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PMC3420747_01

Male

A 50-year-old man was admitted with progressive right-sided hemiparesis and aphasia of 5 days duration. The patient was a diabetic for the last 4 years on oral hypoglycemic drug with good glycemic control. His symptom started as painful ophthalmoplegia in January 2008. He had involvement of 3rd, 4th, and 6th nerve on the left eye and 3rd and 4th nerve on the right eye. His visual acuity was 6/60 in the left eye and 6/36 in the right. Optic fundi were normal. Pupils were normal. Sensory loss was noted over left maxillary nerve distribution. MRI of brain demonstrated (Figure 1) an enhancing lesion in the cavernous sinus bilaterally with sphenoid sinus fullness. Sphenoid mucosal biopsy demonstrated inflammatory tissue with aggregate of lymphoid cell. Patient received a course of oral steroid (prednisolone 40 mg) for 5 days and was lost at followup. In September 2008, he was admitted in another center with severe chemosis and proptosis of right eye and reappearance of diplopia. Examination showed partial 3rd and 6th nerve palsy on the right eye. The left eye was normal. MRI of brain and orbital area showed proptosis of right globe. There was enlargement of the right superior and the lateral recti from the retrobulbar region up to the orbital apex (Figure 2). Lesion appears hypointense on T1 and hyperintense on T2 WI and FLAIR. On contrast scan, there is intense enhancement of the lesion, extending from the orbit through the superior orbital fissure into anterior cavernous sinus. In the left orbit, the medial rectus showed mild enlargement with contrast enhancement. Patient received oral steroid (prednisolone 40 mg) for 1 week with substantial improvement of his chemosis, proptosis, and diplopia. In February 2009, the patient readmitted in our neurology department because of progressive right-sided hemiparesis, aphasia, and headache. There was no proptosis, visual symptom, squint, or extraocular paresis. MRI, brain showed (Figure 3) intensely enhancing extra-axial mass lesion extending from the left cavernous area compressing and invading the left anterior temporal lobe. An area of hemorrhage was noted in the periphery of lesion. There was significant perilesional edema. The lateral ventricle is compressed with midline shift to the right. Orbital globe, intraorbital muscle are normal. Laboratory workup showed normal hemogram and erythrocyte sedimentation rate. His serum bilirubin, urea, creatinine, and glucose levels were respectively 0.8 mg/dL (normal: 0.3-1.3 mg/dL), 24 mg/dL (normal: 10-50 mg/dL, 0.8 mg/dL (normal: 0.3-1.4 mg/dL), and 100 mg/dL (normal: 90-110 mg/dL). Peripheral smear was normal. Thyroid profile and serum cortisol were within normal limits. VDRL was nonreactive. HIV serology, HBsAg, and HCVAb in the blood were negative. Immunological tests (rheumatoid factor, antinuclear antibodies, cANCA, pANCA, SSA, SSB antibodies, and angiotensin-converting enzyme) were normal. Examination of the cerebrospinal fluid revealed 4 lymphocytes, Sugar: 56, and protein: 35 mg, and polymerase chain reaction for tuberculosis was negative. Biopsy specimens from left anterior temporal and extratemporal mass lesion showed aggregates of mature lymphocyte infiltration with occasional macrophage. There were no abnormal cell and histiocyte. Immunohistochemical staining for CD3 and CD20 showed that the lymphocytes were positive for both CD3 and CD20 (Figure 4). Fungal, AFB stains, and culture of biopsy were negative. Histopathology was consistent with IPT. As the patient did not receive a full course of steroid at any time during his illness, the patient was started on high-dose parenteral steroid (Dexamethasone, 12 mg/d). After 1 week, it was changed to oral prednisone (1 mg/kg) for the next one month and then gradually tapered over next 3 months. His glycemic status was controlled with insulin. There was rapid improvement of the symptoms within the first week of treatment. A follow-up MRI study, 1 month later, showed almost complete reduction of the lesion with mild dilatation of the left temporal horn (Figure 5). He was asymptomatic on the last followup after one year.

PMC9679023_01

Male

Case 1: A 26-year-old male sustained an injury to his left knee while fishing. He experienced a twisting of his knee, while a varus impaction force was applied to the slightly flexed knee. He visited the outpatient department of other hospital and was treated with conservative treatment. After 1 year, he had left knee sprain again, accompanied by severe knee joint pain and swelling. Case 2: A 36-year-old female suffered discontinuous pain in left knee that continued for at least 16 years. There was no history of obvious trauma. She had frequent knee joint pain and motion restriction in the past 1 month before hospitalisation. Case 3: A 47-year-old male fell while running 14 years ago. The right knee joint pain was worse with activity and decreased with rest. At that time, he was not receiving any examination or therapy. The right knee joint pain was aggravated in recent months before hospitalisation. Case 4: A 37-year-old male fell while running. After that, he suffered from persistent left joint pain. He could not walk up or down stairs and the quality of his life was seriously influenced. All these four patients were diagnosed as knee joint cartilage defect after physical and MR examination during hospitalization. Demographic information (sex, age, height, weight), medical and previous history, and cartilage defect characteristics of these patients (length, width, depth, shape, localization) were documented (Supplementary Table S1). Surgical treatments were performed for patients. The standard procedure involved two steps. The first step was knee arthroscopy in which healthy cartilage tissue was removed from the intercondylar fossa (non-weightbearing areas) and the characteristics of the cartilage defect (length, width, depth, shape, localization) were checked. The healthy removed cartilage tissue was stored in Dulbecco's modified Eagle's medium (DMEM, Absin, Shanghai, China) at 4 C and sent immediately to the laboratory for cell cultivation. Chondrocytes were isolated enzymatically after digestion by 1% collagenase II (Absin, Shanghai, China) at 37 C for 4 h. Then, they were expanded using culture conditions for autologous cells. DMEM was supplemented with 10% autologous serum (separated from peripheral blood), L-glutamine, and antibiotics (penicillin and streptomycin). Cells were cultured at 37 C in an atmosphere of 5% CO2 and 95% relative humidity. The medium was removed, and a fresh medium was added every three days. A maximum of two passages were undertaken for each culture. The cartilage used for fabrication of acellular cartilage sheets was harvested from the ears of adult pigs. First, the cartilage was cut into a cylindrical shape with a diameters of 2 cm. Then, the cylindrical cartilage was cut into sheets (using a freezing microtome) of thickness 10-mum. The sheets were decellularized in 1% sodium dodecyl sulfate (SDS, Coolaber, Beijing, China) for 24 h. After decellularization, the sheets were rinsed thrice in sterile water. A vacuum freeze-drier was used for lyophilization of the sheets. The diameter of sheets was narrowed to be about 1.8 cm. An acellular cartilage sheet was placed in a culture dish, and 5-mul of the chondrocyte suspension was seeded on it. The concentrations of chondrocyte suspension was 20 x 106 cells/ml. Then, another acellular cartilage sheet was superposed on the first acellular cartilage sheet with 5-mul of the chondrocyte suspension seeded on the surface. These procedures were continued until ten sheets were stacked together. The construct was cultured at 37 C in an atmosphere of 5% CO2 and 95% relative humidity for 4 weeks. After that, the implantation was carried out. Figure 1 provides a brief summary of the construction process of implantation patch. The implantation patch was about 2 cm x 0.4 cm respectively in diameter and thickness. All constructions made by the same method in order to acquire similar sizes of implantation patches. The second step was composed of mini-arthrotomy, curettage, and implantation. During this step (Figure 2), the unhealthy cartilage and subchondral bone plate were cleaned carefully to ensure blood exudation was absent and to leave the base smooth. The patch was placed in physiologic (0.9%) saline <5 min before transplantation. It was trimmed carefully to fit the defect exactly before placed onto the defect. Then, fibrin glue was applied to the surface to fix the patch to the defect without suturing. If a subchondral cystic defect occurred, then debridement was done. A contralateral autogenous posterior iliac bone graft was made, and the bone graft was transplanted into the subchondral defect. Patients accepted routine rehabilitation after arthroscopy. Postoperative rehabilitation after the second step was far more critical. Initially, the patients accepted fixation using a locking hinged knee brace, and the knee was placed in extension for 2-3 days. The purpose was to prevent the patch from dislodging and allow stable adhesion between the patch and subchondral plate. After that, active and passive motions were allowed. First, non-weightbearing quadricep-strengthening exercises on a bed were recommended to patients. Then, a device to ensure continuous passive motion was used for 90-135 min daily until discharge from the hospital. The range of motion (RoM) was from 0 to 30 initially, and the upper-limit RoM was increased 5 per day until 90 (~2 weeks). Afterward, the full RoM was allowed if patients did not feel pain. Partial-weightbearing with a walking aid within 6 weeks was allowed, after which full-weightbearing was allowed. The preoperative and postoperative knee function was evaluated by four subjective evaluation systems: International Knee Documentation Committee Subjective Knee Evaluation Form (IKDC-SKEF); Lysholm Scale; Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); Knee Injury and Osteoarthritis Outcome Score (KOOS). These systems have been demonstrated to be effective and sensitive for evaluation of the repair of articular cartilage and have been used widely for evaluation of outcomes after ACI. MR examination of the operated knee joint was undertaken on a 3.0-T MR scanner (Ingenia 3.0-T CX, Philips Healthcare, Best, the Netherlands) using a sixteen-channel phased-array coil. The quality of repaired tissue was evaluated by Magnetic Resonance Observation of Cartilage Repair Tissue (MOCART). It is a classification system established by Marlovits et al. in 2004 to analyze repaired tissue. Studies have indicated a correlation between the clinical outcome and MOCART score. Some researchers consider it to be a reliable way to evaluate repaired tissue. Overall, the patients were all satisfied with the surgical treatments. All patients showed improvements on all clinical outcomes over the time (Figures 3A,B). As an exception, the scores of one patient were lower than those of other patients in IKDC-SKEF, Lysholm Scale, and KOOS. Accordingly, WOMAC scores were higher. His postoperative WOMAC score at 18-month was higher than that at 12-month, and was similar to the score at 6-month. He complained of knee joint pain after walking for a long time or recreational activities. The MOCART scores increased gradually after procedure (Figure 3C) for all patients. The MR images of patients are shown in Figure 4. As can be seen, the defect area decreased postoperatively, and the signal intensity of the repaired cartilage was close to that of healthy cartilage 12-month postoperatively. There was virtually no sclerosis of subchondral bone or edema 18-month postoperatively.

aci, maci, autologous chondrocyte patch implantation, cartilage defect, cartilage repair, sandwich technique

PMC3660131_01

Female

A previously healthy 40-year-old right-handed female presented with new onset complex partial seizures and occasional secondary generalization. Over the next 5 years, she rapidly became refractory to medical treatment with seizure frequency increasing to almost daily despite attempts to control seizures with multiple anti-epileptic drugs. The patient failed initial monotherapy with valproic acid and progressed to require polytherapy with carbamazepine 600 mg twice a day (BID), lamotrigine 150 mg BID, clobazam 10 mg BID and levetiracetam 1000 mg BID (which was discontinued when the behavioral issues came to light) and yet did not achieve adequate seizure control. Over this same period, the patient developed increasing emotional lability, outbursts of anger and escalating violent behavior coinciding with seizure onset and which was especially worse postictally, lasting 5 to 10 minutes. These explosive episodes led to numerous altercations with police, resulting in multiple arrests for violent behavior. The patient was convicted a total of 32 times prior to the murder for various minor offences and violent incidents, the majority of these occurring in the last 4 years when the patient developed intractable epilepsy. The patient's past medical history was otherwise only remarkable for chronic alcoholism and depression. Although it was offered, the patient repeatedly refused psychiatric evaluation during her disease evolution and was intermittently treated by her family physician for depression with venlafaxine and citalopram. The patient's neurological exam was normal. She presented with two types of seizures. The most common were complex partial seizures characterized by lack of aura, staring, bimanual and oral automatisms and postictal confusion. The patient was able to talk during some of these seizures. The frequency of these complex partial seizures varied but was on average six per month, with one cluster per month. The patient also had complex partial seizures with secondary generalization (one per month). Several interictal electroencephalograms (EEGs) showed right temporal spikes. Video-EEG telemetry was performed and 6 seizures were recorded; all of them had clear onset over the right temporal region at F8-T4 with involvement of the ipsilateral scalp sphenoidal electrode. One pseudo seizure was also recorded. The magnetic resonance imaging (MRI) was reported as normal. At this point, the patient was offered a right temporal lobe resection. After discussion with her family, she declined the procedure. Six months after the video-EEG telemetry investigation was performed, the patient had a disagreement with her basement tenant. During this dispute, the patient stabbed her friend several times, killing her. Thus, the patient was arrested and charged with second-degree murder. Unfortunately, the patient is amnestic of the event and there were no other witnesses, so both the duration of the aggressive episode and whether it was preceded by seizure are unknown. While in jail, the patient and her family wished to revisit the possibility of neurosurgery. At age 46, the patient underwent a standard right temporal lobectomy, twelve months after the video-EEG telemetry investigation. The patient remained in hospital for two weeks post-operatively and was then transferred back to prison. After six months in a maximum security facility, she was transferred to a psychiatric center due to the noted positive behavior change. At two years post-surgical follow up, the patient reported no seizure activity and was on monotherapy with carbamazepine 400 mg BID. The patient's behavior improved dramatically after the temporal resection with no evidence of emotional lability or aggressive outbursts since. This patient was administered a standard battery of neuropsychological tests, assessing the domains of attention, working memory, language, learning and memory and psychological/emotional functioning, on two separate occasions. Her first neuropsychological assessment occurred about 22 months prior to neurosurgery and indicated significantly compromised cognitive functioning, with difficulties most evident on tasks assessing verbal comprehension, working memory and learning of novel material, particularly if the material was visual in nature. She still demonstrated good reasoning and problem solving skills, and adequate learning if provided with an opportunity to first deal with hands-on material. She was also experiencing significant levels of psychological distress due to the limitations imposed by her seizure disorder. The second neuropsychological assessment was undertaken about 15 months post neurosurgery and indicated that this patient was no longer psychologically distressed as she was no longer experiencing seizures. However, her neuropsychological profile indicated that she had experienced further global decline in cognitive functioning with marked impairment and limited function. This decline was attributed to the longstanding history of epilepsy, but could also be partially due to the resection.

aggression, crime, epilepsy surgery, murder, temporal lobectomy

PMC9868302_01

Male

A 47-year-old man was admitted to our ID unit in February 2022 for fever, dyspnea, and confusion. He had a history of mantle cell non-Hodgkin lymphoma, treated with autologous hematopoietic stem-cell transplantation in July 2019, on maintenance therapy with rituximab every 6 months (last administration of rituximab in December 2021). The patient was vaccinated against SARS-CoV-2 with two doses of mRNA vaccine (the last dose in April 2021). In January 2022 he had mild COVID-19 not requiring hospitalization, with spontaneous resolution of symptoms and with consecutive negative molecular NP swabs. At the beginning of February, he developed fever (maximum 39 C), accompanied after 4 days by the onset of dry cough. This event was interpreted as a bacterial lower respiratory tract infection, and the patient was treated at home with empirical oral antibiotic therapy (no corticosteroids were used), without resolution of symptoms. Due to worsening conditions, with spikes of high fever, sweating, persistence of dry cough, and confusion, he was admitted to our ID unit. Blood tests were performed at hospital admission (Day 0): white blood cell 2,640/mul (range 4,500-9,800), neutrophils 2.130/mul (range 1,800-7,800), creatinine 1.2 mg/dl (range 0.67-1.17), mild elevation of liver enzymes (ALT/AST 50/61 UI/ml, range 0-40, 0-40, respectively), lactate dehydrogenase 444U/L (range 135-225), ferritin 1,972 mcg/L (range 30-400), C reactive protein 89.4 mg/L (range 0-3), Interleukin-6 46.5 ng/L (normal value, n.v., <3.4). SARS-CoV-2 serology resulted non-reactive: IgG anti Receptor-Binding Domain (RBD) < 1 U/ml < 12 negative), IgG anti Spike 1 (S1) < 1 U/ml (<21 negative), IgG anti Spike 2 (S2) < 1 U/ml (<9 negative), IgG anti Nucleocapsid < 1 U/ml (<23 negative). Rapid antigenic test and molecular test for SARS-CoV-2 performed on NP swabs were negative on Day 1. Computed tomography (CT) scan performed on Day 1 showed extensive bilateral ground-glass opacities with crazy-paving aspects and more consolidated components, greater at lower lobes in subpleural location (Figure 1A). Given the radiological evidence of pneumonia in a suspected bacterial infection after the recent SARS-CoV2 infection, a bronchoalveolar lavage (BAL) was performed. Empirical antibiotic therapy with ceftobiprole and levofloxacin was started. On day 7, due to the worsening clinical conditions, with fever up to 40.5 C and need for supplemental oxygen, he underwent a second CT scan, showing the extension of pulmonary opacities at the left basal lobe compared to the previous imaging (Figure 1B). The antibiotic therapy was changed to ceftolozane/tazobactam plus linezolid. The same day a RT-PCR on BAL resulted positive for SARS-CoV-2, showing no other concomitant bacterial/fungal/viral infections (culture tests for common bacteria - Aspergillus spp. - M. tuberculosis, M. tuberculosis DNA, Pneumocystis jirovecii DNA, serum beta-D-glucan, BAL galactomannan, BAL CMV-DNA, all tested negative). Blood testing for SARS-CoV-2 RNAemia was performed as well on day 7 and resulted positive. In consideration of worsening bilateral pneumonia in an immunocompromised hematological patient with COVID-19 and no other clear alternative diagnoses for pneumonia, an off-label combination of sotrovimab 500 mg in a single infusion, a seven-day course of IV remdesivir (200 mg of loading dose, 100 mg of maintenance dose) plus a five-day course of oral nirmatrelvir/ritonavir 300 mg/100 mg q12h and intravenous (IV) corticosteroids was then started on day 7. The patient signed the informed consent for off-label treatment. Sotrovimab was chosen over casirivimab/imdevimab due to the prevalence of variant of concern Omicron BA.1 at that time in Italy, on which the latter has reduced efficacy. Adjunctive anti-inflammatory treatment (i.e., IL-6 or IL-1 receptor inhibitors) were not deemed necessary considering the presence of SARS-CoV-2 positive RNAemia and the absence of SARS-CoV-2-related inflammatory pattern. No adverse effects were observed during the course of treatment. From day 9 the patient remained afebrile, with clinical improvement and consequent reduction in oxygen demand on day 10, until complete weaning to room air on day 13. On day 12 SARS-CoV-2 RNAemia resulted negative, as well as RT-PCR on NP swab. A follow up PET scan for the non-Hodgkin lymphoma was performed, showing uptake exclusively at the level of the ground-glass pulmonary thickening, suggesting local inflammatory signs of infection and thus ruling out any sign of progression of his hematological disease. In consideration of the improved conditions and of the reduction of inflammatory parameters, the patient was discharged on day 17.

covid-19, immunocompromised, monoclonal antibodies, nirmatrelvir/ritonavir, remdesivir, salvage therapy, sotrovimab

PMC7712452_01

Female

The patient was a 27-year-old Chinese woman who was a laboratory doctor in a hospital involved in the treatment of sputum samples from patients with TB. The patient had never received immunosuppressive treatment, was serologically negative for HIV and hepatitis, and had no family history of TB. She was admitted to a hospital following a 7-day history of hoarseness without fever, cough, expectoration, emaciation, sweating, sore throat, or other non-specific symptoms such as anorexia, fatigue, and muscle aches. The patient's chest computed tomography (CT) and routine blood chemistry results, erythrocyte sedimentation rate (ESR), and tumour markers were all normal. The results of the acid-fast stain test of sputum smear and mycobacterial identification on throat secretion by the polymerase chain reaction (PCR) were all negative. The laryngoscopy revealed laryngeal mucosa hyperaemia and milky hyperplastic lesion in the bilateral vocal cords (Figure 1a). Histological analysis of the biopsy specimen from the vocal cords revealed granulomas with inflammatory cell infiltration in the squamous epithelium and interstitial tissue (Figure 2a) and negative results of periodic acid-Schiff stain (PAS), acid-fast stain (Figure 2b), and Gomori methenamine silver stain (GMS). We cut the biopsy vocal cords directly, digested the homogenised tissues with proteinase K, and prepared template deoxyribonucleic acid (DNA) for PCR amplification. The mycobacteria gene chips (Mycobacteria Identification Array Kit and Tuberculosis Drug Resistance Detection Array Kit, CapitalBio Corp., China) were used to identify the bacteria and resistance genes. The results showed that MTB was positive (Figure 3a), and the detection of resistance genes indicated that rifampin and isoniazid had a wild-type genotype (Figure 3b and c). Consequently, the patient was diagnosed with laryngeal TB and was treated with an antibiotic regimen combining rifampicin (10 mg/kg/day), isoniazid (5 mg/kg/day), pyrazinamide (30 mg/kg/day), and ethambutol (20 mg/kg/day) for 3 months and subsequently rifampicin (10 mg/kg/day), isoniazid (5 mg/kg/day), and ethambutol (20 mg/kg/day) for 9 months. After 1 year of well-tolerated treatment, the patient recovered, and the hyperplastic lesion in the vocal cords completely disappeared under laryngoscopy (Figure 1b). The authors received research approval from Institutional Medical Ethic Review Board. Informed consent was obtained from the patient included in this study.

gene chips, laryngeal tuberculosis, mycobacterial identification

PMC7673426_01

Female

A 14-year-old Filipina girl of Chinese descent was referred to our hospital due to severe dermatitis with warty lesions. The patient was born to a 34-year-old primigravida, and the mother and the father are first-degree cousins, hence she was born from a consanguineous union (Supplementary Figure 1). Her younger brother who had severe molluscum infection died of brain abscess at 5 years old. She presented with dry erythematous skin and pruritic scales from 3rd day of life, and was diagnosed with atopic dermatitis. At 5 years old, the skin continued to be thickened and lichenified over the entire body. This was associated with food allergy to egg, milk, peanut, chocolate, shellfish, and fish. The patient developed pulmonary tuberculosis, which was successfully treated with quadruple anti-Koch's therapy including isoniazid, rifampicin, pyrazinamide, and ethambutol for 6 months. At 7 years old, the patient developed multiple furuncles, with abscesses, impetigo, and cellulitis. Administration of antibiotics improved the symptoms; however, she developed multiple skin-colored papulonodular skin lesions with central umbilication on the entire skin (Supplementary Figure 2A). She was diagnosed with systemic molluscum contagiosum. Within 1 year of follow-up, the patient showed persistent atopic dermatitis, and developed opacification of the left eye, accompanied by dimming of her vision (Supplementary Figure 2B). Yellowish purulent discharges were noted from both eyes. Her condition was complicated by severe atopic dermatitis, persistent allergic rhinitis, asthma, suspected multiple food and drug allergies, recurrent sinopulmonary infections, recurrent skin and soft tissue abscesses, mucocutaneous fungal lesions, and extensive giant molluscum contagiosum lesions. Therefore, the patient was suspected to have an underlying PID. The patient was stunted but did not show signs of wasting. She did not have dysmorphic facial features or retained primary teeth, but had an oral thrush. She also had a symmetric chest expansion, with rhonchi, coarse crackles, and wheezes over both lungs. Tender, fluctuant, erythematous abscesses were observed on the scalp, as well as in some areas of the trunk. Laboratory tests revealed normal counts of blood neutrophils and lymphocytes, but eosinophil count was elevated with 1,176 cells/muL (Supplementary Table 1). Serum IgG and IgA levels were 1,841 and 181 mg/dL, respectively, whereas IgM level was low (10 mg/dL, normal range: 50-350). Intriguingly, serum IgE level was extremely elevated (>5,000 kU/L). Although kappa-deleting recombination excision circles were normal, T-cell receptor excision circles (TRECs) were undetectable, indicating an impaired T-cell function. Chest X-ray showed no pneumatoceles, and the bacterial cultures of samples collected from eye and skin wound were positive for Staphylococcus aureus. Based on the elevated IgE and eosinophil levels, the patient was suspected to have HIES. According to the National Institute of Health (NIH) scoring system for HIES, the patient scored 49, which indicated a probable HIES (>40) (Supplementary Table 2). However, this score may also be suggestive of AD-HIES. The patient, however, did not have any retained primary teeth, scoliosis, or a characteristic face; features that were frequently observed in patients with STAT3-deficient AD-HIES. To clinically distinguish between DOCK8-deficient HIES and AD-HIES, the DOCK8 scoring system was applied (Supplementary Table 3). The patient scored 111.08 (cut off: <30), which strongly suggested a DOCK8 defect, which is a form of T-cell deficiency. After obtaining a written informed consent from the parents, genetic analysis was performed. Whole-exome sequencing identified a homozygous large deletion of exons 2-4 in the DOCK8 gene, which was confirmed by multiplex polymerase chain reaction (PCR) on genomic DNA for DOCK8 coding regions (Figure 1A). PCR with a forward primer in intron 1 and reverse primer in intron 4 amplified the breakpoint regions. Sanger sequencing of this product revealed a deletion of 80,133 bp with an insertion of "T" (Figure 1B). The 3' breakpoint is located in an Alu transposable element, but the 5' breakpoint is not located in any transposable elements (Figure 2). Both parents were heterozygous for the same allele with the large deletion, indicating that they were obligate carriers (Supplementary Figure 3). The patient had recurrent abscesses, persistent pruritus, and extensive molluscum contagiosum lesions despite the good adherence to the treatment regimen instituted. The result of the exome sequencing bolstered the need for HSCT for the patient to survive. Unfortunately, she died of severe sepsis at the age of 14 years.

t-cell deficiency, dedicator of cytokinesis 8, hyper ige syndrome, severe atopic dermatitis, warts

PMC9563632_02

Male

A 65-year-old man with history of atrial fibrillation, non-ischemic cardiomyopathy, HCV, cirrhosis, COPD, distant pericardial and left pleural TB status post pericardial stripping 10 years prior with a residual pleural rind and complex left pleural space, with persistent loculations seen on chest imaging, was undergoing serial thoracenteses every three months, for dyspnea in the setting of recurrent pleural effusion. He was then referred to our pleural clinic for increasing frequency of left sided thoracentesis and an associated increase in dyspnea on exertion. On initial evaluation, his pleural studies were notable for an empyema (LDH >2700, Glucose<10, pH 6.89) and repeat cultures ultimately grew Staph epidermidus. He was admitted for chest tube placement, which was done under CT guidance and IV antibiotics. The chest tube was subsequently removed 10 days after insertion. No tPA was instilled given ongoing anticoagulation, mild hemoptysis, and the serosanguinous nature of his pleural fluid. One month later, he had persistent symptoms and recurrence of his pleural effusion, so a new pigtail catheter was placed on admission. Pleural fluid studies at that time demonstrated LDH >2,700, glucose<10, pH 7.12, adenosine deaminase 154, WBCs 19,000. He underwent serial irrigation with 250 cc warmed saline three times at the bedside via pigtail. VATS decortication was initially planned; however, the procedure was subsequently deferred because the patient developed flash pulmonary edema. Eleven days after pigtail placement, three doses of tPA were instilled. He was discharged 25 days after pigtail placement with a pneumostat in place. Three weeks after discharge, he followed up in pleural clinic and the pigtail catheter was removed. At one-month follow-up the patient had persistent dyspnea, with interval re-accumulation of pleural fluid and evidence fibrinous stranding on ultrasound. Given re-accumulation, medical pleuroscopy under moderate sedation with TPC placement was performed (Fig. 5). Following TPC placement, the patient did well from a respiratory standpoint, with resolution of his dyspnea on exertion, ongoing relief from weekly pleural drainage, and evidence of pleural symphysis on CT scan (Fig. 6). Following TPC placement he had no further admission for shortness of breath or pleural interventions. His TPC remained in place until his death from hepatocellular carcinoma two years after initial encounter.

empyema, pleural infection, pleuroscopy, tpc, tunneled pleural catheter, tunneled pleural catheter, vats, video-assisted thorascopic surgery

PMC4515332_01

Female

A 45 year-old woman with 6 months history of low back pain, weight loss, night sweat, fever and galactorrhea was referred to our center. Physical examination revealed multiple and palpable masses in both breasts and galactorrhea without peripheral lymphadenopathy. The rest of physical examination was unremarkable. Ultrasonographic evaluation revealed lobular-shaped, partly ill-defined hypoechoic masses with 2-7 cm diameters and a multi-septated nodular (mottled) appearance without acoustic changes in both breasts. Mammography showed an extremely dense pattern with bilateral ill-defined, hypodense mass-like lesions. Computer tomographic (CT) scans of the chest and abdomen were normal. CBC and LDH were completely normal. The patient had no contributory past or family history. Breast lumpectomy was performed in another center and the primary result exhibited malignant non-Hodgkin lymphoma; Malt type and immunohistochemistry (IHC) suggested Maltoma (Figure 1). During the primary work up, her back pain increased and paraplegia occurred. Magnetic resonance imaging (MRI) demonstrated disc protrusion of T8-T9 and spinal surgery was performed immediately. Surgical gross result was extradural soft tissue tumor at T8-T9 with invasion to the bone. Pathologic report revealed malignant high-grade lymphoblastic lymphoma. She was referred to our department (Medical Oncology and Hematology department of the National Institute of Tuberculosis and Lung disease, NRITLD). First, we suggested reviewing of previous pathology result and surprisingly it was different suggesting dense lymphoid infiltration with diffuse growing pattern and malignant lymphoblastic lymphoma, B-cell type (CD20, CD3, CD5, CD10, BCL2 were positive in IHC staining) (Figure 2). In the setting of lymphoma staging, bone marrow aspiration and biopsy were performed and bone marrow involvement was highly suspected. Central nervous system involvement was ruled out by lumbar puncture (LP). The patient was staged IVBE according to the Ann Arbor staging system and International Prognostic Index (IPI) was low-intermediate. We started chemotherapy with hyper CVAD regimen (Course 1: [cyclophosphamide: 300mg/m2; BID days 1-3; vincristine: 2mg/m2 day 1; doxorubicin: 50mg/m2 day 4; dexamethasone 40mg/m2 days 1-4] course 2: [methotrexate: 1000mg/m2 day 1; cytarabine: 3000mg/m2 BID days 2-3], with G-CSF support per 2-3 weeks). CNS prophylaxis was done by methotrexate: 12mg day 2 and cytarabine: 100mg day 7. After 4 courses, the patient did not have any complaint and response evaluation with mammography and bone marrow biopsy was completely normal. She was a candidate for bone marrow transplantation (BMT) due to her stage and IPI but owing to the large number of patients on the waiting list, this process took about 3 months. She developed back pain again and L4/L5 central disc protrusion was seen in MRI. She was admitted to our department. Marked painful swelling of both breasts was detected on physical examination and multiple masses in mammography examination were seen. Chest CT showed minimal pleural effusion in the left side. We treated her by ICE regimen (Ifosfamide 5gr/m2 for 3 days, Etoposide 100mg/m2 for 3 days and Carboplatin AUC 5 day 1) for 8 cycles. Unfortunately, she was expired after 4 months.

breast cancer, lymphoblastic lymphoma, lymphoma

PMC4101947_01

Male

A 27-year-old, right-handed Caucasian male with 13-year history of UC with primary sclerosing cholangitis presented to the ER with acute onset of left sided headache, left eye proptosis, erythema, and painful eye movements without any visual changes. He reported a recent trip to Spain and denied trauma, sick contacts, urinary symptoms, fever, weight loss, sexually transmitted diseases, or similar illness in family and friends. He was diagnosed with UC with primary sclerosing cholangitis at age of 14 following chronic diarrhea, weight loss, guaiac positive stools, and elevated GGT. The colonoscopy then showed pancolitis extending throughout the colon with no evidence of granuloma. Liver biopsy showed onion skinning around the bile ducts. He was initially treated with steroids, mesalamine, and ursodiol. His last flare was a year ago. He had 4-5 blood streaked loose stools per day treated with tapering dose of steroids. Since then he has had no further UC flare and has been on mesalamine and ursodiol. Clinical examination revealed left eye ecchymosis, hemorrhagic chemosis, unilateral proptosis, with no evidence of uveitis, and normal fundus (see Figures 1(a) and 1(b)). Magnetic resonance imaging (MRI) of the face and orbit showed left eye proptosis with inflammation of the extraocular muscle and the periorbital tissue with normal brain and cavernous sinuses. He was treated with high dose steroids (one gram IV methyl prednisone for 3 days) and empiric antibiotics for orbital inflammatory syndrome and an autoimmune and infectious workup was started. His eye symptoms improved on steroids. However, on the third day of hospital admission, he complained of left arm weakness and numbness. A repeat MRI brain showed an interval development of multifocal deep gray nuclei signal abnormalities including diffusion restriction in the caudate nuclei, right globus pallidus, and posterior limb of the internal capsule (see Figure 2(a)). His CSF was essentially normal with 2 WBCS, normal protein, and glucose with few RBCs. He was empirically started on acyclovir. Within the next 36 hours, he rapidly worsened neurologically, became encephalopathic with left side hemiparesis, and had to be intubated for airway protection. His subsequent MRI brain showed further progression of lesions involving the caudate nuclei, thalami, striatum, and brainstem with new areas of hemorrhage and enhancement (Figure 2(b)). Cerebral arteriogram did not show any vasculitis. Laboratory workup revealed mild leukocytosis with normal liver function tests, ESR, CRP, and thyroid function test. His laboratory findings were negative for HIV, hepatitis, toxoplasmosis, Saccharomyces cerevisiae, Ehrlichia, Brucella, Rocky Mountain spotted fever, Q fever, and Lyme disease. His CSF was negative for herpes simplex viruses 1 and 2, Adenovirus, Enterovirus, Cryptococcus, and Mycobacterium tuberculosis. His CSF and blood flow cytometry were negative for lymphoma/leukemia cells. Blood, stool, urine, and sputum cultures were sterile. An eye swab was negative for Chlamydia trachomatis. Skin biopsy was normal. Echocardiogram and CT scan of chest, abdomen, and pelvis were unremarkable. IgG4 was normal. Anticardiolipin antibody and beta 2 glycoprotein were both mildly elevated. He was treated empirically with antibiotics, antivirals, and steroids. He had an ANA titer of 1 : 40 and PANCA titer of 1 : 320; his PR3 antibody was 157 AU per milliliter (normal range, 0 to 19). The brain biopsy showed necrotizing vasculitis (Figure 3) with no evidence of granuloma. Absence of granuloma, in addition to normal lung, kidney, and sinuses ruled out GPA. Based on the serology and brain biopsy results we diagnosed PR3ANCA mediated cerebral and orbital vasculitis. He was treated similar to GPA involving the brain and eye with cyclophosphamide, plasmapheresis, and high dose of steroids. He dramatically improved with residual hemiparesis and was discharged to rehabilitation.

PMC3307465_01

Female

A 15-year-old female presented with multiple, painless enlargement of the cervical and submandibular lymph nodes along with thyromegaly and fever since three months. She was initially diagnosed outside as having tuberculosis and was under antituberculous treatment since two months, to which there was no response. Routine laboratory investigations revealed hemoglobin of 10 gm%, erythrocyte sedimentation rate of 90 mm at the end of first hour, total leukocyte count of 14,600 cells/mm3 and a differential count of neutrophils-44%, lymphocytes-52%, monocytes-2%, eosinophils-2%. Clinical diagnosis given was thyroid malignancy with metastasis. Ultrasound scan diagnosis was papillary carcinoma thyroid with cystic change and lymph nodal metastasis. Fine needle aspiration cytology (FNAC) was performed from the thyroid as well as the lymph nodes. Smears were stained with Giemsa as well as hematoxylin and eosin and found to be richly cellular [Figure 1]. Smears from both the lesions, that is, thyroid and lymph nodes showed a similar cytomorphological picture. Microscopic examination revealed the presence of histiocytes with single to multiple nuclei, fine nuclear chromatin and inconspicuous-to-prominent nucleoli; no nuclear grooving or atypia was noted. The histiocytes had abundant pale cytoplasm containing numerous intact lymphocytes (emperipolesis) [Figure 1 lower inset], plasma cells and neutrophils [Figure 1 upper inset]. The background showed plenty of mature lymphocytes, plasma cells, and neutrophils. Based on this characteristic cytomorphology, a diagnosis of Rosai-Dorfman disease, nodal and extranodal, involving the thyroid, was made, ruling out malignancy. A subsequent histological examination of the lymph node biopsy confirmed the cytological diagnosis. The patient was treated with steroids with a good response and thus an unnecessary total thyroidectomy was prevented.

fine needle aspiration cytology, rosai–dorfman disease, thyroid

PMC5836220_01

Female

A 54-year-old Caucasian woman developed frostbite on her nose after being outside for approximately 3 h in temperatures of -45 C (average). The skin on the nose initially turned pale, followed by desquamation and ulceration that failed to heal (Fig. 1). Six months after the initial frostbite injury, she attended the Astana Oncology Center where an incisional biopsy of the lesion was performed and the histological diagnosis concluded BCC.

carcinogenesis, cold injury, frostbite, skin cancer

PMC5836220_02

Female

A 65-year-old Caucasian woman developed frostbite on her right cheek after waiting at the bus stop in temperatures of approximately -42 C (average). Frostbite occurred within 1 h and initially presented as a white patch on the right cheek. Over time, the lesion developed into a scaly erythematous patch with irregular borders (Fig. 2). The lesion failed to heal and the patient was referred to an oncologist at the Astana Oncology Center 2 years after the frostbite occurred. Biopsy was performed and the specimen was sent for histopathological analysis. The diagnosis was a superficial SCC.

carcinogenesis, cold injury, frostbite, skin cancer

PMC5836220_03

Male

Approximately 20 years ago, a 72-year-old Caucasian man developed frostbite whilst hunting in cold, dry, windy conditions at temperatures of around -35 C. Frostbite appeared after roughly 1 h of extreme cold exposure and presented initially as a white patch which later turned red. The lesion failed to heal, and after approximately 1 year, multiple scattered crusted plaques developed on the forehead at the site of previous cold injury (Fig. 3). Around 20 years after the frostbite incident, the man attended the Astana Oncology Center where an incisional biopsy was performed and a diagnosis of invasive SCC was made.

carcinogenesis, cold injury, frostbite, skin cancer

PMC7334018_01

Male

A 53-year-old male patient was hospitalized in the respiratory outpatient department of our hospital. He had fever with headache for half a month, slight cough, and sore muscles and joints. The patient did not have diabetes or immunosuppressive diseases, and there was no history of hypertension. Considering that no signs of pneumonia were found by thoracic CT, the patient was given cefixime sustained-release capsules plus clarithromycin sustained-release capsules for 4 days. However, the fever with headache remained, and he was admitted to the neurology department. The patient was treated with a three-day course of ceftriaxone, with no signs of improvement. Brain magnetic resonance imaging (MRI) showed a high T2WI signal and T2 flair in the left lateral ventricle, and DWI indicated no significant diffusion restriction. The lesion was not enhanced. Brain MRI showed left paraventricular demyelination (Figure 1). A lumbar puncture was performed, and cerebrospinal fluid (CSF) examination demonstrated a nucleated cell count of 2120 cells/microL, neutrophil percentage of 95%, glucose level of 2.29 mmol/L, protein level of 57.3 mg/dL, and adenosine deaminase activity of 1.5 U/L. The ratio between CSF and blood glucose levels was 0.47. The CSF samples were centrifuged, and the sediment was smeared and stained with Gram, ink, fluorescence and anti-acid stains. No acid-fast bacilli, cryptococci or fungi were detected in the CSF smears; the Xpert MTB/RIF assay was also negative. Hepatitis B surface antigen (HbsAg), hepatitis B core antibody (HbcAb) and hepatitis B e-antigen (HbeAb) were positive, and upper-abdomen enhanced CT showed cirrhosis of the liver, multiple small cysts of the liver, gallstones and cholecystitis. The Child-Pugh score of liver cirrhosis was class A. CSF culture vials were incubated in an automated culture system (Bact/ALERT Virtuo , bioMerieux, France). The bacteria primarily grew under both anaerobic and aerobic conditions. After the CSF culture became positive, 10 microL of fluid was plated on Columbia blood agar, and S. aureus isolate SA17 was cultured. Microbiological identification was performed by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry using a MALDI/TOF Biotyper (Bruker Italia, Milan, Italy). Antimicrobial susceptibility testing was performed using E-test strips in three replicates, revealing that the isolate was methicillin-resistant S. aureus. After multidisciplinary discussion, the patient received antibiotic treatment with 0.6 g linezolid bid intravenously for 17 days, and the patient's platelet counts decreased to 27x109/L. The time course of linezolid administration and the onset of thrombocytopaenia are illustrated in Figure 2. When linezolid was stopped, his platelet counts gradually increased. The patient recovered well, his symptoms and signs improved significantly, and the results of CSF re-examination were normal. S. aureus strain SA17 was detected as a result of routine hospital laboratory procedures. This study was performed in accordance with the Declaration of Helsinki and approved by the Ethics Committee of The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China. Written informed consent, which included publication of the case details, was obtained from the patient.

st59, community-acquired, meningitis, methicillin-resistant staphylococcus aureus, whole-genome sequencing

PMC5932522_01

Male

A 47-year-old male patient who was a rural worker reported "wounds in the mouth" and persistent cough for about 6 months. He reported chronic smoking and denied comorbidities. A granulomatous ulcer with hemorrhagic dots and moriform aspect was observed in the posterior mandibular alveolar ridge and in the right jugal mucosa (Figure 1). Some dental elements presented severe mobility, which began after lesion emergence. He had an ulcerated lesion in the right cervical region with serous exudate (Figure 2). Cervical contrast CT scan revealed images compatible with cervical lymphadenopathy in the right side and exteriorization of the infectious process through cutaneous fistula (Figure 3). Chest X-ray showed infiltrative lesions with reticulonodular aspect in butterfly-wing shape. A direct mycological examination was performed from cervical lymph node puncture, sputum, and intraoral mucosal scraping. The result was positive for the presence of yeasts with multiple buds surrounding mother cells, suggestive of P. brasiliensis. Thus, culture with fungal isolation was carried out, and the final result was Paracoccidioides spp. DNA-PCR examination for Mycobacterium tuberculosis was negative, and the result was nonreagent for the rapid HIV test, revealing leukocytosis (13,500/mm3), without left deviation. Incisional biopsy of the intraoral lesion was performed under local anesthesia. Histological sections revealed a mucosal fragment coated with parakeratinized stratified squamous epithelial tissue, exhibiting pseudoepitheliomatous hyperplasia constituted by dense connective tissue. An intense granulomatous inflammatory infiltrate with predominance of eosinophils and formation of granulomas and microabscesses were observed, as well as numerous multinucleated giant cells. Spherical fungi of different diameters and birefringent membrane located both within multinucleated giant cells or dispersed through the tissue were also present. In depth, there were fragments of mineralized tissue and hemorrhagic areas (Figure 4). The patient was referred to an infectologist who followed up the case. An association of sulfamethoxazole 2400 mg + trimethoprim 480 mg was prescribed three times a day during 12 months. After 1-year follow-up, the patient was asymptomatic and presented remission of the oral and cervical lesions (Figures 5 and 6).

PMC3645454_01

Female

A 17-year-old female patient reported to the Department of Oral Medicine and Radiology at Sri Sai College of Dental Surgery in Vikarabad, complaining of a painful swelling in her right submandibular region that had been present for two months and was originally noticed on June 13th 2009. The swelling was initially the size of a peanut and had been gradually increasing until it reached the present size. (Figure 1) On general examination the patient was thin and malnourished. There were no fever, cough, or weight loss symptoms present. Past medical history and family history was not significant. On extraoral examination, inspection showed a single diffuse swelling with ill-defined borders of approximately 4 x 3 cm in the right submandibular region. The overlying skin was the same as surrounding skin. On palpation a mass was felt in the right submandibular region, which was firm in consistency, tender, nonfluctuant, noncompressible, mobile, and showed signs of matting (Figure 2). On intraoral examination, odontogenic involvement due to the swelling was not present. Other lymph nodes were not palpable. A clinical diagnosis of right submandibular tuberculous lymphadenitis was considered. Differential diagnosis of right submandibular sialadenitis, right submandibular gland calcification was considered. A panoramic radiograph was carried out and it did not reveal odontogenic origin in relation to the swelling (Figure 3). A Mantoux test was positive. No abnormality was detected in chest radiographs (Figure 4). A complete hemogram showed hemoglobin levels to be 8.8 gm%, The red blood cell reading was 3.3 million/cu mm, and the total white blood cell count was 8,200 cells/cu mm. By comparison, normal range hemoglobin is 12%-16 gm%, blood cells 4-5 million/cu mm, and total white blood cells 4000-11000 cells/cu mm. Erythrocyte sedimentation rate (ESR) was raised 1st hour 75 mm, 2nd hour 105 mm. A ultrasound scan of the patient's neck revealed multiple hypoechoic nodular lesions of varying sizes in the right submandibular region, abutting and displacing the right submandibular salivary gland. The largest of the lesions measured 3.4 x 2.9 cm and matting was apparent (Figure 5). There were a number of other similar smaller lesions along the right jugular vein, which is suggestive of lymphadenopathy. The ultrasound report was consistent with that of right submandibular and jugular tuberculous lymphadenopathy. Ultrasound-guided fine-needle aspiration biopsy (FNAB) revealed a cellular aspirate showing plenty of small and large lymphocytes. Necrotic debris was seen in focal areas, and few epithelioid cells or giant cells seen (Figures 6 and 7). The ultrasound-guided FNAB report was compatible with that of tuberculous lymphadenitis. Regarding the clinical presentation of the case and the investigation reports a final diagnosis of right submandibular tuberculous lymphadenitis was arrived at. The patient was referred to the TB hospital for further treatment. Treatment consisted of anti-TB drugs for a period of 6 months. No complications occurred, and no further surgery was required.

primary tuberculous lymphadenitis, submandibular, tuberculosis

PMC3420729_01

Female

A 39-year-old female Caucasian psychologist sought medical attention complaining of cough. Chest radiography showed changes that were attributed to pneumonia, treated with cefuroxime at the time. After eight months, progressive dyspnea was associated. Initial diagnosis by pulmonologist was "organizing pneumonia," based on clinical history and computed tomographic (CT) findings, described as "focal areas of lung parenchymal infiltrates with ground-glass opacities, associated with septal thickening, with peripheral distribution, predominating in the lower lobes" (Figures 1(a) and 1(b)). Transbronchial biopsy was performed, which showed "scant fragments of bronchial wall and adjacent alveolar collapse exhibiting a minimum focus of interstitial inflammatory infiltrate." It was prescribed treatment with prednisone 20 mg/day. After twelve months of evolution since the onset of symptoms, she went to a rheumatologist for differential diagnosis evaluation. On this occasion, the pulmonologist had already searched and excluded tuberculosis and she had dyspnea on minimal exertion. Diffuse pain in arms and legs, burning in the fingertips, fatigue, sleep disorder, Raynaud's phenomenon (RP), xerostomia, and xerophthalmia were present at the symptomatology interrogation and physical examination. She had positive personal and family history of Hashimoto's thyroiditis. On physical examination there was no skin thickening or arthritis, oroscopy was normal, blood pressure was 90 x 60 mmHg, and heart frequency was 96 beats per minute. Upon respiratory system examination basal crackles bilaterally and 20 breaths per minute were observed. There were no changes in cardiovascular and abdominal examination. Tests were requested for the investigation of rheumatic diseases including systemic sclerosis, Sjogren's syndrome, and vasculitis. On this occasion, the prednisone dose was increased to 1 mg/kg/day. Inflammatory activity tests and serologic and antibodies tests are demonstrated in Table 2. In the evaluation of lung function a pattern compatible with incipient restrictive ventilatory disorder was observed. As evidence of inflammatory activity, CRP was always negative and ESR was increased. Autoantibodies were negative (antinuclear antibodies-ANA, rheumatoid factor, anti-SCL 70, anti-Jo-1, anti-RNP, anti-SS-A, anti-SS-B, and c-ANCA), except a 1 : 20 p-ANCA reagent. The patient presented a normocytic normochromic anemia, and the hemoglobin value ranged from 9.8 to 13.3 mg/dL and the hematocrit range was 30.3 to 41.7%, probably due to the underlying disease. In two occasions, the patient presented lymphopenia that could indicate disease activity or could be related to steroid therapy. Chlamydia pneumonia IgG serology was reagent 1 : 512 and IgM was negative. Mycoplasma pneumonia serology was negative. The exams allowed excluding Sjogren's syndrome (negative anti-SS-A and anti-SS-B and normal salivary biopsy). Renal, liver, and hormonal functions were normal. A panoramic nailfold capillaroscopy showed the presence of moderate capillary ectasia and mild devascularization of focal distribution, described as "well-defined scleroderma (SD) standard microangiopathy, consistent with systemic sclerosis, dermatomyositis or overlap syndrome with scleroderma component" (Figure 2). Given the results of capillaroscopy and the presence of RP she was diagnosed with systemic sclerosis in the early stages. Then it was proposed to start cyclophosphamide pulse 1 g. However, after three weeks of diagnosis, the patient developed high fever (39 degrees) and dyspnea at rest, requiring hospitalization. On admission, her respiratory frequency was 40 incursions per minute, the arterial oxygen tension was 48.4 mmHg, and oxygen saturation was 88.5% and she had basal crackles bilaterally. On the third day she developed respiratory failure, requiring ventilatory support and intensive care. The chest CT showed interstitial infiltrate, with diffuse ground-glass opacity in both lungs, associated with foci of parenchymal densification, predominantly peripheral, some air bronchograms and mild pleural thickening marginally, more evident in right lung basis and apex. Small calcified nodules of residual aspect, scattered in both lungs, without pleural effusion (Figures 1(c) and 1(d)), were observed. An echocardiogram was done to exclude pulmonary hypertension. The pulmonary arterial pressure was 31 mmHg. Hemoculture and urine culture were negative. Virus B and C serologies were negative. The CRP increased from 42 to 147 mg/dL. At that moment the pulmonologist considered three possible diagnosis: nonspecific interstitial pneumonia, pneumonia caused by Pneumocystis carinii, or pneumonia caused by virus (CMV, adenovirus, herpes 1 and 2). On the fourth day, she underwent an open biopsy (microthoracotomy), which consisted of pulmonary segmentectomy of right middle and lower lobes. Some part of the material was sent to investigate fungus, mycobacteria, and general culture, all of them presented negative results. The biopsy revealed that there were no infectious process and no granulomas. Histopathological examination showed "a parenchymal diffuse involvement, intra-alveolar fibrin accumulation in the form of solid blocks, pneumocytes hyperplasia, interstitial mild acute inflammatory infiltrate, alveolar septal edema and congestion, intra-alveolar fibroblastic Masson bodies and xantomatososum accumulation of macrophages, a typical pattern of acute Fibrinous and Organizing Pneumonia (AFOP)" (Figure 1(e)). After excluding any infection etiology including bacteria, virus, mycobacteria, and fungus, she received pulse therapy with cyclophosphamide 1 g and methylprednisolone 1 g for three days. Despite treatment, the patient developed respiratory failure by pulmonary hemorrhage.

PMC3356866_01

Male

A 55-year-old Vietnamese male with no significant past medical history presents to a local community hospital emergency department because of abdominal pain and distention of two-week duration. The abdominal pain was generalized, described as cramping, present throughout the day, had no association with meals, and was getting progressively worse. The patient also reported nausea and vomiting clear material. He denied any recent fever, chills, night sweats, weight loss, change in bowel habits, sick contacts, and consumption of raw food. In addition, he denied any chest pain, shortness of breath, joint swelling, and skin rash. After immigration from Vietnam 11 years ago, his only travel outside the USA was back to his homeland one year prior to this illness. The patient was not taking any prescribed or over the counter medications or herbal compounds and denied any allergies. His physical examination showed no skin rash or jaundice, cardiopulmonary examination showed no abnormality, and the abdomen was moderately distended, with active bowel sounds, diffuse tenderness without rebound, and moderate ascites. There was no hepatomegaly or abdominal mass. In the emergency department, a complete blood count and comprehensive metabolic panel were significant for an elevated white blood count of 15.400 with 36% eosinophils. Abdominal and pelvis computer tomography (CT) showed moderate ascites with thickening of the gastric antrum and proximal small bowel (Figure 1). The patient was admitted to the general medical service and placed on bowel rest and intravenous fluid hydration. Further he underwent esophagogastroduodenoscopy (EGD), which demonstrated mild duodenitis and biopsies demonstrated mild nonspecific acute inflammation predominantly lymphocytic. Stool tests were negative for ova and parasites. In addition, a screen for Cryptosporidium, Cyclospora, Isospora, and Sarcocystis did not reveal evidence of recent infection. Over several days, the patient's abdominal pain improved, diet was advanced, and he was discharged home with an empiric trial of albendazole for a presumptive diagnosis of parasitic infection. Two weeks after discharge, the patient was readmitted with worsening abdominal pain. Physical examination showed increased abdomen distention. Repeated blood counts and serum biochemical tests demonstrated an increase in white cell count of 17.100/mL with 71% eosinophils (absolute eosinophil count of 12.141/mul with normal upper limit <450) (Figure 2). Liver function tests continued to be within normal limits. Serum IgE level was elevated at 548 IU/mL (normal < 180). Repeat stool tests were negative for ova and parasites. Furthermore, immunologic studies for Toxocara, Trichinella, Strongyloides, Filiaria, Schistosoma, Echinococcus, and Cysticerus were negative. Repeated EGD was nondiagnostic. Flow cytometry of peripheral blood revealed no myelo- or lymphoproliferative findings. Serum beta-2-microglobulin and LDH were 2.2 mg/dL (normal: 0.8-3.0) and 170 U/L (normal: 80-200), respectively. Ultrasound guided abdominal paracentesis showed WBC count of 6600/mL, 95% of which were eosinophils (Figure 3), LDH 284 mg/dL, albumin 3.2 g/dL (simultaneous serum albumin 4.1 g/dL). In order to exclude small bowel lymphoma, the patient underwent diagnostic laparoscopy with full-thickness biopsy of an inflamed portion of the jejunum. This revealed skipped areas of hyperemia and discoloration involving the small intestine and to a lesser degree the colon in addition to yellow-green ascites (Figure 4). Histopathological evaluation showed marked eosinophilic infiltration of the muscularis propria and serosa with concomitant mild acute inflammatory reaction (Figure 5). There was no evidence of malignancy, granuloma, TB, or parasites. The constellation of clinical presentation and histopathological findings were suggestive of eosinophilic gastroenteritis. Subsequently, the patient was started on oral prednisone (20 mg/day). Two weeks later and with noticeable symptomatic improvement, the prednisone was tapered over a two-week period. After completion of steroids, the patient's abdominal pain and physical finding of ascites completely resolved and a peripheral blood count revealed an absolute eosinophil count of 300/mul (nL < 450). Furthermore, IgE level dropped to 105 IU/mL and CT imaging of the abdominal and pelvis showed complete resolution of the ascites and small bowel thickening. Four months have elapsed since treatment and the patient remains asymptomatic on no medications.

PMC6343228_01

Male

An HIV-infected 32-year-old male presented to Mulago National Referral Hospital, Uganda with a 2-week history of headache with fevers and a 1-day history of confusion ( Figure 1). He had been on ART (zidovudine, lamivudine, efavirenz) and co-trimoxazole prophylaxis for 5 years. 5 months prior, he was diagnosed with pulmonary TB by positive sputum Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA). He had completed 2 months of induction TB therapy (rifampicin, isoniazid, ethambutol, pyrazinamide) and was 3 months into continuation phase (rifampicin, isoniazid). He endorsed poor adherence to both ART and anti-tuberculous medications. On examination, the patient was febrile (38.6 C). His blood pressure was 112/71 mmHg, pulse 94 beats/minute, respiratory rate 48, and oxygen saturation 98%. He was wasted, dehydrated, and had overt rigors. His Glasgow Coma Scale was 14/15 with nuchal rigidity and positive Kernig's sign. Cranial nerves were intact. He had normal tone and power in all limbs. A clinical diagnosis of HIV-associated meningitis was suspected and he was recruited into the 'Improving Diagnostics and Neurocognitive Outcomes in HIV/AIDS-related Meningitis' study (registration: ISRCTN42218549). Whilst awaiting further investigations, he received empiric therapy of ceftriaxone 2 g twice daily for possible bacterial meningitis. A finger stick cryptococcal antigen lateral flow assay (CrAg LFA) (IMMY, Norman, Oklahoma, USA) was negative. Liver and renal function tests were normal. Cerebrospinal fluid (CSF) opening pressure was elevated to 33 cm CSF (normal <20 cm CSF), CSF white cells 590 /microl, protein 419 mg/dl (normal range 15-45 mg/dl), CSF lactate 9.5 mmol/L (normal range <2.5 mmol/l). CSF glucose was unavailable. Mycobacterium tuberculosis in CSF was confirmed on Xpert MTB/RIF Ultra; there was no evidence of rifampicin resistance. On day 2, he was initiated on dexamethasone at 0.4 mg/kg/day and induction TB-medications were re-commenced (rifampicin, isoniazid, ethambutol, pyrazinamide) for TBM. The IV ceftriaxone was stopped, his ART was continued. He continued to spike high-grade fevers (39.6 C.) with tachycardia (pulse 118 beats/min). A peripheral blood smear showed P. falciparum parasites (1+ trophozoites), despite a negative malaria histidine rich protein-2 (PfHPR2)-based rapid diagnostic test (Malaria Plasmodium falciparum Rapid Test Cassette, Vaxpert, Florida, USA). Given his ongoing neurological symptoms, which could be compatible with cerebral malaria, the decision was made to treat for severe malaria. Drug-drug interactions (DDIs) between rifampicin and artemisinin compounds, and rifampicin and quinine are recognized ( Table 1); a decision was made to treat with IV artesunate as the most efficacious anti-malarial for severe malaria . He received three doses of IV artesunate (3 mg/kg), after which a repeat peripheral blood smear showed no malaria parasites. He then completed 3 days of oral artemether/lumefantrine. His fevers subsided on day 6. He was discharged on day 8; medication adherence counselling was provided for the patient and his guardian and outpatient follow-up was arranged for the following week.

hiv/aids, case report, drug-drug interactions, pharmacokinetics, tuberculosis, malaria, tuberculous meningitis

PMC6439282_01

Male

Our patient is a morbidly obese 51-year-old male (BMI 58) who was referred to the pulmonary clinic for progressive shortness of breath on exertion for one year prior to presentation. He is a lifelong non-smoker and has a past medical history of diabetes, hypertension and obstructive sleep apnea. He has no history of occupational/environmental exposures or recent travel. He also reported occasional dysphagia to solid foods. Physical examination was significant for obesity and a normal heart and lung exam. Routine blood tests were unremarkable. His CXR showed prominent mediastinum but clear lungs. An office pulmonary function test showed normal spirometry, lung volumes and diffusion capacity. He had a transthoracic echocardiogram and was found to have a normal ejection fraction and right ventricular systolic pressure. A non-contrast CT of the chest was obtained which showed a large oval shaped fat density, not sharply demarcated measuring approximately 5 cm transverse by 19 cm craniocaudal extending from the lower right neck into the right anterior mediastinum. (Fig. 1, Fig. 2). This displaced the innominate vein anteriorly, the brachiocephalic artery laterally to the left and the superior vena cava anteriorly. Lung parenchyma was essentially preserved. The mass had the consistency of fatty tissue suggesting lipoma. The patient underwent an endobronchial ultrasound guided transbronchial aspiration (EBUS-TBNA) of the mediastinal mass which confirmed a benign lipoma. He is currently undergoing pre-operative work up for resection of the lipoma.

PMC2813613_01

Male

A 50-year-old male diabetic was diagnosed and treated for pulmonary tuberculosis 13 years ago. He presented with a 6-month history of low-grade fever and sweating. He also had frequent hemoptysis for the previous 3 months. He was investigated at his local hospital and referred to us for management of pulmonary aspergiloma. Examination was significant for low-grade fever and bronchial breath sounds with coarse crepitations in the right infrascapular region. A sputum smear was negative for acid-fast bacilli and grew Aspergillus. A plain chest x-ray showed a thick wall cavity in the upper and mid zone adjacent to the right hilum. A high-resolution CT scan revealed a large cavity in the apical segment of the right lower lobe with extensive lamellar internal echoes (Figure 1). Ultrasound of the abdomen revealed a simple hepatic cyst with no internal echoes. Bronchoscopy showed fresh blood and some necrotic material coming out of the superior segment of the right lower lobe. Culture of the material grew Aspergillus. Wedge resection of the apical segment of the right lower lobe was performed due to persistent hemoptysis and growth of Aspergillus species in a possible post tuberculous cavity. Gross examination of the specimen revealed a surprisingly whitish membrane of the cyst wall with fungal necrotic material inside (Figure 2). Histopathological examination confirmed the presence of hydatid cyst along with echinoccocus hooklets with invasive Aspergillus within the cyst wall (Figure 2). Lung tissue around the cyst showed nonspecific chronic inflammation and an absence of fungal hyphae. The patient was treated for hydatid disease with albendazole and itraconazole for aspergillosis. The patient was free of any recurrence of either disease at the 8-month follow-up.

CT scan of the chest showing a cavity in the upper segment of the right lower lobe with lamellar internal echoes.

PMC6890540_01

Unknown

In total, 192 of the 280 eligible PLWDs above 18 years old were screened for hypertension, with 9% (n = 17) referred for follow-up for blood pressures greater than 160 mmHg systolic or 110 mmHg diastolic. An additional 274 and 371 PLWDs were screened for malnutrition and tuberculosis, respectively. Six per cent (n = 18) of those screened for malnutrition were referred to care, as were 2% (n = 10) of those screened for tuberculosis. As Malawi is struggling with a double burden of HIV and non-communicable diseases, programmatic approaches are needed to reach key populations where they live (Malawi Government). Because of a shortage of health workers, it may not be possible to use formally trained professionals to provide household-based screening. Limited information describing the use of task shifting to identify PLWDs and provide household screening exists in Malawi. Household-based studies report on disability identification and linkage to care by CHWs and/or non-clinical staff (Mulwafu et al.; Tataryn et al.). We could not find any programme that employed task shifting to provide integrated household screening, including hypertension screening, for PLWDs. Secondly, the programme demonstrated the feasibility and acceptability of combining screening for HIV and other conditions, including hypertension, in a household setting: a high proportion of PLWDs accepted the services. However, few family members accepted to be screened. The screening team focused screening the PLWDs and it may be the reason that influenced lower uptake, but we were not able to collect information on why family members and some PLWDs refused some of the screening. This could be addressed in programmes similar to this case study. Thirdly, this project provided one approach for household-based targeted disease screening, specifically for HIV, to a vulnerable population. People living with disabilities were targeted because of their limited access to services. Up to 10% of the PLWDs were referred for services. A large majority of the PLWDs had never before had an HIV test, which is striking given the considerable investments on HIV programme in Malawi. We hypothesise that this could be the result of stigma and difficulty accessing available services related to disability (Mcbain et al.). Further efforts will be required to ensure that patients who tested negative remain negative; this will be addressed through continued preventive services by the CHWs. After the pilot, we could not roll out the programme to the whole district because of limited funding; however, with funding, this could be scaled up to other settings, and considering the specific needs of PLWDs is a component of ongoing exploration in Neno for the optimisation of integrated home visits. There are a few notable limitations to this programme. Firstly, the disability identification tool we used mainly identified self-reported functional disability. Additionally, this identifies the most common disabilities and may miss 'invisible disabilities', such as mental health disorders. We also could not measure the severity of the disabilities. Secondly, the programme was carried out with a small population in a remote area of Malawi, making it difficult to generalise to Neno and other district of Malawi. Thirdly, we were not able to cost this programme that would give more information in whether scale-up would be recommended. Fourthly, we referred patients to the nearest health facilities but were not able to ascertain if all PLWDs were successfully linked to care. Future programmes would consider the following steps to improve on our limitations: (1) expand household screening to other common chronic condition such as diabetes as they are also common in low- and middle-income countries, (2) cover a larger population to identify more PLWDs who can benefit from the screening, (3) design efforts that can be made to ensure that many family members of PLWDs are screened and document reasons of refusals for both PLWDs and family members, (4) measure costs to help other programme managers to plan and implement this programme and (5) design strategies to ensure that referred PLWDs receive the care at the facility as they may either not go to facilities or face other barriers once they arrive at the facility. NB: The disability-associated questions were designed by United Nations Washington Group on Disability Statistics (http://www.washingtongroup-disability.com). They were translated to local language by bilingual speaker (both English and Chichewa speaker [local language of Malawi]) and were pre-tested in the initial survey conducted in 2014. The people screened were classified as either having disability (if they have a score 2 or above) or no disability if they score 1. The type of disability was also recorded.

malawi, disability, primary healthcare, screening, task shifting

PMC4502303_01

Male

On February 1, 2013, a 58-year-old man was admitted to the Emergency Department of the Regional Hospital of Zaghouan (Tunisia), with dizziness, weakness, anorexia, and dyspnea. His blood pressure was 130/60 mmHg. The patient has a 15-pack-year history of smoking. He was a mason by occupation. He had 20-year back history of pulmonary tuberculosis and type 2 diabetes revealed one year ago. Two days before his admission, the patient experienced nausea, vomiting, anuria, and hematuria. He reported having daily consumption of a homemade drink based on Rhamnus alaternus roots, during the last 6 months, to control his blood glucose levels. On physical examination, the patient had myalgia. He had no other clinical signs. Cytological reports and sputum smear were negative (three times) for pulmonary tuberculosis. Hepatitis B and hepatitis C serology were also negative. Chest X-ray was normal; blood and urine culture were negative. In renal ultrasonography, there was a significant difference in kidney sizes and the corticomedullary differentiation was altered. Laboratory tests showed glucose 14.44 mmol/L, creatinine 1190 mumol/L, blood urea nitrogen 66.77 mmol/L, creatine phosphokinase (CPK) 2129 UI/L, pH 7.10, a CRP of 8.7 mg/L, and a normal coagulation profile (Table 1). Three dialysis sessions were performed. Samples of the herbal decoction were obtained from the patient's wife. It was a dark brown suspension with fine brown deposit and a clear supernatant. It smelled a strong penetrating odor. Samples of both Rhamnus alaternus root and its decoction were sent to be analyzed in the Laboratory of Toxicology in the Center for Emergency Medical Assistance of Tunis in Tunisia. After the authenticity and the botanical identification of the species were confirmed according to the "Flore de la Tunisie" phytochemical compounds were extracted from the medicinal decoction using routine methods including liquid-liquid extraction procedures with further analysis by gas chromatography/mass spectrometry (GC-MS). The solvents used were dichloromethane, ethyl acetate, and chloroform at different pH values (1.0, 7.0, and 9.0). The different extracts were dehydrated over anhydrous sulfate. The dry residue was diluted with 2 milliliters of ethyl acetate. One or 2 muL was analyzed by GC-MS. Dried roots of "Rhamnus alaternus" were reduced to small fragments and macerated in a water-methanol mixture (1 : 2) during 4 h with magnetic stirring. 24 hours later, the extract was filtered and the alcoholic layer was evaporated. The aqueous layer was collected in a separating funnel and had been alkalinized by the addition of ammonia (NH4OH) and then extracted with dichloromethane by liquid-liquid extraction procedures. The organic phase was dehydrated over anhydrous sulfate and concentrated to 1 mL and then analyzed by GC-MS. The gas chromatograph-mass spectrometer used was a Hewlett Packard 5890-II (Agilent Technologies) fitted with a manual injector and HP5-MS (0.25-mum) capillary column (30 m long and 0.25 mm i.d.). The injection volume was 2 muL; the compounds were separated with helium (carrier gas) at a flow rate of 1 mL/min. The operating conditions were as follows: the injector was programmed to 250 C at 10 C s-1 and held for 2 min. The oven was programmed from 50 C (2 min) to 100 C at 25 C min-1 and then to 200 C at 10 C min-1 (2 min). MS detection was achieved in scan mode for qualitative analysis. Run time was 16 min.

PMC8545816_01

Male

An 86-year-old male patient presented to Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, because of the increase of CA-199 level to 282.9 U/mL in regular physical examination, without nausea, vomiting, acid reflux, belching, or other symptoms with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1. First, abdominal contrast-enhanced CT was performed, and showed that the gastric wall of cardia was thickened with abnormal enhancement in arterial phase, the outer margin of gastric wall was rough, and multiple nodules were scattered in hepatogastric ligament, retroperitoneum, peritoneum, omentum majus and mesangium. The malignant tumor infiltrated the entire layer of gastric cardia, and multiple round lymph node were highly suspicious for metastasis in the abdominal cavity. Second, the upper GI endoscopy subsequently identified proliferative ulcers in the region of the cardia, and signet ring cell carcinoma was confirmed by pathology. PET/CT was also demonstrating obvious cardia thickening with significant FDG uptake (SUvmax 14.3), as well as increased metabolic activities in the enlarged abdominal lymph nodes (SUvmax 4.9 to 6.8), and nodular thickening of the right retroperitoneum (SUvmax 3.8). Immunohistochemical stainings of the gastric tissue demonstrated positive expressions of MLH1, PMS2, MSH2, and MSH6, PD-L1 combined positive score (CPS) of 20, Ki-67 expression level of 90%, and negative HER-2 expression (Figure 1). He was diagnosed with metastatic gastric cancer with multiple abdominal cavity lymph node and peritoneal metastases (HER2 negative, pMMR, and PD-L1 CPS 20). Chemotherapy was recommended as the first-line treatment, but the patient and his family refused due to his old age and frailty. Given his high PD-L1 CPS and the significant overall survival (OS) improvement in patients with CPS >= 10 treated with pembrolizumab compared to those with chemotherapy in the KEYNOTE-062 trail, he was recommended and administered with 100 mg pembrolizumab as the first-line chemotherapy every 2 weeks for 5 cycles (Figure 2). Ten days after the last dose, the patient presented for icteric sclera and skin and generalized pruritus. He was administrated with the ursodeoxycholic acid (250 mg, bid) in other hospitals for 1 week before admission to our hospital, but the above symptoms did not improve. After addimission, the patient remained hemodynamically stable and the abdominal exam findings were benign. On serum biochemical testing, a marked increase in total and direct bilirubin and slight increase in gamma-glutamyl transferase were identified, the level of alkaline phosphatase (ALP; range, 30-120 IU/L) also increased, but alanine aminotransferase (ALT; range, <50 IU/L) and aspartate aminotransferase (AST; range <50 IU/L) were within normal limits (Table 1). We assessed the tumor status, and a partial response (PR) was assigned according to RECIST criteria. Neither magnetic resonance cholangiopancreatography (MRCP) nor abdominal computed tomography (CT) showed significant biliary obstruction or bile duct dilatation (Figure 3). Tumor progression, and biliary inflammation and obstruction were ruled out. We suggested liver biopsy for differential diagnosis, but the patient and his family refused due to his old age and poor physical condition on admission. Given the patient's PD-1 treatment history, we therefore diagnosed him with immune-related cholestatic hepatitis was diagnosed, and ICI treatments were suspended. The patient received pulse therapy with 80 mg methylprednisolone. Simultaneously, ursodesossicolic acid was administrated to this patient daily. Icterus resolved after 3 days, and the pruritus significantly improved. Total bilirubin decreased from 171.4 to 139.3 mumol/L and direct bilirubin decreased from 114.3 to 88.4 mumol/L after 3-day high-dose steroids treatment. Therefore, oral dexamethasone replaced the methylprednisolone with a tapered dose (dexamethasone 7.5 mg for 4 days, 6 mg for 4 days, and 3 mg for 4 days). Total and direct bilirubins continued to decreasedecreasing, and he was discharged from hospital on day 36 (see Table 1). One month later, the patient developed asthma with a low-grade fever that increased slightly (37.8-38.5 C) in the hospital. Oxygen saturation was low at 78-90%, and a decreased white cell count (1.56 x 109/L; range [4-10 x 109/L]), high levels of C-reactive protein (72 mg/L; range, <10 mg/L), and procalcitonin (0.1 ng/ml; range, <0.5 ng/mL) were found on blood tests. The 1, 3-beta-D-glucan detection (G test) and galactomannan antigen detection (GM test) were performed using blood samples, while bacterial and fungal cultures were performed on sputum and blood. In addition, SARS-CoV-2 nucleic acid test through throat swab specimens and tuberculosis -related sputum and blood tests were also performed. All tests were negative and the antibiotic, Cefoperazone Sodium and Sulbactam Sodium(sulperazone), was administered with granulocyte-colony stimulating factor to promote leucocyte production; however, no significant symptomatic improvement was seen. Another chest CT showed interstitial changes, and interstitial pneumonia was considered probable (Figure 4). He was diagnosed with type 1 respiratory failure based on the report of arterial blood gas examination and treated with high-flow nasal oxygen. A multi-disciplinary consultation was completed, and since the patient had received a PD-1 inhibitor, a consensus considered immune-related pneumonia to be likely. However, because the patient was elderly and treated with glucocorticoids for a considerable time, opportunistic infections could not be excluded. Therefore, the patient was given pulse therapy with 80 mg methylprednisolone and levofloxacin, meropenem, and sulfamethoxazole/trimethoprim. No significant improvements were seen after 3 days, and the patient was transferred to ICU for high-flow oxygen and intravenous immunoglobulin (25 g/day) therapy. An antifungal drug, caspofungin(coses), was also added. Symptoms improved 6 days later, and resolution of the interstitial lung changes was seen on CT (Figure 4). The patient was discharged, and antibiotics were discontinued. At a 1 month recheck, the patient was in good general health with an ECOG PS of 1, and bilirubin levels were within normal limits (Table 1). Enhanced CT of the abdominopelvic cavity showed that PR was maintained (Figure 2) with progression-free survival (PFS) of 7 months.

cholestasis, immune checkpoint inhibitor, immune-mediated hepatitis, late-onset pneumonia, multisystem immune-related adverse event

PMC9112311_01

Male

A 25-year-old gentleman, diagnosed at the age of 16 years in 2012 with stage IVB nodular sclerosing Hodgkin's Lymphoma (HL), was treated with 6 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine, followed by complete remission. He then had recurrence twice, the first time in 2013, for which he received salvage therapy with dexamethasone, high dose cytarabine, and cisplatin, and then in 2014, at the age of 18 years, when he received ifosfamide, carboplatin, and etoposide, followed the same year by autologous HSCT. In 2017, he started having night sweats, back pain, and weight loss, and his positron emission tomography (PET) scan showed disease recurrence in supra and infradiaphragmatic regions as well as bone marrow lesions without evidence of lung involvement. The patient then received 6 cycles of brentuximab vedotin and bendamustine and underwent his second HSCT in the form of haplo-HSCT (half-matched) from his sister in April 2018, at the age of 22 years, and continued his maintenance on brentuximab. In July 2018, he started having waxing and waning oral and cutaneous erythematous papules over the torso and extremities, with biopsy of the papules confirming it as cutaneous graft versus host disease (GVHD). He was given topical treatment and was started on dexamethasone syrup gargle and spit 10 mg 3 times daily for 1 month for oral cavity lesions with significant improvement. Meanwhile, he was still maintained on brentuximab. In November 2018, he presented to the clinic for dyspnea and nonproductive cough, for which a computed tomographic (CT) scan of the chest was done and showed scattered ground glass opacities (GGO) in the lung bases bilaterally and mild diffuse bronchiectasis in all lobes (Figure 1). A spirometry was done which showed a new decreased forced vital capacity (FVC) of 67%, compared to a normal baseline prior to the transplant, and a low forced expiratory volume in 1 second (FEV1) of 40% and a low FEV1/FVC of 52% (Table 1). To note that all prior lung imaging and lung function testing was normal. In view of the spirometry results and findings of wheezing on lung examination, he was prescribed a short course of oral prednisone 40 mg that was tapered down then stopped over 2 weeks, oral moxifloxacin, along with vilanterol/fluticasone furoate and tiotropium bromide puffs with partial improvement. Upon follow-up on March 2019, he had persistent dyspnea, but denied the presence of cough or fever. A repeat CT scan of the chest showed development of new lower lobe predominant bilateral, peripheral, peribronchovascular consolidations in the areas of previously seen GGOs, with worsening traction bronchiectasis and evidence of a new architectural distortion (Figure 2), and a suspicion of organizing pneumonia was raised in the radiology report, with a suggestion of chronic pulmonary GVHD, and less likely infection or medication side effect. A list of the medications he was on, along with their pulmonary side effects is shown in Table 2. The patient refused to undergo a lung biopsy as advised to decide for immunosuppression or steroid course, and was prescribed a new course of levofloxacin. In May 2019, he presented back with fever, worsening dyspnea and a new productive cough of yellowish sputum. His procalcitonin level was also elevated of 9.4 ng/mL (normal laboratory value <0.05 ng/mL). A new CT scan of the chest showed further worsening in bilateral, mid-lung predominant consolidations and ground glass opacities, with changes of traction bronchiectasis and appearance of new cystic changes (Figure 3). A bronchoscopy with broncho-alveolar lavage (BAL) was done and detected the following: Para-influenza virus 2 on respiratory polymerase chain reaction (PCR) panel, gram negative rods on Gram stain, and one colony of Aspergillus species on fungal culture. Serum Aspergillus galactomannan was positive with a high index of 1.1 (normal laboratory index expected to be less than 0.5). In addition, the BAL cytology was reported as chronic inflammation with >90% lymphocytes and no malignant cells. Of note that Tuberculosis (TB) and Cytomegalovirus (CMV) PCR, Pneumocystis Jirovecii (PJP) PCR, mycobacterial culture, and Aspergillus galactomannan taken in BAL were all negative. Intravenous (IV) meropenem was given for 7 days for bacterial pneumonia and voriconazole 200 mg orally twice daily for 8 weeks was given for possible pulmonary aspergillosis. Both prophylactic Trimethoprim/sulfamethoxazole and Valacyclovir were added and his home inhalers were continued with significant improvement upon hospital discharge. He also finished his consolidation treatment with brentuximab the same month and his lymphoma was in complete remission. At this point, the diagnosis of pulmonary fibrosis secondary to recurrent pulmonary infections versus chronic pulmonary GVHD in the form of organizing pneumonia was entertained, however, systemic steroid treatment was deferred in view of his active pulmonary fungal infection. In August 2019, he was admitted again for fever and worsening dyspnea, found to have worsening upper lobes predominant pulmonary fibrotic changes and Influenza B infection for which he was treated with Oseltamivir, IV Piperacilin-tazobactam, and Levofloxacin. He was also started on oral prednisone 1 mg/kg daily with slow taper by 10 mg every 1 month, for a presumed diagnosis of organizing pneumonia, and he was maintained on prednisone for several months with inability to wean them off due to recurrence of dyspnea. Subsequent pulmonary imaging over the following year showed a steady progression of his consolidations and traction bronchiectasis, significant decrease in ground-glass abnormalities throughout both lungs, a decrease in FDG uptake indicative of decrease in the inflammatory process and formation of scar tissue with a remarkable spatial shift to the mid and upper lung zones and progressive appearance of new cystic lesions in the upper lobes bilaterally (Figure 4). His pulmonary function test (PFT) also showed further significant drop in his FEV1, and to a greater extent, his FVC (Figure 1).

lung diseases, bronchiolitis obliterans, graft versus host disease, hematopoietic stem cell transplantation, interstitial

PMC7720018_01

Female

A two-year-old Afro-Caribbean female presented with microcephaly during a ZIKV outbreak in Grenada, West Indies. Her mother was recruited from a public health center as part of a larger study investigating the impact of in utero Zika virus exposure on neurodevelopment. The mother provided written informed consent to support her child's participation in the study and also consented to publication of this case study. The mother had serum drawn at 24 (+-2) weeks gestation. Prenatal serology was positive for flavivirus and negative for alphavirus infection using IgM antibody captured enzyme-linked immunosorbent assay (MAC-ELISA). A plasmonic-gold (pGOLD) platform (Nirmidas Biotech, Palo Alto, CA) for measuring IgG against ZIKV and dengue virus (DENV) antigens was used to distinguish these possible flaviviral infections, with IgG avidity used to determine the timing of exposure. The pGOLD IgG immunoassay has demonstrated sensitivity and specificity to ZIKV greater than 90% and 98%, respectively, in the convalescent phase. Maternal pGOLD IgG immunoassay results were positive for ZIKV and DENV antibodies. IgG avidity testing showed ZIKV exposure within the prior 6 months and more remote DENV infection (i.e., prior to pregnancy). The infant had serum drawn at 2 months of age. Results from the pGOLD IgG immunoassay were positive for ZIKV and negative for DENV. The mother was 30 years of age at the time of delivery. Her pregnancy was uncomplicated, with no reported alcohol, drug, or tobacco use. The patient was born full-term via normal vaginal delivery. Meconium aspiration was noted and resuscitative assistance was provided. One-minute APGAR score was 2, 5-minute score was 3, and 10-minute score was 8. Facial dysmorphism was observed. Head circumference was 30 cm at birth (z = -3.5). Reflex testing was performed at 2 months of age with grasping, sucking, and plantar reflexes present and Moro and Galant reflexes absent.

congenital zika syndrome (czs), electroencephalography (eeg), focal epilepsy, microcephaly, telemedicine

PMC6035845_01

Male

A one-year-old Thai boy was referred to Phramongkutklao Hospital due to subacute fever, abdominal distension, mucous diarrhea, and failure to thrive. He was born at term with uneventful pregnancy, and he is the first child of nonconsanguineous parents. There was no history of autoimmune or primary immunodeficiency disorders in the family. Intradermal BCG vaccination was inoculated at the left buttock without any reaction within 3 months of life, and intramuscular vitamin K was routinely given after birth. He was exclusively breastfed. At 3 months of age, he developed frequent vomiting and irritability. Physical examination revealed enlarged and tense anterior fontanelle. CT brain showed hyperdensity lesion size of 1.5 x 1.8 cm at left temporal lobe with perilesional edema (Figure 1(a)) which was confirmed to be intracerebral hemorrhage. All hematologic, coagulation studies and biochemical laboratory tests (Table 1) were consistent with deficiency of vitamin K dependent clotting factors. The cause of vitamin K deficiency in this patient was presumed to be caused by malabsorption mechanism. Therefore, intravenous vitamin K was given for 3 days at initial presentation, and the coagulogram data was corrected within 24 hours. One week later, the patient developed steatorrhea. Fat malabsorption was suspected as the levels of fat-soluble vitamins were evaluated (Table 1). Cystic fibrosis was excluded by the negative sweat chloride test. At 4 months of age, perianal abscess was detected and treated with amoxicillin/clavulanic acid for 7 days without surgical drainage. However, subsequent pus culture was not performed. At the age of 6 months, lymphadenopathy of 3 cm in size at the left groin was detected. Fine needle aspiration was accordingly performed, and pus culture was found to be positive for BCG and the tuberculin skin test was positive at 15 x 20 mm. Chest X-ray revealed no pulmonary infiltration. The patient was diagnosed with BCG lymphadenitis and was treated with isoniazid and rifampicin. Interestingly, there was no history of tuberculosis contact in the family. Nevertheless, the patient did lose to follow-up which resulted in the delay of definite diagnosis in this patient. On physical examination at age of 1 year, his weight was 7.8 kg (<3rd percentile) and height was 69.5 cm (<3rd percentile). Abdominal distension, moderate hepatosplenomegaly, and ascites were detected. Left inguinal lymph node was still palpated with 1.5 cm in size. The site of BCG vaccination showed no induration. Physical examinations were unremarkable. Hematologic and biochemical laboratory tests were described (Table 1), and chest radiography showed consolidation at the left upper lobe (Figure 1(b)). Abdominal CT showed generalized ascites with evidence of hepatosplenomegaly. Abdominal paracentesis was performed, and the results were described (Table 1). Ascitic fluid adenosine deaminase (ADA) was performed because of suspicious of mycobacterial infection, and the result was compatibly high. The ascitic fluid PCR was positive for BCG. Disseminated BCG infection was diagnosed in our patient. IgG was slightly elevated (1,236 mg/dL) while IgM and IgA levels were normal (Table 1). Lymphocyte subset analyses revealed normal T-cell and B-cell counts. The neutrophil dihydrorhodamine (DHR) test revealed no fluorescence detection after granulocyte stimulation. The stimulation index (SI) was 1.21 which was compatible with XL-CGD (Figure 2). Finally, the patient was diagnosed with XL-CGD accompanied with disseminated BCG infection. This clarified the clinical of fat malabsorption leading to vitamin K deficiency since 3 months of age. Treatment was started with antituberculosis including isoniazid, rifampin, pyrazinamide, ethambutol, and amikacin. Itraconazole and co-trimoxazole were given as the prophylactic treatment. The clinical of ascites and steatorrhea was improved after 2 weeks of treatment. The DHR assay was also performed on the mother and revealed bimodal distribution compatible with the XL-CGD carrier (Figure 2). Allogeneic hematopoietic stem cell transplantation (HCT) is therefore planned as the curative treatment since the mother is six months pregnant. After informed consent was obtained from the patient's parents, genomic DNA was extracted from peripheral blood leukocytes using the commercial available kit as per the manufacturer's protocol. Thirteen coding exons and exon-intron boundaries of the CYBB gene were amplified by PCR using specific of primers for each exon as previously described. The PCR products were purified and directly sequenced in both forward and reverse directions. The reference sequences were NM_00397.3 for CYBB cDNA and NP_000388.2 for gp19-phox protein.

PMC4153261_01

Female

A 43 year-old nonsmoker female with progressive dyspnea and hypoxic respiratory failure referred to our transplant center at Imam Khomeini General Hospital with a primary diagnosis of pathologically proven idiopathic interstitial lung fibrosis (IPF) and no response to classic treatment with high dose prednisolone and azathioprine. She was healthy until 10 months before referral when she developed progressive dyspnea and cough with scant sputum. Primary evaluation at that time showed mild restrictive pattern on spirometry, and interstitial process in high resolution CT scan without honey combing suggestive of interstitial process like pulmonary alveolar proteinosis or nonspecific interstitial Pneumonitis (NSIP). Further evaluation with FOB and TBLB was nondiagnostic. An open lung biopsy at that time showed interstitial process compatible with NSIP. Based on the diagnosis of IPF prednisolone one milligram/kg plus azathioprine 150 mg were administered for the patient. No improvement was observed after 3 months of therapy and she got worse. She was put on long term oxygen therapy (5 liters/min) by nasal prong. However, she got worse and became wheelchair bound during the 6 months period of treatment and her physician decided to transfer her to our center for lung transplant. At the time of first visit she had dyspnea and tachypnea on bed despite 5 liters of O2 by nose prong. She had a Cushingoid face with cyanotic lips. Thoracic examination showed no crackles on auscultation and a partial reduction in expansion. No other important findings were seen except for obesity. No clubbing was seen. The patient was put on 12 liters of O2 with mask to improve oxygenation and further evaluations were carried out. Laboratory data showed normal CBC and differential count, hemoglobin = 16.5 mg/dl, hematocrit = 50.7 percent and normal ALT, AST, and Alkaline Phosphatase levels. LDH was minimally elevated. Other lab test results were within the normal range. ESR and CRP were also within the normal range. Antibody for HIV, HCV, and HBS and also HBS antigen were negative. Evaluation of pre-transplant viral and parasitic markers showed positive antibody of IgG type for Epstein-Barr virus, cytomegalovirus and toxoplasmosis with low titer of IgM antibodies. New CT scan of the lungs showed interstitial process with crazy paving pattern and no honey combing despite clinical progression of disease. Plethysmography showed well preserved lung volumes and minimal restriction (Table 1). Diffusion of the lung for CO (DLCO) was severely decreased. Reevaluation of the previous lung biopsy and new section of pathological block by the same and a new expert pathologist did not change the primary diagnosis of NSIP. Despite the pathologic report, re evaluation with FOB and bronchoalveolar lavage (BAL) ruled out PAP as a treatable cause. The patient was admitted to the hospital and FOB was done and BAL was obtained. BAL fluid had a completely turbid and milky appearance, highly suggestive of PAP. Positive PAS staining confirmed PAP and whole lung lavage was considered. Because of very severe hypoxia it was impossible to do the whole lung lavage with the usual technique under general anesthesia and therefore segmental bronchial washing with FOB was considered. FOB was done under local anesthesia at the bronchoscopy unit. Midazolam and morphine sulfate were administered for sedation. Cardiac, blood pressure, and SPO2 monitoring was done at the time of bronchoscopy in the bronchoscopy unit. To preserve oxygenation throughout the procedure, the bronchoscope was passed through a small fit hole in the reservoir mask. Each time the bronchoscope was wedged into segmental bronchi 200 cc of warm saline was injected with 50 milliliter syringe and the fluids were then suctioned out. No balloon was used for blockage of bronchi. Both lungs were washed by warm (34 C) saline solution in 14 sessions, each time 3-5 segments with 3 liters of normal saline, based on the patient's tolerance. After the first 2 sessions, bronchoscopic washing was done as outpatient every 2-3 days. She got better with progression of bronchoalveolar washing and no longer needed oxygen support and function class improved dramatically. At the end of therapy she was symptom free and six-minute walk test was 650 meter. New CT scan showed resolution of the interstitial process ([Figures 1A, B] and [Figures 2A, B]) and the new DLCO and plethysmography results were close to the normal range (Table 1); 12 months after lung washing she was still in good condition with no symptoms at rest or exertion and pulmonary function tests remained unchanged.

fiberoptic bronchoscopy, pulmonary alveolar proteinosis, segmental lung lavage

HRCT of the patient before segmental lung lavage at the level of the bronchus intermedius.

PMC4153261_01

Female

A 43 year-old nonsmoker female with progressive dyspnea and hypoxic respiratory failure referred to our transplant center at Imam Khomeini General Hospital with a primary diagnosis of pathologically proven idiopathic interstitial lung fibrosis (IPF) and no response to classic treatment with high dose prednisolone and azathioprine. She was healthy until 10 months before referral when she developed progressive dyspnea and cough with scant sputum. Primary evaluation at that time showed mild restrictive pattern on spirometry, and interstitial process in high resolution CT scan without honey combing suggestive of interstitial process like pulmonary alveolar proteinosis or nonspecific interstitial Pneumonitis (NSIP). Further evaluation with FOB and TBLB was nondiagnostic. An open lung biopsy at that time showed interstitial process compatible with NSIP. Based on the diagnosis of IPF prednisolone one milligram/kg plus azathioprine 150 mg were administered for the patient. No improvement was observed after 3 months of therapy and she got worse. She was put on long term oxygen therapy (5 liters/min) by nasal prong. However, she got worse and became wheelchair bound during the 6 months period of treatment and her physician decided to transfer her to our center for lung transplant. At the time of first visit she had dyspnea and tachypnea on bed despite 5 liters of O2 by nose prong. She had a Cushingoid face with cyanotic lips. Thoracic examination showed no crackles on auscultation and a partial reduction in expansion. No other important findings were seen except for obesity. No clubbing was seen. The patient was put on 12 liters of O2 with mask to improve oxygenation and further evaluations were carried out. Laboratory data showed normal CBC and differential count, hemoglobin = 16.5 mg/dl, hematocrit = 50.7 percent and normal ALT, AST, and Alkaline Phosphatase levels. LDH was minimally elevated. Other lab test results were within the normal range. ESR and CRP were also within the normal range. Antibody for HIV, HCV, and HBS and also HBS antigen were negative. Evaluation of pre-transplant viral and parasitic markers showed positive antibody of IgG type for Epstein-Barr virus, cytomegalovirus and toxoplasmosis with low titer of IgM antibodies. New CT scan of the lungs showed interstitial process with crazy paving pattern and no honey combing despite clinical progression of disease. Plethysmography showed well preserved lung volumes and minimal restriction (Table 1). Diffusion of the lung for CO (DLCO) was severely decreased. Reevaluation of the previous lung biopsy and new section of pathological block by the same and a new expert pathologist did not change the primary diagnosis of NSIP. Despite the pathologic report, re evaluation with FOB and bronchoalveolar lavage (BAL) ruled out PAP as a treatable cause. The patient was admitted to the hospital and FOB was done and BAL was obtained. BAL fluid had a completely turbid and milky appearance, highly suggestive of PAP. Positive PAS staining confirmed PAP and whole lung lavage was considered. Because of very severe hypoxia it was impossible to do the whole lung lavage with the usual technique under general anesthesia and therefore segmental bronchial washing with FOB was considered. FOB was done under local anesthesia at the bronchoscopy unit. Midazolam and morphine sulfate were administered for sedation. Cardiac, blood pressure, and SPO2 monitoring was done at the time of bronchoscopy in the bronchoscopy unit. To preserve oxygenation throughout the procedure, the bronchoscope was passed through a small fit hole in the reservoir mask. Each time the bronchoscope was wedged into segmental bronchi 200 cc of warm saline was injected with 50 milliliter syringe and the fluids were then suctioned out. No balloon was used for blockage of bronchi. Both lungs were washed by warm (34 C) saline solution in 14 sessions, each time 3-5 segments with 3 liters of normal saline, based on the patient's tolerance. After the first 2 sessions, bronchoscopic washing was done as outpatient every 2-3 days. She got better with progression of bronchoalveolar washing and no longer needed oxygen support and function class improved dramatically. At the end of therapy she was symptom free and six-minute walk test was 650 meter. New CT scan showed resolution of the interstitial process ([Figures 1A, B] and [Figures 2A, B]) and the new DLCO and plethysmography results were close to the normal range (Table 1); 12 months after lung washing she was still in good condition with no symptoms at rest or exertion and pulmonary function tests remained unchanged.

fiberoptic bronchoscopy, pulmonary alveolar proteinosis, segmental lung lavage

HRCT of the patient before segmental lung lavage at the level of the carina.

PMC3038953_02

Male

A 16-year-old Caucasian boy with a history of attention-deficit hyperactivity disorder, asthma, and allergies presented to the emergency department with intoxication and vomiting after falling and sustaining minor head trauma. He had ingested an unknown quantity of Red Bull mixed with vodka at a party. He denied chest pain, syncope, palpitations, shortness of breath, and fever. His home medications included amphetamine and dextroamphetamine (Adderall XL), 30 mg daily; montelucast (Singulair), 10 mg daily; loratadine (Claritin), 10 mg daily; and doxycycline, 100 mg daily for acne. Physical examination revealed an irregularly irregular heartbeat at 160 beats per minute with no murmurs. ECG showed chaotic atrial tachycardia/atrial fibrillation with rapid ventricular response (Figure 3). Blood ethanol level was 155 mg/dl. Cardiac enzymes were unremarkable, and serum electrolytes, thyroid-function tests, and a lipid profile were normal. A cardiac ECG revealed a structurally normal heart without thrombus. Computed tomography of his brain was normal. The patient was given a bolus of 2 L of normal saline, and his heart rate responded by decreasing from 160 beats per minute to 90 to 110 beats per minute. He remained hemodynamically stable and was placed on a cardiac monitor overnight with continued intravenous fluid support. Approximately 12 hours after presentation, he spontaneously reverted to a normal sinus rhythm (Figure 4). He remained asymptomatic with a normal sinus rhythm during subsequent cardiology follow-up the next week. Of note, the Division of Pediatric Cardiology at the Stony Brook University Medical Center has cared for two other cases of atrial fibrillation in healthy adolescents after excessive caffeine consumption in the past five years. These cases were not included in this series, as the patients were unable to be located to provide their consent.

PMC3981337_01

Male

A 46-year-old man complained about 6-month right abdominal quadrant pain with no fever or jaundice. Physical examination did not reveal anything of interest and biological test results were normal. Abdominal ultrasound showed a hypo-echoic mass with peripheral vascularization, located in segment V of the liver and measuring 25x21 mm. Abdominal computed tomography confirmed the presence of a hypodense mass indicating metastasis. Various examinations (endoscopy, tumor markers) undertaken to find a primitive neoplasm were negative and thus it was decided to operate. During surgical exploration, a tumor measuring 3 cm was discovered in segment V (Figure 1). Since the tumor was located near the gallbladder, five segmentectomy with cholecystectomy were conducted. Histological examination confirmed the diagnosis of hepatic tuberculosis. Further examinations gave no indication of the presence of tuberculosis elsewhere. Antibacillary antibiotics were prescribed for a period of six months. The patient was faring well at the one-year check up.

computed tomography, hepatic tuberculosis, magnetic resonance imaging, pseudo-tumoral, surgery

PMC3981337_02

Male

A 49-year-old man underwent an operation for right colon cancer with synchronous metastasis of segment VII of the liver. The right colon, as well as metastasis, were removed. The results of histological examination led to a diagnosis of T3N1M1 carcinoma of the right colon. Adjuvant chemotherapy (FOLFOX) was prescribed. After six months, thoraco abdominal tomography was carried out, showing a hypodense mass measuring 2 cm located on segment VII. The carcinoembryonic antigen level was normal. The patient underwent surgery on the basis of a diagnosis of hepatic metastasis. Histological examination led to a diagnosis of hepatic tuberculosis. The patient received anti-bacillary antibiotics and the clinical and radiological outcomes were expected to be good.

computed tomography, hepatic tuberculosis, magnetic resonance imaging, pseudo-tumoral, surgery

PMC3981337_03

Female

A 36-year-old woman with a history of hydat ic cyst complained about abdominal quadrant pain with fever, night sweats and chills. Physical examination did not find any jaundice or fever. Biological tests were normal. Abdominal ultrasound showed a hypo-echoeic mass in segment VII of the liver. This mass measured 4x3 cm and abdominal computed tomography confirmed the presence of a hypodense mass with a peripheral enhancement of segment VII segment of the liver. Hydatic serology was negative. Upper gastrointestinal endoscopy, colonoscopy, thoraco-abdominal computed tomography scan and pelvic examination did not show anything of interest. Percutaneous ultrasound guided biopsy was negative. No anaphylactic reaction occured during the biopsy. The decision was made to operate. As a liver abcessed tumor was discovered per-operatively, in contact with the diaphragm, a resection of the mass was conducted. Histological examination led to a diagnosis of hepatic tuberculosis. The patient received anti-bacillary antibiotics and the clinical and radiological outcomes were expected to be positive.

computed tomography, hepatic tuberculosis, magnetic resonance imaging, pseudo-tumoral, surgery

PMC4153279_01

Male

A 28 year-old man referred to the emergency department of our hospital with recurrent episodes of hemoptysis in the past few weeks. He was a known case of cervical malignant melanoma from 6 years ago, and had pulmonary metastases from one year ago. He had received 5 complete chemotherapy courses; the last one was 3 months ago. The patient had recurrent episodes of hemoptysis and the amount of blood in the most severe episode was about 100cc. Medical treatment was not effective for reducing the frequency or severity of hemoptysis. The patient also complained of malaise and fatigue as well as minor dyspnea and recurrent coughs with faint streaks of blood. He did not complain of fever, nausea or vomiting and did not give any history in favor of tuberculosis, but his father did have a history of tuberculosis. Likewise, the history of tobacco addiction was negative in the patient. At the time of admission, there was no sign of hypoxemia in the pulse oximetry of the patient. Vital signs were as follows: respiratory rate: 24/min, pulse rate: 88/min, blood pressure: 110/88mmHg and body temperature: 37.5 C. Physical examination revealed no lymphadenopathy in the cervical region. The patient had normal heart sounds but reduced pulmonary sounds at the base of both lungs. There were no abnormal findings in the physical examination elsewhere. Laboratory results at the time of admission showed hemoglobin of 11.8mg/dl, hematocrit of 38.7% and normal coagulation tests. Electrolytes, blood gases and renal function tests were all normal. Primary supportive treatments were started right after admission and then a CXR and a pulmonary CT-scan were obtained. CXR showed multiple nodules and masses of different sizes scattered in both lung parenchyma (Figure 1). CT-scan showed right-sided pleural effusion as well as nodules which were also found on CXR. There was evidence of consolidation and alveolar infiltration around one of the nodules at the posterior segment of the right upper lobe (Figure 2A,B,C). The patient then underwent bronchoscopy which revealed bloody exudates in the orifice of the right main bronchus. No endobronchial lesion was detected. In cytological evaluation of bronchial exudate, there was no evidence of atypical cells. The culture of this exudate was negative as well, and there was no sign of acid fast bacilli. Laboratory data after a week showed hemoglobin of 10mg/dl and hematocrit of 34%. With regard to the recurrence of hemoptysis during hospitalization, the patient was considered for BAE and transferred to the endovascular unit of our teaching hospital. After prepping the patient under heart monitoring, and local anesthesia, right femoral artery was punctured using Seldinger's technique and a 5-French arterial sheath was introduced. Non-selective angiography was preformed after putting a guide wire and a pigtail catheter into the aortic arch. No abnormal finding was detected in aortogram but the approximate anatomical situation of bronchial artery was revealed. After changing the pigtail catheter, and with the use of a 4-French Cobra (C1) catheter, the common trunk of the right and left bronchial arteries was selectively catheterized at the vicinity of the 5th thoracic vertebra and along the left main bronchus. Bronchial arteries had normal diameter and course. There were also fine vessels and abnormal blush along the right and left bronchial arteries coinciding with the location of metastatic pulmonary nodules in both lungs (Figure 3). Under continuous fluoroscopy and after confirming the suitable location of the catheter tip, embolization of the common trunk of both bronchial arteries was concomitantly performed using 300-500 micron polyvinyl alcohol (PVA) particles. A control arteriography was performed afterwards which showed embolization of all of the end branches of both bronchial arteries (Figure 4A,B). The catheter was then removed and after withdrawing the arterial sheath, hematoma at the puncture site was controlled. After 4 hours, the patient was transferred to the ward without any problem and was discharged after 2 days. There was no recurrent episode of hemoptysis during hospitalization and in the next 2 months after embolization.

bronchial artery, embolization, hemoptysis, melanoma

PMC9840545_01

Male

A 46-year-old, 86 kg male with past medical history of non-insulin dependent type II diabetes mellitus, hyperlipidemia, hypothyroidism, gout, history of Hodgkin's lymphoma status after chemoradiation therapy (in remission), and recent diagnosis of bilateral carotid artery stenosis and pheochromocytoma presented for laparoscopic adrenalectomy. Six months prior, the patient experienced acute slurred speech, numbness, and left facial twitching while on a fishing trip. Non-contrast head CT scan was obtained and normal. With spontaneous resolution of symptoms, he was diagnosed with a transient ischemic attack (TIA) and discharged home with close follow-up with his primary care provider. One week later, a non-contrast brain MRI demonstrated a right frontal cortex infarct. CT angiogram of the neck and chest demonstrated 60% stenosis of the left common carotid artery and 60-70% stenosis of the right common carotid artery. Subsequent bilateral carotid artery duplex study showed proximal right common carotid artery with severe stenosis (70-99% occlusion), proximal right internal carotid artery with mild stenosis (1-49% occlusion), proximal left common carotid artery with moderate stenosis (50-69% occlusion), and proximal left internal carotid artery with mild stenosis (1-49% occlusion). His vascular surgeon considered him a poor candidate for minimally invasive intervention of the right and potentially left common carotid arteries due to prior neck radiation, and he was scheduled to undergo carotid endarterectomy. The patient was also being evaluated for a growing right adrenal mass noted on abdominal CT scan obtained to monitor for recurrence of Hodgkin's lymphoma. CT scan 3 years prior demonstrated a 1.2 cm right adrenal mass, but as he was asymptomatic, a watch, wait, and re-evaluate approach was taken. His most recent CT scan demonstrated that the right adrenal mass had increased in size to 2.2 cm. Around this time, the patient endorsed difficulty in managing his previously well-controlled diabetes, orthostasis, neuropathy in bilateral hands and feet, and occasional muscle cramps. He denied any known family history of endocrine tumors or personal history of hypertension, flushing, palpitations, rapid heartbeat, or headache. Subsequent lab testing was notable for a 24-hour urine normetanephrine of 1400 pg/mL and free normetanephrine of 3.9 pg/mL, and the patient developed significantly elevated blood pressures. He was referred to general surgery for consultation regarding right adrenalectomy for suspected pheochromocytoma. During this time, the patient developed worsening symptoms including consistently elevated blood pressure and heart rate and increasing challenges controlling his blood glucose levels. The patient's endocrinologist prescribed PO doxazosin for alpha blockade with instructions for home blood pressure and heart rate monitoring. The patient was instructed to increase his dose of doxazosin every 3-4 days until his seated systolic blood pressure was consistently between 90-120 mmHg and his heart rate between 60-70 bpm. He was additionally instructed to maintain a daily sodium intake of greater than 5000 mg and maintain adequate fluid hydration. Once alpha blockade was achieved, he was started on beta blockade with PO atenolol. On the morning of surgery, the patient presented with well-controlled blood pressure with BP 123/75 mmHg. His anesthesiologist and general surgeon contacted the patient's vascular surgeon to discuss the risks and benefits of proceeding with pheochromocytoma resection prior to carotid intervention. The multidisciplinary team agreed it was appropriate to proceed with adrenalectomy and plan for carotid intervention after postoperative recovery. The patient was subsequently taken to the operating room for retroperitoneoscopic right adrenalectomy. He was premedicated with 4 mg IV midazolam, and a preinduction arterial line was placed. Induction of general anesthesia was achieved with lidocaine and propofol with rocuronium for muscle paralysis, and intubation was performed successfully on the first attempt with direct laryngoscopy. Bilateral cerebral oximetry was used to monitor cerebral oxygen saturation throughout the case. Sevoflurane was used for maintenance of anesthesia. Ketamine boluses were administered for anti-nociception. Dexamethasone and ondansetron were administered for postoperative nausea and vomiting (PONV) prophylaxis. A total of 10 units of insulin were administered to treat blood glucose elevations in the low 300 s. Intraoperative hypotension following resection of the tumor was treated with volume resuscitation with crystalloid and norepinephrine and vasopressin infusions and boluses. Cerebral oximetry remained within 20% of baseline throughout. The operation was performed without complication. Following the operation, the patient was extubated and brought to PACU in stable condition. Postoperative pain was well controlled with oxycodone and acetaminophen. Postoperative course was relatively uneventful with the exception of persistent hyperglycemia requiring consultation of the inpatient endocrinology service, while in the hospital, the patient's blood pressure medications were held and his blood pressure remained well controlled. On postoperative day 1, the patient was alert and oriented, vitals were stable, and pain was well controlled, ambulating with very little assistance, tolerating a regular diet, and voiding independently. He was sent home with instructions to follow-up with endocrinology and general surgery and to continue to closely monitor his blood pressure.

PMC10154083_01

Male

A three-year-old male patient was admitted with complaints of pain and swelling in both ankles and wrists and rash with fever for more than 6 weeks. In addition to these clinical findings, he was referred to our hospital for the evaluation of increased acute phase reactants and examination of splenomegaly and abdominal distension. In the physical examination, the patient had fever and significant swelling especially in the right knee. The patient was the second child of consanguineous parents. There was a third-degree cousin marriage without any other parental comorbidities. The other two children of the family were doing well and did not have any health problems. A preliminary diagnosis of systemic juvenile idiopathic arthritis (JIA) was considered because of complaints of fever, splenomegaly, rash, and arthritis lasting more than 10 days. Laboratory findings revealed an increase in acute phase reactants as C-reactive protein (CRP): 13.4 mg/dl (normal: 0-0.5), ferritin: 143.5 ng/ml (normal: 7-140), erythrocyte sedimentation rate (ESR): 26 mm/h (normal: <15 mm/h), and serum amyloid A (SAA): 209 mg/l (normal: <6.4). Hypergammaglobulinemia (IgG : 3810 mg/dl, IgA : 165 mg/dl, and IgM : 161 mg/dl) and positive antinuclear antibody (ANA) (1/160 cytoplasmic) were detected. Anti-double-stranded DNA antibody (Anti-DsDNA) was negative. His antistreptolysin O titer (ASO), rheumatoid factor (RF), and antineutrophil cytoplasmic antibody tests were all negative. PPD (purified protein derivative) intradermal test for tuberculosis examination resulted as anergic. Brucellosis and toxoplasmosis laboratory tests were both negative. Ophthalmologic examination for uveitis was found to be normal. No pathological findings were detected in the chest X-ray. Since the patient had splenomegaly, bone marrow aspiration was performed for possible malignancies and macrophage activation syndrome. In the bone marrow examination, no signs of hemophagocytosis, atypical cells, and blasts were found while a few hypersegmented neutrophils were observed. Treatment of nonsteroidal anti-inflammatory drugs (NSAIDs) was started. Arthritis, fever, and rash began to recover after two weeks of treatment. However, moniliasis was observed on the oral mucous membranes and tongue in the oropharyngeal examination. Additionally, nail dystrophy and onychomycosis in the right thumb were observed. Nail dystrophy was secondary to onychomycosis and occurred after 4-5 months after onychomycosis. The lymphocyte subset analysis by flow cytometry and T/B cell proliferation tests resulted normal. However, without genetic analysis, we could not exclude innate immune system deficiency, and intravenous immunoglobulin (IVIG) treatment (in a dose of 0.5 gm/kg, once in four weeks) was started as it was used both in systemic juvenile idiopathic arthritis and in innate immune deficiencies. Then, genetic examination could be performed to exclude primary immunodeficiency in this case with chronic onychomycosis. STAT-1 GOF mutation was considered due to moniliasis, onychomycosis, arthritis, hypergammaglobulinemia, and consanguineous marriage. In targeted next-generation sequencing (TNGS), A homozygous mutation in the AIRE gene SAND domain (c.769C > T, p.Arg257Ter) was detected (Figure 1). Then, the patient was diagnosed with APECED syndrome. The parents were heterozygous for the same mutation. After a short while, he had cough and fatigue and was hospitalized with the diagnosis of pneumonia. In the lung examination, diffuse crepitant rales were present, more prominent on the left. Acute phase reactants were found to be high. Community-acquired pneumonia was considered, with no sequelae. Coronavirus 229E/NL6 was detected in the respiratory virus panel. IVIG treatment was given to prevent chronic infections and for immunomodulation purposes, as it is a Th17-mediated disorder, and T cell assistance was not sufficient. Dental caries developed in the follow-up of our patient. No other clinical problems were encountered in the next two years with IVIG treatment and fluconazole and trimethoprim sulfamethoxazole prophylactic treatment. He also recovered from arthritis very well without any other medication. At the age of five, hypoparathyroidism developed with low calcium, high phosphorus, low parathormone, and high 25OHD vitamin levels. He is still on treatment with calcium lactate, calcitriol, trimethoprim sulfamethoxazole, fluconazole prophylaxis, and IVIG, and he is doing well.

PMC7243805_01

Female

In April 2018, a 47-year-old woman came to our attention for dyspnea and tachycardia under exertion. An x-ray of the chest showed a large mass in the left hemithorax. A CT scan with enhancement presented a 40 x30 cm mass involving the left upper lobe of the lung. A CT guided biopsy gave a diagnosis of benign lung tumor. An Emission Tomography - Computed Tomography (PET/CT) scan showed a very mild uptake at the level of the nodule (SUV max = 2.3) with no other signs of uptake in other parts of the body (Figure 1). For the symptomatology and the dimension of the mass, the patient underwent a left upper lobectomy through lateral thoracotomy. The final histology showed an IMT of the lung. The cells were positive for actin in smooth muscle, although negative for ALK, MNF116, and estrogenic receptors, as well as for tuberculosis. Patient underwent a clinical check ten days after surgery by the oncologist who suggested a period of follow up every 6 months for the first and second year from surgery, and every year after the second year, for a total of 5 years of radiological and clinical monitoring.

cancer stem cells, cancer stem-like cells, inflammatory myofibroblastic tumor of the lung, mitosis, target therapy

PMC4715889_01

Male

A 15-year-old, previously healthy boy without a history of smoking or drug abuse, admitted to the hospital with acute epigastric pain without dyspnea or heartburn. On physical examination the boy was pale with tachycardia (110/min), but normal blood pressure (110/70 mmHg) and normal capillary oxygen saturation in room air (SPO2 99%). Tenderness in the upper abdomen was present. Laboratory investigations showed mild iron deficiency anemia (haemoglobin concentration 7.1 mmol/l, mean cellular volume 65 fl, serum iron 4 mmol/l, serum ferritin 3 g/l) with normal infection parameters. X-ray revealed free air under the right diaphragm. Abdominal ultrasound and CT scan were performed in search of underlying abnormalities, but none could be detected. At laparotomy, gastric perforation was found, which was repaired after refreshing the margins and tissue was sent for histopathology. Histopathology of the fragments showed ulceration without demonstrable Helicobacter pylori; recognizable mucosa was lacking. Subsequent gastro-duodenoscopy showed macroscopically a nodular aspect of the corpus with remarkably coarse gastric folds and pseudo-polyps (Fig. 1). Histological examination of gastric biopsies showed active chronic inflammation with lympho-plasma-cellular infiltration and a thickened sub-epithelial collagenous band, up to 23 mum, consistent with the diagnosis collagenous gastritis; the duodenal mucosa was normal. The patient was treated with iron supplementation because of persistent anemia. Repeated gastroscopies over the years yielded similar results with collagen bands of up to 22-29 m (Fig. 2,3); colonoscopy revealed normal colonic mucosa, both macroscopically and on histological examination. At the age of 18 year, the patient is asymptomatic, but needed frequent courses of iron replacement therapy.

acute abdomen, collagenous gastritis, gastric perforation

PMC4411815_01

Female

A 50-year-old female presented to the emergency department with pain in the abdomen since 5 days, vomiting and constipation since 3 days. There was no history of fresh bleeding per rectum or malena. She had a history of abdominal hysterectomy 2 years back for multiple uterine fibroids. She had no other co-morbidities, and her family history was not significant. On examination she was conscious, oriented with a regular low volume pulse of 98/min, blood pressure 98/66 mmHg, respiratory rate 22/min, and temperature of 98.8 F. Abdominal examination revealed mild distension with visible peristalsis. A lower midline irregular scar was seen; no lump was palpable. All the hernial orifices were intact. The patient had generalized tenderness, and the bowel sounds were exaggerated. Rectum was empty on per rectal examination, and there was no evidence of any growth. Clinical impression of acute intestinal obstruction was made, and the patient was subjected to blood and radiological investigations. Her blood investigations were - hemoglobin: 9.1 g/dl, total leucocyte count: 7000 cells/mm3, serum bilirubin 0.9 mg%, serum glutamic-oxaloacetic transaminase: 55 IU, serum glutamic pyruvic transaminase: 48 IU, blood urea: 29 mg%, serum creatinine: 1.4 mg%, potassium: 3.2 meq/l, sodium: 139 meq/l, random blood sugar: 98 mg% Patient was subjected to X-ray abdomen and chest. X-ray abdomen showed multiple air fluid levels while chest X-ray was normal. Computerized tomography scan was not done as it was not available in emergency. Ultrasound Abdomen revealed distended bowel loops. Based on history, clinical examination and X-ray findings, an impression of acute intestinal obstruction secondary to postoperative adhesions was made. Exploratory laparotomy was planned after adequate resuscitation. Exploration revealed distended small bowel and caecum with a circumferential growth at the hepatic flexure of size around 5 cm x 5 cm. Large bowel distal to the lesion was collapsed. The mesenteric lymph nodes were enlarged, and there were three liver lesions, two on the right lobe and one on the left ranging in size from 2 cm to 5 cm. There was no evidence of any free fluid or peritoneal deposits. An extended right-sided hemicolectomy with ileocolic, end-to-end anastomosis was done. Biopsy from the liver lesion of the largest size was taken. Mass closure of the abdomen was done with a single drain in the pelvis. Patient recovered well though she developed superficial surgical wound infection which was treated with irrigation and antibiotics as per the culture and sensitivity. Post-operative contrast enhanced computerized tomography of the abdomen showed multiple hypodense lesions in both lobes of the liver suggestive of metastases [Figure 1a and b]. Histopathological examination of the resected bowel revealed well-differentiated mucin secreting adenocarcinoma invading the muscular layer [Figure 2c and d]. Twelve lymph nodes isolated were uninvolved by the tumor (Stage pT2N0). Biopsy from the liver nodules showed multiple confluent epithelioid granulomas with caseation necrosis suggestive of TB [Figure 2a and b]. No metastatic deposit was seen. Based on the histopathology findings, patient was put on anti-tubercular treatment. Chemotherapy was not started as it was a T2 tumor and patient was put on regular follow-up. Ultrasound abdomen done after 2 months showed absence of any lesions in the liver. Carcinoembryonic antigen done after 3 months of surgery was 1.2 ng/ml. Thus, the patient responded well to anti-tubercular treatment and is still continuing with the treatment.

carcinoma colon, hepatic lesion, hepatic tuberculosis

PMC10259498_01

Male

On 10 April 2017, a 77-year-old male was referred to our department for persistent hyperbilirubinaemia and symptoms, including jaundice, tea-coloured urinary ascites and bilateral leg swelling, approximately 3 months after a few trials of initiation, discontinuation, and switching of anti-TB treatment. Physical examination 1 week prior (3 April 2017), the patient had undergone oesophago-gastro-duodenoscopy and was diagnosed with antral gastritis. Concerning recent medical history, the patient had undergone a thorax CT (1 February 2017) showing widespread, scattered cystic bronchiectasis, and fibrosis in both lung fields affecting more the right apicoposterior, the lateral segment of the right middle lobe, and all segments in the right lower lobe, the left upper lobe, left inferior lingual, and the whole left lower lobe. Acalculous cholecystitis, multiple liver cysts, right exophytic simple renal cyst, and lumbar spondylosis were also observed. Clinical and ultrasound follow-up (17 April 2017) showed a liver homogenously increased in echogenicity and smoothness (liver span measured 14.2 cm) and a well-defined anechoic lesion (1.5x1.3 cm) in segment II in keeping with the liver cyst. Biliary trees were not dilated, the gall bladder was well distended, and there was no calculus or wall thickening. The portal vein was patent and not dilated (7 mm in diameter), the pancreas was normal with no peripancreatic mass or collection, and the spleen was homogeneous with no focal lesions (9.5 cm in length). Moderate ascites in the upper abdomen were observed. Regarding the anti-TB interventions, TB was initially treated as smear-negative pulmonary TB with an EHRZ regimen (1 January 2017), suspended the following month due to deranged liver enzyme activity. The treatment was then resumed with levofloxacin 500 mg once daily and changed to a regimen with streptomycin, ethambutol and moxifloxacin on 5 March 2017; 2 months later (26 April 2017), streptomycin therapy was disrupted and replaced by Augmentin 1.2 g three-times daily (TDS) a few days after. Within 3 weeks (22 May 2017), the treatment was stopped due to the severity of adverse drug reactions from medications. At the physician's examination (10 April 2017), hepatomegaly was palpable and jaundice was present. The patient's whole clinical picture suggested that the clinical features were in keeping with fatty liver disease with a simple liver cyst, and biochemical abnormalities were suggestive of DILI due to anti-TB treatment. To manage liver enzyme activity, the patient was prescribed treatment with silymarin 140 mg TDS for 3 months (10 April to 3 July 2017) because no other treatment-suitable options were available, and the patient was not eligible for clinical trials due to his medical conditions. In routine biochemical and liver function tests (Table 1), altered liver enzyme levels were progressively decreasing, and, at the follow-up visit (17 July 2018), AST and alkaline phosphatase (ALP) levels, in particular, were significantly reduced (Table 1). The patient's clinical events are summarized in Table 2.

case report, deranged liver enzymes, drug-induced liver injury, fatty liver disease, silymarin, tuberculosis treatment

PMC4217757_01

Female

The patient was a 40-year-old female, initially diagnosed as UC (total colitis type) at the age of 15. She received a restorative proctocolectomy with the stapled ileo-anal canal J pouch anastomosis at the age of 22, but developed a rectovaginal fistula originating from the residual rectum at the eighth postoperative day. The surgical treatment of the fistula was repeated four times in our service (first was simple sutures and temporally ileostomy, second was transanal repair using mucosal flap, third was transanal repair using mucosal flap and temporally ileostomy, and fourth was transanal repair using mucosal flap) during the 10-year period, but it recurred in intervals ranging between 2 months and 5 years after the operation. The last recurrence occurred at the age of 32, but the surgical repair was considered to be difficult and a conservative treatment was indicated. At the age of 40, she developed frequent diarrhea (30 times/day), including bloody excrement, with consequent increasing of drainage from the rectovaginal fistula. Due to body weight loss associated with difficulty of dietary ingestion, she was admitted for a treatment. After the hospital admission, intravenous hyperalimentation with restriction of oral administration has been continued for 1 week. Though the dehydration and denutrition were significantly improved as well as the stool frequency, the symptoms from the rectovaginal fistula persisted. Figure 1 shows the abdominal magnetic resonance imaging (MRI) and barium-enema study of the rectovaginal fistula before starting treatment. Surgical treatment was considered unfeasible, therefore the conservative management with infusions of infliximab was advocated. After confirmed to be negative for tuberculosis and the informed consent was obtained, the infliximab-based treatment, consisting of intravenous infusions of infliximab at a dose of 5 mg/kg, at day 0 and weeks 2, 6, 10 and then every 8 weeks, was started. Figure 2 shows the time course of the symptomatic changes after the admission. Four weeks after the first infusion, drainage from the fistula was evidently reduced, and 2 weeks later, the fistula was completely closed. Thereafter, no recurrence of the fistula is observed for at least 26 months. We continue the administration of infliximab at the outpatient. Figure 3 shows the results of the imaging study 1 year after the start of infliximab therapy. The closure of the fistula was confirmed by the abdominal MRI and the barium-enema study.

anti-human tumor necrosis factor alpha antibody, rectovaginal fistula, ulcerative colitis

PMC5343238_01

Male

A 52-year-old man was admitted to the emergency room because of a headache, fever (39 C), alternating with hypothermia, confusion, and weakness in the left leg. The patient also reported diarrhea, loss of appetite, and weight loss of 12 kilograms in the past three months. He had been diagnosed with HIV infection a few days before his admission. He denied previous diseases, using continuous medication, and previous hospital admissions or surgeries. At the physical examination, the patient presented a regular status with confusion, isochoric and photoreactive pupils, and no signs of meningeal irritation, but a loss of force in the left leg. Computed tomography (CT) scan showed an area of hypodensity in the white matter on the upper convexity of the right frontal lobe. A magnetic resonance image (MRI) showed a hypersignal in T2 on the upper and lower right frontal gyri, in the left occipital lobe, and lesions with ring enhancement in the deep upper left temporal sulcus (Figure 1). Laboratory exams showed a lymphocyte CD4 count of 94 cells/mm3, and HIV viral load of 479,365 copies ml. A reactive serological test for syphilis showed a titer 1 : 8, which was previously treated with penicillin G benzathine. A lumbar puncture was performed, and the cerebrospinal fluid (CSF) analysis showed 3 leucocytes/mm3, proteins of 28 mg/dL, and glucose of 39 mg/dL. CSF cultures were negative for bacteria, mycobacteria, and fungi. PCR testing for JCPyV virus was negative. However, PCR testing for BKPyV was positive. Detection of BKPyV consisted of a semi-nested PCR with two 20-base oligomer primers (PEP-1 and PEP-2) followed by second round PCR with 40-nucleotide sequence (BEP-1 and PEP-1), as previously described. The length of the BKPyV targeted for amplification was 176 nucleotide pairs. At this same hospitalization, the patient was diagnosed with pulmonary tuberculosis, and a regime of rifampin, ethambutol, pyrazinamide, and isoniazid was provided. The patient was started on highly active antiretroviral therapy (HAART). However, he presented signs of sepsis of unknown origin twenty days after the admission and died three days later.

PMC7875809_01

Male

Case 1: on March 31st, a 46 years old male patient, with a previous history of mild depressive episode treated with vortioxetine since November 2019, and diagnosed with COVID-19 after he presented with dry cough, fever, sore throat and fatigue. The patient had positive result on reverse transcription polymerase chain reaction (PCR) analysis of nose swab specimen. He was admitted into isolated COVID-19 ward and received chloroquine- azithromycine association. He had an electrocardiogram every two days. QT interval was normal to prolonged (corrected QT max: 490ms). On the ninth day of treatment, the patient showed symptoms of distress and insomnia. On the evening of the same day, he showed abrupt onset of psychotic symptoms such as visual hallucinations and incoherent speech, with the outburst of odd behavior and repeated attempts to run away from hospital. The patient s insight was preserved. The cerebral CT scan was normal. We performed laboratory tests: ionogram, blood count, differential coagulation times, serum glucose, creatinine, sodium, potassium, liver enzymes, HIV, VHB, VHC and Syphilis serologies, who turned out to be normal. We made the decision to interrupt COVID-19 medication protocol as well as vortioxetine, and we initiate amilsulpride at the dose of 100 mg per day. Psychotic symptoms disappeared totally after 48 hours. We tapered off and then stopped amilsulpride within a week. The patient remained asymptomatic, and we evaluated him once in two weeks. On the latest psychiatric assessment (May 20), the patient showed no psychotic symptoms.

covid-19, chloroquine, anxiety, hallucination, psychiatry, side effect

PMC7748891_01

Female

A 31-year-old woman was referred to the retina ward of Farabi eye hospital with a history of sudden decreased vision and metamorphopsia in OD for 3 days. On clinical examination, the best-corrected visual acuity was 20/40 and 20/20 in OD and OS, respectively; with +3.00 diopters of hyperopic refraction in OD and Plano refraction in OS. Funduscopy of the OS was normal and the OD was remarkable for a serous retinal detachment (SRD) and a 4 to 5-disc diameter submacular elevated mass with extension beyond the inferior arcade (Figure 1(a)). Anterior segment examination was normal in both eyes without inflammatory findings. No cells or flare in the vitreous cavity, signs of retinitis, or vasculitis were observed. Spectral-domain optical coherence tomography (SD-OCT) confirmed a dome-shaped elevated choroidal mass with associated SRD (Figure 1(b)) OD. Enhanced depth OCT (EDI-OCT) of the OD demonstrated a homogenous hyporeflective elevated choroidal lesion, with compression of the choroidal vascular structures (Figure 1(c)). Ultrasonography confirmed a hyperechoic choroidal mass (Figure 1(d)). Early-phase fluorescein angiography (FA) showed pooling consistent with SRD and multiple hyperfluorescent dots over the mass with the persistence of these dots through late phases without disc leakage (Figure 1(e)). Indocyanine green angiography (ICGA) revealed diffuse and multiple foci of small, round, hypocyanescent dots in both early and late phases (Figure 1(f)). A complete metastatic workup for detecting malignancy including genitourinary system evaluation (Pap smear, ultrasonography, and urine analysis), gastrointestinal system analysis (upper and lower endoscopy, liver function tests, and abdominopelvic computed tomography with contrast), breast examination, and consult with an internist was done, and all were negative for any malignancy. Other evaluations including sarcoidosis (serum angiotensin-converting enzyme and calcium), tuberculosis (chest X-ray, QuantiFERON Gold, and purified protein derivative (PPD) skin test), syphilis (The Venereal Disease Research Laboratory test (VDRL) and rapid plasma reagin (RPR)), and lupus (Anti-nuclear antibodies (ANA), anti-double-stranded DNA antibody (anti-dsDNA)) were negative. Inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) were within normal limits, and the chest X-ray showed no abnormalities. Two weeks after initial evaluation the patient showed spontaneous resolution with improvement in central vision (BCVA: 20/25) and metamorphopsia. Reevaluation was consistent with decreased SRD and choroidal mass volume. Interestingly, there was disruption of the ellipsoid zone (EZ) and multifocal accumulation of hyperreflective material not previously seen on initial OCT (Figures 2(a) and 2(b)). Ultrasonography confirmed the decrease in the size of choroidal mass (Figure 2(c)). One month after initial presentation visual acuity returned to 20/20 without any refractive error or symptoms. OCT and ultrasonography showed nearly complete resolution choroidal mass effect, SRD, and EZ disruption (Figure 2(d)).

PMC6317299_01

Male

A 26-year-old man without any past medical history presented with a sudden onset of severe right leg pain and six days of subjective fever. Though he was an avid soccer player, the patient denied any antecedent trauma and was able to bear weight on both legs despite the pain. He denied rash, nausea, vomiting, diarrhea, cough, hemoptysis, shortness of breath, and night sweats. He had a single, long-term female sexual partner and used barrier contraceptives intermittently. Having denied any known sexually transmitted infections, his medical history was pertinent only for treated latent tuberculosis prior to his emigration from Ghana 15 years before. Since then the patient had traveled back to Ghana one year and Mexico five months prior. He did not recall any gastrointestinal illness during travel or upon return. Vaccination history was not known. Family history included multiple first-degree relatives who died from sickle cell disease prior to his birth. Upon presentation, the patient was febrile with maximal temperature 40.6 C, heart rate 95, respiratory rate 20 bpm, and blood pressure 132/82 mmHg. Physical examination was significant for marked tenderness on deep palpation over the right middle to distal anterior thigh. There was no outward signs of infection such as joint swelling, erythema, warmth, open wounds, induration, rash or decreased range of motion of the hips or knees. The patient was mildly leukopenic (WBC 4.5 K/mcl, normal 4.8-10.9), anemic (hemoglobin 11.9 g/dL, normal 13.5-17.5; hematocrit 34.3%, normal 41.0-53.0), with a normal platelet count. MCV was 77.6 fL/cell. He had elevated transaminase levels (AST 76 u/L and ALT 124 u/L), and mildly elevated C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) of 13.40 mg/L and 58 mm/hour, respectively. An X-ray of the right lower extremity demonstrated a lucent lesion of the central mid to distal medullary space of the femur (Fig. 1), suspicious for an infarct or chronic osteomyelitis. MRI revealed a 24 cm cystic lesion centered in the diaphysis spanning down to the distal metaphysis, with internal complex fluid levels and thickened cortex surrounding the collection (Fig. 2), concerning for chronic osteomyelitis with abscess formation. Aspiration of the femur on hospital day 2 revealed serosanguinous fluid, with Gram-negative rods visualized on Gram stain. The patient underwent an open biopsy and debridement on day 4; intraoperative findings included a relative decrease of marrow contents and a cystic cavity without purulence. Pathology showed acute on chronic osteomyelitis. Aspirate and open bone cultures grew Salmonella enterica, serovar Typhi, susceptible to levofloxacin, ceftriaxone, trimethoprim/sulfamethoxazole, and ampicillin/sulbactam. Blood cultures remained negative, as were AFB stains of the fluid, bone cultures, N. gonorrhea urine NAAT and HIV Ag/Ab. Based on country of origin, family history of sickle cell disease, and Salmonella osteomyelitis, hemoglobin (Hb) electrophoresis was pursued. Results showed 62.8% HbA, 33.2% HbS, 3.7% HbA2 and 0.3% HbF, consistent with both sickle cell trait and likely thalassemia trait (due to HbS level <35%). Abdominal ultrasound showed normal splenic echotexture and dimensions (11 x 5 x 5.5 cm). The patient received one week of ceftriaxone intravenously while inpatient, followed by ciprofloxacin 750 mg orally twice daily for a planned total 6-week course for Salmonella typhi chronic osteomyelitis. On day 10, CRP had decreased to 5.7 mg/L but ESR had increased to 102 mm/hr. Duration of antimicrobial course was extended to allow for follow up CT imaging, but this was not completed. Patient received approximately 8 weeks of antimicrobials in total. At last known follow up, patient had achieved clinical resolution of all prior symptoms. Given extent of involvement seen on initial imaging and surgery, further surgical intervention was suggested, but not pursued by patient due to lack of health insurance. Radiograph did confirm a healing bone lesion.

hemoglobinopathy, osteomyelitis, salmonella, sickle cell, thalassemia, typhoid fever

PMC4247964_01

Female

A 45-year-old African woman had iron deficiency for 4 years caused by abundant menstruation. Her past medical history included tuberculosis in 1985 and lung lobectomy for aspergilloma five years earlier. She had 4 healthy children and did not smoke. Gastroscopy performed initially was normal. She complained of fatigue and headache. She took oral iron supplementation but developed side effects that led to treatment discontinuation. In 2011, she received two infusions of iron sucrose (total dose: 200 mg) without any impact on the phosphate level (2.7 mg/dL after the second infusion). In 2012, laboratory findings were hemoglobin level (Hb) of 9.9 gr/L, serum ferritin of 6 mug/L (normal range: 13-150), and serum iron saturation of 6.7% (normal range: 15-50). She received 3 additional infusions of iron sucrose (total dose: 300 mg) which slightly reduced the phosphate level (2.1 mg/dL) but without symptoms. In 2014, her Hb was at 9.8 gr/dL with serum iron saturation at 6% and serum ferritin at 13 mug/L, and the plasma phosphate level before injection of FCM was of 2.5 mg/dL with a FEPO4 of 11%. This moderate elevation in phosphate clearance was probably due to 25-hydroxyvitamin D (25(OH)D3) deficiency and secondary hyperparathyroidism (PTH: 147.2 ng/L, normal range: 15-65; 25(OH)D3: 9 ng/mL, normal range: >30). She then received two injections of FCM (Injectafer, Vifor Pharma) (one-week interval, total dose: 1000 mg). Ten days after the second infusion, she complained of intense fatigue. Blood analysis showed a phosphate level at 0.93 mg/dL with FEPO4 at 23% confirming the diagnosis of phosphate diabetes. She received oral phosphate supplementation which improved fatigue and at, one month, the phosphate level increased to 1.2 mg/dL with FEPO4 at 29%. Two months after the first administration, the phosphate level returned to normal value at 2.34 mg/dL with FEPO4 at 13%. Table 1 summarizes the evolution of laboratory results before and after FCM administration and the evolution of fractional phosphate excretion over time is presented in Figure 1.

PMC8429789_01

Female

The three case studies presented in this manuscript are part of a larger research project that examines relations between Palestinians and Israelis in the field of ayahuasca rituals. For detailed methodology section see and its supplementary section. In short, most of the data for this project was gathered in 2018-2019 through 31 in-depth interviews: 13 with Palestinians (five women, and eight men; nine have Israeli citizenship and four live under occupation in the West Bank) and 18 with Jewish Israelis (eight women, nine men, and one non-binary person), all between 28 and 59 years old, who participated to various extents in these mixed rituals. Interviewees belonged to five different ayahuasca groups, mostly facilitate by Israeli Jews. Facilitators and musicians lead the ritual with music, yet most rituals had participatory elements as well. There were moments in which the group sang together, and by the second half of the ritual participants were able to share their own music or prayers. Rituals included around 20 participants in average. The first author had an initial connection to some interviewees, which then introduced him to others through a snowball manner. However, the interviewees sample was a purposeful, so that we attempted to choose diverse informants in order to achieve reliable and generalizable data. In-depth semi-structured interviews were conducted in Hebrew, Arabic, and English7. Each interview lasted from one to two and a half hours. All interviews were recorded and transcribed. The microphenomenological interview technique was used whenever an interviewee reported important experiences and events from the rituals that had political implications. This technique was crucial for "zooming-in" on small details of the revelatory events presented in this paper. Author 1 also conducted participatory observations in five rituals of different such groups for complementary ethnographic data collection. Furthermore, follow-up interviews were conducted 1 year, and 2 years, after the first interview for the three interviewees described in the case studies. The analysis was based on the grounded theory approach. This approach emphasizes hypothesis-free bottom-up generation of concepts and themes. In line with this approach, several stages of analysis were undertaken. The first phase included a thematic analysis of the interviews, which revealed thematic categories. Through a process of reading and re-reading the interviews, the number of categories was reduced by combining similar categories and focusing on those that emerged as most relevant. These categories were scrutinized again for centrality (repeated appearances across interviews and observations), for the connections between them, and for their relevance to the study and the questions it addresses. The software Narralizer was used to organize and codify the interviews. Narralizer is a simple software for organizing and structuring qualitative data, and no automatic analysis was conducted. In a previous paper from the same dataset, fifteen conflict-related revelations were identified. Out of which five were defined as political revelatory events based on the theoretical framework of the current paper. The three revelatory events that are presented here were chosen based on having a detailed description of both the event itself and the developments that followed it. The description of the case studies is mainly based on the three interviewees, yet some information is used from other interviewees who attended the rituals in which the revelatory events took place. The ethnographic analysis of the context section above is based on all of the gathered data. Identifying as an "Israeli Arab," Khalil grew up in the Galilee and went to a Jewish Israeli school, where he was denationalized and assimilated to become very critical toward Palestinians. Looking back, he says that he "was a person who denied his own Arabness." A supporter of right-wing Israeli politics, in his youth, he even wanted to serve in the Israeli army. Dispossessed of his national history and identity, Khalil reached ayahuasca rituals when he was in his 50s. He wanted to heal a personal trauma inflicted upon him by a childhood friend and heard that ayahuasca can help people purge their trauma. As the healing had already taken place in his first session, he became a regular member of one of the Israeli groups that organized ayahuasca rituals. After several sessions with that group, Khalil was invited to a ritual in a private house located in a Jewish Israeli town. As was evident from the architecture, the house had formerly been owned by a Palestinian family who, like many other Palestinians, had been displaced during the Nakba. The current Jewish owners enjoyed hosting many rituals in the large and accommodating house. Guided by the Jewish Israeli shaman that Friday evening, this ritual was somewhat different, as it had a major Jewish influence involving the welcoming of Shabbat. Jewish participants were all dressed in white and were singing Jewish religious songs. Khalil came in jeans and a colorful shirt, like the other three Palestinian participants in the ritual, and was asked by the organizers to change his clothes. This contrast of colors intensified the distinction between the Palestinian minority and Jewish majority of participants, which is probably what summoned Khalil's confrontation with his self-denied Arabness from "the void." While the group was singing the traditional Shabbat song "Shalom Aleichem" (Peace be on you, in Hebrew), Khalil decided to go out to the porch. Separated from the group, he sat under a vine tree that reminded him of his grandfather's house. An intense light started flashing. Sitting outside alone, fear took over him. Khalil felt as if he was losing his mind and would never return to his usual self. He imagined himself becoming a "junkie in the streets," and was wondering "what will I tell my wife and how will I look my children in the eye." His fear intensified his sense of alienation and separation from the world, believing "that no power can release me from where I found myself." Such separation is a necessary step for an Badiouan intervention to take place (, 201, 209). While lifting his head to the sky to pray for God's help, Khalil had a vision of an old Palestinian couple in traditional Arab clothing, sitting in front of him on the same balcony and drinking coffee. They were the previous Palestinian owners of the house where the ritual was taking place. The woman told him: "I know you went to an Israeli school:you hate everything to do with Arabs, and you have anger. But the story is different. You heard only one side, but you haven't heard our side. You are in our house now and we are not here. We were evicted." Khalil deeply identified with the old couple's pain. The revelation confronted him with collective Palestinian traumatic memories of the ongoing effects of the Nakba, which he had previously avoided. Angry at himself, Khalil felt deceived by the Jewish Israeli narrative. Loyal to his vision, he returned to the ritual with the aim of disrupting it. In anger he sang an old Arabic Andalusian song, "Lamma bada yatathanna" (When it began to unfold), in order to declare that this was "in fact a Palestinian house... whether we like it or not." The psychedelic event led to his recognition of the injustice that Israelis perpetrate against Palestinians, after which, in Badiou's terms, he felt compelled to intervene in the "structure" of the ritual and modify it. Singing in Arabic was a political act for Khalil, but the reaction of those responsible for maintaining the structure of the ritual was swift. When Khalil raised his voice, the shaman invited him to sit next to him and played the joyful song "Bint al-shalabiya" (The pretty girl) by Fayrouz, a famous female Arab singer from Lebanon. Khalil recounts the excitement: "I am mad about her [Fayrouz]. Suddenly, the shaman starts singing in Arabic. We were thirty people and everybody got up to dance and hug.... I was shocked; hugging and dancing, Jews and Arabs! It was wonderful, wonderful.... That's where the journey started." Khalil's fidelity to his vision, as we understand it, was expressed through an angry musical interruption. However, this was not enough to change the structure of the ritual that evening. Although it seems that the Jewish-oriented ritual suddenly became Arab, as people cheerfully danced to Fayrouz's song, it became clear to us that the shaman successfully diverted attention from the national political grounds expressed in Khalil's anger to culturally safe grounds. The shaman prevented Khalil's truth from disrupting the harmony of the ritual with Palestinian memories of displacement from the Nakba. However, Khalil considered his bringing himself to sing in Arabic at the Israeli ritual an outstanding achievement, a pivotal moment when his "journey began." "Born again" in this event, he felt his brain was "clean to receive the truth." Attuned to the universal truth that he had attained at the event, Khalil tattooed his chest with a sentence in praise of the land, taken from a poem by Mahmoud Darwish, the Palestinian national poet. This helped him reassemble elements of his Palestinian identity, as he confessed: "I used to be very radical right wing in my opinions.... [But] I have made peace with the Arab in me, with being a Palestinian Arab." Khalil remained loyal to the event after the ritual was over. Uncomfortable with joining Israeli rituals in which he was part of a minority, his fidelity was directed toward the expansion of ayahuasca to Palestinians. He began organizing rituals for Palestinians only, to which he introduced Arab musical instruments, such as the oud and qanun. As a result he became a key figure in the diffusion of ayahuasca to Palestinians living in Israel. Still, he continues to hold a strong universalistic worldview, arguing that what he learned from his event is not specific to Palestinians. This conundrum can be reconciled through Badiou's conceptualization of universalism, in which existing structures are restructured to include the excluded particulars. Khalil's mission to expand ayahuasca to Palestinians led to an empowering and intimate circle, in which they are not dependent on Israeli mediation. Although open to Jewish Israelis, Palestinian ayahuasca rituals offer an alternative structure in which they can reclaim the Arabic language and culture as part of their Palestinian heritage, and not as a denationalized discourse of multiculturalism and interfaith dialog. Such an alternative structure of ayahuasca rituals, as we demonstrate in the following section, also allows Palestinians to produce a safe space with a new cultural vocabulary, where they can share the pain and anger that they experience as a result of the Israeli settler colonial structure. Working at a regular nine-to-five job in finance, Ruqaiya kept away from politics. Although growing up in an Arab family in a village in the north of Israel, she felt an outsider in her Palestinian culture. She married young, in an arranged marriage to an older man, but fell in love outside the marriage. This led to traumatic and violent events. Divorced with two children, Ruqaiya first participated in ayahuasca rituals when she was in her 40s, or as she explains: "Ayahuasca reached me. She searched for me." During that period, Ruqaiya was at a low point in her life. She was "a person who saw everything in black, with no point in life." Ayahuasca, her "teacher," showed her that her trauma was "a gift." It taught her about "the depth of life," and that she was able to "adapt to any place and any situation." Ruqaiya soon became a therapist, "a wounded healer," as she describes it, focusing on treating trauma. Four years into her participation in Israeli ayahuasca rituals, she had her major life-changing revelation. As recounted at the opening of this article, it was on the Jewish holiday of Yom Kippur (Day of Atonement). She joined her regular group, her "tribe," yet was the only Palestinian in the ritual that night. During the ritual someone sang a song about Maria. She felt as if "Maria entered" her, and she soon began vomiting. She then received many insights about Amal, her elder daughter. Similarly to Khalil, Amal attended a Jewish Israeli school. Coming of age at the time of the event, she was considering joining the Israeli army. Although a Muslim, Amal also fasted on Yom Kippur that day, at the house of her Jewish friend. Strongly assimilated into Jewish Israeli society; her Palestinian identity was, to use Badiou's phrasing, on "the edge of the void." In her vision, Ruqaiya saw Amal with some darkness closing in on her, "disappearing into an abyss." She had to reach out to Amal and pull her out of that darkness and away from her confusion. At that point, as Ruqaiya recounted, "something closed and I was higher. Al-Fatiha [the opening verses of the Quran] came out, and another strong frequency was opened." This vision separated her from the rest of the group and allowed the intervention to take place. While singing al-Fatiha to the rest of the group, Ruqaiya had a strong revelation in which she saw Palestinian and Israeli mothers sacrifice their own children to war, while ''Pachamama'' (Mother Earth, in Quechua; a term popularized in neoshamanic practices) absorbed the bloodshed. Ruqaiya experienced the pain of the land.8 The historical vision continued from past traumas into an apocalyptic warning from a potentially disastrous future. As she explained, the vision of mothers who sacrifice their children was related also to her daughter's intention to join the Israeli army. Ruqaiya's singing and vision were simultaneous. She was singing out of agony about the vision, as she recalled: ''The voice came from the center. I cannot say it was in the voice of God, though it was the voice of a messenger.'' When she sang, she ''released a frequency of anger,'' and it felt as if she were telling the other participants to ''listen and awaken. There is a battle here between light and dark. The dark is growing stronger than the light, so understand where we are now.'' When asked about the meaning of al-Fatiha, Ruqaiya chose a universalistic interpretation. She said that it is about not getting lost: ''All those who go by certain laws, which are illusory and fake, separate from the human itself, from humanity, from what we are. We are human.'' After al-Fatiha, she sang, in Hebrew, a song that was popular among the group members, but she added a verse in Arabic.9 While she was singing, there was an intense feeling in the room, and many participants were vomiting. In relation to the group, Ruqaiya said: "I felt each one, each and every one [in the group]. Where they were with their fear, doubt, and ego. The [protecting] net that each person places himself in. The defense of the illusion." Her singing was a pivotal moment in the ritual for other group members, but only few understood the message, as she explained: "Many friends deny it [the message]. They don't want to deal with it.... So who is doing reparation [on Yom Kippur]? No one. They [Jewish Israelis] are just fasting." Ruqaiya's fidelity to her vision was counterhegemonic. As a result, she delivered anger in her song, which we believe was related to a political truth that was concealed by the structure of the ritual. Ruqaiya's critical insight regarding her own ayahuasca "tribe" was that it replicates the power dynamics that exist in larger reality. However, as in the case of Khalil, her attempts to intervene resulted in denial by the representatives of the ritual's structure. While the prophetic interventions of Palestinians channel political anger during rituals, we noticed that New Age spirituality often comes to support the Israeli structure of political denial. For example, Nir, an Israeli shaman, suggested that if political revelations take place during the ritual, they are part of the "shadow work" that one needs to go through. In his instructions, Nir meant that once the political "shadow" becomes conscious, a person will be less guided by it. In this sense, a political revelation is personal, meant only to reveal restrictive identities and traumas to oneself, and through this awareness one can work toward liberating oneself from such restrictions. This argument could be used to reverse Palestinian revelatory truths, as it suggests that their expression of anger was needed for their cathartic personal healing, but not as a message to the group. This reversal is supported by New Age ideology in which "the self" is at the center of transformation. Nevertheless, the revelation that Ruqaiya had during this ritual developed into a sense of mission and meaning in her life. However, we observed that the intensity of her fidelity to the event was reduced, in comparison to the initial intervention, and remained mostly related to the setting of the ayahuasca practice. She explained: "I feel I am an ambassador of the Arabs in that I started to say, 'Yes! We are here. We have a voice and opinion. We have life. We are allowed to live. Not only if the Jews allow it."' Ruqaiya took her destiny in her own hands and began singing to liberate the Arabic language from the oppression of the Israeli state and patriarchy. According to her, it is "the woman who brings revolution and change." This realization came in fidelity to her vision, yet her self-inquiry is still in process: "How to do this? I am checking, receiving answers, in order to extricate the woman who is the educator of all ages and the one who brings children into the world." Ruqaiya's transformation was reflected in Amal, her daughter, who eventually decided not to join the Israeli army, conceivably owing to the event. Considering her singing an empowering political act, Ruqaiya encouraged other Palestinian women to join her rituals and "find their voice." Similarly to Khalil's fidelity, she sought to expand and diversify the ayahuasca rituals, to make them more egalitarian and inclusive for Palestinians. Her politicization did not, however, happen at once. Worried that people would not understand her, it seems that she was divided between fidelity to the event and belonging to the structure. As time passed, and as she remained in fidelity to her vision, the structure around her changed, and she was able to admit to herself that her revelation was political. Throughout her process of political self-exploration, she met like-minded people who could understand her mission. Furthermore, two Jewish Israelis who participated in the Yom Kippur ritual received the message of her song and became musical companions in the rituals that she facilitated.10 Gathering a small group of people around her, Ruqaiya has not only kept her fidelity alive but has been seeking further connections to form a larger social movement. In this sense, she has been trying to establish a politicized collective that she hopes will have a larger impact. On a few occasions since her event, Ruqaiya has attempted to deliver explicit political messages during rituals. For example, during a magic mushroom ritual, which Ruqaiya co-facilitated with a small group of spiritual activists, Adi, a Jewish Israeli woman, announced to the group that she has just decided not to move to Portugal. Addressing both Israelis and Palestinians, she declared: "This is my home and these are my people." Soon after, in a moment of inspiration, Ruqaiya sat in the center of the circle and spoke in archaic Hebrew, which resembled a biblical text. Accusing the "children of Israel" of losing their way, she stated that "those who were liberated by Moses in the past, have now became Pharaoh [to the Palestinians]." Such direct verbal phrasing of the duality of the oppressor/oppressed is a radical break from the previous structure, which sanctified oneness. As part of the inquiry into her truth, we believe that Ruqaiya has been replicating her event and her initial intervention in other contexts. In doing so, she reconnects with the excluded Palestinian identity, by using other parts of which are in either the Israeli structure (Arabic language and music, Islamic religion) or the void (right to the land, historical injustice). Hence, according to Badiou, she became a "subject" through which the restructuring occurs. She admits though that this is not a simple task and that the integration of her event is challenging as it requires replacing the "old language" with a "new language" that fits the event. Such tension is inherent to the truth procedure, as the restructuring cannot be dependent only on the language of the previous structure. Ruqaiya's politicized prophetic deliverance in rituals suggests that she is seeking the reformation of New Age culture so as to make it more politically engaged. While borrowing and decontextualizing different religious practices is central to New Age spirituality, Ruqaiya reconstructs ayahuasca rituals in Palestine/Israel in a political frame. As she puts it, she seeks to "wake up" those who "prefer not to see." Her belief that "all is one" is now aligned with a mission, as her call for action is mobilized to achieve equality at large, beyond the Israeli ritual structure. While the event site is related to the Israeli subjugation of Palestinians, Jewish Israelis can also experience revelatory events that lead to political awakening. Today in his 30s, Amos grew up in a middle-class Jewish Israeli family with a left-wing orientation. Never politically involved himself, he ended up joining the Israeli army as a soldier in an elite unit. He decided to join a combat unit not for patriotic reasons, but "to be a man." During his service, Amos went through a few traumatic events in the West Bank, in which his life was under threat and his comrades were severely injured. After his army service, he felt "very tense" when he heard Arabic spoken near him. After some of his classmates from high school died in combat in the Second Lebanon War (2006), he decided to leave the country to travel. Like many other Israelis, he went on a long journey to India and elsewhere to overcome the harsh memories of military service. Amos had his first experiences with psychedelic drugs as a backpacker-musician. Regularly returning to Israel for occasional jobs, he then became part of the ayahuasca milieu there. Looking back to his first encounters with Palestinians at Israeli rituals, he confesses that he was initially judgmental toward their appearance. Not conforming with the Israeli hippy dress code, they were, according to him, too neatly dressed and showed off their high socioeconomic status. As he recounts half jokingly: "I remember a [Palestinian] guy who came to a ceremony in leather shoes, jeans, cell phone, BMW keys, pack of cigarettes, and even when he changed clothes, everyone else was in hippy clothes." His life-changing revelatory event took place in a session in which he came across Palestinians from the West Bank for the first time in such a setting. As the Palestinian participants began to cry during the ritual, Amos's vision was triggered: Suddenly, the ayahuasca showed me them [the Palestinian group] as a separate unit within us [the Israelis in the ritual]. Another one [Palestinian] began to cry. It took me automatically to the madness of the pain of a whole people.... I felt connected to that pain. I caused the pain of their people. I began to break. I couldn't stand to hear them crying. She [ayahuasca] began showing me so much. I can't describe it visually, just this crazy pain, and hate, and crying for the evil they experienced. It built up and up, until there was a cut. The collective cry of the excluded group of Palestinians separated Amos from the room into his own vision, whereby he had a very detailed flashback of his army service. He saw himself making a casual house arrest of Palestinians, "one of dozens, maybe hundreds," as he confessed. He saw himself with his unit breaking into the house, interrogating the Palestinian family, and then leading a man into a military jeep. Soon Amos had a "cut" in the revelation and he re-experienced the same incident again. This time, however, he experienced the moment from the side of the family, feeling their pain, panic, and heartbreak. Observing himself from the other side, he described himself as looking like "Robocop," or "like someone from a film about Nazis." When the revelation ended and Amos returned to the ritual, he felt intense anger and guilt. "That was the point in my life where I most hated myself," he later admitted. After recognizing the pain that Palestinians go through, Amos became devastated during the ritual. He began singing with much confidence, even though until then he had been embarrassed to sing by himself in rituals. Delivering the message through song broke the barriers of his shyness. Amos was taken up in fidelity. He requested from the facilitators permission to sing relatively early in the ritual. Thus, he intervened in its regular structure. Amos remembers that he did not sing beautifully, but that there was something authentic and honest in the moment. Amos considers the song to be a direct continuation of the revelation. He mentioned that it felt like the "room was electrified," and "the world vibrated with me." He felt as if he embodied the role of a "preacher" delivering a crucial message of truth to the group. "I felt it [the song] was strong, stronger than me, and it came from a black void in the ritual," Amos's words interestingly resonate here with Badiou's terminology. The song that Amos sang was "Mekomi kadosh" (My place is sacred), a Hebrew song influenced by Native American peyote-ritual music. The lyrics had a universal message for him, stating that everyone's connection to the land is sacred and everyone's voice should be heard. Amos, however, gave it also a localized political meaning, in which he expressed his relationship with Palestinians and their mutual connection to the land. Up to that point most of the songs in this specific group were in Spanish, English, and Portuguese, since the facilitator was European. Singing in Hebrew, Amos felt that the song was "stronger than me." Although participants are usually encouraged to stay in their place during the ritual, two of the Palestinian participants came and lay down next to him. According to Amos, this was when "my journey of healing my relations with them [the Palestinians] began." The song ended with a long silence, which allowed people to reflect. Rashid, who went to lie down next to Amos while he was singing, also found the courage to sing later in the same ritual. It was the first time that a Palestinian sang in Arabic in this particular group. As with Khalil and Ruqaiya, the introduction of both Hebrew and Arabic to the singing indicates that the fidelity to truth led to the expansion of the ayahuasca ritualistic practice to include local identities, as well as to greater universality. Eventually, Amos befriended the Palestinian group in the ritual. He left the reserve army and began to learn Arabic. He also developed great interest in Palestinian culture and history. However, in addition to his connection to Palestinians, Amos argues that this specific ritual made him less judgmental and more compassionate toward all humans. This inductive reasoning suggests that through a particular recognition, something universal was revealed to Amos. Another indicator of an essential restructuring of rituals toward universality is related to the connection to the land, a theme that appears in all three of the events and fidelities described in this article. In her vision Ruqaiya identified with the pain of the land; Khalil's new tattoo expresses his belonging to the land; and the lyrics of Amos's song were about everyone's sacred place on the land. Reestablishing the connection of Palestinians to the land is a crucial diversion from the Israeli structure, toward both a particular acknowledgment and a more inclusive universalism. Such universal aspirations require resistance to the Israeli settler-colonial project that supports the Zionist narrative calling for the "redemption of the land" from the Palestinians who "occupy" it. Although Amos was initially in full fidelity to the event, like any other subject he later became divided between his fidelity to the event and his belonging to the structure. As with any Badiouan event, the forces of the structure are always at work to reverse the event's truth. In Amos's case, such a reversal is exemplified by his later reinterpretation of the event based on the previous structure. In the first interview with him, he interpreted the song "Mekomi kadosh" as an expression of Palestinian and Israeli connection to the land. This interpretation is loyal to the event, as it recognizes the Palestinians' right to the land, which is something that the structure denies. However, in a second interview with him, that took place a year later, Amos gave the lyrics another interpretation associated with self-acceptance. He explained: "There is this thing from the North American Dakota tribe about being a man. OK, so you cried, apologized, and you are also evil... now it is time to move forward. What does it mean? Exactly like in the song, your place is your place and you cannot even control it. You are part of a story and your part is sacred." We argue that this new interpretation is a diversion from the truth attained during the event, and does not challenge the structure, as it frames the song in a holistic interpretation that accepts good and evil as "sacred." Thus, the later interpretation waves off Amos's feelings of guilt and desire for reparation. In this sense, it is also compatible with Ruqaiya's critique of Jewish Israelis who prefer "not to see." Aligned with this interpretation, Amos also said that he learned from "the medicine" that friendship with Palestinians is valuable for him, as "peace occurs human to human," so that he need not "worry about the macro." While he indeed overcame some of his stigmatization and fears of Palestinians, it seems he maintained an apolitical position that is centered on harmony and friendship, without actively taking responsibility for and acting against the structure of injustice against Palestinians that he is part of. For example, he was upset every time one of his Palestinian friends from the rituals critiqued the "Zionist occupier" on social media. He felt that such outspoken criticism was not aligned with their friendship with him. Instead, such Palestinian expressions of anger seemed to him a contradiction of the harmony and unity that they experienced together in the ritual. We must ask then, what happened to Amos's fidelity to his event. Why was he diverted from his initial conviction in a politicized universal truth to a more comfortable position that does not challenge the Israeli structure? It is important to note here that Amos has been a helper and musician in the Israeli rituals. Hence, he is a central representative of the structure, unlike Ruqaiya and Khalil, who were marginal to the structure at the moment of their event. In this sense, we argue that the structure was stronger than the event for Amos, so that his fidelity was eventually reversed. Moreover, while Khalil's and Ruqaiya's fidelity was ignited by anger, Amos's fidelity as a Jewish Israeli was ignited by guilt. As such, guilt carries a strong psychological burden, especially when not directed toward reparation. Six years after the revelatory event, Amos went to an MDMA-assisted therapy session and revisited the haunting memory that appeared to him at the event.11 A few weeks after the MDMA session, he said that it had helped him to overcome the memories and to continue with his life.

badiou’s being and event, dmt, israeli-palestinian conflict, new age, activism, prophecy, psychedelics, ritual

PMC6186374_01

Male

A 37-year-old man reported exercise/activity-related muscle pain and fatigue from early childhood. His symptoms were labelled as "growing pains" by different medical professionals, and he was often called "a lazy child". He had difficulties to keep up with his friends and family when walking. He reported physical education classes and school games as bad experiences. Throughout his life he continued to avoid activities that provoked muscle symptoms. Despite not being aware of the second wind phenomenon, he used strategies such as slowing down or stopping and restarting when symptoms eased off. He reported pain in his muscles within a few minutes or sometimes seconds of initiating physical activity, particularly noticeable when walking upstairs, walking up hills, and carrying shopping bags. He had a previous medical history of four episodes of myoglobinuria triggered by playing football or lifting heavy items. He was diagnosed with McArdle disease at the age of 20 years based on an abnormal muscle biopsy. He was later confirmed to have a homozygous mutation (p.Gln567Pro) in PYGM. Physical examination at the age of 29 revealed rounded shoulders with hypertrophy of deltoid, biceps, and calf muscles. He had significantly wasted pectoralis muscles and bilateral scapular winging, but muscle strength was normal. When diagnosed he had been advised to complete at least three sessions of walking 30 minutes per week. However, he did not change his physical activity levels and did not report changes in his quality of life. After graduation he started his first office job. He became more sedentary, his weight increased, and symptoms worsened. He reported difficulties in walking short distances. Everyday tasks such as vacuuming and cutting grass became more difficult. He joined a local gym, where he has been a member for approximately 9 years. Initially exercises included walking on a treadmill and cycling on a stationary bike. He tried resistance machines but was not confident in using them. Four years ago, he approached a personal trainer, who took the time to learn about his metabolic condition. He suggested that weight lifting could be safe and effective if using principles of strength training after considering the pathophysiology of McArdle disease. Initial phase of training consisted of gentle 15-20 minutes aerobic exercise to warm up and get into second wind (walking on a treadmill, cycling on a stationary bike) followed by learning strengthening exercise techniques using body weight and very light weights. Training intensity gradually progressed towards mobility movements (e.g., Turkish get ups, walking lunges), increasing resistance as well as adding high intensity interval training (HIIT) protocol on the rowing ergometer at the end of the session. Strength exercises were mainly performed using compound movements with free weights rather than resistance machines. Currently, he performs a 15-20 minute aerobic warm up. He performs 1-5 repetitions with 2-5 minutes rest in between sets depending on the % of one repetition max (1RM). He also tried a different protocol involving four repetitions with 30 seconds rest followed by another four repetitions of the same weight. He has been doing two sessions with the personal trainer and two sessions on his own each week. When without the trainer, he only performs exercises he is familiar with. Over the past four years of strength training his weight increased from 65kg to 70kg; body composition dramatically changed by significantly increasing muscle bulk, in particular of his quadriceps, gluteus, pectoralis, deltoids, and trapezius muscles. His waist remained the same; collar size increased from size 14.5 to 15.5/16.0. He had to purchase new clothing due to dramatic change in body composition. Importantly, his muscle strength increased significantly as described in Table 1. He also performed other exercises, including lateral pull downs, TRX rows, TRX pull-ups, body weight pull-ups from jumps, Olympic lifting movements, box jumps, medium height approx. 45cm, and pistol squats. He has never experienced any McArdle symptoms during or after strength training and has not had myoglobinuria following his gym sessions. His serum CK level varied as expected in McArdle disease, with a decreasing trend (average CK in 2011-2014: 3,006 IU/L, average in 2015-2017: 1,029 IU/L; last measured in July 2017: 941 IU/L; reference range: up to 240 IU/L). Improvement in McArdle symptoms was described as a delayed onset of skeletal muscle symptoms, which now occurs at much higher physical activity intensity. Reaching the second wind is more efficient. In general, his quality of life improved significantly. He has been eating high protein diet with a bigger portion of carbohydrates on training days. He autonomously chose not to take any supplements containing glucose pre- or intra-training sessions.

PMC5313435_01

Female

A 75-year-old Japanese female was admitted to our hospital with a painful mass on the left anterior chest wall for eight days without any other symptoms. She presented at another hospital with left chest pain 3 days previously without any features suggestive of pneumonia including cough, sputum or dyspnea. Chest computed tomography (CT) obtained at the other hospital showed a mass in the left upper pulmonary lobe without any chest wall abnormalities (Fig. 1). As a result, lung cancer was suspected. She had no significant past medical history, nor did she have any history of smoking or alcohol consumption. She had no known tuberculosis exposure, and had not traveled outside Japan. She had not previously received a pneumococcal vaccine. Her vital signs were within the normal limits. A physical examination revealed a palpable, pink erythematous, warm and tender mass measuring 8 cm in size located close to the sternum overlying the left first to third intercostal spaces (Fig. 2). Her breath sounds were slightly decreased over the left upper zone, but there were no rales. A laboratory test revealed a high white blood cell count (14,310 cells/mm3 with 87.9% of neutrophils) and an elevated C-reactive protein level (33.35 mg/dL). Moreover, she was diagnosed with diabetes mellitus because of her elevated HbA1c level (7.5%). A chest X-ray obtained on admission demonstrated a 7x5 cm mass in the left upper lung field (Fig. 3). Chest contrast-enhanced CT showed a gas-containing lung abscess in the left upper lobe and a chest wall abscess (Fig. 4). There was some air in the first sternocostal joint and no pleural effusion. These findings were thought to indicate that lung abscess had directly extended into the chest wall through the sternocostal joint. Chest ultrasonography showed almost the same findings as those obtained from CT. Surgical debridement of the subcutaneous and intramuscular fluid collection was carried out under local anesthesia (Fig. 5). Then, under ultrasonographic guidance, an 8-Fr aspiration catheter (Argyle Aspiration Catheter; Covidien, Japan) was percutaneously inserted into the lung abscess, and odorless pus was drained (Fig. 6). Gram staining of the pus revealed numerous Gram-positive cocci, and empiric antimicrobial therapy with intravenous meropenem and clindamycin was initiated. On the 5th day, the culture specimens obtained from the lung and subcutaneous abscess grew S. pneumoniae. Mycobacterial and anaerobic cultures of the same specimens and two sets of blood cultures were all negative. Antibiotic susceptibility testing was performed by lung and subcutaneous drainage cultures. The isolate was susceptible to penicillin, ceftriaxone, and vancomycin, and resistant to erythromycin. The patient was considered to have a lung abscess attributable to S. pneumoniae which had directly extended into the chest wall. The antibiotic therapy was changed to intravenous ampicillin/sulbactam according to the results of antimicrobial susceptibility testing. After 16 days of antimicrobial therapy, the catheter was removed because the drainage had become serous and chest CT showed a remarkable improvement (Fig. 7A and B). Oral amoxicillin/clavulanic acid was used for 1 week after 3 weeks of intravenous antibiotic therapy, and the patient was discharged on the 25th day of hospitalization. At a follow-up examination at 1 month after the patient's discharge, she was asymptomatic and demonstrated normal chest radiography findings (Fig. 7C).

Three days before admission, chest CT showed a mass in the left upper pulmonary lobe without any chest wall abnormalities (arrows).

PMC6424059_01

Male

A 65-year-old Russian male, not known to have chronic medical illnesses, came to the ED complaining of painful swelling in the lower abdomen which had been going on for five days. Abdominal pain was severe colicky in nature with no relieving factors, associated with nausea and vomiting multiple times. There had been no change in bowel habits, fever or change in appetite. The patient had a history of lower abdominal surgery at the age of two, but he had no medical report On physical examination the patient was conscious and had a normal body built. His blood pressure was 126/92, pulse was 88 and temperature was 36.2 C. is symmetrically distended with a swelling in the lower abdomen 12 x 15 cm in size with negative cough impulse, erythema and tenderness on the overlying skin. The rest of the abdomen was soft on palpation with positive bowel sounds. Investigation of his hemoglobin gave 10.8 wbc's with 11.5 sodium 139 potassium 3.2 creatinine 0.7. The patient was admitted as a case of abdominal pain for investigation. The CT of abdomen and pelvic with IV and oral contrast was done showing thickened terminal ileum with marked luminal narrowing which appeared adherent to the urinary bladder wall with no line of cleavage. Two fistula tracts were seen superior and inferior; the superior one lead to a pocket of collection filled by contrast 36 x 20 mm in size. The inferior tract was connected to an anterior abdominal wall collection measuring about 18.7 x 14.4 mm with marginal enhancement denoting an abscess. There was diffuse anterior abdominal wall fat stranded with subcutaneous pockets of air denoting infection. Subcentemetric mesenteric lymphadenopathy was observed (Figs.1, 2). Patient was taken to the OR for exploratory laparotomy and drainage of the abscess. Upon internce to the abdomen a large pocket of pus in subcutaneous layer was opened and evacuated and a swab was sent for culture and sensitivity. A firm mass inclosing the pelvic was dissected and found to be a large diverticulum 10 cm from the ileocecal junction. The mass was attaching to the urinary bladder and was fistulating to the subcutaneous pus collection. Urology was called in at this point and the urinary bladder was checked by injecting methylene blue dye; there was no leak. Limited right hemicolectomy was performed with a primary iliocolic anastomosis (Figs. 3,4). Histopathology was consistent with diverticulum of the small bowel and serosal lipoma with a pocket containing multiple staghorn-type black stones, negative to tuberculosis (Fig. 5). Patient wound culture from OR showed E. coli which was sensitive to Tigacyclin. Treatment was started with this antibiotic and patient's condition improved. Postoperative course was uneventful except for a small dehiscence at the lower part of the abdominal wound, which was treated conservatively with VAC dressing. Patient was discharged to travel to his country, and the wound was left for secondary closing.

abdominal wall abscess, enterocutaneous fistula, small bowel diverticulum

PMC10393993_01

Male

Our patient was a 78-year-old man. He smoked 20 cigarettes/day from the age of 30-40. After transurethral resection of a superficial bladder tumor, BCG intravesical injection therapy was administered three times at another hospital, and a cough appeared 3 weeks after BCG commencement. A computerized tomography (CT) scan revealed multiple granular shadows suggestive of miliary tuberculosis, and the patient was referred to our hospital. Upon arrival, his temperature was 35.8 C; respiratory rate, 24 breaths/min; and SpO2, 97% (room air). Physical examination revealed no head and neck lymphadenopathy, normal heart and respiratory sounds, and no other abnormal findings. Blood tests showed a mildly elevated inflammatory reaction but no other abnormal findings. Sputum and urine smears were negative for acid-fast bacilli. The urine anti-acid test was smear-negative, and the TB-polymerase chain reaction (PCR) result was positive (Table 1). Chest radiography showed diffuse small granular shadows in the bilateral lung fields, and chest CT showed multiple small granular shadows in the bilateral lungs (Fig. 1). Miliary tuberculosis was strongly suspected from the chest CT. Based on clinical symptoms, imaging findings, and a positive urinary M. tuberculosis complex group PCR, a preliminary diagnosis of disseminated M. bovis BCG disease mimicking miliary tuberculosis was made. Since BCG infection was suspected from the disease course and the patient was an older adult, treatment was started with three drugs (isoniazid (INH), rifampicin (RFP), and ethambutol (EB)) other than pyrazinamide (PZA) from the beginning of treatment. Anti-tuberculosis chemotherapy with INH 300 mg, RFP 600 mg, and EB 1000 mg was started. Seventeen days later, a urine mycobacteria culture was positive for M. tuberculosis complex, and then the cultured microorganism was identified as M. bovis BCG using multiplex PCR. Drug sensitivity showed that the patient was resistant to pyrazinamide but sensitive to other drugs, and the treatment was continued without any changes. The patient's subjective symptoms improved over time, and the miliary shadowing disappeared on CT (Fig. 1).

bladder cancer, miliary tuberculosis, mycobacterium bovis bcg, mycobacterium tuberculosis intravesical bcg

PMC5779791_01

Male

A 33-year-old man presented with a 6-month history of insidious low back pain intermittently. Twenty days before admission to our hospital, his back pain was significantly aggravated, which caused him to have difficulty in walking and sleeping. He denied the history of systemic disease and trauma. Recently, the pain severely affected his life and work especially when movements. There was no history of exposure to TB, including his family. The patient had systemic TB symptoms and signs including night sweats and decreased appetite with weight loss and progressive low-grade fever. He admitted a history of smoking, alcohol consumption without drug abuse. Physical examination demonstrated there was no visible or palpable spinal deformity, but definite tenderness could be elicited over the spinous processes of the extensive lower thoracic vertebrae. Neurologic examination represented no specific findings including that his reflexes of knee and ankle were normal. Subsequently, muscle strength and tension of lower limbs were also normal, and the straight leg raise test was negative in bilateral lower limbs. No other positive findings were found on physical examination. Laboratory investigations revealed red blood cells count, hemoglobin level, and white blood cells count were all within a normal range in spite of high erythrocyte sedimentation rate (ESR, 48 mm/hour), high C-reactive protein (66.9 mg/L). TB antibody and purified protein in derivate of tuberculin (PPD) test and human immune deficiency viral infection (HIV) were negative, but the TB spot (T-Spot) test was positive. Besides, the result of bone marrow puncture and serum protein electrophoresis (SPE) were all negative. Other laboratory tests were within reference range. During the hospitalization, the patient underwent thorough radiographic examinations. Routine image analysis demonstrated normal chest X-ray and abdominal ultrasound evidenced normal findings. A thoracolumbar spine X-ray was unremarkable. Whereas further computed tomographic of whole spine images surprizing us, indicated multifocal diffuse lesions located in cervical, thoracic, lumbar, and sacral vertebrae showing multiple level worm-eaten and osteolytic bony destruction, including C5, T1-T5, T7-T12, L1-L5, and S1 (Fig. 1). At the bodies of C5, T1, T2, T4-T5 (spinous processes and adjacent ribs), T8-T11, L1-L5, and S1 vertebrae, osteolytic bone lesions were noted along with the similar lesions at the transverse process of T7 (neural arch), T11-T12 (spinous processes, neural arch, and adjacent ribs), L1, and L4. Intervertebral discs spared. There was a paravertebral mass at the T9-T10 level (Fig. 2). On whole spinal magnetic resonance imaging (MRI) examination, there were heterogeneous mixed high-intensity changes at C3, C5, T1-T5, T7-T12, L1-L5, and S1 segments on T2 weighted images and decreased signal intensity on T1 weighted images. Besides, the epidural abscess at the posterior of the spinal canal at T7 and T12 compressed the dural sac distinctly and a fusiform paraspinal abscess located at T9-T10 without obvious collapse of the adjacent vertebral body (Fig. 3). According to the constitutional symptoms of TB and all imaging and laboratory findings of this patient in our department, we hold a multidisciplinary conference including oncologists, radiologists, and orthopedists. Eventually, differential diagnoses such as lymphoma, multiple myeloma, and metastatic disease were suspected. Considering the risk of spinal cord compression and pathologic fracture, which may cause progressive severe neurological symptoms and deformity, could happen at any time. An open biopsy rather than computed tomography (CT)-guided needle biopsy was conducted by our experienced surgeon at the T11 level to make a clear diagnosis. Intraoperatively, we located at the spinous process of T11, then resected the partial lesion of the right transverse process. The excised specimen resembled a kind of cheese with necrosis material. Pathological examination indicated a chronic granulomatous inflammation with abundant caseous necrosis, considering tuberculous inflammation (Fig. 4). And, negative microscopy for acid-fast bacilli from the specimen. However, in some cases, it was difficult to distinguish the lesions caused by Mycobacterium tuberculosis from other bacterial granulomas that may be still misdiagnosed. Meanwhile, we acquired the consent from the patient and his family to start on anti-TB trial chemotherapy, including rifampicin (450 mg/day), isoniazid (300 mg/day), ethambutol (750 mg/day), pyrazinamide (750 mg/day), and levofloxacin (500 mg/day), paying attention to nutrition supplement at the same time. The treatment turned out to be successful based on the lab test results, showing his ESR is reduced to 18 mm/hour, CRP to 11.3 mg/L, and significant improvement of systemic TB symptoms within 8 weeks of starting antitubercular trial therapy. Then the final diagnosis was an unusual presentation of skipped multifocal extensive spinal TB. As a consequence, we switched to a standard anti-TB chemotherapy without levofloxacin for a total duration of 12 months. Furthermore, the patient had achieved complete recovery without any complications. At 18-month follow-up, all the worm-eaten and osteolytic bony lesions were healed apparently, showing the disappearance of paravertebral and epidural abscess, and there was no evidence of recurrence on CT scan (Figs. 5 and 6).

PMC4704296_01

Female

A 60-year-old woman was admitted because of persistent fever of unknown origin lasting for several days. She had been in a good state of health prior to admission and had no specific underlying disease. She had no related family history and medication history. Upon physical examination, the vital signs were as follows: blood pressure, 120/80 mmHg; pulse rate, 87 beats per minute; and body temperature, 37.8 C. There were no palpable lymph nodes in the neck, armpit and groin areas. Both legs had pitting edema and petechial rashes. She also complained of diffuse abdominal pain and oliguria that had been present for several days. Laboratory findings are summarized in Fig. 1. Pancytopenia (white blood cell count, 2750/muL; hemoglobin, 8 g/dL; platelet count, 63,000 /muL) was detected and serum creatinine level was significantly elevated (4.59 mg/dL). Serum ferritin, C-reactive protein and lactate dehydrogenase were increased as well. Prothrombin times (PT), activated partial thromboplastin times (aPTT) and fibrinogen were within normal limits. There was no dyslipidemia, including hypertriglyceridemia. The patient's soluble interleukin-2 receptor level in serum was 5.2 % (normal range 5-30 %) and natural killer (NK) cells activity was decreased (NK cells activity, 3.7 %; normal range 6-29 %). Urinary protein/creatinine ratio was 906.4 mg/g. Peripheral blood smear showed normocytic normochromic anemia and thrombocytopenia. The examination revealed no schistocytes and anisocytosis, which suggested absence of microangiopathic hemolytic anemia (MAHA). Abdominal computerized tomography (CT) scan for the evaluation of abdominal pain showed no abnormal findings for the bowel, pancreas or the biliary tract. Both kidney sizes were normal without chronic change, but there was significant splenomegaly, multifocal ascites and pleural effusion were detected. At first, we used broad-spectrum antibiotics for neutropenic fever and initiated hemodialysis for acute renal failure. However, we did not find any etiology for neutropenic fever from urine or blood culture studies. In addition, virus studies, including epstein-barr virus, parvovirus B19, adenovirus, human immunodeficiency virus, hepatitis B and influenza virus were negative on serologic tests. Anti-hepatitis C virus antibody was positive but alanine transaminase and aspartate transaminase levels were normal, which suggested that hepatitis C virus was in an inactive state. The patient showed no evidence of tuberculosis in chest X-ray, sputum acid-fast bacillus (AFB) stain and AFB culture, sputum and urine tuberculosis polymerase chain reaction. Autoimmune disorders such as systemic lupus erythematosus or rheumatoid arthritis were carefully ruled out by clinical symptoms and signs and by autoantibody tests. Consequently, we decided to perform a bone marrow (BM) biopsy to determine the reason for fever and pancytopenia. BM biopsy revealed about 10 % cellularity and numerous histiocytes with engulfed lymphocytes, polymorphonuclear and red blood cells, which were suggestive of hemophagocytosis (Fig. 2). Finally, the patient was diagnosed with HLH based on fever, progressive pancytopenia, hyperferritinemia, splenomegaly, decreased NK cell activity and hemophagocytosis in BM and negative results on viral and autoimmune marker studies. Meanwhile, a kidney biopsy was performed to investigate the cause of acute kidney injury because renal function did not improve. PT times (PT INR, 1.13) and aPTT times (aPTT, 23.3 seconds) were within normal limits. But complete blood count showed thrombocytopenia. We used prophylactic transfusion of platelets in preparation for a kidney biopsy that could cause bleeding. Under light microscopic examination, glomeruli were slightly enlarged with hypercellularity involving mesangial and endothelial cells. Capillary lumens were frequently filled with fragmented red blood cells and platelet aggregates (Fig. 3a). Tubules revealed focal moderate atrophy and loss with interstitial fibrosis (Fig. 3b). In an immunofluorescence study, staining for immunoglobulin G, immunoglobulin M, immunoglobulin A, C4, fibrinogen, kappa and lambda were negative. In electron microscopy, no electron-dense deposits were found and epithelial foot process showed focal marked effacement (Fig. 3c). The above histologic findings were compatible with renal TMA. At this time, we planned 6 cycles of cytotoxic therapy comprised of dexamethasone, etoposide at 100 mg/m2 and cyclosporine at 200 mg/day for the treatment of HLH based on the HLH-2004 protocol. Dexamethasone started at 10 mg/ m2 for 2 weeks, and then reduced to 50 % of initial dose every 2 weeks. As etoposide is cleared by both renal and hepatic routes, dose adjustment of etoposide based on renal function is recommended for the HLH-2004 protocol. We started at etoposide 100 mg/m2 with dose reductions of 25 % based on the patient's renal function. The general condition of the patient gradually improved and the fever subsided 7 days after the initiation of cytotoxic therapy. Concomitantly, urine output also increased and we ceased hemodialysis at 28 days from the first initiation of hemodialysis. After the 4th cycle of etoposide treatment, she suffered neutropenic fever due to vancomycin-resistant enterococci infection, which was successfully treated with linezolid and recombinant human granulocyte colony stimulating factor. After 7 cycles of etoposide treatment, she was discharged with normal kidney function and no signs of fever or neutropenia. At 6 months after the initial presentation, she showed no signs of HLH recurrence. A bone marrow aspiration and biopsy was done and the bone marrow biopsy looked normal cellular with normal hematopoiesis. Her serum creatinine level were in the normal range (0.99 mg/dL).

PMC10325704_01

Male

Seventeen patients with salivary gland histologies, consistent with SDC, were discussed in the institutional molecular tumor board between 2016 and 2022. After review of final histopathological diagnoses, 4 patients had salivary duct carcinoma with AR expression and HRAS/PIK3CA mutation and were included in the analysis. These patients (3 male, 1 female) were between 48-79 years old at the time of presentation at the MTB. Activating HRAS mutations were identified in the p.Q61 (3 patients) and p.G13 (1 patient) positions. Activating PIK3CA mutations were identified in the p.H1047 (3 patients) and p.E545 (1 patients) positions. Additional molecular findings were low to medium HER2-expression in 3 patients, PD-L1 expression in 2 patients, a tumor mutational burden (TMB) > 10 mutations/Megabase (mut/Mb) and an AR mutation in 1 patient, each. Median follow-up was 14.5 months. Clinical and molecular findings were summarized in Table 2 . The medline searches revealed 37 and 89 results, respectively. Of these, 4 studies with individual follow-up data for patients with AR+, PIK3CA/HRAS co-mutated SDC were included after manual review of the identified publications. The publications yielded a total of 9 cases (7 male, 2 female). Age was reported for 5 patients (range 38-65 years). Concurrent molecular alterations were HER2 amplification and overexpression in 1 and TP53 mutations in 2 patients, respectively. Clinical and molecular findings in these patients were summarized in Table 3 . A consort diagram of patient identification is provided in Supplementary Figure 1 . Overall, 13 patients (10 male, 3 female; median age in 9 evaluable patients 61 years, range 38-79 years) with AR+, PIK3CA/HRAS co-mutated SDC were identified. Combined analysis of 13 evaluable patients yielded information on various targeted systemic treatment strategies. Androgen deprivation therapy (ADT) was reported in 7 patients, HRAS-directed treatment in 6 patients, immune checkpoint inhibition in 1 patient and combinations of tipifarnib and ADT and alpelisib and ADT in 1 patient, each. Treatment data, including line of treatment, best response and progression-free survival (PFS) are provided, as available, in Table 4 and Figure 1 . Seven patients were treated with androgen deprivation therapy alone (ADT). Among 6 patients with available data on the specific type of ADT, 3 received bicalutamide and a GnRH-analogue and 3 received bicalutamide alone. Best response was evaluable in 5 patients (1 PR, 1 SD, 3 PD). 6 patients had evaluable PFS (median PFS = 2 months) and 2 of them had PFS > 6 months. The farnesyltransferase inhibitor tipifarnib as a single agent was administered in 6 patients. Among 5 patients with available data, 1 PR, 2 SD and 2 PD were achieved as best responses. PFS data were available for 6 patients and PFS was more than 6 months in 3 patients. One patient received ADT (bicalutamid/GnRH-Analogue) in combination with tipifarnib after prior progression to tipifarnib after 3 months. This patient achieved stable disease for more than 6 months, which was ongoing at the time of data collection. Another patient achieved a partial response with the PI3K-inhibitor alpelisib in combination with ADT (bicalutamide) for more than 12 months (ongoing at time of publication). Chemotherapy use with carboplatin/paclitaxel alone was reported in 4 patients. Among 3 patients with available data, 1 PR, 1 MR and 1 PD were reported. The use of alpelisib as monotherapy was only reported for one patient without information on treatment response. Immune checkpoint inhibition was also reported for one patient with a mixed response for 7 months. Following progression on the single-agent PD-1 inhibitor, this patient was treated with a combination of a PD-1 and a CTLA-4 inhibitor, which was followed by disease progression. One patient with concurrent HER2 amplification received trastuzumab in combination with chemotherapy and achieved a partial response. No major (common terminology criteria of adverse events, CTCAE grade 4 or higher) or unexpected toxicities were observed in the 4 patients identified from the MTB database and no dose reductions were required. In published data, a dose reduction because of toxicity was required in six patients (46%) receiving tipifarnib (4 because of cytopenia, 2 because of reversible renal failures), hypoglycemia requiring dose reduction was reported for alpelisib. Toxicity data were not reported in the literature for patients receiving antiandrogen therapy in this cohort. Available data from combined ADT in SGC reported no CTCAE grade 4/5 events and discontinuation of part of the combined ADT due to adverse events in 2 out of 36 patients.

head and neck cancer, molecular tumor board, precision oncology, salivary duct carcinoma, salivary gland cancer, targeted therapy

PMC3618104_01

Female

The patient is a 49-year-old woman with a past medical history significant for uterine fibroids and menorrhagia who presented with a complaint of heavy vaginal bleeding over the previous 8 days, progressive weakness, lightheadedness, palpitations, dyspnea on exertion and lower abdominal pain. She denied chest pain, cough, hemoptysis, fever and sick contacts. Her uterine fibroids were treated in the past by blood transfusion and bilateral uterine artery and left ovarian artery embolization. She was treated for tuberculosis and was hepatitis C positive. She was not allergic to any medications and denied smoking tobacco, consuming alcohol or using intravenous drugs. She was noted to have a hemoglobin level of 5.1 g/dl and received 5 units of packed red blood cells and levonorgestrel. Her shortness of breath improved marginally but she continued to have tachycardia. She was noted to have left lower extremity swelling which the patient admitted had started 4-5 days prior to admission. A lower extremity Doppler ultrasound revealed extensive deep venous thrombosis and she was started on systemic anticoagulation with dalteparin. Her chest X-ray revealed multiple bilateral pulmonary modules (fig. 1a, b). A chest CT showed saddle embolus and multiple bilateral pulmonary emboli with evidence of right heart strain. Multiple bilateral pulmonary nodules suspicious for metastatic disease and a moderate right-sided pleural effusion and a trace left-sided pleural effusion were also noted (fig. 2). Her physical examination was pertinent for tachycardia, normal breath sounds, distended abdomen with tenderness to palpation in the lower quadrants (uterus was palpable) and bilateral calf muscle swelling with tenderness. She underwent placement of an inferior vena cava filter and an endometrial biopsy. However, the next day morning the patient was noted to become severely hypoxemic with an altered mental state. She was intubated and started on vasopressors for shock. Due to persistent hypoxemia and hypotension she was taken to the operating room for thrombectomy. Intraoperative transesophageal echocardiography revealed an underfilled left ventricle with interventricular septum flattening, massively dilated right atrium and an extremely dilated right ventricle with reduced function. It also showed a mild-to-moderate pulmonary artery (PA) dilatation with a large mass in the right PA (possibly thrombus) and a severe tricuspid regurgitation with a large pedunculated, very mobile mass attached to the TV leaflets that moved from the right atrium to the right ventricle during the cardiac cycle (fig. 3). Intraoperatively, a large thrombus at the bifurcation of the PA which was extending into the PA branches was removed. The right atrium and the right ventricle were found to be devoid of any clots, but a worm-like mass attached to the anterior TV leaflet was identified and removed. Also a left lower lobe wedge resection was performed on a peripheral nodule and the right pleural effusion was drained. The patient continued to require a maximal dose of vasopressors and had to be maintained on extracorporal membrane oxygenation and renal replacement therapy. She was successfully extubated on postoperative day 6 and was transferred to the medical floor. Histology of the mass attached to the TV and the pulmonary nodule revealed spindle cells with marked nuclear atypia, frequent mitoses, extensive necrosis and vascular invasion consistent with leiomyosarcoma (fig. 4a). Immunohistochemistry was positive for smooth muscle actin (SMA), desmin, ER, PR and cyclin-dependent kinase inhibitor 2A (p16) (fig. 4b-f). It was negative for myogenin, myogenic differentiation 1 (myoD1) and cytokeratins (AE1/3). These findings support a diagnosis of leiomyosarcoma and likely represent metastasis from the uterus. The pleural fluid showed rare, isolated highly atypical cells of uncertain origin and scattered mesothelial cells. The endometrial biopsy revealed an early secretory endometrium. It is likely that this patient suffered from a massive pulmonary embolism due to a combination of a predisposed state of hypercoagulation due to malignancy and due to the possible obstructive nature of the mass on the TV. These findings suggest that uterine leiomyosarcoma may manifest itself as a mass on the heart valves, and early identification may help prevent life-threatening complications.

leiomyosarcoma, metastasis, pulmonary embolism, tricuspid valve

Chest CT with contrast showing pulmonary nodules and a moderate right-sided pleural effusion.

PMC2840966_01

Male

A 30-year-old non-diabetic, non-hypertensive man developed pain in left side of the chest, pleuritic in nature and localized to left lateral aspect not associated with breathlessness and cough. Subsequently, he developed fever not associated with chills and rigor and swelling on the left lateral lower aspect of the chest, which was painful and gradually increasing. X-ray and CT Scan revealed a lytic leision in the anterior end of left sixth rib with associated subcutaneous soft tissue swelling and enlarged mediatsinal lymphnodes. The patient was tested for HIV antigen and was negative. On the left lower aspect of chest, the patient showed a tender swelling which measured 6 x 5 cms. His haemoglobin and total leucocyte count were normal. Patient's CD4 count was normal and Mantoux test was positive, but Quantiferon gold was negative. Computed Tomography (CT) of head was also done, which was normal. Fine needle aspiration cytology (FNAC) was performed outside and suggestive of cryptoccocal infection. The patient was taken for surgery and 6th rib excision was done. Histopatholoical examination showed fragments of partly necrotic bone and diffuse chronic inflammatory cell infiltrate including many giant cells, histiocytes, lymphocytes and plasma cells [Figure 1]. The inflammation extended into the subcutaneous soft tissue forming microabcessess. Numerous encapsulated yeast forms, a few showing budding were present within the giant cells [Figure 2] and extracellulary within florid granulomatous inflammation [Figure 2]. A Gomori methenamine silver stain and mucicarmine stain highlighted yeast formed with narrow based budding [Figures 3 and 4]. A final diagnosis of cryptococcal osteomyelitis was given. Culture done for tuberculosis and sputum sent for acid fast bacilli were negative. The patient was started on antifungal treatment and was doing well in his last follow-up.

cryptococcus, immunocompetent, osteomyelitis

PMC4360725_01

Male

A 63-year-old male was admitted to his regional hospital because of severe weakness, anorexia and weight loss (16 kg in the previous 4 months). Six months earlier, he had been admitted to the same hospital with fatigue, cervical lymphadenopathy, sialadenitis and peripheral facial palsy. He had then received oral steroids for 2 months with significant clinical improvement. Prior medical history included hypertension for 15 years, a self-limited vitiligo 2 years before and an episode of alithiasic cholecystitis, without pancreatic involvement 1 year before. On admission, laboratory tests showed anemia (hemoglobin 8.2 g/dl), leukocytosis (WBCs 18.800/ml) with increased neutrophils (60-88%) and eosinophils (3-18%), increased C-reactive protein, rapid deterioration of renal function (peak urea 87 mg/dl, creatinine 2.8 mg/dl), positive antinuclear antibodies (ANA) 1:1,280, low serum complement, hypoalbuminemia (1.8 g/dl), proteinuria (1.8 g/daily), pyuria and mild hematuria in urinalysis. He was then referred to our hospital for renal biopsy with a presumptive diagnosis of lupus nephritis. On admission to our hospital, the patient had a low-grade fever, intense weakness affecting mobility, absence of arthralgias or arthritis. He was hemodynamically stable and normovolemic. The rest of the physical examination revealed only hepatomegaly and muscle wasting. Laboratory tests confirmed the inflammatory syndrome (elevated erythrocyte sedimentation rate and C-reactive protein) and immunological abnormalities with high IgG (2,020 mg/dl), low complement C3 and C4, positive ANA 1:640 and atypical pANCA 1:160. Antibodies against double-stranded DNA (anti-dsDNA) were found slightly positive only once, whereas the crithidia luciliae immunofluorescence (CLIF) test was negative. Serum and urine immunofixation, MPO/PR3 titers, hepatitis screening, serum cryoglobulins and angiotensin-converting enzyme were negative or normal. Both abdominal ultrasound and CT revealed large kidneys (13 and 14 cm) and marked hepatomegaly. Brain CT was normal and chest CT showed marginally enlarged mediastinal lymph nodes. Further analysis of IgG subclasses revealed extremely high IgG4 levels (1,210 mg/dl). A subsequent kidney biopsy showed irregular thickening of glomerular basement membranes (GBMs) with C4d deposition by immunohistochemistry, thickening of tubular basement membranes (TBMs) and diffuse interstitial inflammatory infiltrates disrupting normal kidney architecture. The infiltrates consisted mainly of polyclonal (kappa and lambda positive) plasma cells, the vast majority being IgG4+ (>50 per high power field, hpf) as well as CD3+ and CD20+ lymphocytes and eosinophils (fig. 1). Congo red stain was negative. Interstitial fibrosis was estimated at 30-35% of the substrate by Masson stain. Immunofluorescence showed moderate IgG and mild C3 depositions in GBMs. IgG was also found in interstitial infiltrates and IgM in the TBMs. Fluorescence for IgA, C4 and C1q was negative. Electron microscopy revealed the presence of several subepithelial dense deposits and scarce mesangial and TBM deposits. Based on biopsy findings, a final diagnosis of IgG4-RKD with TIN and secondary MN was made. Methylprednisolone therapy was started at a dose of 36 mg/day with gradual tapering to 4 mg/day for 1 year. This treatment resulted in a rapid improvement of symptoms and renal function (serum creatinine from 2.8 to 1.8 mg/dl within the first 10 days). At the 6 and 12 months follow-up, clinical, radiologic and laboratory findings have all returned to normal (serum creatinine at 1.1 mg/dl).

igg4-related disease, interstitial nephritis, membranous nephropathy

PMC6204878_01

Female

A 65-year-old Chinese female patient presented a gradually increased mass (4x3 cm) in the left thigh and three separated black skin lesions (1x1 cm or less) on the left foot in December 2015. The resection of the mass in the left thigh and the largest skin lesion on the left foot was performed on December 4, 2015. The pathological exploration showed malignant melanoma with necrosis but no nerve or vascular invasion. The chest computed tomography (CT) scan (Figure 1A) showed a shadow at the posterior segment of the right upper lobe of the lung. However, neither respiratory nor systemic symptoms, such as cough, weight loss, fever, and night sweats, were observed. For the first-line treatment, high-dose IL-2 was the preferred treatment, as is the case for medically fit metastatic melanoma patients for >20 years. Thus, IL-2 was administered to the patient at a dose of 64,000 IU/kg, qd, on days 1-10, repeated every 14 days for 6 cycles. However, a node in the left thigh around the surgical margin (1.5x1.5 cm) and two new lymph nodes in the left groin (2x1 cm) were observed, indicating progressive disease. Another chest CT scan (Figure 1B), performed in March 2016, suggested a slightly reduced lesion of the right lobe of the lung. Then, the patient initiated pembrolizumab treatment at a dose of 2 mg/kg every 3 weeks since June 2016. After 3 cycles of immunotherapy, all the nodes contracted remarkably. Nevertheless, the patient developed fatigue and dry mouth and skin, raising suspicion of Sjogren's syndrome with a positive concentration of the autoimmune antibody RO52 in the peripheral blood test. Thus, the administration of pembrolizumab at 2 mg/kg was continued at every 4 weeks for another 7 cycles until January 2017. The patient responded to pembrolizumab, and the nodes in the left thigh or groin, except for two black skin lesions at the bottom of left foot (decreasing in size from 0.5x0.3 to 0.2x0.1 cm), disappeared, as evaluated by ultrasonic scan in October 2016; however, tolerant oral ulcer, fatigue, and vitiligo were observed. In February 2017, the patient presented about 10 mL of bloody sputum daily for a week without cough, night sweats, fever, or weight loss. The chest CT (Figure 1C) showed the increased size of the lesion in the right upper lobe without lymphadenopathy or pleural effusion. BALF was collected, and transbronchial lung biopsy was performed. Unconcentrated BALF was tested positive for GeneXpert Mycobacterium tuberculosis (MTB)/RIF with low semi-quantitative value. Additionally, mutations in rpoB gene that confer rifampicin resistance were not detected. The liquid culture and drug sensitivity test for BALF indicated MTB to be drug sensitive. Both examinations confirmed the diagnosis of active pulmonary TB. The transbronchial lung biopsy specimen showed a large amount of caseous necrosis (Figure 2A and B) with mediate lymphocyte infiltrate but few acid-fast bacilli. The number of CD4 and CD8 in the peripheral blood was significantly higher than the normal range (1,544/microL and 712/microL, respectively). Consequently, immunotherapy was paused and anti-TB drugs of isoniazid 0.3, qd, rifampin 0.45, qd, pyrazinamide 1.0, qd, and ethambutol 0.75, qd (HRZE) were administered according to the body weight. Bloody sputum ceased with anti-TB treatment 1-week posttreatment and the sputum culture for MTB was negative after 4 weeks. However, the patient complained of nausea and vomiting during the anti-TB treatment since week 4, and the liver function test showed the abnormal level of alanine aminotransferase 240 U/L, aspartate aminotransferase 277 U/L, and total bilirubin 42 micromol/L. Thus, the anti-TB treatment was suspended and liver-protecting drugs were administered. After 2 weeks, the liver function recovered and clinical symptoms improved significantly. HRZ was challenged again; however, the level of transaminases increased and isoniazid-induced fever was observed. Considering the negative sputum culture and side effects of HRZ, the administration of isoniazid, rifampin, and pyrazinamide was discontinued. The second-line anti-TB regimen, including streptomycin 0.75, qd, ethambutol 0.75, qd, and moxifloxacin 0.4, qd, was administered for 4 months. The chest CT scan (Figure 1D) showed that the right pulmonary lesion had shrunk significantly in April 2017. Therefore, the patient was challenged with pembrolizumab monthly for 2 more cycles with the concurrent use of three anti-TB drugs. Combination of PD-1 inhibition and anti-TB treatment kept the patient fit with normal liver function and slightly improved dry mouth. Notably, no steroids were administered throughout the treatment. Then, the patient underwent radical resection of the remaining two black skin lesions at the bottom of the left foot on July 12, 2017, and histology did not show any tumor cells indicating a complete response. Subsequently, the patient was subjected to two consolidation treatments with pembrolizumab per month (total 14 cycles). Anti-TB therapy was discontinued in August 2017. Also, she was under medical surveillance every 3-6 months, and no recurrence was detected. Finally, the patient was under follow-up until the drafting of this case report. The study was approved by the Clinical Research Ethics Committee of Shenzhen People's Hospital, China. Written consent was obtained from the patient and her relatives for publication of the case report.

pd-1, anti-tuberculosis treatment, checkpoint inhibitor, metastatic melanoma, pembrolizumab, pulmonary tuberculosis

CT image. . Notes: (A) Infiltration of the right upper lobe of the lung before treatment.

PMC6204878_01

Female

A 65-year-old Chinese female patient presented a gradually increased mass (4x3 cm) in the left thigh and three separated black skin lesions (1x1 cm or less) on the left foot in December 2015. The resection of the mass in the left thigh and the largest skin lesion on the left foot was performed on December 4, 2015. The pathological exploration showed malignant melanoma with necrosis but no nerve or vascular invasion. The chest computed tomography (CT) scan (Figure 1A) showed a shadow at the posterior segment of the right upper lobe of the lung. However, neither respiratory nor systemic symptoms, such as cough, weight loss, fever, and night sweats, were observed. For the first-line treatment, high-dose IL-2 was the preferred treatment, as is the case for medically fit metastatic melanoma patients for >20 years. Thus, IL-2 was administered to the patient at a dose of 64,000 IU/kg, qd, on days 1-10, repeated every 14 days for 6 cycles. However, a node in the left thigh around the surgical margin (1.5x1.5 cm) and two new lymph nodes in the left groin (2x1 cm) were observed, indicating progressive disease. Another chest CT scan (Figure 1B), performed in March 2016, suggested a slightly reduced lesion of the right lobe of the lung. Then, the patient initiated pembrolizumab treatment at a dose of 2 mg/kg every 3 weeks since June 2016. After 3 cycles of immunotherapy, all the nodes contracted remarkably. Nevertheless, the patient developed fatigue and dry mouth and skin, raising suspicion of Sjogren's syndrome with a positive concentration of the autoimmune antibody RO52 in the peripheral blood test. Thus, the administration of pembrolizumab at 2 mg/kg was continued at every 4 weeks for another 7 cycles until January 2017. The patient responded to pembrolizumab, and the nodes in the left thigh or groin, except for two black skin lesions at the bottom of left foot (decreasing in size from 0.5x0.3 to 0.2x0.1 cm), disappeared, as evaluated by ultrasonic scan in October 2016; however, tolerant oral ulcer, fatigue, and vitiligo were observed. In February 2017, the patient presented about 10 mL of bloody sputum daily for a week without cough, night sweats, fever, or weight loss. The chest CT (Figure 1C) showed the increased size of the lesion in the right upper lobe without lymphadenopathy or pleural effusion. BALF was collected, and transbronchial lung biopsy was performed. Unconcentrated BALF was tested positive for GeneXpert Mycobacterium tuberculosis (MTB)/RIF with low semi-quantitative value. Additionally, mutations in rpoB gene that confer rifampicin resistance were not detected. The liquid culture and drug sensitivity test for BALF indicated MTB to be drug sensitive. Both examinations confirmed the diagnosis of active pulmonary TB. The transbronchial lung biopsy specimen showed a large amount of caseous necrosis (Figure 2A and B) with mediate lymphocyte infiltrate but few acid-fast bacilli. The number of CD4 and CD8 in the peripheral blood was significantly higher than the normal range (1,544/microL and 712/microL, respectively). Consequently, immunotherapy was paused and anti-TB drugs of isoniazid 0.3, qd, rifampin 0.45, qd, pyrazinamide 1.0, qd, and ethambutol 0.75, qd (HRZE) were administered according to the body weight. Bloody sputum ceased with anti-TB treatment 1-week posttreatment and the sputum culture for MTB was negative after 4 weeks. However, the patient complained of nausea and vomiting during the anti-TB treatment since week 4, and the liver function test showed the abnormal level of alanine aminotransferase 240 U/L, aspartate aminotransferase 277 U/L, and total bilirubin 42 micromol/L. Thus, the anti-TB treatment was suspended and liver-protecting drugs were administered. After 2 weeks, the liver function recovered and clinical symptoms improved significantly. HRZ was challenged again; however, the level of transaminases increased and isoniazid-induced fever was observed. Considering the negative sputum culture and side effects of HRZ, the administration of isoniazid, rifampin, and pyrazinamide was discontinued. The second-line anti-TB regimen, including streptomycin 0.75, qd, ethambutol 0.75, qd, and moxifloxacin 0.4, qd, was administered for 4 months. The chest CT scan (Figure 1D) showed that the right pulmonary lesion had shrunk significantly in April 2017. Therefore, the patient was challenged with pembrolizumab monthly for 2 more cycles with the concurrent use of three anti-TB drugs. Combination of PD-1 inhibition and anti-TB treatment kept the patient fit with normal liver function and slightly improved dry mouth. Notably, no steroids were administered throughout the treatment. Then, the patient underwent radical resection of the remaining two black skin lesions at the bottom of the left foot on July 12, 2017, and histology did not show any tumor cells indicating a complete response. Subsequently, the patient was subjected to two consolidation treatments with pembrolizumab per month (total 14 cycles). Anti-TB therapy was discontinued in August 2017. Also, she was under medical surveillance every 3-6 months, and no recurrence was detected. Finally, the patient was under follow-up until the drafting of this case report. The study was approved by the Clinical Research Ethics Committee of Shenzhen People's Hospital, China. Written consent was obtained from the patient and her relatives for publication of the case report.

pd-1, anti-tuberculosis treatment, checkpoint inhibitor, metastatic melanoma, pembrolizumab, pulmonary tuberculosis

CT image. (B) Infiltration of the right upper lobe of the lung after IL-2 therapy.

PMC6204878_01

Female

A 65-year-old Chinese female patient presented a gradually increased mass (4x3 cm) in the left thigh and three separated black skin lesions (1x1 cm or less) on the left foot in December 2015. The resection of the mass in the left thigh and the largest skin lesion on the left foot was performed on December 4, 2015. The pathological exploration showed malignant melanoma with necrosis but no nerve or vascular invasion. The chest computed tomography (CT) scan (Figure 1A) showed a shadow at the posterior segment of the right upper lobe of the lung. However, neither respiratory nor systemic symptoms, such as cough, weight loss, fever, and night sweats, were observed. For the first-line treatment, high-dose IL-2 was the preferred treatment, as is the case for medically fit metastatic melanoma patients for >20 years. Thus, IL-2 was administered to the patient at a dose of 64,000 IU/kg, qd, on days 1-10, repeated every 14 days for 6 cycles. However, a node in the left thigh around the surgical margin (1.5x1.5 cm) and two new lymph nodes in the left groin (2x1 cm) were observed, indicating progressive disease. Another chest CT scan (Figure 1B), performed in March 2016, suggested a slightly reduced lesion of the right lobe of the lung. Then, the patient initiated pembrolizumab treatment at a dose of 2 mg/kg every 3 weeks since June 2016. After 3 cycles of immunotherapy, all the nodes contracted remarkably. Nevertheless, the patient developed fatigue and dry mouth and skin, raising suspicion of Sjogren's syndrome with a positive concentration of the autoimmune antibody RO52 in the peripheral blood test. Thus, the administration of pembrolizumab at 2 mg/kg was continued at every 4 weeks for another 7 cycles until January 2017. The patient responded to pembrolizumab, and the nodes in the left thigh or groin, except for two black skin lesions at the bottom of left foot (decreasing in size from 0.5x0.3 to 0.2x0.1 cm), disappeared, as evaluated by ultrasonic scan in October 2016; however, tolerant oral ulcer, fatigue, and vitiligo were observed. In February 2017, the patient presented about 10 mL of bloody sputum daily for a week without cough, night sweats, fever, or weight loss. The chest CT (Figure 1C) showed the increased size of the lesion in the right upper lobe without lymphadenopathy or pleural effusion. BALF was collected, and transbronchial lung biopsy was performed. Unconcentrated BALF was tested positive for GeneXpert Mycobacterium tuberculosis (MTB)/RIF with low semi-quantitative value. Additionally, mutations in rpoB gene that confer rifampicin resistance were not detected. The liquid culture and drug sensitivity test for BALF indicated MTB to be drug sensitive. Both examinations confirmed the diagnosis of active pulmonary TB. The transbronchial lung biopsy specimen showed a large amount of caseous necrosis (Figure 2A and B) with mediate lymphocyte infiltrate but few acid-fast bacilli. The number of CD4 and CD8 in the peripheral blood was significantly higher than the normal range (1,544/microL and 712/microL, respectively). Consequently, immunotherapy was paused and anti-TB drugs of isoniazid 0.3, qd, rifampin 0.45, qd, pyrazinamide 1.0, qd, and ethambutol 0.75, qd (HRZE) were administered according to the body weight. Bloody sputum ceased with anti-TB treatment 1-week posttreatment and the sputum culture for MTB was negative after 4 weeks. However, the patient complained of nausea and vomiting during the anti-TB treatment since week 4, and the liver function test showed the abnormal level of alanine aminotransferase 240 U/L, aspartate aminotransferase 277 U/L, and total bilirubin 42 micromol/L. Thus, the anti-TB treatment was suspended and liver-protecting drugs were administered. After 2 weeks, the liver function recovered and clinical symptoms improved significantly. HRZ was challenged again; however, the level of transaminases increased and isoniazid-induced fever was observed. Considering the negative sputum culture and side effects of HRZ, the administration of isoniazid, rifampin, and pyrazinamide was discontinued. The second-line anti-TB regimen, including streptomycin 0.75, qd, ethambutol 0.75, qd, and moxifloxacin 0.4, qd, was administered for 4 months. The chest CT scan (Figure 1D) showed that the right pulmonary lesion had shrunk significantly in April 2017. Therefore, the patient was challenged with pembrolizumab monthly for 2 more cycles with the concurrent use of three anti-TB drugs. Combination of PD-1 inhibition and anti-TB treatment kept the patient fit with normal liver function and slightly improved dry mouth. Notably, no steroids were administered throughout the treatment. Then, the patient underwent radical resection of the remaining two black skin lesions at the bottom of the left foot on July 12, 2017, and histology did not show any tumor cells indicating a complete response. Subsequently, the patient was subjected to two consolidation treatments with pembrolizumab per month (total 14 cycles). Anti-TB therapy was discontinued in August 2017. Also, she was under medical surveillance every 3-6 months, and no recurrence was detected. Finally, the patient was under follow-up until the drafting of this case report. The study was approved by the Clinical Research Ethics Committee of Shenzhen People's Hospital, China. Written consent was obtained from the patient and her relatives for publication of the case report.

pd-1, anti-tuberculosis treatment, checkpoint inhibitor, metastatic melanoma, pembrolizumab, pulmonary tuberculosis

CT image. (C) Infiltration of the right upper lobe of lung worsened after PD-1 inhibition.

PMC6204878_01

Female

A 65-year-old Chinese female patient presented a gradually increased mass (4x3 cm) in the left thigh and three separated black skin lesions (1x1 cm or less) on the left foot in December 2015. The resection of the mass in the left thigh and the largest skin lesion on the left foot was performed on December 4, 2015. The pathological exploration showed malignant melanoma with necrosis but no nerve or vascular invasion. The chest computed tomography (CT) scan (Figure 1A) showed a shadow at the posterior segment of the right upper lobe of the lung. However, neither respiratory nor systemic symptoms, such as cough, weight loss, fever, and night sweats, were observed. For the first-line treatment, high-dose IL-2 was the preferred treatment, as is the case for medically fit metastatic melanoma patients for >20 years. Thus, IL-2 was administered to the patient at a dose of 64,000 IU/kg, qd, on days 1-10, repeated every 14 days for 6 cycles. However, a node in the left thigh around the surgical margin (1.5x1.5 cm) and two new lymph nodes in the left groin (2x1 cm) were observed, indicating progressive disease. Another chest CT scan (Figure 1B), performed in March 2016, suggested a slightly reduced lesion of the right lobe of the lung. Then, the patient initiated pembrolizumab treatment at a dose of 2 mg/kg every 3 weeks since June 2016. After 3 cycles of immunotherapy, all the nodes contracted remarkably. Nevertheless, the patient developed fatigue and dry mouth and skin, raising suspicion of Sjogren's syndrome with a positive concentration of the autoimmune antibody RO52 in the peripheral blood test. Thus, the administration of pembrolizumab at 2 mg/kg was continued at every 4 weeks for another 7 cycles until January 2017. The patient responded to pembrolizumab, and the nodes in the left thigh or groin, except for two black skin lesions at the bottom of left foot (decreasing in size from 0.5x0.3 to 0.2x0.1 cm), disappeared, as evaluated by ultrasonic scan in October 2016; however, tolerant oral ulcer, fatigue, and vitiligo were observed. In February 2017, the patient presented about 10 mL of bloody sputum daily for a week without cough, night sweats, fever, or weight loss. The chest CT (Figure 1C) showed the increased size of the lesion in the right upper lobe without lymphadenopathy or pleural effusion. BALF was collected, and transbronchial lung biopsy was performed. Unconcentrated BALF was tested positive for GeneXpert Mycobacterium tuberculosis (MTB)/RIF with low semi-quantitative value. Additionally, mutations in rpoB gene that confer rifampicin resistance were not detected. The liquid culture and drug sensitivity test for BALF indicated MTB to be drug sensitive. Both examinations confirmed the diagnosis of active pulmonary TB. The transbronchial lung biopsy specimen showed a large amount of caseous necrosis (Figure 2A and B) with mediate lymphocyte infiltrate but few acid-fast bacilli. The number of CD4 and CD8 in the peripheral blood was significantly higher than the normal range (1,544/microL and 712/microL, respectively). Consequently, immunotherapy was paused and anti-TB drugs of isoniazid 0.3, qd, rifampin 0.45, qd, pyrazinamide 1.0, qd, and ethambutol 0.75, qd (HRZE) were administered according to the body weight. Bloody sputum ceased with anti-TB treatment 1-week posttreatment and the sputum culture for MTB was negative after 4 weeks. However, the patient complained of nausea and vomiting during the anti-TB treatment since week 4, and the liver function test showed the abnormal level of alanine aminotransferase 240 U/L, aspartate aminotransferase 277 U/L, and total bilirubin 42 micromol/L. Thus, the anti-TB treatment was suspended and liver-protecting drugs were administered. After 2 weeks, the liver function recovered and clinical symptoms improved significantly. HRZ was challenged again; however, the level of transaminases increased and isoniazid-induced fever was observed. Considering the negative sputum culture and side effects of HRZ, the administration of isoniazid, rifampin, and pyrazinamide was discontinued. The second-line anti-TB regimen, including streptomycin 0.75, qd, ethambutol 0.75, qd, and moxifloxacin 0.4, qd, was administered for 4 months. The chest CT scan (Figure 1D) showed that the right pulmonary lesion had shrunk significantly in April 2017. Therefore, the patient was challenged with pembrolizumab monthly for 2 more cycles with the concurrent use of three anti-TB drugs. Combination of PD-1 inhibition and anti-TB treatment kept the patient fit with normal liver function and slightly improved dry mouth. Notably, no steroids were administered throughout the treatment. Then, the patient underwent radical resection of the remaining two black skin lesions at the bottom of the left foot on July 12, 2017, and histology did not show any tumor cells indicating a complete response. Subsequently, the patient was subjected to two consolidation treatments with pembrolizumab per month (total 14 cycles). Anti-TB therapy was discontinued in August 2017. Also, she was under medical surveillance every 3-6 months, and no recurrence was detected. Finally, the patient was under follow-up until the drafting of this case report. The study was approved by the Clinical Research Ethics Committee of Shenzhen People's Hospital, China. Written consent was obtained from the patient and her relatives for publication of the case report.

pd-1, anti-tuberculosis treatment, checkpoint inhibitor, metastatic melanoma, pembrolizumab, pulmonary tuberculosis

CT image. (D) Infiltration of the right upper lobe of lung absorbed after 6 weeks of anti-TB treatment. . Abbreviations: CT, computed tomography; TB, tuberculosis.

PMC4499233_01

Female

The identification of the cause of acute encephalitis is difficult in spite of many developed diagnosis strategies. The cause is unknown in nearly 30 to 40% of cases. Tuberculosis is endemic in Tunisia. Tuberculous encephalitis is rare in immunocompetent adults. We report in this work a rare case report of tuberculous encephalitis in an immunocompetent woman. She was 38 years old and had no medical history. She had a clinical presentation of mental confusion and fever that appeared from ten days. She was agitated with neck stiffness. Her initial Glasgow coma scale was thirteen. The CT scan of the head showed a brain temporal abscess (A). The cerebral spinal fluid examination showed elevated proteinorrachia of 172 mg/dl, normal glycorrachia and lymphocytic pleocytosis (76% of 340 WBC/mm3). The Magnetic resonance imaging (MRI) of the head performed in the second day revealed images of hydrocephalus (B). It showed also two images of brain vermian (C) and temporal abscesses (D). The diagnosis of tuberculous encephalitis was made by computing clinical, laboratory and imaging findings. She was admitted in the intensive care unit and treatment by cefotaxim and acyclovir was initiated. Antituberculous drugs were added at the second day of management after MRI. In the sixth day of management, the patient became comatose and required intubation and mechanical ventilation. She died three days later from neurologic complications. Figure 1

tuberculosis, encepahlitis, immunocompetent, intensive care unit

PMC7273542_01

Female

Our patient is a 42-year-old female who had presented in Ethiopia with vague symptoms of a few months of fatigue, weakness, and unintentional weight loss of 3-4 kg. She was subsequently diagnosed with renal failure, requiring hemodialysis. The etiology of her renal failure was unclear. She went to India to see if she could obtain another explanation for her symptoms and continued hemodialysis there. Due to a lack of improvement in her symptoms, she came to the United States for different treatment options. She presented initially to an American hospital with dyspnea and volume overload. She underwent a chest X-ray for dyspnea (Figure 1) which was largely unremarkable. A computed tomography (CT) angiography of her chest was negative for pulmonary embolism, but notable for non-specific lymphadenopathy and small right-sided pleural effusion. She also underwent CT imaging of her abdomen and pelvis which noted multiple small renal cysts bilaterally, which were too small to characterize. Her symptoms were thought to be secondary to ESRD, and she was advised to continue outpatient hemodialysis. She presented again to the hospital two-and-a-half months later with progressive dyspnea on exertion and right-sided chest pain. The patient denied any hemoptysis, nausea, vomiting, diarrhea, or prior exposure to tuberculosis. Patient had a negative cardiac workup. She underwent another CT angiography of her chest which showed no pulmonary embolism, but now showed loculated right pleural effusion (Figure 2(a)), subcarinal and right hilar adenopathy (Figure 2(b)). Thoracentesis was performed. Analysis of the pleural fluid revealed it was an exudative effusion (pH 7.8, white blood cells 1083 cells/mm3, 24% lymphocytes, <25% polymorphonuclear cells, glucose 84 mg/dL, and Lactate dehydrogenase 270 U/L) with moderately elevated adenosine deaminase (ADA, 57.6 U/L) level. Fungal culture and gram stain of pleural fluid did not reveal any fungal or bacterial organisms. She produced two sputum samples which were both negative for acid fast bacilli smear and culture. Patient was also found to have persistent hypercalcemia (11.7-12.8 mg/dL), elevated 1,25-dihydroxyvitamin D (131 pg/mL), normal parathyroid hormone level (53.8 pg/mL), and surprisingly elevated PTHrP (52 pg/mL). At this point, there was concern for malignancy such as lymphoma, but the pleural fluid did not show any malignant cells and peripheral flow cytometry did not show any abnormal T or B cells. Endobronchial ultrasound was performed with biopsy of lymph node showing necrotic tissue, with insufficient cells to send for lymphoma stains. She was also found to have a positive quantiferon, but negative acid fast stain of bronchoalveolar lavage and sputum samples. She underwent a right pleural biopsy as well, with results pending when patient was discharged from the hospital. Patient was hemodialyzed, treated with 9-day course of piperacillin-tazobactam for fevers of unknown origin, and advised to follow-up in clinic. She presented a week later with similar complaints and worsening tachycardia during her hemodialysis sessions. Chest radiograph showed moderate right pleural effusion with consolidation throughout right lung base. Serum leukemia/lymphoma panel was negative. Patient underwent mediastinoscopy with excisional lymph node biopsy as her previous fine needle aspiration was non-diagnostic. The biopsy of the lymph node showed necrotizing granulomas (Figure 3). Eventually, the acid fast stain of the pleural biopsy sample resulted and showed growth of mycobacterium tuberculosis. Patient was started on medications that were weight-based (patient's weight 48.1 kg), which included oral rifampin 600 mg daily, isoniazid 300 mg daily, pyrazinamide 1500 mg three times a week after dialysis, and ethambutol 1200 mg three times a week after dialysis. Drug susceptibility testing indicated that the mycobacteria was sensitive to the medication regimen. One week after starting therapy, patient's PTHrP decreased to 35 pg/mL and normalization of serum calcium concentration (9.9 mg/dL) occurred. Patient's fevers, tachycardia, and chest pain improved on these antibiotics.

infectious diseases, end-stage renal disease, extra pulmonary, parathyroid hormone–related protein, respiratory medicine

PMC9113868_01

Male

According to the family history inquiry, among the 5 individuals who have passed away in the 1st and 2nd generation, only 1 individual (II-5) died of brain stroke with obesity, hypertension, and gout at the age of 54, while the remaining 4 individuals died of multiple metastases of finger cSCC. II-7 was a tailor. He had several years' history of dorsal digital skin ulcer but never sought for any medical treatment. He finally visited the hospital due to the severe deterioration of the ulcer (finger bone exposing). He took a skin biopsy and was diagnosed as cSCC. He was hospitalized for a finger amputation in Zhuhai People's Hospital in 2010. Although underwent standard chemotherapy, 2 years later, he died of multiple metastasis including lung metastasis and spinal metastasis at 51 years old. II-3, born in 1959, was a blue-collar worker. He was admitted to Tongji Hospital for a nonhealing ulcer of the dorsal finger in 2012. A pathological diagnosis of cSCC was made after the skin biopsy. Axillary metastasis emerged soon after surgical resection of the tumor. Finally, he died of uncontrollable bleeding from axillary metastatic tumor at 57 years old. Two other family members (I-1 and II-1, an accountant and a blue-collar worker) had similar experience and died due to massive bleeding of axillary metastatic tumor at the ages 36 and 45, respectively. To identify the underlying pathological gene, we performed WES for the proband (IV-6). A heterozygous mutation in the SMARCAD1 gene NM_001254949.2: c.-10+5G>A (if counting from the beginning of the noncoding exon 1, this mutation would be named as c.378+5G>A) was identified. The WES result was further confirmed by Sanger sequencing (Figure 4(a)). Sanger sequencing was also performed for III-2, III-6, III-10, III-11, IV-1, and IV-4. As shown in the pedigree chart (Figure 2), (+) indicates the mutation has been confirmed by Sanger sequencing. (-) indicates no mutation was detected by Sanger sequencing. III-2, III-6, III-10, and IV-4 were clinically diagnosed with Basan syndrome. They were also confirmed carrying the same mutation by Sanger sequencing. Figure 4(b) illustrates the mutation of the proband's father (III-10). III-11 and IV-1 did not carry this mutation, while no Basan syndrome was diagnosed. Figure 4(c) illustrates that the mutation was not discovered in the proband's mother (III-11). This revealed that the mutation cosegregated with Basan syndrome in this pedigree. Bioinformatics analysis showed that this mutation was not detected in the 1000 genome database, ExAC databases, or gnomAD database. One of the 7 collected blood samples (III-2) was contaminated due to misoperation before performing WES. Therefore, WES was performed for only 6 individuals. Table 1 summarizes the results. All of the 6 samples had a coverage higher than 98% at 4X. The average depth was 160.22 for III-6, 193.60 for III-10, 136.44 for III-11, 176.87 for IV-1, 157.72 for IV-4, and 136.29 for IV-6. In summary, the sequencing data had reached the required quality for next step analysis. Based on the WES data, we performed target analysis for the SMARCAD1 gene to further confirm the association between SMARCAD1 and Basan syndrome. As shown in Table 2, all Basan syndrome patients carried the mutation SMARCAD1, chr4: 94253676G>A. Specifically, III-6 had 63 reads mapped to SMARCAD1 variant with a frequency of 0.406; III-10 had 60 reads mapped with a frequency of 0.400; IV-4 had 66 reads mapped with a frequency of 0.485; and IV-6 had 54 reads mapped with a frequency of 0.519. Other family member who was not diagnosed with Basan syndrome did not carry this mutation. As described above, the family history revealed 4 affected members with cSCC in the 1st and 2nd generations. This family exhibited high cooccurrence rate between Basan syndrome and cSCC. To discover the potential highly related gene mutations, we further investigated WES results in the ClinVar database and COSMIC database, aiming for cancer-related gene mutations. Due to the limited samples available, we set out to apply strict filtering criteria for finding possible associated gene mutations. The criteria only kept mutations occurring in the four individuals with Basan syndrome (III-6, III-10, IV-4, and IV-6) but not in other two non-Basan individuals (III-11 and IV-1). The results from the filtering criteria retained 3434 mutations. Out of these 3434 mutations, only one mutation, rs751141, was mapped to the ClinVar database. The annotation of rs751141 shows that it is a risk factor related to "hypercholesterolemia, familial." The above-mentioned 3434 mutations were then mapped in the COSMIC database. In order to find more significance related to the FAMILIAL cancer, we only retained the exonic area and presented as "nonsynonymous" or "frameshift." After filtering, three genetic variants appeared in individuals with Basan syndrome but not in non-Basan individuals: rs3085861 (SETBP1), rs663651 (SETBP1), and rs2454206 (TET2). Both SETBP1 gene and TET2 gene have been reported associating with skin cancers, including cSCC. However, according to dbSNP, all of the three genetic variants observed in this study are common variants. Minigene was preformed to further analyze the SMARCAD1 pre-mRNA splicing. We constructed a Minigene containing genomic sequence from intron 1, pseudoexon 1, pseudoexon 2, and exon 2. Our data indicated that the mutation in the SMARCAD1 gene site can lead to splicing variations: pseudoexon 1, pseudoexon 2, and exon 2 were all detected in the wild type, but pseudoexon 2 was skipped in the mutation type (Figure 5). This mutation was located in the intron 1. No other potential splicing site was found. The Minigene result demonstrated that this mutation in intron 1 may cause the gene-splicing variation. Contrarily, no mutation in the intron (wild-type) exhibited normal expression of pseudoexon 1, pseudoexon 2, or exon 2.

PMC9483795_01

Female

A 38-year-old woman with a past medical history of morbid obesity, presented with burns totaling 45 % of her total body surface area (TBSA) following an explosion while cooking cannabis wax. She suffered full thickness burns to the bilateral lower extremities, feet, breasts, buttocks, and abdomen with additional concern for inhalational injury. Aggressive fluid resuscitation using a modified Brooke formula based on the patient's adjusted ideal body weight was given. She was taken emergently to the operating room for escharotomies to release circumferential third-degree burns extending from her bilateral thighs down to her feet. Postoperatively, she remained intubated and was severely hypotensive. Fluid resuscitation was uptitrated to match urine output and she was started on norepinephrine. Her clinical status continued to decline rapidly as she began to have increasing oxygenation demands, renal failure, and metabolic acidosis requiring continuous renal replacement therapy. Unfortunately, she developed ventilator-associated pneumonia with rapid progression to acute respiratory distress syndrome. Low tidal volume ventilation strategies and scheduled proning were used. Early surgical debridement was delayed due to rapidly declining clinical status including hemodynamic instability to reduce the risk for intraoperative complications. On hospital day seven, the patient had sufficiently stabilized and was taken to the operating room for her first debridement. Tangential excision and wound bed preparation of her bilateral lower extremities and feet with cadaver allograft placement was performed. Her surgical wounds were placed in Vashe-soaked gauze and dressed with standard burn dressings. Over the next two weeks she underwent an additional five tangential debridements, including her abdomen and torso. On hospital day 20, the patient demonstrated significant medial foot necrosis down to bone and underwent a left below-the-knee guillotine amputation. On hospital day 24, she underwent placement of a percutaneous tracheostomy, due to chronic ventilator dependence, and placement of split thickness skin graft to her torso. Dressing takedown revealed healthy uptake of the autograft. Despite the patient's encouraging torso grafts, her bilateral lower extremity grafts repeatedly failed. Deep tissue cultures of her bilateral lower extremities grew vancomycin-resistant Enterococcus faecium and a yeast. Bone biopsy of the exposed left tibia was obtained intraoperatively and also grew a fungus. The patient's hospitalization was complicated by numerous nosocomial infections. Three weeks into her stay, she developed fever and worsening leukocytosis. Blood and respiratory cultures were obtained. Blood cultures grew Enterococcus casseliflavus from the arterial line and Lactobacillus species from peripheral blood cultures. Simultaneously, respiratory cultures grew methicillin-sensitive Staphylococcus aureus (MSSA), Group B streptococcus, and Stenotrophomonas. Due to clinical deterioration, the isolates were considered pathogenic and were treated with targeted antimicrobials. The patient's tissue devitalized rapidly after every thorough debridement of her lower extremities, and her cadaver grafts never succeeded. Due to the recurrent allograft failure on day 34, she was taken for fascial excision and wound bed preparation of the bilateral lower extremities, with a right guillotine below-the-knee amputation. Her surgical wounds appeared clean and healthy the following day. Two days later, a visible growth of mold was found across the entire wound bed. Thus, she was taken back to the operating room for a repeat debridement. Operative tissue cultures were obtained. Local wound care was switched to full-strength Dakin's solution. Infectious Disease was updated and the patient was started on liposomal amphotericin B and isavuconazonium. Twenty-four hours later, her wounds demonstrated visible mold again. She continued to deteriorate:developing renal failure and requiring multiple vasopressors. The following day, her wounds developed a thin coating of black tissue, the cause of which was unclear if it was fungal involvement or it was secondary to necrosis. Again, an aggressive debridement was repeated with bilateral guillotine above-the-knee amputations. Within 72 h her wounds became malodorous and showed recurrent fungal growth. At hospital day 43, she was taken back emergently for an aggressive debridement of her bilateral lower extremities. Local wound care was transitioned to acetic acid to enhance inhibition of fungal growth. On hospital day 45, the patient's bilateral lower extremities again showed fungal growth. The option of bilateral hip disarticulation was discussed with her family. Based on what the family believed to be her wishes and in the setting of relentlessly invasive fungal growth, despite aggressive debridements and antifungal therapy, the decision was made to cease further operative intervention. She showed no promise of improvement. The fungal infection appeared to spread past the level of the hip and up to the lower portion of the back within a few days. Palliative care was consulted and her family was allowed to visit. She was placed on comfort care measures and expired within a few hours. The post-mortem report of the fungal culture from the left tibia bone biopsy showed Geotrichum candidum. Fungal culture and mold identification from intraoperative tissue taken after the first identification of clinical mold grew Rhizopus species and Fusarium species. All subsequent cultures obtained during her debridement grew fungi.

burn, fungal infection, mucormycosis, mycology

PMC5518485_01

Male

A 49-year-old Dutch male patient came to King Chulalongkorn Memorial Hospital (KCMH) with a complaint of low-grade fever and profuse sweating at night for 1 week. Three weeks earlier, he was diagnosed HIV infection when antiretroviral medications comprising of tenofovir, emtricitabine, and efavirenz were prescribed. He denied taking any over-the-counter drugs. The physical examination was unremarkable except for a body temperature of 38 C. He also had normotension (blood pressure 125/75 mmHg) without orthostatic hypotension or other signs of volume depletion. The chest X-ray showed miliary pulmonary nodules compatible with miliary tuberculosis which was later confirmed by positive polymerase-chain-reaction for Mycobacterium tuberculosis in his sputum. Disseminated tuberculosis was promptly diagnosed, and antituberculosis treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol) was planned. However, he also had severe azotemia at admission (BUN 53.6 mmol/L, Cr 1,230 micromol/L) in contrast to his baseline values from one month earlier (Cr 115 micromol/L). At that time, there were no evidences of uremic symptoms or volume overload, and he still voided 500 mL of urine per day. Urinalysis revealed isosthenuria with bland urinary sediments (specific gravity 1.010, pH 5.0, albuminuria trace, glycose negative, WBC 0-1/hpf, and RBC 0-1/hpf). Renal ultrasonography demonstrated normal size and contour of both kidneys. Urine biomarker for renal tubular injury, neutrophil gelatinase-associated lipocalin (NGAL), was markedly elevated (7,891 ng/mL). Acute kidney injury was diagnosed and likely caused by nephrotoxic acute tubular necrosis (ATN) even though a renal biopsy had not been done. In the absence of other offending drugs or conditions, tenofovir was suspected to be a causal drug for ATN resulting in an adjustment of the antiretroviral regimen (abacavir, lamivudine, and raltegravir). In the absence of uremic symptom or volume overload, PD was, nevertheless, initiated due to high level of nitrogen catabolites. The flexible double-cuffed PD catheter was inserted on day 4 of admission, and automated PD (Homechoice cycler ; Baxter) using a total dialysate (Dianeal ; Baxter) volume of 10 L (initial fill volume of 700 mL, 14 cycles, 20 hours) was promptly started on the same day of the catheter insertion. PD dose was gradually increased to achieve the total dialysate volume of 20 L per day in the next few days. The delivered dose of PD by total weekly Kt/V and total weekly creatinine clearance (CCr) were 3.23 and 97.84 L/week, respectively. After a week of automated PD, nitrogen catabolites decreased gradually (BUN 27.8 mmol/L, Cr 840 micromol/L). At one month, his urine volume had increased to 1 L per day, but measured renal CCr was still at 4 mL/min/1.73 m2 which reflected inadequate recovery of renal function. He was discharged on day 31 of admission with continuation of automated PD at a total dialysate volume of 10 L per day. At follow-up visit, the patient showed gradually improvement in renal function and the dose of PD was tapered accordingly. Eventually, PD could be discontinued at 4 months after the onset of AKI. The patient attained stable serum Cr of 124 micromol/L and measured CCr of 29 mL/min/1.73 m2 afterwards.

PMC8299274_01

Male

On February 3, 2020, a 43-year-old man developed a fever without a clear cause, and his body temperature was 38 C with no other obvious symptoms. After taking Lianhua Qingwen Capsule himself, his body temperature returned to normal. On February 5, 2020, the patient experienced fever again, with a normal body temperature after measurement, a slight cough, a small amount of white sputum, and reported being more sleepy than usual. On February 6, the patient visited the Fever Clinic of West Lake Hospital, affiliated with Hangzhou Medical College. The patient's past medical history involved generally good health, with no history of high blood pressure, diabetes or heart disease, and no travel to Wuhan, Wenzhou, or other key COVID-19 outbreak areas or exposure history. However, the patient described that he had gone to Lanxi County, Zhejiang Province, where COVID-19 had been confirmed and reported before January 22, and his sister, who lived with him at home, had cough, low fever, diarrhea, and other clinical symptoms before February 3 (later confirmed as COVID-19 by Xixi Hospital in Hangzhou). According to the above description, the patient was immediately requested to undergo chest computed tomography (CT). The CT scans showed multiple lamellar ground glass, nodular, slightly high-density shadows in both lungs, and prominent sculptural shadows. Viral pneumonia was also considered (Figure 1A). As a result, the patient was admitted to the hospital on February 7 with suspected COVID-19. Physical examination on admission showed (Figure 1B) the following: body temperature, 37.6 C; blood pressure, 129/77 mmHg; respiratory rate, 18 times/min; pulse, 82 times/min; and blood oxygen saturation, 98%. After admission, the patient's vital signs were stable, with a few coughs, a small amount of white sputum, mild congestion of the eyelid conjunctiva, pharynx redness, and no obvious tonsil enlargement. Blood tests showed a decrease in lymphocyte percentage (16.8%, normal: 20-50%) and a lymphocyte count of 1.26 x 109/L (normal: 0.8-4 x 109/L). The proportion of neutrophils was increased (76.6%, normal: 40-75%), the absolute value of neutrophils was normal (5.74, normal: 1.40-7.13 x 109/L), and the hypersensitive C-reactive protein (CRP) was increased (10.77 mg/L, normal < 8 mg/L). The test results for influenza A and B, parainfluenza, respiratory syncytial virus, rhinovirus, adenovirus, and mycoplasma pneumoniae antigen were negative. The test results of two specimens (nasopharyngeal swabs and sputum) of SARS-CoV-2 were positive, and the preliminary diagnosis was COVID-19 (common type). On February 7, the patient was treated with moxifloxacin hydrochloride tablets (400 mg, once daily, oral administration) to prevent infection. Abidol hydrochloride granule (0.2 g, three times daily, oral administration), ribavirin injection (0.5 g, twice daily, intravenous injection), recombinant human interferon alpha2b injection (6 million U, twice daily, aerosol inhalation), Lianhua Qingwen capsule (1.4 g, three times daily, oral administration) was used to clear away heat and detoxify, and human immunoglobulin (PH4) was injected intravenously (20 g, once daily) to enhance immunity. In addition, patients were treated with antipyretic and fluid supplements according to their symptoms (Figure 1C). On February 7-9, the patient's vital physical signs were stable, with intermittent fever and blood oxygen saturation fluctuating between 93 and 99%. The patient complained of cough with white mucous sputum, poor gastric uptake, fatigue, loss of appetite, abdominal distension, and occasional retching. Re-examination chest CT showed that the lesion of the bilateral lung infection was larger and thicker than before, and the image showed significant progress compared to before (Figure 1A). On the same day, the ongoing drugs were switched to moxifloxacin hydrochloride injection (0.4 g, once daily, intravenous injection) for anti-infection, the use of lopinavir/ritonavir was increased (2 capsules, twice daily, oral administration), and methylprednisolone sodium succinate was injected (40 mg, once daily, subcutaneous injection) to reduce pulmonary interstitial edema and control the progression of the disease. The patient's third chest CT re-examination on February 11 showed no enlargement of the lesion, and the progress of the disease was basically under control (Figure 1A). Oral Chinese medicine decoction treatment was started on February 12 (the Chinese medicine prescription is shown in Table 1), and Chinese medicine diagnosed "loemia" (damp toxin epidemic). The patient's fourth chest CT on February 14 showed scattered small nodules in the right lung and some absorption of the left lung lesions (Figure 1A). The patient's respiratory symptoms improved, and his body temperature remained normal. The nucleic acid test of SARS-CoV-2 on nasopharyngeal swabs was negative, the sputum specimen was still positive, and as such, the antiviral treatment regimen was maintained. On February 17 and February 24, the fifth and sixth chest CT scans showed that the scope of the lung lesions narrowed and gradually absorbed. The white blood cell (WBC) count, lymphocyte count, and high-sensitivity CRP (hs-CRP) levels were normal. In the evening of February 25, the patient had a fever with a body temperature of 38.2 C. The sputum and feces of SARS-CoV-2 nucleic acids were all positive. The blood routine examination showed that the WBCs were elevated (9.82 x 109/L, normal, 4.0-10.0 x 109/L), the neutrophils were increased (9.05 x 109/L, normal: 1.40-7.13 x 109/L), the lymphocyte count was decreased (0.50 x 109/L, normal: 0.8-4 x 109/L), and the erythrocyte sedimentation rate was increased by 55 mm/h (normal: 0-15 mm /h). According to the results of laboratory examination, considering bacterial infection, meropenem (1 g, once per 8 h, intravenous injection), azithromycin for injection (0.5 g, once daily, intravenous injection) combined with anti-infection, and abidol hydrochloride granules (0.2 g, three times daily, oral administration), recombinant human interferonalpha-2B injection (6 million U, twice daily, aerosol inhalation) were added to continue the antiviral treatment. On February 27, the patient's temperature returned to normal. On February 29, SARS-CoV-2 nucleic acid (nasopharyngeal swab, sputum, urine, blood) was negative, but diarrhea symptoms appeared (from February 27-29, stopping TCM decoction), and chest tightness was more obvious than before. Azithromycin was discontinued considering the side effects. Azithromycin tablets (0.5 g, once daily, oral administration) and ceftriaxone sodium for injection (2 g, once daily, intravenous injection) were used for anti-infection, and Huangqi Shengmai drink (10 mL, three times daily, oral administration) was added for the treatment of chest tightness. On March 3, diarrhea and chest tightness were better than before. The patient's seventh chest CT re-examination showed that the focus of pulmonary infection was further absorbed than on February 24, and the scope of the focus continued to narrow. Symptomatic treatment and TCM adjuvant treatment were continued. On March 9, the sputum SARS-CoV-2 nucleic acid was recovered, the stool nucleic acid was positive, and other specimens (urine, blood, and throat swabs) were negative. The antiviral regimens were continued, and Chinese medicine enema was used to promote the elimination of SARS-CoV-2 and promote the negative conversion of SARS-CoV-2 nucleic acid in the gut. The detailed medication plans are shown in Table 1 and Figure 1C. On March 17, three consecutive re-examinations of the respiratory tract and feces showed SARS-CoV-2 nucleic acid as being negative. The patient's body temperature remained normal for more than 3 days, and re-examination of chest CT showed improvement in absorption. According to the latest version of the Diagnosis and Treatment Protocol for Novel Coronavirus Pneumonia of China, patients who meet the following criteria can be discharged (http://www.nhc.gov.cn/xcs/fkdt/202002/54e1ad5c2aac45c19eb541799bf637e9.shtml), and the patient was discharged into the isolation point for follow-up observation. From the first chest CT examination on February 6, 2020, to the re-examination after discharge, the patient underwent a total of eight chest CT scans. In the early stage of the disease (February 6-8), CT showed that the lung lesions had imaging manifestations of continuous progress. From February 11, CT showed that the lesions gradually shrunk. On March 30, the re-examination CT showed that the lung images had returned to normal (Figure 1A). Clinical samples, nasopharyngeal swabs, feces, urine, whole blood, serum, and sputum were collected. Routine tests were carried out on the day of admission, including blood; sputum; throat swab culture (fungi and bacteria); blood routine (cell count and proportion); liver function [albumin (ALB), alanine aminotransferase (ALT), gamma glutamyl transpeptidase (GGT)]; renal function; inflammatory indexes [hs-CRP, lipopolysaccharide (LPS), procalcitonin (PCT)]; and coagulation function (D-dimer). In addition, common acute respiratory pathogens (influenza A virus, influenza B virus, adenovirus, parainfluenza, and syncytial virus), coronavirus (MERS, SARS, 229E, NL63, OC43, and HKU1), and SARS-CoV-2 nucleic acids were detected. Following identification of the pathogen of infection, serum SARS-CoV-2 antibody, cellular immunity, and humoral immunity were detected. Disease progression was observed by continuous sample collection (Figures 2, 3).

sars-cov-2 infection, discharge standard, fecal-oral transmission, nucleic acid test of sars-cov-2, traditional chinese medicine enema therapy

PMC9879720_01

Male

A 30-year-old man was referred to the local hospital with fever and gingival bleeding for 2 weeks. Peripheral blood test showed white blood cell (WBC) count of 30.35x109/L (10% abnormal promyelocytes), platelet (PLT) count of 94x109/L, and hemoglobin (HGB) level of 110g/L. The results of bone marrow aspirate and immunophenotyping indicated a typical APL. Thus, the patient started the treatment of all-trans retinoic acid (ATRA) (25mg/m2/d) immediately, and occurred a suspicious differentiation syndrome (DS) after 3 days of ATRA treatment with symptoms of unexplained fever (>=38 C), progressive weight gain and dyspnea, which was characterized by progressive leukocytosis. Then the patient was transferred to a superior hospital for further treatment. At admission, the peripheral blood test showed WBC count of 41x109/L (65% abnormal promyelocytes), PLT count of 28x109/L, and HGB level of 68g/L. Prothrombin time (PT) was 17.5s (reference, 10.5-13.0s), fibrinogen level was 0.59 g/L (reference, 2.00-4.00 g/L), and D-dimer level was 126.74mg/L (reference, 0.00-0.55 mg/L). Bone marrow aspirates presented markedly myeloproliferative hyperactivity with 80% hypergranular promyelocytes ( Figure 1A a and b ), and peripheral blood smear showed POX strong positive with 65% hypergranular promyelocytes ( Figure 1A c and d ). Immunophenotyping results showed positive for CD13, CD33, CD117, CD123, CD4, CD9 and CD71, partially expression of CD64 and MPO, but negative for CD34, CD38, HLA-DR, CD11b, CD56, CD7, CD14, CD16, CD19, and CD3. According to the clinical characteristics, BM morphology, and immunophenotype, APL was highly suspected. However, the cytogenetic analysis showed the karyotype of 46, XY, t(12;19)(q13;q13.1), different from the typical reciprocal chromosomal translocation t(15;17)(q24;q21) ( Figure 1B ). And both multiplex polymerase-chain-reaction (PCR) and fluorescence in situ hybridization (FISH) failed to detect the typical PML-RARA transcript in the BM sample ( Figure 1C ). In addition, the common fusion genes of APL variants (PLZF::RARA, NPM::RARA, NuMA::RARA, STAT5b::RARA, PRKAR1A::RARA, FIP1L1::RARA, BCOR::RARA, OBFC2A::RARA, TBLR1::RARA, GTF2I::RARA, IRF2BP2::RARA and STAT3::RARA) were undetected. Targeted next-generation sequencing identified KRAS exon2 [NM_033360:c.34G>C(p.G12R)], NRAS exon2 [NM_002524:c.35G>A(p.G12D)] and BCOR exon4 [NM_017745:c.455C>T(p.P152L)] mutations. The diagnosis was considered to be the acute promyelocytic-like leukemias (APLL). Then the patient received arsenic trioxide (ATO 10mg/d) treatment at the first day. Owing to most variant APL exhibiting resistance to ATRA, ATO combined with traditional chemotherapy (Idarubicin and Cytarabine) was adopted as induction therapy. Then we performed a BM aspiration again, which revealed hypercellularity with 50% promyelocytes ( Figure 2 ). Thus, the patient received a second induction chemotherapy of Idarubicin, Cytarabine combined with Venetoclax and finally achieved a complete remission in this therapy ( Figure 2 ). Subsequently, the patient received three cycles of consolidation chemotherapy, which was combination of Idarubicin, Cytarabine and Venetoclax, the others were intensive treatment of intermediate-dose Cytarabine. Because the patient got an invasive candida infection of liver and lung, and unfortunately the disease relapsed (30% of blasts and abnormal promyelocytes), he failed to receive a hematopoietic stem cell transplantation. The patient underwent a new chemotherapy regimen, consisting of Homoharringtonine, Venetoclax and Azacytidine combination. Unfortunately, the patient died of severe pneumonia in this cycle and the overall survival time less than 10 months. Cytogenetic, FISH, and RT-PCR analysis demonstrated the absence of t(15;17)(q24;q21) and PML::RARA in this patient. To characterize the molecular aberrations, we performed RNA sequencing and found a gene fusion event between HNRNPC and RARG. For validation of this gene fusion, we performed RT-PCR and Sanger sequencing to confirm the HNRNPC::RARG fusion transcript in this patient ( Figures 3A, B ). In HNRNPC::RARG, HNRNPC exon 3 was fused in-frame to RARG exon4, and in RARG::HNRNPC, RARG exon 9 was fused in-frame to HNRNPC exon4 ( Figure 3C ). Sanger sequencing demonstrated that the amplicon sequence can be fully aligned with the RNA-seq sequence. The main domains of RARG and HNRNPC were preserved on HNRNPC::RARG fusion protein ( Figure 3D ).

hnrnpc, rarg, venetoclax, acute promyelocytic leukemia, translocation

PMC5503829_01

Male

A 25 year old african american male with a history of asthma, hypertension and CD4 T lymphocyte deficiency presented to an outside facility with complaints of shortness of breath and musculoskeletal chest pain. He initially was found to have a pneumonia due to Pseudomonas aeruginosa and received a complete a course of meropenem. His dyspnea did not resolve, for which he returned to the outside facility. He underwent a VATS (video assisted thoracoscopic surgery) lung biopsy to get a definitive diagnosis. His lung biopsy showed a necrotizing granuloma and tissue cultures isolated yeast. He was treated with 2 weeks of fluconazole and was started on a steroid taper for presumed sarcoidosis. Unfortunately, he returned again to the outside facility shortly thereafter with worsening dyspnea, productive yellow cough, vision changes, night sweats, 30 pound weight loss, and fevers as high as 102 F. He developed presumptive candidemia (positive blood cultures for yeast with identification pending). The patient was started on vancomycin, aztreonam, levofloxacin, and micafungin prior to being transferred to our tertiary care hospital. Upon admission to our hospital, further history revealed that he was employed as a customs official at an international airport and had a recent trip to the Caribbean for a cruise. He had a skin biopsy due to a papular rash on his face and chest (Fig. 1), and a high resolution CT chest showed cavitary consolidations in the right upper and lower lobe with diffuse bilateral lymphadenopathy (Fig. 2). Infectious and autoimmune workup was ordered (HIV testing by protocol was negative), and he also underwent bronchoscopy and bone marrow biopsy. Immunodeficiency differential included idiopathic CD4 lymphoma, common variable immune deficiency (CVID), systemic lupus erythematosus (SLE), HIV, and other vasculitides. His antibacterial therapy was discontinued, his steroid dose was decreased, and he was continued on micafungin. His clinical course worsened and he became tachycardic, tachypneic, and his lactic acid was increasing despite intravenous fluids, requiring transfer to the intensive care unit. Transesophageal echocardiogram (TEE) showed multiple 1 mm densities on the mitral valve. Fundoscopic examination showed 3 focal white lesions on left optic disc. Intravitreal tap was deferred and his micafungin was switched to amphotericin B. While awaiting speciation of yeast in blood cultures, results of skin biopsy (Fig. 3), bone marrow biopsy (Fig. 4), and bronchoalveolar lavage on bronchoscopy (all preliminary results showing fungal elements), he was persistently febrile to over 102 F, for which voriconazole was added to amphotericin B. Tuberculosis, strongyloidiasis, cryptococcosis, histoplasmosis, blastomycosis, coccidiomycosis, and cytomegalovirus infection were negative. He had low IgG (456 mg/dL) and IgM (30 mg/dL), and elevated IgA (705 mg/dL). He developed diarrhea due to Clostridium difficile (C. difficile PCR positive), and was started on oral vancomycin and metronidazole. Given his progressive worsening clinical status as well as suspicion for a combined immunodeficiency with his T-cell lymphocytopenia and immunoglobulin deficiency, he was given a dose of intravenous immunoglobulin (IVIG), after which he developed respiratory decompensation requiring intubation. He developed worsening acidemia (pH 6.9), hypotension requiring multiple pressors, severe hypoglycemia despite dextrose IV infusion, worsening lactic acidosis ( > 20 mmol/L), and severe hypoxemia despite maximal ventilator support. His family opted to pursue comfort care and the patient passed away peacefully. The fungus/yeast was later identified as Sporothrix schenckii complex.

bone marrow, cd4 lymphocytopenia, immunocompromised, sporothrix schenckii

PMC9386609_01

Female

A 69-year-old woman with a slight shortness of breath was admitted to our hospital (December 26th, 2020), complaining of weakness in her arms and legs for the last week. Almost all the typical symptoms, including fever, cough, rhinobyon, previous asthma, COPD, and poor working or living environment conditions, such as smoking and contact with pets and poultry, were denied by herself. Additionally, she did not contact suspected COVID-19 cases, with negative PCR results for COVID-19 (Table 1). She suffered from RA for 30 years, taking a long-term course of steroids. Recently, as the symptoms progressed, the therapeutic schedule was changed to include methotrexate, leflunomide, and prednisone. Given the suspicion of peripheral neuropathy or anemia, she was treated with neurotrophic agents. Upon admission to our hospital, the physical examination found a body temperature of 36.2 C, blood pressure of 142/83 mmHg, pulse of 105 beats per minute, and a respiration rate of 20 per minute. Fine moist rales appeared in the lower lobes of the lungs. She presented muscle strength of grade 5 for upper limbs and grade 3 for lower ones. Her condition deteriorated at night, with sudden polypnea and low-grade fever. Due to hypoxemia (pO2 68 mmHg, pCO2 21.6 mmHg), the patient was given oxygen therapy with a mask and atomization inhalation. The computed tomography (CT) scan showed diffused effusion and ground glass opacity (GGO) in both lungs (Figure 1). Other laboratory tests revealed three series decrease in peripheral blood, especially in lymphocyte counts, abnormal renal function with creatinine value of 230.5 mumol/L, and blood urea nitrogen value of 16.6 mmol/L. Given the rapid disease progression, the patient was transferred to our intensive care units for further treatment at midnight on December 28th. She was sober but extremely fatigued, breathless, weak in all limbs, with a mild fever. The vital signs indicated a heart rate of 138 per minute, saturation of pulse oxygen (SpO2) of 85% on oxygen therapy with mask, and respiration rate of 31 per minute. Based on all the clinical symptoms and physical examinations, the diagnosis of acute respiratory failure was established. Intubation and mechanical ventilation were performed. At the same time, invasive blood pressure showed 66/42 mmHg, with sequential organ failure assessment score of 18. So, she was considered to be in the status of septic shock. Fluid resuscitation and vasoactive drugs were given following the 1-h bundle principles. To obtain etiological specimens, she underwent electric bronchoscopy with BALF collection. The BALF was tested through various methods, including culture, smear, GeneXpert MTB, and galactomannan test. Considering that the patient was highly suspected of opportunistic infections, such as PJP or cytomegalovirus infection, the mNGS for pathogen detection from serum and BALF were carried out immediately. Meanwhile, she was given oral trimethoprim/sulfamethoxazole (TMP/SMX, 320/1,600 mg q.i.d.) and intravenous acyclovir. Besides, other bacterial infections could not be excluded because of increasing inflammatory biomarkers, and she was given broad-spectrum antimicrobial therapy. Continuous renal replacement therapy was also performed for acute kidney injury. Bone marrow biopsy was carried out on the second day of hospitalization (Day 2). The results revealed that the hemophagocyte was detected in the smear (Figure 2). It was inferred that the condition could be associated with severe infection. On the third day, the sputum, urine, and blood cultures returned with negative results (Table 1). Gram stain of the BALF revealed many Gram-negative organisms. mNGS revealed P. jirovecii in both serum and BALF with reads per million (RPM) of 17 and 437 (Figure 3), while other diagnostic tests did not detect any pathogenic microorganism. The mtSSU region of P. jirovecii was subsequently detected by qPCR using the same samples (Figure 3). Four out of the eight samples gave positive results. The PCR products were sequenced by Sanger and finally identified as P. jirovecii, confirming the mNGS results. The results were verified by qPCR using the same samples. Accordingly, the patient was treated with TMP/SMX, caspofungin, and thymalfasin to boost immunity. Corticosteroids could suppress the acute inflammatory process. However, the X-ray showed that effusion did not decrease as expected. Despite attempts at optimizing gas exchange by prone position ventilation for nearly a week, the arterial blood gas analysis indicated that pO2/FiO2 ratio was still below 100 mmHg, which made it necessary to take a rescue extracorporeal membrane oxygenation (ECMO) therapy. Mechanical ventilation was switched to an ultra-protective strategy using pressure control ventilation. On the 17th day of admission, a chest X-ray revealed an obvious decrease in exudation. She was successfully de-cannulated after 9 days of V-V ECMO support. During the 21-day treatment, the DNA reads of P. jirovecii by mNGS using both serum and BALF disclosed a dramatic increase since the medication of TMP/SMX, then declined gradually (Figure 4). Unfortunately, acute hepatic failure occurred. Plasma bilirubin levels remained high despite the support of plasma exchange and resin plasma perfusion adsorption. mNGS of serum and BALF detected Acinetobacter baumannii on January 13th and Klebsiella pneumoniae on January 19th (Table 1), indicating nosocomial infection. Drug susceptibility tests revealed multidrug-resistant bacteria infection (A. baumannii resistant to quinolones, beta-lactam antibiotics, sulfonamides, and aminoglycosides; K. pneumoniae resistant to quinolones, beta-lactam antibiotics, and sulfonamides), leading to prolonged stay in hospital. Finally, the patient died on the 29th day of admission.

pneumocystis jirovecii pneumonia, case report, diagnosis, metagenomic next-generation sequencing, rheumatoid arthritis

PMC5329686_01

Female

A 29-year-old female from South China with a history of swelling, discharge, and chronic abscesses of the right breast for more than 10 days presented to the Department of Breast Surgery in the Second Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. About one month prior, the patient had noted a painful mass in the right breast and a mini-invasive operation was performed. The patient did not have a history of fever, night sweats, weight loss, and respiratory symptoms. In addition, there was no family history of breast cancer and no personal history of tuberculosis. The patient was referred to an outpatient surgery clinic, where a breast ultrasound demonstrated a duct ectasia hypoechoic lobulated mass measuring 16.7 mm x 9.8 mm in the lower quadrant of the right breast and palpable lymph nodes in the ipsilateral axilla. Blood tests showed that full blood count, renal function, liver function, thyroid function, and blood glucose were all within normal limits. The patient was treated with a variety of antibiotics, including doxycycline, clindamycin, and amoxicillin-clavulanic acid for 10 days, without success. The patient underwent drainage of the right breast and 1 ml of purulent fluid was aspirated. Specimens were sent for routine bacteriology, acid-fast bacteria stain, Gram stain, fungal stains, and culture. Acid-fast bacilli were not found, and Gram staining of the pus showed that numerous polymorphonuclear leukocytes were present, however, without any organisms. The pus was plated on Columbia agar containing 5% sheep blood and incubated at 37 C in air supplemented with 5% CO2. Three days after incubation, the presence of strain GHY 970 was confirmed. The colonies that were present on the blood agar plates were identified with 16S rDNA PCR and phylogenetic analysis. Genomic DNA was extracted with the TIANamp Genomic DNA Kit (cat. No. #DP304-02), according to the manufacturer's guidelines. Bacterial 16S rDNAs were amplified by PCR using the combination of a universal primer 1492r (5' GGT TAC CTT GTT ACG ACT T 3') and bacterial primer 27f (5' AGA GTT TGA TCC TGG CTC AG 3'). PCR was performed using a thermal cycler with the following cycling parameters: 95 C for 5 min as initial denaturation followed by 30 cycles of 94 C for 30 s, 55 C for 30 s, 72 C for 1 min, and 72 C for 7 min as final extension. After purification, the amplified products were sent to BGI Company for sequencing analysis. Homology search was performed using BLAST (https://www.ncbi.nlm.nih.gov) and the differences in nucleotide sequences between various bacteria were determined using the sequence alignment editor "BioEdit". Products were further analyzed by MEGA 6.0. The Neighbor-Joining (NJ) tree was constructed using the Kimura-two-parameter (K2P) distance model. Phylogenetic analysis of the 16S rDNA gene sequence of strain GHY 970 revealed the species of M. abscessus (Figure 1). NCBI data search indicated >99% sequence identity to the M. abscessus DS27 (KU362955). Because the patient's treatment with antibiotics was discontinued, a new breast nodule appeared in the right breast, and the patient was treated with a combination of rifampicin, isoniazid, and pyrazinamide. After 3 months of treatment, the mass in the right breast and axillary lymph nodes had totally disappeared. The entire treatment therapy was completed by 6 months and, at follow-up after 1 year, there were no signs of recurrence or any other issues.

PMC4119435_01

Male

A 6-year-old boy, with no past medical history, presented with progressive headache, vomiting, right side weakness since 3 months without fever or seizures. On examination, he was conscious with a stiff neck and right hemiplegia. Brain computed tomography-scan showed a heterogeneous calcified large mass-like lesion in the left fronto-temporo-parietal region, irregular contrast enhancement and extensive perilesional edema with important mass effect (A-C). There was a strong suspicion of malignant tumor. Routine blood tests and chest X-ray were normal. Magnetic resonance imaging was requested but not made because of the rapid deterioration of the state of consciousness of the child. The patient was operated urgently. At operation there was a large intra-axial yellowish, firm, and relatively avascular lesion. Total excision of the mass was done (D). Histological features were consistent with tuberculoma. Serological test for HIV was negative. The patient improved progressively and was discharged on antituberculous treatment with a good outcome. Intracranial tuberculoma should always be considered in the differential diagnosis of solitary and large focal brain lesions, particularly in patients of tuberculosis endemic areas. In our patient, surgical excision not only helped to establish the histological diagnosis but also helped to resolve the compressive symptoms.

brain tumour, malignant tumor, tuberculoma, tuberculosis

PMC5297267_01

Female

A 61-year-old female patient presented with a 20-year history of swollen masses in her oral mucosa, which sometimes ulcerated. Clinical examination revealed firm nontender infiltrating masses involving the right lateral side of the tongue (3 x 2 cm) [Figure 1a] and right retromolar trigone (2 x 2 cm) [Figure 1b] with granular surfaces, swelling of the lower lip mucosa with cobblestoning [Figure 1c], and multiple palpable, nontender, firm, and mobile lymph nodes on both sides of the neck. She had no symptoms of fever, fatigue, weight loss, or gastrointestinal disturbance, and she had not undergone any investigation or treatment for her complaints before, except using occasional topical corticosteroids and antiseptic mouthwashes. She denied the role of diet on the lesions. Her medical history revealed diabetes mellitus and family history was positive for hypertension in her mother. Laboratory data including complete blood cell count, serum biochemistry analysis, urinalysis, and serum C reactive protein, calcium, vitamin B12, folate, and angiotensin converting enzyme values were normal except elevated serum fasting glucose (143 mg/dl). The erythrocyte sedimentation rate was 41 mm/h, and chest radiography was normal with no signs of sarcoidosis or tuberculosis. The Mantoux test and pathergy test were also negative. An incisional biopsy of the lesion involving the retromolar trigone was performed, and the biopsy materal was split into two pieces for histopathologic examination and mycobacteriologic culture. Soft tissue ultrasonography of the neck revealed lymphadenitis, and the biopsy of the lymph nodes showed noncaseating granulomatous lymphadenitis. The histopathologic examination of the oral lesion together with Erlich-Ziehl-Neelsen stain for acidoresistant bacilli (ARB) and periodic acid schiff (PAS) stain showed well-demarcated granuloma formation consisting of epitheloid cells surrounded by lymphocytes in an edematous stroma [Figure 2]. Although the patient had no gastrointestinal symptoms, a colonoscopy was performed. Minor ulcerations were seen in the descending colon. Mucosal biopsies from the observed lesions revealed aphtous ulcerations; inflammatory bowel disease, neoplasia, and tuberculosis were ruled out. Mycobacterial culture of the oral biopsy sample showed no growth. Based on history, clinical findings, histopathologic examinations, and laboratory data, sarcoidosis, tuberculosis, systemic fungal infections, and Crohn's disease were excluded, and the patient was finally diagnosed as idiopathic orofacial granulomatosis. Oral prednisolone 50 mg/day was started for ten days and then tapered 10 mg every week. The treatment was well tolerated by the patient except for slight increases in serum glucose levels, which were regulated by adjusting the insulin dosages. Lesions showed marked improvement, and no recurrence was observed in a 2-year follow-up.

oral mucosa, orofacial granulomatosis, pathology

PMC9112167_01

Female

A 68-year-old Chinese female kindergarten teacher with a history of hypothyroidism after hyperthyroidism treatment was admitted to our hospital in September 2010 due to cough, expectoration and fever for 15 months and a rash for 1 month. At the end of May 2009, she first developed cough with expectoration accompanied by fever, and her highest body temperature was 39 C. Chest computed tomography (CT) revealed consolidation in the right lower lobe. The patient showed no obvious improvement after treatment at a local hospital. She was first hospitalized at our hospital in August 2009. Routine blood examination showed a white blood cell (WBC) count of 11 x109/L, a neutrophil count of 8.6x109/L and a hemoglobin concentration of 62 g/L. The C-reactive protein (CRP) concentration and erythrocyte sedimentation rate (ESR) were 38.7 mg/L and 105 mm/h, respectively. Chest CT revealed pneumonia in the middle and lower lobes of the right lung, and Klebsiella pneumoniae was identified in the sputum. She was treated with antibiotics and was discharged after her symptoms improved. In October 2009, the patient experienced a recurrence of the above symptoms accompanied by herpes zoster on the right chest wall. Chest CT revealed progressive pulmonary lesions with new consolidation in the apicoposterius segment of the upper lobe of the right lung, and Candida albicans was identified in the sputum. Routine blood examination revealed a WBC count of 23.5x109/L, a neutrophil count of 19.8x109/L, and a hemoglobin concentration of 68 g/L. The CRP concentration and ESR were 91.3 mg/L and 69 mm/h, respectively. The patient was treated with clindamycin, cefoperazone sulbactam, fluconazole and ganciclovir as prescribed. Repeated chest CT revealed that the pulmonary lesions and pleural effusion were slightly absorbed, and the patient was discharged and returned to her local hospital for continuous treatment. In September 2010, the patient was admitted to our hospital for the third time due to fever, cough with expectoration and scattered herpes of various sizes on her limbs for one month. She had lost 15 kg since the onset of illness. The physical examination after admission revealed a body temperature of 38 C; the presence of painful erythematous papules studded with white blisters on her palms, back of the hands, fingers, face and limbs (Figure 1); bilateral axillary and inguinal lymphadenopathy; and moist rales in the bilateral lungs. Routine blood examination revealed that her WBC count, neutrophil count, lymphocyte count and hemoglobin concentration were 24.24x109/L, 20.07x109/L, 2.16x109/L and 85 g/L, respectively. The concentrations of CRP, albumin, globulin, serum immunoglobulin (Ig) G, IgA and IgM were 182 mg/L, 26.2 g/L, 45.9 g/L, 24.53 g/L, 2.64 g/L and 1.38 g/L, respectively. The percentages of total T cells, CD4+ T cells and CD8+ T cells, and CD4/CD8 cells were 50.9%, 29.3%, 17.4% and 1.6, respectively. The levels of creatinine and urea nitrogen were 51 micromol/L and 2.4 mmol/L, respectively. In addition, her transaminase, tumor markers, rheumatoid factor, and anti-Streptococcus hemolysin O were all within normal ranges, and she was negative for plasma human immunodeficiency virus (HIV) antibodies. The results of bone marrow aspiration biopsy suggested iron deficiency anemia. Her lung function test revealed that her forced expiratory volume in the first second (FEV1) was 76.9%, her FEV1/forced vital capacity (FVC) was 78.13%, and her carbon monoxide transfer factor (TLCO) was 46.7%, suggesting mild restrictive ventilatory dysfunction and diffusion disorder. Chest CT showed consolidation and exudation in the apicoposterior segment of the upper lobe and in the posterior basal segment of the lower lobe of the left lung, and a large amount of pleural effusion was noted on the left side. Cytological and biochemical examination of the pleural effusion showed that her total cell count, percent of segmented cells, percent of lymphocytes, adenosine deaminase, and protein concentration were 140x106/L, 70%, 30%, 3.8 U/L, and 37 g/L, respectively. Her Rivalta test was positive, and the effusion was proven to be exudative. Histopathology of the rashes and the lymph node biopsy specimen obtained from the patient confirmed SS (Figure 2). Candida was repeatedly isolated from the sputum, while microbial cultures of the blood and alveolar lavage fluid were negative. In addition, there were no abnormal findings on bronchoscopy. Following treatment with vancomycin, moxifloxacin, cefoperazone, fluconazole and dexamethasone during hospitalization, the patient's symptoms improved, and the rash subsided. Repeated routine blood tests showed a WBC count of 12.4x109/L, a neutrophil count of 7.92x109/L and a hemoglobin concentration of 108 g/L. Chest CT showed absorption of the pulmonary lesions and pleural effusion. The patient was discharged from the hospital on October 20, 2010. She was continuously treated with oral prednisone and thalidomide outside the hospital, and her condition was stable However, the patient was admitted to the People's Hospital of Guangxi Zhuang Autonomous Region due to a pulmonary fungal infection and SS and was hospitalized from March 2011 to May 2011. Her specific process of diagnosis and treatment was unknown, and she was discharged after her condition improved. On May 21, 2011, the patient was admitted to the Nanning Fourth People's Hospital due to cough with expectoration, subcutaneous abscesses on her left chest wall and several palpable soybean-sized lymph nodes on her neck bilaterally. She was diagnosed with bilateral pulmonary tuberculosis and a tuberculous abscess of the left chest wall based on chest CT and was administered anti-tuberculosis therapy for 3 months without clinical improvement. Her chest wall abscess continued to ulcerate and discharge pus and did not heal. Routine blood examination revealed a WBC count of 8.14x109/L, a neutrophil count of 6.07x109/L and a hemoglobin concentration of 75.20 g/L. On August 3, 2011, the culture results of the patient's sputum and chest wall pus were available, and the patient was confirmed to be positive for NTM (unclassified) culture. Based on the results of the antimicrobial susceptibility test (AST) (para-aminosalicylic acid, streptomycin, capreomycin, protionamide, amikacin: R; isoniazide: I; rifampicin, ethambutol, levofloxacin: S), she received combination treatment with isoniazid, rifapentine, ethambutol, and levofloxacin for more than 1 month. Her WBC count, neutrophil count and hemoglobin concentration were 7.58x109/L, 5.42x109/L and 88.7 g/L, respectively. She was discharged after her symptoms improved. She regularly took anti-NTM agents outside the hospital with regular follow-up, and her chest wall lesion had completely healed after 6 months. Repeated routine blood examination showed that her WBC count and hemoglobin concentration were 5.51x109/L and 113 g/L, respectively. The patient was maintained on anti-NTM therapy until December 1, 2012. On March 16, 2013, the patient was admitted to the hospital again due to cough, expectoration and anorexia. Routine blood examination after admission showed a WBC count of 8.98x109/L, a neutrophil count of 6.26x109/L and a hemoglobin concentration of 68.2 g/L. The albumin concentration and ESR were 27.9 g/L and 142 mm/h, respectively. Chest CT revealed exacerbation of her pulmonary lesions, with mottled and linear high-density shadows observed in both lungs. Due to a positive sputum smear for acid-fast bacilli, a recurrence of NTM infection was considered, and clarithromycin was added to the original regimen. The patient's condition improved again, and she was transferred to the outpatient department for treatment. Repeated laboratory tests on January 24, 2015 revealed that her WBC count, hemoglobin concentration, CD3+ T-cell count, CD4+ T-cell count, CD8+ T-cell count, albumin concentration and A/G were 7.20x109/L, 118 g/L, 1109 cells/muL, 686 cells/muL, 397 cells/muL and 1.17, respectively. Her liver and kidney functions were normal. Chest CT showed absorption of her pulmonary lesions, and she subsequently discontinued anti-NTM treatment. In March 2016, 1 year after the discontinuation of anti-NTM therapy, the patient was readmitted to the hospital with a back abscess that had continued to ulcerate and discharge pus for 1 month. Physical examination after admission revealed cervical lymph node enlargement, a few moist rales in the left lower lobe and soft tissue swelling in the upper back. On the left side of the spinous processes of the C7-T1 vertebral bodies, a skin ulcer with a diameter of approximately 0.6 cm and a sinus tract with granulation tissue and purulent exudation (leading to the vicinity of the spinous process of the C7-T1 vertebral bodies, which was approximately 3.5 cm deep) were observed. Her WBC count, hemoglobin concentration, CRP concentration, ESR and A/G were 7.43x109/L, 114 g/L, 8.3 mg/L, 38 mm/h and 0.92, respectively. Serum AIGAs were determined by an enzyme-linked immunosorbent assay (ELISA) kit (Cloud-Clone Corp, Wuhan, China), and the AIGA titer was 79276.59 ng/mL (the cutoff value of the AIGA titers was 9583.21 ng/mL). Chest CT showed increased pulmonary lesions with multiple patchy exudations, fibrous proliferation and ground glass opacity in both lungs and bronchiectasis in the dorsal segment of the left lower lobe (Figure 3A). Bone CT revealed bony destruction in C7-T2 vertebral bodies with surrounding abscess formation (Figure 3B-D). NTM were cultured from the pus obtained from the patient's back abscess, and NTM were further identified as M. phlei using the indirect homologous gene method (gene chip). Given that her AST results were the same as before, the patient continued treatment with the original regimen. Furthermore, the patient underwent local sinus tract grabbing. Three months later, the bone destruction had gradually repaired, the surrounding abscess had disappeared, and the skin ulcer and sinus tract had healed. The patient was discharged and remained on treatment with the above regimen, showing gradual improvement. In July 2017, repeated chest CT showed that the pulmonary lesions were absorbed (Figure 3E). Repeated bone CT showed that the bone destruction had further repaired, and the surrounding abscess had disappeared (Figure 3F-H). No lymph node enlargement was found. Routine blood examination revealed a normal WBC count of 5.06x109/L and a normal hemoglobin concentration of 141 g/L. Her CRP concentration and ESR were within the normal range. In April 2018, the patient returned to the hospital for re-examination, and her clinical indicators showed normal results. The patient was cured after 2 years of regular anti-NTM therapy with no recurrence noted at present.

mycobacterium phlei, anti-ifn-γ autoantibodies, osteolytic destruction, sweet’s syndrome

PMC6262944_01

Female

A 65-year-old woman with unknown past medical history presented after a motor vehicle rollover in which she was restrained with a seatbelt. The patient was intubated at the scene, stabilized at an outside hospital, and transferred to our hospital. She exhibited episodic bradycardia en route but retained reactive pupils. On arrival, the patient's Glasgow Coma Scale (GCS) score was 3T with progressive dilation of her right pupil. Computed tomography (CT) imaging showed a 1.8-cm right epidural hematoma (EDH) with 6-mm right-to-left shift but no acute skull-base fracture or injury in the area of the carotid canal [Figure 1a, b]. Other injuries included extensive osseous and soft tissue injuries in the thorax. The patient was treated with 3% hypertonic saline and mannitol before undergoing emergent hematoma decompression. We completed evacuation of the EDH without difficulty; however, significant unexpected bleeding was uncovered from the skull-base and carotid-cavernous triangle. There was worsening bleeding from deep within the Sylvian fissure, prompting us to open the dura to achieve additional decompression. Extradural coagulation of the middle meningeal artery and ipsilateral neck pressure reduced the bleeding, but incompletely. We packed the wound and proceeded for emergent angiography to identify the source of bleeding. Digital subtraction angiography (DSA) showed a large dissecting pseudoaneurysm of the cavernous segment of the right internal carotid artery (ICA), with arteriovenous shunting into the cavernous sinus consistent with a direct CCF. Outflow was noted through the bilateral inferior petrosal sinuses with no visualized cortical venous reflux [Figure 1c, d]. Flow in the right anterior (ACA) and middle (MCA) cerebral artery circulation was sluggish, and there was displacement of the right MCA branches because of mass effect from residual extra-axial blood and packing material. No abnormal fistula was seen during external carotid artery (ECA) injection (not shown). The left ICA demonstrated extensive dissection and arteriovenous shunting into the cavernous sinus, consistent with a direct CCF. Outflow from the left-sided CCF was noted into the petrosal sinuses and left external jugular veins [Figure 1e, f]. The left ACA and MCA flows were diminished, but no abnormality of the ECA was seen. Endovascular treatment and open surgical carotid bypass were discussed, but the patient proved to be hemodynamically unstable for treatment, and the family chose not to pursue further life-extending measures. This case report does not require patient consent per our institution.

blunt cerebrovascular injury, carotid-cavernous fistula, dissection

PMC6779781_01

Male

A 49-year-old male presented with a 9-month history of multiple anatomical site pain, a localized mass, and swelling of thighs (Figure 1) and calves, which gradually increased in size and quantity without systemic symptoms, such as fever, poor appetite, malaise, weight loss, or perspiration during sleep or after strenuous exercise. One month before admission, he complained of similar symptoms that occurred in the left forearm but to a lesser degree and with no mass present. He had a history of pulmonary tuberculosis. One year previously, the patient presented non-infectious posterior uveitis and had been treated with steroid for half a year. There were no systemic symptoms and no history of trauma, family history, or other disease history. His systemic physical examination was normal. Multiple anatomical sites on the thighs and calves contained masses, the borders of which were well-demarcated and cystic in consistency, but they were not fluctuant and there was no tenderness of the mass or increased local temperature. The skin over the mass was normal, with no rash observed. Musculoskeletal ultrasound examination suggested substantive bilateral lesions in the calves. Chest computed tomography (CT) revealed previous pulmonary tuberculosis. The patient underwent a musculoskeletal magnetic resonance imaging (MRI) examination in a local hospital; the results were reported as suggestive for rhabdomyolysis, only according to his history of strenuous exercise. The patient was admitted to the Department of Neurology, Wuhan University, Renmin Hospital, for diagnosis and treatment. Further examinations, including those for hemogram, rheumatoid factor (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT), aldolase, lactate dehydrogenase (LDH), fungal G-test, and tumor marker levels, were within normal limits. Anti-nuclear antibodies (ANA) were positive at a dilution of 1:100, and blood parasites were negative. Musculoskeletal MRI (Figure 2) examination showed diffuse abnormal signals on the bilateral calf and thigh muscles, suggesting infectious lesions or myopathy. Electromyography (EMG) examination showed that sensory and motor conduction are normal. There was no abnormal spontaneous activity in the anterior muscles of the double tibia and right medial thigh muscles. Paraspinal muscles [L5, S1] have little abnormal spontaneous activity. Motor unit potentials increased in duration and amplitude in the anterior muscles of the double tibia and right medial thigh muscles. It suggested nerve root damage of both lower limbs (may be root damage). In combination with the clinic, there is a great possibility of considering degeneration. A pelvis and lumbar spine MRI showed mild lumbar disc herniation without other abnormal findings. A deep biopsy (including skin, subcutis, fascia, and muscle) was performed on the right gastrocnemius (including the mass and nearby muscles), and the results showed lymphocytes and plasma cell infiltration into and around non-necrotic muscle fibers without muscle fiber necrosis and regeneration. Moreover, inflammation granulomas (including Langerhans cells, epithelioid cells, and lymphocytes) were visible under the microscope (Figure 3), and CD4(+), CD8(-), MHC-I(+), C5b-9(+) (Figure 4), and acid-fast stain(-) results were observed. Sputum examination revealed no evidence of tuberculosis bacilli, and a tuberculin skin test was negative. However, PCR for the M. tuberculosis complex presented positivity, and a tuberculosis T-SPOT test(+); M. tuberculosis was found in biopsy tissue culture of the mass on the calf. A CT scan revealed no bony erosion. A high-probability diagnosis of granulomatous myositis with M. tuberculosis infection in the thighs and calves was considered on the basis of clinical, MRI, culture, histopathology, and gene test results. Therefore, the patient was prescribed standard oral anti-tubercular treatment with four drugs, isoniazid, rifampicin, ethambutol, and pyrazinamide, for 2 months. After treatment, the patient's symptoms were relieved, and the swelling in the thighs and calves appeared to decrease in size. Further isoniazid and rifampicin were given. Currently, the patient is undergoing follow-up.

biopsy, muscle, muscular tuberculosis, pathology, tuberculosis

PMC7340235_01

Male

The patient was a 53-year-old male with no significant past medical history. Since December 2017, the fever up to 40 C emerged intermittently, followed by weight loss and right inguinal lymphadenopathy. In February 2018, a CT scan showed multiple subphrenic lymphadenopathies. A blood culture detected the bloodstream infection of methicillin-resistant Staphylococcus aureus (MRSA), and a gastrointestinal endoscopy revealed the widespread esophageal candidiasis. In March, he was complicated by herpes zoster infection. The right inguinal lymph node biopsy showed mycobacterium infection with malignant lymphoma, and he was transferred to our hospital. On admission, laboratory data showed a white blood cell count of 14,400/muL (band cell 3.0%, segmented cell 81.0%, monocyte 8.5%, lymphocyte 7.5%), hemoglobin level of 9.0 g/dL, platelet count of 18.3 x 104/muL, CD4-positive T cell count of 678/muL (50.3% of T cells), aspartate transaminase (AST) of 16 U/L, alanine aminotransferase (ALT) of 15 U/L, blood urea nitrogen (BUN) of 5.3 mg/dL, creatine of 0.60 mg/dL, C-reactive protein (CRP) of 26.52 mg/dL, immunoglobulin G of 1764 mg/dL, and soluble IL-2R of 16,523 U/mL. HIV antibody, HTLV-1 antibody, mycobacterium avium complex (MAC) antibody, candida antigen, aspergillus antigen and Interferon-Gamma release assay were negative. Polymerase chain reaction (PCR) assays for the detection of clonally rearranged T cell receptors in the peripheral blood showed no clonality, and lymphocyte blastoid transformation test by phytohemagglutinin (PHA) was 29,300 count per minute (cpm) (normal range: 20,500-56,800 cpm), which suggested no apparent T cell dysfunction. PET-CT demonstrated multiple enlargements of subphrenic lymph nodes (SUVmax 11.1 in the right inguinal lymph node) (Figure 1a-b). The histopathological examination of the right inguinal lymph node biopsy showed the destruction of normal structure and the mixture of the proliferation of abnormal large lymphoma cells and epithelioid cell granuloma. With small T cells and histiocytes as a background, Hodgkin cells, Reed-Sternberg cells and Lacunar cells invaded. These malignant cells were positive for CD30 and PD-L1, partially positive for CD15, and negative for CD3, CD4, CD8, and CD20 in immunohistochemistry. EBER-ISH was positive, and LMP-1 and EBNA-2 were also partially positive, which suggested EBV infection with latency type III (Figure 2a-e). This case showed more atypical and various cell appearance than Hodgkin lymphoma (HL). EBV-associated HL typically shows EBV infection with latency type II. Based on these pathological findings, EBV-positive LPD with Hodgkin lymphoma-like features was diagnosed. PCR tests of the right inguinal lymph node were negative for Mycobacterium tuberculosis and MAC, and culture tests of bacteria, fungi, and mycobacterium species were also negative. However, Ziehl-Neelsen staining of the biopsy specimen showed acid-fast bacilli in granulomas (Figure 2a). In PCR, we revealed 100% sequence identity of both 16s ribosomal RNA and heat shock protein 65 (hsp65) of M. genavense, targeting 710 base pair (bp) sequences out of 1500 bp and 361 bp sequences out of 1623 bp respectively. The detection of M. genavense infection by culture is troublesome due to its fastidious growth requirements; therefore, negative culture result cannot exclude M. genavense infection. Consequently, EBV-positive LPD and M. genavense lymphadenitis were concomitantly diagnosed. We treated him with rifampicin, ethambutol and clarithromycin against M. genavense, and adriamycin, vinblastine and dacarbazine for EBV-positive LPD. We excluded bleomycin due to emphysema. Although fever and lymphadenopathy promptly subsided with these double therapies, PET-CT after six cycles showed multiple lymphadenopathies. The right inguinal lymph node re-biopsy demonstrated the relapse of EBV-positive LPD with no signs of mycobacterium infection. We started salvage chemotherapy and continued triplet antibiotics. The optimal treatment duration against M. genavense remains unclear, and we continued the triplet therapy for more than one year. We stopped the triplet antibiotics after 17 months' duration, and subsequently, the patient has had NTM free follow-up for 14 months.

epstein-barr virus-positive lymphoproliferative disorder (ebv-lpd), mycobacterium genavense, programmed cell death 1 ligand 1 (pd-l1)

PMC7986722_01

Male

A previously healthy 52-year-old man presented with a 1-year history of painless left scrotum enlargement and mild discomfort, but no lower urinary tract symptoms. He was admitted 1 month after his symptoms worsened, with subjective fever, but still without lower urinary tract symptoms. Before admission to hospital, he had been treated at a local community hospital and had received oral empiric antibiotic levofloxacin for 2 weeks, with no significant improvement in his symptoms. The patient had no history of cryptorchidism, scrotal trauma, scrotal inflammation, or urinary tuberculosis, and no history of neoplastic disease or family history of genetic diseases. Physical examination of his testes revealed an enlarged, hard, and non-tender left testis, a clinically normal right testis, and no palpable inguinal lymphadenopathy. Ultrasound examination of the scrotum revealed a mainly cystic, heterogeneous echogenic mass occupying most of the left testicle. The tumor had a clear boundary, regular morphology, and disordered internal echo ( Figure 1A ). Viscous fluid was seen in the cystic part, and large calcified spots were detected in some areas ( Figures 1B, C ). A few irregular solid protrusions were visible on the cyst wall with a small blood supply ( Figure 1D ). There were no obvious enlarged lymph nodes in the groin area on either side. The ultrasound findings suggested a testicular tumor or abscess. However, the testicular tumor marker serum alpha-fetoprotein (AFP) was 2.2 ng/mL (normal reference value 0-20 ng/mL), beta-human chorionic gonadotropin (beta-HCG) was 0.6 mIU/mL (normal reference value 0.5-2.67 mIU/mL), and lactate dehydrogenase (LDH) was 136.3 IU/L (normal reference value 120-250 IU/L). Renal function, inflammatory markers, and routine urine and blood tests were all normal. We therefore decided to perform exploratory surgery of the left testicular mass. Surgery revealed a multilocular cystic mass in the left testis. There was no abnormality in the left epididymis or spermatic cord. Intraoperative frozen pathology indicated a testicular mucinous tumor, and radical resection of the left testis was performed. Postoperative gross pathology showed a multilocular cystic mass in the left testis measuring about 4.5x3.5x2.5 cm and occupying almost the entire testicular parenchyma, with irregular thickening of the cyst wall and filled with gray-yellow jelly ( Figure 2A ). Microscopy showed that the inner wall of the capsule was lined with a single layer of pseudo-stratified mucus columnar epithelial cells, some showing mild nuclear atypia, but with no interstitial infiltration. There was also fibrous tissue proliferation of the cyst wall and mucus overflow into the cyst wall in some areas ( Figures 2B, C ). The cyst cavity was filled with mucus, with focal calcification in some areas, but no teratoma component. Based on the pathological characteristics, the diagnosis was primary or secondary testicular mucinous tumor. On the basis of this unexpected pathological finding, a further diagnostic work-up was carried out, including abdominal and pelvic computed tomography (CT) and upper and lower gastrointestinal tract endoscopy, but no other suspicious primary tumors or metastases were found. The tumor was thus finally diagnosed as a primary borderline mucinous tumor of the testis, according to the 2016 edition of the WHO Classification of Tumors of the Urinary System and Male Reproductive Organs. The patient underwent postoperative follow-up examinations once a year for 4 years after surgery. His serum tumor markers remained at normal levels, and scrotal ultrasound, abdominal and pelvic CT scans, and colonoscopy and gastroscopy revealed no evidence of metastases or any other primary adenocarcinoma. His postoperative recovery was uneventful. Patient perspective: "I was previously healthy with no known diseases. Before coming to the hospital, I had had a 1-year history of painless left scrotum enlargement and mild discomfort, and had felt the symptoms worsening for more than a month. After coming to the hospital and undergoing left orchiectomy surgery, my left scrotum discomfort disappeared. My postoperative recovery was uneventful, and there were no abnormal findings during annual postoperative follow-up examinations."

clinical characteristic, differential diagnosis, imaging characteristic, mucinous tumor, testis

PMC3299075_01

Female

A 24-year-old woman presented with history of recurrent episodic right hemicranial headache and seizures of 3 years duration. She also conceded that she used to get vertiginous sensations before the onset of generalized tonic clonic seizures each time. This time she presented with right hemicranial headache of different character, which was more severe and associated with retro-orbital pain 15 days before admission. Ten days after the onset of headache with different character, she noticed double vision followed by progressive drooping of right eye lid. General examination showed asymmetrical upper limb pulses, left radial, and brachial pulse being feeble. Her blood pressure was 170/110 mm Hg on recording from the right upper limb, while on left it was 90/60 mm Hg. In addition, there was evidence for bilateral renal bruit (left more than right). Neurological examination revealed right third and fourth cranial nerve palsies, and the remainder of the examination was normal. Routine urine analysis, complete blood counts, and serum biochemistry (liver and kidney functions, glucose level, and lipid panel) were normal, except for an elevated erythrocyte sedimentation rate (ESR) of 88 mm at the end of an hour. Vasculitic work up in the form of rheumatoid factor, antinuclear antibodies, anti-double stranded DNA antibody, antiphospholipid antibody, proteinase-3-antineutrophil cytoplasmic antibody (ANCA) and myeloperoxidase-ANCA were negative. Serology for syphilis (Venereal Disease Research Laboratory [VDRL] test), HIV, and hepatitis B and C was negative. Chest X-ray, serum calcium, and angiotensin-converting enzyme levels were normal. Tuberculin skin test as well as Quantiferon-TB test were negative. Cerebrospinal fluid (CSF) analysis showed 2 lymphocytes/mm3, protein 75 mg/dl, and glucose 78 mg/dl (serum glucose-112 mg/dl). Cytological examination of the CSF did not show any malignant cell. CSF microbiology in the form of gram staining, acid fast bacilli (AFB) staining, VDRL, panfungal antigen, and cultures for AFB and fungi did not yield positive results, so was polymerase chain reaction for mycobacterium tuberculosis. Magnetic resonance imaging of the brain revealed abnormal, thickened enhancing pachymeninges in bilateral frontal and right temporal region extending to cavernous sinus [Figures 1 a and b]. In addition, there was T2 and FLAIR (Fluid Attenuated Inversion Recovery) hyperintensity in right temporal lobe [Figure 2]. In view of feeble left radial pulse and renal bruit, patient underwent conventional digtal subtraction angiography (DSA), for better characterization of the vascular system. DSA revealed stenosis of left subclavian artery distal to the origin of vertebral artery, osteal stenosis of left renal artery, and narrowing of abdominal aorta at the level of the origin of renal arteries with normal terminal aorta and bilateral common iliac arteries [Figure 1 c and d]. Transthoracic two-dimensional echocardiography revealed mild aortic regurgitation with normal left ventricular function. Electroencephalogram showed intermittent epileptiform discharges over the right temporal region. Meningeal biopsy could not be performed as the patient declined the procedure. A diagnosis of TA was considered as patient satisfied the American College of Rheumatology (ACR) criteria. After starting prednisolone (1 mg/kg/day), there was complete recovery from right third and fourth cranial nerve palsy over a period of 3 weeks along with normalization of ESR. Her blood pressure was well controlled on atenolol, while seizures on 300 mg of phenytoin. However, asymptomatic blood pressure difference in upper limbs was persistent. She was continued on phenytoin, atenolol, and low-dose prednisolone (tapered over a period of 12 weeks to 10 mg alternate days). She remained asymptomatic on these medications at 1-year follow-up. A postcontrast computed tomography (CT) scan at 6 months follow-up was normal and there was no evidence for meningeal enhancement. Her laboratory evaluation including ESR and renal function tests were within normal limits at the last follow-up. As patient remained asymptomatic and did not show signs of vascular insufficiency, a repeat angiogram, being an invasive test, was not considered.

cranial pachymeningitis, hypertrophic pachymeningitis, takayasu arteritis, cranial nerve palsy, large vessel vasculitis

PMC5987150_01

Female

A 44-year-old woman was admitted into the ward on account of three months history of cough and one-week history of fever and difficulty with breathing. The cough was insidious in onset and productive of yellow sputum that is non-bloody and non-foul smelling. The fever was high grade with associated chills and rigor. There was associated history of progressive weight loss and drenching night sweats. There was no history of contact with person with chronic cough. Physical examination revealed a middle-aged woman who was in obvious respiratory distress. The pulse rate was 92 beats per minute (regular and good volume) with a blood pressure of 100/60mmHg and respiratory rate of 36 cycles per minute. Chest examination revealed dull percussion notes and absent breath sounds on the left lower lobes of the left lung. The apex beat was located in the fifth left intercostal space, mid clavicular line. An assessment of pulmonary tuberculosis was entertained to rule out metastatic lung disease. Chest x-ray that was done showed homogenous opacity with circumscribed nodular lesions of the left lower lung zones. Emergency in-patient thoracocentesis (with no imaging guidance) was performed for microbiological studies and cytology with 10mls of haemorrhagic fluid aspirated. However, some minutes after the procedure, patient complained of dizziness and went into coma. She was pronounced dead after failed resuscitation and autopsy was performed in our facility. Findings at autopsy revealed shrunken and partially fibrotic lower lobe of the left lung (about 60% of normal) with the presence of three areas of caseous necrosis located in both the upper and lower lobes (Figure 1). The enlarged heart (due to hypertensive heart disease) had replaced the space left by the shrunken lung. There was about 400mls of serosanguineous left pleural effusion. There were about four puncture wounds located at the apex of the heart, adjacent to the site of the pericardial laceration (Figure 2). Gross examination of the pericardial sac showed a 1.2 x 0.7cm laceration of the pericardial sac at the apex with about 650mls of clotted blood within the pericardial space (Figure 3). Considering the acuteness or sudden nature of the onset of symptoms and the progressive deceleration to death; the puncture was ascertained to be iatrogenic. The cause of death from autopsy findings was presented as cardiac tamponade due to iatrogenic puncture of the heart in a failed thoracocentesis. Histology of samples taken from the left lung tissue confirmed the presence of chronic caseating granulomatous inflammation due to pulmonary tuberculosis.

PMC5771786_01

Female

The study considered four cases of pregnant women with unstable pelvic fractures. Cases were retrospectively analyzed from two University Hospital records. Foetal and mothers conditions at the time of admittance, description of lesions of acetabular/pelvis fractures, type of fractures, performed surgery, pre, intra and post-operatively care, and mother and foetus outcomes were analyzed. The inclusion criteria were pregnant women with unstable pelvic fractures. A literature review considering the subject was performed. Table 1 and Fig. 1, Fig. 2, Fig. 3, Fig. 4 present demographic findings on the four patients and their foetus, including foetal and mothers conditions at the time of admittance, description of lesions of acetabular/pelvis fractures/type of fractures, performed surgery, and mother and foetus outcomes were analyzed. The mean age of the women was 23 years; most of them (3/4) were primiparous with a mean pregnancy age of 23 weeks. Two (2/2) women had Malgaigne-type fractures and the other two (2/2) had symphyseal disjunction associated with acetabular fractures. Considering the first case, the woman was 17 years old. Patient was run over and joined the emergence of hospital with back pain, pelvis pain and the inability to walk. She referred she was pregnant with +-25 weeks, first baby. The radiological evaluation showed fracture with small wedging L4 and disjunction with pelvic right side ascension. Foetal ultrasound evaluation proven foetal viability with normal heartbeats. After two days, under general anaesthesia, she was operated with reduction of the disjunction and fixing it with two perpendicular plates. After surgery, she was monitored in orthopaedics and obstetrics clinic. At 37 weeks it was performed a caesarean, and a girl was born with 3140 g and Apgar 10. After follow-up of 15 years, mother and daughter are completely healthy (Harris Hip Score = 100). In case 2, the woman was 25 years old. After a motorcycle fall, patient arrived unconscious in the hospital. Her family reports pregnancy status. Radiological examination showed disjunction with pelvic symphysis ascension. Obstetric ultrasound diagnosed foetal death with +-16 weeks of gestation. After a week, with clinical and neurological release, surgery was performed with osteosynthesis with two perpendicular plates to fix the symphysis, and the sacral-iliac fixation was done with a plate and two screws. After two days, the patient was transferred to obstetrics, to voluntarily wait for the elimination of the foetus. The deliberate elimination did not occur, and then it was induced with oxytocin. Five days after curettage was performed. After 15 years of follow up, the patient presents Harris Hip Score of 100. In case 3, patient was 16 years old, committed by run over accident. Victim was admitted to the Emergency Room conscious and hemodynamically stable. Patient had pain in the pelvic girdle and hip mobilization of the left leg. Radiological examination showed pelvic disjunction with fracture of the left acetabulum. Uterine ultrasound showed the foetus with gestational age +-21 weeks and normal heartbeat. After clinical compensation, patient was operated on the third day after the accident, with epidural block and ilium inguinal approach. The reduction and fixation of acetabular fracture was performed. The disjunction of the symphysis was performed with two orthogonal plates. Foetal monitoring was conducted throughout surgery. With 35 weeks of pregnancy, caesarean was performed, and a girl with 2160 g was born. After nine years of evolution Mother had HARRIS Hip Score of 98, and the child had normal development. In case IV, the patient was 35 years old. The run over victim was admitted to the hospital unconscious. After radiological examination, it was found the presence of intrapelvic foetus with disjunction of the symphysis, and left the acetabular fracture. Uterine ultrasound diagnosed a viable foetus with 35 or 36 weeks of pregnancy. Two days later, in the same surgery, a caesarean was performed and the baby was born. The fixation of the symphysis fracture and disjunction were fixed with long shaped plate. The foetus was male and weighed 3090 g and received Apgar 9. After follow up of four years, the child was normal and the mother had HARRIS Hip Score 98.

bone fractures, pelvic bones, pregnancy

PMC6139003_01

Female

In 2010 a 75 year-old female patient presented at our clinic with a 2-year history of pain and recent emergence of a discharging sinus at her left upper leg. She had a history of bilateral gonarthrosis and underwent elective right and left knee total arthroplasty 5 years before. The procedures and the post-operative follow-up were uneventful. Her physical examination revealed slight swelling and tenderness with a mild seropurulent discharge on the antero-lateral aspect on her proximal left leg. There was no other systemic complaint. Her personal and family histories were unrevealing. There was no history of fever, trauma, previous tuberculosis or bone tumors. Lower limb x-rays were performed and the radiographic examination revealed a well demarcated cystic structure in her left tibia, 4 cm below the distal tibial component of the knee arthroplasty (Fig. 1). A purulent sample was collected and sent for microbiological study, after which, to better investigate the nature of the cyst, an incisional biopsy of the lesion was performed, and the sample subjected to histopathologic examination. The laboratory study isolated Pseudomonas aeruginosa, and appropriate antibiotics where then administered according to the susceptibility test carried out. Pathology results revealed hydatid cyst of the tibia. Segmental resection was planned, and the surgical approach revealed a diaphyseal cyst adherent to the surrounding tissues, which were markedly oedematous, with multiple membranous whitish tissues in aggregation. Fluid was aspirated from the cyst, and the sample was sent for microbiology and serology tests. After curettage of the lesion and power-pulse lavage, povidone-iodine-alcohol solution was injected. Due to the fragility of the remaining tibial diaphysis, an external fixator was applied. Microscopy confirmed the diagnosis and revealed osseous tissue with hyaline and germinative membranes, lymphocytes, and monocytes. Albendazole and praziquantel, antihelminthic drugs, at doses of 10 and 25 mg/kg, respectively, were started. The patient recovered uneventfully and was discharged shortly after the procedure. She was clinically and radiologically evaluated in the following months, revealing progressive bone growth, remodeling and consolidation, having the external fixator extracted 6 months after the initial procedure. The patient then remained exempt of pain, swelling or other complications, until May 2014, when suddenly she comes to our clinic, complaining of pain and unable to bear weight on her left knee. X-ray studies revealed a pathologic periprosthetic fracture, below the tibial component, resulting from an extension of the previously treated hydatic cyst (Fig. 2). A treatment plan was performed, and our patient underwent surgical intervention. Both of the total knee arthoplasty components exhibited signs of loosening (Fig. 3), and after extraction of them, a total revision knee arthroplasty was performed (Fig. 4). The cancellous bone loss in the tibial component was considerable, and this defect was addressed by autologous bone graft implemention around the tibial stem and plateau. The patient functional outcome was excellent. She recovered motility of her left knee, and now more than 24 months has passed and she is fully weight bearing with no pain, knee instability or discomfort.

echinoccocosis, hydatid cyst, pathologic fracture, total knee replacement

PMC10288404_01

Female

We report on a 65-year-old female patient who was referred to our center with an intraosseous mass of the eighth rib and history of a fall on the left chest wall 2 months ago. A diagnostic outpatient chest radiograph was performed for pain in the left hemithorax, revealing a pathological fracture with an expansive osteolysis and unclear intraosseous of the eighth rib on the left lateral side. Following additional computed tomography (CT) and magnetic resonance imaging (MRI) scans, the patient was referred to our sarcoma center. At the time of presentation, almost 3 months after the fall, the patient no longer reported any symptoms. Pain or shortness of breath was denied, as well as B symptoms or a known tumor disease. The clinical examination showed normal soft tissues on the left hemithorax without triggerable pressure or chest compression pain, a tumor in the area of the ribs/chest wall was not palpable. External X-ray diagnostics showed a pathological fracture of the eighth left lateral rib with an unclear osteolysis (Figure 1(a)). The CT scan of the ribs showed an expansive, osteolytic intraosseous lesion, 3 x 2 cm in size, with a sclerotic rim and accompanying pathological fracture of the eighth rib on the left lateral side (Figure 1(b)). Similarly, the MRI of the thorax demonstrated evidence of a contrast medium-enhancing lesion without a significant surrounding reaction (Figure 1(c)). A staging CT of the thorax, abdomen, and pelvis showed an arterial hypervascularized lesion in the liver, which was constant in size in the CT follow-up controls. There was no evidence of further lesions. No abnormalities were found in the laboratory blood chemistry examination. After presenting the findings to our interdisciplinary tumor board, a biopsy was indicated. For this purpose, a CT-guided biopsy of the mass was performed. Histologically, there was a spindle cell lesion with mild nuclear atypia and pleomorphism with included trabecular bone. The immunohistochemical examination revealed a strong diffuse-positive immune reaction for vimentin, a nuclear-positive immune reaction for special AT-rich sequence-binding protein 2 (SATB2) (partial) and a positive immune reaction for smooth muscle actin (SMA) in the absence of the other markers (Pancytokeratin, S100, CD34, desmin, beta-catenin). Due to the only sparse sample material that was submitted, a further molecular pathological examination was not possible, so that a further classification of the lesion was not possible and an open re-biopsy was recommended. The samples obtained again showed an indicated biphasic neoplasia consisting of fascicular or cell-rich areas next to cell-poor, increasingly hyalinized, or chondroid-appearing areas without higher-grade cellular atypia, which was differentiated myofibroma-like from the histological aspect (Figure 2(a)-(d)). Mitoses were not clearly displayed. However, the performed Ki67 proliferation index showed an inhomogeneous proliferation activity with a Ki67 proliferation index of up to 15% detectable in the hotspots. The lesional cells only showed an immunohistological expression with the antibody against sm-actin. Furthermore, a (possibly unspecific) expression of SATB2 was also found. The remaining immunohistological tests (antibodies against beta-catenin, CD34, desmin, S100, STAT6) were negative again (Figure 2(e)). An insertion in exon 11 of PDGFRB (p.I538_L539insR) could be detected by molecular pathology. This variant was classified as probably activating in vitro (Figure 2(e)) so that in the absence of other tumors, the diagnosis of a solitary intraosseous myofibroma was finally made activating PDGFRB mutations represent a characteristic molecular alteration in these lesions. MDM2 amplification was not present, so that a low-grade osteosarcoma could be ruled out. There was no evidence of malignancy in the material available here. Due to the lack of symptoms, the patient decided against surgical treatment. The CT follow-up after 3 months showed an unchanged lesion of constant size, which is why the patient continues to favor conservative therapy.

myofibroma, adult-onset, chest, intraosseous, rib, solitary

PMC5878847_01

Female

A 37-years-old woman, G0P0, was admitted to the emergency room complainingof lower abdominal-pelvic pain and generally feeling unwell. No trauma or other gastrointestinal or genitourinary system problems were noted. She had started menses the day of admission. The symptomatology was of rough installation for 10 hours. Clinical examination had foundstable hemodynamicstate, an enormous median abdominal mass arriving up to the navel (consistent with a 20-week gestational uterus) and umbilical and right iliac fossa sensitivity.A pelvic ultrasound was performed. She showed polymyomatous uterus with a 11x10 centimeters serosal-type fundal uterine myoma (Figure 1) and 3 centimeters anterior is thmusmyoma with a small quantity of effusion in the Douglaspouch. Ovaries were not identified. The patient was followed for this polymyomatous uterus and myomectomy was programmed one month later in another hospital.Laboratory data were within normal ranges, hemoglobin level of 11.3 g/dL, blood ssHCGvalue was negative.The first evoked diagnosis was aruptured hemorrhagic ovarian cystbecause of the fast increase of the quantity of the effusion (in 12 hours)found on ultrasound. The decision was an urgent surgical exploration by laparotomy because the big size of the fundal myoma could block the access to the ovaries. To our surprise, ovaries had a normal aspect. Operative findings revealed a 1,000-mL hemoperitoneum. A bleedingsite was identified on the surface of the fundal myoma (Figure 2, Figure 3). This bleeder was derived from a superficial, tortuous and dilated vein.She underwent a myomectomy with a good evolution.

hemoperitoneum, gynaecological emergency, leiomyoma

PMC5385225_01

Male

A 24-year-old man with a protein-losing gastroenteropathy due to an intestinal lymphangiectasia was treated with glucocorticoids (prednisolone, 7.5 mg/day) and developed low-grade fevers 7 months before admission. He did not have any remarkable life histories. Five months before admission, the man complained of headaches, fatigue, and a hearing abnormality. Then, he experienced nausea, diarrhea, and drowsiness for 6 days and subsequently sought evaluation at our hospital. The physical examination at the time of admission revealed that he was slow to respond (Japan Coma Scale 1-1). The following measurements were obtained: height, 161.2 cm; weight, 51.0 kg; BMI, 19.6 kg/m2; blood pressure, 119/78 mmHg; heart rate, 62 bpm; and body temperature, 37.4 C. The remainder of the examination findings were normal, without any signs of meningitis. The initial laboratory data showed a white blood cell count of 11700/muL, with 87.0% neutrophils (86% segmented and 1% band neutrophils), 2.0% lymphocytes, 10%monocytes, 0% eosinophils, 1% metamyelocytes, hemoglobin = 15.7 g/dL, and a platelet count of 157,000/muL. The serum C-reactive protein level was slightly elevated (0.80 mg/dL). Although the serum sodium level was slightly decreased (130 mEq/L), the potassium (4.6 mEq/L), chloride (97 mEq/L), creatinine (0.59 mg/dL), fasting glucose (85 mEq/L), and HbA1c (5.1%) concentrations were normal. An abdominal computed tomography (CT) showed bilateral adrenal enlargement (right, 10.0 x 20.0 mm; left, 29.0 x 29.0 mm). A retrospective analysis of the CT images revealed that the enlargement in the left adrenal gland developed 5 months before admission (Figure 1(A)), which coincided with the onset of fevers and headaches. Subsequently, the bilateral adrenal enlargement progressed (Figure 1(B)). The differential diagnosis of adrenal enlargement includes metastatic carcinoma, bilateral adrenal hyperplasia, tuberculosis, and fungal infections. A whole-body examination failed to find a primary malignant lesion. The QuantiFERON-TB test and HIV antibody titer were negative.Although there were no signs of meningeal irritation, a diagnostic lumbar puncture was performed. The cerebrospinal fluid revealed an increased white blood cell count (240/muL), a normal protein level, a decreased glucose level (0.10 g/l), and a positive cryptococcal antigen titer. The pathologic specimen showed the presence of yeast-like organisms, such as Cryptococcus spp. on Alcian blue staining, which was subsequently determined to be Cryptococcus neoformans. Although the level of serum adrenocorticotropic hormone (ACTH) was elevated (131.3 pg/mL; normal range, 7.2-63.3 pg/mL) at the time of the diagnosis of cryptococcosis (Table 1), cortisol release in response to ACTH (Cortrosyn), which was evaluated 1 day after prednisolone cessation, was increased (Table 2). Oral prednisolone (7.5 mg/day) was then resumed as treatment for the protein-losing gastroenteropathy. The other endocrinological data of adrenal gland ruled out the possibility of pheochromocytoma and aldosterone-secreting tumors in this patient (Table 2). Amphotericin B (250 mg/day) was initiated, followed by the addition of fluconazole (400 mg/day). The symptoms improved gradually after beginning antifungal treatment. Fluconazole alone was continued after discharge. After the initiation of antifungal treatment, the elevated ACTH levels were decreased and varied during the treatment (Table 1), suggesting a stressed condition with infection at the diagnosis and unstable absorption of prednisolone due to the protein-losing gastroenteropathy. Mild hyponatremia probably due to relative adrenal insufficiency was improved to the normal range (138 mEq/L) one month after the initiation of the antifungal treatment. An abdominal CT, which was routinely obtained during follow-up, showed that the size of the adrenal glands decreased following antifungal therapy and became normal without any abnormal findings, including calcifications, 6 months after starting treatment (Figure 1(C)).

PMC6974620_01

Male

A 46-year-old male worker was admitted to the hospital with the symptoms of bilateral lower-limb numbness, lower back pain, and irregular defecation for 5 days. The pain gradually spread to the upper abdomen. Physical examination demonstrated muscle strength of grade 4/5 in lower extremities and grade 5 in upper extremities. There was a presence of hyperalgesia below the T7 level. Muscle tension was normal. Further neurologic examinations revealed normal deep tendon reflexes in arms and legs, as well as normal abdominal reflexes. Pathologic reflexes were also negative on both sides. In addition, the patient had a history of hypertension medication and kidney failure in compensated period. The patient had no history of trauma, cancer, diabetes, or allergic diseases. MRI of the spinal cord demonstrated swelling of the thoracic cord with long-segment diffuse high signal intensity and a heterogeneous nodule with hypointense center at the T7 level on T2-weighted imaging. The post-gadolinium imaging indicated peripheral enhancement of the nodule in the dorsal aspect of spinal cord, while no enhancement of the diffuse high-signal lesion was observed on the T2-weighted images (Figures 1A-D). Brain MRI was normal. Performance of MRI may indicate spinal tumors or inflammatory granuloma such as syphilis, tuberculosis, and neurocysticercosis. Cerebrospinal fluid (CSF) examination showed elevated cell (120/mul, 76% lymphocytes) and protein levels (84 mg/dl), while the levels of glucose and chloride were normal. Syphilis serology including the Treponema pallidum particle agglutination (TPPA) and toluidine red unheated serum test (TRUST) demonstrated positive results. The TRUST titer of serum and CSF were 1/128 and 1/32, respectively. Serological test for HIV was negative. Normal results were observed in the tests for AQP4-IgG, antinuclear antibody, rheumatoid factor, tuberculosis antibody, neurocysticercosis antibody, and tumor marker. The patient denied having a history of venereal diseases and exposure to unprotected intercourse with commercial sexual workers or homosexuality, and also denied any previous symptoms relevant to syphilis infection. There were no skin or mucous lesions or chancre at present. However, given the results of syphilis serologic test, CSF examination, and MRI scan, spinal syphilitic gumma was strongly suspected. The patient was treated with penicillin G (24 million U/day intravenously every 6 h for 14 days) and prednisolone (20 mg/day for 3 days). Three days after the treatment, back pain and bilateral lower-limb numbness were obviously lessened, and irregular defecation was changed correctly. One month after the onset, spinal MRI showed that the lesion was reduced compared with that before the treatment (Figures 2A,B), and the result of the CSF routine test was approaching normal. Serum and CSF TPPA were positive, and TRUST titer of serum and CSF were 1/4 and 1/1, respectively. After 6-month follow-up, the symptoms of pain and numbness disappeared, and CSF studies and spinal MRI demonstrated normal results (Figures 3A,B). A definitive diagnosis of spinal syphilitic gumma was made based on the clinical symptoms, MRI findings, and laboratory tests, as well as with the favorable prognosis after the penicillin therapy.

anti-syphilitic treatment, diagnosis, magnetic resonance imaging, neurosyphilis, spinal syphilitic gumma

PMC3634208_01

Male

A 60-year-old male patient visited our hospital with vomiting, pain in abdomen and distension of abdomen since one month. He also gives history of weight loss, loss of appetite, low grade fever. He was non-smoker and non-alcoholic. He had no significant past history of pulmonary tuberculosis or any contact with patient of TB or neither had HIV infection. He was not screened for diabetes mellitus and hypertension. On examination he was afebrile, regular pulse at 84/min. His blood pressure was 120/70 mmhg. He was anicteric and there was no lymphadenopathy. On abdominal examination shifting dullness and fluid thrill suggestive of free fluid in the peritoneal cavity was present. Spleen was not palpable. Investigation revealed haemoglobin of 9 gram percent, fasting blood sugar was 98 mg/dl, erythrocyte sedimentation rate (ESR) of 90 mm/1st hour. His tuberculin test was positive (18 mm). The HIV serologic test was negative. Other Blood biochemical profile like liver function test and kidney function test were within normal limits. The chest X-ray revealed no abnormalities. Abdominal ultrasonography revealed ascites with multiple ill defined areas of hypoechogenesity in spleen. The axial contrast enhanced Computerised Tomography showed irregular hypo dense peripherally enhancing lesions in spleen, and fluid in anterior perihepatic space suggestive of splenic abscess [Figure 1]. There was no bowel thickening, no septa and no lymph node enlargement. The computed tomography (CT) guided fine needle aspiration biopsy from hypo echogenic area of spleen was performed. The cytomorphology showed granulomas with area of caseation in the centre surrounded by variable number of langhans giant cells and epitheloid cells favouring diagnosis of tuberculosis [Figure 2]. Culture and polymerase chain reaction based confirmation could not be contemplated due to inadequacy of sample. Ascitic fluid examination revealed total white cell count of 450 with lymphocyte 85%, protein 4.6 mg/dl, glucose 60 mg/dl, LDH 442 u/l, cholesterol 43 mg/dl. Serum ascitic albumin gradient was 0.8 suggestive of exudative fluid. Tuberculosis is one of the common causes of exudative fluid in this part of the world. Microscopy was requested for malignant cells and mycobacterium which was negative. The final diagnosis was multiple splenic tubercular abscesses with tubercular ascites. We put him on DOTS category two anti tubercular therapy. He was doing well on follow up which was regular for three month.

ascites, immunocompetent, splenic tuberculosis

PMC6346873_01

Male

The authors report the case of 27-year-old male who was aphasic and tetraplegic following a traumatic brain injury (TBI) with severe right hemisphere lesions sustained in a road traffic collision. Five months after the accident, the patient was readmitted to hospital because of nosocomial pneumonia and was started on a 10-day course of the antibiotic meropenem. No pathogens were isolated from blood or sputum cultures and the patient improved clinically to be stable on air, with no respiratory symptoms and negative inflammatory markers. Despite the apparently treated infection, the patient was still febrile with his temperature rising to 39.5 C once or twice a day with very little response to antipyretic drugs. During these episodes, the patient became tachycardic, hypertensive, tachypnoeic and sweated profusely. The patient's mother reported that these episodes were also frequent at home and that because of them, the patient had been refused care in a specialized rehabilitation hospital as he was thought to be infectious. A complete septic screen was performed including blood, sputum (obtained from bronchoscopy), urine and liquor samples but no bacteria, yeast or fungus were found, and no changes were seen on imaging tests. The inflammatory markers were also negative: white cell count 7,000x109/l (normal value <11,000x109/l), C-reactive protein <0.5 mg/dl (normal value <0.5 mg/dl) and erythrocyte sedimentation rate 23 mm/h (normal value <20 mm/h). Both renal and liver function were normal. Paroxysmal sympathetic hyperactivity (PSH) was then considered as the cause of the patient's febrile episodes. PSH is a common but unrecognized complication after TBI and is characterized by hypertension, tachycardia, sweating, tachypnoea and hyperthermia, the last being less frequent than the other signs. A consensus statement was issued only recently on the definition, nomenclature and diagnostic criteria for PSH, an entity that was previously poorly recognized, thus leading to delays in treatment and increased morbidity among TBI patients. In this consensus, an assessment measure was proposed combining a "Clinical Feature Scale" and a "Diagnosis Likelihood Tool". Our patient scored 22 points in this proposed model, indicating a 'Probable' PSH diagnosis (Table 1). Current state-of-the art treatment for this condition with beta-blockers was initiated with propranolol 10 mg every 8 hours up-titrated to 30 mg every 6 hours on discharge. The patient experienced complete resolution of all the described symptoms and no negative beta-blocker side-effects were noticed.

paroxysmal sympathetic hyperactivity (psh), beta-blocker, fever, traumatic brain injury (tbi)

PMC5591983_01

Male

A 43-year-old Hispanic male presented to the hospital with frontal headache, fever, nausea, and vomiting ongoing for 2 weeks. His past medical history was significant for herpes zoster ophthalmicus two years ago. His vital signs on admission were within normal limits. Neurological examination was remarkable for mild cervical stiffness and pain with neck motion. No focal signs were noted. Laboratory studies were remarkable for normal white blood cell count (WBC: 6.7 k/uL), low hemoglobin (10.8 g/dL), and normal platelet count (172 K/uL). Rapid HIV test was reactive. Complete chemistry panel was within normal limits. Chest X-ray did not show any abnormalities. Due to a high suspicion for meningitis, the patient underwent a brain computed tomography (CT) followed by a lumbar puncture. Brain CT scan did not disclose any abnormalities. Cerebrospinal fluid (CSF) analysis revealed high WBC count (73 leukocytes/mm3) with lymphocytic predominance (96%), high protein (112 mg/dL), and low glucose (37 mg/dL). The patient was started on ceftriaxone, vancomycin, and acyclovir empirically. Later on, studies revealed a CD4 count of 83 cells/uL and a HIV viral load of 51,080 copies/mL. Serum RPR was reactive with a titer of 1 : 1024 dils. VDRL from CSF was also reactive. Based on these results, the patient was diagnosed with neurosyphilis and intravenous penicillin was started. At this point, ceftriaxone, vancomycin, and acyclovir were discontinued. Over the following three days, the patient reported worsening headache and neck pain accompanied by nausea and vomiting. He also complained of slurred speech and visual hallucinations. Due to lack of response to neurosyphilis treatment, a magnetic resonance imaging was ordered. It showed T2 and flair hyperintense signal involving the left middle cerebral peduncle and vermis and in the right cerebellar hemisphere medial aspect. Lumbar puncture was repeated and CSF analysis showed a higher number of WBCs (267 leukocytes/mm3) with lymphocytic predominance (74%), low glucose (8 mg/dL), and high protein (94 mg/dL). Cryptococcus antigen from CSF was positive with a titer of 1 : 640 dils. India ink stain and fungal culture were negative. He was started on amphotericin B lipid complex and flucytosine for cryptococcal meningitis. The patient improved clinically over the following week. After two weeks of treatment with amphotericin and flucytosine, he was switched to oral fluconazole 400 mg daily for consolidation therapy. He also completed two weeks of intravenous penicillin for neurosyphilis and was discharged in stable condition with resolution of headaches. After 2 weeks, he started antiretroviral therapy with tenofovir alafenamide/emtricitabine and darunavir-ritonavir. At 1-month follow-up, he complained of malaise and dizziness along with slurred speech and left hand clumsiness. On physical exam, he had an ataxic gait and saccadic eye movements. A repeat MRI showed improvement of leptomeningeal enhancement supratentorially but progression of leptomeningeal enhancement and T2/FLAIR signal abnormality within the posterior fossa (Figure 1). The patient was readmitted to the hospital and underwent a new lumbar puncture. Opening pressure was elevated (26 cm H2O). CSF analysis showed 2 WBCs and normal glucose and protein. India ink stain revealed rare encapsulated yeasts. Cryptococcus antigen from CSF was 1 : 80 dils. Fungal culture did not show any growth. He was restarted on induction therapy with amphotericin B 1 mg/kg/day and flucytosine for a possible relapse of cryptococcal meningitis. After 2 weeks of treatment, his symptoms improved significantly and he was discharged on oral fluconazole 800 mg daily for consolidation therapy. Two weeks after discharge, CSF culture from recent hospital admission grew Mycobacterium tuberculosis. Identification was confirmed by PCR restriction analysis- (PRA-) hsp65. Antibiogram showed resistance only to streptomycin (Table 1). The patient was started on antituberculosis therapy with isoniazid, rifabutin, pyrazinamide, ethambutol, and cycloserine. His antiretroviral therapy was modified to avoid drug interactions with antituberculosis regimen. Darunavir-ritonavir was switched to dolutegravir and he continued with tenofovir alafenamide/emtricitabine. Given his recent episode of possible Cryptococcus relapse, he continued with a high fluconazole dose (800 mg daily) for a prolonged consolidation therapy.

PMC6914976_01

Male

In March 2012, a 42-year-old man was referred to our department for evaluation of whitish and erosive lesions that involved the tongue, buccal mucosa, palate, and lip. The patient previously received PBSCT for treatment of acute lymphocytic leukemia (ALL) in December 2005; his sister was the related donor, and she matched for HLA antigens. PBSCT was carried out after induction by combined chemotherapy and total body irradiation (TBI). The patient's ALL went into remission without evidence of acute GVHD. Cyclosporine A (100 mg) and prednisolone (10 mg) were utilized for posttransplantation GVHD prophylaxis. However, chronic GVHD (cGVHD) of the skin and eyes were developed 3 months after PBSCT. One month later, airflow obstruction developed, which was considered as evidence of BO. Later, white spots and erosions of the oral mucosa were noted, which persisted without significant change during follow-up until the first visit of our department. In August 2008, he became aware of respiratory discomfort due to pneumothorax of the right lung. The pneumothorax was successfully treated with a thoracic cavity drainage. Intraoral examination revealed lichenoid changes and atrophic mucosa located on the buccal mucosa, tongue, and lip, compatible with oral cGVHD (Figure 1(a)). The patient was received plaque control instruction to improve poor oral hygiene associated with severe xerostomia. A lip biopsy for confirmation of oral cGVHD was performed on June 7, 2012. The biopsy specimen demonstrated a lichenoid infiltration compatible with cGVHD (NIH criteria: score 2). In January 2013, 8 years after PBSCT, a raised mucosal lesion appeared on the left dorsal surface of the tongue base, with a background of lichenoid mucositis. This lesion decreased in size by 50% over the next month. However, the lesion then enlarged over the following 3 months and appeared as an exophytic mass (20 x 15 mm) (Figure 1(b)). The lesion was then biopsied; histopathologic examination showed well-differentiated OSCC (T2N0M0: stage II). After preoperative examination, we determined that the patient had adequate cardiorespiratory function to undergo an invasive operation under general anesthesia. In July 2013, hemiglossectomy and left supraomohyoid neck dissection and reconstruction with a rectus abdominis musculocutaneous flap were performed after cessation of immunosuppressants. Histopathologically, the excised specimen revealed a well-keratinized OSCC with negative tumor margins; regional lymph nodes were negative for metastasis. On the 7th day after the operation, the patient's respiratory status was suddenly deteriorated. Bilateral infiltrations were noted on plain chest radiography (Figure 2(a)), and significant ground-glass abnormalities were seen on a chest computed tomography (Figure 2(b)), indicating acute respiratory distress syndrome (ARDS). Subsequently, mechanical ventilation, intravenous antibiotics and sivelestat sodium, and control of body fluids were administered. The ARDS improved over two weeks. Adjuvant therapy for OSCC was not considered, given the patient's status. Although the surgical site remained clinically stable, approximately 2 months later, recurrent pneumothorax developed on the right. In October 2013, the patient was discharged after the pneumothorax improved. Thirteen months after surgery, the patient showed neither recurrence of tumor nor progression of oral GVHD. However, the patient died of respiratory failure due to repeated pneumothorax and deterioration of BO.

PMC5903160_01

Female

We report the case of a 16-year-old girl who presented initially to her local hospital emergency department with headache, vomiting, and hallucinations associated with photophobia and neck stiffness. She underwent an urgent head CT, which was normal. She was commenced on acyclovir and ceftriaxone on the day of admission, and she made a clinical improvement. A lumbar puncture performed 24 h after antimicrobial therapy was commenced, which revealed CSF cell count of 226 (200 lymphocytes, 6 polymorphs), raised protein 1.2 g/L, negative Gram stain and culture, negative viral polymerase chain reaction (PCR). CSF glucose was not sent. In light of a predominantly lymphocytic CSF and presumed viral meningitis with clinical improvement, antibiotics were stopped 4 days after treatment. Three days later, she had acute deterioration in the neurological status with no clear evidence of seizures with a drop in the Glasgow Coma Scale score from 15 to 7 (E1V1M5) requiring intubation. Antimicrobial treatment was recommenced with additional cover for listeria and tuberculosis bacterium (TB). An urgent MRI brain demonstrated evidence of tonsillar herniation and coning which was not present on her previous cranial imaging (Fig. 1). In light of significant clinical and radiological deterioration, she was transferred to our unit for further treatment. On arrival, she had equal and bilaterally reactive pupils to light. She underwent emergency insertion of an external ventricular drain (EVD) and foramen magnum decompression and C1 arch laminectomy. Postoperative MRI demonstrated satisfactory decompression of the foramen magnum (Fig. 2). She was extubated on day 2 with removal of the EVD on day 11 postoperatively. Repeat CSF sampling from the EVD remained culture negative, as well as negative for 16S ribosomal protein, TB PCR, and an extensive viral PCR screen. TB treatment was discontinued following negative TB PCR results. She made a full recovery with no neurological deficit. She was discharged following completion of a full course of intravenous antibiotics.

foramen magnum decompression, hydrocephalus, meningitis, tonsillar herniation

PMC10337830_01

Male

Recently mNGS testing and analyses have become commercially available. For example, Charles Chiu and colleagues from the University of California, San Francisco (UCSF) are pioneers in the development of mNGS testing for the diagnosis of central nervous system (CNS) infections. In 2014, the first use of mNGS was reported for the diagnosis of neuro-leptospirosis on CSF from a 14-year-old boy presenting the signs of meningoencephalitis. This was the first report demonstrating the use of mNGS with medically actionable information and successful clinical diagnosis that led to the appropriate treatment of the patient. Since then, UCSF provides validated mNGS DNA and RNA testing for patients with meningitis and/or encephalitis. The UCSF diagnostic lab also offers mNGS DNA testing for patients with sepsis and disseminated infections. UCSF software analyzes sequence reads, identifies those reads which align to pathogens in the GenBank database, and issues a report showing the presence of pathogens in a clinical sample, along with clinical interpretation. At least 66.7% of pathogens detected from CSF were true positives, and only 5.6% were found to be false positives. The mNGS test at USCF for pathogen detection from CSF specimens showed a sensitivity of 86.1% and a specificity of 97.9%. The mNGS test for pathogen detection from plasma samples showed a sensitivity of 77% and specificity of 86%. The turnaround time from shipping samples to delivery of a report is generally 1-2 weeks. The Karius test (Karius, California, United States) is another example of how mNGS is useful for the diagnosis of bloodstream infections (BSIs) and sepsis. The Karius test involves extraction of cell-free DNA (cfDNA) from plasma, then a sequencing library is created and sequenced using Illumina technology. The sequence data is compared to an internal reference database encompassing a number of microbial genomes. A published study by Thair et al. confirmed that the Karius test detected approximately three times more positive cases than culture-based detection. However, the limitation is that the test can give false positive results. The Arizona-based Fry Laboratories also provides DNA sequencing diagnostic services for cutaneous, gastrointestinal, hematologic, musculoskeletal, and pulmonary infections. The Beijing Genomic Institute (BGI Genomics), a China-based company, is one of the largest companies that provide clinical mNGS services for the detection of pathogens causing respiratory infections such as Coronavirus and other pathogenic microorganisms. The sequencing services by the Zhejiang, China-based IngeniGen XunMinKang Biotechnology company also provide the detection of undiagnosed pathogens in patients with respiratory diseases. mNGS is an unbiased culture-independent and hypothesis-free sequencing technology that has shown tremendous clinical application particularly in the diagnosis of CNS infections, bloodstream infections, and respiratory tract infections. Examples of recent applications of mNGS in the diagnosis of these infections are provided in Table 2. Below is a brief overview of the areas where mNGS has made considerable impact and the implications. Pneumonia is considered among the top 10 causes of death in the United States, especially among immunocompromised patients such as those with hematologic malignancy or undergoing hematopoietic stem cell transplant. The identification of the causative agent of pneumonia is difficult and often inaccurate due to the pathogen diversity, heterogeneity of sampling, and limited detection methods. Traditional molecular diagnosis for pneumonia is pathogen-specific but unreliable for novel or unexpected pathogens. The ability of mNGS to provide a comprehensive view of pathogens makes it useful in the diagnosis of unexplained pneumonia and disease of unknown etiology. Recently, mNGS has improved the diagnosis of pulmonary infections over traditional methods by detecting a broad range of organisms including bacteria, viruses and fungi in a number of recent investigations. Remarkably, the causative agent was identified only by mNGS in two recent studies. Importantly, mNGS led to the treatment modifications and guided treatment decisions for 127 patients with pulmonary infections. Moreover, mNGS detected 50% of cases coinfected with bacteria of different respiratory origin in another study. A mNGS approach can be superior to traditional methods for pathogen detection and confirmation of respiratory infections, particularly for Mycobacterium tuberculosis. Mycobacterium tuberculosis, can be quite challenging to detect, however, it has been shown in the last few years that mNGS could potentially be used as the first-line diagnostic test for tuberculosis. Karius-based mNGS testing of plasma samples detected suspected tuberculosis in 60% of adults and 50% of pediatric patients. Lastly, RNA viruses are also considered one of the primary causes of respiratory infections. mNGS can detect a number of viruses that are usually not screened for in respiratory infections using routine diagnostic assays. It has shown good sensitivity and specificity compared to conventional testing and can identify viruses such as Influenza, Rhinovirus, and HIV. An additional advantage to mNGS is the potential to document and describe emerging, and re-emerging viral infections associated with outbreaks. For example, RNA-based viral metagenomics has detected the presence of novel human coronavirus variants from patients with respiratory symptoms. In 2017, it was estimated that 48.9 million cases and 11 million deaths were related to sepsis globally. Thus, the early and accurate diagnosis of BSI is critical to initiate appropriate antibiotic therapy and for patient survival. Recent findings indicate sequencing microbial cfDNA using mNGS is a valuable approach for the detection of BSI pathogens when the conventional diagnostics fail to detect the etiological agent. A retrospective multi-center study utilizing the cfDNA and RNA showed that mNGS had a positive impact in 7.3% of cases, a negative impact in 3.7% of cases, and no impact in 86.6% of cases in patients with suspicion of multiple infections. Another study applied mNGS on cfDNA in septic and non-septic intensive care unit (ICU) patients and was able to diagnose sepsis and predicted mortality as soon as the first day. Similarly, cfDNA of relevant pathogens was detected in the blood plasma of cystic fibrosis patients. mNGS testing improved the detection rate of BSI in patients having fever of unknown origin or patients with suspected BSI from 38% to 87.1% when compared to conventional methods. However, no difference was observed in specificity between two methods for patients with clinical suspicion of infections. In one report, mNGS pathogen detection rate was comparable with routine diagnostics in 37% of cases. In some scenarios, the pathogen detection rate for mNGS varied by organism. For instance, mNGS was 100% sensitive for the detection of Staphylococcus aureus and Escherichia coli. However, mNGS test missed the presence of Streptococcus pyogenes. In contrast, 37% of BSI cases were found to be positive by only mNGS test in patients with clinical suspicion of sepsis in another study. Neuroinflammatory diseases such as meningitis and encephalitis can be diagnostically challenging due to the requirement of invasive procedures for CSF collection, limited availability/low volume of CNS samples, and difficulty of detection by traditional culture. Furthermore, meningoencephalitis is related with increased risk of morbidity and mortality and thus needs prompt diagnosis and disease management. CSF culture is considered the gold-standard method for the diagnosis of meningitis. However, prior antibiotic therapy may reduce the sensitivity of CSF cultures, increasing the possibility of false-negatives. mNGS has potential to detect pathogens of unknown etiology as evidenced by clinical series demonstrating the success of mNGS in the detection of hard-to-diagnose CNS infection cases. Recently published studies have confirmed the diagnostic sensitivity of mNGS ranging 22% to 95% in patients with CNS infections. mNGS testing guided treatment decisions and clinical actionable management for 34.1%-53% of patients in these reports. However, contaminants from skin flora can lead to false positive bacterial sequences in CSF specimens obtained by lumbar puncture.

diagnostics, meningitis, metagenomics, next-generation sequencing, sepsis

PMC4200876_01

Female

A 49-year-old women presented to the emergency department in April 2005 with right-side epistaxis and a 2-year history of progressive right-side nasal obstruction and anosmia, and a visible mass in the right nasal cavity. The rest of the history and physical examination revealed a history of meningitis and respiratory tuberculosis in infancy and a caesarean section. She had normal neurological and ophthalmological exams and no cutaneous lesions or lymph node enlargement. CT and MRI scans were conducted, which showed a lesion occupying the right nasal fossa with maxillary sinus involvement that extended from the piriform aperture to the cavum and was in contact with the orbital contents (absence of the lamina papyracea) and the dura in the region of the cribriform plate (Fig. 1). Because several different types of malignancy were possible (rhabdomyosarcoma, neuro-endocrine tumour, neuroblastoma, and chordoma), a biopsy was performed under local anaesthesia during her hospitalisation; however, the histological findings were inconclusive. Therefore, another biopsy was performed under general anaesthesia, and the biopsy sample was sent to the central histopathology department in France (Hospital Lariboisere). The microscopic examination showed a very cellular tumour containing spindle-shaped cells with oval and comma shaped nuclei. Eosinophilic cytoplasm was also observed. This aspect was associated with well-differentiated muscle fascicles with a very low mitotic index (1 mitosis per 10 high-power fields).

malignant triton tumour, nasal tumours, peripheral nerve sheet tumour, rhabdomyoblastic differentiation, schwannoma

PMC4898004_01

Male

20-year-old man presented with increasing pain corresponding to the plantar aspect of the second web (intermetatarsal) space for the past three years. The patient was active in sports, particularly football. His past medical history was notable for the presence of a bony prominence over the dorsomedial aspect of the right mid foot since birth. The patient stated that his father had the same bony prominence at the same location of the same foot. He did not complain of any symptoms related to the "bump" other than minor issues of fitting into shoes. The patient had been seen by a podiatrist, who prescribed orthodics with limited relief of symptoms. The pain increased during exercise. He was referred by podiatry to orthopedic surgery for further evaluation. Physical exam was notable for focal bony prominence at the dorsomedial aspect of the right mid foot without tenderness to palpation. The overlying skin was normal in coloration. Patient demonstrated an abnormal gait with persistent minor supination of the right forefoot. During gait, he appeared to bear weight on the second/third metatarsal heads rather than the first. The first web space was noted to be narrowed with the first and second toes in close apposition without syndactyly. The second web space was widened. There was focal tenderness to palpation corresponding to the plantar second web space. MRI was ordered to exclude an osteochondroma. Subsequent MRI demonstrated focal bony prominence projecting dorsally from the base of the first and second metatarsal bones in close apposition with typical appearance of non-osseous coalition (Fig. 1). Mild subchondral marrow signal and cystic changes are noted at this articulation. This finding corresponded to the focal bony prominence that the patient stated he had since birth. Fusiform soft tissue is also noted at the plantar aspect of the second web space consistent with interdigital (Morton) neuroma (Fig. 2). This finding explained the patient's chief complaint of plantar foot pain at second web space.

mri, magnetic resonance imaging

PMC5552024_01

Male

We present a 25 year old male who presented to ED with a 4 day history of severe sore throat, mild diffuse abdominal pain and flu-like symptoms of body aches, weakness, and fever. He had originally visited an urgent care center 2 days prior, where Monospot and Rapid Strep tests were negative. He was discharged at that time with azithromycin and prednisone. His symptoms progressively worsened and he also reported new onset nausea, vomiting, diarrhea, dizziness, sweating, chills and 2 episodes of syncope, which prompted this visit to the ED. He denied any recent dental procedures, sick contacts, recent travel, or IV drug use. His physical exam at that time revealed slightly low but still normotensive blood pressure of 104/60 mmHg, tachycardic heart rate at 133 bpm, respiratory rate 17 bpm, temperature 101.7 F, and oxygen saturation at 93% room air. Significant findings included tonsils with 3+ enlargement, erythematous posterior pharynx with no exudates, dry mucous membranes, and positive lymphadenopathy of anterior and posterior cervical lymph nodes. His chest was clear to auscultation and percussion bilaterally with no tenderness of the chest wall. Exam of his skin did not show any Janeway lesions, Osler nodes or splinter hemorrhages A complete blood count showed significant leukocytosis with WBC 35,400, hemoglobin 13.5 g/dL, hematocrit 39.9%, and platelets 557,000. He was found to have mild hyponatremia with a sodium of 131 mEq/L but with otherwise normal electrolytes (potassium 5 mEq/L, chloride 95 mEq/L, CO2 25 mEq/L), normal kidney function (BUN 12 mg/dL, creatinine 0.85 mEq/L). Liver function was found to be abnormal with ALT 103 IU/L, AST 48 IU/L, alkaline phosphatase 122 IU/L, total bilirubin 2.0 mg/dL. Initial imaging consisted of a chest x-ray which showed no acute cardiopulmonary process. (Fig. 1) A CT-angiogram of the chest with and without contrast showed multiple cavitary lung masses, suggestive of septic emboli, including a dominant cavitary lung mass at the right base measuring up to 4.4 cm. There was also a trace right pleural effusion. (Fig. 2) Tuberculosis testing was performed as well and found to be negative. Patient was subsequently admitted under the Infectious Disease service for diagnosis of septic emboli. He was placed on IV piperacillin/tazobactam and IV vancomycin. Echocardiogram showed normal left ventricular ejection fraction at approximately 65 +/- 5%, mildly enlarged right ventricle. No clots, masses or vegetations were visualized. The patient underwent a right video-assisted thoracoscopic surgery with drainage of pleural effusion (400 mL), partial decortication, and right lower lobe wedge excision of right lower lobe lung abscess by cardiothoracic surgery. Lung tissue and pleural fluid cultures were obtained. There was concern for Lemierre's disease so a Doppler of bilateral internal jugular veins was obtained, which was negative for thrombus. Carotid Dopplers were also performed and showed mild stenosis (0-50%) in internal carotid arteries bilaterally and normal vertebral flow bilaterally. On the 5th day of incubation, the culture of the right lower lung tissue grew fusobacterium necrophorum. Blood and pleural fluid cultures returned negative. Lung tissue pathology for the wedge resection showed acute bronchopneumonia with abscess formation, rare blood vessels with organizing thrombus and focal infarction with no evidence for malignancy. The patient's clinical course continued to improve; WBC count trending down to normal range and his fevers resolved. A PICC line was placed, antibiotics were de-escalated to ceftriaxone and metronidazole and the patient was discharged home. At this time, patient has continued to do well with no recurring symptoms.

PMC5661071_01

Male

A 36-year-old Caucasian Portuguese male was admitted to the hospital in October 2010, with fever (38 C), pallor, weakness, and jaundice. His medical history revealed chronic alcohol abuse. The physical examination showed hepatosplenomegaly and there were no palpable superficial lymph nodes. Blood counts demonstrated pancytopenia: white blood cells 1.80 x 109/L, neutrophils 0.69 x 109/L, lymphocytes 0.64 x 109/L (no evidence for morphologically abnormal cells), platelets 46 x 109/L, and hemoglobin 6.6 g/dl. Biochemistry analysis revealed markedly increased serum lactate dehydrogenase levels (LDH) 2815 IU/L (135-225 IU/L) and abnormal liver tests: total bilirubin (TB) 1.5 mg/dl (<1.2 mg/dL), aspartate transaminase (AST) 124 IU/L (10-37 IU/L), alanine transaminase (ALT) 62 IU/L (10-31 IU/L) and gama-glutamil transferase (GGT) 107 IU/L (10-49 IU/L); coagulation tests were normal. The abdominal computerized tomography (CT) scan confirmed the hepatosplenomegaly (liver and spleen longitudinal axis of 209 cm and 158 cm, resp.) and did not show other abnormalities (Figure 1(a)). The bone marrow (BM) aspirate had more than 80% of morphologically immature cells, with a pale or slightly basophilic cytoplasm sometimes with fine azurophilic granules and a nucleus with an immature chromatin, with one or two distinct nucleoli, and the first hypothesis for the diagnosis was that of an acute leukemia (Figure 2). Flow cytometry (FCM) analysis of the BM aspirate cells using the EuroFlow lymphoid screening tube (LST) and antibody panel for NK cell chronic lymphoproliferative diseases (NK-CLPD), complemented with other cell surface markers, showed that the neoplastic cells were positive for CD45 (high), CD2, CD26, CD38, CD94 (high), and HLA-DR (high, heterogeneous) antigens, and negative for surface CD3, TCR, CD4, CD5, CD7, CD8, CD11b, CD11c, CD16, CD56, CD57, and CD161, as well as for cytoplasmic CD3; in addition, they express intracellular granzyme B and perforin (Figure 3). B cell (CD19, CD20, and CD79a), myeloid (CD13, CD14, CD15, CD64, CD65, and myeloperoxidase), immature (CD34, TdT), and dendritic (CD123) cell associated markers were all negative (data not shown). In the PB there were 10% of phenotypically abnormal CD45+high, CD2+, CD16+low, CD94+high, and HLA-DR+ NK cells, 19% of which expressed dimly and heterogeneously the CD56 molecule, at levels that were much lower than those observed in normal PB NK cells (data not shown). Flow cytometry propidium iodide based NK cell DNA studies revealed a diploid cell DNA content (DNA index 1.02) and a high proliferative rate (G0/G1 phases: 67.4%; S phase: 31.8%; G2/M phases: 0.8%). Polymerase Chain Reaction (PCR) TCRG gene rearrangements studies were consistent with a germ-line configuration. The BM biopsy revealed a hypercellular marrow infiltrated by CD45+, cytoplasmic CD3epsilon+, EBER+ and CD56, CD34, CD20, CD68, myeloperoxidase, and lysozyme-negative atypical lymphoid cells, interpreted individually given rise to the possibility of an immature EBV+ T cell leukemia (Figure 4). The BM karyotype with chromosome banding analysis showed complex aberrancies: 46,add(X)(q27),-Y,i(7q), +8,add(17)(p13),add(19)(q13) (Figure 5). Infection markers were negative for human immunodeficiency virus types 1 and 2, viral hepatitis B and C, and human T cell lymphotropic virus types 1 and 2. The whole blood EBV load, detected by quantitative PCR for viral DNA, was of 57 x 105 copies/ml. As no neurologic symptoms were present, central nervous system involvement was not evaluated. In view of these findings and according to the WHO classification of neoplasms of the hematopoietic and lymphoid tissues, the final diagnosis was an EBV+ ANKL, Ann Arbor stage IVB, high risk NKIPI (NK/T cell lymphoma international prognostic index), ECOG status 4. The patient was treated with a combination of gemcitabine (1 g/m2 days 1, 8, and 15), cisplatin (100 mg/m2 day 15), and methylprednisolone (1 g days 1-5) (GEM-P) repeated every 28 days. The first BM reevaluation, performed on day 23 after the first chemotherapy course, revealed 0.5% of phenotypically abnormal (CD2+, CD56-, CD94+, and HLA-DR+) NK cells and a normal karyotype (46, XY). In addition, there was a marked decrease in the EBV load in the PB to 4 x 105 (day 14) persisting at 6.6 x 105 (day 21) copies/ml. Also, the BM aspirate showed 4.1 x 105 EBV copies/ml. These changes correlated with an improvement in clinical status and blood analysis: WBC 5.14 x 109/L, neutrophils 2.78 x 109/L, lymphocytes 0.92 x 109/L, platelets 45 x 109/L, hemoglobin 8.9 g/dl (not dependent on blood or platelet transfusions), TB 1.10 mg/dl, AST 37 IU/L, ALT 39 IU/L, GGT 71 IU/L, and LDH 425 IU/L. A second evaluation of the BM aspirate after the second GEM-P showed only 0.09% of neoplastic NK cells. At that time, the BM biopsy provided evidence for a partial hematopoietic recovery, although intrasinusoidal niches of neoplastic NK cells were still observed; in addition, the BM karyotype was again abnormal, with different chromosomal aberrancies: 77,add(X)(q27),-Y,i(7)(q10),inc[5]/46,XY[15]. Similarly, an increase of the EBV load was observed (42 x 105 copies/ml). Considering the refractoriness to GEM-P, it was decided to change the chemotherapy. Nearly one month later, when the alternative schema was being discussed, the patient was admitted to urgency reporting loss of vision. At that time, the ophthalmologic and neurological examination revealed an almost total bilateral decline in visual acuity, markedly decreased pupil reflexes, right retinal detachment, and impaired right eye abduction compatible of palsy of the 6th right cranial nerve. Blood analyses were as follows: WBC 4.78 x 109/L, neutrophils 2.14 x 109/L, lymphocytes 1.69 x 109/L, and platelets 155 x 109/L, depending on regular blood transfusions, TB 0.88 mg/dl, AST 34 U/L, ALT 29 U/L, and LDH 429 IU/L. Abnormal NK cells had increased in blood (1.9% by FCM) and there was a marked increment on the EBV load (89 x 105 copies/ml) and on the LDH (1587 IU/L). Head CT revealed a thickening of the right optic nerve, compatible with neoplastic infiltration, without evidence for other abnormalities in brain tissue and structures. Five days later he also developed dysphonia, dysphagia, impaired abduction of the left eye, and left eyelid ptosis and the head MRI showed a thickening of the left lateral rectus muscle (Figure 1(b)). At that time, there was clinical evidence of palsy of multiple cranial nerves (bilateral palsy of the 2nd and 8th left and right cranial pares, left palsy of the 3rd and 5th left cranial pares, and right palsy of the 6th and 7th right cranial pares). The CSF had 262 cells/mul with 88% of atypical mononuclear cells, being consistent with leukemia meningitis. Immunophenotypic characterization was not performed, as on the day of the lumbar puncture flow cytometry was not available at our institution; EBV DNA analysis was not possible due to insufficient sample volume. At this point, no further chemotherapy was administered, and the strategy from here on was best supportive care. Death occurred a few days later, 107 days after the diagnosis.

PMC5442346_01

Male

The patient is a 28-year-old man with a history of major depressive disorder, hepatitis C, biliary colic (status postcomplicated cholecystectomy), multiple concussions, and chronic back pain who presented to the emergency department with abdominal pain clinically concerning for acute appendicitis. He localized his pain to the right lower quadrant, complained of right lower quadrant pain with palpation of the left lower quadrant (Rovsing's sign), and indicated his pain was reproducible with extension of the right hip (psoas sign). His vital signs on presentation were notable for the absence of fever or tachycardia and his initial laboratory findings revealed normal chemistries and a normal white blood cell count of 4.2. He received intravenous morphine and an urgent CT scan of his abdomen. Enroute to the CT scanner, the patient mentioned that he had been struggling with sadness and suicidality since his pregnant fiancee had recently been killed in an automobile accident. The emergency physicians felt the pretest probability for acute appendicitis was extremely high and asked the psychiatry consult-liaison team to "evaluate him quickly before he goes to surgery." Ultimately, the imaging was negative for acute appendicitis, surgery was cancelled, and his disposition from the emergency department was left to psychiatry. Review of the electronic medical record showed that the patient had established care at this institution one month prior to this presentation when he presented with biliary colic resulting in a lengthy hospitalization for a complicated cholecystectomy, challenging postoperative pain management, and a new diagnosis of hepatitis C. During that hospitalization, he was seen by social work who documented that he was baffled as to how he had contracted hepatitis C but offered that he had endured many losses in his life including the death of his mother when he was 6 years of age and the death of his brother when he was 19, so felt he had developed strong coping skills. In terms of his social history, he reported that he was engaged to be married and worked as a mathematics and physics professor at a prestigious university as well as an engineering consultant in the private sector. He also reported that he had sustained a number of musculoskeletal injuries resulting in chronic pain while playing Division I football in college and that he had been drafted by the National Football League. Upon discharge from that admission, he established care with a primary care physician for ongoing management of chronic pain. At his initial appointment he reiterated the social history he provided to the social worker and signed a narcotics agreement. On initial assessment in the emergency department by the psychiatry consult-liaison team, the patient was observed to be a young, overweight Asian male dressed in a plain white T-shirt and track pants. His hair was greasy, his fingernails were long and dirty, and one of the lenses of his eyeglasses had a small crack. He made poor eye contact and focused his gaze on his tablet computer for most of the interview. His affect was withdrawn and had minimal range. On interview, he began the conversation by requesting placement at an inpatient psychiatric facility for electroconvulsive therapy, reporting that he had been suffering from very low mood since his pregnant fiancee had been killed by a drunk driver eight months ago. Because the electronic medical record indicated that he had been engaged to be married just one month ago, we asked him to confirm the date of his fiancee's death, which he could not recall. He answered all questions in a matter-of-fact tone and showed very little range of affect. In terms of his mood, he did not elaborate on his experience other than to say he felt "depressed and suicidal" with the vague plan of jumping in front of a train. He evaded further discussion of his mood symptoms by spontaneously offering details of his social history. He spoke about his profession as a tenured mathematics and physics professor at a prestigious university although when asked about the nature of his research he could only vaguely describe studying "time bends in space using some of Einstein's old formulae." He spoke in some detail about his career as a varsity football player, citing football injuries as the source of chronic back pain. When asked to provide a collateral contact, he reported that both of his parents, multiple siblings, and cousins had died during his early childhood. The patient was accompanied by a male friend who was casually but neatly dressed and of approximately the same age. The patient provided us with permission to speak with his friend who appeared uncomfortable, saying "I didn't know I'd have to talk!" He reported that he and the patient were work colleagues who had known each other for a few years but refused to reveal where they worked. He provided no further information, other than saying "He's been really depressed and I just know he needs help before something happens." He then quickly left the hospital without saying goodbye to the patient. Although, the patient initially reported that both parents were deceased, his father was listed as an emergency contact in his medical record. When confronted with this, the patient said that this was his step-father and gave consent for contact. The father reported that, five years ago, his son graduated with poor grades from a university which does not have a Division I football team. He confirmed the patient had played football in high school and had sustained multiple concussions. The year after graduation, the patient had lived with his parents briefly, but because of escalating narcotic use and lack of employment was asked to leave. Since then, he has suffered from severe opioid use disorder and has been homeless and unemployed. He has travelled to various hospitals within the city and even out of state to seek pain medication and care and has told a similarly fictional narrative to other physicians. We obtained information from a local emergency community outreach agency which indicated that the patient had presented with the chief complaint of suicidality to multiple emergency departments in the city resulting in two previous inpatient psychiatric stays over the past year. We obtained records from his most recent inpatient psychiatric hospitalization about six months ago, where he presented with depression related to his girlfriend's putative recent breast cancer diagnosis. He was discharged on an antidepressant, a mood stabilizer, and oxycodone for chronic back pain. When gently confronted with these inconsistencies, the patient appeared unperturbed and easily provided further elaborate details to explain them. However when further pressed, he stated he believed he needed a "dramatic" reason for his depression and suicidality to receive help and asked, "Can I just be depressed and suicidal?" He appeared perplexed as to why we attempted to clarify his previous statements or their relevance for his care. Despite this, he continued to state that he felt very depressed and would not be able to maintain his safety in the community.

PMC5423323_02

Female

A 40-year-old Japanese woman was admitted to our hospital after a 5-day history of yellowish vaginal discharge, and 3-day history of fever, shaking chills, and appetite loss. She did not have any relevant past medical history and had not been prescribed any medications, including antibiotics. She had never been abroad and had not had any raw foods in the previous month. Her last menstrual period had finished 2 weeks before the day of hospital admission. At first, we diagnosed severe bacterial colitis and hypovolemic shock and started large volumes of hydration, dopamine infusion, and intravenous ciprofloxacin (300 mg, 2 times daily). However, her vital signs did not recover. On day 2, we learned that she had begun menstruating 4 days prior to admission, and that she kept a tampon inserted 3 days until the day of admission. Additional testing of her vaginal discharge showed the following; polymorphonuclear leukocytes 2+, and Nugent score, 1. We suspected TSS or septic shock of unknown origin and changed the antibiotics to vancomycin (1 g, 2 times daily, intravenously), clindamycin (600 mg, 4 times daily, intravenously), and meropenem (500 mg, 4 times daily, intravenously). On day 4, community-acquired S. aureus was detected from the tampon and vaginal discharge and her vital signs gradually recovered enough to stop the dopamine infusion, and her diarrhoea stopped. Two sets of blood culture and urine culture were negative. We diagnosed staphylococcal TSS owing to tampon use, discontinued meropenem on day 11, and continued antibiotic treatment with the combination of vancomycin and clindamycin for 14 days. On day 14, the patient was found to have peeling skin at the end of her fingers (Fig. 1). The patient was discharged on day 18, without any damage to her organs or deterioration in activities of daily living. Her vital signs on the day of admission were as follows: blood pressure, 86/49 mmHg; heart rate, 121 beats per minute; body temperature, 39.8 C; respiratory rate, 36 breaths per minute; and peripheral capillary oxygen saturation level on room air, 96%. She was alert and physical examination showed generalized rash on her hand and neck. Results of cardiovascular, respiratory, and abdominal examinations were normal, except tenderness on the right costal-vertebral angle. Laboratory data revealed WBC of 19,200/mul, CRP level of 14.5 mg/dL, BUN level of 28.4 mg/dL, s-Cre level of 1.7 mg/dL, serum total protein level of 6.0 g/dL, serum albumin level of 3.3 g/dL, and procalcitonin level of 5.4 ng/mL. Results of liver function tests were normal except for an LDH level of 328 IU/L. Urine dipstick examination revealed 3+ protein and 2+ occult blood. A microscopic examination detected 5 to 10 RBCs per high-power field and more than 100 WBCs per high-power field. Testing of her vaginal discharge showed the following: polymorphonuclear leukocytes, 4+; and Nugent score, 4. Gram stain of both urine and vaginal discharge showed clustered gram-positive cocci. At first, we diagnosed severe urinary tract infection and septic shock. We started large volumes of hydration, dopamine infusion, and intravenous ampicillin (2 g, 3 times daily) and gentamicin (120 mg, once daily). However, her vital signs did not recover and she experienced diarrhoea. On day 2, S. aureus was detected from urine and vaginal discharge. We suspected staphylococcal TSS or septic shock of unknown origin, and changed the antibiotics to vancomycin (1 g, 2 times daily, intravenously), clindamycin (600 mg, 4 times daily, intravenously), and meropenem (1 g, 3 times daily, intravenously) for covering enteric bacteria and anaerobes like Bacteroides spp. On day 3, community-acquired S. aureus was detected from both urine and vaginal discharge, and she recovered adequately enough to discontinue dopamine and large volumes of hydration. Two sets of blood cultures were negative. Gynaecological examination revealed narrowing of the vaginal opening caused by vulvar lichen sclerosus, a chronic and progressive dermatologic disorder of genital skin that can cause vulvar pruritus, dysuria, and sexual dysfunction due to cleft narrowing. We diagnosed staphylococcal TSS caused by vaginitis and discontinued meropenem on day 9 and continued vancomycin in combination with clindamycin for 14 days. On day 14, we noted peeling skin at the end of her fingers (Fig. 2). The patient showed full recovery and was discharged on day 17. The following 13 antimicrobials were tested: ampicillin, cefazolin, imipenem, gentamicin, gentamicin, erythromycin, clindamycin, telithromycin, levofloxacin, minocycline, vancomycin, teicoplanin, arbekacin, and trimethoprim/sulfamethoxazole. According to M100-S20, published by the Clinical and Laboratory Standards Institute, the isolates from Case 1 and Case 2 were resistant to ampicillin, cefazolin, imipenem, and gentamicin, but were susceptible to erythromycin, clindamycin, and minocycline. The 2 isolates were tested for genes encoding selected exotoxins including TSST-1, exfoliative toxins A and B (ETA and ETB), staphylococcal enterotoxins A to E (entA, entB, entC, entD, and entE), and Panton-Valentine leukocidin (PVL) by multiplex real-time polymerase chain reaction (PCR) analysis. Both isolates contained genes encoding for the toxins ETA, ETB, and TSST-1, but were negative for other exotoxins, including PVL. The isolates were also typed to determine their staphylococcal cassette chromosome mec (SCCmec) type by multiplex PCR targeting the cassette chromosome recombinases (ccr) and mec gene complex. Both isolates were identified as the group ST8-MRSA with SCCmec type IV, which has recently been one of a major genotype in the community in Japan.

community-acquired methicillin-resistant staphylococcus aureus, menstruation, toxic shock syndrome, vulvar lichen sclerosus

PMC3018956_01

Male

We examined the patient taking into account more than biochemical lab values and CT images (dubitative interpretation). We noticed that she had diffuse abdominal tension and vague hypogastrium pain. Retrograde cystography (Figure 1) showed the flow of contrast substance in the peritoneal space. To be noted that we made this investigation not due to the suspicion of uroperitoneum but because of our previous experience, years ago, of a somewhat similar case: a 35 year old autistic man, sheared between two carriages of a circulating tram, without pelvis fracture but with urinary bladder rupture and consequent uroperitoneum. We intervened surgically through an anterior abdominal incision and intraoperatively, an old an important vesical lesion was seen, on a bladder that looked 'withered', well fixed on an intestinal loop, which explained the almost missing symptoms. Without bringing new information in addition to the ones already reported in literature, we will note in the following, a few aspects on urinary peritonitis, with an intent of more than attracting attention towards this type of pathology Urine may get between intestinal loops by effraction through one of the urinary tract organs and the most frequently involved is the urinary bladder, through the rupture of its peritoneal side. Theoretically, the uroperitoneum can appear also through renal or urethral trauma but, considering their retroperitoneal location, causing agents must have a more complex and aggressive mechanism. (Figure 2) As a consequence, urinary bladder ruptures can be spontaneous, traumatic or iatrogenic.Spontaneous ruptures presume in principle the existence of a thin vesical wall, an immunosuppressant status or a lack in body proteins, such as consumption diseases. Quite a few at a first glance, these pathological situations which lead to the spontaneous effraction of the bladder make us think that they are least probable to be juxtaposed in order to make the optimal frame that causes urinary peritonitis. Nevertheless, it happens! Most frequent vesical ruptures appear in situations like chronic alcohol intakes (drunk man's bladder) [ ], immunosuppression, cirrhosis, diabetes, tuberculosis, scarred or tumoral bladders, when there are large vesical diverticula or chronic vesical obstacles with thin vesical wall. The question of a determining factor of vesical rupture was raised, in spite of the mentioned associated pathology. Most of the times there is a traumatic mechanism involved, brought to light by a very detailed history but there are cases in which no trauma can be traced. Vesical ruptures are induced mainly by action of the injury agent directly on the inferior abdomen. This determines a great and sudden pressure on the abdominal wall which spreads to the bladder, projects itself on the posterior wall of the pelvis and due to its resistance and comes back towards the bladder (anterior), giving it a counter blow. To this mechanism, a series of favourable conditions which may contribute to the extent of the lesions can be variably added. The amount of urine present inside the bladder at the moment of injury plays an important part. If the bladder is empty, it can be torn only through direct impact of the trauma agent on its walls because of its deep location in the pelvis and its protection by pelvic bones. Full bladder comes out of that protection and becomes an intraperitoneal organ. Vesical wall grows thinner in proportion with the quantity of urine and the flexibility of its muscular fibres decreases. Anatomical areas with least resistance are the superior and posterior walls. Vesical pathologies which determine a decline in wall strength (inflammatory, tumoral, scaring processes) favour surprisingly serious lesions following minor traumas. Neurological lesions of vesical wall lower its ability of distension and also muscle tone and consequently allow an accumulation of a great amount of urine. It is the case of neurogenic bladder patients. Last but not least, vesical ruptures can be accidentally produced during surgery of the pelvic area or during endoscopy procedures when, due to vesical wall lesion, the washing endovesical fluid effuses in the peritoneal cavity and produces an iatrogenic uroperitoneum (the patient's abdomen grows 'second by second'). The intimate substratum of urinary peritonitis symptoms is common to every peritonitis but noting that it depends greatly with the quantity and quality of urine, if we're allowed to say it like this. When a sterile urine effuses, the symptoms are minimal, hidden and become clinically obvious when this urine becomes infected. In the same way, the clinical suffering and the expressed symptoms can be seen when urine is infected per primam. Many local defence mechanisms come to aid against infection and other immune as well. Mechanical ones belong to the structural anatomy and to different characteristics of the peritoneum. Inside the immune mechanisms are cellular components, serum ones, unspecific immunity and the complement system. Confinement of infection is realised through direct absorption of bacteria in the lymphatic system, their fagocytosis and formation of intraperitoneal abscesses. The systemic response to bacterial aggression lies in the release of physiological messengers of inflammation: cytokines (TNF alpha, IL-1, IL-6, interferon, etc) and cellular effectors (neutrophils, monocytes, macrophages, endothelial cells). These activated cellular effectors lead to the synthesis and secretion of new cytokines and secondary inflammation mediators (prostaglandins, leucotriens, tromboxans, trombocyte activating factor etc). Loss of local control is clinically identified with SIRS -systemic inflammatory response syndrome - which subsequently evolves toward MODS -multiple organ dysfunction syndrome, which will not be detailed here. Most times, newly diagnosed uroperitoneum cases are comprised in the above mentioned situations. Finally, in serious and delayed treatment cases, multiple organ dysfunction becomes a sombre entity called CHAOS (Cardiovascular shock, Homeostasis, Apoptosis, Organ dysfunction, immune Suppression), with minimal chances of survival [, ]. Symptoms of vesical trauma and namely of urinary peritonitis are not specific. In the case of a pathological bladder, a surprising discordance may appear between the low force of the injury agent and the emergence of vesical lesions (a minor trauma may determine lesions of maximum gravity). Some other times, the tear of vesical wall is distanced from the moment of the accident, representing the so-called 'two-stage vesical rupture' (a temporary obstruction of the lesion with omentum or intestinal loops which determines tardy solution of continuity). The presence of sterile urine in the peritoneal space can be tolerated for many days, with faded, inconclusive local symptoms. In this situation, alteration in general wellbeing and imbalance of electrolytes are more obvious etc. Perforations and ruptures of urinary bladder usually begin with a violent pain, located in the pelvis or the perineum and are relatively constantly accompanied by vesical and rectal tenesmes. If urine emission continues to be spontaneous, it is accompanied by polakiuria, dysuria, haematuria, painful urine emission which is also weak, discontinuous and with a sensation of incomplete evacuation. In principle, the manifestations of uroperitoneum can be organised into the following symptoms and signs, one or two being present in common practice, thus making diagnosis difficult: actual signs of hypogastric lesions (excoriations, haematomas); hypogastrium pain due to trauma; increase of abdomen volume, a consequence of urine accumulation in the peritoneal cavity (ascites); intraperitoneal fluid can be perceived by percussion, inspection and palpation of the abdomen; muscle contraction situated at first in the pelvis takes over the entire superior abdomen; abdominal pain irradiating to the shoulder, consecutive to urine accumulation under the diaphragm, with subsequent irritation of the phrenic nerve (Kehr sign); peritonitis signs in the first hours after vesical tear if urine is highly infected (purulent) or after a few days if urine is initially sterile; abdominal distension caused by paralytic ileus which installs slowly and aggravates itself continuously; partial or complete ceasement or urine emission, with a slow, passive flow of urine in the peritoneum; peritoneal irritation signs on rectal exam; The diagnosis is, as we mentioned before, pretty difficult because the uroperitoneum is a hidden disease, with tardy manifestations most of the times. Diagnosis is based on traumatic history (pelvic fracture for example associates vesical tears in 90% of cases), previous endoscopy manoeuvres and their juxtaposed pathology and presence of more than one of the above mentioned signs. In a book, the only one about this subject published in Romania and also a beginning of trade cornerstone for experienced surgeons - 'Surgical exploration of abdomen' by Dr. Dan Gerota (Medical Publishing House 1969, first edition, page 70, same publishing house 1987, second edition) - the unsurpassed surgeon and teacher pointed out: 'Other effusions (peritoneal effusion, authors note) are rarely encountered and more difficult to diagnose, especially urine, when mixed with blood or in low quantity (the case of urether lesions). Even in the case of a vesical lesion, if empty during trauma, in the case of little continuity fluid, with outlet or situated in an extraperitoneal area, we encounter the same difficulties.' reno-vesical radiograph does not bring many information but can show pelvic bones fractures and eventually detect an area of increased density in the hypogastrium or pelvis consecutive to the accumulation of urine or blood; intravenous urography shows morphological and functional integrity of the superior urinary tract and vesical rupture will appear in late stages or on the cystograms by contrast substance effusion in the peritoneal cavity; retrograde cystography is possibly the most important diagnostic method of vesical rupture and consists in the instillation of a certain quantity of contrast substance in the urinary bladder by means of an urethral-vesical catheter; many films can be obtained, in many views that will show the effusion of contrast substance among intestines; abdominal ultrasonography shows fluid accumulation in the peritoneal cavity, similar to ascites fluid; abdominal and pelvic CT and MRI show the presence of fluid in the peritoneal cavity and if they are done with contrast substance, its effusion can be observed when it reaches the urinary bladder (Figure 3) Information offered by ultrasound and imaging explorations are doubtful and most often the interpretation offered by our specialist colleague is charged with a high, subjective and lacking involvement dose (caused for example by 'the presence of air in between loops, numerous artefacts' and so on). In the case that we presented their help was minimal at most. Urethral cystoscopy is not recommended because the risk of aggravating the lesions is high (washing fluid will effuse in the peritoneum and become an additional factor of infection). If the manoeuvre is done nonetheless, the actual lesion, where intestinal loops or parts of the epiploon enter, can be seen inside the bladder.

PMC153487_01

Female

A 40 years old female patient was admitted with chronic arthritis. Her complaints have begun with swelling and pain on left wrist, eight years ago. At the peak stage of her complaints, restriction of motion developed and white coloured pus drained from volar site of the left hand. She had swelling and pain at her left ankle a year ago. Six months ago her left ankle was twisted. As a consequence, she had difficulty in walking. She did not define fever. She had night sweats during the last 4 months. Additionally, she detected a mass at her left breast 3 moths ago. In physical examination, 3 x 3 cm sized mobile and painless mass was detected at the left breast. Left wrist motions were restricted and painful; two scar lesions were present at volar site probably due to the previous drainage that took place in the history. Left ankle was swollen and painful. Through the follow up, she had night sweats but did not have any fever. Laboratory examination results were: ESR was 70 mm/h, WBC 6700/mm3, Hb 12.2 g/dl, platelet 231000/mm3, CRP 48 mg/dl (normal range <5). The outcome of biochemical tests and urine analysis were normal. Chest x-ray was normal. PPD (5 Todd unit) was performed and 35 mm of induration was measured. Left wrist x-ray showed bone destruction at distal ulna, radiocarpal and intercarpal bones (Figure 1). Periarticular osteoporosis was seen at left ankle x-ray. Magnetic resonance imaging (MRI) demonstrated effusion and contrast enhancement at tibiotalocalcaneal joint and osteomyelitis at talus and calcaneus (Figure 2). Mammography and ultrasonography showed a mass consisted of solid and a cystic component, which was measured to be 30,6 x 22,9 mm in diameter. Synovial biopsy from left ankle and excisional biopsy from left breast were performed. Histopathological examination revealed caseous and granulamatous infection compatible with TB. These samples were cultured in Lowenstein-Jensen culture media and growth was observed at the 4th week. The isolated strains were sent to the national reference laboratory (Refik Saydam Hifzissihha Laboratory, Ankara, Turkey) for confirmation and susceptibility test, and both of them were defined as Mycobacterium tuberculosis. It was reported susceptible to rifampin (RMP), isoniazid (INH), ethambutol (EMB) and streptomycin (STM). INH (300 mg/d), RMP (600 mg/d), PZA (3 gr/d) and STM (1 gr/d) were given for treatment. At the 4th week the patient was improved and discharged. After two months, the therapy was continued with INH and RMP up to 9 months. After the cessation of therapy, in one year follow up the patient did not have any evidence of recurrence.