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PMC3615962_01

Female

A 50 year-old female presented to the emergency room with back pain and left leg numbness of four days duration. The patient did not identify any contributing factors but did recall being thrown to the ground during an assault several weeks earlier. No fecal or urinary incontinence, lower extremity weakness or saddle anesthesia was reported. Her past medical history was significant for a lumbar laminectomy several years prior. The patient denied tobacco, alcohol or illicit drug use. On examination her pulse was 65 beats/minute, respiratory rate 24 breaths/minute, temperature 98.2 F, blood pressure 124/77 mmHg and oxygen saturation of 98% on room air. In general she appeared in mild discomfort. Neurological exam revealed decreased sensation to light touch over the left anterior tibia. The remainder of the physical and neurological exam was unremarkable. Initial laboratory analysis showed a leukocyte count of 11,500 (per mm3) and platelet count of 558,000 (per m3); the hemoglobin, electrolytes and renal function were all within normal limits. Erythrocyte sedimentation rate was 85 mm/Hr and the c-reactive protein was 1.5 nMol/L. A magnetic resonance imaging study of the lumbar spine revealed enhancing paravertebral soft tissue at L4-L5 concerning for underlying infection (Figure 1). The imaging also revealed a probable epidural abscess with significant canal narrowing to 5.5 mm. A computed tomography guided biopsy revealed reactive fibrosis, neovascularization and degenerative changes with acute and chronic inflammatory cells. The patient was begun on intravenous vancomycin and cefepime for the empiric treatment of vertebral osteomyelitis and an accompanying epidural abscess. A neurosurgical consultation was obtained and deemed there was no need for surgical intervention at that time. Cultures from the biopsy were initially negative and the patient was discharged to a skilled nursing facility to complete a six week course of the aforementioned antibiotics. The day following discharge cultures revealed acid fast bacilli, and several days later a specific identification of Mycobacterium abscessus was made. The patient was referred to the county health department tuberculosis clinic but was unfortunately lost to follow up.

mycobacterium abscessus, epidural abscess, osteomyelitis

PMC4153214_01

Male

A 46-year-old man (employee) presented with a history of right upper lobectomy of the lung eight years ago due to complicated tuberculosis with hemoptysis. He complained of chronic cough, severe right upper arm and shoulder pain and sweating. His vital signs were as following: Pulse rate=80, respiratory rate=16, body temperature=37.6 C and tuberculin test=1.5 cm. For the past eight years, he has been suffering from sputum production, weight loss and upper thoracic and right limb pain resulting in repeated admissions. Blood analysis upon admission to our referral hospital was as follows: WBC=14.4x103, Hb =15.7 g/dL, Ca=13.5 mg/dL, P=4.6 mg/dL, Alkaline phosphatase 205 IU/L, ESR=86, and normal ABG findings. Three times sputum analysis and examinations were negative for tuberculosis. Computed Tomography (CT) scan of the chest revealed loculated pneumothorax in the right upper lobe with nodular infiltration in the left lower lobe, and tracheal and mediastinal shift to the left hemithorax. Partial pleural thickening and fibrosis, irregular mass formation and calcification were also reported in the right upper lobe fossa (Figure 1). In flexible bronchoscopy, stricture of the right middle lobe and obstruction of the right upper lobe without evidence of tumor were observed. Electromyography examination of the right arm muscles was in favor of superior sulcus tumor because of severe intolerable right arm and upper shoulder pain. After consultation with a pain clinic, the patient underwent cervicothoracic ganglion block which was performed through 6th cervical transverse process tuberosity with an injection of 10 mL solution of Depo-Medrol (40 mg) + Marcaine 0.05% (4 mg) + fentanyl (10 microg). The infrascapular blockage was performed in prone position. After the emergence of Horner's syndrome and sympathetic block, the patient was scheduled for Transcutaneous Electrical Nerve Stimulation (TENS) therapy and serial blockade. After pain relief, percutaneous transthoracic biopsy was performed from the pleural thickenings. Pathologic examination was negative for the diagnosis of the tumor (Figure 2). The patient was previously hospitalized for 15 days in the Infectious Diseases Ward with diagnosis of TB recurrence; however, BK and cytology examinations of the sputum and BAL smears were negative. In favor of malignancy, the patient was prepared for thoracotomy procedure. On exploration, severe adhesions caused by the previous operation, and tumor lesion invasion to upper brachial plexus and major subclavian vessels were observed. The tumor was inoperable. After sampling abundant biopsies from the tumor and closing bronchial openings, the chest was closed while one chest tube was located in the right upper hemithorax. Pathologic examination confirmed the diagnosis of squamous cell carcinoma. Consequently, the patient was scheduled for radio-therapeutic protocol.

lobectomy, pancoast tumor, squamous cell carcinoma, tuberculosis

PMC6581877_01

Male

A 20-year-old Hispanic male presented with oral ulcers, fever, fatigue and headache. Prior to presenting to the emergency department, he had received a course of antibiotics for suspected sinusitis. He had developed a pruritic drug rash over his legs, buttocks and abdomen following the antibiotic use. His medical history was significant for Henoch Schoenlein purpura as a child and mild autism. No familiar history of hematologic diseases reported by the patient or otherwise documented. On examination, temperature was 38.1 C and heart rate was 125 beats per minute. Blood pressure and respirations were normal. His physical examination showed some non-tender submandibular lymphadenopathy, left upper quadrant tenderness, and a mild maculopapular rash was seen over both legs and lower abdomen. Liver and spleen were not palpable. Initial laboratory studies showed a leukocyte count of 0.85 x 103/microL, a hemoglobin of 5.6 g/dL, and a platelet count of 123 x 103/microL. Leukocyte differential included 2% neutrophils, 3% bands, 13% monocytes, 70% lymphocytes, and 12% blasts. Liver and renal functions were normal. A bone marrow biopsy showed a cellularity of 70-80% with diffuse infiltration by blasts and suppression of normal hematopoiesis (Fig. 1). Blasts showed monocytic features with a variable proportion of the cells displaying "hand-mirror" morphology with pronounced cytoplasmic tails and blebs (Fig. 2). Flow cytometry revealed the blasts to be CD117(+), CD34(-), HLA-DR(+), CD4 (+) and CD64(+). Cytogenetic analysis was performed on bone marrow aspirate. All 22 metaphases analyzed revealed the presence of a derivative chromosome 1 resulting from an unbalanced translocation of the short arm of chromosome 19 proximal to 19p13 to the short arm of chromosome 1 at band 1p13: 46, XY, der(1)t(1;19)(p13;p13.1)[22] (Fig. 3). FISH (Fluorescent in-situ hybridization) analysis was performed using acute leukemia-specific probes. FISH results using the E2A/PBX1 Translocation, Dual Fusion Probe showed the translocation resulted in an extra copy of the E2A gene (19p13.3) on the derivative chromosome (Fig. 4). The E2A probe, labelled in green, contains two probes (110 kb and 146 kb) that cover the 3' end of the E2A (TCF3) gene and flanking region and a 321 kb probe that covers a region 5' (centromeric) to the gene. The PBX1 probe, labelled in red, contains two probes (147 kb and 110 kb) that map within the PBX1 gene and a 117 kb probe that maps 3' (telomeric) to the gene. In a normal cell, two red and two green signals (2R, 2G) should be visible. Due to the close proximity of the green signals, these two signals may overlap and appear as one signal in a small proportion of cells. In this case, since there is gain of an extra E2A gene due to the unbalanced translocation, 2R3G signal pattern was evident by FISH (Fig. 4). DAPI images of the metaphases revealed that this extra E2A gene copy was on the short arm of chromosome 1 at band 1p13 (Fig. 4). In addition, an extra copy of the MLL (11q23.3) gene was also identified (Fig. 5). Molecular testing at diagnosis with FISH using extended pediatric acute lymphoblastic leukemia panels did not show mutations in FLT3 (either ITD or TKD), NPM1, CEBPA or KIT. The patient underwent induction therapy with a typical 7 + 3 regimen (employing 200 mg/m2/day of cytarabine and 12 mg/m2 of idarubicin). Complete remission (by morphology, flow cytometry and FISH) was achieved after induction. Repeat karyotype was 46,XY[20]. The patient was advised to undergo an allogeneic stem cell transplant in 1st remission. He, however, declined and received 4 cycles of consolidation with high dose cytarabine. At the end of 4 cycles of consolidation, a repeat bone marrow aspiration and biopsy showed ongoing morphological and cytogenetic remission. He relapsed 4 months after completing therapy. Bone marrow biopsy and aspirate again showed "hand mirror" myeloblasts with monocytic differentiation and flow cytometry again identified expression of CD 117, CD 4, and CD 64 without CD 34 expression. Cytogenetic findings at relapse, however, continued to show a normal male karyotype (46,XY[20]) and FISH studies looking specifically for E2A and MLL showed normal copy numbers. Next generation sequencing was performed using Illumina sequencing technology to identify variants in genes commonly associated with AML (ASXL1, ATM, BCOR, BCORL1, CBL, CDKN2B,CEBPA, CREBP(ATF2), CSF3R, DDX41, DNMT3A, ETV6, EZH2, FLT3, GATA1, GATA2, IDH1, IDH2, IKZF1, JAK2, KDM6A, KIT, KRAS, MLL, MPL, NF1, NPM1,NRAS, PHF6, PTEN, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, STAG2, STK11, TET2, TP53, U2AF1, WT1, ZRSR2). The above genes, except for MLL, were tested using a commercial bait-capture next generation sequencing platform. MLL was tested by long range PCR which only detected the presence or absence of the partial tandem duplication. This revealed a missense mutation on the RUNX1 gene, c.127C > T variant ID 463,980, with a frequency of 55%, which resulted in the replacement of proline with serine at codon 43 of the RUNX1 protein (p.Pro43Ser). No other variants in the above genes were identified. He received salvage therapy with fludarabine, cytarabine and idarubicin (FLAG-IDA) and was then treated with venetoclax and azacytidine. Second remission lasted 3 months. He then developed leukemia cutis. Repeat therapy with FLAG-IDA was attempted with no response and the patient opted for supportive care alone.

aml, acute myeloid leukemia, hand-mirror blasts, runx1, t(1, 19)

PMC6481144_01

Male

A 79-year-old male with past medical history of hypertension, atrial fibrillation (CHA2DS2-VASc score = 4, only on Aspirin), type 2 diabetes mellitus, and right lower extremity leiomyosarcoma with lymphedema of the affected limb treated with surgical resection and radiotherapy presented to the emergency department with exertional dyspnea, worsening of lower extremity edema, and weight gain. On arrival vitals shows blood pressure 140/95, heart rate 80, and SpO2 98. Physical examination was remarkable for irregular heartbeat, decreased bilateral lung sounds, and bilateral grade 3+ lower extremity edema up to the sacrum. Electrocardiogram (EKG) showed atrial fibrillation with new left bundle branch block (LBBB) (Figure 1). The laboratory workup was significant for brain natriuretic peptide (BNP) 2,233 pg/ml, troponin 0.38 ng/ml, and d-dimer 1.81 mg/l. Otherwise, he had normal basic metabolic panel (BMP) and complete blood count (CBC). Chest X-ray (CXR) and computed tomography (CT) of the chest showed cardiomegaly and moderate pleural effusion in bilateral lung fields (Figure 2). Transthoracic echocardiogram (TTE) showed left ventricular ejection fraction of 20% and severe global hypokinesis. Coronary angiogram revealed minimal coronary artery disease. The patient was diagnosed with nonischemic cardiomyopathy and was treated with lisinopril, metoprolol, spironolactone, diuretics, and enoxaparin. Despite medical management, he remained in atrial fibrillation for which he was scheduled for rhythm restoration with transesophageal echocardiogram- (TEE-) guided DC cardioversion (DCCV). TEE revealed a large multilobulated mobile thrombus in the left atrial appendage, and sessile irregular echogenic material attached to the wall of the left atrium was visualized (Figure 3(a)). Accordingly, cardioversion was aborted. The patient refused anticoagulation with Coumadin therapy and instead opted for rivaroxaban, aware of risks of possible anticoagulation failure or adverse events, as he would not be on standard of therapy. The patient was discharged with guideline-directed management for coronary artery disease and heart failure as well as rivaroxaban 20 mg daily. On subsequent outpatient follow-up three months later, repeat TEE showed no visible thrombus (Figure 3(b)). No evidence of clinical thromboembolic events was noted between initial and follow-up encounters.

PMC6812137_01

Female

A 72-year-old woman was referred to our hospital for evaluation of left pleural effusion of unknown origin. She had a history of bronchial asthma with noteworthy findings in her family history, including autoimmune diseases and tuberculosis. She reported never smoking or drinking. She had general fatigue for 6 months and had reported left dominant pleural effusion to her previous doctor; however, the cause of pleural effusion was unclear. On physical examination, her temperature was 37.0 C, blood pressure was 149/92 mmHg, and pulse was 110 beats per minute. Percutaneous arterial oxygen saturation (SpO2) was 93% on room air. Her right axillary lymph node was palpable. Lung sounds were diminished in the left lung, without the presence of piping rale. Laboratory analysis showed that the erythrocyte sedimentation rate was elevated to 118 mm/h and serum IgG level was 5310 mg/dL, including IgG4 > 1500 mg/dL. Both rheumatoid factor and antinuclear antibody were negative. Analyses of tumor markers and the interferon-gamma release test revealed negative findings (Table 1). Chest radiograph showed left pleural effusion (Fig. 1a). Neck to pelvis computed tomography (CT) revealed swelling of the mediastinal and inguinal lymph nodes as well as left pleural effusion with local pleural thickness (Fig. 1b). Fluorodeoxyglucose (FDG) positron emission tomography imaging showed accumulation of FDG in the mediastinal lymph node, left inguinal lymph node, and left pleura (Fig. 1c). Thoracentesis showed lymphocyte-dominant exudative pleural effusion with a high level of ADA. Culture and polymerase chain reaction analyses of pleural effusion were performed to assess the presence of tuberculosis and nontuberculous mycobacteria. Both tests were negative (Table 2). We suspected the possibility of IgG4-RD based on clinical findings and the elevated level of serum IgG4. However, we needed to confirm the pathological diagnosis and exclude tuberculous pleurisy with elevated ADA in unilateral pleural effusion. Therefore, we performed surgical biopsies of the pleura and left inguinal lymph node (Fig. 2). Histological analysis of the biopsies revealed dense lymphocyte and plasmacyte infiltration accompanied by fibrosis. Immunohistochemical analysis showed that a large number of IgG4+ cells (50 cells or more per high-power field) were found in the pleural membrane and inguinal lymph node; the IgG4+/IgG+ cell ratio exceeded 40%, which met the diagnostic criteria for IgG4-RD. Thus, we diagnosed the patient with definite IgG4-RD with pleural effusion and inguinal lymph node swelling. We then considered initiation of corticosteroid therapy; however, pleural effusion decreased without intervention, and dyspnea improved during the active surveillance period (Fig. 3a). The serum IgG/IgG4 levels gradually decreased (Fig. 3b) and the swelling of the mediastinum and inguinal lymph nodes also subsided (Fig. 3c). Therefore, we continued surveillance of the patient without administration of any drug; there has been neither obvious regrowth nor development of malignant disease for >4 years.

adenosine deaminase, igg4-related disease, pleural biopsy, pleural effusion, spontaneous remission

PMC4532018_01

Male

A 36-year-old man was admitted to Yong Dong Severance Hospital because of a 10-day history of jaundice and epigastric discomfort. He had suffered from pulmonary tuberculosis about 15 years and 6 years before. On admission, he had pruritus, icteric sclerae and skin. The breathing sound was decreased on the right lower lung field. Direct tenderness was noted on the epigastrium, but liver and spleen were not palpable. Abnormal laboratory findings were as follows: platelets 101,000/mm3, total bilirubin 19.6 mg/dl, direct bilirubin 13.4 mg/dl, alkaline phosphatase 188 IU/L, gamma-GTP 133 IU/L, alpha-fetoprotein 22.1 ng/ml, urine bilirubin , urobilinogen +/-. Serum HBsAg, anti-HBc Ab and anti-HBeAb were positive. An ultrasound examination disclosed a mass at the hepatic hilus, dilatation of the intrahepatic bile duct and cirrhotic change of the liver. A dynamic abdominal CT scan showed an enhancing mass at the hepatic hilus, liver cirrhosis and splenomegaly without focal lesion in hepatic parenchyma (Fig. 1). An endoscopic retrograde cholangiography (ERC) revealed a 3x2 cm sized oval shaped filling defect at the upper common hepatic duct, including the porta hepatis. The surface of the mass was smooth and the upstream intrahepatic bile ducts were slightly dilated (Fig. 2A). An endoscopic nasobiliary drainage was attempted, but failed because a hydrophilic guidewire could not be passed over the obstructing mass. On a percutaneous transhepatic cholangiography (PTC) (Fig. 2B), through a percutaneous transhepatic biliary drainage (PTBD) tube, dye was well passed over the obstructing mass. The mass seemed slightly lobulated and the surface was shallowly grooved. A sono-guided fine needle aspiration cytology revealed no malignant cells. On the 24th hospital day, hepatic angiography was performed and did not show any tumor staining. On the 28th hospital day, an explorative laparotomy was performed. Grossly, the liver showed macronodular cirrhosis without any palpable masses. An irregular shaped soft tissue mass admixed with bile was found at the hepatic hilus after the distended commom hepatic duct was opened. The mass was yellowish to grayish in color and very friable. These findings were consistent with a so-called "chicken fat" appearance. Cholecystectomy, segmental resection of the intrahepatic ducts and common hepatic duct, septoplasty of the intrahepatic duct and hepaticojejunostomy were performed. Microscopically, tumor cells appeared as nests in pseudoacinus patterns, and bile pigment was found in the cytoplasm (Fig. 3A, 3B, 3C). The immunohistochemical stain demonstrated positive reaction for alpha-fetoprotein but negative reaction for carinoembryonic antigen (Fig. 4A, 4B). The final diagnosis was hepatocellular carcinoma. The patient was recommended to have adjuvant therapy such as external radiotherapy or systemic chemotherapy, but refused. Three months after the operation, a hepatic angiography with CT arterioportography and lipiodol-CT were performed, which gave no definite mass lesion in the hepatic parenchyma. About 6 months after the operation, a follow-up ultrasound examination disclosed two small hypoechoic lesions (1.2-1.5 cm in diameter) at the segment 8 and the segment 5 (Fig. 5A, 5B). A repeat hepatic angiography with CT arterioportography was performed. Tumor staining was not found on hepatic angiography, but two low density lesions were suspected at the segment 8 and the segment 5 on CT arterioportography (Fig. 6A, 6B). However, no lipiodol remained on lipiodol-CT taken 3 weeks later (Fig. 7A, 7B). The patient has been closely followed up with ultrasonography every 2 months until now (1 year after the operation) and there was no evidence of the growth of two hypoechoic lesions seen on ultrasonography or development of new lesions.

PMC10228720_01

Male

A 79-year-old male was admitted to our hospital with abdominal pain, jaundice and weight loss. No obvious abnormality was found in the physical examination of the patient. Laboratory results: carbohydrate antigen 19-9 (CA19-9)>400 U/ml(normal range <37 U/ml), total bilirubin (TBIL) 267.1 mumol/L (normal range <23 mumol/L). Other laboratory test results were within the normal range. Because the patient had severe jaundice, he first underwent percutaneous transhepatic cholangio drainage. One month later, he was hospitalized again. Laboratory results: CA19-9 125.2 U/ml, TBIL 96.3 mumol/L. Contrast-enhanced computed tomography (CT) showed that the common bile duct was thickened ( Figure 1A ) and the head of the pancreas was enlarged ( Figure 1B ), but no abnormal enhancing shadow was found. Magnetic resonance imaging (MRI) showed dilatation of the extrahepatic bile ducts ( Figure 1C ) and thickening of the gallbladder wall. The pancreatic head was enlarged : the maximum transverse diameter was about 3.7 cm, the pancreatic signal was uniform, and no exact abnormal enhancement shadow was found ( Figure 1D ). On contrast-enhanced ultrasound, an uneven low-intensity lesion with a size of about 2.8 x 2.7 cm was found in the pancreatic head, with an irregular shape and an unclear boundary. We planned to make a further diagnosis with endoscopic ultrasound fine-needle aspiration, but the patient refused. Based on the above findings, the possibility of a pancreatic head malignant tumor was very high. Therefore, a pancreaticoduodenectomy was planned to be performed. During surgery, dilated and completely obstructed common bile ducts were found, and dense adhesions were present around the portal veins, which could not be divided. It was surmised that the mass invaded the portal vein. To relieve the obstruction, a choledochojejunostomy was performed, and some masses were removed for biopsy. Numerous foam cell, lymphocyte, and plasma cell infiltrates were found in the resected mass and gallbladder ( Figures 2A-C ). Immunohistochemical findings showed CD68 (+) ( Figure 2D ), CK (-), VIM (+), CD19 (-), Ki-67 (<1%), ALK1 (-), and p53 (-). Immunohistochemical results supported the diagnosis of xanthogranuloma invading the pancreatic head, common bile duct, and gallbladder. After 10 months of close follow-up ( Figures 1E, F ), the patient had no symptoms and a good quality of life.

xgi, xgp, xanthogranulomatous cholangitis, xanthogranulomatous cholecystitis, xanthogranulomatous pancreatitis

PMC10282974_01

Unknown

We assume that the hydrocephalus and enlarged brain volume were not TBI related. Rather, they were pre-existing, resembling a case recently reported on by Ferris and colleagues, who reported a 1.8-fold increase in brain volume of a 2-year-old R222 RNaseT2 knockout rat with severe "spontaneous hydrocephalus." The etiology of the "pre-existing" hydrocephalus (e.g., genetic) in rat #112 is unknown; another question is how a brain twice the volume of the normal brain could fit into the regular-sized skull. Ferris and colleagues did not report any abnormalities in skull size or shape either, even though the skull appears larger than normal in magnetic resonance imaging (MRI) shown in their Figure 1. Because we did not perform any structural MRI, we cannot conclude whether the thin cortex of rat #112 was folded within the skull or whether the skull was thinner, giving the brain more space. Hydrocephalus can be defined as a pathological increase in cerebral ventricular volume caused by impaired absorption or increased production of cerebrospinal fluid. Edwards and colleagues identified hydrocephalus in 31 of 35 hamsters without a dome-shaped skull. The lack of doming suggested that the condition in the hamster cohort developed after suture closure. In another study, hydrocephalic Wistar rats displayed abnormalities in the ventricular and vascular systems, including aneurysms, intracranial cysts, white matter injury, tissue necrosis, and excessive astrogliosis surrounding the ventricles and blood vessels. We observed no doming of the skull in rat #112; nor did we observe any compression of the ventricular system or the Sylvian aqueduct. Iron deposits in the choroid plexus, which were recently associated with post-TBI ventricle enlargement, were detected in all rats of the cohort with TBI. Therefore, we consider post-injury choroidal hemorrhage as an unlikely etiological factor for the robust ventriculomegaly in rat #112. Gross anatomical analysis of the brain of rat #112 revealed a very thin cerebral cortex. Contrary to our expectations, the cortical volume of rat #112 was 127% that of the cohort mean. We have compared the cortical volume rat #112 to other TBI-induced rats in the same cohort, rather than to naive or sham-operated control rats. Further studies are needed to explore whether the cortical volume increase is related to intracortical edema and/or gliosis or simply to stretching of the cortical tissue surrounding the enlarged ventricles. Interestingly, Ferris and colleagues reported a 7% reduction in cortical volume in the R222 RNaseT2 KO rat with severe spontaneous hydrocephalus.

brain injury, case study, electroencephalography, hydrocephalus, lateral fluid-percussion injury, sleep

PMC10282974_02

Female

The pre-injury performance of rat #112 in the beam walking test was normal given that it scored 5.3 of 6. Consistent with this finding, other laboratories have reported minimal behavioral impairments in uninjured hydrocephalic Sprague-Dawley rats or golden hamsters. Tu and colleagues found no phenotypical signs of hydrocephalus in uninjured adult male and female Wistar rats, among which 43% had mild ventriculomegaly in MRI. Also, the 2-year-old R222 RNaseT2 KO hydrocephalus case reported by Ferris and colleagues appeared to have normal sensory behavior, given that it responded normally to foot shock and flashing light and startled to a loud sound. Interestingly, a minimal cortical lesion induced by FPI resulted in severe impairment in the beam walking test within the 30-day follow-up given that the performance score dropped from 5.3 to 0, which was greater than the mean 2-points drop in the rest of the TBI cohort. Moreover, the lesion was located in the somatosensory cortex (rather than in the auditory cortex), which could explain the behavioral deficits. However, we did not notice any correlation between lesion coverage of the S1 cortices and performance in beam walking, suggesting that the motor impairment related more to hydrocephalus rather than cortical damage. Interestingly, in a model of acquired hydrocephalus induced by an intraventricular kaolin injection, slow motor and cognitive deterioration were reported over an 8-month follow-up, possibly related to stretching of the periventricular axonal pathways because of an increased ventricle volume. Our observations in rat #112 suggest that the rapid, severe post-impact balance impairment triggered by minimal injury to the sensory cortex was augmented by pre-existing hydrocephalus.

brain injury, case study, electroencephalography, hydrocephalus, lateral fluid-percussion injury, sleep

PMC7332489_01

Female

The patient was an obese 31-year-old woman (body mass index: 43.7 kg/m2). She was examined at our hospital laboratory 1-year before severe SAS, with 132 episodes of apnea/hour and significant hypoxia in polysomnography. A 24-h electrocardiogram (ECG) detected an inverted T wave, but no arrhythmias. She denied a history of hypertension, diabetes mellitus, or dyslipidemia. She had no habit of smoking or a family history of SAH or intracranial aneurysm. She presented with a worsening headache, but was alert and oriented, with no neurological deficit (World Federation of Neurosurgical Societies [WFNS] Grade 1). Head computed tomography revealed SAH, and computed tomography arteriogram showed a carotid-posterior communicating artery aneurysm with a bleb [Figure 1]. Continuous ECG monitoring on admission showed sinus tachycardia (mean: 120 beats/min) with frequent ventricular premature complexes [Figure 2]. However, a transient bradycardia (mean: 30 beats/min) was occasionally observed, especially during sleep apnea. The patient agreed to endovascular treatment to prevent rebleeding, and coil embolization for the ruptured aneurysm was performed under general anesthesia on postbleed day (PBD 1) [Figure 3]. Worsening bradycardia and repetitive transient asystole lasting 3-12 s with hypotension occurred during postoperative care in the intensive care unit [Figure 4]. To treat the recurrent severe bradycardia, our cardiologists performed temporary pacemaker insertion (back-up VVI pacing at 40 beats/min) the day after surgery. The patient, who was postoperatively receiving mechanical ventilation under sedation to control her unstable circulatory status, was able to be weaned from ventilation and extubated on the same day. Temporary pacing was induced once per hour to prevent severe asystole until 2 days after insertion, regardless of the presence of sleep apnea. At PBD 5, the back-up pacing was decreased to once per 4 h, and bradycardia only occurred during sleep apnea. The following day, there were only three requirements for back-up pacing, and the bradycardia and ventricular premature complexes were rarely detected, even during sleep apnea. Thereafter, temporary pacing was not required. All types of arrhythmia decreased, and a final 3 s episode of sinus arrest was observed 7 days later. The 24-h ECG monitoring was continued until 21 days after admission. She did not experience any other complications such as cerebral vasospasm or hydrocephalus caused by SAH and was discharged home with no neurological deficit at 30 days after admission.

endovascular surgery, sinus arrest, sleep apnea syndrome, subarachnoid hemorrhage

PMC7773813_01

Male

A 45-year-old male underwent a left upper lobectomy and postoperative pathology revealed invasive stage IIIA lung adenocarcinoma ( Figure 1 ). Targeted next- generation sequencing (NGS) with a customized panel (Geneseeq Prime panel) designed to target 425 cancer-specific genes was performed, and four somatic mutations and copy number alterations (CNAs) were identified, including EGFR-KDD of exon 18-25 [mutant allele frequency (MAF): 13.5%], EGFR amplification (4.5-fold), TP53 p.Y220C (MAF: 37.0%), and RB1 single copy loss ( Figure 1 ). The tumor mutation burden (TMB) was estimated to be 1.1 mutation/Mb. The patient received pemetrexed and cisplatin as adjuvant chemotherapy. Four months later, he progressed with liver metastasis in left lobe ( Figure 1 ). Then, the patient was treated with Icotinib and the metastasis shrunk. Unfortunately, the drug resistance was observed only after 4 months, as evidenced by the fact that previously responsive liver lesion progressed. Left hepatic re-biopsy confirmed metastatic adenocarcinoma and target sequencing (Geneseeq Prime panel) detected the same EGFR-KDD (MAF: 4.9%) as well as mutation of TP53 p.Y220C (MAF: 0.5%) ( Figure 1 ). The TMB was calculated as 2.2 mutation/Mb. Docetaxel and cisplatin were initiated as the second-line therapy. However, the left hepatic metastasis enlarged rapidly after 2 cycles of chemotherapy. The blood carcinoembryonic antigen (CEA) level increased from 9.5 mg/ml (before chemotherapy) to 22.7 mg/ml. Even worse, a right hepatic metastasis appeared soon afterward. Radiofrequency ablation (RFA) of liver was conducted on both of the left and right hepatic metastases, but no reduction in liver lesions was observed, and the CEA level showed a slight increase from 7.3 to 10.3 mg/ml. Afterward, the patient started taking Osimertinib (80 mg once daily). Encouragingly, both liver lesions showed significant regression ( Figure 1 ). One month after initiation of Osimertinib, the CEA level decreased to 5.4 mg/ml, and remained at normal level for 18 months. Moreover, the progression-free survival (PFS) reached 21 months. However, the CEA level increased to 23.1 mg/ml at the 19th month after the initiation of Osimertinib treatment, and 2 months later, the patient progressed with enlarged mediastinal lymph nodes ( Figure 1 ) with the CEA level of 73.9 mg/ml. Resampling and targeted sequencing (Geneseeq Prime panel) consistently identified EGFR-KDD (MAF: 33.9%), as well as EGFR amplification (6.6-fold), TP53 p.Y220C (MAF: 53.3%), and a new mutation of RELN p.G1774E (MAF: 45.4%) ( Figure 1 ). The estimated TMB increased to 3.4 mutation/Mb. In addition, the assessment of PD-L1 expression using antibody 28-8 (pharm Dx, Dako's Platform) showed tumor proportion score (TPS) of 1%. On these bases, the fourth-line salvage therapy using Nivolumab was prescribed and the therapeutic efficacy was considerable, as evidenced by the decreased CEA, regressed mediastinal lymph nodes, reduced metastases in both left and right liver ( Figure 1 ). Specifically, the CEA level decreased from 143.6 to 41.8 mg/ml one month later. The PFS reached 7 months and no obvious adverse effects were observed. The quality of life was in good status during the Nivolumab treatment. After that, the patient progressed with enlarged liver metastasis. Unfortunately, the patient was also infected with tuberculosis, and his condition took a sharp turn for the worse due to both tumor progression and tuberculosis. The families gave up further treatment and the patient died 4 months later.

egfr-kdd, nivolumab, osimertinib, lung adenocarcinoma, targeted next-generation sequencing

PMC9168402_01

Female

Five patients diagnosed with spinal TB with the average age are 25.8 years old, and included two males and three females [Table 1]. Four patients presented with paraparesis and one patient presented with low back pain that radiates to both legs. MR studies showed hypointense to isointense lesion in T1-weighted images and isohyperintense and hyperintense lesion in T2-wighted images [Figures 1-5]. CT scan showed destruction of vertebral body, pathological fracture, and kyphotic deformity [Figure 6]. Intervention given includes laminectomy debridement and decompression with or without posterior stabilization. Postoperatively, two patients demonstrated partial recoveries of neurological function and three patients demonstrated full recoveries of neurological function. Postoperative MRI/CT demonstrated progressive bony healing with improvement of deformity.

diagnosis, management, pott’s disease, spinal tuberculosis, spondylitis tuberculosis

PMC6664009_01

Male

A 40 years old man, was injured in a car accident as a front passenger, occurred during a frontal collision with another vehicle passing illegally in continuous white line down the center of a national road, the impact speed was 100 km per hour. Unfortunately, the patient was not restrained by seatbelt and sustained lower extremity and head impacts without loss of consciousness, he experienced a severe pain in his hips. On presentation to the emergency department, patient was hemodynamically stable and conscious, examination of the chest and abdomen was normal. However, both hips were deformed in flexion, internal rotation and adduction (Fig. 1), without neurovascular deficit or skin lesions of the lower limbs. Radiographs displayed bilateral posterior hip dislocation combined with right femoral head fracture, and small posterior wall fracture of the left acetabulum. (Fig. 2) Prompt hips reduction was performed within one hour of presentation through closed manipulation below general anesthesia, curarisation and controlled by fluoroscopy, patient was maintained in supine position on the ground and the aide applied a hand pression on the iliac wings of the pelvis, while the operator exerted a traction on the leg then flexed the hip with adduction and external rotation, the same technique was applied successfully to the second hip. The Left hip was stable up to 100 flexion and 45 internal and external rotation after reduction. However, the right hip was unstable, for this reason, we have positioned a posterior knee splint for temporary stabilization. Reduction of each hip was checked by antero-posterior pelvic radiograph (Fig. 3) and CT-scan (Fig. 4). X-ray showed an irreducible right femoral head fracture, but in the other side it showed a concentric reduction of the left hip joint. CT scan showed in the right side a one-third of femoral head suprafoveal fracture Pipkin type II that was anterior, rotated and incarcerated associated with two small fragments; one was superior and the second inferior. In the left side we have detected a minor posterior wall fracture of the left acetabulum without any intra-articular fragments. Surgical treatment was planned next day to accomplish anatomic open reduction of the right femoral head fracture and its internal fixation (ORIF) using a modified Hardinge approach that was chosen because the Pipkin II fragment was switched, therefore its reduction need surgical dislocation of the hip and a wide access to the femoral head. Moreover, this approach is known to have less risk of sciatic nerve injury, preserve the pelvitrochanteric muscles and have less risk of limping in comparison with the conventional Hardinge approach, because we spread the fibers of the gluteus medius just at its anterior middle one-third, preserving a great portion of this muscle insertions and function. In the operational room, under general anesthesia the patient was placed in the full lateral position with pubic and sacral support, left leg was maintained in extension to stabilize ipsilateral hip, then a modified external approach of Hardinge was performed exposing the fascia lata that was incised in line with skin incision and retracted anteriorly while the gluteus maximus was retracted posteriorly to expose the common tendon of vastus lateralis and the gluteus medius, it was split longitudinally at the anterior third and sharply separated from the greater trochanter. Without extension more than 3 cm proximally to the insertion of the great trochanter to avoid inferior branch of the superior gluteal nerve injury. An anterior flap was formed by the anterior portion of the gluteus medius, the underlying gluteus minimus, and the anterior portion of the vastus lateralis. A T-shaped capsulotomy was performed to release the anterior capsule. The hip joint was then dislocated, and the femoral head fracture was exposed, we have explored a rotated pipkin II fragment and extracted two small parts that had footprints in the not weight bearing area in the distal part of the femoral head (Fig. 5). After cleaning and washing hip joint, we have reduced the Pipkin fragment and fixed them by two small pins that was over-drilled with a cannulated drill bit, followed by osteosynthesis with two Herbert screws, then hip was reduced and the flaps was repaired by transosseuses sutures to the great trochanter layer by layer using a vicryl number 2. Postoperative examination revealed no neurological deficit and the postoperative imaging of the pelvis showed an anatomic reduction of the femoral head fracture and a good position of the two Herbert screws (Fig. 6). The patient was kept on bed rest for three weeks, followed by a further six weeks of right non-weight bearing. At 6 months there was a good fracture healing, the patient had no limited hip motion, without limping and normal return to his daily activity (Fig. 7). Then at one and two years follow up there was no signs of osteoarthritis or avascular necrosis detected on the pelvic X-rays. However, a right hip non-bridging Brooker type I heterotopic ossification was noticed (Fig. 8).

bilateral, femoral head, fracture, hip dislocation, pipkin

PMC6804672_01

Female

A 72-year-old female patient developed a gallbladder tumor in December 2017 due to pain in the right upper quadrant. The biopsy showed poorly differentiated adenocarcinoma. She was diagnosed as stage IIIA gallbladder carcinoma (T3N1M0) bacause of lymph node metastases at hepatic hilar and pancreatic head by positron emission tomography (PET) scan. Since the patient had been previously diagnosed with rheumatic heart disease and diabetes, irreversible electroporation ablation was performed. The patient's abdominal pain was relieved after ablation and she then received oral tegafur (a fluoropyrimidine derivative) chemotherapy. In September 2018, the patient developed severe pain in her upper right abdomen, with vomiting associated with the inability to eat, and a subsequent rapid reduction in body weight. After being admitted to our hospital, the patient was diagnosed with heart failure (class IV heart function), severe anemia, and hypoproteinemia. A computed tomography (CT) examination revealed gallbladder tumors (6.3 x 4.9 cm), multiple spotted high-density lesions in the liver parenchyma, tumor invasion of the duodenum, accompanied by gallbladder-duodenal descending fistula, multiple enlarged lymph nodes around the pancreatic head (maximum 2.7 x 2.1 cm), and compression of the inferior vena cava. Moreover, the gallbladder cancer had progressed to stage IV (T4N1aM0). On the second day after admission, the patient entered the Intensive Care Unit and received both symptomatic and systemic supportive treatments, including parenteral nutrition, an infusion of albumin, red blood cells, insulin, cardiotonic diuretics, and antibiotics, as well as gastrointestinal catheter drainage. This patient was enrolled in a hydrogen therapy clinical trial (NCT03818347) on October 24, 2018. The inhalation of hydrogen gas via a hydrogen oxygen atomizer (AMS-H-03, Asclepius Meditec, Shanghai, China) was initiated simultaneously with symptomatic treatments. Initially, the patient underwent hydrogen inhalation for 2 h/day (3 L/min), and was gradually increased to 6 h/day. In addition to continuing to administer the above symptomatic and systemic supportive treatments, no routine anti-cancer therapy was provided. Post-treatment evaluations included: 1) adverse reactions: referred to in the Common Terminology Standard Version 5.0 (CTCAE 5.0). Adverse events were classified and scored weekly after treatment initiation. Laboratory indicators included peripheral blood cell subsets, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), and gamma-glutamyl transpeptidase (GGT), and expression of tumor markers; 2) clinical symptoms and PS scores; 3) imaging changes: the tumor response was measured using computed tomography (CT) according to the RECIST 1.1 guidelines, and the tumor response was classified as complete remission (CR), partial remission (PR), stable disease (SD), or progressive disease (PD). Following hydrogen inhalation, the patient's daily agitation gradually decreased and disappeared completely after two weeks. In addition, the patient's sleep time was extended from 4-5 h/day to 8-10 h/day within two weeks. No adverse reactions related to hydrogen inhalation were observed during the first three months. The patient's upper abdominal pain persisted, requiring the daily use of analgesics prior to hydrogen treatment; however, after two weeks of hydrogen inhalation, the pain gradually decreased and painkillers were no longer required. The PS score gradually decreased from 4 points prior to hydrogen treatment to 1 point after two and a half months. By the end of April 2019, the patient had a PS score of 0 and had resumed normal diet and activity. The disease has been continuously relieved for 10 months and has exhibited increased improvement. During the entire period of hydrogen treatment, serum levels of ALT, AST, TB, and GGT exhibited no abnormalities; the red blood cell count and hemoglobin levels stopped decreasing; and the interval between blood transfusions was extended from one week before hydrogen inhalation to two weeks. Moreover, these two indexes began to increase continuously one month later (Figure 1A), and the blood transfusion was completely stopped after two months. The level of serum total protein and albumin began to rise after supportive treatments and continued to increase after hydrogen inhalation, reaching a normal range after two and a half months, at which time, supplements were no longer required (Figure 1B). In the two weeks before hydrogen treatment, the peripheral blood leukocyte count was significantly increased due to the intestinal fistula. The leukocyte count decreased to the upper limit of the reference range after antibiotic treatment and continued to decrease after hydrogen inhalation, falling to normal levels after 1.5 months (Figure 1C left). The total number of lymphocytes was low at the time of admission, and the number began to rebound after one and a half months of hydrogen inhalation, returning to normal after two and a half months (Figure 1C right). Serum CA19-9, AFP, and CEA were all elevated at the time of admission (2, 1.8, and 8 times the upper limit of the reference values, respectively). Following hydrogen inhalation, the three markers did not decline and the AFP even exceeded the level at the time of admission; however, these levels rapidly declined afterwards, and all fell to within the normal reference range after two and a half months (Figure 2). Abdominal CT images were analyzed at different time points before and after hydrogen treatment (Figure 3A). Before hydrogen treatment, the sum of the diameter of multiple tumors was 12.2 cm. After hydrogen treatment for: 1) one month, the sum was 16.7 cm (37% increase compared with pretreatment, PD); 2) two and a half months, the sum was 12.9 cm (6% increase compared with pretreatment, SD); and 3) six months, the total was 8.1 cm (33% decrease compared with pretreatment, PR) (Figure 3B). The patient was tested for immunological function before hydrogen treatment, as well as at six and nine months after treatment. In the terminally differentiated CD8+ T cells, the proportion of exhausted cells was 46.8% at two weeks before treatment, 31.3% at six months after treatment, and 27.6% after nine months (Figure 4).

hydrogen gas, metastatic gallbladder cancer, programmed cell death receptor-1, pseudo-progression

PMC9610691_01

Male

A 31-year-old male patient presented with a 3-month history of gradually worsening headache and progressive left-sided weakness. He denied any history of seizures or any other significant medical or surgical history. On examination, the patient had papilledema, left-sided upper motor neuron type facial weakness, and left hemiparesis (MRC Grade 4) with pronator drift. Plantars were upgoing on the left side, suggesting complete lateralization. Rest of the examination was unremarkable. Magnetic resonance imaging (MRI) revealed diffuse signal abnormality, multifocal lesions in the right frontal, temporal lobes with an involvement of the right thalamus, and extension into the right half of the brainstem up to the pons. Some of the lesions were cortical and subcortical in location and cystic changes were also seen in the tumor on T2-weighted imaging [Figure 1]. There was infiltration of the corpus callosum and extension to the contralateral left side and patchy lace-like enhancement on postcontrast T1-weighted images [Figure 2]. No diffusion restriction or susceptibility was noted. Along with MR spectroscopy (MRS) findings [Figure 3], a radiological diagnosis of low-grade multifocal glioma was made. Biopsy was done and microscopy of the lesion revealed a tumor invading glial tissue composed of sheets of round cells with moderate, pale eosinophilic to clear cytoplasm, round to slightly oval vesicular nuclei, and predominantly inconspicuous nucleoli. Characteristic chicken-wire vasculature was present. Occasional scattered mitoses were seen without any endothelial vascular proliferation or necrosis. Tumor cells showed positivity for immunostain glial fibrillary acidic protein, occasional weak positivity for p53, and low Mib-1 (Ki-67) index (1-2%). Immunostain alpha-thalassemia/mental retardation syndrome, X-linked was intact. Based on these combined features, diagnosis of oligodendroglioma, not otherwise specified, WHO Grade II was favored [Figure 4]. No further surgical treatment was offered due to extensive involvement with a grave patient prognosis. A postbiopsy computed tomography (CT) scan was carried out because the patient had a sudden drop in his Glasgow Coma Scale. The CT scan showed diffuse brain edema and confirmed coarse calcifications within parts of the lesion [Figure 5]. Efforts were made to reduce the intracranial pressure with osmotic therapy, but the patient remained in a vegetative state.

brain, infiltration, oligodendroglioma, spectroscopy, tumor

PMC4407774_01

Male

The patient in our case was a 66-year-old man. His chief complaint was the abnormality observed in his chest computed tomography (CT) images. The patient was initially suspected of having an ulcerative invasive tumor in his stomach based on endoscopic findings by a clinic in Pusan on September 8, 2012. He then underwent total gastrectomy for gastric cancer at Pusan National University Yangsan Hospital on October 2, 2012, followed by six cycles of chemotherapy between January 27, and May 28, 2013. After a chest CT scan on November 11, 2013, he was diagnosed with asbestosis and transferred to the Department of OEM for further evaluation of the association between asbestosis and gastric cancer in his case. The patient in this case had a history of hypertension. He reported smoking 23-packs-per-year until 1995 and consuming one bottle of Soju (alcohol) per week prior to his gastric cancer surgery. The patient worked in a textile factory with no asbestos exposure for 18 years (from 1966 to 1983). He later performed asbestos spinning and weaving work for 11 years (from 1983 to 1993) using chrysotile at Masan Gwangsum (1983 - 1984), Seongjin Chemical (1985 - 1992), and in Taehwa Capaxeal (1993). His asbestos-spinning job involved mixing chrysotile with synthetic fiber during a 12-hour shift (from 8 a.m. to 8 p.m.).The job site was full of white dust, and despite wearing a mask, he still found dust around his nose when finishing work. Between 1987 and1990, as a plant manager, he managed the entire process that involved mixing asbestos and synthetic fiber, spinning, twisting, and weaving. Additionally, he directly spun asbestos. The patient looked healthy at presentation. His blood pressure was 130/70 mmHg; body temperature was 36.6 C; pulse rate was 80 beats/minute, and respiratory rate was 20 times/minute. His conjunctiva was not anemic, and anicteric sclera was observed. His chest auscultation revealed fine crackles of end inspiration in the lower areas of both lungs. His heartbeat was regular, and no heart murmur was detected. The physical examinations showed no abnormal findings in his abdomen or skin, and no club fingers or cyanosis in his extremities. In a pulmonary function test conducted on November 18, 2013, the patient's forced expiratory volume at timed intervals of a second (FEV1) was 2.24 L (72% of the expected value); his forced volume vital capacity (FVC) was 2.52 L (61% of the expected value), and his FEV1/FVC was 89% of the expected value, which showed a mildly restrictive ventilator disturbance. His pulmonary diffusion capacity of carbon monoxide (DLco) was within the normal range at 15.9 ml/min/mmHg (77% of the expected value). The chest CT images obtained on November 11, 2013 showed typical asbestosis findings of pleural thickening and calcification in both thoracopulmonary cavities, subpleural fine reticular opacity in the lungs, ground glass opacity, and honeycomb appearance (Figure 1). There were no significant findings from the chest X-ray images. In the upper gastrointestinal (GI) tract endoscopy conducted at a clinic in Pusan on July 3, 2010, reflux esophagitis and erosive gastritis were observed. Another upper GI tract endoscopy conducted on September 8, 2012 showed campylobacter-like organisms (CLOs) (+), suspected progressive gastric cancer, and atrophic gastritis (Figure 2). The post-operative pathologic examination conducted on October 4, 2012 confirmed that the mass measuring 4.9 x 4.5 cm and located in the anterior wall of the stomach body was an adenocarcinoma (Figure 3). According to studies on asbestos levels in factories handling the chemical, the mean value before 1990 was 4.3 f/cc (standard deviation[SD] 4.3 f/cc), and that in 1990 was 2.3 f/cc (SD = 1.7 f/cc). The cumulated exposure of the patient in this case was calculated as follows: Thus, his level of cumulated exposure in the patient was estimated to be 38.0-71.0 f-yr/cc. According to the Helsinki criteria for asbestos-related diseases, the relative risk of developing lung cancer more than doubles when the cumulated exposure to asbestos is 25 f-yr/cc or higher. Considering the patient's work experience with chrysotile in the textile factory and his past working environment, he was thought to have been exposed to high level of asbestos. Asbestos fiber exposure is reportedly associated with gastric cancer. In this case, the patient worked for 11 years weaving and spinning asbestos. Therefore, the possibility of gastric cancer caused by asbestos fiber exposure could not be completely excluded. In the meta-analysis of the association between asbestos fiber exposure and gastric cancer that compared any exposure versus none, the summary relative risk was calculated to be 1.17 (95% confidence interval [CI], 1.07-1.28). Similarly, in the comparison of high-dose asbestos fiber exposure versus no exposure, the summary relative risk was calculated to be 1.31-1.33. The standard mortality rate (SMR) of gastric cancer tends to increase when that of lung cancer does. Since the cumulative asbestos fiber exposure of this patient was 38.0-71.0 f-yr/cc, and his relative risk of developing lung cancer was more than two times, the SMR of gastric cancer was 1.34 (95% CI, 1.07-1.67) when that of lung cancer was > 2.00. When the SMR of lung cancer was >3.00, that of gastric cancer was 1.43 times higher. The risk of asbestos fiber exposure was determined based on the incidence of lung cancer caused by such exposure and information obtained from the exposure evaluation. According to the United States Environmental Protection Agency (US EPA), there are three routes of asbestos fiber exposure: ingestion, respiration, and skin exposure. However, asbestos is rarely absorbed through the skin, and no carcinogenic risk from ingestion has been reported. Therefore, the ELCR from respiration was calculated to evaluate the health risk from asbestos exposure using the following equation. EPC was calculated as 4.3 f/cc x 24/8 h using the reported asbestos concentration in factories handling the chemical. Time weighted average in this case was calculated using asbestos fiber exposure time, considering that the patient worked for 12 hours per day and 5 days per week (12/24 h/day x 260/365 days/yr). During his 11 years of exposure, the IUR was 2.1 x 10-2. The theoretically acceptable carcinogen risk that corresponds to the natural death rate is 1.0 x 10-6 (one out of one million). However, in cases of environmental carcinogens, the acceptable risk is practically one in 100,000, considering the profit/loss against investments and status of engineering and analytical technologies. The World Health Organization also suggests that the ELCR of carcinogenic substances is 1.0 x 10-5 (one out of 100,000). The ELCR of lung cancer for this patient was 9,648 x 10-5, which translated to an excess cancer risk of 9,648 in 100,000.

asbestos, asbestosis, gastric cancer, risk assessment, spinning, textile

PMC8390688_01

Male

A 77-year-old man with a smoking history (96 pack-years) was diagnosed with T4aN1M1 liver and peritoneal metastasis, stage IVB advanced gastric cancer (Japanese Classification of Gastric Carcinoma, 15th Edition). He had no recent history of exposure to dust. He was prescribed acetaminophen and acetaminophen, started 3 months before admission, and the newest oral drug was an antipyretic and analgesic drug for fever, postoperative pain, and chemotherapy-related lower limb pain. The patient characteristics are shown in Table 1. He was treated with capecitabine, oxaliplatin, and trastuzumab as first-line chemotherapy. After four cycles, prolonged nausea and fatigue developed. Abdominal CT revealed progression of gastric cancer and gastric dilation with gastric outlet obstruction. He underwent laparoscopic gastrojejunostomy and was discharged 2 weeks after surgery. Nano albumin-bound (nab)-paclitaxel and ramucirumab were induced as second-line chemotherapy. On day 8 of the first cycle, nab-paclitaxel administration was interrupted because of neutropenia. On day 18, he had a high-grade fever (38 C) and malaise and was started on levofloxacin. On day 22, the high-grade fever persisted, and chest CT showed an abnormal shadow in the lung fields. He was then referred to our hospital. On admission, the findings of his physical examination were unremarkable. A peripheral blood test showed elevated levels of C-reactive protein (CRP) (8.44 mg/dL). Krebs von den Lungen (KL)-6 (342 U/mL) and beta-D glucan (14.4 pg/mL) were within the normal limits (Table 2). Arterial blood analysis showed that the arterial partial pressure of oxygen (PaO2) was 86.4 Torr in ambient air. Chest CT showed bilateral diffuse GGO and ill-defined centrilobular nodules (Fig. 1A and B), suggesting a non-fibrotic typical HP pattern. Bronchoscopy for bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) were performed. BAL fluid analysis showed a total cell count of 1.07 x 106 and an increase in lymphocytes (43.8%) with a CD 4/8 ratio of 4.2% and eosinophils (16.6%). Culture of BAL fluid yielded negative results for bacteria, fungi, mycobacteria, and pneumocystis spp. There was no evidence of suspected infectious diseases. TBLB showed fibro-cellular alveolitis and accumulation of histiocytes without granulomas (Fig. 2). He was negative for the anti-Trichosporon asahii (T. asahii) antibody and parakeet IgG (2.21 mg A/L), parrot IgG (3.93 mg A/L), and pigeon IgG (4.53 mg A/L) were within normal limits. Serum IgG against bird antigens was measured with ImmunoCAP system (Thermo Fisher Scientific, Uppsala, Sweden). He was diagnosed as DRP with radiographic HP pattern, probably due to nab-paclitaxel, after excluding other possible ILD caused by infection (pneumocystis spp. or mycobacterium spp.), connective tissue disease, and hypersensitivity pneumonitis (summer type or bird fancier's lung). His DRP was categorized as grade 2 according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Chemotherapy was discontinued, and his condition was carefully monitored. He had no respiratory symptoms and oxygen desaturation during the 6-min walk test; however, high fever did not improve. On day 33 of the admission, steroid pulse therapy with methylprednisolone (500 mg/day) was started for 3 days. His fever and abnormal shadow improved, without maintenance of steroid therapy (Fig. 1C). He was discharged 8 days after initiation of steroid therapy. Acetaminophen was discontinued after symptom relief. One month after discharge, nivolumab as the third-line therapy was started, and he was diagnosed with nivolumab-related renal failure at the previous hospital. He subsequently underwent temporary hemodialysis and was treated with prednisolone 50 mg per day. Thereafter, his chest CT showed complete resolution of the shadow (Fig. 1D). For a diagnosis of DRP, scores according to the Naranjo Scale were five points (probable confidence). If we judge as exposure to nab-paclitaxel, his ILD could be diagnosed as HP with high confidence (80-89% confidence), according to the ATS/JRS/ALAT HP guideline.

drug related pneumonitis, everolimus, hypersensitivity pneumonitis, nab-paclitaxel, nivolumub

PMC7528204_01

Male

A 16-year-old left-handed male patient of Caucasian British ancestry presented with a mild, non-progressive upper limb postural tremor but no other symptoms for several years until, without clear precipitant, he experienced two unprovoked generalised tonic-clonic seizures, both occurring in sleep. His antecedent history was unremarkable except for a viral respiratory infection at birth requiring 2 days of mechanical ventilation on the neonatal intensive care unit. He attained his cognitive and motor milestones appropriately, attended mainstream school and completed 14 GCSEs. He was otherwise well, except for ichthyosis. There is no history of parental consanguinity. There is a family history of neurofibromatosis type 1 in a nephew and Perthes disease in a brother, and a history of diabetes and hypertension in his father and mother, respectively. His father also had ichthyosis. Following the nocturnal seizures, he underwent a number of investigations. His initial MRI and EEG were normal. Anticonvulsant medication, specifically sodium valproate, was commenced following a further convulsive seizure fourteen months later. He continued to experience convulsive seizures every 3 to 6 months; these were initially nocturnal, but later arose from wakefulness. Some of the seizures were preceded by a visual aura, consisting of superimposition of peripheral vision into the central field (polyopia). There was also gradual worsening of his upper limb tremor, manifesting as an irregular jerky tremor at rest which worsened on action, especially in the right hand. It improved significantly on distraction. He also noticed lower limb tremor with associated unsteadiness, especially when descending stairs or slopes, with his left leg being more affected than the right. He described his legs as feeling 'like jelly' with occasional falls. He also noticed general cognitive slowing, fatigue and effortfulness when engaging in conversations with people less well known to him. The motor symptoms were initially attributed to valproate therapy and he was switched to levetiracetam with no clear improvement. He underwent further investigations at 20 years of age. An MRI at this time showed some prominence of the cerebellar folia suggestive of mild generalised cerebellar parenchymal volume loss. White cell enzyme analysis was normal. Cerebrospinal fluid analysis revealed normal cell counts and protein values, with no evidence of unmatched oligoclonal bands. No mutations were identified in SLC2A1 or DYT-1a. Total cholesterol was elevated at 6.5 and he tested positive for pANCA but negative for serine proteinase 3 (PR3) antibodies. He was diagnosed with functional movement disorder and referred for specialist physiotherapy with some improvement in his symptoms. However, his symptoms progressed and by the age of 22 years, he was wheelchair-bound. Fine motor skills had deteriorated such that he was unable to cut up food and his handwriting was illegible. He had prominent and widespread spontaneous and action myoclonus, to the extent that even dreaming about movement would precipitate myoclonus. His voice had developed a stuttering stammer. He had also developed 'twitching' and 'rippling' of muscles in his shoulders, upper limbs and torso. There were no sensory changes or sphincter disturbance. His convulsive seizures had also become more frequent, occurring on average once per week. Clinical examination at this time revealed occasional facial myoclonus (resembling myokymia) and hypermetric saccades with nystagmus on horizontal gaze. Ophthalmic review revealed normal appearances of the discs and retina. Limb tone and power were normal. Deep tendon reflexes were present and symmetrical in the upper limbs, brisk in the lower limbs with flexor plantar responses. There was a postural tremor markedly exacerbated by action with some action myoclonus. Marked orthostatic tremor was noted on standing. There was subtle dysmetria and dysdiadokokinesia on the right. There was no evidence of telangiectasia or oculomotor apraxia. Systemic examination revealed marked ichthyoses but no organomegaly. Neuropsychometry, including screens of intellect (WAIS-IV), memory (BMIPB), language (graded naming test) and executive function (Wiegl and verbal fluency tests), showed him to be functioning within the normal range without any specific cognitive deficits. He was admitted for further investigations including prolonged EEG monitoring with video telemetry. There were independent runs of fast activity seen equally in both centroparietal regions. One seizure was captured with head turning to right and posturing of the left arm without a clear focus of onset (Fig. 1). There was no photosensitivity. EMG showed frequent interruptions of muscle tone intermixed with brief muscle jerks whilst holding his limbs against gravity. Short duration (20-30 ms) jerks, a rostrocaudal pattern of muscle activation, negative myoclonus and giant cortical somatosensory evoked potentials (SEPs) suggested a cortical origin of jerks, and a syndrome of progressive myoclonic epilepsy was suspected (Fig. 2). Genetic analysis was undertaken. There were no pathogenic mutations or large-scale rearrangements of mtDNA detected and no CSTB expansion suggestive of Unverricht-Lundborg disease. His muscle biopsy was unremarkable and a skin biopsy could not be processed due to technical issues. Whole genome sequencing was performed as part of the 100,000 Genomes Project. This showed one pathogenic variant in CLN6 and two other variants of unknown significance in CLN6. Subsequent targeted sequence analysis of CLN6 showed compound heterozygosity for CLN6 c.13C > T p.(Arg5Trp) & c.150C > G p.(Tyr50*). His mother was heterozygous for the c.13C > T sequence variant and his father heterozygous for the c.150C > G sequence variant, providing evidence that these variants were on opposite alleles and therefore together likely to be pathogenic. The results fully explained the clinical phenotype and confirmed the diagnosis of Kufs disease/cerebral neuronal lipofuscinosis. A repeat MRI brain scan showed no change in the degree of cerebellar volume loss. However, there were new T2 FLAIR hyperintensities in the right cerebral hemispheric white matter with minor neuroparenchymal volume loss in the right cerebral hemisphere, consistent with either a vascular or infective/inflammatory process. Imaging of the cord was normal (Fig. 3). Vascular imaging revealed stenoses of the terminal and para-ophthalmic internal carotid arteries (ICAs) and proximal middle cerebral arteries (MCAs) (right worse than left), with collateral vessels. Extracranial vasculature was unremarkable. The features were in keeping with intradural arterial occlusive vasculopathy/Moyamoya disease. He was commenced on a statin and amlodipine for blood pressure management, and bilateral superficial temporal artery to middle cerebral artery (extracranial-intracranial) vascular anastomoses were undertaken to reduce the risk of further ischaemic injury, without post-operative neurological sequelae. Additional genetic sequencing has identified no pathogenic variants in the RNF213 gene on the long arm of chromosome 17 (17q25), the most common genetic mutation associated with Moyamoya disease, and no significant variants in Cerebrovascular disorders (version 1.34) or Cerebral vascular malformations (version 1.36) 100,000 Genomes Project gene panels.

ancl, ancl, adult neuronal ceroid lipofuscinosis, bmipb, the brain injury rehabilitation trust memory and information processing battery, cln6, kufs disease, lincl, late-infantile neuronal ceroid lipofuscinosis, merrf, mitochondrial epilepsy with ragged red fibres, moyamoya, ncl, ncl, neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis, ppt1, palmitoyl-protein thioesterase 1, sep, somatosensory evoked potentials, tpp1, tripeptidyl peptidase 1, wais-iv, wechsler adult intelligence scale (4th edition), wiegl, weigl color form sorting test, mtdna, mitochondrial dna

PMC3339714_01

Female

In 1996, a 43-year-old Hispanic female was diagnosed and treated for breast cancer. After a recurrence 11 years later, she underwent a bilateral mastectomy in 2007. In January 2008, she complained of a 2-week history of worsening headaches, photophobia, and vertigo. Computed tomography and magnetic resonance imaging showed metastases to the occipital and parietal brain and spine. On February 3, 2008, she was started on palliative cranial irradiation of 45 Gy delivered in 22 fractions at 2 Gy/fraction. At that time, she had the following medications: a tapering dose of dexamethasone (4 mg 4 times daily), phenytoin (100 mg 3 times daily) for seizure prophylaxis, and antacids. Twenty-three days later, she had developed facial swelling and a diffuse maculopapular eruption of the head, scalp, and upper body. She was initially diagnosed with cellulitis and treated with clindamycin (900 mg i.v. 3 times daily) and levofloxacin (750 mg i.v. daily), along with methylprednisolone (125 mg i.v. 4 times daily). Twenty-six days after the start of her radiation therapy, she developed intractable vomiting and blisters, requiring admission for further evaluation. She had completed 3 weeks of cranial irradiation, receiving 32 Gy of a planned 45-Gy regimen. Despite initiation of antibiotics, her facial swelling worsened and blisters progressed to involve her ears. She also experienced odynophagia and dysuria. Phenytoin was discontinued 2 days after admission due to a suspicion of a possible drug reaction. Intravenous fluconazole (200 mg daily) was given for oral candidiasis and enoxaparin for deep-vein thrombosis prophylaxis. On March 5, 2008, she was transferred to the burn center for treatment of TENS. The patient had diffuse erythema and bullae with sloughing of facial and scalp epidermis, bilateral conjunctivitis, xerostomia, and oral mucosal ulceration with sloughing of the hard and soft palate, and dorsal tongue surface. Widespread bullae with a positive Nikolsky sign spread laterally with pressure, to the face, chest, breasts, abdomen, back, upper extremities, pelvis, perineum, buttocks, and bilateral thighs, involving 80% TBSA (fig. 1). Skin biopsy confirmed the diagnosis of TENS. Due to respiratory failure, the patient was intubated on the second day of admission and underwent a tracheostomy to maintain patency of her airway. Her laboratory values were within the normal range except for the following (normal values are indicated in parentheses): hemoglobin 11.7 (11.5-15.5) g/dl, Hct 33% (35.0-45.0), MCV 79.9 (81.1-96.6), white blood count 3.2 (4.5-13.0) x103/mm3 with 84% neutrophils, 12.8% lymphocytes, 1.9% monocytes, 0.1% eosinophils, 0.3% basophils, platelets 174 (185-395) x103/mm3, PT 14.5 (11.8-13.8) s, INR 1.19 (2.0-3.0), PTT 36.3 (25.6-34.4) s, fibrinogen 525 (196-457) mg/dl, D-dimer 4.89 (0.22-0.43), C-reactive protein 27.01 (0.0-0.50) mg/dl, prealbumin 8 (18-45) mg/dl, BUN 9 (10.0-20.0) mg/dl, creatinine 0.4 (0.6-1.4) mg/dl, calcium 7.3 (8.5-10.5) mg/dl, glucose 159 (65-110) mg/dl, phosphorus 2.4 (2.5-4.5) mg/dl, GGT 130 (3.0-60) mg/dl, LDH 246 (85-210) mg/dl, and Na 129 (135-145) mEq/l. She became coagulopathic (PT 17.4 s, PTT 38.3 s). Sheet-like sloughing of her skin progressed, including the entire back. Her wounds were cleaned and covered with a silver dressing (ActicoatTM; Smith and Nephew, St. Petersburg, Fla., USA). Dressing changes occurred every 3-4 days. Bacitracin with zinc oxide was used to lubricate the face, scalp, and neck. She received a 5-day course of intravenous gamma globulin at 5 mg/kg/day. Corticosteroids were continued, and parenteral nutrition was initiated. After 2 weeks of electrolyte correction, fluid resuscitation, and topical wound care, she was stabilized, extubated, and her skin reaction resolved; the hospitalization lasted 23 days.

anticonvulsants, nanocrystalline silver dressing, radiotherapy, toxic epidermal necrolysis syndrome

PMC4549551_01

Female

Fitzgerald et al. report rTMS treatment for a pharmacotherapy-resistant 41-year-old female patient with severe recurrent depression [Montgomery-Asberg Depression Rating Scale (MADRS) = 34; Inventory of Depressive Symptomology-Clinical Rated (IDS-CR) = 49] persisting for 14 years with onset following a mild closed-head TBI and no prior history of brain injury. Magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) demonstrated no contraindication to rTMS and no presence of diffuse axonal injuries. Desvenlafaxine was held at a constant dosage 8 weeks prior to treatment and throughout the course of rTMS. Active sequential bilateral rTMS was administered to the DLPFC (right-sided low-frequency rTMS followed by left-sided high-frequency rTMS). A single stimulation train (1 Hz, 900 pulses/session) administered at 110% of resting MT during right-sided low-frequency rTMS was immediately followed by 30 trains (10 Hz, 5 s train duration, 25 s inter-train interval), at 110% of resting MT for left-sided high-frequency rTMS. The patient showed a positive response to treatment with a greater than 50% reduction in depressive symptoms (MADRS = 14; IDS-CR = 21). Neuropsychological assessments of attention, concentration, working memory, speed of information processing, verbal and visual memory, perceptual ability, and executive functioning showed no deleterious changes in cognitive performance. No adverse side effects of treatment were reported. George et al. administered high-frequency rTMS (10 Hz, 5 s train duration, 10 s IT for 30 min) at 110% resting MT over the left prefrontal cortex to suicidal inpatients (Beck Scale of Suicidal Ideation score >=12 and >=3 on Question #3 of the Ham-D) in a randomized, sham-controlled study. Each session delivered 6000 pulses over 30 min, and sessions were repeated three times daily with 1 h between sessions for 3 days (total 9 sessions and 54,000 pulses). 41 patients with a diagnosis of either PTSD or mTBI were recruited for this study (20 active and 21 sham). Of these patients, 21 individuals had previously suffered a TBI (13 active and 11 sham). The protocol was generally well tolerated with no major side effects, although one patient suffered a first-degree scalp burn from coil overheating. The authors report a trend toward a more rapid change in SSI in the active rTMS group compared to the sham group, but there was no overall difference in the change in SSI between groups. Patients showed a reduction in how much they were bothered by thoughts of suicide, but they demonstrated no difference in future intent of suicide, thoughts of suicide, self-rated sadness, tiredness, or happiness. The authors note that patients continued to receive standard inpatient care - including changes in medication - throughout the study, so the observed results cannot be separated from any non-specific hospitalization effect. Results were not broken down between patients with PTSD and TBI, so conclusions cannot be drawn regarding the efficacy of this protocol specifically in relation to TBI. However, the fact that this rather aggressive protocol was generally well tolerated demonstrates its feasibility.

altered states of consciousness, depression, non-invasive brain stimulation, rehabilitation, repetitive transcranial magnetic stimulation, trancranial direct current stimulation, traumatic brain injury

PMC4549551_02

Male

Kreuzer et al. report rTMS treatment of severe tinnitus [tinnitus questionnaire (TQ) = 53] persisting for 4 years following a severe TBI in a complex 53-year-old male patient. The patient presented with co-morbid post-injury onset depression and associated severe sleep disorder, alcohol and benzodiazepine abuse, as well as a single symptomatic seizure immediately following injury with no subsequent seizures. Tinnitus symptoms displayed resistance to prior treatments of acupuncture, osteopathy, hyperbaric oxygen therapy, intravenous application of steroids, and acoustic stimulation. Treatment began once alcohol and benzodiazepine intake were excluded via laboratory screening tests administered through the course of rTMS, with antidepressant (75 mg amitriptyline) and antiepileptic (150-300 mg pregabalin) dosage kept constant throughout treatment. Trains of stimulation at 110% resting MT (1 Hz, 2000 stimuli/session) applied to the left primary auditory cortex for 10 sessions demonstrated a positive effect lasting 3 months after the first treatment series (TQ = 38). Four subsequent treatment series over the course of 3 years demonstrated effects lasting 6 months (TQ = 26 after third session, no ratings taken after fourth session). The fifth and final series followed a modified protocol targeted at the right DLPFC (1 Hz, 1000 pulses/session) followed by stimulation applied to the left primary auditory cortex (1 Hz, 1000 pulses/session) for a duration of 5 days (beginning of fifth session TQ = 50; following treatment TQ = 33). The authors state that the patient remained abstinent from alcohol and benzodiazepines throughout treatment. The patient reported a reduction in loudness of tinnitus, and treatment was reported to be well tolerated without adverse effects or seizures as a result of rTMS intervention.

altered states of consciousness, depression, non-invasive brain stimulation, rehabilitation, repetitive transcranial magnetic stimulation, trancranial direct current stimulation, traumatic brain injury

PMC4549551_04

Male

Theta burst stimulation (short trains of rTMS at high frequencies) applied to the left hemisphere has been seen to improve the symptoms of hemispatial neglect in patients with brain injury due to stroke. Bonni et al. extended these insights for use in a patient with brain injury due to trauma. The authors used continuous theta burst stimulation (cTBS) to treat severe hemispatial neglect in a 20-year-old male patient with onset following a severe TBI [Behavioral Inattention Test-Conventional (BIT-C) scale ~28] sustained 2 years prior to intervention. Neuropsychological assessments demonstrated mild attentional and executive deficits and minimal memory impairment. Three pulse bursts were applied to the left posterior parietal cortex at 80% active MT (50 Hz, 600 pulses/session; 40 s train interval, 200 ms inter-train interval) twice daily (15 min inter-session interval) for 2 weeks. Functional magnetic resonance images (fMRI) demonstrated decreased excitability of posterior parietal cortex-M1 connections in the left hemisphere and a bilateral increase of functional connectivity in the frontal-parietal network. In conjunction with these functional changes, marked cognitive and clinical improvements were reported and seen to persist 2 weeks following intervention (BIT-C ~ 58). No adverse effects were reported.

altered states of consciousness, depression, non-invasive brain stimulation, rehabilitation, repetitive transcranial magnetic stimulation, trancranial direct current stimulation, traumatic brain injury

PMC4549551_05

Male

Pachalska et al. administered rTMS to a 26-year-old male who had previously (3-5 years) suffered a severe TBI which left him in a coma for 2 months. Brain scans revealed diffuse atrophy and enlarged ventricles in the right hemisphere, and the patient exhibited anosognosia, executive dysfunction, behavioral changes; perseverations, fits of uncontrolled laughter, and was sporadically aggressive and impulsive. Twenty sessions of low-frequency (1 Hz) rTMS were administered over left frontal and temporal regions along with high-frequency (5 Hz) rTMS to right frontal and temporal regions. Following rTMS, the patient showed large improvements in most tests of executive functioning, including: general intelligence, attention, visuospatial ability, and logical memory. He also showed improvement on all categories of the frontal behavioral inventory, including: social conduct, personal conduct, mood disorders, and control disorders. The authors state that the patient had previously shown little progress following "traditional rehabilitation" and only small changes following beta training. Although EEG spectra were no different post-rTMS, NO-GO ERP recordings showed improvement compared to pre-rTMS, though still much different from healthy controls. No seizure events or significant adverse side effects were reported. Recently, Koski et al. examined the effect of high-frequency rTMS on individuals experiencing post-concussion syndrome (PCS) at least 6 months post-injury. 15 patients with a score of 22 or greater on the PCS Scale received 20 daily sessions of rTMS (10 Hz at 110% resting MT; 20 5 s trains with 25 s ITI; 1000 pulses/session) over the left DLPFC. Two patients quit due to worsening symptoms and one for unrelated reasons. Of the 12 patients who completed treatment, 9 showed an improvement in symptoms (>5 point decrease on PCS scale) and 1 patient worsened. Patients also showed an overall decrease in ratings of headaches, as well as a (statistically uncorrected) decrease in symptoms of fatigue, trouble falling asleep, difficulty remembering, and numbness or tingling. No seizure events or serious side effects were reported. Nine out of twelve patients found 110% MT stimulation to be intolerable in the first session, but all patients tolerated this intensity by the sixth session following gradual intensity increases. fMRI scans demonstrated greater activations in DLPFC and greater deactivation of the rostral ACC during a working memory task following the last session compared to pre-treatment. Results of a 3-month follow-up with some patients indicate that maintenance treatments may be required to sustain the observed gains.

altered states of consciousness, depression, non-invasive brain stimulation, rehabilitation, repetitive transcranial magnetic stimulation, trancranial direct current stimulation, traumatic brain injury

PMC4549551_06

Male

Louise-Bender Pape et al. examined the safety and restorative effects of rTMS by attempting to restore consciousness following a severe TBI. They used rTMS to induce neurobehavioral changes in a 26-year-old male who remained in a vegetative state 287 days after a severe TBI. Computerized tomography (CT) scans revealed hemorrhage in the right temporal lobe as well as diffuse traumatic subarachnoid hemorrhage. The patient was described to be in a state of arousal without behavioral evidence of awareness of self or capacity to interact with the environment [Disorders of Consciousness Scale (DOCS) = 50.3]. Prior to treatment, the patient was titrated off neurostimulants (amantadine and methylphenidate) and antispasticity medications and did not receive any neurological medication during the course of the intervention. Safety was ensured by administering a modified lower-than-normal frequency rTMS protocol following completion of a daily medical examination, with an electroencephalogram (EEG) conducted before and after each session and continued bi-weekly for 6 weeks post-treatment. Stimulation was administered to the right DLPFC at 110% abductor pollicis brevis MT (300 trains/session with a 5 s inter-train interval, where each train consisted of a paired-pulse with a 100 ms inter-pulse interval) for 6 weeks. The patient experienced complications that the authors concluded were not related to the rTMS intervention. The patient was treated with 2 g Ceftazidime, 1 g vancomycin, 900 mg amikacin, and 500 mg Cipro. No adverse effects were reported as a result of rTMS treatment, and EEGs performed throughout and following the treatment revealed lack of epileptiform discharges following rTMS. The authors report a change in classification of state of consciousness from vegetative state to minimally conscious (DOCS: 15th session = 58.6; 30th = 53.7; 6 weeks post-treatment = 56.7). Qualitative improvements through the course of rTMS were reported, including markedly improved motor skills and visual ability, the appearance of vocalizations, and the development of basic communication. Continued qualitative improvements were reported a year following rTMS treatment by the patient's family, with no reported adverse events. Manganotti and colleagues administered high-frequency rTMS to three patients with severe brain injuries due to TBI. Two patients were classified as minimally conscious, while the third was in a vegetative state. Safety criteria included absence of contraindication to rTMS, stability of vital parameters, and more than 12 months since injury. A single session was administered to the primary motor cortex at 100% MT (20 Hz, 1000 pulses/session; 5 s train duration, 20 s inter-train interval) for 10 trains. A clinical response was not witnessed in any of the three patients, with EEG demonstrating no reaction to brain stimulation and a decrease in MT. No adverse effects or seizures were reported. Similarly, Giovannelli and colleagues reported no clinically significant neurobehavioral change following rTMS therapy for two patients in a vegetative state due to TBI. Using a randomized, double-blind cross-over design with a sham stimulation control, high-frequency rTMS was applied to the left M1 at 60% stimulator output (20 Hz or sham; 1000 pulses/session) for five consecutive days. The patients did not demonstrate statistically significant improvement compared to sham stimulation as measured using the JFK Coma Recovery Scale-Revised (CRS-R) and Clinical Global Impression (CGI) rating.

altered states of consciousness, depression, non-invasive brain stimulation, rehabilitation, repetitive transcranial magnetic stimulation, trancranial direct current stimulation, traumatic brain injury

PMC4549551_07

Male

Cavinato et al. report the occurrence of a partial and secondarily generalized tonic-clonic seizure in a 31-year-old male patient who suffered a severe TBI 8 months prior to rTMS intervention. MRIs following the TBI revealed diffuse hematoma in corpus callosum with mass effect over the fourth ventricle and upstream hydrocephalus. Prior to treatment, the patient received medication for gastric disorder and spasticity (2 ml Diazepam), and he had no prior personal or family history of epilepsy or seizure disorder. Treatment began once stable clinical conditions were demonstrated and baseline EEG excluded epileptiform and paroxysmal activity. Three of ten daily sessions at 90% abductor pollicis brevis MT (20 Hz, 1 s train duration, 1 min inter-train interval) applied to the DLPFC were tolerated without adverse effects. Three hours after the fourth rTMS session, the patient experienced an adversive seizure followed by a secondary generalized seizure and a complete loss of consciousness, with no urinary or bladder incontinence or tongue beating. EEG reports following the seizure showed slowing with focal spike discharges in the left fronto-central areas. Reports taken 2 days following the seizure displayed no epileptiform activity and demonstrated a return to baseline levels, with no antiepileptic medication administered at any time.

altered states of consciousness, depression, non-invasive brain stimulation, rehabilitation, repetitive transcranial magnetic stimulation, trancranial direct current stimulation, traumatic brain injury

PMC4549551_08

Male

Louise-Bender Pape et al. report an electrographic seizure with no clinical accompaniment in a patient in a vegetative state following 21 sessions of rTMS. The patient was a 32-year-old male who had suffered a TBI 9 years prior and had a GCS score of 6 at injury. Head CT prior to treatment revealed "multicystic encephalomalacia of almost the entire right cerebral hemisphere and most of the basal ganglia as well as hypoattenuation in the anterior frontal lobe and dilatation of third and lateral ventricles." Stimulation was applied using a paired-pulse technique with two 100 mus pulses applied at an interval of 100 ms, followed by 5 s of rest. Daily sessions of 300 pulses at 110% MT were administered over the left DLPFC. Neural activity was monitored using daily EEG recordings pre- and post-rTMS. Prior to the seizure, EEGs showed no evidence of epileptiform discharges or periodic complexes, but the authors note the presence of some neurophysiological disturbances indicated by slow wave abnormalities in the right central-parietal, right temporal, and left temporal areas. The electrographic activity originated in the right central-parietal region and extended to the mid-central and right temporal areas. The event lasted longer than 90 s, but stopped without medication. Subsequent EEGs were no different from recordings taken prior to the seizure. The patient was placed on 1000 mg levetiracetam and monitored carefully for a week. rTMS treatments were then resumed at 2% lower stimulation intensity and with 100 fewer pulses per session for an additional 19 sessions. No further adverse events were reported. The authors note that this rTMS-triggered seizure is unusual as it originated contralateral to site of stimulation. In a double-blind cross-over study (N = 9), Kang et al. reported immediate but not lasting improvement in the attention of patients with TBI following a single tDCS session. MRI and anatomical CT scans demonstrated no significant brain atrophy or implants prior to intervention. Patients with a history of seizure or co-morbid medical/neurological conditions were excluded, and medication was kept constant throughout treatment. A single session of tDCS was administered with the anode over the left DLPFC (2 mA/25 cm2 x 20 min; sham 1 min on/19 min off) and the cathode over the contralateral supraorbital region. Attention was measured using a mini-mental status exam (MMSE) and computerized contrast reaction time task (CCRTT). The treatment group demonstrated improved attention from baseline compared to sham at 1-h follow-up but no significant differences were observed at 3 and 24 h post-treatment. In a randomized double-blind controlled pilot study, Lesniak et al. found that repeated applications of tDCS in addition to daily rehabilitative cognitive training did not enhance attention or memory in patients with severe TBI. The study consisted of patients (N = 23) aged 18-45 who had experienced a TBI a minimum of 4 months prior to the study accompanied by loss of consciousness and/or post-traumatic amnesia, and no prior history of neurological/psychiatric conditions, post-injury seizures, or skull fractures/implants in the area of stimulation. Sham and treatment groups were randomized and matched by age, time since TBI, and severity of symptoms. Fifteen sessions of tDCS with the anode over the left DLPFC (1 mA/35 cm2 x 10 min, decreased intensity at start and finish; sham 25 s on/9.75 min off) and the cathode over the right supraorbital area were administered. Treatment was reported to be well tolerated with minor side effects. Fifteen computerized cognitive training sessions to improve memory were administered following tDCS intervention. Large effect sizes for treatment and sham group were reported but no statistically significant difference between the two groups was found. Ulam et al. used a randomized, double-blind design to test the effect of repeated sessions of anodal tDCS on EEG oscillations and neuropsychological tests (attention, working memory, inhibitory control, cognitive flexibility, immediate and delayed memory for verbal and visual-spatial material, and emotion recognition) in patients with TBI. 23 patients (13 active tDCS and 13 sham) received anodal tDCS to the left PFC (1 mA/25 cm2 x 20 min) with the cathode over the right supraorbital area. EEG immediately after one session of tDCS demonstrated increased cortical excitability at the location of the anode. This increased excitability continued to be present 1 day following the 10th session, but was no longer restricted to the anodal location. There was no significant difference between the active and sham groups in their performance change on the neuropsychological tests, though both groups showed an overall improvement. However, there was a significant correlation between change in cortical excitability and neuropsychological improvement in the active group but not the sham group. Additionally, individuals in the active group who showed a greater slowing in EEG prior to tDCS intervention improved on a greater number of neuropsychological tests than did the rest of the active tDCS group. Middleton et al. report the use of tDCS in conjunction with upper extremity physical therapy for patients with motor impairments resulting for stroke and/or TBI (N = 5, one with TBI, one with TBI + stroke). Bihemispheric tDCS was delivered with the anode over the ipsilesional motor cortex (1.5 mA/25 cm2 x 15 min) and cathode over the contralesional motor cortex, three times a week for 24 sessions, during strengthening and functional activities. Both TBI patients showed improvement on the Fugl-Meyer Assessment of Sensorimotor Impairment UE section (UE-FM), which assesses reflexes, range of motion, pain, light touch sensation, proprioception, movements in and out of synergy, grasp, and coordination. This improvement persisted at a 6-month follow-up. Performance changes in robotic reach and object-hit tasks were less consistent. No adverse effects of tDCS were reported. This small proof-of-concept study showed that tDCS was well tolerated by patients and can be incorporated into physical training without being a hindrance.

altered states of consciousness, depression, non-invasive brain stimulation, rehabilitation, repetitive transcranial magnetic stimulation, trancranial direct current stimulation, traumatic brain injury

PMC4549551_09

Female

Angelakis et al. report an attempt to restore consciousness through the use of tDCS in patients with persistent unresponsive wakefulness syndrome (UWS) following a severe TBI. Five daily sessions of tDCS were administered with the anode over the left DLPFC or left primary sensorimotor cortex (1 mA/35 cm2 x 20 min) and the cathode over the right orbital region to participants (N = 10, four with TBI, open head TBI excluded) with varying degrees of consciousness (assessed by JFK Coma Recovery Scale-Revised, JFK CRS-R; monitored by EEG and fMRI/FDG-PET). A 22-year-old male patient with TBI sustained 6 months prior to treatment (baseline CRS-R: 9) showed immediate improvement after a week of (CRS-R: 17) and continued improvement after second participation 3 months later (CRS-R: 19). A 19-year-old female patient with a TBI sustained 6 years prior (baseline CRS-R: 8) to intervention demonstrated no immediate response to tDCS but improved at a 1-year follow-up (CSR-R: 9). Two patients (CRS-R: 6 and 9, respectively) did not show any immediate effects (no change in CRS-R) or changes at a 1-year follow-up. Both patients were males (aged 35 and 37) with severe TBIs sustained 7 and 10 years prior, respectively. Based on the response of all patients in the study (not just those with TBI), the authors observed that the efficacy of tDCS intervention seemed to be dependent on the severity of the disordered conscious, with MCS patients responding better than UWS, and the time since injury, with more recent injuries faring better. Thibaut et al. performed a sham-controlled randomized double-blind study to determine the effect of tDCS on consciousness in patients with UWS (N = 25; 6 post-traumatic) and patients in a minimally conscious state (MCS; N = 30; 19 post-traumatic). The study employed a cross-over design in which each patient received one session of both sham and real tDCS in a randomized order. The anodal electrode was placed over the left dlPFC with the cathodal (reference) electrode over the right suborbital region (2 mA/35 cm2 x 20 min). A subset of patients showed a transient improvement in CRS-R score following a single session of tDCS. A group effect was seen for the MCS but not for the UWS patient group. Although the authors did not assess the effect of treatment specifically for post-traumatic patients, their presented data show that treatment had no significant effect for the 6 post-traumatic UWS patients but produced some improvement for 5 of the 19 post-traumatic MCS patients. No adverse tDCS-related side effects were observed.

altered states of consciousness, depression, non-invasive brain stimulation, rehabilitation, repetitive transcranial magnetic stimulation, trancranial direct current stimulation, traumatic brain injury

PMC9809383_01

Male

The patient was a 31-year-old homosexual Chinese male with a 6-year history of multiple erythematous scaly plaques. Since June 2016, he has developed erythema, papules, plaques, and scales of various sizes throughout his body. Four months later, the rash increased rapidly, diffusing erythema all over the body, accompanied by a fever. He does not have a regular homosexual partners (regular homosexual partners), with some breaching the safe sex measures. The patient visited with the history of type 2 diabetes and penicillin allergy but no family history of psoriasis. A typical psoriatic rash covered over 90% of his body surface area, and he was admitted to the hospital with "erythrodermic psoriasis". Erythrodermic psoriasis was diagnosed in the context of the pathological examination and clinical features during hospitalization. The pathological manifestations indicated hyperkeratosis, confluent parakeratosis, Munro microabscesses, acanthosis hypertrophy, regular elongation of the rete ridges, papillary dermal edema, mildly dilated blood vessels, scattered perivascular lymphocytes, and neutrophils infiltrated around the upper epidermis and superficial dermis (Figure 1), which are typical characteristics of erythrodermic psoriasis. Simultaneously, the patient tested positive for the human immunodeficiency virus (HIV) antibody. The CD4+ T lymphocyte count was 28 cells/muL, and the HIV viral load was 5.05 x 104 IU/mL. The diagnosis was "HIV infection". The psoriasis was treated successively for 3 weeks with acitretin capsules, total glucosides of peony capsules, compound glycyrrhizin tablets, topical glucocorticoid cream, and moisturizers, and the condition was controlled. Oral tenofovir 200 mg once a day, 100 mg of oral lamivudine once a day, and 50 mg of oral lopinavir and ritonavir tablets twice a day were administered for continuous anti-HIV treatment, and the laboratory indicators were reviewed every six months. The re-examination results on December 11, 2019, showed that the CD4+ T cell count was greater than 200 cells/muL and the viral load was less than 100 IU/mL. During the period from November 2016 to March 2020, the patient took acitretin capsules orally for a long time for maintenance treatment. With the prolongation of the use time of acitretin A capsule, its efficacy gradually declined. The recurrence of psoriasis increased. In March 2020, the psoriasis rash recurred and aggravated, accompanied by noticeable pain in the cervical spine and sacroiliac joints, with unfavorable flexion, extension and rotation. On April 8, 2020, the results of the spine and hip joint MRI performed in another hospital (Figure 2A) suggested abnormal changes in the bilateral sacroiliac and hip joints, slight swelling of the surrounding soft tissue, and right external obturator muscle swelling. Sacroiliitis was considered. On May 5, 2020, he was admitted to our hospital again and diagnosed with psoriatic arthritis (involvement of axial joints) and psoriasis vulgaris (Figure 2B). Laboratory data revealed an CD4+ T lymphocyte number of 278 cells/muL, HIV viral load was less than 100 IU/mL, the eosinophil number of 0x109/L , the red blood cell number of 2.66x1012/L , the level of hemoglobin was 101 g/l , the C-reactive protein level was 33.91 mg/l , the erythrocyte sedimentation rate was 138.00 mm/h , with negative serologic examination for hepatitis A virus, hepatitis B virus, hepatitis C virus, and syphilis. The remaining hematological, biochemical investigations and urine analysis were in the normal ranges. Pre-treatment screening was negative for tuberculosis, including chest X-rays, an interferon-gamma release assay, whereas the Echocardiography (ECG) showed sinus arrhythmia. The psoriasis area and severity index (PASI) score of the skin lesion was 14.4 (Figure 3A), and the Disease Activity Index for Psoriatic Arthritis (DAPSA) score was 52. On May 7, 2020, after the patient was fully informed and signed the informed consent form, subcutaneous injections of 25 mg of etanercept twice weekly combined with 20 mg of acitretin capsules per day were administered. After three weeks, erythema and scales were significantly ameliorated (Figure 3B). After four weeks, the joint symptoms had almost subsided, and the DAPSA score was 0. Acitretin capsules were discontinued, and subcutaneous injection of 25 mg etanercept twice weekly was continued. The rash largely resolved after 21 weeks (Figure 3C), and the PASI score was 1.4. Subsequently, the etanercept dose was modified to a subcutaneous injection of 25 mg once weekly for eight weeks and once every two weeks for another eight weeks. The patient spontaneously discontinued etanercept treatment in February 2021. After 2 months, the rash recurred and worsened (Figure 4A). The PASI score was 20.2, and mild pain was observed in the cervical spine and spinal joints. The DAPSA score was 34, CD4+ lymphocyte count was 353 cells/muL, and HIV viral load was less than 100 IU/mL. On May 31, 2021, after repeatedly excluding any abnormalities in the examinations for the administration of biologics, secukinumab 300 mg was prescribed for treatment in the 0th, 1st, 2nd, 3rd, and 4th weeks in the context of anti-HIV treatment. Subsequently, it was administered at a dose of 300 mg every four weeks. After four weeks, the patient's joint symptoms completely disappeared, and the DAPSA score was 0. The times to achieve PASI 40, PASI 75, PASI 90, and PASI 100 were 2 weeks (Figure 4B), 4 weeks, 8 weeks (Figure 4C), and 29 weeks (Figure 4D), respectively. At present, secukinumab has been maintained for 1 year, and the clinical symptoms of psoriasis have stabilized (Figure 4E and the specific treatment timeline is shown in Figure 5). The CD4+ T lymphocyte count was 327 cells/muL, and the HIV viral load was less than 100 IU/mL. The results of the spine and hip joint MRI on April 25, 2022, indicated straightened physiological curvature of the cervical spine compared with the MRI results on April 8, 2020, before the use of biologics, with no abnormalities in height and signal of the vertebral body and less severe bilateral sacroiliac joint inflammation. The patient provided written informed permission to have any accompanying photos and case details published. The Hospital Ethics Committees of Dermatology Hospital of Jiangxi Province approved to publish the case details.

hiv, biologics, etanercept, psoriasis, secukinumab

PMC10225632_01

Female

Our patient was a 30 year-old female, 5-weeks pregnant at presentation, with no history of epilepsy or neurological disease. She was brought to her local emergency department (ED) after she was found shaking and unresponsive by her partner. The seizure lasted for more than 1 h, and was aborted by 10 mg diazepam given by ambulance paramedics. Seizures recommenced in ED and were refractory to intravenous (IV) lorazepam (4 mg) and levetiracetam 1 g. She was subsequently intubated in ED and started on a propofol infusion (100 mg/h). CT head and lumbar puncture on admission were both unremarkable. Magnetic resonance imaging (MRI) and Magnetic resonance venogram (MRV) conducted on day two after onset were normal. The day after admission, the propofol infusion was held, which restarted seizure activity. The seizures started as distal limb myoclonic jerks in the upper and lower limbs, and then progressed to stimulus-sensitive (touch and sound), generalized myoclonus. Sedation was recommenced with propofol, fentanyl (200 micrograms/h) and midazolam (10 mg/h), and the levetiracetam dose was increased to 1.5 g BD. Clobazam 5 mg BD was also added. Generalized myoclonus/myoclonic jerks continued while she was on propofol, fentanyl, clobazam, levetiracetam, and midazolam. Obstetric input was sought, and phenytoin (100 mg TDS), lacosamide (100 mg BD), topiramate (100 mg BD) were added, in sequence. She was pulsed with methylprednisolone from day 5 of presentation. Seven days after initial presentation, the patient was transferred to our center with ongoing right arm and left leg myoclonic jerks and head movements suggesting ongoing status epilepticus. Two hundred milligram biotin and pyridoxine 50 mg were commenced on arrival. The patient's lumbar puncture was repeated on day 7 when she was admitted to our center and she was found to be HSV negative, and aciclovir was stopped. MRI head (Figure 1A) and spine were also repeated (day 11 after onset) and were unremarkable. On admission to our center metabolic, CSF virology, and autoimmune and paraneoplastic panels were all negative (detailed in Table 1), as were QuantiFERON-TB Gold, and blood, CSF and sputum cultures. Vitamin B12, folate and serum ferritin were normal. At this point, a diagnosis of NORSE was suspected, and the patient was managed as such. The patient also underwent three EEGs: soon after admission to the local hospital CCU, a prolonged study after admission to our center, and after VNS implantation (Table 1; Figure 1B). Propofol weaning was attempted again, 9 days after onset but this led to increased myoclonic jerks and it was reintroduced. Perampanel 6 mg was commenced via a nasogastric tube 11 days after onset. Five sessions of plasmapheresis (PLEX) were commenced 12 days after presentation. The patient was started on Anakinra (100 mg daily) after the last PLEX. Propofol was cross-tapered with ketamine (2.5 mg/kg/h) to reduce the risk of propofol infusion syndrome as the ketogenic diet as started. The ketogenic diet was commenced 22 days after onset, and Levetiracetam was switched to Brivaracetam (100 mg BD). An CT chest abdomen and pelvis was performed and ruled out trophoblastic disease or ovarian teratoma. Whilst there had been no collateral history or evidence of overdose, the toxicology panel conducted on admission to her local hospital, which was made available to us 20 days after onset, demonstrated grossly elevated levels of morphine, fentanyl, pregabalin, and cocaine. Two past admissions for ecstasy and pregabalin overdose also came to light. Based on these results, possible anoxic brain injury was considered although subsequent MRI Brain scans did not show any evidence of hypoxic injury. Due to refractoriness of her myoclonus on weaning sedation, an unremarkable MRI brain study and difficulty in assessing her level of consciousness off sedation, the Epilepsy Surgery MDT agreed on VNS implantation. VNS was implanted 26 days after seizure onset. The clinical outcomes post-VNS implantation have been outlined in Table 2. The VNS was switched on day 0 with immediate post-operative settings 0.25 mA, 30 Hz, 500 mus, 30 s on, 5 min off, Duty cycle 10%. VNS output was increased till day 7 post-op according to Figure 2. All other parameters stayed the same. No intraoperative or post-operative complications were noted. Two days post-operatively, myoclonic jerks were still occurring, but eye opening to voice and apparent purposeful movements (including reaching for the tube) were noted. On day 3 post-operatively slow ketamine weaning was started. The patient was extubated on day 5 post-op. Semi-purposeful movement in all four limbs was noted, and the stimulus-sensitive myoclonic jerks had diminished significantly. Midazolam was stopped. No myoclonus was noted 7 days post-op. The patient was discharged to a neurology ward in our center. Anakinra, the ketogenic diet, and prednisolone were weaned. Thirteen days after VNS implantation, the patient demonstrated full passive range of motion in all limbs. After 18 days, normal power was noted in all limbs (MRC 4+/5). Nineteen days later the GCS had improved to 15/15. The patient showed comprehensible speech, and was oriented to place and person. Twenty days after VNS implantation, no myoclonic jerks were noted, and the patient was transferred back to her local hospital for further rehabilitation. Four months after VNS implantation, occasional, inconsistent tremors in upper and lower limbs were noted thought to be either a functional overlay or enhanced physiological tremor: these movements were clinically distinctively different from myoclonic jerks, were distractable and could be voluntarily suppressed. A repeat EEG performed at about 5 months from hospital admission did not capture the tremor-like movements; it showed background slowing and occasional spikes with no clinical correlate (no motor manifestations). Five months after VNS implantation, no further seizures or focal neurology were reported. The patient continued to take clonazepam and perampanel and mobilized using a Sara Steady sit-to-stand aid. Fatigue and low mood were reported. Except for a minor vaginal bleed lasting 2 days, pregnancy was uneventful: repeat fetal monitoring by ultrasound at day 17, 4 and 5 months after VNS implantation and a fetal anomaly scan were unremarkable and a spontaneous vaginal delivery was planned. The patient experienced preterm premature rupture of membranes (PPROM) at 33 + 2 weeks gestation, and went into preterm labor with transverse fetal lie and fetal bradycardia. The baby was delivered via emergency cesarean section under spinal anesthesia, and admitted to the neonatal ICU due to prematurity, but was discharged without neonatal concerns. Our patient made an unremarkable obstetric recovery.

norse, vns, outcomes, pregnancy, status epilepticus

PMC6479155_01

Female

A 12-year-old girl presented with a 2-week history of coryza, cough, poor appetite and localised left sided chest pain. There was no history of fever or notable weight loss. Important aspects of her past medical history included a liver transplant nine years previously for idiopathic liver cirrhosis and subsequent right diaphragmatic repair. She previously had a Broviac line (long term intravenous catheter) inserted in her left subclavian vein. She had received all her early childhood immunisation including BCG at birth. She had hypertension which was controlled on atenolol. Her immunosuppressive medications included oral prednisone 4mg daily and tacrolimus 2mg daily. She was on co-trimoxazole prophylaxis (60 mg daily) but not on isoniazid (TB) prophylaxis. There was no known household TB exposure. Clinical examination showed a well-nourished child with no evidence of peripheral lymph node enlargement and no other constitutional symptoms. Examination and chest radiograph were in keeping with a left sided pleural effusion, Fig. 1a. A pigtail intercostal drain (ICD), was inserted and drained an initial 260mls of cream-coloured fluid, Fig. 1b. Abdominal ultrasound did not reveal ascites. Results of laboratory investigations and pleural fluid analysis are shown in Table 1 and were consistent with a chylous pleural effusion. The child received a combination of antibiotics - initially parenteral ampicillin, gentamicin and cloxacillin for 3 days and changed to oral ciprofloxacin and amoxycillin for 5 days. The ICD was removed after seven days, at which time the daily drainage was now less than 10mls with clinical resolution of presenting symptoms. As part of her investigations, the two induced sputum samples taken for culture and PCR for M. tuberculosis (Xpert MTB/Rif Ultra) were negative for M. tuberculosis, but the from the bronchoalveolar lavage sample, rifampicin sensitive M. tuberculosis complex was detected. Her liver function tests were normal on admission, but she developed a transient transaminitis on commencement of first line anti-TB medications (isoniazid, rifampicin, ethambutol and pyrazinamide). This resolved with drug withdrawal. The very raised liver enzymes were attributed to rifampicin and pyrazinamide side effects and thus she was then recommenced on the alternative regimen of 300mg of isoniazid, 400mg of ethambutol, 500mg of ethionamide, and 375mg of levofloxacin. She was additionally commenced on medium chain triglyceride diet by the dieticians. She did well on this therapy and has continued to do well on follow-up, with complete clinical resolution of chest symptoms.

chylothorax, lymphadenopathy, parapneumonic effusion, pleural fluid, tuberculosis

PMC6479155_02

Male

A 10-year-old male presented with 3 weeks of chest pain that was worse on the right side, dry cough, poor appetite, fever and night sweats with progressively worsening respiratory distress and weight loss. He was HIV-exposed but un-infected and there was no household TB exposure. He had received all childhood immunizations. His mother had died 4 years previously of an HIV-related illness. The child appeared unwell with examination findings of fever, respiratory distress requiring oxygen; enlarged cervical lymph nodes, mild hepatosplenomegaly, and features consistent with a right sided pleural effusion and left lower lobe pneumonia, confirmed on chest radiograph, Fig. 2a. Abdominal ultrasound showing multiple splenic micro abscesses (Fig. 2b). As bacterial empyema was suspected, a pigtail intercostal drain was inserted and drained 330mls of milky-serous fluid (Fig. 2c) which appeared to be pus. Investigations on pleural fluid and sputum confirmed pulmonary tuberculosis and chylous pleural effusion are shown in Table 1. The child was treated with intravenous ceftriaxone for 7 days. The pleural drain was removed after 8 days, at which time the daily drainage was now less than 10mls with clinical resolution of presenting symptoms. Tuberculosis was proven on an induced sputum (Xpert MTB/Rif Ultra positive, rifampicin sensitive) and he was commenced on the standard anti-TB medications: isoniazid, rifampicin, ethambutol and pyrazinamide. He was also started on medium chain triglyceride diet. On follow-up, he has done well with complete clinical and radiological resolution of chest symptoms.

chylothorax, lymphadenopathy, parapneumonic effusion, pleural fluid, tuberculosis

PMC3964902_01

Male

A 25-year-old Caucasian male patient presented with a three-week history of a red right eye. He complained of blurred vision on the affected eye without pain or other sensations. He had no fever, fatigue, and denied weight loss. His past medical and family history were unremarkable. On examination, the patient's visual acuity was 14/20 OD and 20/20 OS. A prominent vascularized iris lesion located at 7 o'clock was present in the right eye in addition to mutton-fat keratic precipitates, predominantly in Arlt's triangle, anterior chamber cells, and mixed conjunctival and ciliary injection (Figure 1(a)). Neither fundoscopy of the right eye nor examination of the left eye disclosed any pathological findings. An ultrasound biomicroscopy (UBM) of the right eye revealed a prominent iris process with extension into ciliary body which measured 4.7 x 4.0 x 1.8 mm with middle internal reflectivity (Figure 1(b)). Laboratory findings were unremarkable including serum ACE level and tuberculin testing. Chest computed tomography (CT) revealed bilateral hilar lymphadenopathy and reticulonodular parenchymal involvement. To confirm the suggested diagnosis of sarcoidosis, conjunctival biopsy was performed. Histopathological work-up showed granulomatous epithelioid cell inflammation with insular central necrosis without acid-fast bacilli (Figures 1(c) and 1(d)). The diagnosis of tuberculosis was suspected and further examinations were initiated. Extensive systemic checkup, including bronchoscopy, bronchoalveolar lavage (BAL) with CD4/CD8 ratio evaluation, and transbronchial biopsy, revealed no evidence of acid-fast organisms. Transbronchial biopsy showed noncaseating granulomatous inflammation, typical for sarcoidosis. PCR showed no mycobacterial DNA in the biopsy specimen. Systemic and topical steroid therapy was initiated with oral prednisolone 100 mg daily and prednisolone acetate 1% eye drops hourly. Under this treatment our patient recovered completely. Eight weeks after the first presentation, no signs of intraocular inflammation were detectable, the iris tumor resolved completely, and the patient was free of any complaints.

PMC7750025_01

Female

An 82-year-old woman presented to our hospital emergency department because of repeated vomiting that persisted for 2 days without induction. She had a history of cerebral infarction, hypertension, dementia, and surgery for a perforated sigmoid diverticulum. An upper gastrointestinal endoscopy had been performed at another hospital a month ago, but no abnormalities were noted. A physical examination revealed consciousness corresponding to the Glasgow Coma Scale score of 12 (E4V3M5), blood pressure of 98/71 mmHg, pulse of 119/min, temperature of 36.5 C, tachypnea (>=30 times/min), and 85% oxygen saturation (on room air), with diminished breath sounds on the left side. Chest X-ray revealed a large gastric bubble in the left chest cavity, with the mediastinum strongly displaced to the right side (Fig. 1A). Oxygen at 5 L/min improved the oxygen saturation (SpO2) to 92%, but tachypnea and tachycardia persisted. We speculated that a worsening esophageal hiatal hernia was probably responsible for the deterioration in respiration and circulation. Computed tomography (CT) performed for a definitive diagnosis showed that the entire stomach had escaped into the mediastinum and that it was craniocaudally inverted with axial torsion. In addition, the mediastinum had undergone a remarkable shift to the right owing to the presence of the dilated stomach; other structures, such as the left lung, heart, and inferior vena cava, were also highly displaced. There was no evidence of pneumonia (Fig. 2). Her condition deteriorated to agonal respiration with worsening tachycardia (120-150 times/min) when she returned to the emergency room after the CT scan, and assisted ventilation was immediately initiated. Subsequently, she developed pulseless electrical activity. Cardiopulmonary resuscitation was immediately initiated. CT findings suggested that the dilated stomach, along with the esophageal hiatal hernia, was strongly pressing on the heart, thereby disrupting circulation. Therefore, a gastric tube was used to decompress the stomach through which 1,400 mL of gastric fluid was aspirated. A spontaneous heartbeat resumed immediately, with stable circulation. Chest X-ray performed after the gastric tube insertion revealed normal mediastinal structures and the absence of the previously present giant gastric bubble in the mediastinum (Fig. 1B). Subsequently, the correction of dehydration by infusion stabilized both the blood pressure and tachycardia; however, because she developed aspiration pneumonia, her respiratory status did not improve and she died on the fourth hospital day (Fig. 3).

circulatory failure, diaphragmatic hernia, esophageal hiatal hernia, tension gastrothorax, upside‐down stomach

Chest and abdominal computed tomography scans (plain films) showing a significantly dilated stomach incarcerated within the mediastinum. A marked displacement of the heart and the left lung can be observed. Craniocaudal inversion of the incarcerated stomach, leading to an "upside-down stomach," can also be visualized. IVC, inferior vena cava.

PMC4070324_01

Female

The patient is a 66-year-old Caucasian female who presented to our hospital with three weeks history of fever of unknown origin with no specific pattern, associated with nausea, vomiting, fatigue, and pruritus. The patient was already admitted twice to an outside hospital within the last month and underwent extensive diagnostic workup. She had a bronchoscopy with BAL studies as well as lung biopsy of an incidental 1.6 cm right lower lobe lung nodule, seen on imaging studies, with no definite diagnosis. Her past medical history is significant for 16 years history of rheumatoid arthritis, for which she has been on methotrexate for the last 8 years and infliximab for the last 6 years. At the outside hospital, she was found to have elevated liver enzymes with subsequent discontinuation of methotrexate and infliximab. The patient was started on prednisone at a dose of 40 mg daily. Upon arrival to our hospital, the patient was found to have a fever of 103 F with chills and tachycardia, along with painless jaundice, fatigue, nausea, and vomiting. She denies any history of sick contacts, unpasteurized milk, or undercooked meat intake. Upon further questioning, she reports that her fever started only two days after a long road trip with her husband, from Michigan to Florida. On their way, and 11 days prior to her symptoms started, they stopped at Pittsburg, Kansas, where they stayed for 6 days. The patient endorsed horseback riding in Pittsburg but, however, denied any sick contacts. Her examination was notable for an awake, alert, and oriented patient with icteric sclerae. Her respiratory rate was 18 breaths per minute and was saturating 98% on room air. There was no hepatosplenomegaly or abdominal tenderness and the rest of the examination was normal. Laboratory examination revealed hemoglobin of 12.3 g/dL, white cell count of 7.9 with 40% granulocytes, 43% lymphocytes and 7% monocytes, and platelets of 230. Liver function tests revealed alanine aminotransferase 252 IU/L (0-60 IU/L), aspartate aminotransferase 173 IU/L (0-46 IU/L), alkaline phosphatase of 375 IU/L (44-147 IU/L), total bilirubin 4.2 mg/dL (0-1 mg/dL), corrected calcium 8.7 mg/dL (8.5-10.5 mg/dL), PT 11.4 (9-12.5 sec), total protein of 7 mg/dL, and an albumin of 2.5 mg/dL. Autoimmune markers, including serum antimitochondrial antibodies, were negative, except for RF and anti-CCP. Blood cultures and urine culture remained negative. Ultrasound of the abdomen was normal. The chest X-ray again revealed a right lower lobe pulmonary nodule. Computed tomography (CT) of the chest showed a 1.3 cm right lower lobe pulmonary nodule which corresponds to the abnormality seen on chest X-ray. CT of the abdomen showed normal appearance and size of liver, pancreas, spleen, and adrenals. Outside records were reviewed and bronchial washings had grown only Candida albicans on routine bacterial and fungal cultures. Cytology was consistent with mixed inflammatory cells with no evidence of microorganism on Grocott's methenamine silver (GMS) stain. Right lower lobe nodule CT guided needle biopsy was only consistent with focal acute and chronic inflammation, along with scattered yeast elements consistent with candida species, with no evidence of granulomas or tumor. CMV PCR and hepatitis serologies were negative. EBV blood PCR came back positive with 1959 copies/cc (IgG VCA positive, IgM VCA negative). Serum RPR and QuantiFERON test for tuberculosis were negative. Serum cryptococcal antigen from outside hospital was negative. Empiric antibiotics consisting of vancomycin and piperacillin-tazobactam were discontinued after final blood cultures reported no growth and patient remained febrile. Transthoracic echocardiogram was compatible with grade 1 diastolic dysfunction, normal ejection fraction, and no vegetation. An ultrasound guided liver biopsy, done on hospital day two, was consistent with granulomatous hepatitis with negative acid fast stain, and subsequently steroids were restarted. Cryptococcal antigen and Brucella, Bartonella and Q fever serologies were all negative. Liver biopsy immunohistochemical stain with in situ hybridization studies was also negative for EBV. On hospital day five, after additional stains on liver specimen were performed, pathological examination reported that fungal organism was identified within areas of granulomatous inflammation, largely within histiocytes on hematoxylin and eosin staining. They were further described as round to ovoid 2-4 micrometers narrow based budding fungal organisms on GMS staining suggestive of histoplasmosis (Figure 1). Three days later, serum histoplasma antigen, by quantitative MVista Histoplasma antigen enzyme immunoassay (EIA) detection test, reported strongly positive with titers above the limit of quantification, above 19 ng/mL. Meanwhile, patient clinical condition deteriorated and progressed into a respiratory failure with bilateral interstitial infiltrates on chest imaging requiring mechanical ventilation. Intravenous liposomal amphotericin B at a dose of 3 mg/kg q 24 hrs was ultimately started. Fungal culture from bronchoalveolar lavage eventually grew Histoplasma capsulatum. The patient became afebrile on day five of amphotericin and her jaundice started to resolve. Her chest X-ray cleared and was extubated. The patient was switched on day seven to itraconazole secondary to acute kidney injury. Antifungal therapy was subsequently switched to voriconazole once she developed a bleeding peptic ulcer disease requiring intravenous proton pomp inhibitor while being on itraconazole. Patient's liver function tests completely normalized in six weeks.

PMC3924946_01

Female

Mr. A, 30 years old, small and shy, was born in a north-western Portuguese village near an internationally renowned Casino-beach-resort and lived there until the age of 18. He is the only son of a working-class couple, both in employment. Mr. A attended a college in Lisbon, which was a three hour drive from his parent's home. None of his peers from the village went to college. Mr. A was a driven individual and achieved his goal of pursuing further education. At home his parents "always quarreled" about his father's infidelities but they stayed together to finance his studies. When they divorced after his graduation, he felt sad and developed gradually a depressed mood. His symptoms lasted for one year before he came for a consultation to the first author Fatima Gysin. Additionally, he broke two toes kick-boxing, causing him to stop practicing his favorite sport. During this period he also started to date a girl who had a poor education and no fixed job. She envied him for his higher income and she was unfaithful to him. For these reasons and with a noticeable low performance in his engineering job, he was encouraged by his friends and pressured by his superiors at work to see a psychiatrist, whom he selected from a health insurance list. During his first sessions in September 2011 he showed low mood, he was resentful for not being promoted at work, had lack of motivation, social isolation and criticized his bizarre feelings when he was irrationally afraid of being attacked in a familiar and secure night club. He had outbursts with friends, anhedonia, a lesser sexual drive, fear of losing his hair and of gaining weight against the evidence and he was excessively dysphoric of his small height of 1.59m. He wanted help but without medication. For Mr. A, paid sex was not a problematic issue, nor a direct motive for his consultation. When questioned about his sex-life he was comfortable talking about his experiences, and showed a consumer pride in prostitution. At the age of 22, after breaking up a four-year relationship, out of curiosity and revenge, he purchased for the first time sexual services in a sex-worker's apartment. This use of prostitution escalated when back in his native village, where a Saturday night ritual with a group of friends started. After dinner they would bring home their official girlfriends and then, only the four or five boys, visit a brothel, have a drink, have fun and sometimes have paid sex with prostitutes, using protection. This kind of prostitution use became a peer group standard and, for Mr. A, an easy victory over his shyness. Mr. A became hooked and hyper-seduced by a specific prostitute, and he fantasized about living with her in an exotic land. However, to have or to maintain a full erection during paid sex he needed to think and imagine that he was making love to a romantic partner. The patient referred to exclusive heterosexual orientation and sexual desire, however revealed that he would suffer a loss of erection when either nervous or stressed.

PMC8222915_01

Male

A 33-year-old Indian male had the following subjective symptoms from June 2016 till November 2016: Sharp pain in the right testicle radiating to the right buttock, right lower back, pelvic region both left and right sides, and perineal pain. He also experienced perspiration, generalized weakness and malaise in the body through the day. The patient had a daily low-grade fever and chills: 37.5-37.7 C. No antipyretic was taken to reduce body temperature. He felt chills every morning that would last for about 1.5 h. At this time, a urine culture was ordered, which was sterile after 48 h of aerobic incubation. A kidney, ureter, and urinary bladder (KUB) ultrasound showed both kidneys to be normal in size, shape, position, and echotexture. No evidence of any calculus or hydronephrosis was noted. The urinary bladder was normally distended with normal wall thickness. No calculus was observed. The prostate gland was considered to be of normal size. A digital rectal exam (DRE) by a urologist revealed a tender prostate, and the patient was diagnosed with CBP. He had no history of urological problems before this diagnosis. Multiple antibiotic treatments were administered empirically in the patient's home country over a period of four months. These included single dose Azithromycin 1 g, followed by a course of Doxycycline 200 mg for 10 days, then the third course of antibiotics with Ofloxacin 400 mg for 23 days, and finally a combination of Ciprofloxacin 1 g taken orally and Amikacin 750 mg given intravenously for 10 days. The patient experienced no improvement in symptoms during or after these antibiotic courses. A transrectal ultrasound (TRUS) done in October 2016 showed the prostate size to be 21.98 ml. In November 2016, the patient traveled to Tbilisi, Georgia, to explore phage therapy at the EPTC as a potential treatment for his condition. At the clinic, a full urologic workup was performed. The patient's prostate was found to be tender and boggy by rectal palpation. The patient's EPS and semen samples were collected and observed microscopically, as well as cultured for aerobic bacteria. The cultures were tested for sensitivity against Eliava Institute's standard phage cocktail preparations. The details of these phage preparations are given in Appendix Table A1. Table 1 shows the outcomes of these tests. No fungal growth was detected in either sample. There was no presence of gonococcus. Blood tests showed normal blood counts, leukocyte counts, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and prostate-specific antigen (PSA) levels. Urinalysis and culture were sterile. S. epidermidis was considered non-pathogenic due to its low growth and low virulence. The patient decided to undergo phage therapy. Pyo, Intesti, and Staphylococcal phage preparations were used for his treatment. The preparations were administered in three forms:oral liquid, rectal suppositories, and urethral instillations. 20 ml each of Pyo and Intesti oral phages were given to the patient per day for the first 14 days. Concurrently, the patient self-administered Staphylococcal phage suppositories twice a day for 10 days, and urethral instillations with Intesti phage were administered to him by the urologist at the EPTC once a day for 10 days. On the fifth day after starting phage therapy, the patient's body temperature normalized, and did not subsequently increase beyond 37 C. After the first 2 weeks, a long-term daily dose of 10 ml each of Pyo and Intesti oral phages was established for the next 2 months. Rectal suppositories of Pyo, Intesti, and Staphylococcal bacteriophages were used in rotation for 10 days each, with breaks of 10 days between different phage suppositories. Urethral instillations were not done after the initial 10 days to avoid urethral irritation. The testicular and back pains increased initially after starting treatment and began to subside after 3 weeks of starting phage therapy. Subjective symptoms of weakness, night sweating, and chills also decreased gradually. In March 2017, the patient visited the EPTC again, and his EPS and semen were tested to ascertain his progress. Table 2 shows the outcomes of the tests. S. aureus did not grow in this or any subsequent cultures. S. mitis was a new bacterium that grew in the EPS. This strain was resistant to all of Eliava Institute's standard phage preparations. The other bacteria were treated with Intesti and Fersis phage preparations from March till June 2017. A combination of oral phage, rectal suppositories, and urethral instillations was administered, similar to the previous course of treatment. Through this course of treatment, the patient's symptoms continued to improve. Night sweats, chills, excessive perspiration, and weakness had fully subsided by the end of June 2017. A custom phage (autophage) was prepared in September 2017 that was fully sensitive against the S. mitis isolated from the patient's sample. This was administered according to the previous protocol, along with Staphylococcal bacteriophage, from November 2017 till January 2018, during which time his only remaining symptoms of pelvic and perineum pain decreased in intensity and frequency. A TRUS performed in November 2017 revealed that the prostate size had reduced to 14.38 ml, with no prostatic inflammation present. Figure 1 shows a comparison between the ultrasound images before, during and towards the end of the patient's phage therapy. The patient's EPS and semen were tested again in May 2018. No pathogenic bacteria grew in these cultures, and the leukocyte counts in the EPS and semen were normal. The prostate was small and firm by rectal palpation. Repeated testing has continued to show the same results. The patient is in full remission, and his chief complaints have not returned.

antibiotic resistance, bacteriophages, biofilm, case report, chronic bacterial prostatitis, phage therapy

PMC7171671_01

Female

A heterotopic pancreas (HP) is a congenital anomaly that is anatomically separate yet histologically the same as the pancreas. This anomaly is also known as ectopic, aberrant, or as an accessory pancreas as it does not have anatomic, vascular, or ductal continuity. Cases are most commonly seen in the upper gastrointestinal tract (GIT) such as the stomach, duodenum, and proximal jejunum. Although less common, HP may also be seen in the esophagus, ileum, Meckel diverticulum, and biliary tree. HP affects males two times more than females and typically is not discovered until the fifth to sixth decade of life despite a few cases in children and young adults. HP presenting in the esophagus is uncommon with approximately fifteen adult cases reported in the medical literature. We present a case of a 70-year-old male who was incidentally found to have HP located in the distal esophagus on EGD after reported complaints of heartburn, nausea, and abdominal bloating.

PMC7171671_02

Male

This is a case of a 70-year-old male with a medical history significant for hypertension, hypercholesterolemia, melanoma, and atrial fibrillation who presented with complaints of heartburn, nausea, and abdominal bloating. Patient reported to also have hiccups along with nausea but no episodes of vomiting. Patient endorsed mild abdominal distention. He denied abdominal pain, hematochezia, melena, hematemesis, change in bowel movements, or weight loss. Physical exam did not reveal any abnormalities. Routine blood work was unremarkable. Initially, our patient was treated for dyspepsia with a trial of PPI. He was scheduled for an EGD, which revealed an incidental 5 mm polypoid appearing lesion in the distal esophagus above the gastroesophageal junction (Figures 1 and 2). Biopsy results revealed squamous mucosa with active esophagitis and associated cardiac-type mucosa with focal pancreatic heterotopia and chronic inflammation in the distal esophagus (Figures 3-5). Given the relatively small size of the lesion, it was resected endoscopically. The patient was treated conservatively with supportive with PPI for his gastric inflammation and symptoms. Patient is to be followed in one year for surveillance of the lesion with biopsy. Patient may need an endoscopic ultrasound (EUS) depending on his surveillance EGD results.

PMC4782473_01

Female

A 3-year-old girl presented with cyanosis. On examination heart rate of 130/min, blood pressure of 100/64 mmHg, and arterial oxygen saturation of 81% were noted. Echocardiography revealed an unbalanced atrioventricular septal defect with double outlet right ventricle and left atrioventricular valve stenosis. The ostium primum atrial septal defect was tiny and restrictive. The ventricular septal defect was very large and biventricular repair was not feasible. A patent ductus arteriosus was also present. Cardiac catheterization showed mean pulmonary artery pressure of 77 mmHg with pulmonary artery wedge pressure of 37 mmHg. Atrial septectomy and ligation of the patent ductus were done along with pulmonary artery banding with 34 mm Mersilene. The postoperative course was uneventful. Two years later, the child presented with massive ascites with pedal edema and facial puffiness. There was no history of fever, recurrent chest pain, or any other systemic illness during this time. The ascites was gradually progressive. On physical examination, she had elevated jugular venous pressure with hepatomegaly and ascites. There was no pulsus paradoxus. Routine blood investigations were normal. Abdominal ultrasound showed free fluid, hepatomegaly, single left sided spleen, and no other abnormality. Her chest X-ray [Figure 1] showed cardiomegaly and pulmonary venous hypertension. Electrocardiography showed ectopic atrial rhythm, first-degree atrioventricular block, and poor R wave progression but was unchanged from the previous recording. Echocardiography showed features of congestion such as dilated inferior vena cava and lack of inspiratory collapse. There was no pericardial effusion. Biatrial enlargement was also present. There was no significant atrioventricular valve regurgitation, and systemic ventricular function was normal. Respiratory variation in inflow velocities across the atrioventricular valves or septal bounce were not appreciated due to the presence of a large ventricular septal defect and atrial septectomy. Diagnosis of constrictive pericarditis (CP) was suspected despite cardiomegaly and atrial dilation. CT angiogram, [Figure 2] however, did not reveal pericardial thickening or calcification. Previous records did not suggest any evidence of the development of postpericardiotomy syndrome (PPS) in the first year after surgery. There was no history of tuberculosis. A repeat cardiac catheterization showed elevation of right atrial, ventricular diastolic, and pulmonary artery diastolic pressures all being nearly equal around 20 mmHg. Mean pulmonary artery pressure was 33 mmHg with pulmonary vascular resistance index (PVRI) of 2.9 Wood units. The right atrial pressure of 22 mmHg in the absence of a significant left to right shunt, ventricular dysfunction, or atrioventricular regurgitation was suggestive of a constrictive physiology. The diagnosis was confirmed at operation. The pericardium was found to be adherent to the underlying epicardium over the right atrial and ventricular walls. The pericardium, however, was not significantly thickened. Histopathological examination of the excised pericardial tissue showed fibrosis, hyalinization, and focal chronic inflammation consistent with pericarditis [Figure 3]. Since the calculated PVRI at preoperative catheterization was 2.9 Wood units, and the pulmonary arteries were thin walled at pulmonary arteriotomy, bilateral bidirectional cavopulmonary shunt with antegrade flow interruption was carried out 4 days after pericardiectomy as an intermediate palliation for the future. The staged surgery was done in view of the unusual combination of POCP and the presence of an underlying condition requiring univentricular palliation and can be argued. This is, however, not the point of this communication. There was a remarkable regression in the ascites and marked symptomatic improvement. On follow-up 1-year after pericardiectomy the child is active and growing adequately [Figure 4].

constrictive pericarditis, heart surgery, postoperative

PMC10332765_01

Male

The patient was a 49-year-old male visiting Catalina Island when he suffered a fall from the back row of a concrete amphitheater. He described a fall of approximately ten feet, where he landed on the lateral aspect of his right heel on concrete ground. He then fell sideways and rolled through the rest of the fall. The patient described constant, severe, sharp pain in the right heel after the fall, which made him unable to ambulate at the scene without assistance. He could not put weight on the affected foot due to pain. He did not strike his head, nor did not lose consciousness, and he had no back pain. His review of systems was grossly unremarkable, except for pain in the posterior ankle and nausea when the pain was worst. His vital signs were unremarkable throughout his presentation. His medical, family, and social history were noncontributory. Examination of the right ankle demonstrated a large deformity of the superior talus with bruising and blanching of the overlying skin in the area of the Achilles tendon (see images 2,3). The remaining bones of the foot were not tender to palpation and the foot was neurovascularly intact throughout with only mild numbness in the area of the tented skin. Completing the trauma exam, the patient had no signs of head injury and no midline spinal tenderness to palpation. Inspection of the remaining long bones and joints showed no other injuries. There were mild skin scrapes on the right flank from the fall. X-rays of the right foot and ankle showed a longitudinal fracture of the calcaneal tuberosity from the articular surface to the posterior surface (see red outline) with extension into the subtalar joint (blue lines) and roughly 1.8 cm displacement between the fracture segments (yellow double arrow). These findings represented a tongue-type calcaneal bone fracture. Based on history, physical exam, and imaging, the diagnosis of tongue-type calcaneus fracture was made. A tongue-type calcaneal fracture is a longitudinal fracture that involves a portion of the articular surface and exits the calcaneal tuberosity posteriorly. The skin tenting, blanching, decreased sensation, and bruising suggested pressure from the fracture fragment on the skin was limiting perfusion and putting the tissue at risk of necrosis. This constellation of findings indicated a need for emergency surgery to preserve the tissue and limit complications. Since the patient was on an island at a critical-access emergency department (ED), resources were limited, with no orthopedic surgeons available to perform the surgery. To reduce pressure on the skin, the patient's lower leg was wrapped in bulky padding with anterior and posterior splints placed to hold the foot in plantarflexion. The patient was then endorsed to an orthopedic surgeon and airlifted by helicopter to a mainland hospital where he could be taken to the operating room immediately. On arrival, he was taken for emergent open reduction internal fixation (ORIF) of the right calcaneus to relieve the stress on the skin and align the tongue fragments using three orthopedic screws. The patient tolerated the procedure well with no complications. He was discharged one day after surgery, non-weightbearing on the right lower extremity. Unfortunately, the patient's post operative course was complicated by a fall in the shower which broke his original hardware, requiring two additional surgeries to repair. Fortunately, the patient recovered well after the third surgery, approximately 3 months after his original injury.

PMC7265266_01

Female

A seven-year-old female patient with clinical manifestations of PCG referred to us [Table 1] to receive genetic counseling and molecular testing. The subject was born of consanguineous marriage [Figure 1a]. All family members received genetic counseling, and informed consent was obtained from her parents for participation in the study and publishing the results. We conducted the targeted sequence analysis for the genes associated with PCG (ASB10, CYP1B1, FOXC1, LTBP2, TEK, MYOC, NTF4, OPA1, OPTN, TBK1, and WDR36). Accordingly, we identified a homozygous single base pair deletion in exon 3 of the CYP1B1 gene in reverse strand of genomic position as follows: (chr2:38298398_38298398delC) (NM_00010 4(CYP1B1):c. 1099_1099delG), p.(D367Tfs*61) [Figure 1b]. This variant is theoretically predicted as a disease-causing factor by Sorting Intolerant From Tolerant (SIFT) (https://sift.bii.a-star.edu.sg/), Protein Variation Effect Analyzer. (PROVEAN) (http://provean.jcvi.org/index.php), and MutationTaster (http://www.mutationtaster.org/) software and classified as very strong pathogenic (PVS1) null variant according to the ACMG guidelines and standards. This variant is also absent from the 1000 genomes (http://browser. 1000genomes.org/index.html), ExAC browser (http://exac.broadinstitute.org/), Exome Variant Server (EVS) (http://evs.gs.washington. edu/EVS/), and Iranome databases (http://www.iranome.com/). This deletion variant may lead to a frameshift in the translation process, causing the conversion of an amino acid at the position of 367 into the threonine residue. This procedure is probably followed by the emergence of a stop-codon located at 61 codons downstream of the mutation position p.(Asp367Thrfs*61). The Sanger sequencing and segregation analysis confirmed homozygosity of the variant in the patient, while her parents were heterozygote [Figure 1a and b]. The prediction of the 3D structure of the mutated form of the CYP1B1 protein was conducted by the Phyre 2 web portal. (http://www.sbg.bio.ic.ac.uk/phyre2/html/page.cgi?id=index) and then visualized by the Yet Another Scientific Artificial Reality Application (YASARA) view software (http://www. yasara.org/viewdl.html). The results of the 3D structure prediction for both mutant and wild-type forms of the CYP1B1 protein revealed that some features might be affected in the mutant form of the protein [Figure 2a and b]. It was also demonstrated that several protein features of the mutant form of CYP1B1 would be lost in each output pairwise alignment when compared with its reference alignment [Figure 2c]. These data were consistent with the stereochemistry analysis obtained from the COACH server, COFACTOR server, and PSIPRED workbench [Table 2].

cyp1b1, cytochrome p450 family 1 subfamily b member 1, deletion mutation, iran, primary congenital glaucoma

PMC3471405_01

Male

The patient was a 33-year-old Caucasian male with advanced AIDS (CD4+ cell count: 59 cells/mm3, HIV-1 RNA level of 308,000 copies/mL) and an extensive history of opportunistic infections including prior disseminated histoplasmosis, disseminated Mycobacterium avium complex (MAC), Pneumocystis jirovecii (PCP) pneumonia, cutaneous varicella-zoster infection, and cytomegalovirus (CMV) gastric ulcer. He had been placed on combination antiretroviral therapy (cART) with emtricitabine/tenofovir and raltegravir as well as opportunistic infection prophylaxis with itraconazole, azithromycin, trimethoprim/sulfamethoxazole (TMP/SMX), and valganciclovir, although the patient reported being poorly adherent to all prescribed medications. He presented to the hospital with a two-week history of worsening cough, shortness of breath, intermittent fever and chills, and black tarry stools. On admission, he appeared cachectic, chronically ill, and in obvious distress. Vital signs were notable for tachycardia and mild tachypnea. Physical examination revealed facial Molluscum contagiosum, ulcerations on the right lateral tongue, oropharyngeal thrush, mild diffuse abdominal pain, and moderate hepatosplenomegaly. A complete blood count was significant for pancytopenia with a leukocyte count of 2,800 cells/muL (93% neutrophils, 4% lymphocytes, and 1% monocytes), hematocrit of 20% (down from the patient's baseline of 30%), and platelet count of 28,000/mL. The results of a comprehensive metabolic panel were as follows: sodium 133 mmol/L, potassium 4.1 mmol/L, chloride 102 mmol/L, bicarbonate 22 mmol/L, blood urea nitrogen 16 mg/dL, creatinine 0.76 mg/dL, glucose 103 mg/dL, calcium 7.7 mg/dL, AST 113 units/L, ALT 25 units/L, and alkaline phosphatase 450 units/L. On the evening of admission, the patient became febrile to 39.5 C and increasingly tachycardic, tachypneic, and hypoxic requiring supplemental oxygen, several liters of intravenous fluids, and two units of packed red blood cells. A chest radiograph was obtained which showed a diffuse miliary pattern concerning for PCP pneumonia and/or disseminated opportunistic infectious process such as tuberculosis, MAC, or fungal infection. He was started on empiric treatment with vancomycin, piperacillin/tazobactam, high dose TMP/SMX, prednisone, ethambutol, azithromycin, and liposomal amphotericin B. He responded well to broad-spectrum treatment over the next few days and subsequently underwent diagnostic bronchoscopy with bronchoalveolar lavage (BAL). BAL cultures returned positive for H. capsulatum. The patient also underwent esophagogastroduodenoscopy (EGD) given his persistent melanotic stools and progressively declining hematocrit (nadir of 18%) requiring multiple blood transfusions. EGD was significant for a well-healed scar on the greater curvature of the stomach from prior CMV gastric ulcer and new diffuse erosions throughout the second, third, and fourth segments of the duodenum (Figure 1). Multiple biopsies were taken which showed duodenal mucosa with granulomatous inflammation. Gomori's methenamine silver (GMS) stain identified macrophages with small intracellular yeasts consistent with disseminated histoplasmosis (Figure 2). Bone marrow involvement was also suspected in light of the patient's significant pancytopenia, but he had previously refused bone marrow biopsy. Urine Histoplasma antigen came back markedly elevated at >39 ng/mL (above the upper limit of detection for this particular assay) confirming the diagnosis, and the patient was treated with a two-week course of intravenous liposomal amphotericin B followed by indefinite oral itraconazole. Following a two-week inpatient hospitalization, the patient demonstrated excellent improvement. All major presenting symptoms were resolved, including the melanotic stools, and his hematocrit was stable at his baseline. By the time of discharge, the patient had regained his prior level of functioning including full ambulatory capacity. Several weeks after discharge, sputum acid-fast culture returned positive for MAC for which he was continued on ethambutol and azithromycin.

PMC3275940_01

Female

A 65-year-old woman with a medical history significant for diabetes mellitus, hypertension, peripheral vascular disease, and stage IV chronic kidney disease was scheduled for urgent coronary artery bypass grafting surgery (CABG). She was found to have severe triple vessel coronary artery disease after she sustained a non-ST elevation myocardial infarction three days postoperatively from a left lower extremity revascularization procedure. She had had a prior revascularization procedure on the left lower extremity for which she was taking clopidogrel. The clopidogrel was stopped 5 days prior to her most recent revascularization procedure. The postoperative myocardial infarction was initially managed medically and therapy included a heparin infusion. On day 3 of heparin therapy, her platelet count dropped greater than 50% from a baseline of 197,000/cmm reaching a nadir of 36,000/cmm on day 4 of therapy. At this point HIT was suspected and heparin therapy was discontinued. Argatroban was selected for continued anticoagulation therapy because the patient had significant renal disease. Argatroban infusion was started at 0.8 mcg/kg/min and kept between 0.8 and 1.5 mcg/kg/min to maintain a target aPTT of 48-78 s. The patient was brought to the operating room where she underwent an uneventful induction of general endotracheal anesthesia. Her baseline lab work included the following: aPTT 42.1 s, PT 14.7 s, and INR 1.4. Her ACT measured using a Hepcon HMS Plus System (Medtronic Inc., Minneapolis, MN) was 161 s. Aminocaproic acid (Amicar , American Reagent Inc., Shirley, NC) bolus of 5 mg was given on skin incision, followed by infusion of 1 gm per hour for the duration of the surgery. In preparation for CPB, an initial bolus of 6.5 mg argatroban (0.1 mg/kg) was administered, followed by the commencement of a 5 mcg/kg/min infusion with a goal ACT greater than 500 s. Thirty minutes after the initial bolus, the ACT was found to be 313 s, prompting an additional 3 mg argatroban bolus and an upward adjustment of the infusion to 7.5 mcg/kg/min. A sample drawn 20 min after the second bolus returned an ACT of 765. At this point, retrograde arterial and venous autologous priming of the CPB was done and CPB was started. The CPB circuit consisted of a Sarns disposable centrifugal pump with Capiox RX25RW hollow fiber oxygenator and hardshell venous reservoir, arterial filter, and tubing. All of these listed components were X-coatedTM from Terumo (Terumo Cardiovascular Systems, Ann Arbor, MI, USA). The circuit was primed with 1000cc of Normosol -R (Hospira, Inc., Lake Forest, IL, USA), 12.5G/250cc albumin (Telecris Biotherapeutics, Inc., Research Triangle Park, NC, USA), and 50meq NaHCO3. Hypothermia was permitted to 32.5 C measured rectally. After about 15 min of CPB, a clot was noted to be forming on the mesh sock of the venous reservoir. At the same time, the ACT results on the blood that was drawn earlier came back at 409 s, which prompted administration of a 3 mg bolus of argatroban. About 12 min later, blood was redrawn to check the ACT and other labs. The hematocrit values had fallen to 20% from the initial bypass hematocrit of 24%; so, two units of packed red blood cells were added to the CPB circuit. The repeat ACT values after the 3 mg argatroban bolus had increased only marginally to 499 s; so, another bolus of 1.5 mg was given followed by an upward adjustment of the infusion to 10 mcg/kg/min. This increased the ACT to 605 when measured 20 min later. As there was no further evidence of a compromised CPB circuit, and because of the risks of changing the CPB circuit including the need for circulatory arrest, a decision was made to continue with the present CPB circuit while carefully monitoring the clot in the reservoir and other CPB circuit parameters that would indicate further problems. After the clot discovery, another ACT machine was brought into the room, and the two machines were run in a staggered fashion to prevent the delay in obtaining results. Additionally, given that clot formed with an ACT between 409 and 499 s, the remainder of the bypass run was carried out with an ACT greater than 600 s with a peak of 775 s. Ultrafiltration was started midway through the case, followed by zero balance ultrafiltration with Hemoflow F50NR Fresenius Polysulfone Capillary Dialyzer (Fresenius Medical Care, Inc, Waukegan, IL) and a total of about 1200 cc of ultrafiltrate was removed by the end of bypass. Anastomosis of the grafts proceeded uneventfully. In order to avoid prolonged coagulopathy in the postoperative period and because of ACTs consistently staying above 600 s, we decided not to continue the argatroban infusion until the termination of bypass. Thus, the argatroban infusion was stopped about 15 min after removal of aortic cross clamp and recovery of patient's native rhythm. CPB was continued for another 40 min after cessation of the argatroban infusion because of trouble in achieving hemostasis by the surgeon. The subsequent separation from CPB was successful on first attempt with a total bypass time of 150 min. BRAT 2 Autologous Transfusion System (Sorin Group USA, Inc., Arvada, CO) was employed during the case for recovery of shed blood, using acid citrate dextrose solution as anticoagulant instead of heparin, but a decision was made to not reinfuse the processed blood. During the latter half of the CPB, relatively lower hematocrit levels were deliberately tolerated in order to preserve packed cells for after bypass. The hematocrit at the time of CPB termination was 20%; so, two units of banked packed cells were transfused immediately thereafter by the anesthesiologist. In the postbypass period, there was considerable difficulty in achieving hemostasis, which required further transfusion of 6 units of fresh frozen plasma, 5 units of platelets, and 8 more units of packed red cells. The last ACT before leaving the OR was 447 s. Drainage of the bypass circuit revealed no visible clots in the circuit other than the original one in the hardshell venous reservoir which appeared attached to the mesh material [Figure 1]. The aPTT on arrival to the ICU was more than 200 s and the ACT done 2 h later was 227 s. The first 24 h of the ICU stay required transfusion of 9 units of packed red cells, 10 units of fresh frozen plasma, and 10 units of platelets in order to correct the coagulopathy. The coagulation parameters did stabilize by post-op day 1 and so did the bleeding. She was subsequently discharged home on post-op day 26 without any obvious neurological deficits. Her delayed hospital discharge was because other medical conditions unrelated to coagulopathy.

anti-coagulation, argatroban, cardio-pulmonary bypass, heparin alternative, heparin induced thrombocytopenia

PMC7068122_01

Male

The patient was an 85-year-old man who had undergone a total gastrectomy because of gastric cancer 8 years prior and had been diagnosed with myelodysplastic syndrome (RAEB-T, IPSS-IR 8.5 points) 2 years prior. He was categorized as "high risk" when considering hematopoietic stem cell transplantation, therefore azacitidine therapy had been continued. Six months before the current hospitalization he was diagnosed with pulmonary tuberculosis and administered rifampicin, isoniazid and ethambutol for 2 months, then switched to maintenance therapy consisting of rifampicin and isoniazid. He developed thrombocytopenia due to myelodysplastic syndrome and rifampicin 4 months after treatment initiation. He was hospitalized with fever and left chest pain 5 months after treatment initiation and was diagnosed with aspiration pneumonia and pleuritis. Despite the administration of broad-spectrum antibiotics his symptoms deteriorated, in conjunction with gradually increasing oxygen demand. His sputum mycobacterial smear converted to positive, suggesting the possibility of tuberculosis recurrence. Eleven days after the initiation of treatment contrast-enhanced chest CT revealed tumor-like consolidation without enhancement expanding from the left lower lobe, which was diagnosed as pulmonary abscess. He was treated with several broad-spectrum antibiotics including moxifloxacin in view of the possibility of Citrobacter and/or anaerobic bacteria. Acid-fast sputum culture collected 4 days before admission proved positive, prompting the addition of streptomycin to isoniazid to treat active pulmonary tuberculosis. When pleural effusion increased, a chest drainage tube was inserted into his left thorax in view of a possible empyema with fistula on hospitalization day 17. His respiratory condition improved transiently after insertion of the chest drain tube, but fever and inflammation increased again a few days later. Contrast-enhanced chest CT on day 21 depicted massive tumor-like consolidation without enhancement expanding from the left lower lobe. Emboli were also detected in the left descending pulmonary artery (Fig. 1). Because he had developed disseminated intravascular coagulation and that was thought to be the cause of pulmonary embolism, anticoagulants were administered. They were discontinued 5 days thereafter however, due to hemoptysis. On day 25, an exploratory puncture to the remaining abscess was performed. No pus was aspirated, but a small amount of bloody effusion was collected. Enterococcus faecium was cultured from the bloody clot, but no fungal species or mycobacteria were detected. Because the bacteria were repeatedly detected in sputum and pleural effusion and were thought to be the cause of the pulmonary abscess, vancomycin was administered. Despite intensive treatment he developed multiple organ failure and died 47 days after hospitalization. Gross pathology of a lung autopsy specimen revealed left lower pulmonary arterial embolism (Fig. 2) and pulmonary infarction (Fig. 3). Acute myeloid leukemia with myelodysplasia-related changes was detected in the bone marrow. Histopathology of the necrotic lesion and the emboli revealed that mycelia had grown inside the mass and fungal emboli had spread from the pulmonary artery trunk over the left pulmonary artery proximal portion. The artery wall was destroyed by granulomatous inflammation and fungal invasion, which had also spread outside the artery. Pulmonary arterial embolism composed of invasive mycelia in conjunction with acute myeloid leukemia associated with myelodysplastic syndrome was deemed to be the direct cause of death. As well as the above, E. faecium was detected via necrotic lung tissue culture. Real-time polymerase chain reaction (PCR) was performed to identify the species responsible for the mycosis. DNA was extracted from two samples cut from formalin-fixed paraffin-embedded specimens that had been obtained from a bacterial mass in a proximal portion of the pulmonary artery. A real-time PCR protocol designed to detect 15 types of fungi identified Mucor sp. genes in the specimens. Immunohistochemistry using a mouse anti-Rhizopus arrhizus antibody (clone WSSA-RA-1; BioRad, New York, USA) as the primary antibody revealed that the mold in the blood vessels of lung tissue was partially positive for the mucor antigen (Fig. 4).

lung abscess, mucormycosis, myelodysplastic syndrome, pulmonary infarction, superinfection

Enhanced chest computed tomography (CT) images on the 21st day after admission. Pulmonary embolism of the left descending pulmonary artery was observed. . a. The arrow indicates the left anterior descending pulmonary artery and the arrowhead indicates the point where blood flow is interrupted by the embolus in the middle of the descending pulmonary artery. The separated arrow indicates a tuberculosis legion in the right upper lobe.

PMC7068122_01

Male

The patient was an 85-year-old man who had undergone a total gastrectomy because of gastric cancer 8 years prior and had been diagnosed with myelodysplastic syndrome (RAEB-T, IPSS-IR 8.5 points) 2 years prior. He was categorized as "high risk" when considering hematopoietic stem cell transplantation, therefore azacitidine therapy had been continued. Six months before the current hospitalization he was diagnosed with pulmonary tuberculosis and administered rifampicin, isoniazid and ethambutol for 2 months, then switched to maintenance therapy consisting of rifampicin and isoniazid. He developed thrombocytopenia due to myelodysplastic syndrome and rifampicin 4 months after treatment initiation. He was hospitalized with fever and left chest pain 5 months after treatment initiation and was diagnosed with aspiration pneumonia and pleuritis. Despite the administration of broad-spectrum antibiotics his symptoms deteriorated, in conjunction with gradually increasing oxygen demand. His sputum mycobacterial smear converted to positive, suggesting the possibility of tuberculosis recurrence. Eleven days after the initiation of treatment contrast-enhanced chest CT revealed tumor-like consolidation without enhancement expanding from the left lower lobe, which was diagnosed as pulmonary abscess. He was treated with several broad-spectrum antibiotics including moxifloxacin in view of the possibility of Citrobacter and/or anaerobic bacteria. Acid-fast sputum culture collected 4 days before admission proved positive, prompting the addition of streptomycin to isoniazid to treat active pulmonary tuberculosis. When pleural effusion increased, a chest drainage tube was inserted into his left thorax in view of a possible empyema with fistula on hospitalization day 17. His respiratory condition improved transiently after insertion of the chest drain tube, but fever and inflammation increased again a few days later. Contrast-enhanced chest CT on day 21 depicted massive tumor-like consolidation without enhancement expanding from the left lower lobe. Emboli were also detected in the left descending pulmonary artery (Fig. 1). Because he had developed disseminated intravascular coagulation and that was thought to be the cause of pulmonary embolism, anticoagulants were administered. They were discontinued 5 days thereafter however, due to hemoptysis. On day 25, an exploratory puncture to the remaining abscess was performed. No pus was aspirated, but a small amount of bloody effusion was collected. Enterococcus faecium was cultured from the bloody clot, but no fungal species or mycobacteria were detected. Because the bacteria were repeatedly detected in sputum and pleural effusion and were thought to be the cause of the pulmonary abscess, vancomycin was administered. Despite intensive treatment he developed multiple organ failure and died 47 days after hospitalization. Gross pathology of a lung autopsy specimen revealed left lower pulmonary arterial embolism (Fig. 2) and pulmonary infarction (Fig. 3). Acute myeloid leukemia with myelodysplasia-related changes was detected in the bone marrow. Histopathology of the necrotic lesion and the emboli revealed that mycelia had grown inside the mass and fungal emboli had spread from the pulmonary artery trunk over the left pulmonary artery proximal portion. The artery wall was destroyed by granulomatous inflammation and fungal invasion, which had also spread outside the artery. Pulmonary arterial embolism composed of invasive mycelia in conjunction with acute myeloid leukemia associated with myelodysplastic syndrome was deemed to be the direct cause of death. As well as the above, E. faecium was detected via necrotic lung tissue culture. Real-time polymerase chain reaction (PCR) was performed to identify the species responsible for the mycosis. DNA was extracted from two samples cut from formalin-fixed paraffin-embedded specimens that had been obtained from a bacterial mass in a proximal portion of the pulmonary artery. A real-time PCR protocol designed to detect 15 types of fungi identified Mucor sp. genes in the specimens. Immunohistochemistry using a mouse anti-Rhizopus arrhizus antibody (clone WSSA-RA-1; BioRad, New York, USA) as the primary antibody revealed that the mold in the blood vessels of lung tissue was partially positive for the mucor antigen (Fig. 4).

lung abscess, mucormycosis, myelodysplastic syndrome, pulmonary infarction, superinfection

Enhanced chest computed tomography (CT) images on the 21st day after admission. Pulmonary embolism of the left descending pulmonary artery was observed. . b. The arrow indicates a wide homogenous poor-contrast region of the left lower lobe. The arrowhead indicates the left descending pulmonary artery filled with the embolus.

PMC7068122_01

Male

The patient was an 85-year-old man who had undergone a total gastrectomy because of gastric cancer 8 years prior and had been diagnosed with myelodysplastic syndrome (RAEB-T, IPSS-IR 8.5 points) 2 years prior. He was categorized as "high risk" when considering hematopoietic stem cell transplantation, therefore azacitidine therapy had been continued. Six months before the current hospitalization he was diagnosed with pulmonary tuberculosis and administered rifampicin, isoniazid and ethambutol for 2 months, then switched to maintenance therapy consisting of rifampicin and isoniazid. He developed thrombocytopenia due to myelodysplastic syndrome and rifampicin 4 months after treatment initiation. He was hospitalized with fever and left chest pain 5 months after treatment initiation and was diagnosed with aspiration pneumonia and pleuritis. Despite the administration of broad-spectrum antibiotics his symptoms deteriorated, in conjunction with gradually increasing oxygen demand. His sputum mycobacterial smear converted to positive, suggesting the possibility of tuberculosis recurrence. Eleven days after the initiation of treatment contrast-enhanced chest CT revealed tumor-like consolidation without enhancement expanding from the left lower lobe, which was diagnosed as pulmonary abscess. He was treated with several broad-spectrum antibiotics including moxifloxacin in view of the possibility of Citrobacter and/or anaerobic bacteria. Acid-fast sputum culture collected 4 days before admission proved positive, prompting the addition of streptomycin to isoniazid to treat active pulmonary tuberculosis. When pleural effusion increased, a chest drainage tube was inserted into his left thorax in view of a possible empyema with fistula on hospitalization day 17. His respiratory condition improved transiently after insertion of the chest drain tube, but fever and inflammation increased again a few days later. Contrast-enhanced chest CT on day 21 depicted massive tumor-like consolidation without enhancement expanding from the left lower lobe. Emboli were also detected in the left descending pulmonary artery (Fig. 1). Because he had developed disseminated intravascular coagulation and that was thought to be the cause of pulmonary embolism, anticoagulants were administered. They were discontinued 5 days thereafter however, due to hemoptysis. On day 25, an exploratory puncture to the remaining abscess was performed. No pus was aspirated, but a small amount of bloody effusion was collected. Enterococcus faecium was cultured from the bloody clot, but no fungal species or mycobacteria were detected. Because the bacteria were repeatedly detected in sputum and pleural effusion and were thought to be the cause of the pulmonary abscess, vancomycin was administered. Despite intensive treatment he developed multiple organ failure and died 47 days after hospitalization. Gross pathology of a lung autopsy specimen revealed left lower pulmonary arterial embolism (Fig. 2) and pulmonary infarction (Fig. 3). Acute myeloid leukemia with myelodysplasia-related changes was detected in the bone marrow. Histopathology of the necrotic lesion and the emboli revealed that mycelia had grown inside the mass and fungal emboli had spread from the pulmonary artery trunk over the left pulmonary artery proximal portion. The artery wall was destroyed by granulomatous inflammation and fungal invasion, which had also spread outside the artery. Pulmonary arterial embolism composed of invasive mycelia in conjunction with acute myeloid leukemia associated with myelodysplastic syndrome was deemed to be the direct cause of death. As well as the above, E. faecium was detected via necrotic lung tissue culture. Real-time polymerase chain reaction (PCR) was performed to identify the species responsible for the mycosis. DNA was extracted from two samples cut from formalin-fixed paraffin-embedded specimens that had been obtained from a bacterial mass in a proximal portion of the pulmonary artery. A real-time PCR protocol designed to detect 15 types of fungi identified Mucor sp. genes in the specimens. Immunohistochemistry using a mouse anti-Rhizopus arrhizus antibody (clone WSSA-RA-1; BioRad, New York, USA) as the primary antibody revealed that the mold in the blood vessels of lung tissue was partially positive for the mucor antigen (Fig. 4).

lung abscess, mucormycosis, myelodysplastic syndrome, pulmonary infarction, superinfection

Enhanced chest computed tomography (CT) images on the 21st day after admission. Pulmonary embolism of the left descending pulmonary artery was observed. . c. Ground-glass opacity, which is one of the typical CT finding in invasive fungal infection, was not observed in the pulmonary window setting.

PMC5851171_01

Female

A 71-year-old right hand dominant female patient with no comorbidities was admitted in our institution after suffering a fall from her own height. Plain radiographs and CT scan were performed. The patient had a C2 fracture according to AO/ASIF classification with dorsal metaphyseal comminution (Figure 1). Seven days later, the patient underwent surgical treatment: using a volar approach, open reduction and internal fixation with volar locking plate was performed. Drilling was performed only through the volar cortex without violating dorsal cortex as we usually do when performing this technique, in order to avoid extensor tendon erosion. Attention was specially paid to restoration of the articular surface and radial bone angles. Dorsal fragments from metaphyseal comminution were left in site, maintained by the dorsal periosteum. Postoperative X-rays showed adequate fracture reduction. However, dorsal metaphyseal fragments were larger than usual and displaced in a perpendicular plane in relation with the dorsal radial cortex (Figure 2). The patient was splinted for 15 days and then moved onto a removable wristband, starting rehabilitation protocol. Three-month follow-up showed that the patient's wrist had full-range motion, no pain, and the Disabilities of the Arm, Shoulder and Hand (DASH) score of 37. Six months after surgery, the patient's DASH score improved to 9, maintaining a full range of motion, but she addressed dorsal wrist tenderness, with incomplete extension of the index finger. Her Visual Analogue Scale (VAS) for pain at rest was 1 but increased to 4 with activity. Normal "tenodesis effect" was reported, but the patient could not further extend her index finger with the hand on top of a table, as she could do with the other three ulnar fingers. Musculoskeletal ultrasound showed the presence of tenosynovitis of the fourth compartment and thinning of the index extensors at the radioulnar space, compatible with tendon rupture. New X-rays and CT scan showed sequel bone spicules at the dorsal epiphysis of the radius (Figure 3). Fracture was already consolidated, and there was no screw protrusion through the dorsal radial cortex. Surgical exploration was performed. A dorsal longitudinal approach through Lister's tubercle and third compartment with extensor retinaculum exposure was done. Extensor pollicis longus was unscathed. The fourth compartment was explored, with evidence of EDC rupture and EIP laceration (Figure 4). Large bone spurs from the dorsal radius were observed below the tendon plane in relation to Lister's tubercle, generating friction with the extensor apparatus. We confirmed no screws were prominent through the dorsal cortex. Dorsal bone spurs were resected, and tenodesis of EDC to the middle finger tendon was performed. A retinacular flap was designed to protect the tendons from the underlying bone. Volar plate was removed using the previous volar approach, and fracture consolidation was evidenced. The patient underwent physiotherapy rehabilitation, wearing a dynamic elastic band splint. At three-month follow-up, the patient had complete flexion and extension of the fingers, with some slight extensor plus noted as she fully flexed her wrist while her fingers were passively flexed.

PMC6250891_01

Male

A 23-year-old man was admitted in a local general hospital on Dec. 12, 2015, because of complaints of chest tightness, shortness of breath, and dyspnea starting a week prior. He was diagnosed as bilateral tuberculous pleural effusion. Anti-tuberculosis treatment with four drugs (rifampin, isoniazid, pyrazinamide, and ethambutol) and thoracentesis therapy were given, and the specific volume of fluid was unknown. After a month the patient stopped pyrazinamide by himself. The left pleural effusion was controlled, but the right pleural effusion recurred repeatedly. Because of chest tightness and wheezing, the patient was referred to our hospital on March 29, 2016. Pyrazinamide rejoined the anti-TB regimen. On the day of admission and April 3, about 500 ml and 300 ml of pyogenic pleural effusion were respectively removed from the right pleural cavity, and operations were forced to stop because of severe chest pain. Ultra-sonography guided thoracentesis and thoracic close drainages were done, but there was no effect. Chest CT still showed right thoracic pleural effusion (Fig. 1) and pleural purulent fluid grew Mycobacterium tuberculosis until June 2016. However, the patient refused VATS and traditional thoracotomy. Therefore, we injected anhydrous ethanol into pleural cavity after getting the patient's consent on July 5, 2016. Pyothorax was controlled after 6 intrapleural injections of anhydrous ethanol. Table 1 shows volumes, methods of draining and characteristics of pleural effusion. Intrapleural injection of anhydrous ethanol: After obtaining the patient's consent, centesis of pleural effusion guided by color Doppler ultrasound was performed. The first step: drain pleural fluid as much as possible; The second step: normal saline was injected into and drawn away from the pleural cavity. The amount of normal saline used for irrigation of the pleural cavity was the same volume as pus removed (For example, if we draw out 100ml pus, we should inject 100ml normal saline into the pleural cavity). We washed the pleural cavity with normal saline in order to determine whether the patient had bronchopleural fistula. The third step: 10-15 ml of anhydrous ethanol was injected every time, rinsing the pleural cavity repeatedly (Fig. 2), until the liquid was clear. No normal saline was used in this process. Finally: 10-15 ml of anhydrous ethanol was retained in the pleural cavity, waiting for the next fluid extraction. We repeated the procedure every 1-2 weeks in the first month and every 2-4 weeks in the following months until color Doppler ultrasound showed no pleural effusion. It should be stressed in particular that we must observe whether the patient has a severe cough while washing the pleural cavity with normal saline. If the patient coughs out salty liquid, it suggests that the patient may have bronchopleural fistula, and we should stop washing the pleural cavity and the injection of anhydrous ethanol. If necessary, intrapleural injections of methylene blue will further confirm whether there is bronchopleural fistula or not. Of course, it is best to ask patients if they have any history of alcohol allergy before intrapleural injection of anhydrous ethanol. The patient stopped antituberculous treatment in June 2017 and finally recovered fully. Re-examination of lung CT showed that the patient's right pyothorax was significantly improved on February 23, 2018 (Fig. 3). Meanwhile, color Doppler showed only pleural thickening without pleural effusion.

anhydrous ethanol, chronic empyema, tuberculous

PMC3263066_01

Male

A 27-year-old man with end-stage kidney disease from chronic glomerulonephritis received a renal allograft from his mother in 2005 using prednisolone, cyclosporine and azathioprine, without induction therapy. During the immediate post transplant period, he received three intravenous pulses of methylprednisolone 1 g each daily for acute cellular rejection. He did not develop major infections till the current episode. His weight was 58 kg. He had stable graft function, with serum creatinine at 1.6 mg/dl and was on prednisolone 10 mg/d, azathioprine 100 mg/d and cyclosporine 175 mg/d, with the trough (C0) and 2-hour (C2) cyclosporine levels being 368 and 1280 ng/ml, respectively, at 6 months after transplantation. Three years after transplantation, he presented to us with 4 months history of fever, weight loss of 16 kg in 4 months, episodic small volume diarrhea and diffuse abdominal pain with occasional hematochezia. He did not have pulmonary or other gastrointestinal symptoms. He discontinued cyclosporine 4 months prior to visiting our center. At presentation, he was on prednisolone (10 mg/d) and azathioprine (100 mg/d). On examination, his weight was 38 kg, and pulse rate, blood pressure, respiratory rate were normal. He was pale but did not have icterus or peripheral lymphadenopathy or allograft tenderness. He had a diffuse, ill-defined, firm, tender mass (9 x 7 cm) in the right hypochondrium. There was no hepatosplenomegaly or ascites. Laboratory investigations revealed anemia (hemoglobin of 6.7 g/dl), a total leukocyte count of 4200/mm3, a normal platelet count and serum albumin of 2.2 g/dl. He had renal allograft dysfunction (serum creatinine of 3.1 mg/dl) with normal electrolyte profile and liver enzymes. His chest radiograph revealed an ill-defined minimal haziness in the right upper and midzones with minimal pleural effusion. Ultrasonogram of abdomen showed an intussusception mass measuring 7.1 x 5.0 x 10.1 cm in the right hypochondrium with a few enlarged mesenteric nodes and fat within and adjacent to it [Figure 1a]. The renal allograft appeared normal. Computed tomogram (CT) scan of abdomen with rectal contrast revealed an ileocolic intussusception up to the hepatic flexure with multiple enlarged mesenteric nodes and mesenteric fat pulled into it [Figure 1b]. The ascending colon was thick. The para-aortic, mesenteric and para-iliac nodes were enlarged and showed central necrosis. The patient underwent an emergency exploratory laparotomy with resection of the ileocolic intussusception, the adjacent ascending colon and terminal ileum [Figure 2a]. Histopathological examination of the ileocolic intussusception revealed fragments of a lymph node with extensive caseation necrosis and many acid-fast bacilli (AFB). The proximal polypoidal lesion of the intussusceptum and the mucosal ulcerations of the intussuscepient colonic segment revealed dense inflammatory infiltrates of lymphocytes and plasma cells, along with microabscesses in the submucosa and lamina propria, transmural granulomas with epitheloid histiocytes, lymphocytes; Langhans type multinucleated giant cells and central foci of caseation [Figure 2b and d]. Long, curved and beaded AFB, morphologically typical of Mycobacterium tuberculosis (MTB), were detected in all the above-mentioned lesions [Figure 2c]. On the first postoperative day, the patient received hydrocortisone 100 mg thrice daily, but azathioprine was discontinued due to leukopenia (WBC count 1900/mm3). He received granulocyte colony stimulating factor for leukopenia. On the second postoperative day, he was weaned off mechanical ventilation. On the fourth postoperative day, he received ATT with isoniazid 300 mg/d, rifampicin 450 mg/d, pyrazinamide 750 mg/d and ethambutol 400 mg/d. On the fifth postoperative day, 36 hours after starting ATT, he developed tachycardia, tachypnea, hypotension, oliguria and worsening of pulmonary oxygenation [partial pressure to inspired fraction of oxygen ratio (P-F ratio)]. The chest radiograph revealed worsening of the preexisting haziness. However, there was no bacteremia or evidence of invasive fungal infection.The total leukocyte count had remained about 4500 cells/mm3 during this period. His condition subsequently worsened, and he received broad-spectrum antibiotics (piperacillin with tazobactam) while routine cultures remained sterile. A tracheal aspirate showed numerous AFB morphologically typical of MTB, though there was no growth in culture. In addition, tracheal aspirate grew mixture of non-fermenting gram negative bacilli and Candida glabrata, which were probably contaminants. He continued to develop worsening features of a systemic inflammatory response syndrome, lung infiltrates, and disseminated intravascular coagulation. Steroids were continued, antibiotics were changed empirically to meropenem with teicoplanin and liposomal amphotericin B. The patient died on the 11th postoperative day. The next of kin declined post-mortem examination.

immune reconstitution inflammatory syndrome, intussusception, kidney transplantation, renal allograft recipient, tuberculosis

PMC5768976_01

Female

A 39-year-old woman (gravida 6, para 3-0-3-3) underwent a standard protocol of artificial cycle FET and had been transferred two in vitro fertilization-derived embryos at a fertility clinic. Detailed information about the transferred embryos was not available for this case. The patient had episodes of spontaneous and artificial abortions and a salpingectomy for an ectopic pregnancy, but had no history of a cesarean section. She became pregnant by FET and was treated with progesterone agents, an estrogen patch, and aspirin. At 5-2/7 weeks of gestation, she presented to our hospital with hemorrhagic shock due to persistent genital bleeding. A transvaginal ultrasonography detected an intrauterine gestational sac of age-appropriate size and a squashed cystic lesion in the cervix. A blood examination indicated a hemoglobin level of 4.8 g/dL. Blood coagulum from the genitalia contained decidual tissues. Her genital bleeding was successfully controlled by manual compression of the external cervical os and the blood pressure and heart rate were stabilized after transfusing four units of red cell concentrates. She was diagnosed with a cervical heterotopic pregnancy. All the medications that had been prescribed at the fertility clinic were withdrawn, with the intention to terminate the pregnancy. However, despite the discontinuation of progesterone supplementation, the gestational sacs in the cervix and uterus continued to develop and formed yolk sacs (Figs 1a and 1b). At 8 weeks of gestation, the patient expressed her desire to maintain the intrauterine pregnancy, despite being fully informed of the risk of hemorrhage and other complications. As there was growth discordancy in the two pregnancies and the fetal heartbeat was not observed in the gestational sac in the cervical canal,7 the gestational sac was manually removed with forceps under ultrasound guidance, instead of local potassium chloride injection. The cervical bleeding was controlled by astriction. Histological analyses of the removed specimen confirmed the presence of fetal tissues. The subsequent course of the pregnancy was uneventful until delivery, except for a vasa previa that was detected at 28 weeks of gestation (Figs 1c and 1d). In order to avoid the rupture of the vasa previa, a cesarean section was performed at 36 weeks of gestation, which resulted in the birth of a healthy female infant. However, at the delivery, massive bleeding occurred from the region around the internal cervical os. A total hysterectomy was performed because the placenta was not able to be manually separated from the uterus. A histological examination of the uterus indicated a total placenta accreta; placental villi had invaded the myometrium (Figs 2a and 2b). There was no histological abnormality in the cervix or in the region around the internal os.

artificial cycle, cervical heterotopic pregnancy, frozen‐thawed embryo transfer, placenta accreta, progesterone

PMC6657625_01

Male

A 45-year-old male was admitted to the hospital with a one-day history of abdominal pain and dyspnea. The abdominal pain started the day of admission; however, he noted worsening shortness of breath and a productive cough with clear sputum over the course of several days. He also noted a 20-pound weight loss occurring over a three-month period but denied fevers, chills, or night sweats. Physical exam was notable for tachycardia, distant heart sounds, and decreased breath sounds of the lung bases bilaterally. Vitals at presentation included a temperature of 99.2 F, heart rate of 104, respiratory rate of 20, blood pressure 182/106 mmHg, and an oxygen saturation of 95% of 2 liters via nasal cannula. Our patient has a past medical history significant for hypertension, chronic anemia, and end stage renal disease, due to focal segmental glomerular nephritis, on hemodialysis three times per week. He has required hemodialysis for approximately four years and unfortunately does not have an arteriovenous fistula due to financial restraints; therefore, his dialysis access is via a left jugular tunneled catheter. He has required multiple tunneled catheters over the past four years. Initial metabolic panel was within normal limits except for his creatinine of 7.99 mg/dL. Complete blood cell count revealed anemia with a hemoglobin of 10.6 g/dL and hematocrit of 33.7% but otherwise within normal limits. Chest x-ray was remarkable for bilateral pleural effusions and prominence of the cardiopericardial silhouette consistent with pericardial effusion (Figure 1). Given his abdominal pain a CT of the abdomen and pelvis without intravenous contrast was performed showing large right and small left pleural effusions and a large pericardial effusion. Since the CT scan was able to capture a majority of both the pleural and pericardial effusions a dedicated CT scan of the thorax was initially deferred. Given his dyspnea and pleural effusions our patient underwent a right-sided thoracentesis by interventional radiology with removal of 1.5 liters of cloudy amber-colored fluid. Body fluid studies revealed a total protein of 3.3 g/dL, LDH 110, glucose 106, RBC 45, WBC 993, lymphocyte predominance of 91%, and pH of 7.0. Serum LDH was 247 and serum protein was of 6.6 g/dL. Using Light's Criteria (Table 1) our patient did not meet criteria for exudative effusion; however, results were borderline with a pleural fluid protein/serum protein ratio of 0.5 and pleural fluid LDH/serum LDH ratio of 0.445. Acid fast smear and cultures were obtained and resulted negative. Cytology was negative for malignancy but showed many small mature lymphocytes, mesothelial cells, and a few acute inflammatory cells. Following thoracentesis, he had significant improvement in dyspnea and oxygen saturation improved to the upper 90s on room air. Regarding the pericardial effusion, a transthoracic echocardiogram was obtained revealing a large circumferential pericardial effusion measuring 1.67 cm anteriorly and 1.29 cm posteriorly. The chambers of the right atrium (RA) and right ventricle (RV) were very small, with complete obliteration of the RV chamber during systole, suggesting high intrapericardial pressure. The IVC was collapsible, measuring 1.67 cm, with a 50% collapse during inspiration. No diastolic collapse of the RV or complete systolic collapse of the RA was noted. Cardiology was consulted and during their physical exam he displayed no jugular venous distention, negative Kusmaul's sign, and no clinical signs of tamponade. An EKG was obtained showing sinus rhythm and no electrical alternans; thus pericardiocentesis was deferred. Over the next four days he continued his regularly scheduled hemodialysis sessions and showed improvement in the pericardial effusion. Give hemodynamic stability and significant improvement there were no plans for intervention and the decision was made to closely follow with cardiology as an outpatient. However, on the planned day of discharge he developed supraventricular tachycardia and was kept another night for observation and evaluation by electrophysiology. During this time a repeat chest X-ray was performed revealing a reoccurrence of his pleural effusions; therefore, pulmonary medicine was consulted to further investigate. Previous body fluid studies were reviewed, and, given significantly elevated lymphocytes of 91% and borderline Light's Criteria for exudative effusion, there was initial concern for common etiologies including tuberculosis, sarcoidosis, and malignancy. Our patient immigrated from Mexico to the United States approximately 20 years ago but denied any Tuberculosis exposure or previous diagnosis. He did have a 20-pound weight loss but denied other B like symptoms. We elected to further investigate the thorax for the presences of anatomical abnormalities, so a CT thorax was obtained. CT demonstrated a reaccumulation of the right pleural effusion and persistent moderate to large pericardial effusion (Figure 2) but surprisingly showed stenosis or occlusion of the superior vena cava (Figure 3). This new finding was discussed with radiology that further commented on mediastinal collaterals and evidence of SVC stenosis particularly around the patient's tunneled catheter. A repeat thoracentesis was performed and 1.6 liters of milky fluid with a pink tinge was removed. Body fluid was remarkable for total protein of 4.6 g/dL, glucose 72, triglycerides 1,056 mg/dL, cholesterol 116 mg/dL, RBC 423,195, WBC 1,760, lymphocytes 86%, and pH 8.0. These findings were consistent with chylothorax likely form newly discovered SVC stenosis. Other labs to evaluate for autoimmune etiology including rheumatoid factor, c-ANCA, p-ANCA, ANA, and hepatitis screen were also obtained and were unremarkable. Repeat echocardiogram was performed and worsening pericardial effusion was noted revealing RA collapse and diastolic RV collapse suggestive of cardiac tamponade (Figure 4). Hemodynamically the patient remained stable and a scheduled pericardial drain was placed with aspiration of 775 mL of bloody fluid consistent with chylopericardium. Given recurrent pleural and pericardial effusions vascular surgery was consulted for SVC stenosis. He underwent angioplasty of the SVC and left brachiocephalic vein using a 12x4 angioplasty balloon and replacement of the tunneled hemodialysis catheter into the left jugular vein. Ultimately, after balloon angioplasty, high triglyceride diet, and draining both the pleural and pericardial effusion his symptoms significantly improved, and he was discharged home. There are plans to establish permanent hemodialysis access by creating an AV fistula in the near future.

PMC5337328_01

Female

A 52-year-old female patient, who works as a microbiologist, presented with a headache, dizziness, and partial seizures. The onset of symptoms was subacute with gradual progression. She was previously healthy with no past medical or surgical diseases or events, and she was not using any medications. There was no history of blood transfusion, raw milk ingestion, tick bites, or drug abuse. She was married with three children. Physical examination showed normal higher mental functions including speech. Cranial nerve examination was unremarkable apart from mild papilledema. Her tendon reflexes were symmetrical and normal with downgoing toes. The rest of her neurological and systemic examination was normal including vital signs. Basic hematological workup including complete blood count, liver function test, erythrocyte sedimentation rate, C-reactive protein, and connective tissue screen were all unremarkable. Other unremarkable important tests included syphilis serology, HIV test, mammogram, and tumor markers. Serum Brucella melitensis immunoglobulins were both high measuring IgM 12.2 U/ml and IgG 127.4 U/ml (normal range <12 U/ml). Using enzyme-linked immunosorbent assay (ELISA) for cerebrospinal fluid (CSF), Brucella titer was high at 1 : 40 (normal <1 : 20). CSF analysis showed lymphocytic pleocytosis at 63 cells and 88% lymphocytes. Protein was slightly increased, but glucose was normal. Her bacterial culture was negative for both aerobic and anaerobic organisms. Polymerase chain reaction (PCR) for tuberculosis, herpes simplex virus, Epstein-Barr virus, and cytomegalovirus was negative. Both CSF Brucella total antibodies and oligoclonal bands were positive with five well defined gamma restriction bands which were not present in the corresponding serum sample. Magnetic resonance imaging (MRI) of the brain revealed peritrigonal (temporal lobe) deep white matter mass measuring 2.6 x 3.5 cm with surrounding vasogenic edema. There was no restricted diffusion with slightly increased flow at the affected area and normal cerebral blood volume on MR perfusion. Axial and sagittal T1 postgadolinium studies showed minimal enhancement (Figure 1). Diffusion tensor imaging (DTI) revealed a slight reduction in anisotropy and diminished color brightness at the affected region with a normal organization of the fiber tract (Figure 2). MR spectroscopy was suggestive of inflammatory rather than a neoplastic process. The radiological deferential diagnosis included neurosarcoidosis, lymphoma, and low-grade glioma. CSF cytology and flow cytometry were normal. Given the clinical, laboratory, and radiological features, the patient was diagnosed with neurobrucellosis and was started on rifampicin (600 mg/day), doxycycline (100 mg twice a day), and sulfamethoxazole-trimethoprim (960 mg twice a day). The patient's symptoms resolved gradually with concomitant improvement in her MRI images. She was treated for a period of 45 days with clinical but no radiological improvement. CSF analysis was repeated which showed improvement of cell count and protein concentration, but the values were not normalized yet. We instructed the patient to continue using the medications for a minimum of 6 months. The CSF analysis was repeated and completely normalized, and her MRI showed almost complete resolution of the previously noted changes. She remained symptom-free until now (Figure 3).

PMC8529316_01

Female

A 22-year-old Hispanic woman was in her usual state of health until she developed severe headache (8 of 10 scale) and blurred vision for last 5 days. She was seen at the ophthalmology clinic with marked reduction in vision of her right eye more than left that slowly progressed over 5 days. The patient reported this progressive loss of vision was interfering with her daily activities. She denied flashes of light and floaters in either eye. Her visual acuity examination showed right eye 20/70 and left eye 20/200. Her intraocular pressures and examination of conjunctivae, corneas, anterior chamber, and irises were within normal limits. The examination of posterior chamber after dilation revealed congestion of optic nerves and prepapilledema. There was subretinal fluid beneath the maculae and surrounding the optic nerves. Due to initial diagnosis of serous chorioretinopathy and its underlying differential diagnosis of autoimmune, infectious, carcinomatous, or paraneoplastic conditions and with coexistence of headache, she was sent to the hospital for evaluation. Upon admission, magnetic resonance imaging (MRI) of brain with contrast revealed generalized leptomeningeal enhancement with "sugar-coating" or "zuckerguss pattern" in her vermis region of cerebellum (Figures 1 and 2). Her orbital MRI showed increased signal thickening at the posterior aspect of globes and focal enhancements (Figure 3). Lumbar puncture showed an opening pressure of 150 mm H2O, glucose 58 (normal range: 40-75) mg/dL, protein 46 (normal range: 15-45) mg/dL, WBC (white blood cell) 180 cells/muL, RBC (red blood cell) count 25, lymphocytes 96%, neutrophils 3%, and macrophages 1%. She was started on empirical antifungal and antituberculosis medications due to the chronic aseptic meningitis picture. In the next following 15 days, she did not improve clinically and instead developed new symptoms. Her new symptoms included tinnitus in left ear, vertigo, hyperacusis, photophobia, retroorbital pain, and loss of color perception. She underwent 3 additional lumbar punctures to rule out increased intracranial pressure with similar cerebrospinal fluid (CSF) findings (Table 1). Comprehensive workup (Table 2) was unrevealing; therefore, her antifungal treatment was stopped. Upon further detail intake of her medical history, it was found that she had an episode of epistaxis accompanied with nasal cartilage inflammation and nasal septal deviation in the past. She has complained of rib cage pain on multiple occasions and also endorsed joint stiffness and pain involving her hands and back in the past. Her chest x-ray (CXR) and hand x-rays were unremarkable. The thoracic spine x-ray revealed moderate degenerative arthritis. Her mother disclosed to have a known diagnosis of seronegative rheumatoid arthritis and it was always a fear that she had passed it to her daughter. She also mentioned that she sought medical evaluation for her daughter at the age of 12 but never followed up thereafter. On further examination, she was found to have thinning of bilateral pinna without erythema. She met the criteria and diagnosis of RP with chorioretinitis and CNS involvement. She was initiated on pulse therapy with high dose of methylprednisolone 1000 mg for 3 days. During her pulse therapy and following days after, her visual acuity improved, color vision returned, and vertigo and hyperacusis resolved. Her multidisciplinary team decided to complete 12 months of empirical tuberculosis treatment and she was discharged on prednisone 60 mg daily with plan to slowly taper and move to steroid-sparing immunosuppression. Follow-up lumbar punctures showed significant improvement (Table 1). Her follow-up brain MRI also showed resolution of leptomeningeal enhancement and sugar-coating enhancements in her vermis. Since then, over the last 3 years she has been followed up in ophthalmology and rheumatology clinics. She also underwent several minor relapses of her chorioretinitis without CNS involvement. She is currently responding to sulfasalazine, methotrexate, and ophthalmic steroid drops.

mcadam criteria, aseptic meningitis, glucocorticosteroids, pleocytosis, relapsing polychondritis

PMC8034239_01

Male

A 65-year-old man underwent radical esophagectomy 5 months ago following the diagnosis of esophageal cancer by gastroscopy. The postoperative pathology was well-differentiated squamous cell carcinoma of the esophagus, involving the adventitia and local foci around the esophagus. Approximately 40 days later, mediastinal lymph node metastasis was observed. Capecitabine was administered at a dosage of 1.5 g per os, twice daily for 14 days. At that time, the patient's liver and kidney function tests were normal, and 1 week later, an anti-programmed death-ligand 1 agent (camrelizumab 200 mg) was administered twice with a 2-week interval between each dose. Around 20 days later, abnormal liver function was detected: total bilirubin (TBIL), 52.2 micromol/L; direct bilirubin (DBIL), 38.8 micromol/L; alanine aminotransferase (ALT), 176.7 U/L; aspartate aminotransferase (AST), 250.5 U/L; alkaline phosphatase (ALP), 336 U/L; and gamma-glutamyl transpeptidase (GGT), 638 U/L. He received a diagnosis of drug-induced liver injury (DILI). Approximately 1 week later, his ALT and AST levels decreased rapidly, and TBIL continued to deteriorate (Figure 1). Considering the possibility of intrahepatic cholestasis, the physician added ursodeoxycholic acid (25 mg/kg/day) and methylprednisolone (20 mg/day). However, the cholestasis did not improve notably. Then, plasma exchange (PE) and a double plasma molecular absorption system (DPMAS) for blood purification were added, and cholestasis improved within a short time (Figure 1). During this period, except for yellow skin and dark urine, the patient had no other symptoms. Nonetheless, chest tightness and shortness of breath developed after 1 month of hospitalization. Chest computed tomography (CT) scanning revealed interstitial inflammatory lesions in both lower lungs (Figure 2). Liver biopsy revealed nonspecific immune injury (Figure 3). The doctor revised the diagnosis as immune-related pneumonia and hepatitis associated with camrelizumab. The treatment regimen of methylprednisolone was adjusted to 40 mg/day and gradually increased to 80 mg/day and mycophenolate mofetil 2 g/day was also added. Consequently, chest tightness and shortness of breath resolved, and pulmonary inflammation improved (Figure 2). Nevertheless, jaundice did not improve and continued to exacerbate. During the last 2 weeks of hospitalization, the patient showed symptoms such as high fever, decreased appetite, vomiting, and diarrhea. He was treated with human serum albumin (0.5-1.0 g/day), human hemoglobin (1.0-1.5 g/day), cefoperazone sulbactam (2 g, q12h), and caspofungin (50 mg). The last measured prothrombin time was 41 s, prothrombin activity was 19%, and the international normalized ratio was 4.03. The cause of death was diagnosed as liver failure, cardiopulmonary failure, and septic shock. The serum markers of hepatitis A-E were negative; nuclear antibody, mitochondrial antibody, liver, and kidney microsomal antibody, and anti-liver soluble antigen-antibody were negative; and immunoglobulin G value was 8.93 g/L (<16 g/L). Obstructive jaundice was excluded by multiple imaging examinations. Contrast-enhanced abdominal CT showed heterogeneous enhancement of liver density (Figure 4).

camrelizumab, immune-related hepatitis, immune-related pneumonia, intrahepatic cholestasis

PMC5610866_01

Male

A 56-year-old male with obesity, hypertension, diabetes mellitus type 2, and dyslipidemia presented with nonexertional chest pain that wakes him up at night exacerbated by coughing and laying supine. There were no associated fever, dizziness syncope, and palpitation. He recalls symptoms of an upper respiratory tract infection which have resolved a few weeks earlier. Our patient is an office worker with no additional risk factors as smoking, chest trauma, recent travel, significant outdoor exposure, and family history of malignancy. On evaluation, blood pressure was 144/68 mmhg, HR was 101 bpm, RR was 24 cpm, and the patient was afebrile. Eye and oral examination showed no suspicious lesions. There was no skin rash and synovitis. Cardiovascular examination was negative for jugular venous distention and hepatojugular reflex. Precordium was mildly tender, point of maximal impulse was adynamic and nondisplaced, and there was no palpable ventricular heave. On auscultation, S1 and S2 sounds were muffled; a precordial rub was appreciated over the left sternal border and is heard throughout the cardiac cycle. The remainder of the physical examination was unremarkable. Electrocardiography showed nonspecific ST-T wave changes and no PR abnormalities. Troponin values were normal. A transthoracic echocardiogram demonstrated a mildly thickened pericardium with no pericardial effusion. Global ventricular wall motion was normal. Results of the initial laboratory investigation are outlined in Table 1. This shows leukocytosis with lymphopenia and monocytosis, elevated ESR, and normal renal function. The patient was then started on a course of Ibuprofen and Prednisone for suspected viral pericarditis. During his 4-week follow-up, the patient reported some improvement of the chest discomfort but now endorses decreased exercise tolerance, exertional dyspnea, and worsening fatigue. D-Dimer was obtained and was slightly elevated, 0.47 (reference: 0.27-0.40 mcg/ml). Computed tomography of the chest demonstrated no pulmonary artery embolism. The pericardium was markedly thickened, along with a small amount of nonloculated pericardial effusion. Visualized were multiple enlarged mediastinal and subcarinal lymph nodes and a 1.2 cm pulmonary nodule in the left lower lobe (Figure 1). Taking his risk factors into account, his symptoms were now concerning for coronary ischemia. Myocardial Perfusion Scanning revealed a moderately intense area of reversible defect consistent with ischemia and infarction of the inferior wall. There were no features of hemodynamic collapse. Subsequent Coronary Angiography confirmed severe three-vessel coronary artery disease (mid-LAD 80%, 1st Diagonal 90% ostial lesion, 2nd Diagonal 80%, and RCA 100% with collaterals). Left ventriculogram showed hypokinesis of the basal inferior myocardium with an estimated EF of 50%. The patient underwent urgent Coronary Artery Bypass Grafting (CABG). Intraoperatively, upon violating the pericardial sac, it was immediately evident that he had extensive nodular adhesions on the visceral and parietal pericardium. Gram stain and cultures for bacteria and acid fast bacilli were negative. Histopathology demonstrated a necrotizing granulomatous inflammation that stained positive for fungal elements within the central necrotic tissue. No malignant cells were identified (Figure 2). Screening for sarcoidosis, tuberculosis, and HIV infection was negative. Further serologic testing confirms H. capsulatum infection (Table 1). His postoperative course remained unremarkable. Treatment with Itraconazole was initiated with instructions to complete a 6-month course and a follow-up chest CT scan to monitor progression of the visualized solitary pulmonary nodule.

PMC3075160_01

Female

A 30-year-old woman was admitted to our hospital with a history of abdominal pain, anorexia, weight loss and fever for one month. On physical examination, except hepatomegaly, no other physical finding was detected. Liver function tests (ALT 64 U/l, AST 76 U/l) and alkaline phosphatase (ALP 310 U/l) were elevated. Chest x-ray was normal. Ultrasonography (US) of the abdomen revealed a lobulated cystic mass with air in the right lobe of the liver. Computerized tomography (CT) of the abdomen showed an ill-defined cystic mass with air-fluid level in the anterior segments of right liver lobe (fig. 1). Liver abscess or infected hydatid disease was considered with these radiologic and clinical findings. Liver wedge biopsy was performed during laparotomy. Histopathological examination of the specimen demonstrated granulomas, epithelioid histiocytes and Langhans giant cells, and caseating granulomatous inflammation. Hepatic tuberculosis was diagnosed based on these pathologic findings. Unfortunately we did not perform culture of the specimen for tuberculosis, because tuberculosis was not taken in account in the differential diagnosis. The patient was treated with anti-tuberculous drugs for one year. She recovered clinically and abdominal US was normal after one year.

cystic liver lesions, hepatic tuberculosis, liver abscesses

PMC5458703_01

Male

A 57-year-old obese (body mass index = 39) afebrile male patient, with breathing, constrained disturbances, resident of the province with domestic animals was transferred to our clinic from another hospital, where he was treated with bed rest for 2 weeks for spine fracture (Fig. 1) due to misdiagnosis. On admission, he claimed dyspnea, severe back pain of 2-month duration, left knee pain and swelling. He mentioned recent (2 months before) asymptomatic consumption of domestic poultry. Physical examination revealed no pathologic neurological findings. His left osteoarthritic knee was swollen, while chest roentgenogram showed pleural effusion on the left side (Fig. 2). Lateral plain roentgenogram (Fig. 3) and computed tomography (CT)-scan (Fig. 4) of the spine revealed destruction of the T12-vertebral body and intervertebral discs T11-T12 and T12-L1 associated with paravertebral abscess formation (Fig. 5). White blood cells (WBC's) were 17.5 k/Mul (normal limits: 4-10.0 k/Mul), C-reactive protein (CRP) was 23.1 mg/dL (<0.3 mg/dL), and ESR was 86 mm/1st h (0-20 mm/1st h). Tuberculosis antibody test, virological, rheumatologic laboratory tests, Widal-Wright, urine and stool cultures were within normal limits. Blood cultures revealed SE. A thoracic drainage tube was inserted for 10 days, and a total 3000 cc of seropurulent fluid was evacuated with gradual improvement of respiratory function. Knee puncture evacuated 120 cc of purulent fluid. Under local anesthesia percutaneous transpedicular biopsy and specimen culture were taken from T12 vertebra. All cultures (pleural fluid, spine, knee joint fluid and specimens) isolated SE. Unfortunately, phage typing is not available in our laboratory. T12 biopsy disclosed chronic osteomyelitis. On the basis of antibiograms, quinolone and 3rd generation cephalosporin were intravenously (IV) given. Through the left thoracotomy with resection of the 11th rib, left lung was found stuck to the parietal pleura with residual empyema and meticulously mobilized. 7 ml of purulent material was evacuated from the paravertebral space. A T12-vertebrectomy was performed with disc resection and bone debridement to healthy tissue. An expandable titanium mesh cage (TMC) filled with resected rib bone graft was inserted, and the spine was stabilized through a minimally invasive posterior instrumentation (Fig. 6). Our patient was neurologically intact, although the severe back pain, the obesity, the breathing constrained disturbances and the pleural effusion with the chest tube made our patient's breathing unable to cope with his needs. Paravertebral abscess formation, instability, and breathing difficulty were the main reasons for the surgery decision. After consensus with our patient, his knee was fused 1 month following admission with an Illizarov device. The post-operative course was complicated with superficial wound infection at the thoracotomy skin incision, knee arthrodesis incision and the insertion of the left L2 screw close to the thoracotomy wound with Acinetobacter. All sites required local debridement and secondary closure. The left knee fused completely 3 months following surgery. On the basis of antibiotic susceptibility pattern, quinolone and ceftriaxone were IV given. The patient received 3 months IV antibiotic treatment and was discharged with instructions for a monthly check of inflammatory markers. Antibiograms is the safe way for the antibiotics selection, although ciprofloxacin, 3rd generation cephalosporin, ampicillin, and chloramphenicol are the most common antibiotics in such infections. The IV administration was combined with our patient hospitalization due to his impaired general condition and the post-operative complications. The duration of the antibiotic treatment was determined on the basis of the evidence-based guidelines, to minimize relapse possibility. At the 6-month follow-up, CRP and ESR remained within normal limits. Radiograms and CT scan showed a good result of fusion in both sites (Fig. 7 and 8). The patient was free of pain, and he had started to return to his daily routine. There was not any sign of recurrence. Although 2 months later, our patient became anxious and his family found him with an altered state of consciousness and cognition. On admission to the hospital, our patient lost his consciousness and had to be intubated and transferred to intensive care unit. Brain CT scan revealed edema and hydrocephalus that required drainage tube installation (Fig. 9). The lumbar puncture of cerebrospinal fluid was indicative of viral infection. EEG showed slow waves and based on the previous medical history all possible cultures were taken. Blood cultures revealed again SE. Our patient did not recover from this meningoencephalitis, and his relatives decided to disconnect him from the ventilator on the day 11th being clinically dead. We believe that SE infection recurrence caused immunosuppression to this impaired patient making him unable to manage this central nervous system viral infection.

immunocompetent patient, salmonella enteritis spondylodiscitis, extra-intestinal focal infections, immunosuppression, relapse, thoracic vertebrae, titanium mesh cage

PMC1065094_02

Male

Dr A As we stand at the bedside, reviewing the admission laboratory findings and waiting impatiently for a chest radiograph, let us try and put these findings together. First of all, this patient presents with an acute illness with fever, chills, a cough that is productive of purulent sputum, and 3 days of watery diarrhea. At first thought this sounds like community-acquired pneumonia (CAP), possibly with an atypical pathogen. Perhaps the diarrhea is a red herring. Weight loss and left shoulder pain in a 53-year-old former smoker raises concern for lung cancer with possible postobstructive pneumonia, and we shall look for signs of volume loss or chest wall metastasis on the chest radiograph. This patient also has evidence of severe sepsis, with a left shift, and tachycardia. He has signs of impending organ failures with renal dysfunction, a creatinine level of 1.9 mg/dl, metabolic acidosis, a coagulopathy with an elevated prothrombin time and D-dimer, and low platelets that could signal early disseminated intravascular coagulation (DIC). He has respiratory failure, with an A-a gradient over 500. He is probably hemoconcentrated, and clinically we would expect him to be hypovolemic from diarrhea, high insensible losses, and poor oral intake. My immediate therapeutic concern is the tachycardia, the nature of the cardiac rhythm, and the possibility of myocardial ischemia. Dr D I might disagree with you that this patient has severe sepsis. What if, after 2 or 3 l saline, his blood pressure, heart rate, and creatinine normalize? I think this illustrates one of the greatest triage challenges in this area, and that is differentiating infection with sepsis from another very common scenario - infection with dehydration and hypovolemia. I think the most important point is not to confuse sepsis with hypovolemia from any cause, including hemorrhage. Dr B The firsts steps in the care of patients like this should be very systematic. Once the tachycardia was assessed and assuming the chest readiograph confirms pneumonia, I would initiate prompt antibiotic therapy based on the most likely type(s) of infection; ensure adequate hemodynamic and respiratory support; try to identify the source of infection; identify and ascertain the extent of his organ dysfunction; and, based on that, develop an overall treatment plan. Dr C I agree - we need to treat this suspected infection. Although a chest radiograph is not initially available, there is a strong clinical suspicion for pneumonia, as a source of major infection, and empiric antibiotic coverage should be started. When the differential diagnosis includes a central nervous system infection, there is never a question in regard to early antibiotic coverage, and in fact antibiotics are started within a window of 6-8 hours. Data for most infections, especially pneumonia, have the same window of opportunity in regard to mortality. Animal models of septic shock also indicate that mortality can directly relate to time delay in antibiotics. If there is any delay in the work up, including a delay in obtaining a chest radiograph, then empiric treatment for CAP with ceftriaxone and azithromycin should be initiated. The patient was given 2 l of normal saline and a chest radiograph was obtained. He was given a total of 18 mg adenosine with no response; and then 2.5 mg intravenous verapamil in three doses, with a decrease in heart rate to 110 beats/min. Atrial fibrillation was diagnosed. His blood pressure fell with these interventions. The chest radiograph showed a dense opacity in the right-upper lobe with patchy opacities in the right-lower lobe, the lingula, and left-upper lobe. There were no clear air bronchograms or lateral shift to suggest lobar collapse (Fig. 1). Dr B There are now additional diagnostic data available, and clinically important interventions have been done that raise important considerations. The additional radiographic information addresses the concerns raised about the 30 lb weight loss and any chronic process that may be acutely infected. There is no clear evidence of an endobronchial lesion or airway obstruction. This, along with the history of a recent negative bone scan, makes cancer less likely. Active tuberculosis is possible, and sputum should be sent for appropriate studies. With the complaint of midsternal pleuritic chest pain, there is concern of pericardial involvement. However, there are no suggestive changes on the ECG, and the heart size looks normal, somewhat narrow, and probably under-filled, which is consistent with hypovolemia. Dr A Do we need to consider any other diagnostic tests for CAP in a patient with severe sepsis? Dr C It can be very helpful in cases like this to have blood and sputum cultures. It is usually possible to get a set of blood cultures in patients like this, prior to starting antibiotics. Although they do not have a high yield, they can play an important role in the treatment of the infection by identifying possible sources and unusual or resistant organisms. They can also help to identify high-risk patients. Dr B The purist's goal is to try to establish a bacteriologic diagnosis, but the realization is that one must initially treat broadly because no single test has the sensitivity and specificity to allow one to treat narrowly. Regardless, the coverage we use includes coverage for almost every possible bacteriologic pathogen. Knowing that this patient is from the community, we do not need to consider double Gram-negative coverage, even in a septic patient. If a patient is from the community but has recently been hospitalized, is immunosuppressed, is being treated with steroids, or has structural lung disease, such as bronchiectasis, then we would consider alternative or additional antibiotic coverage to cover for Pseudomonas spp. or other resistant Gram-negative rods. For the time being there is no indication to change either the azithromycin or ceftriaxone. I agree that to try to obtain a bacteriologic diagnosis, we use blood, urine and sputum cultures, if available, and might perform bronchoscopy once the patient is hemodynamically stable. Dr C Getting back to the ECG, the patient has a narrow complex tachycardia with a rate of 190 beats/min with 2-3 mm ST-segment depressions across the precordium. Should the heart rate be directly controlled? Could the patient be having a myocardial infarction or is he simply volume depleted? I am concerned about using adenosine before adequately addressing the patient's volume status. The initial approach should be to volume replete him aggressively and see whether the hemodynamics improve, and then address any persistent tachycardia only after he is volume replete. In this case, rate controlling agents may not be the first line of therapy, given a strong suspicion for sepsis. One question that comes up is, what if he is ischemic and you start volume resuscitating him? Is he going to go into heart failure? Does that matter? This should not be an issue. If the need arises then support him with invasive or noninvasive ventilation and get him through this. Regardless of the cause of the tachycardia, fluid load this patient.

PMC5960857_01

Female

This is a case of an 18-year-old Caucasian female who was referred to us from an outlying facility for evaluation of heartburn and chronic abdominal pain. The patient started experiencing the pain several months before presentation. The pain was cramping in nature, intermittent, occurring approximately 3 times per week, lasting for a few hours with no relieving or aggravating factors. There was no history of altered bowel habits. The patient gave no history of previous surgeries. On further questioning, a positive history of hair eating (trichophagia) was obtained but with no history of alopecia, eating pattern change, thoughts of body image distortion, or previous psychiatric disorders. General examination of the patient was unremarkable with no signs of dehydration, halitosis, or lymphadenopathy. Local abdominal examination revealed diffuse mild tenderness of the abdomen. No palpable masses were appreciated. Normal bowel sounds were present on auscultation. Laboratory investigations detected microscopic anemia and mild leukocytosis. An upper gastrointestinal X-ray with air contrast was performed at an outlying facility and showed a distended stomach that appeared to be filled with debris, along with a normally filled duodenum. Esophagogastroduodenoscopy was performed at our institution, which demonstrated a trichobezoar occupying 75% of the gastric lumen extending down through the pylorus and into the duodenal bulb (Figure 1). A few attempts to remove the hair with scissors and forceps were made, but none were successful. Exploratory laparotomy and gastrostomy were performed afterward in which the bezoar was removed successfully and without any complications. It measured 17 x 6 x 7 cm and weighed 2.33 lbs. The patient recovered well and was discharged home with psychiatry clinic follow-up.

abdomen, abdominal pain, bezoars, gastric outlet obstruction, heartburn, trichobezoar, trichophagia, trichotillomania

PMC5523342_01

Female

A 76-year-old woman with a long history of diabetes mellitus was referred to our hospital with complaints of severe claudication in bilateral lower limbs. She had noticed claudication symptoms approximately 10 years earlier. Recently, she could not walk 100 m without needing to rest. Her long history of diabetes mellitus required that she take multiple oral medications but not insulin. Unfortunately, her condition was complicated by diabetic nephropathy. Laboratory studies revealed increased HbA1c level [6.7% (NGSP); reference value (RV) 4.6%-6.2%], blood urea nitrogen (45.3 mg/dL; RV 7-22 mg/dL), creatinine (2.07 mg/dL; RV 0.4-0.8 mg/dL), and a decreased estimated glomerular filtration rate of 19.16. The ankle-brachial pressure index (ABI) was 0.72 on the right side and 0.74 on the left side. We gave her the option of one of two revascularization methods: femoropopliteal bypass surgery or EVT. Both treatments have benefits and disadvantages for patients. After careful consideration, she decided to undergo revascularization by EVT. Before EVT, we needed more information about the status of her arteries in both legs; therefore, we performed magnetic resonance imaging (MRI). The MRI results confirmed that both of her SFAs were occluded from bifurcation of the deep femoral artery (Figure 1). Initially, we performed EVT for the left SFA-CTO. A 6 Fr Destination catheter (Terumo Corporation, Tokyo, Japan) was inserted from the right femoral artery into the left common femoral artery as a contralateral antegrade wiring approach. A 0.018-inch Treasure guidewire (Asahi Intecc Co., Ltd., Nagoya, Japan) with a NaviCross microcatheter (Terumo Corporation, Tokyo, Japan) was able to penetrate the proximal fibrous cap of the CTO. After advancing the microcatheter into the CTO site a little, we exchanged the 0.018-inch wire for a hydrophilic 0.035-inch, 1.5-mm, J-type, shaped-tip wire. A knuckle-shaped hydrophilic 0.035-inch wire was used to easily cross the middle of the CTO site and to eventually capture the distal site of the CTO. The 0.035-inch wire was not in the true lumen, however, so we subsequently used a reentry device called an Outback Elite catheter (Cordis, Florida, USA) to attempt to gain access to the true lumen. The device was delivered to the distal subintimal space adjacent to the reconstructed area of the distal true lumen, and some effort was needed to successfully penetrate using a hollow needle. Two orthogonal angiographic views were taken to confirm the correct direction: an L-shaped fluoroscopic marker enabled orientation of the tip toward the reentry site and, to attain the appropriate position, we needed to fine-tune the positioning at the site and used a T-shaped fluoroscopic marker to confirm the desired alignment. Next, a 22 G nitinol reentry cannula was plunged into the distal true lumen in the distal SFA. A 0.014-inch Chevalier Floppy extrasupport wire (Cordis, Florida, USA) was advanced into the true lumen. Then, the reentry device was removed, and we used a SABER X 5 x 60 mm (Cordis, Florida, USA) to perform balloon dilatation in the CTO lesion. Next, two 6.0 x 100 mm SMART stents (Cordis, Florida, USA) were implanted from the proximal to middle portion of the left SFA. We performed postballoon dilatation using the same balloon. All procedures were performed without iodine contrast medium. The patient's left ABI improved from 0.74 to 0.98. One month after the procedure for the left SFA-CTO, we performed EVT for the right SFA-CTO. A 6 Fr Parent Plus60 sheath was inserted from the right femoral artery as an ipsilateral antegrade wiring approach. A 0.018-inch Treasure guidewire with a 4.0 Fr CXI support catheter (Cook Medical, Bloomington, IN, USA) was used to penetrate the fibrous cap of the CTO. Advancing the microcatheter into the CTO site, we exchanged the 0.018-inch wire for a hydrophilic 0.035-inch, 1.5-mm, J-type, shaped-tip wire. A knuckle-shaped hydrophilic 0.035-inch wire was used to reach the distal site of the CTO. The 0.035-inch wire was intended to be placed in the false lumen, but subsequent attempts to gain access to the true lumen were performed using an Outback Elite catheter. We performed CO2 angiography to guide exact positioning of the needle and stents. A 0.014-inch extrasupport wire was advanced into the true lumen. Then, the reentry device was removed, and we performed balloon dilatation using a 5 x 60 mm balloon in the CTO lesion. Subsequently, two SMART stents (7.0 x 100 mm and 6.0 x 150 mm) were implanted from the proximal to middle portion of the right SFA. We performed postballoon dilatation using the same balloon. All procedures were performed without iodine contrast medium. Subsequent examinations showed that the patient's left ABI improved from 0.72 to 0.91.

PMC9749414_01

Male

A 50-year-old Chinese male presented to a local hospital with right ankle pain and limited mobility 23 months ago and underwent a synovectomy of the ankle. Specimen culture revealed brucellosis infection in sheep. The patient came to the department of Orthopaedics of our hospital 18 months ago because his symptoms did not improve. His case history indicated that he had worked in a Sheep farm for 9 months. We, therefore, suspected that he might have acquired Brucella infection through ingestion or contact with injured skin. A 37 C temperature, no sweating, weight loss, and no personal or family history of tuberculosis were all present on admission. Physical examination showed significant tenderness on the lateral side of the right ankle without fever. Blood flow to right toe is good, right ankle varus pressure test is positive. Laboratory tests were as follows: Hemoglobin (Hb) 136 g/L, Red blood cell count (RBC) 4.25x1012/L, White blood cell (WBC) 10.09x109/L accompanied by neutrophil elevation, Platelet 363x109/ L, Erythrocyte sedimentation rate (ESR) 31 mm/h, C-reactive protein (CRP) 32 mg/L. Rose-Bengal Plate Agglutination Test (RBPT) was positive. Anteroposterior and lateral X-ray of the right ankle showed arrowed joint spaces (Figure 1A and B). CT showed multiple cysts were noted below the articular surface of the right ankle, and the articular surface of the talus collapsed (Figure 2A-D). MRI showed the right ankle joint space was significantly narrowed, the articular surface was coarse, the articular cartilage was thinned, the talus articular surface collapsed, and multiple cysts were found in the subchondral bone (Figure 3A-D). Joint synovial fluid of right ankle was extracted by joint aspiration and sent to the laboratory for Real-time PCR examination, and the results showed that there was B. melitensis in the synovial fluid (Figure 4). The HE staining of ankle fluid revealed inflammatory cell infiltration, while acid-fast staining was negative (Figure 5A and B). We concluded that the patient had recurrent Brucella ankle arthritis and was treated with doxycycline (0.1 g po bid), rifampicin (0.6 g po qd) and cefotaxime-sulbactam (2.25 g ivgtt q8h) for six weeks during hospitalization. ESR and CRP levels declined significantly after drug treatment, returning to normal levels of 17.00 mm/h and 7.88 mg/L, respectively. The right ankle movement of the patient was basically normal at discharge, and the pain was significantly reduced. Laboratory tests after drug treatment showed erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels of 17.00 mm/h and 7.88 mg/L, respectively, significantly decreased and returned to normal. At following-up 18 months later, the patient had no discomfort in the right ankle and all inflammatory markers were normal. RBPT was negative.

brucella arthritis, ankle arthritis, brucellosis, synovitis

PMC7440848_01

Female

A 55-year-old woman with a history of adjustment disorder with anxiety, eczema, seasonal rhinitis, and cough variant asthma was referred to pulmonology for 1 month of worsening wheezing, cough, and dyspnea. Her asthma had been diagnosed 2 years prior, and her moderate persistent symptoms remained uncontrolled despite twice-daily usage of the long-acting beta2 agonist, salmeterol, and the inhaled corticosteroid, fluticasone, which had both recently been increased. She had no clinically significant history of smoking or occupational exposures. Her spirometry had recently been normal. Physical exam initially revealed mild crackles in bilateral lower lung fields and was otherwise unremarkable. Initial laboratory evaluation revealed an immunoglobulin E (IgE) of 1850 IU/mL, peripheral eosinophilia (31.2% and absolute count 2.45 x 109/L), and elevated acute phase reactants. Normal laboratory findings included Aspergillus antibodies, a tuberculosis interferon-gamma release assay, hemoglobin, platelet count, and calcium. A chest computed tomography demonstrated bi-apical patchy consolidation with left upper lobe mass-like consolidation and with enlarged mediastinal and perihilar lymph nodes. These findings led to a differential diagnosis, which included ICEP, eosinophilic granulomatosis with polyangiitis, lymphoma, sarcoidosis, parasitic infection, or tuberculosis. Her symptoms continued to progress despite adjustment of pharmacotherapy. A bronchoscopy was performed, and a BALF and an endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) were obtained. The BALF revealed profound alveolar eosinophilia (86%), and the cytology of the BALF revealed abundant eosinophils without atypical cells (Figure 1). Anaerobic, fungal, and acid fast bacilli cultures of the BALF were negative. The EBUS-TBNA of a lymph node revealed a heterogeneous lymphoid population and eosinophils consistent with a reactive lymph node (Figure 2). Flow cytometry was normal. Tissue exam of alveolated lung parenchyma revealed reactive pneumocytes and eosinophils. Laboratory evaluation revealed an antinuclear antibody of 1:1280 and normal cytoplasmic antineutrophil cytoplasmic antibodies, perinuclear antineutrophil cytoplasmic antibodies, myeloperoxidase, proteinase 3 antibodies, and serum complement C3 and C4. A viral respiratory panel was negative. Following bronchoscopy, the patient developed worsening cough, dyspnea, and new hypoxemia requiring supplemental oxygen at 2 LPM via nasal cannula. A chest x-ray revealed a small left apical pneumothorax, and she was admitted for treatment and monitoring. Empiric treatment of ICEP was initiated with methylprednisolone, 125 mg, every 6 hours for 1 day, and then transitioned to oral prednisone. As expected, this resulted in resolution of her respiratory symptoms, supplemental oxygen requirement, peripheral eosinophilia (0.2% and absolute count 0.02 x 109/L), and radiographic abnormalities. She was discharged on oral prednisone, 20 mg, daily. Following hospital discharge, the patient repeatedly self-discontinued prednisone therapy due to concern for possible complications related to her adjustment disorder with anxiety, as well as possible steroid-induced paranoia, anxiety, irritability, and insomnia. This intolerance and non-compliance to her corticosteroid treatment was likely the reason that her ICEP was not responsive to a short course as would otherwise be expected. She experienced a resurgence of respiratory symptoms and peripheral eosinophilia with each discontinuation of steroids. Frequent discontinuation led to repeat administration of higher prednisone doses than would likely have otherwise been necessary, inadequate symptom control, and a high number of healthcare visits, which includes emergency room visits and physician appointments related to the diagnosis of ICEP. In the first two and a half months after diagnosis when steroid monotherapy was employed, the patient had 22 healthcare encounters that were directly related to ICEP (Figure 3). Given her inability to tolerate standard therapy, alternatives were explored. Mepolizumab was selected as a disease-specific alternative therapy with physiologic and clinical evidence supporting its potential for disease control and its corticosteroid-sparing potential. Additionally, mepolizumab would have a long-acting effect with the goal of minimizing the impact of therapy non-compliance. Mepolizumab, 300 mg, every 4 weeks subcutaneously, allowed successful treatment of ICEP. Her daily prednisone dose was subsequently halved to 20 mg by mouth every other day. The patient's serum immunoglobulin E (IgE) was periodically measured over the course of her treatment. It decreased drastically with treatment, but never reached normal levels. Without an increase in compliance, she had dramatically decreased symptoms, serum IgE, peripheral eosinophilia, and healthcare utilization since starting mepolizumab (Figures 3-5). Prednisone, 20 mg, by mouth every other day was continued for 15 months. During this period, compliance continued to be limited by her anxiety with specific patient concerns being the risk of infection, weight gain, and glucose intolerance. However, during that time, she was consistently compliant with mepolizumab and had no significant relapses of ICEP symptoms or mepolizumab adverse effects. She is currently being tapered to prednisone, 5 mg, by mouth daily with the goal of tapering off of corticosteroids completely.

complementary therapies, glucocorticoids, humanized monoclonal antibodies, mepolizumab, pulmonary eosinophilia

PMC5580054_01

Female

A 37-year-old woman, born in September 1977, first presented to our clinic in February 2015 because of severe aggressive outbursts. She was the only child of healthy, unrelated Caucasian parents with an unremarkable family history. She was born 3 days after the due date following an uneventful pregnancy with a birth weight of 3900 g (43rd centile) and a birth length of 52 cm (55th centile). Occipitofrontal circumference and Apgar scores were not reported. Cleft palate and craniofacial dysmorphic signs were noted at birth. She had problems with swallowing. She began sitting at 9 months and walked at 18 months. Her speech development was delayed; her vocabulary consisted of only a few words (mama, papa). She pointed with her hands to indicate what she wanted. At the age of 6 years, the patient achieved a mental age of 3 years, with an intelligence quotient (IQ) in the mild mental retardation range (IQ 50-55) on the Wechsler Intelligence Scale for Children (WISC). She was hyperkinetic, with behavioural problems that were still manageable. She attended a special school, where she coped well with the programme. She learned to ride a tricycle. She had only a few, poorly-developed, protruding teeth. At the age of 12 years, the patient's mental state deteriorated. She regressed to the level of severe mental retardation, achieving an IQ of 25-30 points on WISC. Her speech deteriorated and she was no longer able to speak any words. Her height was 142 cm (10th centile) and her weight was 37 kg (26th centile). She understood and carried out only very simple instructions and tasks. She disliked the company of children of her age, preferring the company of adults. Her hyperkinetic and behavioural problems increased at this time, together with auto- and heteroaggression. Left facial hypotrophy was evident, and her walk was rigid and broad-based. She was admitted to a care home for mentally handicapped children. In May 2015, when she was last examined for this report, the patient's aggressive outbursts were even more frequent and persistent than they had been previously. Her behaviour was unpredictable, with shouting, throwing herself on the floor, hitting her head on the floor (causing nose bleeds), refusing to eat and being aggressive towards others. Swallowing problems were still present. Computed tomography scans, before and after the application of contrast media, revealed no abnormalities in the skull or brain matter. The patient was of normal height and weight; she had sparse hair, thin, pale skin, craniofacial dysmorphism (a long and asymmetric face, short and flat philtrum, and pointed chin), oligodontia and a left periorbital dermoid cyst (Figure 1). Molecular karyotyping was performed on this patient and her parents using DNA extracted from peripheral blood leukocytes with the QIAamp DNA Blood Midi Kit (QIAGEN, Hilden, Germany). Analysis was carried out using the BlueGnome CytoChip ISCA 8x60K platform (Illumina UK, Cambridge, UK). The protocol was performed according to the manufacturer's instructions and data were analysed using the BlueFuse Multi v3.1 software tool (Illumina UK). The deletion was confirmed using a paralogue ratio test (PRT) according to a previously described protocol. For this, a pair of oligonucleotides (identification number: chr2ppn1p449839453) was selected, which coamplify a region within the deletion (chr2: 196,578,414-196,578,640; 226 base pairs [bp]) and a reference region from chromosome 17 (chr17: 58,027,459-58,027,690; 231 bp). Molecular karyotyping in this patient revealed an 8.6 Mb interstitial deletion of the chromosomal region on the long arm of chromosome 2, between 191,711,722 bp and 200,347,340 bp (GRCh37/hg19). The deletion lies within the chromosomal bands 2q32.22q33.1 and encompassed 22 known genes listed in the Online Mendelian Inheritance in Man (OMIM) database, including the GLS, MYO1B, TMEFF2, PGAP1 and SATB2 genes. The chromosomal position of the deletion in the present case is labelled red on Figure 2. Molecular karyotyping of the patient's parents did not show any aberrations. The PRT analysis showed an ~50% reduction in signal height for the chromosome 2 target locus (226 bp fragment) compared with the signal height from the reference 231 bp fragment from chromosome 17. Statistical analysis yielded a Z-score of 5.2 with a corresponding P-value <0.001. Thus, the PRT result confirmed the presence of copy number variation on chromosome 2 in this patient. Ethics approval for this analysis was obtained from the Republic of Slovenia National Medical Ethics Committee (NMEC), Ljubljana, Slovenia (NMEC 89/01/11). Written informed consent was obtained from the parents of the patient for publication of this case report and its accompanying images.

2q32q33 microdeletion syndrome, satb2 gene, behavioural problems, developmental delay, secondary cognitive decline

PMC5676088_01

Female

We present a 25 year old lady, recently diagnosed asthmatic who presented to Emergency Department (ED), with sudden onset of difficulty breathing associated with noisy breathing for 3 days and hoarseness of voice for 6 months. A year ago, she was treated as PTB and had completed treatment. Since then, she had multiple episodes of bronchospasm that required nebulization at a local clinic precipitating the diagnosis of bronchial asthma. On presentation, she was in respiratory distress with silent chest and marked use of accessory respiratory muscles. An arterial blood gas revealed a severe respiratory acidaemia. She received treatment including hydrocortisone, continuous nebulised beta-2 agonists, magnesium, antibiotics, and a salbutamol infusion. As her bronchospasm was not responding, ED team decided for intubation. Multiple attempts at intubation at ED before an alert to ICU was made, as although the larynx was visualized as Cormack-Lehane I, they were unable to advance the Endotracheal Tube (ETT) beyond more than 1 cm past the vocal cord. Finally, she was intubated with ETT size 6.0mm Internal Diameter where cuff was just after the vocal cord and anchored at 16 cm. We had difficulty ventilating her as her peak airway pressure's was persistently high with severe respiratory acidosis. With the abnormal laryngoscopy and life-threatening bronchospasm and alternative diagnoses were explored. She underwent flexible nasopharyngolaryngoscope (FNPLS) that revealed subglottic stenosis (Fig. 1). CT Thorax/Neck showed features of tracheobronchial stenosis with post primary PTB changes (Fig. 2). Patient was subsequently treated successfully with anti TB medication and underwent multiple sessions of tracheal dilatation (Fig. 3a-c).

bronchial asthma, bronchospasm, ct, computed tomography, ebtb, endobronchial tuberculosis, ed, emergency department, ett, endotracheal tube, endobronchial tuberculosis, fnpls, flexible nasopharyngolaryngoscope, ptb, pulmonary tuberculosis, subglottic stenosis

CT Thorax pre intervention, Sagittal plane: Trachea narrowing 4.6 cm from hyoid bone, 0.8 cm length and 9.5 cm from hyoid bone, 8.7cm length. Right main bronchus narrowest diameter was 0.3 cm.

PMC7239889_01

Female

Recent thymic emigrants (RTE) influence the rate of infections and deaths in patients with renal transplants. The immunophenotype of the naive RTE is CD45RA+CD45RO- CCR7+CD62L+. In a study by Bugault et al, CD45RA+ CD62L+CD4+ T cell population in patients with ICL was reduced, while CD45RA-CD62L- effector memory cells were increased. In another study of 20 patients with ICL, the expansion of terminally differentiated effector memory cells and contraction of the naive T cells was observed. CD45RA+CD31+ are thymus-derived naive T cells, while CD45RA+CD31- are peripherally expanded naive T cells. Levels of the latter are reduced in patients with ICL. In a study by Kovacs et al, patients with ICL had a lower percentage of naive cells in the rectosigmoid mucosa compared to effector and central memory cells. A higher proportion of Tregs (CD25+FoxP3+CD4+) is also seen in ICL. Enhanced CD45RO expression with reduced CD45RA expression (lower naive T cell) and increase in gammadelta-TCR cells was reported in a 9-year old boy with ICL and was suggestive of a maturation defect. Lee et al observed that CD4 cells from patients with HIV and ICL showed greater levels of activation and levels of lipopolysaccharide, a marker for microbial translocation, was also similar between the two groups. The dual-specificity phosphatases (DUSP) family downregulate TCR signalling. Overexpression of DUSP4 reflects T cell activation strength and the cumulative number of cell cycles. Their overexpression in CD4 cells of patients with ICL suggests chronic TCR stimulation. In vitro TCR signalling improved with silencing of DUSP4. Multipotent double-negative T cells differentiate into alphabeta and gammadelta cell populations based upon the surface TCR expression and DNA rearrangements. gammadeltaTCR is expressed by 2-5% of T lymphocytes in the thymus and peripheral blood. The analysis of alphabeta and gammadelta type TCRs in three patients of ICL showed that their repertoire was severely affected, though it was not related to the severity of infections. In a study by Sheikh et al, gammadelta CD4 T cells were found in higher proportions in ICL. Several hypotheses proposed to explain the selective depletion of CD4 cells, are discussed in the following sections. Fas (CD95), a member of TNF family trimerizes with the Fas ligand leading to thymocyte apoptosis during negative selection and during peripheral deletion of activated T cells. Low levels of Fas are seen in quiescent peripheral mononuclear blood cells. In a study of eight patients with ICL and clinical immune deficiency, seven had accelerated apoptosis of CD4 cells. Increased activated T cell markers-CD25, CD69, and Fas/CD95+ was seen in a patient with ICL compared with normal controls, resulting in more spontaneous and Fas-induced apoptosis. Uncoordinated 119 (Unc119) is a transport adaptor protein essential for Lck activation. Lck reduction and Unc119 mutations lead to severe combined immune deficiency phenotypes. In a study of three subjects with ICL and impaired Lck activity, one patient had a heterozygous missense mutation in the Unc119 gene that resulted in an inability of Unc119 to interact with Lck. Homozygosity mapping revealed a mutation in the first exon of the ITK gene in another patient with ICL. Recombination activation gene (RAG) encodes proteins that regulate recombination in the beta chain of the TCR. Two novel heterozygous missense mutations in the RAG1 gene were found in a young girl with ICL. STK4 is necessary for T cell migration and has both proapoptotic and antiapoptotic functions. An STK4 mutation was seen in a patient with ICL who presented with EBV-related MALT lymphoma. MAGT1, a magnesium transporter gene mediates magnesium flux following TCR activation. Mutations lead to impaired downstream signalling events. Characteristically, they present with CD4 lymphopenia, EBV infection and neoplasia. This condition is called XMEN syndrome and closely mimics ICL. IL-7 is a cytokine produced by non-hematopoietic cells that binds to its receptor CD127 on CD4 cells. This leads to phosphorylation of janus kinases (JAK) that activate the signal transducer and activator of transcription 5 (STAT5) pathway. It also activates the src kinases pathway that regulate TCR signaling, and the PI3-K pathway that regulates protein kinase B (Akt) involved in cell cycle progression. IL-7 is thus critical for survival (JAK3/STAT5/Bcl2), cell cycle progression (p38 MAP kinase/CD25), and reduced apoptosis of T cells. In ICL, CD127 receptor expression was lower and was associated with reduced responsiveness to IL-7. IL-7 release is increased following depletion of CD4 cells and levels correlate with T cell consumption. However, this is insufficient to restore CD4 counts. Reduced upregulation of IL-7 induced genes, lower STAT-5 phosphorylation in response to IL-7, and reduced signalling in response to IL-2 were seen in patients with ICL. Both IL-2 and IL-7 control CD4 pool size. IL-7 and IL-2 responses were reduced and STAT5 activation responses impaired in a study of 15 patients with ICL from France. IL-2 and IL-7 induce CXCR4 that enables migration of the cell along the gradient of the CXCL12. CXCR expression on the T cells was reduced and low levels of CXCR correlated with lymphopenia in patients with ICL. CXCR4 expression increased with IL-2 therapy. A virus has been suggested to be the cause of ICL. In a study of seronegative haemophiliacs, five patients were noted to have persistent lymphocytopenia fulfilling criteria for ICL. This was attributed to cirrhosis due to chronic hepatitis C infection in these patients. When peripheral blood mononuclear cells from a patient with ICL were co-cultured with HUT78 T-lymphoblastoid cells, an acute cytopathic effect was seen. Those surviving the cytopathic effect showed an intracisternal retroviral particle that reacted with antibodies of sera from ICL patients. However, to date, no definite virus has been isolated from patients with ICL. In rectosigmoid endoscopies of 12 patients with ICL, reduced CD4 lymphocytes with normal functional indicators of enterocyte turnover (intestinal fatty acid-binding protein and inflammatory biomarkers) were observed. In this study, patients with ICL had a higher percentage of DN T cells when compared to controls, but TH1 and TH17 cell subsets were normal. This suggested tissue depletion of CD4+ and not entrapment of CD4+ cells in the mucosa. This contrasted with the observation by Griffiths et al. In three cases of erythroderma, one each due to cutaneous T cell lymphoma, atopic dermatitis, and psoriasis, they found CD4+ counts were markedly increased in the skin with high CD4:CD8 ratios and simultaneous peripheral blood CD4 lymphocytopenia. In these patients, resolution of the erythroderma resulted in normalization of CD4 counts. They proposed erythroderma be considered an exclusion criterion for ICL. In normal individuals, 80% of CD4+ cells express CD28. Immune senescence is associated with CD28 loss due to chronic stimulation. Defective TCR responses and telomere shortening were observed in a T cell subset of ICL patients. CXCR expression is reduced following TCR stimulation which was observed in patients with ICL. CD27- and CD28- costimulatory molecules, and CD57+ and KLRG-1+ are markers of T cell senescence. These were also higher in patients with ICL when compared to healthy subjects. HLA-DR and Ki-67 suggestive of activation and cell cycle turnover, respectively, were both increased in CD4 cells of patients with ICL. Proportion of Tregs cells was higher and the naive T cells were lower in these patients. Increased activation of CD4 lymphocytes may result in depletion. Some patients also have also been reported with CD19 B-cell deficiency, CD8 T-cell deficiency, or CD3-CD16+CD56+ NK cell deficiency. The percentage of transitional B cells (CD10+/CD27-) was higher and had a strong inverse relationship with CD4+ counts in a cohort of 25 patients with ICL. This suggested that either CD4 and/or IL-7 had an impact on B cell maturation as well. Isgro et al evaluated the bone marrow of five patients with ICL and found a reduction in lymphoid precursor cells, suggesting reduced clonogenic potential of the bone marrow. In a patient with cryptococcal meningitis and ICL, Salit et al demonstrated anti CD4+ T cell antibodies in greater concentration than controls. In summary, diminished precursors (reduced clonogenic potential), accelerated apoptosis (Fas/Fas ligand), reduced chemotaxis (reduced CXCR expression), poor response to TCR stimulation, impairment of activation (low expression of Lck, MAGT1 defect), defective cytokine production (TNF-alpha and IFN-Y), elevated IL-17, dysregulation of IL-7 and its downstream targets, others mutations involving RAG1, UNC119, ITK, STK4, and CD45, cytotoxic antibodies to T cells, and sequestration all can contribute to reduced CD4 T cell counts. Clinical manifestations arise due to immune deficiency, disparate infections, neoplastic and autoimmune conditions. The presentation is diverse - the patient may be asymptomatic or may have florid infection(s) that ends fatally. The presentations can differ despite similar CD4 counts. Long disease-free intervals have been reported with low CD4 counts. The most common organ-systems involved are the skin, central nervous system, and lungs. Less commonly the musculoskeletal system, lymphoreticular system, gastrointestinal tract, hematopoietic system, eyes, ears, and the genitalia and reproductive system involvement have been described. Patients develop both opportunistic and non-opportunistic infections. Table 2 provides a summary of the reported infectious agents. Most patients with ICL have had at least one OI. OI in ICL are related to mycobacteria (M. avium-Intercellulare (MAC), M. tuberculosis, M. genavense M. mucogencium, M. kansasii), viruses (Human Herpes Viruses, John-Cunningham virus (JCV), Human Papilloma Virus (HPV)), fungi (Cryptococci, Candida, Histoplasma, Blastomyces, Pneumocystis) and protozoa (Leishmania and Toxoplasma). In a follow-up study of 39 patients by Zonios et al, the commonest infections were due to cryptococci, HPV, and nontuberculous mycobacteria. Varicella zoster virus (VZV), HPV and cytomegalovirus (CMV) were the most common viral infections reported from another study. Leishmaniasis is the most common parasitic infection in ICL. Single or multiple infections may coexist in a single patient as it did in a patient with vertebral osteomyelitis (Acinetobacter species, M. abscessus, and Mucormycosis). Multiorgan involvement has been reported in infections due to Cryptococcus, CMV, VZV, Blastomyces, and MAC. In our review of 164 cases, we found 89 (52%) had skin manifestations. Most were due to infections. The symptoms varied and included pruritus, erythroderma, vesicles, warts, verrucous papules and plaques, condylomata, and mycetoma (Exophiala jeanselmei and M. chelonae). Infection of the skin included viral, bacterial, fungal and parasitic infections like herpes zoster, HPV, molluscum contagiosum, Stenotrophomonas maltophilia, MAC, Candida albicans, tinea corporis, tinea pedis, cryptococci, Aureobasidium species, Alternaria species, and Hortaea werneckii, leishmaniasis. Premalignant lesions (vulval intraepithelial neoplasia, Bowen disease) and malignancies (e.g., Kaposi sarcoma, squamous cells carcinoma and basal cell carcinoma) have been reported. Signs of autoimmune disease (e.g. dermatomyositis, vitiligo, and psoriasis) have been described. Often these patients have had a previous history of skin diseases such as atopic dermatitis, psoriasis, herpes zoster and recurrent staphylococcal furunculosis. Skin abscesses have also been reported. Neurological manifestations involve the meninges, the cerebrum, brainstem, cerebellum, cranial and peripheral nerves. The commonest reported neurological disorder was cryptococcosis, followed by progressive multifocal leukoencephalopathy (PMLE). Zonios et al, studied 53 patients with ICL and cryptococcosis and found many with other underlying diseases like cirrhosis, diabetes, tuberculosis, and sarcoidosis. They presented with headache and fever. Other symptoms were diplopia, confusion, imbalance, dizziness, photophobia, limb weakness, seizures and slurred speech. Disseminated cryptococcosis involving lung, bone, bone marrow, lymph node, muscle, and blood has been reported. Eighteen patients of PMLE with ICL were identified in 2017 and most presented with cognitive decline and progressive focal deficits. Other causes of neurological infections were bacterial (Nocardia abscessus, N. farcinia and N. asteroids), viral (JCV) mycobacterial (MAC), fungal (cryptococci), and parasitic (toxoplasmosis) organisms. Guillain-Barre syndrome and sensorimotor polyneuropathy have also been reported in ICL. Respiratory symptoms included ear pain, productive cough, and breathlessness. Manifestations reported include nasal polypoid tumors, otitis media, laryngeal papillomas, reticulonodular infiltrates, pneumonia, bronchiectasis, nodules, masses, cysts, mediastinal lymphadenopathy, pleural effusion, and empyema. Organisms comprised of mycobacteria (M. tuberculosis, MAC), bacteria (Nocardia, H. infleunzae), viruses (VZV, CMV, HPV, and EBV) and fungi (Pneumocystis jirovecii, cryptococcosis, mucormycosis, aspergillosis, istoplasmosis). According to Ahmad et al, Pneumocystis jirovecci was the most common respiratory pathogen.

cd4 t cell lymphocytopenia, autoimmune disease, neoplasia, opportunistic infections

PMC7784812_01

Female

A 44-year-old previously healthy woman with a body mass index of 33.5 sustained a motor vehicle accident in March 2018. Patient's vehicle was rear-ended on the driver's side, in a diagonal manner. She was restrained with a seatbelt. She sustained lower back injury and reported experiencing numbness and tingling in the legs, as well as headaches and muscle spasms. MRI of the lumbar spine done at that time showed multilevel disk pathology, including disk herniation at L2/L3, L3/4, L4/L5, and L5/S1. Additional findings at the L5/S1 level also demonstrated a radial tear and impingement on bilateral lateral recesses. There was no fracture noted. Approximately 3 months later, she started experiencing an intermittent tingling feeling in her clitoris, which progressively worsened to constantly feeling like she was on the verge of orgasm. Orgasm did not provide any relief of her symptoms and at times the patient felt like it was worsening them. Of note, the patient had not been on antidepressant medication before or during the onset of undesired genital arousal. When asked about her quality of life, the patient stated, "It was terrible, you can't focus on anything, you can't wear any clothes from the waist down to try not to put any pressure at all in that area." Driving, sitting in church, studying at her desk, and any other kind of pressure or vibrations in the genital area exacerbated her symptoms. After 3 months of undesired genital arousal and feeling ashamed, "dirty and perverted," she expressed her concerns to her medical team and was subsequently referred to the gynecology team. MRI of the pelvis 6 months after the injury showed disk pathology within the visualized lumbar spine (consistent with initial post-trauma MRI), no Tarlov cysts or bony fractures were identified. There was no radiological evidence of peripheral pudendal nerve compression. Physical examination revealed no abnormalities but was limited by her fear of response. After careful review of her symptoms, medications, and contributing factors, a trial of lidocaine 4% patches, measuring 10 x 14 cm, applied to the sacrum was initiated. The patient was instructed to place the lidocaine patch centrally, right above the buttock crease. She subsequently stated that the patches provided significant relief of symptoms. At her 3-month follow-up visit, she reported that, while wearing the patch, she experienced full resolution of the clitoral tingling sensation. She also reported the emergence of a new tingling sensation in the vagina. She was prescribed lidocaine gel, which initially provided limited relief. Overall, she reports great improvement in her quality of life since the onset of treatment with lidocaine patches. Although response to therapy has been adequate, she would prefer a more long-term alternative treatment over having to constantly reapply the lidocaine patch. She was presented with the various options to include pudendal nerve block and various medications but elected to continue with lidocaine as needed. She returned to the office a year after the motor vehicle accident. At that visit, the patient was still experiencing residual back pain and reported that PGAD symptoms appeared to be linked to exacerbations in her back pain. She denied urinary urgency, urinary frequency, bladder or pelvic pain, or symptoms of restless leg syndrome. She started attending physical therapy for back pain and has noticed improvement with her back pain and associated PGAD symptoms. She reported being able to sleep through the night now, without having to wake up due to the genital arousal. At 18 months follow-up, patient reported continued improvement but incomplete resolution. She experiences about one episode per week, which is always associated with increased lower back pain. She uses lidocaine patches during these episodes, which continue to provide relief. As of her last visit, she plans to continue using lidocaine and focus on improving back pain.

gynecology, persistent genital arousal disorder, women's health

PMC6057532_01

Female

We present a 23 years old woman case known epilepsy treated with carbamazepine and phenobarbitalum, 26-28 weeks pregnant brought by the ordinary ambulance to a level III medical center in epileptic status since 1 hour. The patient was out with HIV encephalitis and pulmonary TB in inconsistent treatment. BP 96/68mmHg. HR - 134/min. Normal blood glucose level and ECG, negative toxicological report. Fetal HR 100-115/min. Normal uterine tone. After repeated diazepam administration with no significant response in crisis suppression, the patient was air evacuated (HEMS resuscitation team) to the regional medical center (general anesthesia, endotracheal intubation, mechanical ventilation / volume IPPV cycled) with IV. benzodiazepine dose supplementation and IV. Phenytoin administration - 15mg/kg. Air evacuation to County University Hospital Craiova Initial crush induction sequence (succinylcholine) sustained by deep sedation (fentanyl, etomidate, diazepam). Under general anesthesia (maintained over 6 hours by the anesthesiologist) has cupped seizures but maintained tachycardia. At 7 hours, she has been extubated without further medical events. At 24 hours conscious, without focal signs or subsequent seizures. Favorable ongoing pregnancy. After 5 weeks - natural delivery of a 1936 grams, male newborn. No any signs of abnormal brain electrical activity or seizures to the baby related to the mother medical problems during the first 8 months of life, but considering the severe event and therapy cerebral palsy remains under suspicion until 24 months.

cesarean section, eclampsia, pregnancy, seizures, tocography

PMC1334183_01

Female

Conflict in Sudan has displaced millions of people and forced hundreds of thousands to flee across borders. In the south of the country, the 21-year old war between the Government of Sudan and the Sudan People Liberation Movement/Army has caused the internal displacement of approximately 4 million people, to which the more than 1.5 million displaced as a consequence of the more recent conflict in Darfur must be added. As of the end of 2003, more than 500,000 Sudanese refugees were residing mainly in Uganda, Ethiopia, Kenya and Chad. By the end of 2003, the overall HIV prevalence among adults in Sudan was estimated at 2.3% (95% confidence interval (CI) 0.7 to 7.2). In 2002, the Sudanese government undertook an HIV survey in 14 of 26 states with the following results: pregnant women at antenatal clinics (1.0%), tuberculosis (TB) patients (1.6%), sexually transmitted infections (STI) patients (1.1%), sex workers (4.4%), tea sellers (2.5%), IDPs (1.0%) and Eritrean refugees (4.0%). Following progress in the negotiations between the Government of Sudan and the Sudan People Liberation Movement/Army, future peace in South Sudan and the consequent return home of refugees and IDPs was reported widely in the media. Particular attention was expressed regarding high infection rates among Sudanese IDPs and refugees, and the fear that refugees living in host countries with high prevalence rates will return and exacerbate the epidemic in South Sudan. The situation was described as "severe", "on the verge of an HIV/AIDS epidemic" and a "disaster" that was going to "doubtless increase the likelihood of a further spread of the epidemic". Headline: "HIV/AIDS soars in war-torn northern Uganda" .

PMC5011344_01

Female

A 15-year-old girl was referred to our centre at day 3 post-burn to her thigh. She dropped a small amount of nail glue onto her thigh when she had been applying nail glue on to her fake nails (Fig. 1). The nail glue remained in contact for a total of 5 min before she felt the burning sensation. She then removed her trousers and noticed the burns. No first aid was instituted. She attended the local emergency department (ED) on the same day. At her initial assessment, the wound was irrigated for 30 min with cold water and dressed, then she was discharged home. However, she returned to the ED 2 days later due to increasing erythema around the burn. She was started on oral antibiotics and was referred to the burns centre. On examination, a 0.5 % total body surface area (TBSA) burn of mixed depth was observed on the upper medial aspect of her right thigh (Fig. 2), and it was approximately 7 x 5 cm in size. She was initially managed with Mepilex Ag (Molnlycke Health Care, Gothenburg, Sweden) and then with flamazine cream and daily dressings. She was reviewed a week later, and due to the delayed wound healing, she was counselled to proceed with surgical excision of the burn and reconstruction with split-thickness skin grafting. The patient underwent surgery and was discharged home the same day. The graft was successful and healed completely without complications within 2 weeks.

chemical burn, first aid, nail adhesive, nail glue, paediatric burns

PMC8260849_01

Male

There were two patients enrolled in this study. The proband was a 4-year-old boy and the other patient was his mother, both of them manifested with recurrent urticaria and arthralgia. Clinical data, family history and blood samples were collected when the proband first visited us in May 2019. Informed consent was obtained from all of the participants. This study was conducted in accordance with the tenets of the Declaration of Helsinki and was approved by the ethics committee of the Children's Hospital of Chongqing Medical University. Peripheral blood was collected from members of this family after written informed consent obtained. Whole blood samples were sent to MyGenostics (Beijing, China) and subjected to whole-exome sequencing (WES). The pathogenicity of the mutations was assessed following the American College of Medical Genetics and Genomics guidelines (ACMG). Mutations in NLRC4 were confirmed by using Sanger sequencing. Briefly, genomic DNA was extracted from peripheral blood mononuclear cells (PBMCs) using the QIAamp DNA Mini Kit (Qiagen, Shanghai, China). Polymerase chain reaction (PCR) was performed to amplify the genomic NLRC4 gene. The products of the PCR reactions were sent for Sanger sequencing. The crystal structure of NLRC4 (4KXF from the Protein Data Bank) was used as the template, which was determined by X-ray diffraction at a resolution of 3.20 A. Although the 4KXF is the crystal structure of mouse NLRC4, it does reveal the auto-inhibition mechanism. And previous studies also used it as the template to study the effect of NLRC4 mutation. Herein the structural impact of mutant Gly172Ser was analyzed by Swiss-PdbViewer. Residue 172 and certain nearby residues within 3 A are illustrated. For clear demonstration of the interresidue relationship, some residues were highlighted in the indicated colors with the computed hydrogen bonds being labeled. Peripheral blood was collected in vacutainers containing sodium heparin. Centrifugation was performed at 2500 rpm for 5 minutes at room temperature to separate the plasma from the peripheral blood cells. The cells were diluted in PBS and added to the top of Ficoll-Paque PREMIUM (GE Healthcare, Sweden) and centrifuged at 800 g for 20 minutes at room temperature to separate the PBMCs fraction. PBMCs were cultured in RPMI 1640 (Gibco, USA) at a density of 0.8x 106 cells/ml containing 10% FBS (Gibco, USA), and penicillin-streptomycin (100 U/mL each; Sigma-Aldrich, USA) was added. Lipopolysaccharide (Sigma Aldrich, USA) was added to cell culture at a final concentration of 100 ng/ml for stimulation. After 24 hours of culture, the cells were collected for the subsequent experiments. After cell stimulation, the plate was centrifuged to pellet the cells. The presence of cytokines in the supernatants was determined by using Multi-Analyte Flow Assay Kit (Human Inflammation Panel(13-plex), Biolegend, San Diego, CA) according to the manufacturer's guidelines. Caspase-Glo 1 inflammasome assay kit (Promega, USA) was used to measure the caspase-1 activation in the PBMCs culture supernatant. Caspase-1 and caspase-1 inhibitor reagents were prepared and added to the supernatant directly as described by the manufacturer. Fifty microliters of supernatant was transferred to a white 96-well plate. Caspase-Glo 1 Reagent or Caspase-Glo 1 YVAD-CHO Reagent was added to the wells (50 microl/well) and gently mixed on a plate shaker at 300 rpm for 30 s. The mixture was then incubated for 60 minutes at room temperature before measuring the luminescence on a Berthold Technologies luminometer. Cells were immediately washed with PBS and lysed in RIPA buffer with complete protease inhibitor (Sigma-Aldrich) immediately. Protein lysates in protein loading buffer were separated in 10% SDS-PAGE gels, transferred to PVDF membranes (Millipore, Germany), blocked with 5% milk, and then probed overnight at 4 C with primary antibodies, including anti-NLRC4 (ab115537; Abcam, UK) and anti-GAPDH (Bioss antibodies, Woburn, MA). After incubation with an HRP-conjugated secondary antibody (Bioss, USA), the blots were washed with TBST and imaged using an enhanced chemiluminescence system (Thermo Scientific, USA). A literature review of NLRC4 mutations was performed in PubMed using the terms "NLRC4" and ''mutation''. All types of publications (articles, reviews, editorials, letters, and correspondence), written in English, and published online between January 2014 and June 2020 were included. Only pathogenic and likely pathogenic mutations were considered. All statistical analyses were conducted with GraphPad Prism 8 software (GraphPad Software, Inc., San Diego, CA). Data were analyzed using an unpaired two-tailed Student t test. P-values < 0.05 were considered to indicate a significant difference.

nlrc4, autoinflammatory disease, mild phenotype, novel mutation, urticaria

PMC8502103_01

Male

A 31-year-old man with no significant past medical history presented to an urgent care center with complaints of fatigue, rash, and epistaxis. Two and a half weeks prior, he received his second scheduled dose of the Pfizer-BioNTech mRNA SARS-CoV-2 vaccine. Within twenty-four hours of vaccine administration, he developed fatigue and a petechial rash across his waistband. Symptoms worsened over the next several weeks, and he noted easy bruising as well as additional petechial lesions. Of note, the patient had received the first scheduled dose of the two-dose live measles, mumps, and rubella (MMR) vaccine series exactly three and six weeks prior to receiving the first and second doses of the Pfizer-BioNTech mRNA SARS-CoV-2 vaccinations, respectively. Complete blood count showed a white cell count of 5.1 x 109/L, hemoglobin 14.8 g/dL, and platelet count of 1,000/microL, and he was subsequently admitted to hospital for additional evaluation and management. Physical examination was notable for a well-appearing young male with normal vital signs. Skin examination revealed a scattered petechial rash along the right scapular area of the patient's back and across the patient's waistline (Figure 1). The remainder of his exam was unremarkable. Additional laboratory testing showed a normal lactate dehydrogenase of 173 IU/mL, haptoglobin 22 mg/dL, and fibrinogen 233 mg/dL. Testing for HIV and hepatitis C was negative. Vitamin B12 and folate were within the normal range. Review of the peripheral blood smear was notable for markedly reduced platelet count with rare, large circulating platelets. No schistocytes or other distinctive erythrocyte abnormalities were identified (Figure 2). A diagnosis of immune thrombocytopenia purpura (ITP) was made, and the patient was treated with intravenous immune globulin 1 g/kg and glucocorticoids. He was also transfused 2 units of platelets. Platelet count improved significantly to 95,000/microL by hospital day 2, and he was subsequently discharged home. Repeat measurement of his platelet count 3 days after discharge was 472,000/microL. Glucocorticoids were discontinued, and he remained with normal hematologic parameters at 5 weeks after diagnosis.

PMC6589228_01

Male

A 28-year-old male semiprofessional basketball player presented to our orthopaedic practice with pain proximal and lateral to the left knee joint. He was treated for a tibial shaft stress fracture with tibial intramedullary nail (IMN) fixation 1 year prior at an outside hospital. He first noticed pain proximal and lateral to the left knee 2 weeks after surgery, and it persisted for the entire year. He had no complaints of pain in other joints and he denied any history of trauma since surgery. X-ray images taken during initial evaluation at our clinic showed no evidence of fractures, appropriate position of hardware, and presence of heterotopic bone at the proximal TFJ (Figure 1(a)). We ordered a CT scan to further evaluate the heterotopic bone and rule out implant problems including screw breakage, loosening, or prominent position. The CT scan demonstrated that the implant was properly positioned with no protruding or loosening screws (Figures 1(a)-1(d)). We posited that the implant likely had little to no impact on the patient's pain. The scan also displayed no acute fracture consistent with the patient's reported level of pain (Figures 1(a)-1(e)). However, it showed that the drill for the proximal locking screw may have penetrated through the tibia and into the fibula (Figure 1(d)). It also revealed proximal tibiofibular synostosis immediately distal to the proximal TFJ joint (Figures 1(a)-1(e)) aligned with the bone reaming along the drill path (Figure 1(d)). Following a literature review and a discussion with our patient, we decided to proceed with nonoperative management. The patient declined a steroid injection. The patient's knee pain resolved without intervention, and he was able to return to playing semiprofessional basketball. At 13 months postoperation, he reported intermittent, mild pain on the medial side of the knee while playing basketball, but this did not limit his participation. At the final follow-up 16 months postoperation, he reported no pain.

PMC8634897_01

Female

A 52-year-old female from a remote village in southern India, who is a known case of uncontrolled type 2 diabetes and hypothyroidism for the past 5 years, presented with a 1-year history of pain over her left shoulder and 2 months of increasing swelling of the same shoulder after a trivial fall. She had undergone an arthroscopic rotator cuff repair for the same side in 2019, with metal and bioabsorbable suture anchors from elsewhere. After the surgery, she was doing well with her shoulder, except for the occasional pain, that aggravated to the present status in 2 years. Owing to the COVID-19 pandemic, she did not have regular post-operative follow-ups. In March 2021, she had a trivial fall over the same shoulder, and since then, she noticed an increasing swelling around the same shoulder, which grew from the size of a lemon to a half-cut watermelon spanning in between her neck and affected shoulder (Figure 1). Owing to the raging COVID situations in India, she could not attend a specialist hospital and took treatment at a local bonesetter with herbal massages until she presented here. She also had a few courses of broad-spectrum antibiotics from local hospitals with no resolution of her symptoms. The swelling looked fiery red at the time of presentation and had a local rise in temperature, and her shoulder movements were painful. There was no distal neurovascular deficit. There was no history of fever, chills or rigour, loss of weight or loss of appetite, or evening rise of temperature, or involvement of any other joints. There was no past or contact history of Tuberculosis (TB) nor any history of recent COVID infection. The pre-operative evaluation revealed normal leukocyte and neutrophil counts but raised C-reactive protein (CRP) - 67.6 and a normal erythrocyte sedimentation rate (ESR) - 06 mm. Her Hba1c was 10 depicting her uncontrolled diabetic status. Her blood culture was negative. An X-ray revealed bony destruction at the lateral end of the clavicle with the metal anchor in situ in the shoulder (Figure 2). Magnetic resonance imaging (MRI) revealed a large fluid collection with few septations in the subcutaneous tissue in the supraclavicular region communicating to the acromioclavicular (AC) joint, which was widened and eroded. Moderate glenohumeral joint effusion extending into the subacromial and subdeltoid spaces were also reported suggestive of corresponding bursitis (Figure 3). Our differential diagnosis where pyogenic/tubercular/fungal septic arthritis, which are the usual afflictions. The patient underwent swelling excision in toto and debridement of the left acromioclavicular and shoulder joint (Figures 4, 5, and 7). Surprisingly the whole sac of swelling was traced from the subcutaneous plane through the AC joint to the subacromial and subdeltoid bursae up to the humeral head entry site for the metal anchor. Around 500 mL of straw yellow pus was drained out of the excised sac and from the shoulder joint (Figure 6). The deep-seated metal anchor in the humeral head was surrounded by a nidus of osteomyelitis sequestrum, which was debrided and retrieved along with the metal and bio absorbable anchors (Figure 8). Multiple specimens of infected tissue and pus were sent for histopathology, aerobic and anaerobic bacterial cultures, acid-fast bacteria (AFB), gram staining, TB GeneXpert, and Fungal DNA-PCR. The bacterial and tubercular reports were all negative and eventually, the fungal DNA detection by PCR was positive for Debaryomyces subglobosus, an extremely rare fungi to infect the shoulder joint, even in immunocompromised patients. HPE was consistent with chronic granulomatous infection (Figures 9 and 10). The patient was started on Voriconazole, the specific anti-fungal for the same and got a complete resolution of her symptoms within 6 weeks of initiation of treatment. The serum markers for infection, CRP and ESR, returned to normal within this period, and her surgical wound healed completely. However, her functional recovery was lagging behind, even at two months follow-up, owing to the chronicity of the infection and the residual damages it has already made to the rotator cuff muscles and the joint.

arthroscopy, fungal septic arthritis, rotator cuff repair, shoulder, uncontrolled diabetic

PMC5739149_01

Male

The patient was a 66-year-old man with a 1.15-mm thick, nonulcerated primary melanoma on the upper back diagnosed in October 2011 who had undergone wide local excision and left axillary sentinel lymph node dissection, revealing 1 lymph node positive for metastatic melanoma. In May 2015, he had a locoregional recurrence with 3 new hypermetabolic subcutaneous metastases in the left axilla and the left upper back confirmed by cytology. His tumor did not harbor a BRAF mutation. He started treatment with a combination of ipilimumab and nivolumab in July 2015. A positron emission tomography (PET)/computed tomography (CT) scan of the body in September 2015 showed resolution of the subcutaneous nodules in the left axilla. However, after 2 doses, a grade 3 diffuse papular skin rash and grade 3 hepatitis developed, and the combination therapy was discontinued. After his rash and hepatitis resolved with corticosteroid treatment, he started treatment with nivolumab alone in September 2015, without recurrence of the severe rash or hepatitis. In December 2015, a PET/CT scan showed ill-defined subcutaneous fat stranding in the medial left lower extremity, without apparent skin abnormalities on physical examination. In January 2016, he presented with small skin nodules in the left calf that were mildly tender to palpation. In March 2016, he noted an increasing number of diffuse erythematous nontender subcutaneous nodules on his bilateral lower extremities (Fig 1, A). A PET/CT scan at that time showed interval development of approximately 50 hypermetabolic subcutaneous nodules in the upper extremities, pelvis, and lower extremities, mostly concentrated in the lower extremities below the knees (Fig 1, B), raising a high suspicion for disease progression in the subcutaneous tissue. Results of blood tests at the time showed elevated erythrocyte sedimentation rate at 100 mm/h (normal range, 0-20 mm/h), slightly elevated rheumatoid factor at 17 IU/mL (normal, <15 IU/mL), and C-reactive protein at 9.0 mg/L (normal, 0-8.0 mg/L). Complete blood counts, liver function results, and serum creatinine level were within normal limits, and antinuclear antibody titer was negative. Excisional biopsy of 3 of the subcutaneous nodules on his lower extremities and the forearm found a robust lobular, septal, and paraseptal lymphohistiocytic infiltrate that was overtly granulomatous in nature in some areas in which multinucleate histiocytes were noted. No vasculitis was observed, and no bacterial, fungal, or mycobacterium tuberculosis DNA was detected in the samples. On the basis of pathologic evaluation, a diagnosis of granulomatous panniculitis was made. Nivolumab treatment was discontinued at the time of panniculitis diagnosis, and the patient was observed clinically without corticosteroid treatment. However, by May 2016, an increasing number of subcutaneous lesions developed throughout his body, more prominently in the lower legs. Although some of the existing lesions had resolved, some of the lesions became tender. C-reactive protein was further elevated (36.1 mg/L), but erythrocyte sedimentation rate was normal. A PET/CT scan showed further progression of the subcutaneous nodules throughout the body. He was started on 20 mg of oral prednisone daily, and his subcutaneous nodules regressed quite rapidly. Prednisone was slowly tapered off over the next 3 months. A follow-up PET/CT scan performed in August 2016 showed near complete resolution of the subcutaneous lesions.

pet/ct, positron emission tomography/computed tomography, anti–pd-1 antibody, granulomatous, immune-related, melanoma, nivolumab, panniculitis

PMC4654435_01

Male

The patient was a 77 year-old Hispanic male who initially presented to the emergency room with a 6-week history of progressive dyspnea on exertion, cough productive of yellow sputum, intermittent hemoptysis, worsening fatigue and weight loss of 10 lbs. On admission, he denied fever, chills, chest pain, sick contacts, recent travel, or tuberculosis exposure and history. His past medical history was significant for Non-Hodgkin follicular B cell lymphoma (NHL) diagnosed in 1997, treated with Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone (RCHOP) three times. Last treatment was completed 1 year prior to presentation. He also had biopsy-confirmed cutaneous Kaposi's Sarcoma (KS), identified within the same year of presentation, treated with pegylated liposomal doxorubicin 20 mg/m 2 once every 21 days for two cycles. On admission, he had a low grade fever and was tachycardic. His physical exam was remarkable for a 2 cm firm, non-tender, mobile right submandibular lymph node. Lungs were clear to auscultation bilaterally. He was grossly anasarcic with 4 (+) pitting edema of the lower extremities. He also had multiple violet, non-tender skin lesions localized to the lower extremities, mainly around the medial aspect of his ankles and anterior thighs bilaterally. His labs revealed a normal cardiac panel, a white blood cell (WBC) count of 8,100/mm 3 with no leukocytosis. Manual differentiation of the white blood cells showed 28% neutrophils, 48% lymphocytes, 17% monocytes and 5% eosinophils. Urinalysis and urine culture were negative for infections. Blood cultures were positive for Streptococcus pneumoniae. A chest X-ray done on admission showed a right lung consolidation consistent with pneumonia thus the patient was started on empiric vancomycin 1gm every 12 hours and piperacillin-tazobactam 4.5gm every 8 hours for a duration of 8 days. A computerized axial tomographic (CT) scan of the chest, abdomen and pelvis, showed numerous nodular opacities throughout each lung which were suspected to be consistent with KS as well as small pleural effusions in both lungs ( Figure 1). Despite completing a course of antibiotics for pneumonia, his symptoms did not improve. A follow-up CT scan of the chest demonstrated that the bilateral pleural effusions had worsened ( Figure 2). Patient underwent a thoracentesis of the larger effusion in the right lung which showed a sero-sanguineous and exudative fluid based on chemistry analysis. Histopathology failed to demonstrate malignant cells. A bronchoscopy was also performed, revealing diffusely hyperemic and edematous mucosa of the lower airways with mucopurulent secretions ( Figure 3). Biopsy was not performed at this time given concern for endobronchial bleeding. Bronchoalveolar lavage (BAL) stains and cultures were negative for bacteria, fungi or acid fast bacilli. Pneumocystis jiroveci PCR and fluid cytology were also negative but PCR for HHV-8 showed 5800 DNA copies/mL. The patient had a HIV p24 rapid antigen test done which was negative. After two weeks of supportive treatment, the patient's symptoms began to improve. He continued to have numerous indurated confluent lesions on his body and face consistent with KS. His pulmonary symptoms were thought to be due to disseminated KS. Following significant discussions with the patient and his family regarding the poor prognosis of his disease, he decided not to undergo any further antineoplastic treatments and eventually was discharged home with hospice.

kaposi sarcoma, lymphoma, pulmonary, bronchoscopy

CT of the chest on admission to hospital. . CT of the chest demonstrating several nodular opacities throughout both lungs. Two nodules are measured to show size. Arrows point to pleural effusions on both lungs.

PMC4654435_01

Male

The patient was a 77 year-old Hispanic male who initially presented to the emergency room with a 6-week history of progressive dyspnea on exertion, cough productive of yellow sputum, intermittent hemoptysis, worsening fatigue and weight loss of 10 lbs. On admission, he denied fever, chills, chest pain, sick contacts, recent travel, or tuberculosis exposure and history. His past medical history was significant for Non-Hodgkin follicular B cell lymphoma (NHL) diagnosed in 1997, treated with Rituximab, Cyclophosphamide, Hydroxydaunorubicin, Oncovin and Prednisone (RCHOP) three times. Last treatment was completed 1 year prior to presentation. He also had biopsy-confirmed cutaneous Kaposi's Sarcoma (KS), identified within the same year of presentation, treated with pegylated liposomal doxorubicin 20 mg/m 2 once every 21 days for two cycles. On admission, he had a low grade fever and was tachycardic. His physical exam was remarkable for a 2 cm firm, non-tender, mobile right submandibular lymph node. Lungs were clear to auscultation bilaterally. He was grossly anasarcic with 4 (+) pitting edema of the lower extremities. He also had multiple violet, non-tender skin lesions localized to the lower extremities, mainly around the medial aspect of his ankles and anterior thighs bilaterally. His labs revealed a normal cardiac panel, a white blood cell (WBC) count of 8,100/mm 3 with no leukocytosis. Manual differentiation of the white blood cells showed 28% neutrophils, 48% lymphocytes, 17% monocytes and 5% eosinophils. Urinalysis and urine culture were negative for infections. Blood cultures were positive for Streptococcus pneumoniae. A chest X-ray done on admission showed a right lung consolidation consistent with pneumonia thus the patient was started on empiric vancomycin 1gm every 12 hours and piperacillin-tazobactam 4.5gm every 8 hours for a duration of 8 days. A computerized axial tomographic (CT) scan of the chest, abdomen and pelvis, showed numerous nodular opacities throughout each lung which were suspected to be consistent with KS as well as small pleural effusions in both lungs ( Figure 1). Despite completing a course of antibiotics for pneumonia, his symptoms did not improve. A follow-up CT scan of the chest demonstrated that the bilateral pleural effusions had worsened ( Figure 2). Patient underwent a thoracentesis of the larger effusion in the right lung which showed a sero-sanguineous and exudative fluid based on chemistry analysis. Histopathology failed to demonstrate malignant cells. A bronchoscopy was also performed, revealing diffusely hyperemic and edematous mucosa of the lower airways with mucopurulent secretions ( Figure 3). Biopsy was not performed at this time given concern for endobronchial bleeding. Bronchoalveolar lavage (BAL) stains and cultures were negative for bacteria, fungi or acid fast bacilli. Pneumocystis jiroveci PCR and fluid cytology were also negative but PCR for HHV-8 showed 5800 DNA copies/mL. The patient had a HIV p24 rapid antigen test done which was negative. After two weeks of supportive treatment, the patient's symptoms began to improve. He continued to have numerous indurated confluent lesions on his body and face consistent with KS. His pulmonary symptoms were thought to be due to disseminated KS. Following significant discussions with the patient and his family regarding the poor prognosis of his disease, he decided not to undergo any further antineoplastic treatments and eventually was discharged home with hospice.

kaposi sarcoma, lymphoma, pulmonary, bronchoscopy

CT of the chest during hospitalization. . CT of the chest showing nodular opacities that persisted in both lung fields and worsening bilateral pleural effusions (arrows).

PMC5264175_01

Unknown

We report the case of a 55-year-old patient, active smoker without occupational exposure who, after the discovery of a pulmonary nodule on thoracic computed tomography (CT), underwent a right upper lobectomy with lymphadenectomy that was diagnostic of pulmonary adenocarcinoma (pT1b pN0). All the lymph nodes sampled in the surgery (10R, 11R, 7, 4R, and 9R) presented sinus histiocytosis and anthracosis and were negative for metastasis. Lymph node from region 4R had fragments of bronchial cartilage introduced by EBUS-TBNA performed previously [Figure 1a]. One year later, during outpatient thoracic surgery monitoring, thoracic CT evidenced a low right paratracheal lymph node [Figure 1b]. With the suspicion of pulmonary neoplasm recurrence, EBUS-TBNA was performed [Figure 2a]. The lymphadenopathy cytology showed a nonnecrotizing granulomatous reaction secondary to amorphous fragments of an acellular material that were birefringent under polarized light, compatible with Surgicel [Figure 2b]. The culture and polymerase chain reaction testing for Mycobacterium tuberculosis were negative. At 6 months of follow-up, no significant changes in the lymph node were observed.

endobronchial ultrasound-guided transbronchial needle aspiration, surgicel®, foreign body reaction, lung cancer

(a) Lymph node 4R with sinus histiocytosis, anthracosis, and a piece of bronchial cartilage (H and E, x4). (b) Thoracic computed tomography axial section showing the right low paratracheal lymph node of 14 mm.

PMC5264175_01

Unknown

We report the case of a 55-year-old patient, active smoker without occupational exposure who, after the discovery of a pulmonary nodule on thoracic computed tomography (CT), underwent a right upper lobectomy with lymphadenectomy that was diagnostic of pulmonary adenocarcinoma (pT1b pN0). All the lymph nodes sampled in the surgery (10R, 11R, 7, 4R, and 9R) presented sinus histiocytosis and anthracosis and were negative for metastasis. Lymph node from region 4R had fragments of bronchial cartilage introduced by EBUS-TBNA performed previously [Figure 1a]. One year later, during outpatient thoracic surgery monitoring, thoracic CT evidenced a low right paratracheal lymph node [Figure 1b]. With the suspicion of pulmonary neoplasm recurrence, EBUS-TBNA was performed [Figure 2a]. The lymphadenopathy cytology showed a nonnecrotizing granulomatous reaction secondary to amorphous fragments of an acellular material that were birefringent under polarized light, compatible with Surgicel [Figure 2b]. The culture and polymerase chain reaction testing for Mycobacterium tuberculosis were negative. At 6 months of follow-up, no significant changes in the lymph node were observed.

endobronchial ultrasound-guided transbronchial needle aspiration, surgicel®, foreign body reaction, lung cancer

(a) Lymph node 4R with sinus histiocytosis, anthracosis, and a piece of bronchial cartilage (H and E, x4). (b) Thoracic computed tomography axial section showing the right low paratracheal lymph node of 14 mm.

PMC3033829_01

Male

A 32 year old male who was a known IVDU, presented with a 12 hour history of increasing swelling in his left leg. He had a purulent discharge from a chronic sinus in his left groin. On examination, he had warm erythematous sinuses in both groins. The left sinus was discharging foul smelling pus. He had a tachycardia 120 bpm and pyrexia 38.2 degrees C, blood pressure (BP) 136/86. He was alert and orientated to time, place and person. Blood tests revealed a white cell count (WCC) of 15.9 x 109/l, a C-Reactive Protein (CRP) of 21 mg/dl and blood cultures were taken. He was treated with broad spectrum antibiotics Vancomycin, Clindamycin, Ciprofloxacin, Gentamicin and Metronidazole in line with the latest advice from microbiology because of a recent outbreak of anthrax in the local IVDU population. Within 24 hours of collection, all 6 blood culture bottles grew gram positive organisms suggestive of Bacillus anthracis and he was referred for consideration of surgery. The cultured Bacillus anthracis organism was susceptible to all the above antibiotics. Clinically there was no abscess to drain so he had a computed tomography (CT) scan of his abdomen, pelvis and thighs performed. This showed loculated fluid and inflammatory change anterior to the left psoas muscle extending down to the iliacus [Figure 1]. In the pelvis, the left pectineus and adductor magnus were oedematous possibly reflecting muscle necrosis [Figure 2]. Given that he was clinically well his conservative management and monitoring continued. Over the next five days there were signs of improvement with a reduction in the inflammatory markers and no evidence of organ dysfunction. In consultation with colleagues in microbiology, infectious diseases and public health a further CT scan was performed to ensure that there was no collection to drain as the limited local experience suggested that drainage and debridement of collections and necrotic tissues resulted in optimal management. This scan showed that the retroperitoneal and thigh changes had improved slightly. Within a further 24 hours he had developed an area of cellulitis over the left thigh and lower abdomen and a Magnetic Resonance Imaging (MRI) was carried out. This showed diffuse oedematous change in the muscles and subcutaneous fat of the left leg from the level of the inguinal region to below the knee. After contrast, there were areas which did not show evidence of contrast enhancement with an irregular enhancing margin. The absence of discrete high signal on the STIR images was thought to represent areas of non-perfused musculature, possible undergoing necrotic change [Figure 3]. He underwent an exploration of his left thigh. This revealed chronically indurated subcutaneous tissues in keeping with his long history of injecting into the area. There was some oedematous fluid but no evidence of a collection or necrotic muscle. Post-operatively he made a steady recovery. Treatment with Vancomycin, Ciprofloxacin and Clindamycin continued for 14 days. Negative Pressure Wound Therapy (NPWT) device was applied utilising the Venturi wound sealing kit. This followed the therapy application technique first described by Chariker et al using saline-moistened gauze, a silicone drain and clear, semi-permeable adhesive film, together with lower pressures, usually between 60-80 mmHg.15 The dressings were changed three times per week and wound exudate collection canisters changed as required when full. He was discharged on a 4 week course of oral Ciprofloxacin 400 mg twice a day and continued with NPWT. Following 4 weeks of treatment, the wound dimensions had reduced from 300 cm3 [Figure 4] to 68 cm3 [Figure 5], a reduction in size of 77%. He remains well and attends regular review at outpatient clinic.

PMC9129884_01

Male

A 28-year-old male patient was admitted to the hospital after having oral pain for 1 month, skin ecchymosis with ulceration for 20 days, and abnormal renal function test results for 3 days. He had a medical history of chronic, untreated hepatitis-B for 18 years. One month prior to the admission, the patient began to experience oral pain. He was diagnosed with oral tuberculosis and received anti-tuberculosis treatment with rifampin and isoniazid, as well as appropriate analgesics when needed. He showed no improvement after 10 days of the treatment and developed ecchymosis and petechiae in both lower extremities. He was diagnosed with allergic purpura and received anti-allergic treatment with loratadine. Three days before coming to the hospital, he had shown no improvement with respect to oral pain or skin ecchymosis and had also developed foot ulcers. He returned to the hospital for further care. After hospital admission, a physical examination revealed an anemic appearance, with no edema in the face or lower extremities. The patient had coarse breath sounds with wet rales on lung auscultation. There was a 5 cm x 5 cm grayish-white necrotic tissue bulging from the right side of the oral palate (Figure 1A). The lower extremities showed ecchymosis with skin ulceration and necrosis in the left toes (Figures 1B,C). Laboratory test results were as follows: Red blood cell count, 2.56 x 1012/L; hemoglobin, 67 g/L; eosinophils, 21.2%; serum albumin, 31.9 g/L; alanine aminotransferase, 81.3 U/L; aspartate aminotransferase, 106 U/L; serum creatinine, 538 mumol/L; uric acid, 584 mumol/L; cholesterol, 6.37 mmol/L; low-density lipoprotein, 4.06 mmol/L; C-reactive protein, 34.4 mg/L; hepatitis-B surface antigen HBsAg positive, hepatitis-B virus DNA <102, negative anti-nuclear antibody, and anti-double-stranded DNA antibody, normal serum immunoglobulin (Ig), IgA, IgM, and IgG, complement C3 and C4, and serum-free k- and lambda-levels; normal serum anti-myeloperoxidase antibody level; and anti-proteinase 3 (PR3) antibody > 400 RU/ml. Urinary analysis showed urine protein 4+, urine microalbumin/creatinine 2,654 mg/g Cr. A T-SPOT tuberculosis test and myocardial injury markers were negative. The oral ulcer smear was negative under acid-fast staining. Chest computerized tomography (CT) examination revealed bilateral multiple nodular shadows and pulmonary infection. Otolaryngoscopy suggested nasal mucosal erosion and necrosis. Sinus CT showed maxillary and ethmoid sinusitis. The Birmingham Vasculitis Activity Score was 27. Echocardiography showed mild mitral regurgitation. Electromyogram of extremities was unremarkable with normal sensory and motor functions. Pathological examination of the renal biopsy specimen showed that 2 of 14 glomeruli had global sclerosis. Two glomeruli had segmental necrosis of the capillary loops, with no cellular or fibrous crescents. There were extensive detachments of renal tubular epithelial cells and exposure of the basement membrane, with infiltration of small focal individual nucleated cells and eosinophils in the renal interstitium. The electron microscopic findings were consistent with the light microscopy findings. Immunofluorescence examination showed linear depositions of IgG(+) along the glomerular basement membrane, with negative staining for IgG1, IgG2, IgG3, IgG4, IgA, IgM, C3, C4, k, lambda, and C1q. The final renal pathology diagnoses were acute tubulointerstitial kidney injury and antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with kidney injury (nodular necrotic lesions) (Figures 2A,B). Based on the 2016 treatment guidelines for vasculitis issued by the European League Against Rheumatism, we administered methylprednisolone 40 mg/day and cyclophosphamide 0.6 g intravenously for 10 days. The patient showed gradual improvement, including less oral pain, reduced size of skin ulcers, the disappearance of ecchymosis, and healing toe ulcers. His serum creatinine also decreased to 125 mumol/L. We followed up with this patient every 1-2 months and performed CT scanning and laryngoscopy at the second follow-up. Results suggested that pulmonary nodules dissipated and ethmoid sinusitis improved. There had been a total of eight follow-up visits to date. His symptoms have significantly improved. Furthermore, the vasculitis score decreased to 4. Serum PR3 was normalized and anemia was corrected. Serum creatinine and estimated glomerular filtration rate returned to normal. Urine microalbumin/creatinine decreased to <1,000 mg/g Cr. Oral granuloma, foot ulcers, and nose and throat lesions were also healed (Figures 3A,B).

anca-associated vasculitis (aav), antineutrophil cytoplasmic antibody, case report, eosinophilic granulomatosis with polyangiitis, myeloperoxidase

PMC9986552_01

Male

Mr. A, a 21-year-old male with no prior psychiatric history, was brought to the emergency room by police after being found wandering outside talking to himself. On arrival, the patient was afebrile at 98.1 F, with a heart rate (HR) of 64, respiratory rate (RR) of 18, and blood pressure (BP) of 136/96. The patient's complete blood count (CBC) and complete metabolic panel (CMP) were unremarkable, and a urine drug screen (UDS) was not obtained due to the patient being uncooperative with sample collection. Computed tomography (CT) of the head was negative for acute intracranial findings. On psychiatric evaluation, the patient was noted to have psychosis, as evidenced by responding to internal stimuli, laughing inappropriately, disorganization of thought process, reports of significant paranoia, hearing voices, and visual hallucinations. His behavior displayed disorganization with psychomotor agitation and suspiciousness of medical providers. Patient A endorsed vaping Delta8-THC but denied all other drug use. The patient was admitted to inpatient psychiatry. The family reported that there was no family history of psychiatric illness. They also reported that patient A had a decline in behavior over the 8 months preceding his hospitalization but had no formal psychiatric diagnosis or psychological disturbance before this time. He displayed aggressive, violent outbursts and once got into a physical altercation with the family's landlord, causing them to be evicted from their home. Due to the patient's unpredictable behavior, the family feared him and had not recently allowed him to live in their home. On day 1 of admission, the patient was started on oral risperidone 0.5 mg twice daily to address continued signs of psychosis. The patient exhibited disorganization, illogical thought process, and auditory and visual hallucinations. On day 3, his risperidone was increased to 1 mg twice daily and switched to 2 mg nightly on day 5. On the 10th day of admission, the patient still had poor insight into his hospital presentation. He continued to appear confused and disorganized during the interview, with difficulties in attention and concentration, as well as signs of paranoia. His risperidone was increased to 3 mg nightly; however, the above symptoms persisted. On day 20, his risperidone was increased to 4 mg nightly. On day 22, it was suspected that the patient was cheeking his medication, and was switched to risperidone orally disintegrating tablet 4 mg. By day 28, the patient was no longer endorsing visual or auditory hallucinations, was no longer paranoid, and was participating in group therapy. During the hospitalization, the treatment team learned that the patient started using Delta8-THC around the same time that the family reported a decline in his behavior. This is also when the patient endorsed auditory hallucinations; however, the patient was unable to give a clear history of whether he started Delta8-THC to try and prevent the voices or if the voices occurred after the Delta8-THC use. He was started on an intramuscular paliperidone long-acting injectable (LAI) on the 28th day of admission and an oral risperidone taper was begun. Patient A was discharged on the 32nd day after admission on a regimen of intramuscular paliperidone LAI 156 mg every 4 weeks (its metabolite is the same as risperidone and can be given every 4 weeks for improved adherence). He was back to his baseline functioning at discharge and was no longer endorsing signs or symptoms of psychosis and had an organized thought process without emotional lability. He was encouraged to abstain from any cannabis products. Patient A, unfortunately, did not follow-up for his scheduled outpatient appointment after discharge; however, he has not presented to our hospital's ER in the 7 months following discharge.

cannabis sativa, case report, delta-8-thc, delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol, psychosis

PMC9986552_02

Male

Mr. B is a 23-year-old male with a past medical history of schizophrenia and intellectual disability who presented to the emergency department via EMS after having a violent outburst at home. He broke the windows out of his house and tried to "arrest" his mother, stealing her car keys and breaking her arm. The patient was currently treated with intramuscular aripiprazole LAI 400 mg every 4 weeks and was 3 weeks post-last injection. His other home medication was divalproex delayed-release (DR) tablets 500 mg twice daily. His last inpatient psychiatric admission was a year before his presentation to the hospital. On arrival to the emergency department, he was afebrile, with HR 100, RR 15, BP 132/86, and labs were notable for a valproic acid level <10 and standard UDS positive for only THC. CMP, liver function tests (LFTs), CBC, and urinalysis (UA) were unremarkable. The patient's mother reported that he had never been violent before, but that she had seen a change in his behavior over the previous several weeks, where he was talking and laughing to himself more, was preoccupied, and had been destroying things in his house. Patient B had been having difficulty sleeping and was self-medicating with Delta8-THC gummies for several months, which his mother reported buying him. On psychiatric exam, the patient was significantly withdrawn, disorganized, paranoid, and responding to auditory and visual hallucinations. The patient was also unkempt and malodorous, seemingly having difficulty with self-care. The patient was admitted to inpatient psychiatry for acute care. On his first day of admission, he was maintained on his home dose of oral divalproex 500 mg twice daily and started on 6 mg of oral paliperidone daily. His aripiprazole LAI was not continued. He was still exhibiting disorganization, had visual hallucinations he was responding to, and continued to have poor hygiene. On day 3, his paliperidone was increased to 9 mg daily, and by day 6, the patient was more organized and able to hold a full conversation with the treatment team. He showed insight by recognizing that he could have hurt his mother and expressed remorse for his actions. On day 13, his paliperidone was increased to 12 mg daily, as the patient was remaining in his room and continued to have poor hygiene. By day 15, the patient was attending group therapy in the milieu and was bathing appropriately. He was given his first loading dose of intramuscular paliperidone LAI on day 16 of hospitalization, and his oral paliperidone was decreased by 3 mg daily until discontinuation. He was discharged on day 19 on a regimen of oral divalproex DR 500 mg twice daily and intramuscular paliperidone LAI 234 mg every 4 weeks (its metabolite is the same as risperidone and can be given every 4 weeks for improved adherence). On the day of discharge, he was no longer responding to internal stimuli, was not paranoid, and was performing his activities of daily living. Patient B has continued to follow-up with his outpatient provider and has done well on this regimen in the 8 months following inpatient treatment. He has abstained from Delta8-THC use and has not had further psychiatric emergencies requiring hospitalization.

cannabis sativa, case report, delta-8-thc, delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol, psychosis

PMC9986552_03

Male

Mr. C is a 39-year-old male with a history of schizoaffective disorder, traumatic brain injury (TBI), and borderline intellectual functioning, who presented to the ER complaining that he felt unsafe at home. Patient C was historically prescribed oral aripiprazole 2 mg daily. On arrival, he was afebrile, with HR 68, RR 18, and BP 127/83. CBC, CMP, and UA were unremarkable. UDS was positive for only THC. On psychiatric evaluation, the patient reported paranoid and bizarre delusions that someone was dissolving puppies in his bathtub at home with various chemicals. He had tried to involve the local and federal authorities and was encouraged by his minister to come to the hospital. The patient was perseverative on delusions and exhibited disorganization in speech, and was endorsing low mood and energy, poor sleep, and feelings of emptiness. He was disheveled with limited hygiene. The patient reported smoking Delta8-THC daily for 8 months, and self-discontinuation of his aripiprazole 4 months prior. Per the family reports, though the patient has a TBI, he is the primary caretaker for his mother who has chronic medical issues. The family reports that the patient behaves appropriately when on his medications and does not mention delusions or display confusion throughout the day. On the second day of admission, patient C was started on oral aripiprazole 2 mg, after he initially refused medication. He began to gain some insight that some of his delusions might not be true. After he was increased to aripiprazole 5 mg daily on the 3rd day of admission, he showed less perseveration on the delusions and was more future-oriented thinking about the need to help his mother around the house. On the 4th day of admission, he was discharged with instructions to increase his aripiprazole to 10 mg daily at home and follow up closely with his outpatient psychiatric provider, as well as to abstain from Delta8-THC products. Patient C did not show up for his 3-week outpatient follow-up appointment but has left messages at the nurses' line stating similar delusions from his presentation to the hospital. He has not presented to the hospital again in the 3 months following discharge.

cannabis sativa, case report, delta-8-thc, delta-8-tetrahydrocannabinol, delta-9-tetrahydrocannabinol, psychosis

PMC5390657_01

Male

The patient is a 66-year-old male with stage IV chronic kidney disease (CKD) who was admitted with right sided chest pain and transient hypotension which resolved with fluid resuscitation on arrival. Computed tomography angiography (CTA) was performed immediately and revealed a 5 cm aneurysm confined to proximal descending thoracic aorta with evidence of contained rupture. It also demonstrated the presence of an acute type B thoracic aortic dissection (TBAD) and a right-sided aortic arch. The dissection began just distal to the right common carotid artery and involved the origin of the left subclavian artery (SCA). The left common carotid artery arose proximally on the arch and was uninvolved (Fig. 1). Using a totally percutaneous approach, a 37 mm by 20 cm long conformable Gore TAG thoracic endoprosthesis (Flagstaff, Arizona) was placed in proximal descending thoracic aorta covering the left SCA (Fig. 2). A chest tube was inserted to evacuate the right hemothorax. Aside from the institution of hemodialysis due to progression of his pre-existing CKD, the patient had an uneventful recovery. CTA one-month post-procedure revealed a type IB endoleak due to degeneration of the distal descending thoracic aorta. To exclude the endoleak, the repair was extended distally using a repeat percutaneous approach and a 38 mm by 107 mm long Medtronic Valiant thoracic stent graft (Minneapolis, Minnesota) (Fig. 3). Six months later, the left subclavian artery was coil embolized to treat an additional retrograde (Type II) endoleak (Fig. 4). The patient has done well with no further evidence of endoleak or aneurysm expansion (Fig. 5). Autologous dialysis access was created in his right upper extremity. Emergency treatment of complex aortic pathology is challenging in the setting of a right-sided aortic arch. CTA, along with post-processing reconstructions, is always helpful. Initial limited stent graft coverage of the thoracic aortic pathology seemed very appropriate until the follow-up CTA revealed a Type IB endoleak. While the endoleak prompted additional intervention, the end result was excellent. This case displays the importance of careful attention to detail and close follow-up in these complicated patients. Please note this case report follows the CARE guidelines and has also been reported in line with the SCARE criteria. The patient has given informed consent for publication of this case report and the Geisinger IRB has approved case presentations.

aortic arch, aortic dissection, endovascular surgery, thoracic aneurysm

PMC3420786_01

Male

A 30-year-old man, of East African origin, was admitted to our hospital for a constrictive chest pain. The patient's history included acute methanol intoxication with bilateral permanent blindness, due to necrosis in bilateral putamen demonstrated on magnetic resonance imaging (MRI). The patient was followed in the rheumatology outpatient clinic for AS. There was no history of smoking or illicit drug consumption but the patient admitted drinking alcohol occasionally. The patient reported low inflammatory back pain for more than one year, good response to nonsteroid anti-inflammatory drugs (NSAIDs) and computer tomography imaging (CT) of bilateral sacroiliitis (grade 2), leading to the diagnosis of AS according to the ASAS criteria (Figure 1). The initial physical examination revealed a satisfactory general condition, no fever, normal vital signs, and synovitis of the knees. The cardiopulmonary examination was normal. Initial blood examination showed increased ESR at 80 mm/h (N < 20 mm/h) and CRP 5.8 mg/dL (N < 0.5 mg/dL), moderate hepatic cytolysis (<2X Normal values), and anicteric cholestasis. Total bilirubin, hematological tests, and renal function were normal. Troponin level was initially increased to 0.091 mg/dL; it decreased after 3 hours to 0.023 mg/dL. Chest radiography revealed no abnormalities. An electrocardiogram revealed widespread concave S-T elevation and a P-R depression (D2 D3). Cardiac echography was normal. Myocardial infarction was ruled out, and the patient was treated with NSAIDs with good clinical response. Because of the persistence of increased inflammatory markers and negative biological infectious investigations and first imaging studies (chest X-Ray and abdominal ultrasound), a whole-body positron emission tomography combined with a computed tomography (PET/CT) using F18-fluorodeoxyglucose as radiotracer (18F-FDG) was performed to detect any occult infectious or inflammatory sites. The 18F-FDG-PET/CT revealed mediastinal, hilar pulmonary, supraclavicular and cervical bilateral hypermetabolic lymph nodes, hypermetabolic condensation in the right lung, multiple hypermetabolic lesions of axial skeleton (Figure 2(a)), in particular the thoracic spine, rib cage, and bilateral sacroiliac joints (Figure 3). This was suggestive of either DT or lymphoma. A tuberculin skin test was done and was highly positive (22 x 27 mm), whereas analysis for TB was negative in the sputum and urine. Bronchoscopy with biopsy of the right pulmonary lesion was performed. Histological analysis of the lesions showed the presence of necrotic granuloma, and microbiological examination revealed mycobacterium tuberculosis. The diagnosis of DT with axial skeleton, lung, and lymph node involvement was retained, and the patient was treated with Isoniazid 300 mg/d, Rifampicin 300 mg bid, Pyrazinamide 500 mg/d, and Ethambutol 400 mg qid. 18FDG-PET/CT was repeated after 1 year of treatment and showed total disappearance of the aforementioned lesions (Figure 2(b)).

PMC9583524_01

Male

A 55-year-old-male was admitted due to dark urine and jaundice. Before admission, he took two capsules of artemisinin extract (containing 200 mg artemisinin extract + 10 mg alkaloid) per day for 1 month for shoulder pain. Gradually, he developed symptoms such as loss of appetite, tiredness of oil and itchy skin. He had no abdominal pain, vomiting, fever, diarrhea, etc. He has no history of hypertension, diabetes, hepatitis and tuberculosis. He did not smoke or drink alcohol. Physical examination revealed tachycardia. His BMI was normal (22.22 kg/m2). Abnormal liver function was found on admission (e.g., serum alanine aminotransferase of 908 IU/L [normal: 10-55 IU/L], total bilirubin 151.0 umol/L [normal: 3-22 IU/L], direct bilirubin 83.4 umol/L [normal: 0.5-7 IU/L], indirect bilirubin 83.4 umol/L [normal: 3-15 IU/L], blood ammonia 40 umol/L [normal: 9--33 IU/L]. International normalized ratio (INR) was normal. His glycated hemoglobin (HBA1c) was high (8.70%). Tests for hepatitis A, B, C, D, E, and Epstein-Barr virus were negative. Alpha-fetoprotein, carbohydrate antigen 19-9, ceruloplasmin, and antinuclear antibody ANA were negative. Anti-mitochondrial M2 antibody was weakly positive (+-). Laboratory tests did not support known infection (white blood cell, procalcitonin, cytomegalovirus CMV-DNA, human immunodeficiency virus type I type II, Treponema pallidum antibody were all negative). Resonance Cholangiopancreatography of upper abdomen showed a decreased liver uptake and bile duct excretion of Gd-EOB-DTPA, suggesting liver function impairment (Figure 1). He was diagnosed with drug-induced liver injury, hepatocellular injury type (R ratio 9.3), acute, RUCAM eight points (very likely), severity level three. After admission, polyene phosphatidylcholine, reduced glutathione, ursodeoxycholic acid capsules, and insulin were given. Bilirubin continued to rise after artemisinin was discontinued. On day 12, 14, and 18 after admission, plasma exchange plus bilirubin adsorption therapy was performed three times. His symptoms improved and discharged on day 22. Bilirubin decreased to baseline after 40 days (Figure 2).

artemisinin, cholestatic hepatitis, drug-induced liver injury, jaundice, plasma exchange (pe)

PMC9427407_01

Male

A 21-year-old man presented with sloping cervical mass. He was diagnosed with lymphadenitis caused by tuberculosis and taking antituberculosis drugs for 5 months. He received isoniazid, rifampin, ethambutol, and morfosinamide for 2 months and then continue with isoniazid and rifampin. At the end of second month the leakage stopped, but one month later, leakage from the lymphadenitis reoccurred. He had night sweats, and weight loss that never decreased with antibiotherapy. He presented with serious back pain since last year. He had no history of lung tuberculosis, but his family members presented with tuberculosis. His father had lung tuberculosis whereas his mother and sister had tuberculosis lymphadenitis. All of them received standard antituberculosis therapy and their therapy was successfully completed. In our patient computerized tomography (CT) scanning of thorax demonstrated a Pott abscess formation, nearly 15 cm length between thoracic vertebrae 5 and 11, which may be easily misdiagnosed as an aortic aneurism with the imagination on chest X-ray (Fig. 1, Fig. 2). Microbiological sample was taken with CT-guided biopsy. Only one acid fast bacilli (AFB) was seen with AFB stain. Mycobacterium tuberculosis yielded at Lowenstein-Jensen culture medium. This bacilli was found resistant to all primary antituberculosis therapeutic agents that he was taking. His therapy was stopped and amikacin 1 g/day + ethionamide 1000 mg/day + cycloserine 1000 mg/day + ofloxacin 400 mg/day + prazinamide 2500 mg/day was given. Drug resistance must be thought in patients who do not improve with standard antituberculosis therapy. According to our knowledge this was the first case of vertebral osteomyelitis caused by MDR tuberculosis in Turkey.

PMC9758986_01

Male

A 31-year-old man presented to our outpatient clinic with redness, swelling, and severe pain in both knees as well as an inability to walk since one year ago. The patient who has been HIV positive for 7 years had a history of severe prurigo nodularis for four years and had tubercle bacillus bloodstream infection two years ago. His antiretroviral treatment was successful. He did not have any relevant family history or history of genetic diseases. After admission, the patient underwent bilateral curettage for tibial osteomyelitis under epidural anesthesia. An anterior incision was made at the proximal end of the tibia. Bone destruction was observed at up to a depth of approximately 2 cm inside the tibial tubercle, and a large amount of purulent secretion was discharged from the anterior tibial incision. The inflammatory granulation tissue and scar tissue were removed. A small curette was used to eliminate the inflammatory granulation tissues and pus in the remaining dead space, and the removed material was placed in a sterile bag. Bone cement was used to fill in the tibial defect, and the wound surface was covered with VSD dressing and fixed on the peripheral skin. Continuous vacuum aspiration was performed to drain the wound (Figure 1). Culture of the wound drainage fluid showed no growth of mycobacteria or other bacteria after 1 week, but a small number of red acid-fast positive spheroids were detected on smear microscopy (Figure 2). Considering that the patient had a history of tuberculous bloodstream infection and had symptoms of low fever and fatigue, we initially suspected a diagnosis of tuberculous osteomyelitis. The patient was immediately administered anti- multidrug-resistant tuberculosis (MDR-TB) treatment, but the response was not good. After 21 days of culture, no M. tuberculosis growth was observed, and the Xpert MTB/RIF and T-SPOT.TB tests were negative, indicating that there was no TB infection and explaining the patient's lack of response to the anti-MDR-TB treatment. As some red acid-fast spheroids had been observed on microscopy, we now considered the possibility of infection with the L-forms of M. tuberculosis or NTM. Culture, microscopic examination, electron microscopy (Figure 3), polymerase chain reaction (PCR) assays and a reversion test (Figure 4) confirmed the presence of NTM and its L-forms. The patient was therefore treated with moxifloxacin, protionamide, linezolid, isoniazid, rifampicin, and ethambutol for 10 months, according to the results of the drug-sensitivity test. After this treatment, the wounds appeared clean, with no evidence of redness, swelling, heat, or pain. Thus, amputation of the affected legs was avoided.

hiv, bone and bone marrow infection, non-tuberculous mycobacteria

PMC8517639_01

Female

A 66-year-old woman, a retired hotel caretaker, was admitted to the Respiratory Department of the First Hospital of the China Medical University with the chief complaint of 'intermittent fever and lung occupation for 2 months'. Six months prior, the patient was diagnosed with primary nephrotic syndrome (idiopathic membranous nephropathy stage I) and chronic renal insufficiency (G5 stage). After tacrolimus administration, the patient received corticosteroid therapy (oral prednisone 50 mg once a day, 5 mg reduced every half month) combined with cyclophosphamide (1.0 g per month), and her kidney function was found to have improved since then (Figure 1C and D). Three months prior, her chest computed tomography (CT) scan showed multiple nodules in both lungs (Figure 2B), which were not observed in prior CT scans (Figure 2A). An enhanced chest CT also revealed irregular nodules around the right lung hilum with mild enhancement, right pleural effusion, and enlarged mediastinal and right hilar lymph nodes (Figure 2C). Initially, these lesions were suspected to be malignant, however, after administration of cephalosporin combined with levofloxacin intravenous for 3 weeks, including three times for bronchoscopies and tissue biopsies and one time for mediastinal lymph nodes inspected by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) were all failed to detect any malignant tissue, aside from benign pathologic changes such as chronic inflammation. To rule out the possibility of tuberculosis, relevant blood tests were performed, all of which had a negative result. Notably, the patient persistently presented with an intermittent fever during hospitalization, and her highest body temperature was reported to reach 39.8 C. As such, the patient was transferred to our department for further diagnosis and treatment, following a multidisciplinary team consultation. The patient still presented with fever without chills, and the highest body temperature reached 38 C. On physical examination, rough breath sounds were heard in both lungs. Moreover, significantly increased levels of inflammation-related indicators (WBC: 26.72x109 /L, NE: 23.14x109/L, CRP: 57.4 mg/L, PCT: 0.206 ng/L) were seen on laboratory examinations (Figure 1A and B), along with increasing levels of coagulation indicators (Fg: 6.31 g/L, D-D: 4.4 ug/mL), and slightly higher levels of serum tumour markers (CA125: 63 U/mL, CA199: 38.4 U/mL, Cyfra21-1: 3.38U/mL). After testing for penicillin allergy, intravenous piperacillin-tazobactam (2.5 g every 12 hours) was initiated, and prednisone was still used for primary nephrotic syndrome concurrently. For further diagnosis, the patient underwent endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy again, and cultures from pulmonary lesions revealed Nocardia species which was a gram-positive, partial acid-fast positive, rod-shaped bacterium (Figure 3A-C). A further species identification was subjected to MALDI-TOF MS (VITEK MS, BioMerieux), which was identified as Nocardia farcinica (99.9% confidence). Following pathological diagnosis, the patient underwent brain contrast-enhanced MRI and abdominal enhanced CT scans to exclude other foci. The brain contrast-enhanced magnetic resonance imaging (MRI) images showed mixed solid cystic lesions (Figure 4A), additional diffusion-weighted imaging (DWI) results are showed in Figure 5. Meanwhile, on whole-abdominal-enhanced CT, right abdominal encapsulated effusion and space-occupying lesions were reported (Figure 6B), which were not found in the previous inspection (Figure 6A). We administered to intravenous meropenem (1 g every 12 hours) and oral TMP-SMX (3 pieces every 8 hours, each piece containing 80 mg of trimethoprim and 400mg of sulfamethoxazole). About half month later, another brain contrast-enhanced MRI was performed, revealing the ring-like enhancement lesion was smaller than the previous one (Figure 4B), and a chest-enhanced CT scan also showed lesion size reduction (Figure 2D). Furthermore, laboratory tests revealed that infection-related indicators were all significantly lower than them before (Figure 1A and B). Since treatment was well tolerated with no adverse events, we advised the patient to continue oral TMP-SMX 3 pieces three times a day for 6 months, and to undergo regular follow-ups with blood tests and related imaging examinations. The relevant examination results are presented in Figures 1, 2E-G, 4C, 6C-E and 7. The clinical course is summarized in Figure 8.

brain abscess, disseminated nocardiosis, fever, renal insufficiency, space-occupying lesions

PMC4531972_01

Female

A 55-year-old woman with end-stage renal failure due to chronic glomerulonephritis was hospitalized for severe pain, numbness and paresthesia in both wrists, with progressive paralysis of the thenar muscles and both shoulders' pain for about 1 year. She had been on maintenance hemodialysis for 14 years at Chonnam University Hospital. Dialysis had been performed for 4 hours, 3 times weekly with hollow-fiber cuprophan dialyzers that were not reused. She had been on hemodialysis therapy since 1983 via a side to side cephalic vein-radial artery arteriovenous fistula in the left distal forearm and then, 5 years later, arteriovenous fistula in the right distal forearm due to loss of the function of the left arteriovenous fistula. Maintenance hemodialysis had been continued using this fistula. Symptoms mentioned above had been aggravated during hemodialysis and often awakened her at night. On admission, blood pressure was 90/60mmHg, body temperature 37 C, pulse rate 94/min and respiration rate was 22/min. On physical examination, she was alert, obese and a chronically ill-looking appearance. She had pale conjunctiva and anicteric sclerae. Physical examination showed positive Phalen's wrist flexion test and positive Tinel's test at the wrist with thenar muscle atrophy. Her both knee joints were markedly swelled and their motions were moderately limited. On auscultation, her heart beat was regular and no murmur was heard. Her breathing sound was clear and no abnormal sound was heard. On abdominal palpation, liver, spleen or kidneys were not palpable. Peripheral lymph nodes were also not palpable. She had not suffered from tuberculosis or diabetes mellitus, but she had a trauma history at the right knee joint and the right thumb 4 years ago. Laboratory findings were as follows: red blood cell count 2.87 x 106/mm3, white blood cell count 5.7 x 103/mm3, hematocrit 23.7%, hemoglobin 8.1 g/dL, platelet 179x 103/mm3 and the reticulocyte count 3.3%. Peripheral blood smear showed microcytic and hypochromic anemia (MCV: 80.3 fl, MCHC: 32.1%) with anisocytosis but preserved platelet and white blood cell counts. Blood chemistry studies showed serum electrolyte were normal, except for total serum calcium 8.1mg/dl and inorganic phosphate 6.6mg/dl. The AST was 65IU/I, ALT 51IU/I, alkaline phosphatase 143IU/I (liver origin 71.7%, and bone origin 28.3%), total bilirubin 0.4mg/dl, total serum protein 7.1g/dl and albumin 3.5g/dl, globulin 3.6g/dl and LDH 509IU/I. Renal function test revealed serum creatinine 8.6mg/dl, and blood urea nitrogen 44mg/dl and other laboratory tests showed that rheumatoid factor was 20IU/ml, C-reactive protein 2.8mg/dl, serum ferritin 210ng/ml, the erythrocyte sedimentation rate 78 mm/hr, serum beta2-microglobulin 60.5ug/l (normal: 1.1 to 2.7mg/ml), intact parathyroid hormone 147pg/ml, 1alpha, 25(OH)2D3 8.9pg/ml (normal: 16 to 45pg/ml) and serum osteocalcin 13.9ng/ml (normal: 4 to 12ng/ml). Radiologic examination showed bony destructive changes at right first interphalangeal joints in both hands and narrowing of joint space in right knee joint and bony destructive lesions with sclerotic border of left tibial plate, but otherwise nonspecific. Bone mineral density was examined, and the total body bone mineral density of our patient was within normal limit (1.191+-0.0 g/cm2), compared with the normal controls (control group: 1.15+- 0.10g/cm2). Whole body bone scan showed that hot spot uptake was noted in the areas of middle phalanx of right thumb, 4th and 5th left posterior ribs, left carpal bones, right distal femur and right lower sacroiliac joint. Electrocardiography showed left ventricular hypertrophy, but otherwise nonspecific. Echocardiogram showed marked concentric hypertrophy with diastolic dysfunction. Electromyographic examinations were performed in both median motor and sensory nerves: Nerve conduction studies demonstrated delayed distal latency and conduction velocity in both median motor nerves, and sensory nerves were not evoked and these findings were compatible with compression of the median nerves within the carpal tunnels (left side was more severely involved). Needle electromyography showed profusely abnormal spontaneous activities at rest and increased polyphasic Voluntary Motor Unit Action Potentials (MUAP) on minimal vibration in both abductor pollicis brevis innervated by median nerves. On 7th hospital day, abdominal fat aspiration biopsy was done, and the biopsy was negative for amyloid on Congo red staining. On 15th hospital day, she underwent an open surgical release and epineurolysis at the left carpal tunnel with an impression of carpal tunnel syndrome. At the time of the surgical release and exploration of the carpal tunnel in left hand, she had moderate thickening of the transverse carpal ligament, hyperemia of the median nerve epineurium and compression and narrowing of the median nerve. Flexor tenosynovial hypertrophy on the left wrist and degeneration of transverse carpal ligament and synovium were seen, and dilatation of proximal fragment of left median nerve was also seen. Epineurolysis of left median nerve and left synovectomy were performed. Histologic examinations of the transverse carpal ligament and epineurium of median nerve for amyloid deposition by Congo red staining, fluorescence microscopy and electronmicroscopy were performed. These tissues specimens showed multifocal amorphous pinkish deposits in the dense collagenous fibrous bundles in light microscopy, and red colored in hematoxylin and eosin, and Congo red staining (Fig. 1). The amyloid protein with Congo red staining exhibited apple-green birefringence under polarized light microscopy (Fig. 2) and electron microscopic examination showed numerous short but thick, nonbranching curvilinear fibrills aligned in parallel and aggregated in bundles (Fig. 3). After surgical release of CTS, she had dramatic relief of pain and numbness in left hand and wrist joint during dialysis at night, did well for the following 3 months.

PMC6610690_01

Male

The patient was a 63-year-old male smoker (40 pack-years). He presented with symptoms of cough, hemoptysis, fever, and weight loss for 2 months. The patient was admitted to the local hospital in 2016-03-21. The chest CT scan showed a soft tissue shadow of 2.8*3.5 cm with large patchy shadows around the upper lobe of the right lung (Fig. 1 A). A PET-CT scan revealed a mass of 2.5*3.5 cm near the right hilar and a patchy shadow of 4.9*3.3 cm in the upper lobe of the right lung. The mean FDG metabolism of the mass near the right hilar was 4.9 (the highest was 9.6). The mean FDG metabolism of the patchy shadow was 4.7 (the highest was 6.0). The CT scan-guided percutaneous biopsy in the right pulmonary apex and right upper lobe (area indicated by the white arrow in Fig. 1 A) was performed twice in 2016-03-25 and 2016-03-30, and pathology results showed chronic pneumonia and OP with local necrosis. The TBLB pathobiology in 2016-04-05 showed chronic inflammation of some bronchial mucosa in the right upper lobe. Community-acquired pneumonia was diagnosed. Cefotiam and Clindamycin were given as anti-infection therapies, and his body temperature dropped to normal, but cough and bloody sputum had not been well improved. A chest CT scan in 2016-04-11 showed that lesions in the upper lobe of the right lung had shrunk, but other lesions enlarged, and the lymph nodes in the right hilum and mediastinum were still swollen (Fig. 1 B). The patient was admitted to Zhongshan Hospital, Fudan University in 2016-05-10 for further diagnosis and treatment. Physical examination showed that he was well developed and nourished. The sounds in both lungs are clear and regular, with no abnormal changes in the heart or abdomen. Bilateral supraclavicular and cervical lymph nodes were not enlarged. Blood routine and blood biochemistry showed the following: white cell count 10.81*109/l with 65.6% granulocytes and 16.4% lymphocytes, hemoglobin 119 g/l, platelet count 246*109/l, erythrocyte sedimentation rate 73 mm/H and C reactive protein 52.2 mg/l. T-spot test: antigen-A 1, antigen-B 0. Arterial blood gas analysis showed PO2 69.0 mmHg and PCO2 40 mmHg. Tumor marker: CA125 68.3 U/ml and Cyfra211 3.7 ng/ml were slightly elevated, and other markers, such as CEA, CA199, NSE, SCC and proGRP, were all normal. Antinuclear antibody (cytoplasmic pattern) 1:100 and other autoantibody or rheumatoid factors were all negative. The pathological sections from the local hospital were rechecked by our pathology department, considering OP with eosinophil infiltration and scattered hemosiderin deposition (Fig. 2 A). Initial diagnosis of OP was made, and intravenous corticosteroid therapy was started for 2 weeks. Most symptoms disappeared, except for occasional hemoptysis. However, the follow-up chest CT scan in 2016-05-18 showed that lesions in the puncture site of the right lung were significantly reduced, but other lesions expanded, and the lymph nodes remained swollen (Fig. 1 C, D). We persuaded the patient to receive EBUS in 2016-05-20, and the examination showed slightly swollen mucosa and narrow lumen in the right upper bronchial. The lower segment of the right middle bronchial was external compressive stenosis with congestive mucosa. TBLB was performed under the guidance of ultrasound in the shadow of the posterior segment of the right upper lobe, and pathobiology showed alveolar septal fibrous tissue hyperplasia, with organizing pneumonia lesions in some areas (Fig. 2 B). TBNA from 4R mediastinal lymph nodes showed atypical cells (Fig. 2 C). The immunohistochemical results were CD1a(-), CD21(-), CD23(-), CD30(-), CD33(-), CD68(+), CKpan(++), D2-40(-), EMA(+++), Langerin(-), S-100(+), Vim(+++), CD10(+), CD15(+), CD79a(+), ALK-1(-), PAX-5(-), P63(-), SPA(-), NapsinA(+), TTF-1(+), suggesting poorly differentiated carcinoma (sarcomatoid carcinoma is more likely) which arose from the alveolar epithelium. Bronchial aspiration cultures were negative for bacteria, mycobacteria and fungi. The final diagnosis was lung cancer and secondary organizing pneumonia. The patient received one cycle of chemotherapy (gemcitabine 2.0 d1, cisplatin 120 mg d1) and then lost follow-up.

lung cancer, secondary organizing pneumonia

Pathology of lung and lymph node from March 2016 to May 2016. . (A) Pathology of CT scan-guided percutaneous lung biopsy in the apical segment of the right lung's upper lobe. HE staining of the lung biopsy showed organizing pneumonia lesions (white arrow).

PMC9376587_01

Male

An 80-year-old Chinese man who had a more than 50-year smoking history and occasionally consumed alcohol was admitted to the local hospital in October 2020 because of hoarseness, shortness of breath after activity, decreased activity endurance, and chest tightness. The patient was otherwise in good health and did not have a history of hypertension, diabetes, coronary heart disease, pneumonia, tuberculosis, or other infectious disease. In 2007, he had undergone cystectomy for bladder cancer, and a percutaneous urine bag was indwelled for a long period after the operation. The patient underwent a physical examination and a series of auxiliary examinations. Enhanced computed tomography (CT) showed a mass in the middle and lower lobes of the right lung (57 x 35 mm), which was considered central lung cancer with obstructive inflammation and segmental atelectasis, and pericardial metastasis. The pathological report of the puncture effusion smear of the lung tumor under the fiberoptic bronchoscope indicated adenocarcinoma. Therefore, the patient was diagnosed with stage IVA non-small cell lung cancer (T3N2M1), ECOG PS 2. Next-generation sequencing (NGS) targeting 1,267 genes identified a rare novel rhabdomyosarcoma 2-associated transcript (RMST)-ALK translocation (R5'UTR: A20) and an ALK-intergenic (A19: intergenic) rearrangement (Figure 1A). The immunohistochemical (IHC) results confirmed that the tumor was ALK fusion positive (Figure 1B). Besides, no EGFR mutations and ROS1 rearrangements were found. Based on the genetic test results, the patient was administered ceritinib treatment (450 mg P.0 QD) in November 2020. After treatment, his CEA declined from 13.38 to 4.2 mug/l, and his CA 125 declined from 465.7 to 54.6 U/ml (Figure 2A). Chest CT demonstrated significantly reduced hydropericardium 1.5 months later, confirming a partial response (Figure 2B). As of July 2022, the patient has retained a partial response to ceritinib treatment.

rmst-alk rearrangement, ceritinib, next-generation sequencing, non-small cell lung cancer, sensitive

PMC3915437_01

Male

A 1/5 year old boy was hospitalized for lymphadenopathy and low grade fever for 1 week. His weight was 7 kg. In physical examination, multiple lymphadenopathy in cervical and inguinal areas together with hepatosplenomegaly were diagnosed. He was the second child of non relative parents. The first child of family died because of respiratory infection at the age of 6 months old. Results of Para clinic evaluation were reported as below: WBC /9000, Hb/8/5. Plt /51000, ESR/92, CRP/Neg, LDH/normal , TG/277, uric acid /3, AST/36, ALT/14, Alp/306, Total bilirubin /0.4, Total protein/8.7 Alb/4.6, Urea/ 27, Cr/0.5, Urine analysis. Stool examination, Bone marrow aspiration and CXR were all normal. Abdominal sonography / enlarged liver and spleen with normal echo, liver biopsy/Mononuclear cell infiltration in portal tracts, in addition to expanded fibrotic spaces and mild to moderate piecemeal necrosis. Immunologic and virology assessment were requested, but his parents refused to do it, and as a result he was discharged. In an outpatient visit, in 3 months later, he improved significantly, but thrombocytopenia had been persisted. They did not return for follow up till nine months later. One year after the first visit, the boy was hospitalized again with FUO and protracted cough for 20 days. In physical examination weight was 9 kg, Height/80 cm and head circumference/ 47cm; all of them were below 3 percentile. Hepatosplenomegaly and cervical lymphadenopathy were apparent. We thought about viral infections, TB, salmonellosis, malignancy, immune deficiency and collagen vascular diseases for this patient. Para clinic data have shown as following: WBC/8000, Hb/8.4, plt/147000, ESR/97, CRP/negative, TG/353, Total protein /9.8.AST/31, ALT/26, ALP/286.Alb/3.2, Bil/0.3, LDH/838, Retic/2%, Coombs/ negative and EBV( Ig M and IgG) was found to be Positive. Abdominal sonography showed enlargement of liver and spleen but bone marrow aspiration was normal with no acid fast bacillus , PPD test / negative and lymph node biopsy showed reactive lymphadenitis , flow cytometry / CD4: 26.8,CD3: 75,CD16: 10.2,CD19: 4.5,CD56 : 9 ,CD18: 95. In ophthalmologic consultation, bilateral optic neuritis was seen, and brain MRI showed thrombosis of right transverse sinus. Echocardiography was normal, but antipospholipid antibodies were present and decreased level of protein S and factor 5 Leiden and increased level of anti thrombin III was detected. HIV antibody was reported positive in the patient and his parents. By reviewing the family history, it was apparent that the patient s father had been drug abuser from two years before. Therapy with Warfarin and Cotrimoxazole was prescribed for the patient and they were referred to the special center for further treatment.

child, hiv, signs and symptoms

PMC5369255_01

Male

A 34-year-old man with a medical history of cerebral palsy and spastic quadriparesis underwent an ITB Prometra programmable 20 ml pump (Flowonix Medical Inc., New Jersey, USA) implantation for spasticity refractory to high doses oral baclofen 2 years ago. ITB therapy resulted in a progressive improvement in patient's spasticity, functional capacity, daily activity, and social interactions, with a reduction in his previous disability. Three weeks ago, he had a routine refill procedure of the intrathecal pump programmed to deliver baclofen at a dose of 250 mug/day to control his spasticity. He was admitted suffering from a pyrexia and headache, however, he had no other symptoms. On examination, he had a temperature of 38.5 C, but was not clinically toxic. He was alert, cooperative, and obeyed commands. He had no meningism and no obvious source of infection. A chest radiograph was normal. Empirical treatment with intravenous vancomycin (500 mg/6 h) and cefotaxime (1 g/12 h) was started, however, the next day vancomycin was switched to teicoplanin (400 mg/12 h) due to a "red man syndrome" onset. Microscopy and culture of the urine and three sets of blood cultures were negative. Specimens obtained by aspiration from the residual baclofen-containing reservoir and the side port of the cerebrospinal fluid (CSF) confirmed the presence of a S. epidermidis infection with high sensitivity to above antibiotics. Other CSF parameters included an elevated protein and white blood cell count. Patient's clinical condition was such that immediate removal of the device was not considered mandatory. However, despite receiving high doses antibiotics treatment, the patient remained febrile over the next few days but still without meningism. Further aspiration and CSF culture from the access port confirmed the persistence of the S. epidermidis. As the patient was unwilling to undergo surgery to replace the pump if the present one had to be removed, an attempt was made to sterilize the pump while in situ. Therefore, consent was obtained from both the patient and his family to maintain the implanted drug delivery system and administer a baclofen/teicoplanin solution intrathecally by using the pump that was already in place. After emptying of the reservoir and the catheter from baclofen independently, the pump was aseptically refilled with a 20-ml solution prepared containing 10 mg baclofen (5 ml), 800 mg teicoplanin (6 ml), and 9 ml normal saline. This provided a final concentration of 500 mug/ml baclofen and 40 mg/ml teicoplanin. The pump was programmed to run by simple continuous infusion at a rate of 0.5 ml of solution daily, which provided 250 mug of baclofen and 20 mg of teicoplanin intrathecally every 24 hours. Although pharmaceutical data suggests that teicoplanin is stable, it was decided to empty and refill the pump every 4 days as there was a possibility that bacteria would start to grow in the solution if resistant strains developed. Five days after initiation of baclofen/teicoplanin infusion, the patient became afebrile. In CSF collected from the access port, white blood cell (WBC) and protein counts were shown to have fallen significantly. On the 11th day of intrathecal coadministration of baclofen and teicoplanin, the cultures of CSF via catheter access port and of the residual fluid in the reservoir became sterile. The intravenous administration of teicoplanin and cefotaxime were discontinued, and a regimen of 600 mg rifampin administered orally per day was initiated to augment the intrathecal teicoplanin therapy, which was continued for 9 more days. The patient was treated with oral rifampin for the next month. At the time of writing this study, our patient is still well 1 year after completion of therapy, without new clinical or laboratory signs of recurrence of infection, showing a good therapeutic reduction in his spasticity.

infection, intrathecal baclofen pump, intrathecal teicoplanin

PMC8053494_01

Male

A 53-year-old man presented to our hospital with a 4-month history of cough and polypnea for 2 months. He was a former smoker and consumed 30 cigarettes daily for 40 years, and no particular personal or family medical history was reported. Physical examination showed stable vital signs, including blood pressure of 126/86 mmHg, pulse rate of 92 beats/min, respiratory rate of 20/min, and temperature of 36.4 C. Weakened breathing sounds were detected in the right lung. Cytokeratin fragment (CYFRA) 21-1 was elevated to 4.62 ng/mL, while other laboratory parameters were unremarkable. Bacteriology of sputum was negative for tubercle bacilli. The chest CT at admission showed a 5.9cmx3.9cm-sized lobular mass in the right hilar region with an irregular margin. The contrast-enhanced CT demonstrated heterogeneous enhancement of the mass, without necrosis or cavity, but with a contiguous tracheobronchial stenosis in the right upper-middle lobe. Adenopathy in the right hilar and mediastinum region was observed. Lesions did not demonstrate any cavitary, fiber, strips, and calcified shadow changes (Figure 1). Besides, distant metastasis was not found by an enhanced head magnetic resonance imaging, an enhanced abdominal CT and a full-body bone scan. The patient underwent the TBLB in the hilar region, which showed that the mucosa in the right main bronchus swelled, and the right upper bronchial linear narrowed. When the tracheoscopy passed through the right middle bronchus, the mass in the hilar region was seen to invading the carina tracheal tube and easily to bleed when touched. Pathologic results by the TBLB revealed the mass in the right hilar region as chronic inflammation with necrosis, and the DNA fragment of Mycobacterium tuberculosis (Mtb) was found in the specimen (Figure 2). Considering that the patient had no history of tuberculosis and the CT scan showed no features of obsolete tuberculosis, the patient was diagnosed with TB. However, the CT and the TBLB findings still indicated highly possibility of coexisting lung cancer. Thus, the patient received a CT-guided percutaneous lung biopsy at the periphery of the same mass (Figure 3). The pathology showed a poorly differentiated squamous cell carcinoma (Figure 2). Thus, the final main diagnosis was squamous cell lung cancer (cT4N2M0, stage IIIB). The second diagnosis was pulmonary TB. The patient was then suggested to start anti-TB treatment and assess chemotherapy with a readmission after anti-TB therapy for more than two weeks. Meanwhile, genetic testing for lung cancer was also recommended to conduct for the further evaluation of possible targeted drug therapy. Unfortunately, the patient was discharged after diagnosed with lung squamous cell carcinoma in consideration of medical expenses and poor prognosis. No more data was collected, and the patient died 6 months later in the telephone return visit.

case report, pulmonary tuberculosis, squamous cell carcinoma

Chest CT on admission. The lung window of the left upper lobar bronchus level.

PMC8053494_01

Male

A 53-year-old man presented to our hospital with a 4-month history of cough and polypnea for 2 months. He was a former smoker and consumed 30 cigarettes daily for 40 years, and no particular personal or family medical history was reported. Physical examination showed stable vital signs, including blood pressure of 126/86 mmHg, pulse rate of 92 beats/min, respiratory rate of 20/min, and temperature of 36.4 C. Weakened breathing sounds were detected in the right lung. Cytokeratin fragment (CYFRA) 21-1 was elevated to 4.62 ng/mL, while other laboratory parameters were unremarkable. Bacteriology of sputum was negative for tubercle bacilli. The chest CT at admission showed a 5.9cmx3.9cm-sized lobular mass in the right hilar region with an irregular margin. The contrast-enhanced CT demonstrated heterogeneous enhancement of the mass, without necrosis or cavity, but with a contiguous tracheobronchial stenosis in the right upper-middle lobe. Adenopathy in the right hilar and mediastinum region was observed. Lesions did not demonstrate any cavitary, fiber, strips, and calcified shadow changes (Figure 1). Besides, distant metastasis was not found by an enhanced head magnetic resonance imaging, an enhanced abdominal CT and a full-body bone scan. The patient underwent the TBLB in the hilar region, which showed that the mucosa in the right main bronchus swelled, and the right upper bronchial linear narrowed. When the tracheoscopy passed through the right middle bronchus, the mass in the hilar region was seen to invading the carina tracheal tube and easily to bleed when touched. Pathologic results by the TBLB revealed the mass in the right hilar region as chronic inflammation with necrosis, and the DNA fragment of Mycobacterium tuberculosis (Mtb) was found in the specimen (Figure 2). Considering that the patient had no history of tuberculosis and the CT scan showed no features of obsolete tuberculosis, the patient was diagnosed with TB. However, the CT and the TBLB findings still indicated highly possibility of coexisting lung cancer. Thus, the patient received a CT-guided percutaneous lung biopsy at the periphery of the same mass (Figure 3). The pathology showed a poorly differentiated squamous cell carcinoma (Figure 2). Thus, the final main diagnosis was squamous cell lung cancer (cT4N2M0, stage IIIB). The second diagnosis was pulmonary TB. The patient was then suggested to start anti-TB treatment and assess chemotherapy with a readmission after anti-TB therapy for more than two weeks. Meanwhile, genetic testing for lung cancer was also recommended to conduct for the further evaluation of possible targeted drug therapy. Unfortunately, the patient was discharged after diagnosed with lung squamous cell carcinoma in consideration of medical expenses and poor prognosis. No more data was collected, and the patient died 6 months later in the telephone return visit.

case report, pulmonary tuberculosis, squamous cell carcinoma

Chest CT on admission. The white arrow indicated the lobular mass with heterogeneous enhancement on mediastinal window in the right hilar region (B).

PMC8053494_01

Male

A 53-year-old man presented to our hospital with a 4-month history of cough and polypnea for 2 months. He was a former smoker and consumed 30 cigarettes daily for 40 years, and no particular personal or family medical history was reported. Physical examination showed stable vital signs, including blood pressure of 126/86 mmHg, pulse rate of 92 beats/min, respiratory rate of 20/min, and temperature of 36.4 C. Weakened breathing sounds were detected in the right lung. Cytokeratin fragment (CYFRA) 21-1 was elevated to 4.62 ng/mL, while other laboratory parameters were unremarkable. Bacteriology of sputum was negative for tubercle bacilli. The chest CT at admission showed a 5.9cmx3.9cm-sized lobular mass in the right hilar region with an irregular margin. The contrast-enhanced CT demonstrated heterogeneous enhancement of the mass, without necrosis or cavity, but with a contiguous tracheobronchial stenosis in the right upper-middle lobe. Adenopathy in the right hilar and mediastinum region was observed. Lesions did not demonstrate any cavitary, fiber, strips, and calcified shadow changes (Figure 1). Besides, distant metastasis was not found by an enhanced head magnetic resonance imaging, an enhanced abdominal CT and a full-body bone scan. The patient underwent the TBLB in the hilar region, which showed that the mucosa in the right main bronchus swelled, and the right upper bronchial linear narrowed. When the tracheoscopy passed through the right middle bronchus, the mass in the hilar region was seen to invading the carina tracheal tube and easily to bleed when touched. Pathologic results by the TBLB revealed the mass in the right hilar region as chronic inflammation with necrosis, and the DNA fragment of Mycobacterium tuberculosis (Mtb) was found in the specimen (Figure 2). Considering that the patient had no history of tuberculosis and the CT scan showed no features of obsolete tuberculosis, the patient was diagnosed with TB. However, the CT and the TBLB findings still indicated highly possibility of coexisting lung cancer. Thus, the patient received a CT-guided percutaneous lung biopsy at the periphery of the same mass (Figure 3). The pathology showed a poorly differentiated squamous cell carcinoma (Figure 2). Thus, the final main diagnosis was squamous cell lung cancer (cT4N2M0, stage IIIB). The second diagnosis was pulmonary TB. The patient was then suggested to start anti-TB treatment and assess chemotherapy with a readmission after anti-TB therapy for more than two weeks. Meanwhile, genetic testing for lung cancer was also recommended to conduct for the further evaluation of possible targeted drug therapy. Unfortunately, the patient was discharged after diagnosed with lung squamous cell carcinoma in consideration of medical expenses and poor prognosis. No more data was collected, and the patient died 6 months later in the telephone return visit.

case report, pulmonary tuberculosis, squamous cell carcinoma

Chest CT on admission. , the left lung basal trunk bronchus level.

PMC8053494_01

Male

A 53-year-old man presented to our hospital with a 4-month history of cough and polypnea for 2 months. He was a former smoker and consumed 30 cigarettes daily for 40 years, and no particular personal or family medical history was reported. Physical examination showed stable vital signs, including blood pressure of 126/86 mmHg, pulse rate of 92 beats/min, respiratory rate of 20/min, and temperature of 36.4 C. Weakened breathing sounds were detected in the right lung. Cytokeratin fragment (CYFRA) 21-1 was elevated to 4.62 ng/mL, while other laboratory parameters were unremarkable. Bacteriology of sputum was negative for tubercle bacilli. The chest CT at admission showed a 5.9cmx3.9cm-sized lobular mass in the right hilar region with an irregular margin. The contrast-enhanced CT demonstrated heterogeneous enhancement of the mass, without necrosis or cavity, but with a contiguous tracheobronchial stenosis in the right upper-middle lobe. Adenopathy in the right hilar and mediastinum region was observed. Lesions did not demonstrate any cavitary, fiber, strips, and calcified shadow changes (Figure 1). Besides, distant metastasis was not found by an enhanced head magnetic resonance imaging, an enhanced abdominal CT and a full-body bone scan. The patient underwent the TBLB in the hilar region, which showed that the mucosa in the right main bronchus swelled, and the right upper bronchial linear narrowed. When the tracheoscopy passed through the right middle bronchus, the mass in the hilar region was seen to invading the carina tracheal tube and easily to bleed when touched. Pathologic results by the TBLB revealed the mass in the right hilar region as chronic inflammation with necrosis, and the DNA fragment of Mycobacterium tuberculosis (Mtb) was found in the specimen (Figure 2). Considering that the patient had no history of tuberculosis and the CT scan showed no features of obsolete tuberculosis, the patient was diagnosed with TB. However, the CT and the TBLB findings still indicated highly possibility of coexisting lung cancer. Thus, the patient received a CT-guided percutaneous lung biopsy at the periphery of the same mass (Figure 3). The pathology showed a poorly differentiated squamous cell carcinoma (Figure 2). Thus, the final main diagnosis was squamous cell lung cancer (cT4N2M0, stage IIIB). The second diagnosis was pulmonary TB. The patient was then suggested to start anti-TB treatment and assess chemotherapy with a readmission after anti-TB therapy for more than two weeks. Meanwhile, genetic testing for lung cancer was also recommended to conduct for the further evaluation of possible targeted drug therapy. Unfortunately, the patient was discharged after diagnosed with lung squamous cell carcinoma in consideration of medical expenses and poor prognosis. No more data was collected, and the patient died 6 months later in the telephone return visit.

case report, pulmonary tuberculosis, squamous cell carcinoma

CT-guided percutaneous lung biopsy. The second specimen was obtained at the peripheral site of the mass.

PMC2631494_01

Male

A 91-year-old Caucasian male farmer presented at the Mayo Clinic, Rochester, Minnesota for evaluation of the acute complaint, "My feet aren't working." Specifically, he reported difficulty with balance leading to inability to walk, and extensive, painful bilateral ecchymoses of his heels (Figures 1 and 2). His distress and instability were alleviated only modestly by the use of a non-prescription cane. Barefoot ambulation was impossible. Barely functional ambulation was accomplished by wearing hard-soled shoes. One month prior, the patient had been diagnosed with bronchitis at an outside clinic and was treated with a seven-day course of levofloxacin 500 mg by mouth, taken once a day (his estimated creatinine clearance was 32 mL/min using the Cockcroft-Gault equation). His bilateral heel pain developed insidiously over the first four days of fluoroquinolone treatment. Even at 91, the patient had led an active lifestyle on his farm. He cooked all of his own meals, drove a tractor, and performed many other physical farm chores. On day seven of treatment, upon dismounting his tractor, he noticed sudden, severe pain in both of his heels and a compromised ability to ambulate independently. The patient's medical history was otherwise notable for a mitral valve replacement with porcine xenograft 25 years prior, chronic hypertension, hyperlipidemia, degenerative spondylosis, depression and gastroesophageal reflux disease (GERD). He had no history of tendinopathy. The patient had never smoked, and had no exposure to second-hand smoke. He reported alcohol ingestion of two beers per month and caffeine consumption of three 8 oz cups of coffee per day. In addition to the levofloxacin, the patient was on the following medications, with no recent changes: metoprolol ER 100 mg/d, isosorbide mononitrate ER 60 mg/d, hydrochlorothiazide/triamterene 25 mg/37.5 mg/d, spironolactone/hydrochlorothiazide 25 mg/25 mg/d, quinapril 20 mg/d, celecoxib 200 mg/d, glucosamine 1500 mg/d, sertraline 100 mg/d, omeprazole 20 mg/d, and acetaminophen 1000 mg every six hours as needed for arthritis-related pain. He had no known food or medication allergies. On presentation to the hospital, the patient was afebrile and all vital signs were stable. Both heels were mildly edematous with overlying ecchymoses and were tender to palpation bilaterally. The patient had a palpable gap and mass-like defect distally with palpation along the left Achilles tendon. There was a similar gap, although no palpable mass defect, on the right. Dorsalis pedis and posterior tibial pulses were 2+ bilaterally, and capillary refill was less than two seconds in the great toes bilaterally. Thompson's test (also known as Simmond's sign) was abnormal bilaterally, with no movement of either foot. The patient could barely raise himself up on his tiptoes. In both lower extremities, ankle plantar flexion strength was 3/5, great toe flexion to test the flexor hallucis longus was 5/5, and ankle dorsiflexion to test the extensor hallucis longus was 5/5. The patient maintained full active and passive knee range of motion bilaterally. He demonstrated antalgic gait with significant difficulty in the toe-off (propulsion) phases bilaterally. Radiographs of the lower extremities noted soft-tissue edema of the ankles. There were no noted bony abnormalities. The patient was initially admitted to the hospital for in-patient care and placed on non-weightbearing status. Magnetic resonance imaging (MRI) of the ankles noted complete rupture of both Achilles tendons approximately 6 cm proximal from insertion upon the calcaneus, with the two ends approximately 3 cm apart on the left and 2 cm apart on the right. The patient was fitted with gravity equinus casts with heel extensions to keep the feet in plantar flexion. He was discharged from the hospital one day after admission. Five weeks after hospital admission, the patient's casts were removed and he was fitted with controlled ankle motion (CAM) boots that were in plantar flexion at 15 degrees with resultant full equinus. Nine weeks after hospitalization, the patient was instructed to stop wearing the CAM boots and began wearing his own tennis shoes with three-quarter inch heel lifts to maintain relative plantar flexion. At his initial presentation to the outpatient care center on the day of admission, the patient's primary care physician noted, "History of depression and anxiety: He is not anxious and depression is currently not a problem. He looks much brighter." However, at the meeting with his orthopedic surgeon nine weeks after hospital discharge, both the patient and family members noted decreased energy levels and general lack of enthusiasm. There was concern that these symptoms were fueled by his immobility. Ten weeks after diagnosis, the patient presented to the Emergency Department with a 22-pound weight loss over the prior two months as well as generalized lethargy. He was hospitalized for evaluation where he was hydrated and his antihypertensive regimen was modified (quinapril, spironolactone, and hydrochlorothiazide were discontinued). He was discharged with blood pressures well within the normal range and with close follow-up with his primary care physician. The patient was readmitted for inpatient care the following day with hospital-acquired pneumonia. He subsequently developed kidney failure, sepsis, heart failure, and a myocardial infarction. After consultation with the patient and his family, care was withdrawn and comfort care measures were initiated until the patient passed away 11 weeks after the initial diagnosis of bilateral complete Achilles tendon rupture.

PMC5750492_01

Female

In the last five years of our clinical and surgical activity 3800 cesarean deliveries (CS) have been performed and in 57 cases (1.5%) cesarean deliveries followed a laparoscopic myomectomy. We report the only two cases (3.5%) of uterine rupture that occurred among these 57 CS following laparoscopic myomectomy. The first case was a 31-year-old woman para 0/0/1/0 hospitalized for abdominal pain of sudden onset in the 34th week of gestation. She had undergone laparoscopic multiple myomectomy 2 years earlier, when different types of myoma were excised: one intramural- (IM-) G4 myoma of the posterior wall of the uterus with a mean diameter (diam.) of 5 cm, one IM-G5 left isthmic myoma (diam. 3 cm), one IM-G4 on the fundus (diam. 3 cm), one subserosal- (SS-) G6 of the right wall (diam. 2 cm), and two IM-G4 of the anterior wall of the uterus (diam. 2 cm each one). At the first clinical examination, the findings were deep abdominal pain, dysuria, and a positive Giordano's sign on the right. Her blood pressure was 132/66 mmHg and heart rate 77 beats/min. She was afebrile and not pale. The fetus was alive at cardiotocographic evaluation. There were no palpable uterine contractions, although the patient was groaning with pain. The cervix was closed and there was no evidence of vaginal bleeding. We performed transabdominal 2D ultrasound that showed an alive intrauterine podalic fetus with normal Doppler flowmetry, oligohydramnios, and minimal intraperitoneal fluid; the patient complained of increasing pain on the left side of the abdomen, where ultrasound revealed the presence of a vascularised area whose venous and arterial flow seemed to be in continuity with the umbilical cord and had the same ultrasound characteristics (Figure 1(a)). This vascularised area was located outside the left wall of the uterus and was likely an early sign of uterine rupture (Figure 1(b)). The breach seemed to be 2 cm long on the left wall of the uterus, at the level of one of the previous laparoscopic myomectomy wounds. Continuous cardiotocographic assessment showed a normal fetal heartbeat and the absence of uterine contractions, but the patient continued to complain of abdominal discomfort and started vomiting. An emergency laparotomy was performed. Surgical findings included a breach running horizontally through the entire anterior wall of the uterus (Figure 1(c)), a moderate quantity of hemoperitoneum, while the fetus had turned so that the left shoulder was facing the abdominal cavity. The baby was delivered alive with the placenta, and no emergency procedure was required. The tear was repaired and the hemoperitoneum drained. The patient made satisfactory clinical progress and was discharged home with a healthy baby on the fifth postoperative day; neonatal follow-up was regular.