) (omeprazole 40 mg) and an H2 receptor antagonist (ranitidine 150 mg b.d.) that settled the symptoms for a short period of time but eventually had to be abandoned due to severe diarrhoea. Aspirin was discontinued by the general practitioner and the patient was free of dyspepsia symptoms. He demonstrated a normal appetite and denied any dysphagia. When seen at the outpatient department by the gastroenterology team, his physical examination demonstrated a soft and nontender abdomen. Bowel sounds were normal and no masses were identified. The remainder of the physical examination was normal. His past medical history included a duodenal ulcer diagnosed more than 40 years earlier that had led to upper gastrointestinal tract bleeding, and he was interestingly found to be one of the pioneers of the first combination treatment for Helicobacter pylori eradication. He also had hypertension, hypercholesterolemia and was a smoker of 10 cigarettes daily. 10 months prior to his referral he had suffered a left hemisphere lacunar stroke with persistent paraesthesia that was treated with double antiplatelet regime (aspirin + dipyridamole). He had no family history of peptic ulceration or upper gastrointestinal bleeding. An oesophagogastroduodenoscopy (fig. 1) was performed in an attempt to identify the cause of his symptoms and a middle-sized diverticulum was found in the prepyloric region only a few centimetres from the pyloric opening without causing outflow obstruction. The rest of the examination revealed multiple noncircumferential erosions of the oesophagus, without confluence affecting more than one longitudinal fold and suggestive of reflux oesophagitis. The appearance of the duodenum was normal. Multiple oesophageal biopsies were taken that showed fragments of stratified squamous epithelium with an inflammatory infiltrate including eosinophils and congested capillaries suggestive of reflux oesophagitis, but there was no evidence of dysplasia or malignancy. In view of his past medical history and the nature of his symptoms, a decision was taken to treat the patient conservatively. An alternative PPI agent was commenced (lansoprazole 30 mg o.d.), but aspirin was not restarted since it was considered that dipyridamole would cover him from any further cerebrovascular events with a reduced risk of gastrointestinal bleeding. He was not given a follow-up appointment for review at the outpatient clinic, but 6 months after the initiation of the PPI treatment he remains asymptomatic and his general practitioner confirms his steady progress.

gastric diverticulum, prepyloric region, proton pump inhibitors

PMC6311875_01

Female

An 80-year-old retired woman was referred to our cardiothoracic centre in February 2016 with an incidental finding of 1 cm lung nodule in the left midzone, after having presented to her local hospital with chest discomfort. Her past medical history included previous right nephrectomy for a nonmalignant lesion of the urethra, a previous transient ischaemic attack, polymyalgia rheumatica, hypothyroidism, hypertension, and osteoporosis. Positron emission tomography-computed tomography (PET-CT) showed a T1a N0 M0 left upper lobe cancer with small-cell lung carcinoma confirmed on CT-guided biopsy. The multidisciplinary team decision was for surgical management; therefore, she was admitted for elective lobectomy. This was undertaken in March 2016 using a single-port VATS technique and included lymph node sampling. Sequential identification, dissection, and division of the pulmonary vessels and bronchi were performed as standard. The procedure was uncomplicated, and the patient was discharged 3 days later. She then received adjuvant carboplatin/etoposide chemotherapy and was re-referred in December 2016 with a contralateral right lower lobe nodule found on surveillance CT. The patient underwent single-port VATS wedge resection of the nodule in February 2017, which was again uncomplicated. Interestingly, histopathological examination revealed the nodule to be an area of necrotising granulomatous inflammation with acid-fast bacilli, consistent with past tuberculosis, rather than a metastasis. On postoperative day 1, the patient had a self-resolving episode of ventricular tachycardia following by bradycardia, with chest tightness on minimal exertion. Troponin T was performed which was <20 ng/L. She subsequently underwent a variety of cardiac investigations. Computed tomography coronary angiogram (CTCA) was performed the following day, which showed diffuse disease in all major epicardial vessels, with possible lesions in the left anterior descending (LAD) artery and right coronary artery (RCA), and a coronary calcification score of 1800. A 24-hour Holter investigation revealed bradycardia throughout with rare ventricular ectopics. A subsequent echocardiogram showed normal left ventricular size and function with an ejection fraction of 60-65%, and a myocardial perfusion scan showed an overall ischaemic burden of 7%. Finally, cardiac catheterisation on postoperative day 8 revealed 85% tubular stenosis of the distal left main stem (LMS) artery and minor irregularity in the dominant right coronary artery (RCA). The patient was symptomatically managed on the ward, and the multidisciplinary team discussed the case. Bearing in mind the patient's comorbidities, a decision was made for Endo-ACAB, rather than conventional cardiac artery bypass grafting (CABG) or percutaneous coronary intervention (PCI), which took place 18 days after the initial thoracic surgery. 3 ports were utilised to harvest the left internal mammary artery (LIMA), and a submammary incision was performed in the 5th intercostal space to enable anastomosis to the LAD. She developed no further complications and was discharged 17 days later. She is awaiting cardiothoracic follow-up.

PMC9375119_01

Female

A 27-year-old female referred, complaining of an extraoral sinus tract opening. The patient's medical history was unremarkable, and she was categorized as ASA I. The patient recalled the development of an extraoral sinus tract on the right submandibular region from six years ago. The patient visited an ear, nose, and throat (ENT) specialist upon noticing it. The specialist had prescribed chlorhexidine (CHX) mouthwash for 2 weeks. Due to no recovery and continuous pus discharge from the sinus tract, the patient referred to an infectious disease specialist, who prescribed daily use of 100 mg doxycycline for 6 months. The patient underwent sonography, which revealed a hypoechoic mass with unclear margins and no calcification. Due to the continuation of pus discharge, the patient was admitted to a hospital, and a general surgeon surgically resected the lesion. However, the patient did not have the pathology report of the lesion with her. Pus discharge and the symptoms were resolved after the surgical procedure. However, the symptoms recurred one year later. The patient presented again to the general surgeon, and this time, she was diagnosed with tuberculosis. Polymerase chain reaction and cell culture were performed, which were found to be negative for Mycobacterium tuberculosis. The patient was scheduled for another surgical procedure with a diagnosis of a branchial cyst. The surgical procedure was performed, and the pathology report indicated an infected wall of a sinus tract. Pus discharge continued for another year after surgery, and the patient was referred to a maxillofacial surgeon, who recommended another surgical procedure, which was rejected by the patient. The patient used herbal medications for one year but the pus discharge continued. The patient presented to our dental school. In the first visit, a fistula on the right side of the neck was noticed. The clinical and radiographic examinations were performed (Fig. 1 A-D). The right mandibular first and second molars gave a negative response to pulp vitality tests. Teeth #30 and #31 were not sensitive to percussion and had no mobility. Periapical radiographs revealed severe bone destruction in the periapical region of tooth #31 and periodontal ligament (PDL) widening around the apex of tooth #30. Cone-beam computed tomography (CBCT) was then requested for the patient, which indicated extensive bone destruction in the body of the mandible (Fig. 1E). Teeth #30 and #31 underwent root canal treatment (RCT). In the first treatment session, local anesthesia was induced by the injection of 2% lidocaine and 1:80,000 epinephrine (Persocaine-E, Daru Pakhsh, Tehran, Iran), and an access cavity was prepared in tooth #31. The working length was then determined. The canals were cleaned using the Edge Taper Platinum rotary system (EdgeEndo, Albuquerque, NM, USA) to #F2 file along with irrigation with 5.25% sodium hypochlorite (NaOCl; Hypo-EndoX, Morvabon, Iran). A mixture of calcium hydroxide powder (Golchadent, Tehran, Iran) and 2% CHX (MORVA-Sept, Morvabon, Tehran, Iran) was applied to the canals as an intracanal medicament. The second session was scheduled one week later. In the second session, there was no pus discharge, and the sinus tract was closed (Fig. 2A). Thus, RCT was completed, and the canals were filled with gutta-percha and AH-26 sealer (Dentsply, Konstanz, Germany) using the cold lateral compaction technique. Tooth #30 also underwent RCT, and the patient was referred to a prosthodontist for the final restoration of the respective teeth. The first follow-up session was scheduled at 3 months after the final restoration of the teeth. At the 3- and 6-month follow-ups, the patient was asymptomatic clinically and radiographically, and the periapical radiograph showed evidence of bone regeneration (Fig. 2B-E).

endodontics, infection, misdiagnosis, odontogenic cysts

PMC1181810_01

Female

A 41-year-old female NF1 patient was admitted for the evaluation of a 3-year history of recurrent epigastric soreness, heartburn, and diarrhea. Repeated endoscopic examinations revealed recurrent duodenal ulcers. The symptoms were relieved by proton-pump inhibitors, but recurred when the medication was withdrawn. She was previously diagnosed with NF1 based on clinical features and family history. Her first-degree relatives (i.e., brother, sister, and second son) were also affected by fully developed features of NF1. She had no cognitive dysfunction or learning disabilities, and showed normal intellectual development. A physical examination revealed several cafe-au-lait spots and multiple small nodules on the anterior chest and areolar area, and also multiple axillary freckles. A skin-nodule biopsy demonstrated characteristic neurofibromas. On admission, upper gastrointestinal endoscopy revealed multiple shallow ulcers in the descending duodenum. The rapid urease test and urea breath test for Helicobacter pylori were both negative. The serum fasting gastrin level was >1,000 pg/mL and 837 pg/mL in two consecutive measurements. A secretin stimulation test was not performed due to the unavailability of secretin. As a diagnosis of gastrinoma was strongly suggested, radiologic evaluations were performed to locate the lesion. Abdominal computed tomography (CT) and magnetic resonance imaging (MRI) scans showed a 3 x 2-cm, clearly defined, well-enhanced mass adjacent to the duodenal loop in the subhepatic space (Figure 1). No metastatic lesions were observed in the liver or regional lymph nodes. The association with MEN1 status was evaluated by hormonal and radiologic investigations of the parathyroid, pituitary, pancreas, and adrenal gland, which proved to be negative. As a definitive treatment, an intraabdominal mass of about 2.5 x 2 cm with a thick fibrous capsular outer layer was surgically isolated and completely resected from the right lateral border of the descending duodenum. Gastrinoma was finally diagnosed by immunohistochemical staining (Figures 2, 3). An incidental finding during the operation was numerous, small (<1.0 cm), whitish nodular masses on the serosal surface of the small bowel, many of which were enucleated. The pathologic diagnosis was gastrointestinal stromal tumor (GIST) with a low mitotic index as evidenced by C-kit positivity (Figures 4, 5). The serum gastrin level decreased markedly to 99.1 pg/mL at 1 month after the operation, and to 53.2 pg/mL 3 months later. There were no symptomatic or radiologic recurrences during a 14-month follow up.

PMC7165349_01

Male

A 24-year-old male is admitted to our clinic presenting a behavioral trouble described by his parents as a disorganized speech, disorientation, and memory deficits during the last few days. His medical examination at the ECU does not reveal any organic abnormalities, with the exception of a mild leukocytosis (total WBC count: 13.380) without an infection outbreak. His medical history includes a meningoencephalitis of unknown origins at the age of 3 weeks and a diagnosis of an attention deficit hyperactivity disorder (ADHD) at the age of 9, treated with methylphenidate (40 mg per day). He experienced difficulties at school; he is described as having always been slightly intellectually inferior to his peers, with a hyperactive behavior. At the age of 20, after he got his certificate of commercial apprenticeship, the methylphenidate was stopped, but had to be reintroduced because of a "strange, impulsive behavior, marked by aggressiveness and excessive anger, where it was difficult for him to express himself," according to his parents. He is not a smoker, nor does he use other psychotropic substances, and he is not known by the psychiatric services. He does not work, lives with his parents, and has a poor social life. He has never taken any antipsychotic treatment in his life. Upon admission, we can observe a calm, distant, excessively cooperative patient with a nonspontaneous speech, with a prolonged latency in his answers and a poor production. Nonetheless, it is mostly comprehensible and coherent. The mood is labile, passing quickly from laughs to tears to anger, often inappropriate and out of context of the discussion. His thought process is characterized by poverty of production and a content marked by somatic delusions (that his organs do not work properly). He describes auditory hallucinations: different voices shouting at the same time or talking about him. The next day, he presents an episode of agitation and is withheld in therapeutic isolation. After the first evaluation, given his clinical status, we stop the methylphenidate and introduce an antipsychotic treatment of olanzapine 20 mg/day, and given that after five days we do not get any positive evolution, we add amisulpride at 400 mg/day, as the psychotic symptoms and especially hallucinations are predominant in his clinical state. During the next few days, he develops rigidity, posturing, waxy flexibility, withdrawal from food and water, a repetitive speech, and automatic obedience. The Bush scale of catatonia score was 23, corresponding to a severe catatonia. We diagnose a catatonic syndrome probably caused by a psychotic disease, and as a result, we discontinue all antipsychotic treatment. We reintroduce methylphenidate, as according to some studies it has a role in catatonia treatment and also lorazepam at 4 mg/day at the beginning, augmenting the dose until 10 mg/day, with a very poor response. We also schedule a brain MRI. In the meantime, he is transferred to the ECU with an edema of the right leg with no pain or erythema and a body temperature of 37.8 C. A deep vein thrombosis and a right pneumonia are diagnosed, and he receives an antithrombotic and an antibiotic treatment. The brain MRI does not reveal any organic troubles. During his stay in the medical department, we gradually reduce the lorazepam treatment. When he returns to the psychiatric department, after a thorough blood control and an ECG, we discontinue progressively lorazepam and introduce clozapine until the dose of 250 mg/day, following a classical titration, with a rapid and significant improvement of the catatonic symptoms after a few days. Soon, he eats and drinks normally, the motor disturbances disappear, and he is able to form spontaneous phrases from start to end. After two weeks, the CGI improvement scale (CGI-I) is at two; after three weeks, it lowers to 1 (very much improved). We also add mirtazapine (until 30 mg/day) to potentialize the effects of the clozapine. The regular blood tests and ECGs show a good tolerance to the treatment. He is discharged with a treatment of clozapine, mirtazapine, and methylphenidate at the usual doses. One month after discharge from hospital, our patient returns to his usual state: he told us that the auditory hallucinations were present since his adolescence and that they consisted of several voices talking among them or talking about him, so we can confirm the presence of the first rank of criteria for schizophrenia. The Bush catatonia rating scale score is down to 3/69.

PMC2786997_01

Female

A 60-year-old woman presented to our medical center for evaluation of acute onset headache and confusion. Her past medical history was remarkable for alcoholic cirrhosis and hepatitis C. Physical examination revealed the presence of mild ascites and hypoxemia (91%) on room air with no response to supplemental oxygen. Noncontract head CT was without focal abnormality, but cerebrospinal spinal fluid analysis showed xanthrochromia suggestive of subarachnoid hemorrhage. Catheter angiography of the cerebral vessels confirmed the presence of a right middle cerebral artery (MCA) aneurysm, and the patient underwent endovascular coiling without complication. Postprocedure day number two, the patient decompensated and developed respiratory and congestive heart failure. A right internal jugular catheter was placed for venous access and hemodynamic monitoring. Daily surveillance transcranial Doppler (TCD) and noncontrast head CT showed no abnormality until postprocedure day number four when embolic signatures were detected in the basilar and bilateral MCAs. Given the multiple vascular territories involved in the ultrasound findings, a search for the source of emboli was initiated. The patient was unable to undergo transesophageal echocardiogram due to the presence of varices, but transthoracic echocardiogram with agitated saline contrast was performed while mechanically ventilated and repeated once she was extubated. No patent foramen ovale was identified, but a large amount of echogenic contrast was detected in the left atrium after 3-4 heartbeats. The delayed appearance of saline contrast in the left atrium and its origination from the right pulmonary vein were anatomically consistent with shunting through the pulmonary circuit, and similarly confirmed by TCD. The patient was started on daily antiplatelet therapy with 325 mg aspirin and the embolic signatures on TCD ceased within three days. She soon recovered from the events surrounding her hospitalization, however suffered a fatal intracranial hemorrhage five months later.

PMC6112268_01

Female

A 13-year-old female of the Marshallese origin presented to the emergency department with complaints of nausea; nonbloody, nonbilious vomiting; and abdominal pain. The patient denied any recent fevers, and no rash was reported. Review of systems was notable for the left ear drainage. Immunization status was unknown, and she was not reported to have been previously treated for any significant illness, though the history was limited by the patient's custodial circumstances. She lived in a small house in rural North Carolina with 21 other Marshallese immigrants and was cared for by relatives who had assumed care for her at the time of her immigration five years before. Examination during the initial hospital visit revealed dehydration and acute otitis media with rupture of the tympanic membrane. Laboratory results revealed leukocytosis, prerenal azotemia, elevated liver enzymes, and mildly elevated lipase (Table 1). Computed tomography (CT) showed scattered focal pulmonary infiltrates, splenomegaly, and a markedly distended stomach without an obvious focus of mechanical obstruction (Figure 1). Cytomegalovirus and Epstein-Barr virus serology were requested with results suggesting prior exposure. She was admitted with a presumptive diagnosis of gastroparesis secondary to a nonspecific viral infection and possible mild pancreatitis. An NG tube was placed resulting in high volume output. Her symptoms gradually improved over several days with IV fluid support and bowel rest; her NG was successfully removed, and she was discharged home tolerating a regular diet. Two days after discharge, the patient returned with recurrence of her prior symptoms. The patient appeared acutely ill with dehydration. On lung exam, scattered crackles were noted. She was also noted to have diffuse small nodular lesions most apparent on her hands, feet, lower legs, and face (Figure 2). An advocate placed with the family reported her concern for additional symptoms of chronic weight loss and productive cough with posttussive emesis and reported the skin changes to have been present for months. Prior exposure to or testing for tuberculosis was unknown. The patient did not report symptoms of peripheral neuropathy. Laboratory results revealed a relatively increased white blood cell count (21.4 x 109 per liter) with significant worsening of her renal function (creatinine of 2.45 mg/dL which had previously been normalized with rehydration) and persistent mild elevation in liver enzymes and lipase. Respiratory viral screening was positive for rhino/enterovirus. Repeat CT imaging showed persistent gastric dilation and splenomegaly (Figure 3). The patient was placed on empiric antibiotics for community-acquired pneumonia and put on reverse isolation with concern for tuberculosis. Skin biopsies of multiple lesions were obtained and sent for pathology and culture (Figure 4). Because multiple attempts to place an NG tube failed and vomiting failed to respond to conservative measures, endogastroduodenoscopy was pursued. The scope passed into the stomach and through the pylorus easily, reaching a normal-appearing proximal duodenum. However, a feeding tube could not be passed beyond the pylorus and was left just proximal to the pylorus for decompression. Stomach mucosa was described as having a "cobblestone" appearance in places, with one area of ulceration possibly due to prior nasogastric tube. Stomach biopsies revealed Helicobacter pylori and chronic active gastritis, but were negative for AFB. Due to persistent evidence of gastric outlet obstruction, an upper gastrointestinal study was performed which suggested gastric volvulus. The patient proceeded to gastropexy via open gastrostomy tube placement. The surgeons reported an extremely large and patulous stomach that had twisted mesenteroaxially. Gastric aspirates were negative for AFB. Biopsies of the skin lesions confirmed the presence of many AFB with changes consistent with lepromatous leprosy due to M. leprae (Figure 4). Additionally, the serial sputum samples were positive for AFB, and culture of the skin sample for AFB showed evidence of growth within a few days, suggesting Mycobacterium tuberculosis (MTB) pulmonary infection and possibly disseminated MTB given selectivity of the culture medium. In coordination with the health department and the infectious disease service, the patient was initiated on treatment for presumed disseminated MTB, noting that this would also provide coverage for M. leprae. However, polymerase chain reaction (PCR) testing from the sputum samples and skin samples failed to demonstrate MTB, while PCR testing performed at the Hansen's Disease Center of skin samples was positive for M. leprae. Retrospectively, it was felt that growth detected on the AFB culture was due to metabolism by an unusually large inoculum. Gradually, the patient's oral intake improved. With hydration, her renal function again returned to normal. After several weeks of inpatient treatment, the patient discharged to complete therapy through the health department. Symptoms of gastric outlet obstruction have not returned.

PMC7263116_01

Female

A 47-year-old Caucasian woman was admitted to our Rheumatology Unit, complaining a 6-month history of progressive appearance of tender ill-defined hard swellings on the right leg and the abdominal wall with severe erythema in overlying skin, associated with intermittent fever up to 39 C, not relieved by antipyretics and antibiotics. The patient had fever up to 39 C, multiple tender erythematous swellings on abdomen wall and right leg, and several palpable lymphadenopathies on abdomen, neck, and right groin during admission to our Unit. She denied drug abuse, recent travel, or use of nonsteroidal anti-inflammatory drugs. Complete blood count revealed microcytic hypochromic anemia with hemoglobin 9.8 gm/dL, mean corpuscular volume 69 fl, and leucopenia with neutropenia (WBCs 1.3 x 103/L; N 48.3%, L 43.8%, M 3.8%, E 0.4%, B 2.2%). Thrombocytopenia (up to 67 000/microL) had been briefly observed during the recovery period. There was an increase in alanine transaminase (ALT) 104 IU/L (normal range, 2-40) and aspartate aminotransferase (AST) 91 IU/L (normal range, 2-40), with an AST/ALT ratio < 1 and an increase of gamma GT 67 IU/L (normal range, 7-38). A slightly high serum lipid profile (triglycerides, total cholesterol, and low-density lipoprotein) was observed. Erythrocyte sedimentation rate (ESR) was 17 mm/h, C reactive protein (CPR) was 0.05 mg/dL. Normal immunoglobulin assay except high levels of IgM 443 mg/dL (n. 40-230) and of IgE 857 mg/dL (n. 2-200) was noticed. Complement 3, complement 4, cryoglobulin levels, serum lipase, serum amylase, alpha-1 antitrypsin, procalcitonin, haptoglobin, creatine phosphokinase, creatinine, azotemia, serum glucose concentration, bilirubin and bilirubin fraction, serum corrected calcium, and alkaline phosphatase were within normal range. Antithrombin was mildly elevated, 165% (normal range, 70-130). Severe hypofibrinogenemia 40 mg/dL (normal range, 200-450) with high levels of D-dimer 23 701 microg/mL (normal range, 0-500) were detected. The 24-hour urinary sample showed moderate proteinuria (1.6 gm/24 h). An increase of lactate dehydrogenase (LDH) 500 IU/L (n. 40-250) and beta-2 microglobulin 7.34 microg/mL (normal range, 0.8-2.7) was revealed. Partial thromboplastin time (PTT) was shorter. Prothrombin time and iron profile were normal. Albumin level was 3.2 gm/dL. A hypergammaglobulinemia (23.78%) was noted by protein electrophoresis. Serum and urine immunofixation were negative for free light chains. TORCH screening, tuberculosis screening, Coxsackie IgM, Brucella IgG and IgM, Borrelia IgG and IgM, and Parvovirus B19 were negative. The antinuclear antibodies, lupus anticoagulant screening, antineutrophil cytoplasmic antibodies, cryoglobulin, and antiphospholipid antibodies were negative. Viral hepatitis, autoimmune hepatitis, metabolic factors and in-born or hereditary disorders (Wilson disease, lypodystrophy), drug and toxins associated to high liver enzymes and excessive alcohol consumption, obesity, and diabetes mellitus were excluded. A mild hepatosplenomegaly with widespread lymphadenopathy and left pleural effusion were detected using sonography and confirmed by neck, chest, and abdomen computed tomographic scan. The echocardiography detected a small pericardial effusion, with normal eject fraction and preserved systolic function. The endocrine and genital organs and the breast showed no clinical abnormalities. Surgical skin sample showed lobular panniculitis with a lymph-histiocytic and neutrophilic infiltrates with necrosis of adipocytes, as seen in PWCD. Bone marrow biopsy displayed a discrete hypercellular bone marrow with an increase of megakaryocytic proliferation and low grade of dysmorphia of myeloid cells. A widespread boost of stromal fibers was noticed at silver impregnation. The marrow changes were reactive and did not reflect a myelodysplastic syndrome. Axillary lymph-node biopsy confirmed a reactive lymphadenopathy. The hematological specialist excluded hematological malignancies. The liver biopsy evidenced a macro-vesicular steatosis with hepatocytes ballooning, as in NAFLD. Spotty necrosis, scattered mixed neutrophilic-lymphocytic inflammation, Mallory hyaline, and perisinusoidal fibrosis were absent. On admission, levofloxacin (750 mg daily) and minocycline (200 mg daily) were empirically started and discontinued after 8 days for negative blood cultures. Mycophenolate mofetil (MMF) (2 gm daily) and prednisone (1 mg/kg daily, tapered to 5 mg daily in 3 months) were started. At 1-month follow-up, the improvement of skin lesion, the remission of fever, and complete normalization of blood count, proteinuria, and liver enzymes were recorded. A complete remission state, with just slightly hyper-pigmentated skin scares, was recorded at sixth month follow-up. Of note, considering the prompt remission of proteinuria after prednisone and mycophenolate mofetil treatment, the kidney biopsy was not more performed.

pfeifer-weber-christian disease, hematologic dyscrasia, liver biopsy, mycophenolate mofetil, nonalcoholic fatty liver disease, pleural effusion

PMC3469074_01

Male

A 61-year-old African American male with no significant past medical history presented to our institution's emergency department complaining of six-month history of progressively worse abdominal pain associated with anorexia and unintended weight loss. Computerized tomography (CT) scan of abdomen showed mild ascites and right pleural effusion; a subsequent CT of the chest revealed a large right pleural effusion with multiple subcentimeter (less than 4 millimeters) pulmonary nodules in the right upper and lower lobes. Initial laboratory workup revealed a complete blood count (CBC) with normochromic normocytic anemia (hemoglobin 7.3 g/dL), thrombocytopenia (platelets 36,000), and reticulocytosis (10%). Lactate dehydrogenase (LDH) was found elevated with a low haptoglobin. Coombs test was negative, and renal and liver functions were within normal limits. A peripheral blood smear confirmed CBC findings and showed schistocytes and microspherocytes. Given the likely diagnosis of thrombotic thrombocytopenic purpura (TTP), ADAMTS 13 activity was ordered and reported as 14% (low), which led to the initial confirmation of this disorder. The patient was started on high-dose steroids, plasmapheresis (PE), and fresh frozen plasma (FFP). After seven days of treatment, his platelet count increased to 428,000 and LDH decreased to 839. Extensive workup for secondary causes of TTP including malignancy was negative. Human immunodeficiency virus and hepatitis serologies were nonreactive. Pleural fluid analysis of right pleural effusion was consistent with an exudate; however, cytology and flow cytometry were negative for malignant cells. Quantiferon for tuberculosis was positive but acid fast bacilli stains and viral, fungal, mycobacterial, and bacterial cultures were negative. The possibility of latent tuberculosis was raised, and the patient was started on isoniazid. Once the patient was stable, video-assisted thoracoscopic surgery (VATS) with multiple pleural biopsies was done; however, no lesions were seen during the procedure, and pathology did not reveal any evidence of malignancy. Plasmapheresis and FFP were discontinued, steroids were tapered off, and eventually the patient was discharged with outpatient followup. After 9 days, the patient returned to the emergency department complaining of worsening of abdominal pain and altered mental statues with dysarthria and bradypsychia. Once again, he was found thrombocytopenic (<10,000) and his LDH was very high (4000). CT brain showed no hemorrhage and electroencephalogram (EEG) revealed encephalopathy but no epileptogenic foci were found. The patient was admitted to medical intensive care unit, and PE and FFP infusions were started after a new peripheral blood smear led to confirmation of relapsed TTP. Subsequent magnetic resonance imaging (MRI) of the brain did not show any abnormalities. The patient eventually recovered with instaurated treatment, and he was discharged again with oral steroids. ADAMTS 13 activity at the time of discharge was 19%. However, after only 6 days, he was admitted again complaining of the same symptoms of abdominal pain and altered mental status. He was also found febrile, oliguric, and azotemic. Relapsed TTP was once again diagnosed, and ADAMTS13 activity was reported to be less than 10%. During his hospital stay he had two episodes of seizures and for that reason he was started on levetiracetam. EEG showed diffuse encephalopathy. Following seven days of treatment with PE and FFP, the patient had a significant overall improvement, and, after no hemolysis was found, the patient was transitioned to daily FFP infusions. Despite this, ADAMTS activity remained low, and, once FFP infusions were discontinued, his TTP relapsed again. After reinitiating treatment, rituximab 375 mg/m2 was started as second-line therapy. After seven days of immunotherapy along with PR and FFP, ADAMTS13 remained persistently low (10%). Chemotherapy with CVP (cyclophosphamide, vincristine, and prednisone) was added for empiric treatment of potential low-grade lymphoma, with no significant response after two cycles of immunochemotherapy. He started complaining again of intense abdominal pain leading to acute abdomen that prompted an exploratory laparotomy. Surgical exploration revealed diffuse carcinomatosis with a tumor located on the left pelvis that was encasing the distal sigmoid colon. Pathology reported mesothelioma with malignant cells positive by immunohistochemistry to calretinin and D240, and negative for CEA and MOC31 (Figures 1, 2, 3, 4, and 5). Due to the extension of his disease, it was considered nonresectable. Based on his poor response to TTP treatment and concomitant primary malignancy, the diagnosis of paraneoplastic TTP-like syndrome (TTP-LS) was made. The patient continued with FFP while recovering from surgery, and then he was started on palliative chemotherapy with cisplatin plus pemetrexed, the best chemotherapy available for mesothelioma, aiming to control both his TTP-LS and malignancy. After four weeks of treatment, there were no signs of improvement and he was transferred to hospice to receive best supportive care.

PMC9924633_01

Male

A 33-year-old African American man presented to the emergency department (ED) with the complaint of chest pain along with shortness of breath while taking a shower at home. He didn't have any past medical or surgical history and worked as a schoolteacher. He had no known family history of any heart disease. He had played basketball and football during high school with no issues. In the ED, he was noted to be tachycardic with heart rate 119/min. The rest of his vital signs were blood pressure 123/87 mmHg and respiratory rate 18/min. Laboratory investigations were within normal limits with a normal renal and liver function tests and a complete blood count was within normal limits. A urine drug screen was positive for opiates, benzodiazepines and cannabinoids. He developed palpitations in the ED, during which an electrocardiogram (ECG) showed a wide complex tachycardia with heart rate of 240/minute (Fig. 1). He was administered 6mg adenosine which was followed by second dose of 12mg adenosine which did not terminate the arrhythmia. He received 150mg of Amiodarone with no response. This was followed by another 150mg after which his ECG revealed a normal sinus rhythm. He was maintained on an Amiodarone drip and admitted to the cardiac critical care unit (CCU) for closer monitoring. On hospital day 1, he developed bradycardia with ECG revealing sinus bradycardia with heart rate 44/minute (Fig. 2). Amiodarone drip was discontinued. An echocardiogram showed normal left ventricular (LV) function with normal ejection fraction. He underwent cardiac catheterization which did not reveal any coronary abnormalities or obstruction. A cardiac magnetic resonance imaging (MRI) was done which showed multiple patchy areas of midwall late gadolinium enhancement particularly prominent as transmural enhancement in the inferolateral mid myocardium (Fig. 3). He was started on pindolol and was evaluated by electrophysiological cardiologist for implantable cardiac defibrillator (ICD). A high-resolution computerized tomography (CT) of chest done with contrast did not show any reticular opacities in lung parenchyma or hilar adenopathy. An endomyocardial biopsy was done which was negative for myocarditis or any granulomatous disease, and Congo Red stain was negative for amyloidosis. Serum angiotensinogen converting enzyme (ACE) level was 35 U/L (within normal limits). He underwent an ICD placement for secondary prevention of ventricular arrhythmias and was discharged from the hospital with a plan to pursue a positron emission tomography (PET) scan as an outpatient and discuss further treatment options. As an outpatient, he underwent a PET scan which did not show any tracer activity in the myocardium or any evidence of cardiac sarcoidosis. He was also evaluated by Ophthalmologist and was not found to have any manifestations of ocular sarcoidosis. He was referred for genetic testing which revealed heterozygous mutation in LMNA gene. Interrogation of his ICD did not show any further VT in subsequent office visit and his family members including children were recommended to get genetic testing for screening. In the absence of other identifiable etiology and a known association of LMNA gene mutation with ventricular arrhythmia, we think the VT in this young patient is due to LMNA gene mutation.

cardiac sarcoidosis, dilated cardiomyopathy, genetic testing, lmna gene, nuclear lamins, ventricular tachycardia

PMC7572676_02

Female

An 18-year-old female with acute lymphoblastic leukemia (ALL) was hospitalized in hematology department because of abdominal pain for 24 hours which was not associated with heartburn or vomiting. On examination, the patient s temperature was 38.4, heart rate was 85 beats per minute, blood pressure was 115/71 and respiratory rate was 14 breaths per minute. Her abdomen was soft, without distension and only mild tenderness in the lower right quadrant was found. The initial haemoglobin was 9.46g/dL, white blood cells were 1.55K/mul, platelets were 58.800K/mul and C-reactive protein level was 1.35U/l. Liver and renal function test and serum amylase were normal. According to the real time ultrasound (US) of the abdomen which was performed immediately, the diameter of the appendix was found 9mm as well as hyperechoic mucosa and free fluid surrounding appendix was recognized. The patient underwent open appendectomy through a right lower abdominal incision (Figure 1). She had no intra-operative or postoperative complications. On day 3 of surgery, patient was discharged in good condition and referred to hematology department for further management. Her final histopathology report was suggestive of acute appendicitis. In addition, Roseomonas gilardii was detected from blood and peritoneal fluid cultures that were taken the day of the operation.

appendicitis, roseomonas gilardii, acute lymphoblastic leukemia

PMC4386441_01

Female

A 25-year-old female patient presented with a two-month history of vague upper abdominal pain, jaundice and weight loss. Her general physical examination revealed icterus, and mild hepatomegaly was observed on per abdominal examination. Ultrasound of the abdomen was advised which showed a well-defined rounded hypoechoic mass involving the left lobe of the liver with a central stellate echogenic scar (Figure 1A). The lesion showed evidence of internal vascularity on Color Doppler (Figure 1B). There was evidence of another small rounded hypoechoic lesion at the porta with dilatation of intrahepatic biliary radicals with blocked confluence of the right and left hepatic ducts (Figure 1C). Plain and triple-phase contrast-enhanced computed tomography of the abdomen was advised which showed a well-defined isodense mass in the left lobe of the liver with no calcification and with central stellate hypodensity (Figure 2), showing enhancement in the arterial phase (Figure 3A, 3B). The tumor was isodense to liver in the portal venous phase with a central non-enhancing stellate scar (Figure 4A, 4B). There was evidence of a partial washout in the equilibrium phase with a part of the scar showing enhancement (Figure 5). Additionally, T2-weighted Magnetic Resonance Imaging of the abdomen was performed (to search for signal intensity of the scar), which showed an isointense lesion with a central hypointense stellate scar (Figure 6). The diagnosis of fibrolamellar hepatocellular carcinoma was made based on pathognomonic features on imaging. Preoperative PTBD (percutaneous transhepatic biliary drainage) was carried out in this patient to relieve obstructive jaundice and hepatic derangement before surgery. The patient was advised to undergo surgery after 2 weeks. However, the patient did not turn up later on.

carcinoma, hepatocellular, magnetic resonance imaging, tomography, spiral computed

PMC7718649_01

Female

The patient is a 65-year-old woman with well-controlled SLE. Her long-term treatment for SLE is prednisone (10 mg p.o., once daily) and hydroxychloroquine (0.2 g p.o., twice daily). She lived 6 miles away from Huanan Seafood Wholesale Market where was the earliest epidemic focus of COVID-19 in Wuhan. She had neither been to the market nor closely contacted with confirmed or suspected COVID-19 patients. On January 22, 2020, the patient presented fever (peak value: 39 C) with chills, rigor, muscular soreness and fatigue. She coughed with small amount of white sputum occasionally. Sometimes, she felt suffocated after movements. The next day, she developed nausea, anorexia, heartburn and diarrhea (liquid stool, three times per day). On January 25, she visited the clinic for the first time and was given oral medicines (oseltamivir 75 mg twice daily, arbidol 0.3 g twice daily, moxifloxacin 0.4 g once daily and Lianhuaqingwen capsules 1.4 g three times daily). The dosage of prednisone and hydroxychloroquine remained the same as her usually used. After taking the aforementioned drugs for 7 days, the patients' symptoms did not improve and returned to the clinic. The outpatient doctor took nasopharyngeal swabs to test SARS-CoV-2 and influenza A virus by real-time reverse transcription polymerase chain reaction (rRT-PCR), both of which were positive. At the same time, her thoracic CT showed bilateral patchy ground-glass opacities (according to the medical records, images not available). Hence, human immunoglobulin was given intravenously (IVIg, 5 g once daily) with the aforementioned oral medicines and increased dose of prednisone (25 mg once daily) for 5 days since February 4. Intravenous immunoglobulin is immunoglobulin G made from healthy human plasma, and low dose of IVIg was used for nonspecific and wide-spectrum antiviral and antibacterial therapies. On February 8, the patient' symptoms were relieved partially, but the second thoracic CT showed pulmonary lesions extension (according to the medical records, images not available). Laboratory tests found leucocytosis (11.09 x 109/L), neutrophilic leucocytosis (9.46 x 109/L) and normal lymphocyte count (1.33 x 109/L) (Table 1). Then, the patient was admitted to fever ward of Sino-French New City Branch of Tongji Hospital, a designated hospital for diagnosis and treatment of COVID-19 in Wuhan. On admission, the patient presented with mild coughing. Physical examination revealed that the conscious of the patient was clear, temperature was 37.1 C, blood pressure was 136/74 mmHg, pulse rate was 77 beats per minute, respiratory rate was 18 breaths per minute and peripheral oxygen saturation under oxygen inhalation (3 L/min) through nasal catheter was 98%. The results of laboratory examinations were presented in Table 1. White blood cell count, neutrophilic granulocyte count and lymphocyte count were normal. Several inflammatory indicators were high. Mild injuries of kidney, myocardium, liver and coagulation function were observed. M. pneumoniae infection was found by serology (Figure 1). Glycosylated hemoglobin was 7.1%, and postprandial blood sugar was higher than 11.1 mmol/L. Routine tests of stool and urine samples were normal. The patient was diagnosed of SLE combined with COVID-19, influenza A, M. pneumoniae infection and diabetes mellitus. Prednisone (25 mg p.o., once daily) and hydroxychloroquine (0.2 g p.o., twice daily) were given to cover the concurrence of SLE and COVID-19. Pantoprazole (40 mg p.o., once daily) was used to prevent gastric mucosal injury caused by prednisone. Levofloxacin (0.5 g p.o., once daily) was given to deal with bacterial and M. pneumoniae infection. Then, acarbose (50 mg before lunch and dinner daily) was applied to control the blood glucose. On the 6th day of hospitalization, the symptoms of the patient eased. Thoracic CT (February 14, 2020) showed bilateral ground-glass, patchy and cord-like shadows (Figure 2a), which was better than the second CT (February 8, 2020) before admission (according to the medical records). On the 8th day of hospitalization, some laboratory examinations were retested, and most of which were improved (Table 1). Dosage of prednisone was reduced to 15 mg once daily as pneumonia improved. On day 15 of hospitalization, laboratory tests revealed that most of the values were better than previous tests (Table 1). Inflammatory indicators such as serum ferritin, high-sensitivity C-reactive protein (hsCRP), erythrocyte sedimentation rate (ESR) and interleukin-6 were lower. Subgroup typing of lymphocytes represented elevation of CD4+ T cells (1517/muL) and reduction of CD8+ T cell (252/muL). The ratio of helper T cell versus suppressor T cell was elevated (6.01). The thoracic CT (February 23, 2020) showed a modest upturn in the lesions (Figure 2b). The dosage of prednisone was then reduced to 10 mg once daily as pneumonia improved. Nasopharyngeal swabs were collected for rRT-PCR of SARS-CoV-2 on day 16 and 18, both of which were negative. Two days later (day 20), the patient developed wrist pain, and loxoprofen (60 mg p.o., twice daily) was used to alleviate it. On day 22 of hospitalization, no symptoms of the patient were observed. Laboratory findings (Table 1) and thoracic CT (Figure 2c) indicated improvement relative to last time. The rRT-PCR of SARS-CoV-2 of the third nasopharyngeal swab was still negative. Serum immunoglobulin M (IgM) and immunoglobulin G (IgG) of SARS-CoV-2 were 33.73 AU/mL (normal range: <=10 AU/mL) and 198.77 AU/mL (normal range: <=10 AU/mL), respectively. Since the patient met the criteria of discharge (temperature came back to normal for over 3 days, respiratory symptoms significantly improved, thoracic radiology showed obvious improvement in acute exudative lesions and negative results of rRT-PCR of SARS-CoV-2 for two nasal pharyngeal swabs over 24 h), she was discharged on March 4, 2020. She has been in good health without any symptoms after discharge. Ethical statements: This study was approved by the Ethics Committee of Tongji hospital, Huazhong University of Science and Technology. All the materials of the patient were anonymous and written informed consent was waived by the ethics committee.

covid-19, sars-cov-2, sle, hydroxychloroquine, multiple infections

PMC6430034_02

Male

A 52-year-old man from Western Province, Saudi Arabia was referred for a possible right-hand palm tumor. He had a history of uncontrolled diabetes mellitus and a 5-year history of a recurrent painless mass involving his right middle finger, extending proximally to the palm, progressing in size over 6 months prior to presentation. The mass started as a tiny painless nodule that subsequently enlarged, thereby restricting hand motion. A trial surgical excision 2 years prior to presentation was successful in removing the mass, which did not recur for almost a year. However, the mass subsequently enlarged and began producing a whitish discharge. Multiple sinuses were noted (Fig. 2A). Initial laboratory examinations, including a CBC and chemistry panel, revealed normal results. HIV test results were negative. Plain radiography and magnetic resonance imaging (MRI) of the right hand showed multi-lobulated enhancing soft tissue conglomerated masses at the base of the middle finger, extending along its volar proximal aspect, circumferentially surrounding the finger and its tendons. No signs of tenosynovitis or osteomyelitis were observed (Fig. 2B). The patient underwent an incisional biopsy and mass debridement. Tissue Gram staining and culture showed negative findings. AFB smear and polymerase chain reaction (PCR) findings were also negative for tuberculosis. Macroscopic examination of the sample revealed a mass approximately 2.0 x 1.5 cm in size and pinkish tan in color. Microscopic examination revealed skin with underlying tissue showing heavy infiltration by actinomycetes (positive results for the gomori methanamine silver [GMS] and periodic acid-Schiff [PAS] tests) that caused a severe inflammatory reaction and tissue destruction (Fig. 3C and D). The patient was treated with oral amoxicillin/clavulanic acid (1 g) every 12 h and then discharged home. During the follow-up 2 months later, a whitish discharge was observed. He was referred for further debridement. After six months of treatment, he showed marked improvement.

PMC6430034_03

Male

A 49-year-old man presented to us after undergoing right hemimandibulectomy and right neck dissection in July 2011, followed by chemoradiation for submandibular cystic adenocarcinoma (T4N2M0). Following the surgery, he developed trismus and difficulty in brushing his teeth. Five years later, he developed chronic right sided facial pain associated with recurrent purulent skin discharge and fever. Multiple trials of antibiotics including ciprofloxacin failed to achieve complete recovery. A dental assessment showed multiple decayed teeth. Dental treatment could not be administered due to his markedly reduced ability to open his mouth (8 mm). His temperature, heart rate, and blood pressure were 37.1 C, 95 beats/minutes, and 131/82 mmHg. A small right sided sub-mandibular fistula draining a minimal amount of pus was observed on examination. His CBC, ESR, and CRP laboratory results were all normal. Enhanced head and neck CT did not reveal any underlying fluid collection, and no apparent fistula was observed on radiological evaluation. The right mandible bone biopsy was negative for AFB, TB-PCR, and bacterial cultures. Another biopsy taken from the right upper alveolar edge consisted of yellowish tan colored soft tissue. The bacterial culture was negative; however, heavy growth of mixed candida species was noted on tissue culture. Histopathology revealed necrotic tissue with positive PAS and GMS staining, suggesting actinomycosis (Fig. 3). Chest CT showed pulmonary nodules enlargement, which was also noted 2 years prior to this presentation [(Fig. 3B]. The patient received a high dose of intravenous penicillin (6 million units/day) for 6 weeks followed by ceftriaxone for 1 month through a peripherally inserted central catheter. He also received 6 weeks of oral voriconazole for a non-albicans candida tissue infection. Oral amoxicillin was then continued for one year. Furthermore, hyperbaric oxygen (HBO) therapy was also administered, leading to dramatic improvement.

(A) CT scan of the chest showing pulmonary metastatic nodules.

PMC6668214_01

Female

Written informed consent was obtained for the publication of this "Case Report." The patient was a 56-year-old Caucasian female accountant who was initially diagnosed with NSCLC in 2013. She presented with coughing, weight loss and progressive shortness of breath. The patient had severe chronic obstructive airway disease as a result of a 30-pack year history. The diagnosis was made on the basis of the findings of fine needle aspiration cytology and a confirmatory biopsy of a right-sided cervical lymph node. Histology showed a moderately differentiated adenocarcinoma with an immunohistochemical profile, which was consistent with that of lung cancer (CK7 Positive, CK 20 Negative, and TTF1 Positive). Her initial staging CT showed a large right-sided perihilar mass with significant left and right hilar nodes, sub-carinal and para-tracheal lymphadenopathy, as well as multiple satellite nodules in both lungs. A metastatic work-up was requested. An abdominal CT scan and a bone scan showed no evidence of metastatic disease. At diagnosis, the patient had stage IV disease (T4N3M1a). The patient was given first line treatment of carboplatin and gemcitabine. She had a partial response to treatment with a 60% reduction in the size of tumor bulk according to RECIST. In early 2014, the patient presented with progressive dyspnoea and radiological evidence of cut-off obstruction of the bronchus. This event was assessed as disease progression. Treatment consisted of palliative radiation to the hilar mass. She subsequently received 6 cycles of single-agent pemetrexed when her symptoms became significantly worse (Figure 1A) up to mid-2015. Later in the year the patient's disease progressed and she received treatment with nivolumab as part of a South African expanded access program (EAP). This program was available for patients with NSCLC failing platinum-based chemotherapy in the first-line metastatic setting. The patient experienced clinical improvement on nivolumab. However, in early 2016 she developed new symptoms of shortness of breath, cough and weight loss. A CT scan of the chest showed evidence of progressive disease, with new nodules bilaterally as well as new features of lymphangitis carcinomatosis. (Figures 1B,C). The new infiltrate was evident on the two different scans. An increasing right lung infiltration was noted, which was radiologically reported as either a secondary infection or disease progression. Pneumonitis was a differential diagnosis at the time. The patient was hospitalized as her symptoms were severe. She was treated with intravenous corticosteroids and broad-spectrum antibiotics for possible bacterial infection. The infiltrate was atypical and sputum was tested for acid-fast bacilli (AFB) to check for PTB. It is relevant to note that this patient came from a good socioeconomic area with no known exposure to TB. Her HIV status was negative. Sputum test was positive for AFB with numerous organisms observed microscopically (>10 per field in 20 fields). The patient was referred to an infectious diseases specialist for PTB management (isoniazid, ethambutol, rifampicin and pyrazinamide). She improved clinically and was discharged on anti-TB medication and steroids tapered. An attempt was made to restart nivolumab therapy, but the patient developed grade 2 diarrhea. After infectious causes were excluded, the diarrhea resolved with low dose oral corticosteroids. Shortly after that, the patient was readmitted for shortness of breath and respiratory symptoms and died in May 2016. Follow-up radiological investigation demonstrated cancer progression (Figure 1D).

checkpoint inhibitors, immune reconstitution, non-small cell lung cancer, pulmonary infiltrates, tuberculosis

PMC5371719_01

Female

A 41-year-old woman presented with chronic diarrhea for 3 years associated with significant weight loss. An ileocolonoscopy showed multiple well-defined rectal ulcers (Figure 1). Biopsies revealed reactive hyperplasia of the superficial and cryptic epithelium with extensive ulceration translated by the presence of exudate, as well as epithelioid granulomas with nucleated giant cells (Figure 2). Histiocytes containing brown pigment in the cytoplasm were observed in the lamina propria. Biopsies from the colon showed mild chronic inflammatory changes with an epithelioid granuloma. Immunohistochemistry for cytomegalovirus, periodic acid-Schiff, and Ziehl-Neelsen stains were negative. Abdominopelvic computed tomography enterography showed only circumferential thickening of the rectum. After reviewing the patient's medical history, we found that one of her children had died at the age of 9 years with a septic complication due to CGD. A cellular immunity and oxidative burst of granulocytes study showed a shortfall in the production of oxidative metabolites in 35% of granulocytes, therefore establishing the diagnosis of CGD carrier linked to chromosome X. A repeat colonoscopy was performed due to her high risk for recurrent infections. A rectal ulcer biopsy was positive for Nocardia through polymerase chain reaction (PCR). After excluding cerebral disease, she was started on cotrimoxazole for 3 months, followed by continuous weekly prophylaxis. Forty-two days after colonic biopsies were performed, a positive cultural result for mycobacterium tuberculosis (TB) was depicted. Standard anti-TB therapy was started, consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide; symptoms persisted after 12 months of treatment. Three months after the end of antibiotics, a new colonoscopy revealed that the ulceration had extended to the proximal colonic segments. Histological evaluation showed similar histological findings to what was described initially, including pigmented histiocytes and epithelioid granulomas (Figure 3). Biopsies for Mycobacteria and Nocardia were negative; however biopsies were now positive for herpes simplex 1 PCR and Aspergillus PCR. There was no evidence of herpes viremia. Blood cultures for fungi were also negative. The patient was treated with valacyclovir and subsequently maintained prophylaxis with itraconazole. After controlling these infections, she continued to complain of diarrhea (>10 bowel movements per day) with further weight loss. The patient was reluctant to start systemic steroids, so a multidisciplinary meeting led to the initiation of infliximab 5 mg/kg with cotrimoxazole and itraconazole prophylaxis. After 15 months of infliximab 5 mg/kg every 8 weeks, she had decreased her bowel movements to 3 per day and gained 5 kg. Subsequent laboratory tests showed consecutively normal complete blood counts, increased serum albumin, and normal C-reactive protein. During this period, the patient did not have any infectious complications. As such, anti-tumor necrosis factor (anti-TNF) therapy will be maintained indefinitely under close surveillance for the appearance of complications, especially infectious complications.

PMC6430003_01

Male

A 42-year-old Chinese man was admitted to the hospital with a generalized seizure, which was witnessed. He recalled feeling twitching of his eyes and mouth prior to a brief period of loss of consciousness. The patient felt well after the episode, with the exception of fatigue. There was no fever, chills, headache, or visual disturbances. The patient is from China, and has resided in the United States for 8 years. He has used intravenous heroin and alcohol but stopped 10 years previously. He smoked 1 package of cigarettes daily for 20 years. Past medical history is significant for HIV, hepatitis B and C (HCV), all diagnosed 3 months prior to this admission when he presented with progressive swelling of the lower extremities and elevated blood pressure. A renal biopsy showed membranoproliferative glomerulonephritis. The initial CD4+ cell count was 389/mm3, quantitative HIV RNA 58,254 copies/ml and HCV viral load 202,489 IU/mL. Treatment with dolutegravir and emtricitabine/tenofovir alafenamide was started 6 weeks previously, followed by sofosbuvir/velpatasvir. On admission, the oral temperature was 99.30F, pulse 100 beats/minute, respiratory rate 16 breaths/min, blood pressure 155/104 mmHg and oxygen saturation 99% on room air. Physical examination showed a laceration on the lateral aspect of the tongue and bilateral axillary lymphadenopathy. Neurological assessment revealed an alert and oriented patient with normal speech. No motor deficits were noted, and sensation was intact bilaterally. There was no facial weakness, and the tongue was midline. Cranial nerves were intact, with normal visual fields. Deep tendon reflexes were normal and symmetrical. No gait abnormalities were appreciated, and cerebellar function was intact. The leukocyte count was 7900/UL, hemoglobin 10.2 g/dL, and platelet count 177,000/UL. Blood urea nitrogen was 16 mg/dL, and creatinine was 1.2 mg/dL. The erythrocyte sedimentation rate was greater than 145 mm/h. Cerebrospinal fluid (CSF) analysis showed 10 leukocytes/mm3, glucose of 45 mg/dL (serum glucose 90 mg/dL) and protein of 48 mg/dL. CSF cryptococcal antigen, VDRL and bacterial cultures were negative. Absolute CD4+ count was 343/mm3 and HIV RNA was undetectable. Hepatitis B viral DNA and hepatitis C RNA were undetectable. Blood cultures, urine culture, urine toxicology and an echocardiogram were normal. Chest radiograph (CXR) was also normal. Parasitological investigation of stool samples did not reveal pathogens. The initial brain computed tomography (CT) showed numerous areas of white matter edema at the gray-white junction within the bilateral hemispheres, as well as in the left cerebellum (Fig. 1). Gadolinium-enhanced magnetic resonance imaging (MRI) revealed numerous small ring-enhancing masses with targetoid appearance and moderate surrounding vasogenic edema (Fig. 2). Serum cysticercus IgG and toxoplasma IgM and IgG antibodies were negative. Although the CXR was normal, the CT of the chest (Fig. 3) showed extensive lymphadenopathy, with bilateral apical airspace disease with tree-in-bud like appearance. Initial sputum acid-fast smears were negative. An axillary lymph node biopsy showed granulomatous inflammation with necrosis. Acid fast and fungal stains were negative. Treatment with isoniazid, rifabutin, ethambutol, and pyrazinamide was started. In addition, dexamethasone 0.3 mg/kg/day was given together with anti-tuberculous medication and gradually tapered over six weeks. The patient was discharged on hospital day 23. Three weeks later, the axillary lymph node and sputum cultures grew Mycobacterium tuberculosis. Follow-up brain MRI with gadolinium five months later showed that nearly all of the previously demonstrated ring enhancing masses had decreased in size and markedly decreased surrounding vasogenic edema (Fig. 4). In addition, follow-up CT of the chest 2 weeks after initiation of treatment revealed partial resolution of the previously seen bronchial and bronchiolar inspissation in both upper lobes (Fig. 5).

antiretroviral therapy, hiv, immune reconstitution inflammatory syndrome, tuberculosis, unmasking

Post-treatment computed tomography of the chest revealing partial resolution of the previously seen bronchial and bronchiolar inspissation in both upper lobes.

PMC8769448_01

Female

A 50-year-old previously healthy woman suddenly lost consciousness while on the toilet at home. Her husband, a firefighter, immediately performed CPR and called an ambulance. When the ambulance crew arrived, Glasgow coma scale score was 3, both pupils were 4.0 mm in diameter, and cardiac rhythm was ventricular fibrillation (VF). Therefore, shock resuscitation was implemented. The patient's heartbeat resumed in 5 min but she suffered repeated cardiac arrest during transport to the hospital and was in cardiac arrest on arrival at the hospital. Immediately after arrival, her heartbeat resumed but this was again followed by cardiac arrest. As the patient continued to repeatedly experience cardiac arrest, percutaneous cardiopulmonary support (PCPS) was initiated. Pupil contraction and spontaneous respiration subsequently resumed 77 min after onset (Table 1).

coil embolization, extracorporeal cardiopulmonary resuscitation, out-of-hospital cardiac arrest, percutaneous cardiopulmonary support, subarachnoid hemorrhage

PMC3885780_01

Male

Nocardiosis is a rare and potentially life-threatening infection. Nocardia species are a group of aerobic actinomycetes, which are filamentous, branching, gram-positive, and acid-fast bacilli. Worldwide, respiratory and disseminated infections are most often due to N. asteroids complex, which is increasingly recognized as an opportunistic infection in immunocompromised hosts with underlying HIV infection, neoplastic disease, or long-term high-dose corticosteroid therapy. Recently, infection of N. cyriacigeorgica was reported in an immunocompromised patient in Korea, which was identified by 16S rRNA sequencing analysis and additional biochemical tests combined to draw a conclusion. Here, we describe a case of necrotizing pneumonia and empyema caused by N. cyriacigeorgica in a 77-yr-old Korean male patient who was immunocompetent. This case was diagnosed by DNA amplification and sequence analyses of the 16S rRNA and secA1 genes. The patient was referred to our hospital from a local clinic because of dyspnea and right-side chest pain after he had a fall from a bed 2 days before presentation. He had no underlying medical problems except controlled hypertension. On initial clinical examination in the emergency room, oxygen saturation was 89.7%, but it improved to 97% after initiation of 5 L oxygen. The patient had normal vital sign and electrocardiogram. Chest radiography revealed a pleural effusion on the right side (Fig. 1A). The pleural effusion was drained by chest tube placement, and it was reddish and had many red blood cells (RBCs) (>10,000/L) and 850 leukocytes/L (96% of polymorphonuclear cells). Laboratory investigation showed a leukocyte count of 6,900/L with 97.2% segmented neutrophils and elevation of serum C-reactive protein level of 27.8 mg/dL, erythrocyte sedimentation rate of 53 mm/hr, and serum lactate dehydrogenase of 575 IU/L. Mycobacterium tuberculosis PCR performed using the pleural fluid isolate tested negative. Chest computed tomography (CT) scan with contrast showed pleural effusion of both lungs with pleural thickening (Fig. 1B). Pleural fluid cytology was negative for malignant or severe inflammatory changes. Whole body fusion positron emission tomography (PET)/CT showed diffuse hypermetabolism of both pleural surfaces, but it was more suggestive of an inflammatory lesion than malignancy. The patient was clinically diagnosed as having both necrotizing pneumonia and hemothorax and was empirically treated intravenously with a third-generation cephalosporin and aminoglycoside. Although fever was observed on admission day 7 and aggravation of pneumonia was noted on a follow-up CT scan taken on day 15, no organism was obtained from subsequent sputum, pleural fluid, or blood cultures. On day 17, the patient was transferred to the intensive care unit and received ventilator support because of altered mental status and respiratory distress. On day 23, pleural fluid cultures on sheep blood agar plates (BAP) grew rough, chalky-white colonies with an earthy odor; the presence of abundant thin, modified acid-fast, and gram-positive branching filaments was observed on microscopic examination (Fig. 2). The same organism was isolated once again from pleural fluid; thus, the patient was suggested to have a nocardial infection. We decided to obtain further information using molecular methods for 16S rRNA and secA1 sequence analysis. However, multidrug-resistant Acinetobacter baumannii was identified from the patient's sputum obtained on day 36, and the patient died from progression of hospital/ventilator-associated pneumonia and respiratory failure. The etiologic diagnosis was established post-mortem by means of molecular analysis. To identify the bacterium, molecular identification was performed by DNA amplification and sequencing analysis of the 16S rRNA and secA1 genes from the chest tube drainage isolate. 16S rRNA and secA1 gene fragments were amplified by standard methods according to CLSI guidelines. The secA1 protein is an essential component of the preprotein translocase ATPase, which provides the driving force for the export of proteins across the bacterial cytoplasmic membrane. The secA1 locus has potential for nocardia species identification as an adjunct to 16S rRNA gene sequencing. Two sub-regions of the 16S rRNA and secA1 genes were amplified and sequencing analysis using the previously reported primer pairs. Purified PCR products were sequenced directly using the BigDye Terminator Cycle Sequencing Kit 3.1 (Applied Biosystems; Foster City, CA, USA) on an ABI Prism 3100 genetic analyzer (Applied Biosystems). A GenBank Basic Local Alignment Search Tool (BLAST) search revealed that the 16S rRNA gene sequence of the isolate showed 100% and 98% homology of 695 base pairs to corresponding sequences of the previously sequenced N. cyriacigeorgica and N. farcinica (GenBank accession numbers NR_074699.1 and AB162791.1). Moreover, for the secA1 gene, we confirmed the corresponding sequence from N. cyriacigeorgica (JQ773455.1) with 100% homology of 505 base pairs, whereas less than 94% homology was noted for other Nocardia species. For further phylogenetic analysis, 16S rRNA and secA1 gene sequences isolated from the chest tube drainage fluid were aligned using ClustalW. Phylogenetic trees were constructed with the neighbor-joining method using the MEGA 5 software package (http://www.megasoftware.net) and Kimura 2 parameters as the substitution model. Statistical significance of the phylogenies was assessed by bootstrap analysis with 1,000 pseudoreplicate datasets. The tree is drawn to scale, with branch lengths in the same units as those of the evolutionary distances used to infer the phylogenetic tree (Fig. 3). Prior to the advent of molecular biological techniques, traditional diagnostic methods for identifying these organisms were often ambiguous. Rapid and accurate identification of aerobic actinomycetes is becoming increasingly important in clinical microbiology laboratories. Pulmonary nocardiosis may clinically be acute, subacute, or chronic. Acute nocardiosis often occurs in severely immunocompromised patients and correlates with a poor prognosis, with a high mortality of more than 40% in cases of disseminated disease. Subacute lung nocardiosis, the most common clinically encountered form, often mimics tuberculosis, pneumocystosis, invasive fungal infection, and/or malignancy. Currently, the Nocardia genus has approximately 100 reported species of different taxonomic statuses (http://www.bacterio.cict.fr/n/nocardia.html). According to Wallace et al., the heterogeneity of the Nocardia group in terms of drug susceptibility patterns requires frequent new taxon formation to account for new species. Of the known Nocardia species, the species most frequently involved in human infection are members of the N. asteroides complex. The members of this complex have been sub-classified into 6 separate groups according to drug susceptibility patterns with numerous new species described. N. cyriacigeorgica was first characterized in 2001 by Yassin et al. from the bronchial secretions of a patient with chronic bronchitis. At that time, this organism was identified as a novel species that was both molecularly and biochemically different from previously described members of the genus Nocardia. It corresponds to strains of the drug pattern type VI of the N. asteroides complex. They reported that this new species had different DNA-DNA hybridization with N. abscessus (45% reassociation) and N. asteroides complex type strains (61% reassociation). Nocardia species do not typically affect immunocompetent hosts. Clinically oriented criteria for nocardiosis may be useful for evaluating the significance of a positive culture from isolated specimens. Criteria include direct visualization of a rod-form microorganism with gram-positive and acid-fast microscopic findings and repeated isolation from serial clinical samples in immunocompromised hosts. However, their presence should suggest a careful evaluation of clinical conditions. In a retrospective study, 20% of Nocardia species isolates were found not to be associated with the clinical disease. Most nocardiosis cases are not rapidly recognized because of lack of pathognomonic clinical signs, limitations of conventional biochemical tests for slow-growing bacteria, and the presence of commensal flora on culture. In the present case, when gram-positive bacilli were isolated for the first time from the pleural fluid of our patient, we considered that this strain was present owing to the transient colonization in response to chest tube replacement. However, subsequent pleural fluid cultures obtained the same results, along with aggravation of the patient's clinical status and the lack of any other documented organism. The strain was presumed to be a member of the genus Nocardia, and further molecular analysis was planned. For therapy, Nocardia, and especially N. cyriacigeorgica, is typically susceptible to sulfonamide, amikacin, linezolid, imipenem, and broad-spectrum cephalosporins, which are often used empirically in the absence of antibiotic susceptibility information. In this study, the strain was tested for susceptibility using the Sensititre RAPMYCOI plate (Trek Diagnostic Systems, Cleveland, OH, USA) according to CLSI guidelines. The isolate was susceptible to trimethoprim/sulfamethoxazole (minimum inhibitory concentration [MIC]: 0.5/9.5 microg/mL), amikacin (<=1 microg/mL), linezolid (<=1 microg/mL), ceftriaxone (<=4 microg/mL), minocycline (<=1 microg/mL), and tobramycin (<=1 microg/mL), and it was resistant to ciprofloxacin (>4 microg/mL), moxifloxacin (4 microg/mL), imipenem (64 microg/mL), cefepime (32 microg/mL), and amoxicillin/clavulanic acid (64/32 microg/mL). Although the patient received empirical treatment with third-generation cephalosporin and aminoglycoside, he died from progression of hospital/ventilator-associated pneumonia and respiratory failure. Application of molecular methods for sequence analysis of the 16S rRNA and secA1 genes can assist in a quicker diagnosis of most Nocardia species. For certain groups of aerobic actinomycetes, the use of alternative gene targets such as the secA1 gene can serve as adjuncts to 16S rRNA sequencing of Nocardia species. The use of targeted genes is useful because some species may share 99.6-100% 16S rRNA sequence homology, despite being different species. Thus, definitive identification was obtained by 16S rRNA analysis and alternate DNA target analysis with the secA1 gene. Although this is the second case of pulmonary nocardiosis caused by N. cyriacigeorgica in Korea, to the best of our knowledge, this is the first report on an immunocompetent patient with N. cyriacigeorgica infection, which was identified using molecular analysis for 16S rRNA and secA1 sequences. This case shows that necrotizing pneumonia and empyema can occur in an immunocompetent patient and should be considered in the differential diagnosis of suspected cases.

PMC6091280_01

Male

A 19-year-old African American man was brought to the emergency department (ED) by emergency medical services (EMS) after an episode of syncope earlier on the day of admission while playing basketball at his college. This occurred suddenly and was associated with a transient episode of lightheadedness, diaphoresis, and blurred vision. This was followed by lost consciousness for less than 10 seconds, with spontaneous recovery as witnessed by his friends on the sidelines. There was not any involuntary movement of the body, urinary or bowel incontinence, or postictal confusion as per the witnesses. After regaining consciousness, there was a complaint of nonradiating, substernal, burning chest pain with a "6 out of 10" intensity, which lasted approximately 20-30 minutes and was relieved with a nitroglycerin sublingual pill given by EMS. On arrival to the ED, the patient was asymptomatic. Blood pressure was 103/67 mmHg, heart rate 85 bpm and regular, afebrile oxygen saturation > 95% on room air, and respiratory rate 12 per minute. Physical examination findings revealed a supple neck with no jugular venous distention; no carotid bruits were audible. Cardiovascular examination revealed a regular heart rhythm with normal S1 and S2 and no significant audible murmurs, parasternal heave, or thrill. The lungs were clear to auscultation bilaterally. There was no pitting pedal edema, and all peripheral pulses were palpable. The abdomen was soft and nondistended; no focal neurological deficits were evident. History was positive for two similar events in the past. The first episode occurred approximately 10 years ago in Nigeria while playing soccer, and another event occurred a year ago year while running a block to catch a bus. Medical attention was not sought on both occasions. Family history was negative for similar syncopal attacks, sudden cardiac arrest, or arrhythmias. Social history was positive for drinking heavy amounts of Vodka with friends occasionally on the weekends along with marijuana but negative for cigarette smoking or other illicit drug use. Initial laboratory values in the ED showed hemoglobin of 12.3 gm %, serum creatinine of 1.4 mg/dl (normal reference range 0.50 to 1.20 mg/dl) and BUN of 24 mg/dl, elevated initial troponin I of 0.23 ng/ml (normal reference range 0.00 to 0.07 ng/ml), total creatinine kinase level of 585 units/liter (normal reference range: 49 to 397 U/l), and urine with 11-20 hyaline casts. Thyroid stimulating hormone, serum potassium, and serum magnesium were within normal limits. His chest X-ray did not reveal any acute cardiopulmonary process (Figure 1). His initial electrocardiogram (EKG) revealed significant 4 mm to 5 mm ST depression in the anterolateral leads but otherwise unremarkable (Figure 2). A repeat EKG done within 2 hours of the initial presentation showed reversal of ST depression (Figure 3). A repeat troponin done in 6 hours revealed staggering troponin I of 53.30 ng/ml. Immediate bedside echocardiogram showed a nondilated left ventricular cavity with normal LV wall thickness and a mildly diminished LV ejection fraction at 45-50% (Figure 4). In the emergency room, immediate treatment with 325 mg of Aspirin and therapeutic Lovenox (1 mg/kg) was given. Overnight, periodic 5-7-beat runs of nonsustained ventricular tachycardia on the cardiac monitor occurred. Cardiac tomography (CT) angiography of the heart revealed a common trunk for the right and left coronary arteries arising from the right coronary cusp. The right coronary artery had a normal course. The LMCA traveled posteriorly between the ascending aorta and pulmonary outflow tract before resuming its normal course. The LMCA narrowed in its midportion as it passed between these two structures (Figures 5(a) and 5(b)). These findings were confirmed by cardiac catheterization which showed an anomalous origin of the LMCA, originating from the right sinus of Valsalva (Figures 6(a) and 6(b)). The LMCA narrowed in its midportion with over 60-70% luminal stenosis due to a stricture present between the ascending aorta and the left ventricular outflow track. Afterwards, medical stabilization was achieved and a transfer to a tertiary care center was carried out. Upon arrival at the tertiary care center, a procedure was performed involving the unroofing of the anomalous aortic origin of the left main coronary artery, including retro pulmonary unroofing by a congenital cardiothoracic surgeon. Recovery was satisfactory after the surgery, and postoperative complications did not occur.

PMC7412810_01

Male

The patient is a 21-year-old young man without significant past medical history. He initially presented with a complaint of intermittent abdominal pain, and a CT scan revealed an abnormal paraspinal lesion. He underwent MRI which demonstrated the lesion extending from T12-L2 and measured 8.7 cm x 3.9 cm x 6.9 cm (Fig. 1a, b). Subsequent biopsy revealed a spindle cell mesenchymal tumor with monotonous, bland spindle cells admixed with mature fat and occasional ectatic blood vessels (Fig. 2). Neither necrosis nor brisk mitotic activity were noted. IHC studies demonstrated positivity for CD34, pan-TRK, S-100 and SMA (not shown); the tumor was negative for Pankeratin cocktail, STAT6, DOG1, desmin, TLE1, panmelanocytic cocktail, and Sox10. Scattered cells labeled for SATB2 and H3K27me3. The tumor was negative for MDM2 amplification or FUS gene rearrangement using fluorescent in situ hybridization (FISH). The S-100 staining raised the possibility of a peripheral nerve sheath origin. Given the pan-TRK immunoreactivity, the diagnosis of LPF-NT was considered; however, the site was unusual as it was not superficial. Thus, further molecular testing was performed. A custom-designed, clinically-validated anchored multiplex PCR-based targeted next-generation sequencing (NGS) RNA fusion panel that covers 485 exons from 81 genes and is optimized for formalin-fixed, paraffin-embedded (FFPE) samples, revealed a fusion between exon 2 of LMNA (NM_005572.3; chr1:156100564) and exon 11 of NTRK1 (NM_002529.3; chr1:156844698), predicted to encode an in-frame LMNA-NTRK1 fusion protein retaining the C-terminal kinase domain of NTRK1 (Fig. 3a). The fusion transcripts were confirmed with orthogonal RT-PCR and Sanger sequencing (Fig. 3b). Identification of this fusion reclassified the putative diagnosis to an S-100 positive LPF-NT of the spine. Due to size and location, primary surgical resection would have been exceedingly morbid. Thus, the patient was entered into a phase II basket trial enrolling patients with NTRK 1/2/3, ROS1, or ALK gene rearrangements to be treated with entrectinib. He received a dose of 600 mg daily, and the only adverse effects were grade 1 diarrhea and taste alterations. Early response assessment after 1 month demonstrated a near-complete loss of enhancement and density of the mass, with the hounsfield units dropping from 200 on the initial scan to 55-60 at follow up (Figs. 1a, b, and 4). He had an excellent therapeutic response, with a 45% reduction in tumor size by RECIST criteria, measuring 4.0 x 2.8 cm (Fig. 5). Although the patient was not initially a surgical candidate due to unacceptable morbidity, his response to therapy was so exceptional that he ultimately qualified for surgical resection. Therefore, he underwent vertebrectomy, which revealed a 7.0 x 5.2 x 3 cm mass with tan-white pink cut surface involving paraspinal soft tissue and protruding into the vertebral body, with underlying bony sclerosis. Histologically, there was extensive treatment response (> 95%) with decreased cellularity, marked hyalinization and focal areas of viable tumor cells (Fig. 6). The tumor focally involved soft tissue margins however bone margins were tumor-free. The patient has continued on entrectinib following surgery and remains without evidence of recurrence at 7 months.

entrectinib, lpf-nt, lipofibromatosis-like neural tumors, ntrk

PMC4913963_01

Female

This study was approved by the review boards of Jishuitan Hospital and Fourth Medical College of Peking University. Patient consent to this study was not required because the retrospective nature of the study. A 56-year-old woman was admitted to our hospital on July 1, 2015 because of intermittent fever and nonproductive cough for 2 weeks and exertional dyspnea and chest pain for 1 week. She described no chills, rigors, and night sweats. The patient developed abdominal pain and had mucus stools on April 20, 2015. Laboratory tests at a local clinic on May 20, 2015 showed leukocytes at 6.9x109/L with 67.9% neutrophils and 0.12% eosinophils. Her hemoglobin level was 129 g/L and platelet count was 276x109/L. The occult stool test was weakly positive. She started mesalazine 0.5 g three times a day for 6 weeks without a prescription. The patient began coughing on June 17, 2015 and also had fatigue and fever (as high as 39.4 C). Laboratory examinations revealed leukocytes at 12.75x109/L with 76.2% neutrophils and 6.9% eosinophils. Her hemoglobin level stood at 124 g/L and platelet count was 485x109/L. A chest radiograph and computed tomography (CT) scan showed minor peripheral patchy opacity in bilateral upper and mid lungs with a narrowed right costophrenic angle (Figure 1A and B). A 10-day course of intravenous levofloxacin and ceftazidine was administered, and the patient continued mesalazine. Nevertheless, the patient was still febrile. On June 24, 2015, the patient developed right chest pain and aggravating exertional dyspnea. She denied symptoms of palpitations and paroxysmal nocturnal dyspnea. She denied the use of tobacco products and had no occupational exposure to chemical fumes, including biomass fuel. The patient was allergic to penicillin and metronidazole. She had hypertension for 5 years, which was controlled by taking sustained release nifedipine. There was no family history of asthma. Physical examination at admission showed a blood pressure of 117/70 mmHg, a pulse rate of 101 beats/min, a respiratory rate of 20 breaths/min, and a temperature of 37.4 C. No crackles were noted in both lungs. Clubbing, cyanosis, or peripheral edema was absent. Cardiovascular and abdominal examinations were unremarkable. Review of the systems was unremarkable for skin rashes, joint pain, and weight loss. Laboratory investigations revealed leukocytes at 25.54x109/L with 67.4% neutrophils and 21.8% eosinophils. Her hemoglobin was 111 g/L and platelet count 593x109/L. Renal and liver function were normal, and no splenomegaly was noted. Chest radiograph showed progressing opacity predominantly in bilateral upper lungs (Figure 1C). Chest CT scan revealed bilateral patchy consolidations with interlobular septal thickening (Figure 1D and 1E). The single-breath diffusing capacity of the lung for carbon monoxide (DLco) was 46% of the predicted values. Transbronchial biopsy revealed chronic inflammation and exudation of fibrin (Figure 2A), and bronchoalveolar lavage fluid (BALF) showed 1x106 cells/mL with 18% macrophages, 22% neutrophils, 33% eosinophils, and 27% lymphocytes (Figure 2B). Bone marrow aspirate showed infiltration by mature eosinophils (Figure 2C), but the ratio of promyelocytes to their precursors was normal, and the percentage of eosinophils was 18, with normal morphology. Arterial blood gas analysis revealed a pH of 7.523, a partial pressure of carbon dioxide (pCO2) of 29.7 mmHg, a partial pressure of oxygen (pO2) of 59.5 mmHg, and a bicarbonate level of 23.2 mmol/L on room air. Tests for adenovirus, respiratory syncytial virus, seasonal influenza A and B, parainfluenza virus, Mycoplasma pneumoniae, Chlamydia, and Legionella pneumophila were negative. Tuberculin skin test and sputum and BALF tests for acid-fast bacilli excluded tuberculosis. Rheumatoid factor, antinuclear antibodies, anti-double-strand DNA antibody, antiextractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibody were negative. C-reactive protein was at 191 mg/dL, erythrocyte sedimentation rate was at 65 mm/h, and immunoglobulin E was at >100 IU/mL. Colonoscopy at 2 weeks after admission demonstrated focal erythema, erosions, and edematous swollen mucosa in the rectum. Mesalazine-induced eosinophilic pneumonia was diagnosed, and mesalazine was discontinued. Currently, there is no consensus for the use of corticosteroid therapy for mesalazine-induced eosinophilic pneumonia, and our patient was not given corticosteroids. Besides, four out of nine reported cases also recovered without corticosteroid therapy. The patient improved in symptoms, and 4 weeks after cessation of mesalazine, she was discharged. CT scan showed bilateral ground glass opacity (Figure 1E). At 5 weeks of follow-up after discharge, the patient was asymptomatic with a normalized eosinophil count (Figure 3). Spirometry continued to show a restrictive defect and a reduced DLco (44%) (Table 1), but the patient felt no apparent exertional dyspnea after discharge.

colitis, eosinophil, mesalazine, pneumonia

Radiologic features of eosinophilic pneumonia in a 56-year-old woman who took mesalazine for suspected ulcerative colitis. chest CT scan (June 27, 2015) reveals peripheral opacity in both lungs.

PMC4913963_01

Female

This study was approved by the review boards of Jishuitan Hospital and Fourth Medical College of Peking University. Patient consent to this study was not required because the retrospective nature of the study. A 56-year-old woman was admitted to our hospital on July 1, 2015 because of intermittent fever and nonproductive cough for 2 weeks and exertional dyspnea and chest pain for 1 week. She described no chills, rigors, and night sweats. The patient developed abdominal pain and had mucus stools on April 20, 2015. Laboratory tests at a local clinic on May 20, 2015 showed leukocytes at 6.9x109/L with 67.9% neutrophils and 0.12% eosinophils. Her hemoglobin level was 129 g/L and platelet count was 276x109/L. The occult stool test was weakly positive. She started mesalazine 0.5 g three times a day for 6 weeks without a prescription. The patient began coughing on June 17, 2015 and also had fatigue and fever (as high as 39.4 C). Laboratory examinations revealed leukocytes at 12.75x109/L with 76.2% neutrophils and 6.9% eosinophils. Her hemoglobin level stood at 124 g/L and platelet count was 485x109/L. A chest radiograph and computed tomography (CT) scan showed minor peripheral patchy opacity in bilateral upper and mid lungs with a narrowed right costophrenic angle (Figure 1A and B). A 10-day course of intravenous levofloxacin and ceftazidine was administered, and the patient continued mesalazine. Nevertheless, the patient was still febrile. On June 24, 2015, the patient developed right chest pain and aggravating exertional dyspnea. She denied symptoms of palpitations and paroxysmal nocturnal dyspnea. She denied the use of tobacco products and had no occupational exposure to chemical fumes, including biomass fuel. The patient was allergic to penicillin and metronidazole. She had hypertension for 5 years, which was controlled by taking sustained release nifedipine. There was no family history of asthma. Physical examination at admission showed a blood pressure of 117/70 mmHg, a pulse rate of 101 beats/min, a respiratory rate of 20 breaths/min, and a temperature of 37.4 C. No crackles were noted in both lungs. Clubbing, cyanosis, or peripheral edema was absent. Cardiovascular and abdominal examinations were unremarkable. Review of the systems was unremarkable for skin rashes, joint pain, and weight loss. Laboratory investigations revealed leukocytes at 25.54x109/L with 67.4% neutrophils and 21.8% eosinophils. Her hemoglobin was 111 g/L and platelet count 593x109/L. Renal and liver function were normal, and no splenomegaly was noted. Chest radiograph showed progressing opacity predominantly in bilateral upper lungs (Figure 1C). Chest CT scan revealed bilateral patchy consolidations with interlobular septal thickening (Figure 1D and 1E). The single-breath diffusing capacity of the lung for carbon monoxide (DLco) was 46% of the predicted values. Transbronchial biopsy revealed chronic inflammation and exudation of fibrin (Figure 2A), and bronchoalveolar lavage fluid (BALF) showed 1x106 cells/mL with 18% macrophages, 22% neutrophils, 33% eosinophils, and 27% lymphocytes (Figure 2B). Bone marrow aspirate showed infiltration by mature eosinophils (Figure 2C), but the ratio of promyelocytes to their precursors was normal, and the percentage of eosinophils was 18, with normal morphology. Arterial blood gas analysis revealed a pH of 7.523, a partial pressure of carbon dioxide (pCO2) of 29.7 mmHg, a partial pressure of oxygen (pO2) of 59.5 mmHg, and a bicarbonate level of 23.2 mmol/L on room air. Tests for adenovirus, respiratory syncytial virus, seasonal influenza A and B, parainfluenza virus, Mycoplasma pneumoniae, Chlamydia, and Legionella pneumophila were negative. Tuberculin skin test and sputum and BALF tests for acid-fast bacilli excluded tuberculosis. Rheumatoid factor, antinuclear antibodies, anti-double-strand DNA antibody, antiextractable nuclear antigen antibodies, and antineutrophil cytoplasmic antibody were negative. C-reactive protein was at 191 mg/dL, erythrocyte sedimentation rate was at 65 mm/h, and immunoglobulin E was at >100 IU/mL. Colonoscopy at 2 weeks after admission demonstrated focal erythema, erosions, and edematous swollen mucosa in the rectum. Mesalazine-induced eosinophilic pneumonia was diagnosed, and mesalazine was discontinued. Currently, there is no consensus for the use of corticosteroid therapy for mesalazine-induced eosinophilic pneumonia, and our patient was not given corticosteroids. Besides, four out of nine reported cases also recovered without corticosteroid therapy. The patient improved in symptoms, and 4 weeks after cessation of mesalazine, she was discharged. CT scan showed bilateral ground glass opacity (Figure 1E). At 5 weeks of follow-up after discharge, the patient was asymptomatic with a normalized eosinophil count (Figure 3). Spirometry continued to show a restrictive defect and a reduced DLco (44%) (Table 1), but the patient felt no apparent exertional dyspnea after discharge.

colitis, eosinophil, mesalazine, pneumonia

Radiologic features of eosinophilic pneumonia in a 56-year-old woman who took mesalazine for suspected ulcerative colitis. bilateral patchy consolidations with interlobular septal thickening in both lungs on CT scan (July 15, 2015).

PMC9207951_01

Male

A 14-year-old boy was admitted to our hospital because of diarrhea, hypoalbuminemia, and gross hematuria. He had been well until 5 years earlier, when he developed edema in the eyelid and lower extremities. At that time, he had a serum albumin concentration of 2.63 g/dL and 24-h urinary protein quantitation of 4,400 mg. Stool cultures were sterile, and a stool examination showed no ova or parasites. A tuberculin skin test (purified protein derivative, 5 TU) was strongly positive at the 72-h timepoint. The TSPOT.TB assay qualitative results were positive. A patchy shadow was present in a computed tomography (CT) scan of the chest. The clinical diagnosis was pulmonary tuberculosis. The patient was treated with a combination of isoniazid, rifampin, and pyrazinamide for 6 months. However, his serum albumin concentration remained at 2.5-3.6 g/dL after the therapy. Two years before the present admission, he developed diarrhea with watery stools, but had no fever or vomiting. A physical examination showed hepatic and splenic enlargement. Laboratory tests showed that his serum albumin concentration was low at 1.75 g/dL. The qualitative results of the TSPOT.TB assay were positive. A dense consolidation was present in the right lobe with enlarged mediastinal lymph nodes, ascites, and pleural and pericardial effusions on chest CT. Cardiac CT showed a calcified cardiac base and pericardium. Echocardiography showed moderate right ventricular and auricular dilatation with pulmonary arterial hypertension. The clinical diagnoses were pulmonary tuberculosis, hypoproteinemia, and diarrhea. The patient was treated with a combination of isoniazid, rifampin, ethambutol, and pyrazinamide for 8 months. Albumin infusions were also administered. However, the albumin infusions had only short-term effects and could be used only as a bridging intervention. Serum albumin concentrations remained at 1.5-2.5 g/dL. The diarrhea was still present. Four months before the present admission, the patient visited a local hospital because of hematuria. Persistent splenomegaly and hepatomegaly were found. The serum albumin concentration was 2.17 g/dL. Urinalysis showed a protein concentration of 220 mg/24 h and a red cell count of 8,634/muL. Cardiac CT showed a calcified pericardium. Chest CT showed right-lobe pneumonia with pleural effusion. The patient began treatment with captopril (an angiotensin-converting enzyme inhibitor) and dipyridamole. The diarrhea persisted. On admission to our hospital, the patient had a normal temperature, pulse rate, respiratory rate, and blood pressure. A physical examination showed eyelid edema and jugular vein engorgement. The lungs were clear. The heart sounds were slightly weak without murmurs. Palpable splenomegaly and hepatomegaly were found. The urine was positive for protein (+), with a protein concentration of 160 mg/24 h. The sediment contained 100-200 red cells/high-powered field. The patient had pulmonary tuberculosis. Cardiac CT showed a calcified pericardium (Figure 1). Echocardiography showed decreased cardiac function underlying protein-losing enteropathy (PLE; Figure 2). The inferior vena cava was widened. Ultrasonographic examination findings of the urinary tract were normal. Functional imaging with technetium-99m serum albumin identified the region of protein leakage as the intestine (Figure 3). A biopsy of the liver showed fibrotic changes. On the basis of these findings, the patient was diagnosed with tuberculosis-related constrictive pericarditis, which was considered to have caused the PLE. Pericardiectomy was then performed. A pathological examination of the pericardium showed hyaline degeneration (Figure 4). The diarrhea ceased completely soon after the pericardiectomy. The patient's cardiac condition then improved. During a 2-year follow-up, the patient reported no symptoms, edema of the extremities, or pleural effusion. His serum albumin concentrations were increased (3.3-3.7 g/dL), which indicated resolution of the PLE (Figure 5).

constrictive pericarditis, hematuria, hypoalbuminemia, intestinal lymphangiectasia, protein-losing enteropathy

PMC4719905_01

Male

In October 2007, an 82 year-old male presented for investigation of painless macroscopic hematuria on a background of BPH and emphysema. Initial investigations included urine cytology, urine culture, TRUS and CT of the abdomen and pelvis. Laboratory investigations were unremarkable, while imaging results demonstrated an enlarged prostate measuring 130 cc. Diagnostic cystoscopy conducted in the same month demonstrated a lesion on the right bladder wall that was resected. Histology showed a high-grade papillary bladder cancer. His repeat cystoscopy 6 weeks later was clear. On surveillance cystoscopy 6 months later, an area of erythema suggestive of carcinoma-in-situ (CIS) near the right ureteric orifice was noted and resected; this was confirmed on histology. Given his tumor profile, the patient was commenced on a 6-weeks course of induction BCG therapy in March 2008. The patient completed six rounds of induction intravesical BCG therapy that was well tolerated. No maintenance therapy was given. The patient underwent TURP in July 2008, following an episode of urinary retention in conjunction with a history of obstructive voiding symptoms. At the time of the TURP, the bladder looked macroscopically normal with a good capacity and no sign of contractions. The histology of the prostate specimen showed nodular hyperplasia of the prostate in addition to granulomatous inflammation indicative of the BCG effect. Serial surveillance cystoscopies and urine cytology were clear. By late 2010, almost 3 years following BCG therapy, the patient began experiencing issues with nocturnal frequency and incontinence. Urine cultures taken were positive for mycobacteria. A repeat cystoscopy showed marked inflammatory changes within the bladder, with associated thickened bladder mucosa; biopsies taken at the time confirmed BCG cystitis. The patient was commenced on a course of oral Rifampicin, Isoniazid and Pyridoxinein in standard doses for a total of 9 months for reactivation of BCG. Ongoing daytime frequency and urge incontinence prompted repeat urine cultures that grew Klebsiella oxytoca and was appropriately treated based on sensitivities. In spite of appropriate antibiotic treatment, the patient's symptoms persisted. Further investigation with a CT abdomen and pelvis in September 2011 demonstrated marked mural thickening of the bladder with bilateral hydro-ureter and hydronephrosis. Check cystoscopy in the same month showed significant improvement in the inflammation, however, some areas of bullous edema persisted. Biopsies taken at the time revealed congestion and inflammatory cell infiltrate, but no evidence of malignancy. Additionally, repeat urine cultures were negative for Mycobacterium bovis BCG but did show a small number of atypical cells that were considered to be reactive in nature. The patient was advised to undertake bladder training, wear a urodome and was commenced on solifenacin succinate. Repeat urine cultures following the completion of tuberculosis treatment were all negative for M. bovis, suggesting successful treatment of his BCG reactivation. However, his symptoms of frequency and urge incontinence persisted despite medication and behavioral therapy. Subsequent surveillance cystoscopy showed no cancer recurrence, but did demonstrate bladder irregularity with multiple septae, diverticuli and evidence of contractures. Over the next 2 years continued surveillance did not identify a recurrence of bladder cancer, though the bladder remained fibrotic and poorly contractile. The patient was not a candidate for surgery due to his anesthetic risk, thus his ongoing incontinence was managed with incontinence pads and urodomes indefinitely (Figure 1, Figure 2).

bcg, bladder cancer, contracture, side effect

PMC8492417_01

Female

An 11-year-old, Indonesian girl has been complaining persistent headache in the past 3 years. The headache was getting worse. The patient had a history of surgical excision of craniopharyngioma [Figure 1] 8 years ago, and placement of VP shunt flat bottom type, medium pressure, on the right Kocher point due to postoperative hydrocephalus. After the craniopharyngioma excision surgery, the patient never had radiotherapy due to her young age. From the anamnesis, the patient did not have TB symptoms such as prolonged cough, unexplained fever, weight loss, and night sweats. The patient had no history of contact with family, friends, or surrounding people with TB disease. The patient had no history of previous routine antibiotics treatment. On examination, the patient had a stable vital sign with normothermia. She was fully conscious with GCS E4M6V5. There were no meningeal sign nor nuchal rigidity. Other neurological examinations were normal. The patient was immunocompetent and well-nourished. There was no sign of systemic TB nor meningoencephalitis. Routine laboratory tests and chest X-ray were all normal. Brain magnetic resonance imaging (MRI) [Figure 2] revealed a 4 x 2.3 x 2.1 cm mass surrounding the ventricular drain which was attached in the anterior horn of the right lateral ventricle to the right frontal cortex. The mass was isointense in T1 and hypointense in T2. After administration of gadolinium, the mass was highly heterogenous contrast enhancement. There was perifocal edema around the tumor. On dynamic susceptibility contrast (DSC) MRI perfusion, the relative cerebral blood volume appeared to be elevated, leading to a malignant process. On MR Spectroscopy (MRS) [Figure 3], the Choline/Creatine and Choline/NAA ratio appeared to be elevated with Choline map also increased. There was no sign of hydrocephalus nor residual of craniopharyngioma. No sign of meningoencephalitis was seen. From brain MRI examination suggested a process of seeding metastases surrounding the ventricular drain in the area of the anterior horn of the right lateral ventricle to the right frontal cortex. From the preoperative anamnesis, physical examination, and imaging, the mass suggested a metastatic process with no suspicion of tuberculoma. Therefore, we did not give trial antibiotics or TB treatment before surgery. Surgery was done to reduce mass effect symptoms, as well as to obtain tissue to establish the diagnosis. The initial goal of surgery was gross total resection. A right frontotemporal craniotomy was performed. The existing chamber and peritoneal drain of VP shunt were disconnected and removed. The lesion appeared to be surrounding the ventricular drain. The lesion was solid, firm, calcified, and adheres tightly to the ventricular drain. The lesion was very hard and cannot be easily separated by electrocautery and suction. Therefore, careful piecemeal debulking of the tumor was carried out using scissors, until the tumor was completely removed and healthy parenchymal tissue was seen. Histopathology examination [Figure 4] revealed a large fibrotic area containing many granulomas, consisting of epithelial cells surrounded by lymphocytes. An area of necrosis was seen in the center of the granuloma with foci of calcification. Langhans giant cells were also seen at the periphery of the granuloma. There was no sign of malignancy. Histopathological findings were consistent with tuberculoma. Unfortunately, the samples of operation were only examined for histopathology. There were no samples sent to the microbiology department for culture examination. There was no complication after surgery. The patient was discharged on postoperative day 3 in good condition. Five months after surgery, the patient is still routinely checked in to the outpatient clinic. There are no complaints or neurological deficits. Currently, the patient is receiving treatment for extrapulmonary TB.

brain tumor, craniopharyngioma, tuberculoma, tuberculosis, ventriculoperitoneal shunt seeding