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PMC7276389_01

Female

A 29 years old female, physician by profession presented to the emergency department with a history of aggressive vomiting five weeks back followed by left upper abdominal, a single episode of loose motion, subcostal pain radiating to left shoulder associated with shortness of breath (SOB) and was unable to take full inspiration. The patient has a history of heartburn, early satiety, indigestion, and food regurgitation six years ago and diagnosed and managed as gastroesophageal reflux disease in her native country. The primary evaluation shows a toxic looking afebrile patient with vitals as; respiratory rate-27/min, pulse 87/min. Along with first-level management, abdominal ultrasonography (US) and initial laboratory workup were done in ED with no abnormal findings and the patient discharged home after the primary management independently and not asking surgeon on-call help. Upon no improvement, the patient revisited the ED where chest x-ray (CXR) as primary imaging modality was requested by surgeon on-call that showed raised right hemidiaphragm with no well discernible outlines, air-filled bowel loops above the hepatic shadow, a chilaiditi's sign, with no mediastinal shift (Fig. 1a), thus a provisional diagnosis of the right-sided diagrammatic hernia was made. Following CXR, a non-contrast CT requested showing stomach and parts of the colon in the right thoracic cavity (Fig. 2a) along with spleen located posterior to the heart - the retrocardiac spleen (Fig. 2b), thus a final diagnosis of Bochdalek hernia was made. Severe vomiting, a few weeks earlier was the triggering event in the patient that led to the initiation of the clinical picture. After initial stabilization, the patient was transferred to a regional tertiary care facility for cardiothoracic surgeon evaluation and management where via open thoracotomy, contents reduced and fortunately there was no vascular compromise. Repair done. Post-operative chest x-ray shows normal findings (Fig. 1b). The patient had uneventful recovery and discharged home on 10th post-operative day. The patient did well in her follow-up period. To the best of our knowledge, it is the first reported case of Bochdalek hernia associated with the retrocardiac spleen in an adult female in the published literature.

bochdalek, diaphragm, emergency care, hernia, physician, retrocardiac, spleen

PMC6288572_01

Male

A 53-year-old male, smoker (20 pack-years), occasional alcoholic, presented with complaints of blood expectoration of 400 ml in one episode followed by 100-150 ml for 2-3 days. He had 3 episodes of similar history which required hospitalizations and emergency care since 9 months. He denied history of fever, chest pain, and loss of appetite. He underwent cholecystectomy 3 years ago. There was no history of systemic immune suppression like diabetes. He had undergone bronchial artery embolization for massive haemoptysis; however, his haemoptysis persisted and diagnosis remained elusive after evaluation with sputum studies and CT-guided aspiration cytology, biopsy, and bronchoscopic lavage. He was treated for LRTI with multiple courses of antibiotics for more than 9 months. On examination, vitals were normal with no respiratory distress. Oral hygiene was poor with dental caries. Respiratory examination revealed scattered crackles in the left lower lobe area. Chest X-ray showed an inhomogeneous opacity in the left lower zone with raised left diaphragm (Figure 1), and CECT (contrast-enhanced computer tomogram) chest showed a hypodense lesion with irregular margins in the anterior segment of the left lower lobe adjacent to the descending aorta and associated subcarinal lymphadenopathy (Figures 2 and 3). Image-guided transthoracic biopsy showed type 2 alveolar cell hyperplasia with negative immunohistochemistry. Bronchoscopy confirmed left lower lobe bleed with any endoluminal lesion. Bronchial wash was negative for microbiological and cytological studies including AFB stain, geneXpert for MTB complex, and pyogenic culture. Patient's symptoms of haemoptysis persisted; hence, CT angiogram was performed, which showed dilated vascular channels within the lesion without any obvious extravasations of contrast and no aortic abnormality. Probable diagnosis of the left intrapulmonary vascular lesion was made and hence the patient underwent left lower lobe lobectomy. Intraoperatively, the left lower lobe was adherent posterolaterally to the aorta and diaphragm. Multiple prominent blood vessels in areas of adhesion were seen. Histopathology was suggestive of chronic inflammatory cells with focal aggregates of lymphocytes with positive GMS staining for actinomycosis (Figure 4). Postoperatively, the patient received parenteral benzylpenicillin 20 lakh units 6th hourly for 3 months. The patient was in regular follow-up, and no further episodes of haemoptysis and no recent respiratory complaints are reported.

PMC9869191_01

Female

The patient was a 36-year-old female. The left side chest pain occurred more than 1 month ago and continued to deteriorate for 10 days. She had repeated pulmonary infection, accompanied by cough and expectoration. Her maximum temperature was 38.5 C, without chest tightness and dyspnea. Physical examination: the chest was barrel shaped, and no definite abnormality was found in chest auscultation and palpation. Cardiac examination was normal. The laboratory test of human immunodeficiency virus (HIV) was negative, and there was no contact history of tuberculosis. The patient's abdominal CT plain scan showed no obvious abnormality. The lung window in axial and sagittal position of multi-detector spiral CT showed that the bilateral basal lung isthmus was connected, extending behind the pericardium and crossing the midline for fusion. The left lower lung basal segment had sparse lung markings, with increased transparency, and patchy shadows could be seen near the spine at the bottom of both lungs. There was an obvious pleural interface between the isthmus and the left lung (arrow) (Figures 1 and 2). Transparent imaging (Figure 3) showed the isthmus lung tissue among the lungs (arrow). The three-dimensional volume-rendered imaging of the bronchus (Figure 4) showed that the bronchial branches of the lower lobe of the left lung were thinner than those of the right side. Cystic changes could be seen at the beginning of the lower lobe of the left lung. The outer and posterior basal segments of the lower lobe of the left lung fused at the beginning, and the distal branches were sparse. Thoracic CT angiography scanning (Figures 5 and 6): consolidation shadow could be seen in the basal segment of the lower lobe of both lungs, with the left lung as the focus, and multiple calcified nodules could be seen in it. The blood supply arteries of bilateral lesions directly originated from the adjacent trunk of thoracic aorta (arrows).

cta, horseshoe lung, adults, pulmonary sequestration

PMC3108731_01

Male

A 41-year-old male was admitted to the hospital with symptoms of diarrhea, fever, dyspnea and right pleural effusion. The illness began in the latter part of August 2008, initially presenting with diarrhea and fever. He was an MSM and the serology for HIV antibody was positive. He had no history of traveling abroad, alcoholism, any medication or intravenous drug use. His vital signs on admission were; conscious, blood pressure 95/60 mmHg, pulse late 146 beats/min, respiration, 45 breaths/min, saturation O2 (room air), 88% and body temperature 39 C. The notable findings of a physical examination included emaciation (BMI 16.1), oral candidasis and decreased breath sounds on the right side of his chest. A chest radiograph and computed tomography (CT) of the chest showed a large amount of right pleural effusion (Figure 1). A CT scan of the abdomen detected large liver abscess (Figure 2). The laboratory data included a leukocyte count of 10,320/muL with 89% neutrophils, 8% lymphocytes, 3% monocytes, hemoglobin 8.8 g/dL, C-reactive protein 23.6 mg/dL, aspirate aminotransferase 95 U/L, alanine aminotransferase 74 U/L, alkaline phosphatase 478 U/L, gamma-glutamyl transpeptidase 134 U/L, albumin 2.1 g/dL, total cholesterol 57 mg/dL, blood urea nitrogen 18.4 mg/dL, creatine 0.57 mg/dL and hyponatremia (123 mEq/L). The findings of human immunodeficiency virus type 1 antibody tests were positive for enzyme immunoassays (EIA) and also based on the Western blot method. Thoracentesis revealed milk chocolate or cafe au lait colored pleural fluid (Figure 3). In an examination of the pleural fluid, cytology, bacterial culture, smear and polymerase chain reaction to detect Mycobacterium tuberculosis DNA were negative, the adenosine deaminase activity was 240 IU/L. The pleural fluid showed a cell count of 40125/mL (74.3% neutrocytes, 25.7% monocytes). Other examinations of the laboratory findings detected cysts of Entamoeba histolytica in the patient's stool. The CD4 lymphocyte count in the peripheral blood was 179/muL (repeated counts for CD4 lymphocytes ranged from 286 to 359/muL) and the amount of HIV-RNA was 3700 copies/muL (repeated counts for HIV-RNA ranged from 43,000 to 90,000 copies/mL). Although E. histolytica was not identified from the pleural fluid, antibodies (fluorescence antibody technique) against E. histolytica were demonstrated in the serum (200x). The patient was thus diagnosed to have amoebic colitis, amoebic liver abscess and amoebic empyema complicated with an HIV infection. The right side pleural effusion was drained using a chest tube and he was administered metronidazole (2250 mg/day) orally for 28 days in total. A large volume of pus was drained from the right thoracic space. A small volume remained. The right lung was re-expanded. His fever, dyspnea and general condition significantly improved thereafter. The patient was therefore administered trimethoprim-sulfamethoxazole to prevent pneumocystis pneumonia and itraconazole to prevent fungal infections. However, he developed agranulocytosis 22 days after administration. The absolute neutrophil count was 0/muL. Agranulocytosis in this case was therefore considered to have been caused by the administration of trimethoprim-sulfamethoxazole. After the discontinuation of trimethoprim-sulfamethoxazole, the recombinant human granulocyte colony-stimulating factor (G-CSF) drug filgrastim was administered daily at a dose of 200 mug/m2 intravenously. Following 4 days of treatment with G-CSF, the patient's absolute neutrophil count was above 9/muL, while after 7 days of treatment it was 2990/muL (white blood cell count 4600/muL, neutrophils 65%). The patient did not demonstrate any further infection during the clinical course. He was discharged 45 days after admission.

hiv, agranulocytosis, amebiasis, amoebic empyema, trimethoprim-sulfamethoxazole

PMC6396444_01

Male

We present the case of a 26-year-old male who is referred to the digestive consultation by two episodes of spontaneous paraesophageal abscess in an interval of 2 years. It is a patient with no pathological history of interest that is presented in the Emergency Service for dysphagia for solids of 3 days of evolution that at the same time was suffering stabbing chest pain and fever of up to 38.8 C in the last 24 h. In the last year the patient had already been in the Emergency Room (ER) twice for chest pain with non-altered complementary tests. The patient denies having any traumatic history or onset of symptomatology after food impaction. The physical examination shows no abnormality on a hemodynamically stable patient. It is performed a blood test showed a C reactive protein (CRP) 190 mg/L (Normal values 0-5 mg/L), and white blood cells 12,000/muL (Normal values 4000-10,000). For that reason it is decided to perform thoracic-abdominal computed tomography (CT), where a collection of 8 x 4 x 5 cm is displayed in the third inferior-posterior of the esophagus compatible with hematoma vs mediastinal abscess (Fig. 1). The surgery service is contacted and it is decided to choose the conservative treatment with broad-spectrum antibiotics and absolute diet. During the admission, a echocardiogram with normal results was performed, an esophagogram that does not present alterations and a gastroscopy, where a linear ulcer of 5 mm in distal third of esophagus with biopsy that shows granulation tissue was found. The patient is discharged 7 days after, with the normalization of his analytical and clinical parameters, and showing a correct oral tolerance for later control in consultations. An outpatient USE is requested 3 weeks later, after being discharged, where no paraesophageal collection is displayed. Gastroscopy was repeated where the esophageal ulcer is not visualized and biopsies are taken from the distal and proximal esophagus. In those biopsies, it is noticed an eosinophilic inflammatory infiltration of 40 eosinophils per field. The patient does not attend any control, so no treatment is started. One year later the patient returns to the emergency department with chest pain and dysphagia with same characteristics, and elevation of CRP and white blood cells. Again, a toraco-abdominal CT is performed, objectivizing mediastinal collection in the same location as 1 year before, with a size of 7 x 4 x 4 cm, compatible with abscess, which is retreated in a conservative manner with broad spectrum antibiotics. After 10 days, a CT control confirms resolution of the collection. Ambulatory gastroscopy is performed with biopsy-taking by objectivizing an eosinophilic inflammatory infiltrate compatible with eosinophilic esophagitis. The patient denies dysphagia, chest pain, heartburn or any other clinic between episodes of mediastinal abscess. It starts treatment with proton pump inhibitor in double doses during 8 weeks, persisting the eosinophilic inflammatory infiltrate in the biopsies. It is agreed a diet with the patient where two foods will be removed (milk and wheat), obtaining histological remission, and identifying the milk as the cause of the inflammation. After 2 years of follow-up, the patient maintains milk and derivatives restriction, and has not shown again any episodes of mediastinal abscess.

eosinophilic, eosinophilic esophagitis, esophagitis, mediastinal abscess

PMC9302883_01

Male

The patient, a 21-year-old Uygur male, had a history of fever and diarrhea for 8 days, with the highest body temperature of about 38.6 C, accompanied by chills, and sparse watery stool several times, without abdominal pain. Due to the intermittently increased temperature after taking non-steroidal anti-inflammatory drugs (NSAIDs), the patient was treated in the fever clinic but got a poor treatment effect, therefore he was admitted to the emergency department on October 10, 2021. Physical examination on admission showed a body temperature of 38 C, pulse of 102 times/min, respiration of 23 times/min, and blood pressure of 125/72 mmHg, with clear consciousness, palpable spleen under the ribs. No other significant abnormalities were found in other physical examinations. Emergency laboratory analysis in the emergency department indicated the following: white blood cell count decreased from normal range to 1.56 x 109/L (reference value, RV 3.5-9.5 x 109/L), hemoglobin was 166 g/L (RV 130-175 g/L), platelet decreased from normal range to 74 x 109/L (RV 125-350 x 109/L), aspartate aminotransferase was 150u/L (RV 15-40 u/L), lactate dehydrogenase was 1249 u/L (RV 109-245 u/L), triglyceride was 2.29 mmol/L (RV 0.45-1.7 mmol/L), sodium was 124.2 mmol/L (RV 137-147 mmol/L), fibrinogen decreased from normal range to 1.27 g/L (RV 2-4 g/L), sCD25 was 25,398 pg/mL (RV < 6,400pg/mL), ferritin was 3671u g/L (RV 30-400ng/mL), natural killer cell activity was 18.48% (RV >= 15.11%). G-test (serum (1,3)-beta-D-glucan test) was positive, GM-test (galactomannan test) was negative, and blood culture, procalcitonin, c-reactive protein, erythrocyte sedimentation rate and T-SPOT.TB test were all negative. Mycoplasma pneumoniae antibody IgM (Passive Particle Agglutination, FUJIREBIO) was 1:80 positive (RV < 1:20), Legionella pneumophila antibody IgM (ELISA, Euroimmun) was 0.82 positive (RV < 0.8). The detection of Cytomegalovirus (CMV), Epstein Barr virus (EBV), Adenovirus and Coxsackievirus were all negative (real-time PCR). The oncological and immunological indexes were normal. Plain CT scan of the thoracoabdominal basin showed mild fatty liver and splenomegaly (Figure 1). There are many small lymph nodes in the hepatogastric space and retroperitoneal space. Referring to HLH-2004 diagnostic criteria, the patient met the following conditions: (1) Temperature > 38.5 C for more than 7 days; (2) Hemocytopenia (WBC <10 x 109/L, PLT <100 x 109/L, hemoglobin 166 g/L); (3)Splenomegaly; (4)Low fibrinogen (FIB <1.5 g/L) and high triglycerides (2.29 mmol/L), although not meeting the diagnostic criteria (3 mmol/L); (5)Ferritin > 500u g/L;(6)sCD25 > 6,400 pg/mL. Considering the definitive diagnosis of HLH, the patient was treated with 20 g immunoglobulin QD (8 days) and 0.5 g imipenem cilastatin sodium Q8H, and his leukocytes, platelets, and fibrinogen gradually returned to normal levels. However, on day 14 after his onset, the patient developed a series of symptoms of peripheral nerve involvement, as shown in Table 1. Lumbar puncture was performed on the 16th day. Cerebrospinal fluid showed a low pressure and turbid appearance, containing 150 white cells/muL (90% lymphocytes, 10% neutrophils), protein 1.09 g/L, glucose 2.37 mmol/L, and chlorine 100.6 mmol/L; Bacteria, fungi, cryptococcus, and Mycobacterium tuberculosis were all negative; Rubella virus, CMV and EBV IgM antibody and DNA were later reported as negative. CSF and serum albumin data: CSF and serum albumin was 3.27 and 37 g/L, respectively (October 19); while 1.09 and 32.6 g/L, respectively (October 22). The albumin quotient (albumin in CSF/albumin in serum) indicated that an increased permeability of the blood-brain. No abnormality was found in CSF next-generation sequencing technology (NGS) implemented by Biotechnology Co., Ltd. Briefly, they optimized the internal index adapter and real-time analysis pipeline, established the optimal threshold for pathogen identification, and performed rapid metagenomic-NGS analysis. Peripheral neuropathy, demyelination, paraneoplastic tumor, autoimmune brain-related antibodies, serum antibodies IgM and IgG of C. jejuni were positive by enzyme-linked immunosorbent assay (ELISA), performed by Dr. Hao from the first hospital of Peking University, The values of IgM and IgG were greater than the negative control values (the cut-off values were 0.08 and 0.16 respectively) even after 1:160 dilution. Given the clinical presentation and CSF findings, based on intravenous dexamethasone of 20mg QD, the treatment regimen was adjusted to meropenem 1000 mg Q8H combined with acyclovir 60 mg Q8H and Mecobalamin 500 ug QD. On the 18th day, the patient's body temperature dropped to normal. On the 19th day, the lumbar puncture was performed again, and the cerebrospinal fluid became clear. CSF laboratory examination showed white blood cell count of 91/muL (92% single nucleus, 8% multiple nuclei), protein level of 3.27 g/L, normal glucose and chlorine, as well as negative NGS. Electromyography (Table 2) and cranial MRI were generally normal. Considering the peripheral nerve injury and cerebrospinal fluid protein cell separation, GBS secondary to C. jejuni infection was specifically classified as Miller Fisher syndrome (MFS) and Bickerstaff brainstem encephalitis. On the 23rd day of onset, the diameter of the right pupil gradually recovered to 4 mm the pupillary light reflex, and the closing function of the right upper eyelid gradually recovered. On the 26th day, dexamethasone was reduced to 10 mg QD. On the 27th day, the left pupil diameter recovered to about 4 mm, and the pupillary light reflex recovered. On the 28th day, the patient defecated autonomously. On the 41st day, spontaneous urination recovered, and the patient was hospitalized for 42 days. Before discharge, the patient had left bilateral facial paralysis and mild diplopia in both eyes. One month after discharge, the patient was followed up, leaving slight facial paralysis, and other symptoms returned to normal.

campylobacter jejuni, guillain-barre syndrome, facial paralysis, hemophagocytic lymphohistiocytosis, ophthalmoplegia, peripheral nerve injury

PMC10323808_01

Female

A 62-year-old female renal transplant recipient was admitted to hospital on 20 August 2021, with a 5 week history of recurrent fevers and progressive dry cough without haemoptysis or dyspnoea. She did not report any unintentional weight loss, night sweats, fatigue or altered mentation. She had no recent sick contact exposures (including no prior risk of exposure to tuberculosis) or significant travel history. Her past medical history included deceased donor renal transplant in October 2012, stable on tacrolimus and mycophenolate mofetil without any history of rejection. Other medical and surgical history included workup for chronic hypophosphataemia and hypocalcaemia requiring weekly electrolyte replacement infusions via Groshong line (inserted March 2021), prior hemicolectomy for diverticular disease and parathyroidectomy. On examination, she was haemodynamically stable with blood pressure of 151/67, pulse rate of 69 beats min-1 and body temperature of 36.8 C. Lung auscultation was normal without any bilateral adventitious sounds, and cardiovascular examination did not reveal any murmurs or other stigmata of infective endocarditis. Groshong line site did not demonstrate purulent discharge or overlying cellulitis. Laboratory investigations showed a peripheral white blood cell count of 5.1x109 l-1 (normal range 4.5-11.0x109 l-1) with a neutrophil count of 3.4x109 l-1 (normal range 2.0-8.0 x 109 l-1). Inflammatory markers were elevated with C-reactive protein of 23.2 mg l-1 (normal <3.1 mg l-1). Chest radiograph followed by whole-body computed tomography (CT) scan revealed multifocal ground-glass opacities suspicious for pulmonary septic emboli, without cavitary lesions (Fig. 1). Transthoracic and subsequent trans-oesophageal echocardiography were negative for vegetations or haemodynamically significant valvular dysfunction. In the context of recurrent fevers occurring in temporal relation to weekly electrolyte infusions, outpatient blood cultures were initially obtained 2 weeks prior to admission and Gram-positive bacilli were only isolated from the aerobic bottle. The patient was initiated on intravenous (IV) vancomycin. Questions remained as to whether the positive blood culture was attributable to contamination and initially the organism was not identified using MALDI-TOF VITEK MS V3 (bioMerieux, Marcy L'Etoile, France). Subsequent repeat blood cultures collected both from peripheral draw and tunnelled Groshong line over a 2 week period continued to isolate Gram-positive bacilli only in aerobic bottles (Figs 2 and 3). The organism showed beige, non-haemolytic colonies that were mucoid in appearance and adherent to media, catalase-positive and partially acid-fast. In our local microbiology laboratory, API Coryne system (bioMerieux, Marcy L'Etoile, France) gave an identification of Rhodococcus spp. Inoculum was prepared from blood agar after incubating the isolate for 3-5 days at 35 C (+/- 2 C), with suspension made to 0.5 McFarland standard. The minimum inhibitory concentrations (MICs) were determined using E-test gradient strip (bioMerieux, France) as part of non-standardized susceptibility testing for this isolate. Findings were interpreted as per Clinical and Laboratory Standards Institute (CLSI) M24. The results showed susceptibility to amoxicillin/clavulanate, azithromycin, ciprofloxacin, linezolid, penicillin and vancomycin; it was intermediate to doxycycline. Hence, oral ciprofloxacin 500 mg twice daily was added to the patient's regimen on the third day of admission as combination antimicrobial therapy. As her Groshong line was the suspected source of bacteraemia, it was subsequently removed and the catheter tip bacterial culture isolated Gram-positive bacilli after 4 days of incubation. Repeat blood cultures after 5 days of antibiotics (1 day post-line removal) were negative.

16s rrna, actinomycetes, gordonia, central line-associated bloodstream infection

PMC9273775_01

Male

Both the patient, a 19-year-old male who was previously healthy, and his father had weakness of the left eyelid muscle (Figures 1, 2), although their vision was normal. The patient's mother and sister were in good health. After lifting heavy objects, the patient presented with intermittent distending pain and discomfort in the right inguinal region, he did not pay attention to these symptoms and did not seek medical treatment. As the patient's symptoms worsened, a right inguinal hernia was suspected and diagnosed by the family doctor but was not treated further. 2 days later, there was skin itching in the right inguinal area, accompanied by redness, swelling and discomfort of the right scrotum, and he went to the local hospital again. Ultrasound examination showed that a contusion of the right testis may have been complicated with orchitis (no specific medical data). Rest was recommended. The pain was not relieved by oral levofloxacin but resolved on its own 3 days later; nevertheless, it became aggravated and unbearable after exercise. At the same time, the scrotal swelling had significantly increased. He came to the emergency room of our hospital, where a plain CT scan showed scrotal enlargement of unknown cause. Upon admission, the right scrotum was obviously enlarged and tender. It had a high surface temperature, normal skin color, negative scrotal elevation test, negative light transmission test, normal sex hormones and normal tumor markers (including Alpha-fetoprotein, chorionic gonadotropin, carbohydrate antigen-199, carbohydrate antigen-125, serum ferritin, and carcinoembryonic antigen). After admission, the patient was treated with levofloxacin, but the pain was still not relieved. On the second day after admission, ultrasound showed heterogenous echo of the right testis. Considering the possibility of inflammatory lesions, neither testicular tuberculosis nor a tumor could be ruled out. A plain + enhanced abdominal CT scan suggested that inflammatory lesions of the testis with necrosis were possible. In addition, there were some secondary changes in the spermatic vessels, and the spermatic vessels could be seen more clearly (Figure 3). After communicating with the patient and his family, he gave informed consent for exploration of the right scrotum, which was performed under general anesthesia. We made a right groin incision and cut the skin subcutaneously and each layer of muscle in turn, exposing the spermatic cord. We observed hyperaemia and oedema of the spermatic cord blood vessels and surrounding tissue. We rotated the testis approximately 90 degrees, lifted the testis out of the scrotum, opened the testicular sheath, and observed a small amount of bloody fluid within. We opened the tunica albuginea, where we observed a large amount of bloody fluid and a fish-like tissue bulge. The whole testicular boundary was unclear, the epididymis was enlarged, and the tunica albuginea had a visible tear of approximately 1.5 cm in length (Figure 4). Radical orchiectomy was performed on the right side, the spermatic cord was resected in a high position, and the incision was sutured step by step. Haematoxylin-eosin staining (Figure 5). Immunohistochemistry results: Desmin (partly +, Figure 6), SMA (-), MyoD1 (+, Figure 7), Myogenin (+, Figure 8), CD34 (1), STAT-6 (1), S-100 (-), SOX-10 (-), CK (-), EMA (-), TLE1 (-), Ki-67 (80%+, Figure 9). The pathological diagnosis was rhabdomyosarco-ma of the right testis. The postoperative chromosome karyotype analysis showed that there was no Y chromosome microdeletion. Positron emission tomography (PET) examination showed no systemic metabolic abnormalities and no systemic metastasis. These findings suggested that the patient should be treated with a VAC regimen (vincristine, doxorubicin, cyclophosphamide). The patient refused further systemic treatment for personal reasons and is currently under follow-up.

case report, rhabdomyosarcoma, spontaneous rupture, testis, unilateral ptosis

PMC10415754_01

Male

A 31-year-old man with a past medical history of intravenous drug use (IVDU), specifically heroin and cocaine, and untreated hepatitis C virus infection presented to the emergency department for the evaluation of chest pain. The patient's chest pain began approximately 5 days prior to presentation as a sharp, non-radiating, persistent pain, which was worse with inspiration and on movement. The pain progressed to 10/10 in intensity below the nipples bilaterally. Our patient endorsed exertional dyspnea mostly because of the inability to inspire without significant pain and subjective fever. He also reported worsening cough productive of light green sputum and, at times, a scant amount of blood. Moreover, approximately a week prior, the patient missed a vein while injecting the drug in the right side of his neck which led to swelling and redness of the area. The remainder of the review of systems was noncontributory. As for his past medical history, our patient reported being informed he was positive for hepatitis C 10 years prior, but he did not seek treatment nor did he follow up with medical providers for the same. The patient has a smoking history of 15 pack years and has been injecting "speedball", a mixture of cocaine and heroin, almost daily for the last 10 years. Our patient reported using "a bundle and a half" of heroin together with "few grams" of cocaine in powder form with water daily. When the patient was not able to acquire cocaine, he used crack which comes in solid "rock" form. He reported crushing the rock form and diluting it with vinegar. He heated the mixture after filtering through cotton-wool before injecting himself using a syringe. The patient generally uses his neck and left arm veins to inject drugs. Our patient used the same syringe for up to a month. He reported that, at times, the needle tip would break off in tiny fragments and it would become difficult to acquire access through it. The patient's last use of these drugs was the day of admission. Our patient admitted to being homeless and has been living on the streets for the last 3 years. Initial vital signs demonstrated a temperature of 98.7 F, pulse of 135/min, respiratory rate of 19/min and blood pressure of 108/72 mmHg. He appeared to be in mild distress, with poor inspiratory effort due to pain. Physical examination was significant for poor dentition including a few chipped and missing teeth but no oral lesions or thrush. There was an area of erythema, induration and tenderness on the right side of the neck, about 4 x 10cm in size. Lungs were clear to auscultation bilaterally. Cardiac auscultation revealed normal S1 and S2, with no murmurs, rubs or gallops. Examination of the extremities revealed track marks on left antecubital fossa and onychomycosis of the nail beds. Stigmata of bacterial endocarditis were not seen. Initial laboratory data was significant for a normal white blood cell (WBC) count of 8.5 K/muL, hemoglobin of 10.2 gm/dL and platelet count of 106 K/muL. The patient's mean corpuscular volume (MCV) was 73.6 fL, with red cell distribution width of 15.3%. Serum sodium was 129 mEq/L, with otherwise unremarkable basic metabolic panel. Serum lactic acid was 1.2 mmol/L (normal 0.5-2.2 mmol/L) and D-dimer was 1197 ng/mL (normal 0-230 ng/mL). Erythrocyte sedimentation rate (ESR) was 95 mm/hr (normal 0-15 mm/hr) and C-reactive protein (CRP) was 15.2 ng/dL (normal <1.0 ng/dL). Urine drug screen was positive for cocaine and opiates but negative for amphetamines. Chest X-ray indicated a patchy increased density in the left lower lobe, lingula, and right middle and lower lobes (Fig. 1). Given a significantly elevated d-dimer in the setting of tachycardia, CT angiography of the chest was performed which excluded pulmonary embolism. However, multiple, fluffy, nodules of varying size and ill-defined margins were seen throughout both lungs (Fig. 2). Some of these nodules were cavitary. Larger coalescent areas were seen in the left lower lobe and the lingula. These findings were concerning for septic emboli or metastatic disease. As a result, CT abdomen and pelvis with contrast was performed which did not show any masses. The only finding was splenomegaly, measuring 18cm in length. Furthermore, given the findings of tenderness on the right side of the neck, CT of the neck with contrast performed to exclude septic jugular vein phlebitis or Lemierre's syndrome was unremarkable. Meanwhile, blood cultures were drawn and our patient was empirically administered intravenous (IV) Vancomycin 1 g and Piperacillin-Tazobactam 3.375 g. Emergent transthoracic echocardiogram (TTE) was performed which did not show valvular vegetation or abscess. Given a high suspicion of bacterial endocarditis (BE), trans-esophageal echocardiogram (TEE) was performed which also did not show any vegetations or abscess. Piperacillin-tazobactam was changed to IV Cefepime 2 g every 12 hours. IV Vancomycin was continued to achieve a therapeutic vancomycin trough level. Pulmonology was consulted and, based on the findings on high resolution CT scan of the chest (Fig. 3), the decision was made to perform navigational bronchoscopy to obtain endobronchial and transbronchial lung biopsies. Specimens were obtained from the right lower lobe using a needle biopsy, and near the pleura using the forceps. A few specimens were also obtained using triple needle brush. In addition, specimens from bronchial washings were sent for cytologic analysis, routine cultures, acid-fast bacilli (AFB) culture and fungal culture. Additional diagnostic evaluation included HIV testing, QuantiFeron TB, hepatitis panel, rapid plasma reagin (RPR), antinuclear antibody (ANA), anti-double stranded DNA (DsDNA) antibody, anti-glomerular basement membrane (GBM) antibody, anti-neutrophil cytoplasmic antibody (ANCA) and complement levels. Results were unremarkable. Histopathology report of right lower lobe biopsy specimen was normal with no mononuclear infiltration. A brush tip specimen was also obtained from right lower lobe. Moreover, approximately 55 cc of thick pale orange fluid was obtained via bronchial wash of right lower lobe which showed scattered refractile material surrounded by dense neutrophilic and mononuclear infiltration (Fig. 4, Fig. 5). Gomori methenamine silver (GMS) stain for Pneumocystis jirovecii was negative. The patient's maximum temperature was 100.1 F five days after the admission on antibiotics. The patient's heart rate normalized to 70-90/min and WBC count remained in between 6 and 8 K/muL throughout admission. The patient's chest pain improved over the course of days but mild discomfort with breathing persisted. Blood, respiratory and bronchial wash cultures for bacteria, AFB and fungi remained negative. Because of ongoing concern for bacterial septic emboli, the patient was continued on IV Vancomycin and IV Cefepime for a total of 6 weeks. The patient completed the final 3 weeks of antibiotics at a sub-acute facility.

ntpe, nonthrombotic pulmonary emboli, pwid, patients with injection drug use, septic emboli

PMC9641636_01

Female

A 67-year-old female patient was admitted to the local hospital because of epigastric pain and discomfort for one month. She was diagnosed as a malignant tumor of the gastric body by electronic gastroscopy and biopsy pathology. The abdominal enhanced CT shows multiple lymph nodes enlargement in the abdominal and retroperitoneum in the outpatient clinic of our hospital ( Figures 1A, B ). The patient received six cycles of chemotherapy in another hospital (SOX regimen for 1 cycle; S-1 and oxaliplatin. Paclitaxel, oxaliplatin, S-1, and Sintilimab for 5 cycles). After the end of chemotherapy, the effect of chmotherapy was evaluated as partial remission (PR). The patient asked for surgical treatment in our hospital. Physical examination showed that the abdomen was flat, the abdominal muscles were soft, the upper abdomen was mild deep tenderness, there was no rebound pain, and there was no obvious abdominal mass. Laboratory results showed that hemoglobin content decreased: 97g/L (normal range 110-150g/L). CA72-4:4.90U/mL (normal range 0-6.9U/mL), AFP: 1.30ng/mL (normal range 0-8.1ng/mL), CEA:1.13ng/mL (normal range 0-10ng/mL), CA199:17.71U/mL (normal range 0-37U/mL), CA125:2.85U/mL (normal range 0-30.2U/mL). There was no significant increase in serum tumor markers. After the end of neoadjuvant chemotherapy, we performed a PET-CT examination for the patient. 18F-FDG PET-CT showed that the mass showed changes after chemotherapy, slight thickening of the lesser curvature of the stomach, the mass did not significantly absorb FDG, and it was found that the left axillary lymph node was enlarged, and the mass uptake of FDG increased slightly, but it was considered as an inflammatory lesion ( Figures 1C ). After multidisciplinary tumor consultation, we decided to perform the radical total gastrectomy on the patient, and regular examination of the enlarged lymph nodes in the left axilla. After obtaining the consent of the patient and her family, the patient underwent radical total gastrectomy (Roux-en-Y digestive tract reconstruction) in August 2021. Postoperative pathology showed that the area of ulcerative gastric cancer was about 4 x 3cm. The main tumor cells were poorly differentiated adenocarcinoma, local invasion of the deep muscular layer of the gastric wall, and tumor cells can be seen in the lymphatic vessels but no definite nerve invasion. Lauren's classification was the diffuse type ( Figure 2A ). Only one of the 21 lymph nodes had metastasis, which was located on the lesser curvature of the gastric wall, and no obvious tumor metastasis was found in the rest of the lymph nodes (ypT2N1M0 IIA). Immunohistochemical staining showed that tumor cells expressed CK8/18, individual cells expressed Syn, and did not express CgA, CD56, SALL4, Oct3/4, C-erb-B-2, and Ki-67 proliferative index was approximately 90%. The patient recovered smoothly without obvious postoperative complications and was discharged 13 days after radical total gastrectomy. One month after radical total gastrectomy, the patient found that the left axillary mass grew faster than before and was accompanied by the limitation of left upper limb movement. Physical examination showed that the left axillary mass was about 4 x 2cm in size, hard, had an unclear boundary, and had a poor range of motion. Ultrasound examination of the bilateral breast and axilla showed that there was no obvious mass in the bilateral breast, and several hypoechoic lesions were found in the left axilla, the size of which was about 4.3 x 1.9cm, the boundary was clear, the cortex was thickened, the medulla was eccentric and the blood flow signal was abundant ( Figure 3A ). No obvious abnormality was found in mammary gland molybdenum target X-ray ( Figures 3B, C ), mediastinal and supraclavicular enlarged lymph nodes were not found in CT, and no obvious bone metastasis in whole-body bone scintigraphy ( Figure 3D ). The patient underwent the axillary lymph node biopsy in October 2021. During the operation, the enlarged lymph nodes were located next to the axillary vein, fused into clumps, hard texture, and closely combined with the surrounding tissues. Intraoperative frozen sections showed that there were 5 lymph nodes in the left axilla, and all of them had cancer metastasis. After that, we performed radical axillary lymph node dissection and 14 of the 18 lymph nodes had metastases. Pathology showed that the tumor cells were poorly differentiated adenocarcinoma. immunohistochemical staining showed that most of the tumor cells expressed Caudal-type homeobox 2 (CDX2), CK20, GATA binding protein 3 (GATA-3), and a small amount of sequence-binding protein (SATB) 2 and Mucin-5AC (MUC5AC), but no expression of CK7 and TTF-1 was found ( Figures 2B-E ). After communicating with pathologists, considering the immunohistochemical results and the history of gastric cancer, we considered that the left axillary lymph node tumor was metastasized by gastric cancer. The patient received docetaxel and fluorouracil chemotherapy after radical axillary lymph node dissection, and a progressive increase in CEA, CA19-9, and CA72-4 was found ( Figure 4 ). Three months after the second operation, the MR examination of cervical and thoracic vertebrae due to back pain revealed secondary malignant tumors of the spine, but the patient refused to undergo whole-body bone imaging. CT of the chest and abdomen showed double clavicular and mediastinal enlarged lymph nodes, considering the malignant tumor. But the patient refused any treatment and died 11 months after the second operation.

axillary lymph node metastasis, gastric cancer, immunohistochemical staining, radical total gastrectomy, tumor markers

PMC9463015_01

Female

A 58-year-old patient presented molar and canine Class II relationships on both sides (Figure 1). Maxillary and mandibular interincisal midlines did not coincide. Clinical intraoral examination showed the maxillary arch quite aligned, with mild rotations of the left incisors. On the other hand, the mandibular arch presented a multibraided fixed retainer bonded to all six anterior teeth with the right canine root lingually torqued. The root was exposed, almost revealing the apex, and the element was not vital. Elements 3.2 and 3.3 resulted retroclined, withdiastemas between elements 3.1-3.2 and 3.2-3.3, a 90 rotation of 3.3. Calculus in the fifth sextant, multiple recessions, and restorations were present. A cone-beam computed tomography (Orthophos SL 3D, Sirona, Bensheim, Germany) was performed, confirming the former periodontal findings (Figure 2(a)). The root of the right canine was not covered by cortical bone anymore (Figures 2(b) and 2(c)). Clinicians suggested different solutions to the patient. The first alternative involved the extraction of all lower incisors and the right canine, followed by the placement of dental implants with guided surgery and, finally, a prosthetic rehabilitation. However, this alternative would have not solved the rotation of element 3.3. The second alternative considered every other prosthetic solution without implant placement, but it would have led to treatment failure as extracting lower cuspids would have meant removing the anchor teeth or pillars for the prosthetic rehabilitation. These alternatives were too invasive and radical, in particular, the former alternative could have led to failures and peri-implantitis. The most conservative solution was fixed orthodontic treatment with multibracket appliance aiming at preserving the affected teeth. This option was the least invasive, but it could have been complex from a biomechanical point of view and challenging for the retrieval of the right canine, with poor prognosis. Consequently, after being informed of all risks and having signed an informed consent, the patient chose to undergo orthodontic treatment only for the lower arch. The primary objective was to correctly reposition the mandibular right canine, in order to avoid the placement of a dental implant or fixed dental bridge. As the patient requested a noninvasive treatment, it was decided to start fixed orthodontic treatment only on the lower arch. After the removal of the fixed retainer, periodontal probing, supra and subgingival professional oral hygiene was performed. Periodontal probing and supragingival oral hygiene sessions were repeated if needed for calculus accumulations during all orthodontic treatment. A multibracket treatment was performed with the MTB technique. Brackets (3M Unitek, Monrovia, CA, USA) were bonded from elements 3.5 to 4.5, and molar bands with double tubes (3M Unitek) were cemented to elements 3.6 and 4.6. On the lingual side of molar bands, Wilson 3D lingual tubes (Rocky Mountain Orthodontics, Denver, USA) with vertical insertion were welded. In order to obtain additional torque on the right mandibular canine, a lower second premolar bracket (3M Unitek) was bonded. A 0.012-in NiTi archwire 3M (Figure 3) was ligated. A Wilson 3D sectional archwire (Rocky Mountain Orthodontics) was inserted on element 4.6 (Figures 4(a) and 4(b)) as an additional lingual/apical force became necessary to help the root apex return in the alveolar bone base. Its mesial extremity was placed on the most apical point of the root of the right canine, distant from lingual mucosa. The lingual sectional was removed after three months of treatment. Meanwhile, the following arch sequence was used: 0.014-in NiTi (Figure 5), 0.016-in NiTi, and a 0.019 x 0.025-in NiTi (3M Unitek). Light archwires were used for a long time in order to achieve a good alignment; considering the age of the patient, continuous and light forces were exerted to respect periodontal tissues. Subsequently, a 0.019 x 0.025-in TMA (3M Unitek) was used. Additional torque was progressively added on the right canine for the next three months. Treatment continued with the addition of radicular-vestibular torque on the IV quadrant and an elastic chain (3M Unitek) applied to close spaces. The multibracket treatment lasted a year and a half. The mandibular right canine was repositioned (Figure 6) and a periodontal examination showed probing pocket depth values of 3 mm. In addition, the general dentist decided to perform root canal treatment of the canine one year after the beginning of orthodontic treatment as the tooth was not vital and not symptomatic. Elements 3.2 and 3.3 were repositioned too, and spaces were closed (Figure 7). A spring retainer was delivered to the patient (Figure 8). It consisted of an anterior stainless-steel wire with vestibular and lingual resin components. The latter extended to the molars to improve stability. The patient was visited after 1, 5, 12, and 18 months from the end of the orthodontic treatment. The stability of the results was observed after 18 months (Figure 9). The patient was satisfied by the result of the therapy but was aware that unwanted tooth movement could occur in the upper arch anyway as she excluded every kind of retention. The patient will continue to be under close observation through regular follow-up examinations.

PMC3736967_01

Male

A 57-year-old man had noticed a right chest wall mass lesion for 15 years, but had ignored the lesion in the 5 years before presentation. He was admitted to our hospital without significant symptoms and with no history of tuberculosis. Magnetic resonance imaging (MRI) was performed, and a 5-cm-diameter lesion was found. The signal was isointense on T1-weighted imaging (T1WI) and hyperintense on T2-weighted imaging (T2WI) (Fig. 1). Needle biopsy was performed, and histopathology showed lymphocyte infiltration with no evidence of malignancy. The patient was followed up for the next 7 years, and during that interval he had no significant symptoms. On MRI after 7 years of follow-up, the primary chest wall mass lesion was without any significant change, but a small subcutaneous mass lesion was found nearby. The MRI signal of this subcutaneous mass was almost identical with the original mass (Fig. 2). Diffusion-weighted imaging (DWI) was performed and both lesions exhibited high signal on DWI and a low apparent diffusion coefficient (ADC) (about 0.5) on the ADC map (Fig. 3). In light of the MRI findings, hypercellular malignant tumors (including melanoma and lymphoma), atheroma, and nodular fasciitis were suspected. Excisional biopsy was not performed since that would make definitive re-excision more extensive due to the contamination of surrounding tissue planes. Therefore an open biopsy of both lesions was performed. The mass lesions were both found to be marginal zone B-cell lymphomas (Fig. 4). In this case, no other tumors were found, so radiation therapy only (36 Gy/20 French) was given. The patient was discharged, and follow-up found the patient in good condition with no apparent signs of recurrence after 2 years.

mri, marginal zone b-cell lymphoma, chest wall, slow growing

PMC5491809_01

Female

A 24-year-old woman with UC diagnosed 2 years previously was transferred to our hospital due to a 1-week history of a high-grade fever, bloody diarrhea, frequent bowel movements, and severe pain on the left side of the abdomen. Her UC was not well controlled with an oral 5-ASA therapy, so she was started on IFX in July 2014. She had already received the induction doses as well as 8 maintenance doses at 5 mg/kg, and she had maintained clinical remission for about 1.5 years. The final administration was 8 weeks prior to the start of the above-mentioned symptoms. She had neither history of travel nor any recent exposure with sick individuals, and her medical history was unremarkable except for UC. On a physical examination, the patient was febrile (39.5 C) with mild tachycardia, and an abdominal examination revealed moderate tenderness with hyperactive bowel sounds and mild rebound tenderness in the left side of the abdomen. Her laboratory examination revealed a decreased albumin of 3.4 (g/dL), elevated C-reactive protein of 8.53 (mg/dL), elevated erythrocyte sedimentation rate of 47.1 (mm), elevated white blood cell count of 124 (102/muL), with 81.0% neutrophils (normal range: 42-77%), hemoglobin within normal limits at 13.0 (g/dL), blood platelet count within normal limits at 29.9 (104/muL), negativity for hepatitis B virus antigen and antibody, negativity for hepatitis C virus antibody, negativity for chlamydia trachomatis antibody, negativity for syphilis, beta-D-glucan within normal limits at <6.0 (pg/mL), negativity for tuberculosis bacterium specific interferon gamma, and negativity for cytomegalovirus antigen. Polymerase chain reaction analyses were negative for both cytomegalovirus and tuberculosis bacterium genes in the colon lesions. No significant pathogens, including bacteria, fungi, viruses, and parasites, were isolated from her blood or were found in the contents of her colon. She tested negative for HIV and human T-lymphotropic virus type (HTLV)-I viruses. Colonoscopy on admission revealed widespread shallow ulcers in the rectum and coarse mucosa with mucous, pus, and blood in the sigmoid colon (Fig. 1A and B). The mucosal vascular pattern disappeared, and the erythematous mucosa was friable and bled easily. Although there were no active UC findings from the cecum (terminal ileum) to the splenic flexure (Fig. 1C), we found long luminal edematous swelling and multifocal discharge of pus throughout the descending colon (Fig. 1D and E). The mucosa of the descending colon appeared to be nearly intact. Computed tomography immediately after colonoscopy showed a diffusely thickened wall with a narrowed lumen and intramural air-filled abscess cavities and multifocal low-density areas of abscesses (Fig. 2), particularly within the wall of the descending colon. There were no diverticula of the colon, which was confirmed by the prior findings of colonoscopy and computed tomography. Antimicrobial therapy with doripenem hydrate 0.5 g intravenously every 8 h was started, as well as intravenous hyperalimentation. 2 weeks after starting treatment, she became afebrile and pain-free, and her C-reactive protein level was normalized. Oral intake was restarted with an elemental diet, and she was later discharged home after confirmation of the improvement of her condition via colonoscopy (Fig. 3A and B) and computed tomography (Fig. 3C). She is still being followed up at our out-patient department, and both oral and anal administration of 5-ASA have maintained clinical remission of her UC. IFX has not been reintroduced.

abscess, adverse drug event, biologics, ulcerative colitis

PMC9282816_01

Female

A 25-year-old female presented with the left dull mid-back pain for 3 months' duration. The pain was moderate and radiated to the left breast/precordium. The physical examination just revealed focal tenderness over the inferior angle of the left scapula/7th costovertebral junction, without swelling or erythema. The patient had a raised erythrocyte sedimentation rate of 40 and C-reactive protein of 6. Serological testing for HIV, hepatitis B, and hepatitis C was all negative. The anteroposterior X-rays of the thoracic spine showed that the T7 vertebral body was scalloped on the left side, and there erosion of the T7 left pedicle and adjoining rib [Figure 1]. The MR showed; a left-sided T7 enhancing periarticular erosive lesion, marrow edema in the posteromedial portion of the left 7th rib, the left posterolateral portion of the T7 vertebral body, and lateral left T7 pedicle. There was also thickening/ enhancement of the synovium of the left 7th costotransverse joint with enhancing soft tissue elevating the overlying pleura, and abutting the descending aorta [Figure 2]. A CT-guided biopsy was diagnostic for TB; it demonstrated caseous necrosis with epithelioid and Langerhans giant cells [Figure 3]. In addition, GeneXpert detected Mycobacterium tuberculosis that showed sensitivity to both isoniazid and rifampicin. ATT for the first 4 months included rifampicin, isoniazid, pyrazinamide, and ethambutol (HRZE) (intensive phase). For the next 8 months, the patient received rifampicin and isoniazid (HR) (continuation phase). At follow-up (12 months), the patient showed clinical and radiological signs of healing [Figure 4].

atypical tb, costotransverse joint, tuberculosis

PMC4000300_01

Male

A 35-year-old Japanese male presented to the Emergency Department of Okinawa Chubu Hospital with right hemiparesis. He had awakened from sleep with severe, sharp chest pain that was not accompanied by dyspnea. The chest pain subsided within 1 min without treatment, but medical evaluation was sought due to obvious dysarthria and weakness of the right upper and lower limbs. The patient was previously healthy, with no prior hospital admissions, surgeries, medications, or allergies, but bilateral pedal edema had developed 3 months prior to presentation. He had no dyspnea or ambulatory dysfunction and did not seek medical intervention. He worked as a house painter and lived with his wife and children. He had 15 pack-years of exposure to tobacco, and consumed 400 ml of Okinawan spirits nightly. There was no family history of cardiovascular disease, thromboembolism, or chronic kidney disease. Physical examination revealed that the patient was alert with no distress. He was not obese (BMI 21.4 on admission, when he was edematous), and he was afebrile with a blood pressure of 140/90 mm Hg, a regular pulse of 85 beats/min, and a respiration rate of 25 breaths/min. Oxygen saturation in the room air was 100%. An examination of the head revealed a marked, right-sided facial droop, but was otherwise normal. Carotid upstrokes were symmetric without bruits. The heartbeat was regular without gallops or murmurs, and the lungs were clear; the abdominal examination was also normal. Bilateral pitting edema was present to the knees. There were no rashes or petechiae. Neurological examination revealed intense dysarthria, which made it difficult for him to communicate with others, and right-sided central facial nerve palsy. Both the right arm and leg were at Brunnstrom stage 1, with complete flaccidity and no voluntary movement. Pain and light touch sensation were absent on the right side of his body. Table 1 contains initial laboratory data. Blood counts revealed leukocytosis and hemoconcentration. Serum albumin was markedly low at 1.8 g/dl. Serum cholesterol, triglyceride, and low-density lipoprotein cholesterol were elevated. The urine protein to creatinine ratio was 7.5 g/g Cr, indicative of high-grade proteinuria. The examination of the urine sediment revealed oval fat bodies, and testing for anti-nuclear antibodies, anti-neutrophil cytoplasmic antibodies, and anti-phospholipid antibodies were all negative. Hepatitis B and C serologies were negative. Diffusion-weighted magnetic resonance imaging showed high-intensity areas consistent with acute infarction in the left basal ganglia, left corona radiata, and left cerebral cortex (fig. 1). Contrast-enhanced computed tomography of the neck revealed collateral blood flow around a large embolus in the left carotid artery (fig. 2). Ultrasound of the left carotid revealed the embolus without any plaques or ulcers at the vessel wall (fig. 3). There were no aortic dissections, pulmonary emboli, renal vein thromboses, or deep vein thromboses on the computed tomography. A transthoracic echocardiogram showed normal contractility without dilated chambers, valvular disease, vegetations, intraluminal thrombi, or any findings suggesting pulmonary embolism, such as pulmonary hypertension or right ventricular stress. A presumptive diagnosis of ischemic cerebrovascular accident caused by a left carotid thromboembolism was attributed to a hypercoagulable state due to NS. Because of the lack of any findings of atherosclerosis or plaques at the left carotid, we believed that embolism was more likely than thrombosis. The origin of the embolus was not detected despite a thorough cardiovascular evaluation. Immediate anticoagulation with unfractionated heparin was employed, and the renal biopsy was deferred. Intravenous methylprednisolone was administered empirically at 1,000 mg/day for 3 days, followed by oral prednisone at 60 mg/day. Cyclosporine was added 30 days later in response to persistent nephrotic-range proteinuria (5.5 g/day on the 28th day). The patient was transferred to a rehabilitation hospital 47 days after first admission. However, the blood examination performed after transfer revealed abnormal liver function on the 74th day from the first admission, the results of which are detailed in table 1. Serological studies and abdominal ultrasound excluded viral hepatitis or biliary obstruction. He was immediately readmitted under suspicion of drug-induced hepatotoxicity. Medications on admission included prednisolone (50 mg/day), warfarin (2.75 mg/day), cyclosporine (70 mg b.i.d.), sulfamethoxazole/trimethoprim (400/80 mg daily), eicosapentaenoic acid (900 mg b.i.d.), atorvastatin (10 mg/day), lansoprazole (30 mg/day), alfacalcidol (0.25 mug/day), andronate (35 mg/week), and calcium lactate (1 g b.i.d.). All medications except for prednisone were subsequently withheld, and warfarin was replaced by intravenous heparin. The liver test results normalized, but they deteriorated upon rechallenge with warfarin. At this time, heparin therapy was briefly interrupted to permit a renal biopsy to evaluate refractory NS, with hypoalbuminemia (2.1 g/dl) and proteinuria (5.7 g/day). The biopsy showed MN at stage III of the Ehrenreich and Churg classification. Continued anticoagulation was deemed necessary due to severe persistent hypoalbuminemia and the severe cerebrovascular accident. Warfarin appeared to be clinically intolerable due to idiopathic hepatotoxicity despite a negative lymphocyte stimulation test. Intravenous heparin therapy was incompatible with outpatient rehabilitation. We discussed the indication of dabigatran, the only available novel oral anticoagulant in Japan at that time, with the patient and also with cardiologists, a neurologist, and the vice-principal of our hospital, all of whom were responsible for the prescription of dabigatran, and we decided to initiate treatment. We also explained and discussed the risks and benefits of dabigatran with the patient and obtained his written and informed consent in advance. Oral dabigatran was administered at a dose of 110 mg b.i.d., and MN was treated with oral prednisone and cyclophosphamide according to Jindal's regimen. Proteinuria decreased from a ratio of 5.1 to 1.6 g/g Cr, and serum albumin rose from 2.3 to 3.7 g/dl over 7 months. He was transferred to the rehabilitation hospital 137 days after stroke onset. At the outpatient clinic, his renal function remained stable, and he did not experience any episodes of edema, bleeding, or thromboembolism. We monitored the activated partial thromboplastin time (aPTT) to predict the risk of bleeding due to excessive anticoagulation. The aPTT values taken 4 h following administration of dabigatran in the morning were stable at around 40 s (standard aPTT was 30 s). A carotid echogram performed 2 years after the initiation of dabigatran revealed a reduced embolus, although it did still occlude the internal carotid.

carotid thromboembolism, cerebral infarction, dabigatran, membranous nephropathy, nephrotic syndrome

PMC6949674_01

Female

In July 2015, a 24-year-old woman was referred to our Department of Internal Medicine for a high fever (39 C) lasting 3 days, fatigue, myalgias, chills, and vomiting. She had been followed since 2008 for primary ITP, initially treated with oral prednisone (1 mg/kg/day), which achieved complete remission. Because of occasional severe relapses (two between 2009 and 2012, with gynecological bleeding), she was subsequently treated with Intravenous Immunoglobulin (IVIg) with good responses. In January 2012, at age 21, she suffered a severe relapse, again justifying the use of IVIg and corticosteroids. At that time, she had detectable autoimmunity with an antinuclear antibody titer of 1 : 250 (anti-SSA specificity but without any sign suggestive of lupus) and platelet-directed anti-glycoprotein IIb/IIIa antibodies. In June 2012 (baseline), a new IVIg cycle was administered, followed by RTX (375 mg/m2 once-a-week for 4 consecutive weeks). A complete platelet response was obtained within 6 weeks and, at the last follow-up (March 2015), her blood platelet level was normal (321 x 109/L) without treatment. Before RTX infusion (June 2012), her blood total gamma-globulin level >3 months before IVIg infusion had been normal (8.9 g/L) but she was lymphopenic (total lymphocytes: 0.513 x 109/L), while her peripheral blood lymphocyte count had been normal at ITP diagnosis (1.199 x 109/L). The previously available phenotype profiles of her peripheral circulating lymphocytes are reported in Table 1. No infection occurred during the 3 years following the last RTX administration and she remained clinically well at biannual consultations in our department. At admission, in July 2015, at age 24, her temperature was 39.2 C and she complained of lower abdominal pain, vomiting but without diarrhea; her physical examination was normal. Laboratory tests showed elevated C-reactive protein (CRP: 114 mg/L, normal range (NR): <5 mg/L), hepatic cytolysis (aspartate aminotransferase: 144 U/L, NR: 7-40 U/L; alanine aminotransferase: 265 U/L, NR: 5-50 U/L) and cholestasis (alkaline phosphatase: 389 IU/L, NR: 40-130 U/L; gamma-glutamyltranspeptidase: 698 U/L, NR: 5-38 U/L). The hemogram revealed agranulocytosis and thrombocytopenia (leukocytes: 4.9 x 109/L; neutrophils: 0.02 x 109/L; hemoglobin: 14.5 g/dL; platelets: 46 x 109/L). Bone-marrow aspirate showed normal density, several megakaryocytes but hypoplastic granulopoiesis in blocked maturation, without blasts. Computed-tomography (CT) scans of the thorax and abdomen were normal. Once urine and blood samples had been collected, empirical ceftazidime and gentamicin were begun, and achieved apyrexia within 48 h. After 46 h, blood cultures came back positive for Campylobacter jejuni, and the identical strain isolated from the patient's feces; amoxicillin-clavulanic acid (1 g 3 times a day for 2 weeks) was prescribed. Seven days postadmission, CRP, neutrophil and platelet levels returned to normal (3 mg/L, 6.61 x 109/L and 521 x 109/L, respectively); blood cultures were negative; and liver function was improved. Laboratory evaluation for immunodeficiency yielded: negative serology for human immunodeficiency viruses-1 and -2, very low serum Ig levels (Table 1) and no circulating B cells. Flow-cytometry quantification of T-cell subsets found expansion of circulating CD4+ T lymphocytes expressing surface DR, suggesting their activation; low natural killer cells and CD8+ T-lymphocyte levels. Urine immunofixation electrophoresis was negative. Ig-replacement therapy was started but not pursued by the patient. Ten months later (May 2016, age 25) she was hospitalized for a 15-day low-grade fever, weight loss, nonproductive cough and progressive dyspnea. CRP, lactate dehydrogenase and beta2-microglobulin levels were 40 mg/L, 340 U/L (NR 5-240 U/L) and 3.53 mg/L (NR 1.2-2.5 mg/L), respectively. As shown in Table 1, hypogammaglobulinemia, CD19+ B lymphopenia and low peripheral CD8+ T-cell count persisted but without T activation, as assessed by HLADR-positivity. CT scans visualized bilateral diffuse infiltrates, ground-glass opacities and large nodules. Bronchoalveolar lavage analysis revealed Pneumocystis jiroveci cysts with positive polymerase chain reaction (PCR) (4,000 copies/mL); high-dose trimethoprim-sulfamethoxazole and corticosteroids were prescribed. Searches for other pathogens, including Mycobacterium tuberculosis, atypical mycobacteria, cytomegalovirus, Cryptococcus and Aspergillus species, were negative. At that time, her bone-marrow biopsy was normal. Despite appropriate antibiotics and clinical improvement, thoracic CT scans revealed worsened dense infiltrates (Figure 1(a)), pleural effusions, hepatosplenomegaly and nodular lesions of both kidneys (Figure 1(b)). A new bronchoscopy with biopsies found CD20+ large lymphomatous cell infiltration (Figure 2) in bronchi. Those large atypical lymphoid tumor cells were CD10-BCL-6- and MUM1+BCL-2+, with an 80% Ki-67-proliferation index on immunolabeling. EBV, as assessed by in situ hybridization with an EBV-encoded small RNA probe, was diffusely positive in about 80% of tumor cells (Figure 2). The FISH assay for MYC gene rearrangement (MYC FISH DNA Probe, Split Signal, (Y5410), Dako, Locus 8q24) was negative. EBV-positive DLBCL with a nongerminal center phenotype was diagnosed without bone-marrow infiltration. Circulating EBV-DNA was positive (2,430,000 IU/mL). DLBCL treatment consisted of RTX, cyclophosphamide, doxorubicin, vincristine and prednisone. Even with EB viremia becoming negative, she developed fever, cytopenias, liver damage and neurological manifestations, as a consequence of her prominent bone-marrow hemophagocytosis. Unfortunately, she died of multiorgan failure at age 25.

PMC8081048_01

Male

A 2-month-old male infant was admitted to our hospital with a 1 month history of persistent white stools. The meconium of the child was dark green. Three days later, his stool turned yellow. After that, the stool color gradually became white stool over the next month. The test results of the infant's liver function were: albumin 16.5 g/L, total bilirubin (TB) 35.2 mumol/l, direct bilirubin (DB) 27.7 mumol/l, and total bile acid (TBA) 63.0 mumol/l. The child had taken probiotics and the symptoms did not improve. The patient had no significant past medical history. And the mother's pregnancy was uneventful. At the time of admission, the infant's body weight was 3400 g (<3rd percentile) and his height was 60 cm (50-70th percentile). The physical examination revealed hepatomegaly (4 cm below the ribs with soft texture) and pitting edema of both lower limbs. No abnormality was revealed for the consciousness, cardiopulmonary examination, and nervous system examination. Routine laboratory testing upon admission showed hemoglobin was 63 g/L, packed cell volume 19.9%, normal mean-cell volume, mean cell hemoglobin concentration was at the lower end of normal, and platelets 304 x 109/L. The patient was tested negative for hepatitis A, B, and, C, syphilis, HIV, TORCH, EBV-IgM antibody, and EBV DNA; his thyroid function and blood coagulation function were within the normal range. The patient's blood glucose during admission was normal and blood and urine tandem mass spectrometry showed that the amino acid and acylcarnitine spectrum analysis were normal. Cytomegalovirus IgM test was positive. Liver function tests revealed slightly elevated levels of TB, DB, and gamma-glutamyltransferase (gamma-GT) (shown in Table 1). The cardiac ultrasound showed no abnormalities. The chest radiograph was normal. Abdominal ultrasound showed hepatosplenomegaly, liver parenchyma echoes, but the gallbladder and pancreas were normal. In order to differentially diagnose whether there is biliary atresia (BA), we perfected the examination of liver, gallbladder, spleen color Doppler ultrasound, and gallbladder contraction. In order to differentially diagnose cardiogenic edema, we perfected the cardiac color Doppler ultrasound. The infant's parents refused to permit cholangiography and a liver biopsy. Due to the unclear diagnosis, we performed a genetic test. The infant's genetic analysis showed a CFTR hemizygous mutation site (c.223C>T) in exon 3 and exon 2-3 heterozygous deletion mutation. A genetic verification of the infant's parents was also performed; the father had a point mutation and the mother had a CFTR gene exon 2-3 heterozygous deletion mutation (shown in Figure 1). To further verify whether the child had pancreatic exocrine insufficiency, we tested fecal pancreas elastase 1 and the result was 0.6 mug/g, significantly lower than the normal value of 200 mug/g. Stool testing showed fat globules of 70-80/HP. These findings, combined with the manifestations of cholestasis, supported the diagnosis of CF. Because our hospitals and other testing institutions cannot perform a sweat chloride test, we did not perform it. After hospital admission, the infant was placed on a lactose-free fortified medium-chain fatty acid milk powder feeding, oral ursodeoxycholic acid (UDCA) 30 mg/(kg.d), and supplemented with fat-soluble vitamins A, D, E, and K. The stool color remained unchanged. Fecal pancreas elastase 1 suggested that the child had insufficient pancreatic exocrine function, so aspergillus oryzae pancreatic enzymes tablets (half a tablet once, three times per day) were added 2 weeks after diagnosis. Two weeks after the oral pancreatic enzyme tablets were administered, the color of the infant's stool changed to yellow and his weight increased (shown in Figure 2).

cftr, cystic fibrosis, edema, hypoproteinemia, white stool

PMC8081048_02

Female

On follow-up, liver function test was performed every 1 month and abdominal ultrasound every 2 months. The oral medication was well-tolerated by the child without adverse reactions. Two months after diagnosing the infant with CF, his TB, DB, and TBA decreased to normal levels (shown in Table 1), but the infant had a cough for 1 month, and his chest CT scan showed he had sacculus expansion of the lungs. The infant's physical examination revealed an enlarged liver (4 cm below the ribs with soft texture) in a 6-month old. Now, he is 1 year old with yellow soft stools, his body weight is 8500 g (3rd percentile), his height is 72 cm (3rd percentile). He has not had a cough for nearly 4 months, but still has an enlarged liver (2 cm below the ribs with soft texture). Using "cystic fibrosis," "* stool," and "infant*" as keywords, we found three relevant articles in PubMed consisting of a total of four case reports with white stool as the first symptom; one was a domestic case report (seen in Table 2). Including this infant, there are a total of five children (three males and two females) with an average age of 2 months that have presented with white stools and diagnosed with CF. Anemia was present in all five children, edema and hypoproteinemia in four, changes in stool color in five (pistachio-green in two patients, pale colored stool one, acholic stool in one, and white stool in one patient), cholestasis in two patients, delayed meconium discharge in one, delayed growth in three, hepatomegaly in three, and splenomegaly in two infants. One child presented with respiratory symptoms at the onset. Two children had an abnormal sweat test: one had a F508del compound heterozygous mutation and the other child had three mutation sites (C.214G>G/A, P.A72T; C.650A>A/G, P.E217G, and C.3406G>G/A, P. A1136T), which was a compound heterozygous mutation. The female infant (the fourth case) died because of a massive pulmonary hemorrhage. The stool changed to yellow in two infants after oral pancreatic enzymes were administered. The prognosis of the male infant (the third case) was good by UDCA and supporting treatment.

cftr, cystic fibrosis, edema, hypoproteinemia, white stool

PMC7527615_01

Male

An 11-year-old male presented with gradual left breast enlargement for one year duration. Frequently he visited pediatricians and provisionally diagnosed as a case of gynecomastia with reassurance and observation. Past medical, surgical, family and drug history, all were negative. A firm swelling involving left anterior chest wall elevating the nipple and areolar region. The swelling was ill-defined, non-tender, non-fluctuating, non-illuminating with normal overlying skin. Vital signs were with the normal ranges. Hematological tests were normal. Ultrasound examination showed a thick wall cystic lesion with internal debris and bone erosion suspecting chronic infection. CT scan of chest revealed a cystic lesion with fluid content measuring 12 x 8 cm in size connecting with a similar cystic lesion in the substernal area through a hole in the fifth rib (Fig. 1, Fig. 2). Under general anesthesia, in supine position, through anterolateral incision, a thick wall cystic lesion under the skin with a very thick pus content was found connecting to another similar lesion in the anterior mediastinum through a hole in the fifth rib with localized thickening of the pleura. Both of the lesions, the fifth rib with a part of fourth rib and a piece of pleura were resected and sent for histopathological examination which revealed multiple granuloma with caseating material, typical for TB. The wound was closed in layers after insertion of intrathoracic drain (Fig. 3). The postoperative course was uneventful. The patient was put on anti-TB regular regimen for three months.

chest wall, gynecomastia, tuberculosis

PMC8110827_10

Female

Because of her missing sucking reflex, feeding was difficult and she developed a severe malnutrition necessitating gastric tube feeding. Furthermore, the patient developed a duodeno-gastro-esophageal reflux disease (Table 1). Patient II died at the age of 14 months due to a bronchopulmonary infection in the course of which she developed a rapidly decreasing oxygen saturation and an increasing bradycardia. Whole exome sequencing of patients I and II revealed the homozygous stop mutation c.6016C>T (p.R2006*protein with 2564 aa, Mut. Ex 28 of 36) in the SPTBN4 gene in both patients. Homozygous carrier status was confirmed by Sanger sequencing in both patients. Heterozygous carrier status of the mother and the healthy sister was confirmed by Sanger sequencing as well. DNA of the father has been unavailable.

cardiomyopathy, case report, mitochondrial dysfunction, neurodegeneration, psychomotor developmental arrest, ßiv-spectrin deficiency

PMC6446130_01

Male

A 23-year-old man with a medical history of treated TB presented to the emergency department with hemoptysis for one week. His symptoms started with a dry cough that progressed from blood-tinged sputum to frank blood over three weeks. He had associated fever, chills, night sweats and subjective weight loss. His previous symptoms had completely resolved and he moved to the United States from Nepal one year prior to the hospital admission. On physical examination, the patient was afebrile, hemodynamically stable with a generalized cachectic appearance and diffuse rhonchi bilaterally on pulmonary auscultation. His labs were notable for a normal leukocyte count, a hemoglobin of 11.7 g/dL, and normal chemistries. The chest x-ray, Fig. 1, had a lucency in the left suprahilar region and bilateral peribronchial thickening of the upper lobes. A follow up CT scan, Fig. 2, showed multiple cavitary lesions at the superior segment of the left lower lobe. On hospitalization day 2, a microscopic smear of his sputum showed many acid-fast bacilli that was later identify in cultures as Mycobacterium tuberculosis complex. He was started on a 5-drug regimen with rifampin, isoniazid, pyrazinamide, ethambutol and moxifloxacin due to his prior history of possible resistant TB. He continued to have persistent hemoptysis and worsening anemia requiring a transfusion due tachycardia and dyspnea, suggesting massive hemoptysis. Four days after the anti-tuberculosis medication was initiated, he developed respiratory distress and was transferred to the medical intensive care unit and was placed on non-invasive positive pressure ventilation but did not improve. Thus, he underwent an urgent bronchoscopy, revealing a significant burden of blood clots in the left main bronchus that did not allow for a complete survey of the airway. As a result, an endobronchial blocker was placed and the patient was evaluated by interventional radiology. He underwent urgent left bronchial artery angiography with embolization of two abnormally hypertrophied left bronchial arteries. The following day, he underwent repeat bronchoscopy that showed persistent clot burden in the left main bronchus. Given his active tuberculosis, difficulty with oxygenation, and multiple cavitary lesions, the decision was made to proceed with left lower lobectomy. On gross examination, the lobe of lung was severely congested weighing 645 g (normal weight of a complete left lung: 395 g). There was widespread consolidation with nodules containing caseous material, Fig. 3A. It corresponded to necrotizing nonsuppurative granulomas with a peribronchial and subpleural distribution in a miliary pattern, Fig. 3B. The granulomatous inflammation extended around medium sized vessels causing destruction of the vasa vasorum and secondary obliterative endarteritis, Fig. 3C. Numerous cavities developed in relation to necrotizing granulomas with suppuration and hemorrhage, Fig. 3D. Round foreign particles were deposited in the arterial lumina, consistent with a prior embolization procedure. Intra-alveolar hemorrhage emerged after bleeding into the cavitating granulomas due to destruction of vessel walls, Fig. 3E and F. Few acid-fast organisms consistent with L-shaped mycobacteria were identified on FITE stain, Fig. 3G-I. Other special stains including Kinyoun cold procedure, auramine-rhodamine staining, and mycobacterium immunostaining, were negative for acid fast bacilli. On hospitalization day 6 the patient's family, who was previously unable to contacted, arrived at the hospital and the team was able to provide additional history regarding his previous TB therapy. He was diagnosed with multidrug resistant (MDR) TB seven years prior to admission and treated for 18 months with rifampin, isoniazid, pyrazinamide, ethambutol, moxifloxacin and an injectable medication, the name of which they could not recall. The following day, the Health Department confirmed fluoroquinolone-resistant tuberculosis by nucleic acid amplification testing (NAAT). Rifampin, isoniazid, and moxifloxacin were discontinued and the patient was started on amikacin, linezolid, meropenem, clavulanate, para-aminosalicylic acid and ethionamide. Bedaquiline was requested from the Centers for Disease Prevention and Control (CDC). After his lobectomy, he required persistent intensive care unit monitoring because he would not tolerate extubation trials along with multiple episodes of mucous plugging, which required multiple bronchoalveolar lavages. He was successfully extubated on hospitalization day 14. The patient was transferred to the regional TB center of Florida on hospitalization day 21. After an additional two months of being monitored and treated at the regional tuberculosis center, the patient was discharged to the community and continued his treatment under directly observed treatment through the department of health.

cardiothoracic surgery, fluoroquinolone-resistant tuberculosis, infectious diseases, l-form transformation, public health, tuberculosis

PMC7218215_01

Male

A 64-year old man presented for evaluation of chronic shortness of breath associated with recurrent episodes of lower respiratory tract infections. He also reported two episodes of expectoration of frothy, bloody streaked sputum 3 days ago. He was a never smoker and worked as a constructor and welder. He denied having symptoms of dry eyes or dry mouth. There was a history of arterial hypertension, hypercholesterolemia and gastroesophageal reflux disease. His medication included nifedipine 5mg o.d., nebivolol 2.5mg o.d. and esomeprazole 40mg o.d. There was no family history of lung diseases. On examination the patient was afebrile, with a heart rate of 63 beats/min, respiratory rate of 12 breaths/min, BP of 130/70 mm Hg and oxygen saturation of 97% on ambient air. Chest auscultation revealed expiratory wheezing. There were also multiple whitish papules in the face, nose and retroauricular area (Fig. 1). According to the patient they were attributed to his welding history and were considered a manifestation of allergic/photosensitive dermatitis. The rest of the physical examination was normal. Complete blood count (CBC) revealed a mild increase in eosinophils (420/mm3). Rest of CBC and metabolic panel were within normal limits. Pulmonary function test revealed an obstructive pattern with significant bronchodilator reversibility: FEV1/FVC ratio was of 69%. FEV1 pre bronchodilation was 2.82 lt (81% predicted), FVC was 4.09 lt (100% predicted) and FEV1 post bronchodilation was 3.28 lt (+460ml, +16.3%). DLco and TLC were within normal limits, 88% and 94% predicted respectively. Chest X-Ray was reported as normal but because of the history of hemoptysis multidetector Computed Tomography (MDCT) of the thorax was performed. It revealed multiple lung cysts with lower lung predominance. Some cysts appeared to be septated, elliptical and the majority of them were located in the subpleural and paramediastinal region (Fig. 2). Due to the reported hemoptysis bronchoscopy with BAL was performed. Airways were patent and there were no signs of active or recent hemorrhage. BAL revealed 74% macrophages, 21% lymphocytes, 1% eosinophils and 4% neutrophils. Cultures were negative for common pathogens, fungi, Mycobacterium Tuberculosis and Nontuberculous Mycobacteria. The combination of isolated diffuse cystic lung disease (with the aforementioned morphological and distribution characteristics) and skin findings raised suspicion of BHDS. Biopsy of the skin lesions revealed follicular epithelium proliferation surrounded by perifollicular fibrous sheaths, diagnostic of fibrofolliculomas (Fig. 3). Thus, the diagnosis of BHDS was established.

PMC8010170_01

Male

A 35-year-old male presented with diarrhea and abdominal pain after eating seafood and drinking 5 months before admission. The abdominal pain could be relieved after defecation. Two weeks later, he began to have a fever, up to 39.8 C, accompanied by chills. He was admitted to the local hospital and broad spectrum antibacterial drugs were started empirically. Despite antibiotics, the fever continued to occur repeatedly, in peaks up to 41 C, and the diarrhea persisted. Then the patient was suggested to be transferred to our institution. Laboratory tests showed leukocytosis (20.79 x 109/L), moderate anemia (69 g/L), increased percent of neutrophils (91.6%), increased C-reactive protein (CRP) (80.90 mg/L), procalcitonin (PCT) (5.87 ng/ml) and erythrocyte sedimentation rate (ESR) (106.0 mm/h) level, and mild hypoalbuminemia (31.0 g/L). Stool routine revealed Leukocyte ++++/HP, pus cell ++++/HP, stool blood was positive. Amoeba cysts were found after repeated stool examinations, but no trophozoites. Blood cultures, HBV, CMV-DNA, TORCH-IgM, G/GM, TB-IGRA, parasite antibody were negative. The plasma biochemistry of liver and kidney functions were normal. A total of three colonoscopes and biopsies were performed for the patient, and the results showed multiple irregular ulcers in the whole colon (Figure 1). Colonic biopsies diagnosed Epstein-barr virus-associated lymphoproliferative disorder, but the sample was inadequate for definitive diagnosis. Bone marrow examination showed the proliferation of hematopoietic cells were active, mainly granulocytes, and immature granulocytes increased. Findings of CT images of chest and neck were normal. Contrast-enhanced CT scan of the whole abdomen revealed multi-segmental intestinal wall thickening and enhancement (Figure 2A). 18F-FDG PET/CT demonstrated increased FDG uptake in the whole colon, bone marrow and spleen (Figure 3). Treatment of the patient was provided with anti-infective (moxifloxacin, rifaximin, metronidazole and imipenem, vancomycin, and cefperazone-sulbactam, tigecycline were given successively). However, he still had diarrhea and recurrent fever, the body temperature fluctuated at 39-40 C. Blood cultures were still negative. No positive bacilli was found by acid fast staining and no DNA fragment of Mycobacterium tuberculosis was found by qPCR. During the hospitalization, the patient developed a fierce abdominal pain, CT indicated gastrointestinal perforation (Figure 2B). An emergency surgery was performed. During surgery, it was found that there were two 0.5 cm breaks in the ileocecal junction, a 3 cm break in the descending colon, three perforation holes of varying sizes were seen in the sigmoid colon with a diameter of about 0.5-1 cm, and three 0.5-4 cm breaks in the upper rectal segment 3 cm from the peritoneal reflection. The intestinal wall around the breaks was edematous and congestive. He underwent total colectomy and enterostomy. ENKTL was diagnosed for pathological diagnosis of surgical samples. Histologically, the tumor cells were medium in size with irregular nuclei (Figure 4B). There were mixed inflammatory infiltrated mainly including lymphocytes and plasmacytes. The tumor cells infiltrated the whole wall of the intestinal wall with ulcer, necrosis (Figure 4A). Immunohistochemical staining showed that CD3, CD2, CD43, granzyme B (GB), TIA-1 were positive, while CD20, CD5, CD7, CD4, CD8, CD56 were negative (Figures 4B-G). CD30 was focally positive. The Ki-67 labeling index was 60% (Figure 4I). EBV-encoded small RNA (EBER) analysis showed positive (Figure 4H). Gene rearrangement test found the low amplification peak of TR gene. After recovering from surgery, the patient was treated with two courses of etoposide 50 mg and dexamethasone 5 mg (ED) regimen. Gemcitabine was added on the third day of the second course of therapy. Two weeks later, PD-1 monoclonal antibody 100 mg was used to replace ED regimen because his general condition and the expected chemotherapy tolerance were poor (A total of 3 times, each interval of 3 weeks). Fortunately, the patient was discharged the next day after the last treatment with PD-1 monoclonal antibody. By the time he was discharged from the hospital, his general condition improved significantly. PD-1 monoclonal antibody 100 mg was used on day 23, 56, 85 after discharged. To date, the patient has treated with a total of six courses of PD-1 monoclonal antibody. Eleven months follow-up was uneventful.

intestinal neoplasm, nk/t cell lymphoma, extranodal, non-hodgkin lymphoma, perforation

PMC4367057_01

Female

A 27-year-old unbooked G3P1L1A1 at 39 weeks 5 days of gestational age with previous one live vaginal birth and one first trimester spontaneous abortion was admitted in the labor room with pain in the abdomen. She had no history of prior antenatal care and belonged to a tribal community with lower socioeconomic status. There was history of tobacco use both before and during pregnancy. She was otherwise healthy with no known history of genetic or congenital anomaly in her family. On examination, she was observed to be in the second stage of labor with cephalic presentation and regular fetal heart rate. She delivered a term 2.5 kg baby with multiple congenital anomalies. The Apgar score was 3 at 1' and 0 at 5 min. The baby died within 30 min postbirth in spite of resuscitation attempts by neonatologist. On physical examination, the infant showed narrow chest, bilateral hypoplastic thumb, fused lower limbs with a single foot and 5 toes, absent external genitalia, imperforate anus and umbilical cord with single umbilical artery [Figure 1]. There were also prominent epicanthal folds, hypertelorism, downward curved nose, receding chin, low-set soft dysplastic ears and small slit-like mouth suggestive of Potter's facies [Figure 2]. Autopsy was declined by the parents. Intrapartum and the postpartum period of mother was uneventful.

caudal regression syndrome, potter's facies, mermaid syndrome, sirenomelia

PMC4367057_02

Unknown

A preterm baby weighing 1.6 kg was delivered vaginally at 34 weeks gestation by a 23-year-old primigravida with an unsupervised pregnancy. Postpartum investigation revealed the presence of diabetes mellitus. There was no history of drug intake and radiation exposure. The Apgar score was 3 at 1' and same at 5 min following which the baby was shifted to neonatal intensive care unit, but died 12 h postbirth due to severe respiratory distress. There was very scanty amniotic fluid drained at the time of delivery. The new born baby had gross anomalies like narrow chest indicating lung hypoplasia, fused both lower limbs and feet with 10 toes, absence of external genitalia, imperforate anus and single umbilical artery [Figures 3 and 4]. Examination of the fused lower limbs showed the presence of all thigh and leg bones thus classifying our patient as Type I of Stocker and Heifetz classification. The infant also had features of Potter's facies including prominent infraorbital folds, small slit-like mouth, receding chin, downward curved nose, and low-set ears. Ultrasonography revealed bilateral renal agenesis. On autopsy, there was an absence of both kidneys, ureters, urinary bladder, seminal vesicle, and urethra. The gastrointestinal system ended in a blind loop at the rectosigmoid area and was filled with meconium. Two pea sized gonads suggestive of testes were seen bilaterally posterior to pubis. Right pneumothorax with collapsed right lung was evident. Examination of brain, heart, liver, adrenal glands, and pancreas revealed normal anatomy.

caudal regression syndrome, potter's facies, mermaid syndrome, sirenomelia

PMC7876995_01

Male

A 60 years-old Caucasian male came to emergency room with diffuse abdominal pain, leukocytosis on blood tests (WBC 19 x 103/mmc) and increased C-reactive protein (120 mg/L). The patient suffered from hypertension and he had a medical history of previous appendectomy and repair of umbilical hernia. Family history was negative for other diseases. He underwent an urgent contrast enhanced CT abdominal scan that showed a dilated stomach with hyperdense material of hematic nature in the lumen. At the level of the pyloric portion we found irregularly thickened walls associated with a small fluid collection and bubbles of free air (Fig. 1). These radiological and clinical findings appeared compatible with diagnosis of complicated peptic ulcer with covered perforation. Because of the worsening of the patient's clinical condition, we carried out an emergency surgery with distal gastrectomy for the large diameter and position of perforation. The procedure was performed by a young surgeon in urgent setting. We decided for a laparoscopic approach with pneumoperitoneum via trans-umbilical open Hasson technique. We used a 12-mm trocar in the left hypochondrium and other two 5-mm trocars respectively in the right flank and in xiphoid region. On exploratory laparoscopy we found a large perforation (about 5 cm of size) in the first duodenum portion (Fig. 2). We converted the procedure to open surgery in consideration of the extension and position of the lesion that did not allow us to continue safely in laparoscopy. We achieved a distal gastrectomy with Roux-en-Y side-to-side gastro-jejunostomy. The patients were satisfied with the treatment received, the postoperative course was uneventful and the patient was discharged on POD 7. The intraoperative findings appeared to be not unequivocal, configuring on the one hand the hypothesis of perforation on a large peptic ulcer or on a chronic pancreatitic process but we could not exclude the presence of a neoplasm by a gastro-duodenal origin. The histopathological examination described, 2 cm from the distal pyloric margin and in the context of the pyloric type mucosa, a centimetric neoformation with histological and immunophenotypic characteristics of well-differentiated neuroendocrine tumor (NET G.1 s. WHO 2019 classification, Synaptofisina + and Chromogranina +). In the adjacent mucosa we saw multiple erosion/ulceration phenomena, with bleeding spillage and vascular congestion. The gastric wall was all affected by outbreaks of chronic inflammation, sometimes in follicular aggregation and with fibrosis also extended to the subserosa. These aspects, in relation to the presence of a NET G1 and multiple erosive/ulcerative areas near the pyloric margin, were suggestive of a clinical picture of Zollinger Ellison syndrome.

emergency surgery, exploratory laparoscopy, gastric net, gastric perforation

PMC10368104_01

Male

A 25-year-old previously healthy man was admitted to a local hospital for progressive hypersomnolence preceded by 1 week of fever and 2 days of headache. General convulsions developed the next day after admission, therefore, he was transferred to our hospital. On examination, his body temperature was 38.6 C, blood pressure 143/94 mm Hg, and he was in a stuporous status with prominent nuchal rigidity and bilateral rales on chest auscultation. His chest X-ray showed patchy consolidation over the right lower lung zone (shown in Fig. 1). The initial brain MRI showed prominent leptomeningeal enhancement at bilateral brainstem, cerebellum, and right cerebral sulci (shown in Fig. 2a, b) and a non-enhanced oval shape lesion at the SCC with increased signals in diffusion-weighted imaging (DWI), low signals in apparent diffusion coefficient (ADC), and hyperintensity in T2-weighted fluid-attenuated inversion recovery (T2-FLAIR) (shown in Fig. 3a-d). The cerebrospinal fluid (CSF) analysis revealed turbid appearance, significantly high pressure (420 mmH2O), lymphocyte-predominant pleocytosis (white blood cells 148/muL, lymphocytes 95/muL), reduced glucose (43 mg/dL), and elevated protein (519 mg/dL). The biochemistry assay was all normal, including sodium, which was 136 mmol/L. The CSF pathogen studies were negative in bacteria, syphilis, fungus, tuberculosis, and virus via multiple polymerase chain reaction (FilmArray Meningitis/Encephalitis). The viral serology surveys including varicella zoster virus, herpes simplex virus, cytomegalovirus, and Japanese encephalitis virus were also negative. Serology detection for M. pneumoniae using rapid immunochromatographic test (Biocard M. penunoniae IgM kit, Labsystems Diagnostics, Finland) showed IgM positive at a titer of 1:320 (normal value <1:40) on the 2nd admission day, indicating an acute M. pneumoniae infection. Neither polymerase chain reaction analysis nor antibody detection of M. pneumoniae in the CSF was available in our hospital. He was treated with empirical antibiotics, antiviral agents, antiseizure medications, osmotic diuretics, and steroids. Resolution of the pneumonic patch was noted in the subsequent chest X-ray. The repeated CSF analysis 10 days later showed improvement, with a white cell count of 1/muL and a normal protein level at 13.2 mg/dL. However, his neurological condition deteriorated into a comatose state with full-dilated unreactive pupils, flaccid quadriplegia, and ventilator support. The follow-up MRI 3 weeks after admission revealed apparent regression of the leptomeningeal inflammation (shown in Fig. 2c, d), but emergence of symmetric confluent hyperintensities on T2-weighted fluid-attenuated inversion recovery images involving the whole corpus callosum, bilateral internal capsules, and adjacent subcortical areas were without enhancement (shown in Fig. 3e-g). The extensive and symmetric white matter changes on the MRI did not conform to the typical findings in ADEM. Moreover, a nerve conduction velocity study disclosed severe amplitude reduction of compound muscle action potentials and mild reduction in sensory action potentials, compatible with a critical-illness polyneuropathy. Under the presumption of extensive inflammation affecting the central nervous system, we tried immunotherapies with intravenous methylprednisolone pulse therapy and intravenous immunoglobulin successively. His pupil responses recovered rapidly 2 days after completing the immunotherapies, and the consciousness and brainstem reflexes improved gradually within 2 weeks. The ventilator-support was weaned off successfully. The follow-up MRI on the 44th and the 79th admission day displayed continuing regression of the cytotoxic change in the corpus callosum and the white matter (shown in Fig. 3h-m). Three months after admission, he was discharged to a rehabilitation institution with clear consciousness and paraplegia. Six months after discharge, he could speak, eat, and move his upper limbs without efforts but still continued his rehabilitation for the moderate paraparesis.

cytotoxic lesions of the corpus callosum, immunotherapy, meningoencephalitis, mycoplasma pneumoniae, splenial lesion

PMC4242899_01

Female

A 71 year-old woman had intermittent pyrexia (>38 C) for 1 week in May 2009. Her family doctor treated her with a course of antibiotics to no effect. Computed tomography (CT), cardiac ultrasonography, and tuberculosis skin test detected no abnormalities. General malaise gradually developed, and hemoglobin (Hb) level fell from 10.2 g/dL to 9.0 g/dL over 2 weeks. She was admitted to our hospital as a case of fever of unknown origin. On admission, pyrexia was the only abnormality on vital signs. She was taking no medications other than verapamil and digoxin for paroxysmal supraventricular tachycardia. Meticulous physical examination detected anemic conjunctivae and edema of the bilateral lower extremities. No skin lesions, palpable lymph nodes, or neurological abnormalities were evident. Laboratory findings showed anemia (Hb, 8.8 g/dL) and elevated levels of lactate dehydrogenase (454 IU/L) and soluble interleukin-2 receptor (sIL2-R, 6,030 U/mL). Commonly used autoantibodies and tumor markers for assessment of collagen diseases and cancers were all negative. CT scan revealed no lymphadenopathy, hepatosplenomegaly, or abnormal lung lesions. Gallium scintigraphy showed no abnormal accumulations. Brain magnetic resonance imaging (MRI) revealed a non-enhancing, high-intensity area of 17 mm in diameter in the pons on T2- and diffusion-weighted imaging (Figure 1A and B); however, no abnormal neurological signs were observed. Cerebrospinal fluid examination likewise found no abnormalities. Based on the high sIL2-R level, IVLBCL was suspected. A bone marrow biopsy showed a normocellular marrow with no apparent lymphoma cells. Genetic analysis of the bone marrow specimen showed no clonal rearrangement of T-cell receptor Cbeta1 or the immunoglobulin heavy chain JH region gene. We took healthy-appearing skin randomly from the forearm, lower abdomen, and thigh for biopsy although no skin lesions were observed. All specimens revealed large B lymphoma cells within small veins and capillaries of the subcutaneous fat tissues but not outside the vessels (Figure 2A and B). Immunohistochemical studies showed that lymphoma cells were positive for CD20 (Figure 3), a B-cell marker, and negative for CD3, a T-cell marker. Based on these findings, a diagnosis of IVLBCL was made. The patient's poor general condition required a less toxic regimen, thus conventional R-CHOP therapy, consisting of rituximab (375 mg/m2), cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), vincristine (1.4 mg/m2), and prednisolone (60 mg/m2), was started within 1 month of initial symptoms. After the first lumbar puncture for spinal fluid examination, the patient did not accept repeating it due to its invasiveness. For this reason, we treated the patient without any intrathecal treatment. After the first cycle of systemic chemotherapy, the patient had resolution of fever and peripheral edema, as well as improvement in Hb, lactate dehydrogenase, and sIL2-R levels. After eight cycles of R-CHOP therapy, the pontine lesion had completely disappeared (Figure 4A and B). Therefore, the asymptomatic reversible pontine lesion was considered as IVLBCL involvement. During follow-up, the value of sIL2-R had been within reference range. Currently at 5 years after diagnosis, the patient has been doing well with no recurrence and returned to work without any neurological disorders.

cns involvement, blood–brain barrier, intravascular large b-cell lymphoma, random skin biopsy, rituximab, verapamil

PMC9133385_01

Female

A 62-year-old woman was admitted to the neurology department of Tianjin Huanhu Hospital. The patient complained of paroxysmal falls accompanied by impaired consciousness for the last nine days and paroxysmal limb twitch accompanied by gibberish speech for four days. Initially, the patient experienced tonic-clonic seizures, accompanied by impaired consciousness. Later, the patient experienced tonic seizures with head turning to the right and retained consciousness similar to faciobrachial dystonic seizures (FBDS) (Supplementary Materials S1). These incidences occurred more than ten times in a day. The patient was first seen in another hospital, and a brain MRI was done. The MRI showed no abnormalities. The patient was started on sodium valproate, diazepam, and levetiracetam (drug doses unknown). Due to no clinical improvement, the patient was referred for further management. The patient had no previous history of hypertension, coronary heart disease, diabetes, cerebrovascular disease, mental illness, hepatitis, tuberculosis, and no family history of any hereditary disease. On admission, the patient had a body temperature of 36.3 C, a heart rate of 91 beats/min, a respiratory rate of 20 breaths/min, and a blood pressure of 162/85 mmHg. The neurological assessment revealed that the patient had cognitive dysfunction (poor memory and poor calculation ability). However, other categories of the neurological examination, including cranial nerves, motor system, reflexes, sensation, coordination, movement, gait, and signs of meningeal irritation, were normal. The serum testing of routine blood tests, coagulation profile, liver function and kidney function tests, blood sugars, lipid profile, and serological testing for hepatitis B, syphilis, and HIV were negative. In addition, the results of anti-nuclear antibodies, antineutrophil cytoplasmic antibodies, rheumatoid factors, thyroid-stimulating hormone receptor antibodies, anti-thyroglobulin antibodies, and serum tumor markers, including carcinoembryonic antigen, squamous cell carcinoma antigen, cytokeratin-19 fragment, carbohydrate antigen 199, carbohydrate antigen 125, and neuron-specific enolase were normal. The patient had abnormal serum chloride levels of 95mmol/L. Further, the serum AE-related antibodies determined with both tissue-based and cell-based indirect immunofluorescence (IIF) assay in V-Medical Laboratory (Guangzhou, China), including anti-N-methyl-D-aspartate receptor (NMDAR), anti-leucine-rich glioma-inactivated 1 (LGI1), anti-contactin-associated protein-like 2 (CASPR2), anti-gamma-aminobutyric-acid B receptor (GABABR), anti-dipeptidyl-peptidase-like protein-6 (DPPX), and anti-glutamic acid decarboxylase 65 (GAD65) and paraneoplastic neurological syndrome (PNS)-related antibodies including anti-Hu, anti-Ri, anti-Yo, anti-Ma2, anti-CV2, and anti-amphiphysin, was remarkable only for positive anti-LGI1 antibody with a titer of 1:16 (normal <1:10). The CSF showed slight leukocytosis of 10 x 106 / L with lymphocytic predominance. However, the pressure, color, turbidity, glucose levels, chloride levels, Gram staining, acid-fast staining, ink staining, metagenomic next-generation sequencing (mNGS), AE-related antibodies which were also determined with both tissue-based and cell-based IIF assay in V-Medical Laboratory (Guangzhou, China), and PNS-related antibodies of the CSF were normal. The patient had a positive RPR with a serum titer of 1:16 and a positive TPPA. Subsequently, TPPA and RPR in CSF were tested, and both results were positive. The electroencephalography (EEG)showed irregular slow waves with medium to high amplitudes in the right temporal lobe, which spread to the other lobes and showed sharp waves (Figure 1). The brain MRI showed increased signals on T2-weighted and FLAIR imaging in the medial temporal lobe (Figure 2A). The gadolinium-enhanced MRI of the brain showed mild to moderate cord enhancement in the right temporal lobe (Figure 2B). Syphilis can cause multiple system damage. Therefore, magnetic resonance angiography (MRA) was carried out to investigate vascular stenosis or vasculitis-like changes. However, the results revealed no abnormalities (Figure 2C). Moreover, CT of the chest, echocardiography, abdominal ultrasound, urinary tract ultrasound, electromyography, and nerve conduction velocities of the limbs were normal. Therefore, uncertainty arose as to whether the patient had both anti-LGI1 encephalitis and NS or whether the LGI1 antibody and LE manifestations were due to the NS. The patient received intravenous penicillin sodium 3.5 million units every 4 h for 14 days to treat the NS. Furthermore, the patient was initiated on intravenous sodium valproate 400 mg two times daily and oral levetiracetam 500 mg two times daily. The drugs were then changed to oral sodium valproate 500 mg two times daily and oral levetiracetam 750 mg two times daily. Improvement was noted with no convulsions and normal cognitive function. Two months later, the serum TPPA was still positive. In addition, the serum RPR was still positive with a titer of 1:8, while the serum LGI1 antibody was positive with a titer of 1:10. Furthermore, a revaluation of the CSF showed that the CSF TPPA and RPR were positive. However, the other CSF tests remained negative. In addition, a repeat of the EEG showed no epileptiform wave emission (Figure 3). Moreover, a repeat of the brain MRI showed no abnormality (Figure 2D). A second course of intravenous penicillin G sodium 3.2 million units every 4 h for 14 days was started. After another four months, the serum TPPA was still positive, the serum RPR test was positive with a titer of 1:8, while the serum LGI1 antibody was negative. Changes in TPPA, RPR, and LGI1 antibodies during the syphilitic treatment are shown in Figure 4. A repeat of the EEG and brain MRI showed normal findings. The third course of intravenous penicillin G sodium 3.2 million units every four hours, was given for 14 days. In addition, oral doses of sodium valproate 500 mg two times daily and levetiracetam 750 mg two times daily were continued. The patient was then followed up for additional three months. The patient reported no further convulsive episodes. In addition, the memory and calculation ability were noted to be normal.

case report, encephalitis, leucine-rich glioma inactivated 1 protein, neurosyphilis, penicillin

PMC9852504_01

Male

A 54-year-old male, a ceramic worker with no previous history of immune dysfunction, was admitted to the hospital with persistent fever for 19 days. The patient had a cough occasionally and joint soreness but denied any other symptoms. On initial clinical evaluation, the patient's body temperature was 38.4 C, and other signs were within normal limits. Pulmonary, abdominal, cardiac, and neurologic examinations showed unremarkable findings. Laboratory tests revealed that the patient had leukocytosis (20.72 x 109/ml) with 87.4% neutrophils. His C-reactive protein level was high (90.61 mg/L), and a procalcitonin level was slightly increased (0.173 ng/ml). Contrast-enhanced chest CT revealed a large mediastinal mass measuring approximately 7.76 x 4.55 cm (Figure 1A). The rest of the examination was regular. At initial admission, the patient was treated with empiric antibiotic therapy, including piperacillin and sulbactam. However, he still had a recurrent fever, and there was no significant improvement in inflammatory indicators and blood routine examination. To determine the etiology, the patient underwent Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) on the fifth day of admission. The Virtual bronchoscopic navigation (VBN) system is a method to guide the bronchoscope to the lesion by making a bronchial path on a virtual image. The digitized information from the patient's CT scan was imported into the Archimedes VBN system, in which multislice views of the chest and virtual bronchoscopy images were reconstructed. The VBN system shows the bronchial tree, the anatomical structure of the mediastinal mass and visualizes the best path to reach the mediastinal mass (Figures 2A-E). With the guidance of the VBN system, the bronchoscope was navigated to the target bronchus and advanced to the lesion, and then EBUS-TBNA was performed to obtain purulent exudate (Figures 3A-D). Biopsy showed more purulent secretions and a few lymphocytes and macrophages (Figure 4A). Microscopic analysis revealed numerous weakly acid-fast and branching filamentous rod bacteria were identified from the samples on the aspirate smear, and a presumptive microbiological diagnosis (Nocardia) was made (Figure 4B). Metagenomic next-generation sequencing (mNGS) subsequently identified the pathogens as Nocardia species (Nocardia arizonensis and Nocardia cyriacigeorgica). And after seven days of culture, the cultures of purulent exudates ultimately grew the Nocardia species (Figure 4C). After microscopic examination and mNGS confirmed Nocardia, intravenous imipenem/amikacin was given. The clinical symptoms of the patient were significantly improved after 6 days of treatment. Then he was switched to intravenous imipenem with oral trimethoprim/sulfamethoxazole (TMP/SMX, 80 mg of TMP, and 400 mg of SMZ/tablet) 3 tablets q6h. One month after treatment, the patient improved, and their Chest CT showed a decrease in the size of the mediastinal mass (Figure 1B). He was discharged and continued to be treated with oral TMP/SMX 3 tablets q8h and sodium bicarbonate for 3 months. Over the next 3 months, he continued on oral TMP/SMX 2 tablets q8h and sodium bicarbonate. After six months of treatment, the patient was asymptomatic. His CT showed significant improvement in the mediastinal mass size (Figure 1C). At one and a half years of follow-up, the patient recovered well, and no complications were noted (Figure 1D).

ebus-tbna, mngs, mediastinal mass, nocardia, weakly acid-fast stain

PMC5648305_01

Male

Written consent was obtained from the patient for the publication of his case and images. A 66-year-old Indian male patient presented to the Tuberculosis Control Unit after sudden onset of near syncope, nausea, diaphoresis, light-headedness, and a wide-staring gaze with upward and lateral deviation of eyes 30 minutes after consuming newly-prescribed RHEZ. These symptoms resolved on the administration of diphenhydramine 25 mg intravenously at the Emergency Department. The patient was referred, initially, to the Department of Rheumatology, Allergy and Immunology based on the suspicion of a reaction to RHEZ. A diagnosis of anaphylaxis-like and possibly idiosyncratic reaction to rifampicin was made. On further questioning by the primary team, the patient reported that while he was aware of his surroundings and was able to hear conversations around him, he felt "physical blocked" in that he was unable to respond with purposeful voluntary movements or speech; he additionally described abdominal discomfort and generalized weakness. The patient had just been prescribed daily rifampicin 600 mg, isoniazid 300 mg, ethambutol 1.6 g, pyrazinamide 1.75 g (i.e., standard RHEZ combination therapy for TB of uncertain origin and resistance, according to his weight of 98.3 kg) and pyridoxine 10 mg after increased nodular opacities in the left upper zone were observed on sequential chest X-rays (Figures 1 and 2), suggestive of granulomata. A small calcified pleural plaque was also noted. Blood cultures, sputum cultures, and Mycobacterium tuberculosis polymerase chain reaction were negative. On his initial presentation after the near syncope, the patient's vitals were stable and physical examination, including neurological examination, did not reveal any conclusive findings. A full blood count, liver function test, thyroid function test, drug screen, troponin I, electrocardiogram (Figure 3), and a two-dimensional echocardiography were performed. However, the diagnosis was subsequently changed to OGC based on the more complete history recorded. Another possible cause of OGC would include trauma. However, the patient did not suffer from any trauma recently.

adverse drug reaction, ethambutol, isoniazid, oculogyric crisis, rifampicin, tuberculosis

PMC8605226_01

Male

A-3 months-old-boy presented with severe malnutrition, known cholestatic jaundice diagnosed as congenital cytomegalovirus infection and contact of his father who was diagnosed with MDR-TB but was not compliant with his treatment. His tuberculin skin test was positive, chest radiograph revealed right perihilar infiltrate and X-pert MTB/RIF on gastric aspirate was positive for M. tuberculosis complex with resistance to rifampicin. Other baseline investigations revealed a small atrial septal defect on echocardiography, mild to moderate hearing loss on audiology, normal vision and retinas on ophthalmological evaluation, raised bilirubin and liver enzymes (alanine and aspartate transaminases) and positive cytomegalovirus (CMV) IgM with a negative CMV PCR. He was HIV-unexposed and his HIV ELISA was negative, but CD4% was low (19%). Culture of the gastric aspirate eventually was positive, confirming M. tuberculosis resistant to isoniazid and rifampicin on line-probe assay as well as resistant to second-line injectable agents with second-line LPA, but susceptible to the fluoroquinolones. He was therefore confirmed as pre-XDR-TB. The mother's sputum was X-pert MTB/RIF negative. The chest x-ray showed active tuberculosis with infiltrates at the right upper-middle lung field with an increased of bronchovascular marking (Fig. 1). We treated him with five kind of less hepatotoxic anti tuberculosis drugs by individualized treatment based on the updated WHO 2018 guidelines. He commenced the treatment with moxifloxacin (10 mg/kg/day divided in tow dose), linezolid (10 mg/kg/day once daily), cycloserin (10 mg/kg/day once daily), ethambutol (20 mg/kg/day once daily) and para-aminosalysilic acid (200 mg/kg/day divided in two dose). After seven days receiving the pre- XDR-TB treatment, the liver enzymes improved, no adverse reaction such as vomiting, dhiarrea was reported. He also recieved gancyclovir for the CMV infection. He was followed every one month, he shows weight increment to 5.8 kg from 3.6 kg in 3 months and increased gradually every month. His nutritional status improved to normal from severe malnutrition after 20 months of treatment. No adverse reaction such as vomiting nor dhiarrea was reported. The growth and milestones development were appropriate. Laboratory evaluation showed improvement of liver function. Hematologic and neurologic (peripheral and toxic optic neuropathy) adverse effects were monitored during linezolid treatment. No anemia nor thrombocytopenia was found. For the optic toxic neuropathy evaluation, normal vision was concluded through examination of response to light, pupil response, ability to follow a target and ophthalmoscopy examination of the retina was also done to exclude CMV retinitis symptom and the result was normal. The M.tuberculosis culture evaluation result was negative on the first and third month of treatment.

case report, children, pre-extensively drug resistant tuberculosis

PMC8605226_02

Female

A-14 years-old-girl presented with severe weight loss (severe malnutrition), with chief complaint of fever since 1 month and hemoptysis since 2 days prior. Her parents showed negative for TB screening. History of tuberculosis contact is her neighbour identified MDR-TB and received treatment in our hospital. Her X-pert MTB/RIF revealed positive Mycobacterium tuberculosis with Rifampicin resistant. Culture M. tuberculosis was positive, confirming M. tuberculosis resistant to isoniazid and rifampicin on line-probe assay as well as resistant to second-line injectable agents with second-line LPA, but susceptible to the fluoroquinolones. The chest x-ray showed active tuberculosis with opacity at the right hilar, lobulated infiltrate in the left apex, nodular at left hilar, and enlarged bilateral peri-hilar lymph nodes (Fig. 2). Before starting the therapy she was consulted to the Psychiatry, Ophthalmology and Ear, Nose and Throat department. Baseline electrocardiography (ECG) showed normal QT interval. HIV screening was negative. She started on individualized drugs regimen for pre-XDR TB with levofloxacin (10 mg/kg/day once daily), ethionamide (15 mg/kg/day once daily), cycloserine (10 mg/kg/day once daily), pyrazinamide (35 mg/kg/day once daily), para-aminosalicylic acid (PAS 200 mg/kg/day divided in two dose), bedaquiline (200 mg once daily for 2 weeks). On the second day receiving bedaquiline, the ECG showed prolonged QT interval >500 ms without any electrolyte imbalance, so bedaquiline was stopped and ECG was examined every day. She started to receive linezolid 400 mg per day (10 mg/kg/day once daily) replacing bedaquiline. There was no more prolonged QT after given linezolid. Laboratory examination and clinical manifestation was monitored due to the side effects of the therapy. During hospitalization no other adverse reaction occurred. The laboratory examination is within normal limit. After two weeks hospitalized, she was discharged. She was followed every one month, no adverse reaction of nausea, vomit, jaundice was reported. Linezolid toxicity was also observed during treatment, hematologic value was normal, no anemia nor thrombocytopenia was found, there were no vision loss and color vision test result was normal (evaluated through Ishihara test). No peripheral neuropathy signs (paresthesia, numbness in extremities) were reported. Her weight increased 2 kg after 3 months treatment and her nutritional status improved to normal weight from severe malnutrition after 20 months of treatment. The M.tuberculosis culture result was negative on the first and third month of treatment.

case report, children, pre-extensively drug resistant tuberculosis

PMC6390555_01

Female

A forty-nine-year-old female from a suburban community in Sri Lanka presented with insidious high grade intermittent fever with chills and rigors for 2 months. She experienced one to two febrile episodes daily with complete defervescence in between. She also had anorexia, weight loss, sore-throat and symmetrical large joint arthritis without morning stiffness. Small joints and axial skeleton were spared. She also noticed an itchy desquamating erythematous rash over back of the trunk and proximal limbs. Erythematous patches were transient and recurring but did not temporally correspond to febrile peaks. The patient did not have any symptoms referable to a focus of infection and did not report photosensitivity, Raynaud phenomenon, past history of tuberculosis, or high risk sexual behaviours. The patient was averagely built (BMI: 23.1 kg/m2), febrile (39.9 C), ill and pale. A firm 1.5 cm lymph node in the right posterior cervical group was noted. Throat was non-inflamed. Erythematous macules noted over the trunk and proximal limbs were transient. Symmetric arthritis affected elbow, wrist and knee joints. A smooth non-tender 2 cm hepatomegaly was noted. The rest of the examination was unremarkable. Investigations revealed a normocytic normochromic anaemia, neutrophil leukocytosis with toxic changes, reactive thrombocytosis, elevated ESR (110 mm 1st hour), CRP (165 U/L) and ferritin (3200 U/L). Renal function was normal and liver enzymes were mildly elevated (AST 66 U/L, ALT 57 U/L). Auto antibody panel, including rheumatoid factor, antinuclear antibodies (ANA), dsDNA antibodies, pANCA and cANCA were negative. Contrast enhanced computerized tomography of the neck, chest, abdomen and pelvis demonstrated enlarged cervical lymph nodes and fatty liver. Radiographs of large joints were normal. Biopsy of the lymph node showed reactive lymphoid hyperplasia with no evidence of neoplastic changes, suppuration or granuloma. Bone marrow aspiration and trephine showed no abnormalities. Blood and bone marrow cultures for bacteria, tuberculosis, brucellosis, melioidosis and fungi were negative. Serum protein electrophoresis showed polyclonal gamma-globulinaemia and reduced albumin fraction. As she had been exposed to flood water 2 weeks prior to symptom onset (compatible with incubation period of 1-3 weeks) and several cases of melioidosis had been reported in her residential area, antibodies against Burkholderia pseudomallei were tested. It turned positive (1:640, indirect haemagglutination) and titre continued to rise over time (Fig. 1). Febrile illness, possible exposure to infectious agents during floods and elevated inflammatory markers necessitated consideration of empiric antibiotic therapy. The patient was treated with ceftazidime (2 g 6 hourly IV) and imipenem (1 g 8 hourly IV) for 14 days and ceftazidime and cotrimoxazole (1440 mg bid orally) for another 14 days, due to positive serology for melioidosis. However she did not show clinical improvement. Fever persisted and inflammatory markers remained elevated. Serum ferritin and melioidosis antibody titre continued to rise exponentially. However repeated peripheral blood cultures for melioidosis did not isolate any bacteria and repeated imaging did not reveal a focus of infection. Despite a month of broad spectrum antibiotics she remained febrile with persistently elevated inflammatory markers. In retrospect, AOSD was considered as a possible diagnosis. She showed partial response to NSAIDs, further favouring this diagnosis. Subsequently, she was commenced on high dose steroids (prednisolone 1 mg/kg/day). Within 2 days she achieved complete defervescence and made a good clinical recovery. Serum ferritin level and melioidosis antibody titre declined over time (Fig. 1). After one month of steroid therapy she remained afebrile, but had mild residual large joint arthritis with minimal functional impairment. Methotrexate was commenced and steroids were tapered over next 2 months and at 6 months she remained asymptomatic on methotrexate with normal inflammatory markers. Long term follow up was arranged. The final diagnosis of AOSD was made based on clinical features and exclusion of other connective tissue disorders, neoplasms and infections. During the course of her illness the patient did not develop Macrophage Activation Syndrome, a serious complication of AOSD.

adult onset still’s disease, false positive antibodies, melioidosis

PMC6744365_01

Male

A 25-year-old man, previously healthy, was initially admitted due to slowly progressive headache with blurry vision and fever for nine months. The patient recalls ingesting raw camel milk, which is a major risk factor for brucellosis. There was no previous contact with a tuberculosis case. The headache worsened one week before his admission and the patient lost vision in the left eye. His vital signs and cognitive function were normal. Pupils were reactive, but the patient was barely seeing the flash light with his left eye. Ophthalmologic examination revealed an atrophic optic disc mainly with decreased visual acuity bilaterally. Extraocular muscles were intact. The remaining neurological examination was unremarkable. His diagnostic work up showed total white blood cell (WBC) count of 5.61 x 109 cells/mm3 and a C-reactive protein (CRP) level of 3.76 mg/L. His cerebrospinal fluid (CSF) acid fast bacilli (AFB) stain and Mycobacterium tuberculosis polymerase chain reaction (MTB-PCR) were both negative. Blood and CSF cultures were positive for Brucella spp. His serum serological test was positive for B. melitensis and B. abortus. Antibody titers were 1:640 for both strains, just at the cutoff level for the serological diagnosis of the infection. CSF analysis showed elevated WBC count (170 cells/mm3 with 34.9% lymphocytes) and decreased glucose level (34.2 mg/dL). Serum glucose level at that time was 99 mg/dL. CSF protein level was 1.5 g/L while red blood cell (RBC) count was 7 cells/mm3. A magnetic resonance imaging (MRI) of his brain showed multiple, bilateral small dural-based nodular enhancements in both upper frontal lobes (Image 1). The patient was diagnosed with neurobrucellosis. Unfortunately, the patient has completely lost his vision in the left eye with weakened vision in the right eye because of a late presentation and delayed diagnosis. As such, the patient was immediately started on ceftriaxone 2 g intravenously (IV) every 12 h, doxycycline 100 mg orally every 12 h and rifampin 900 mg orally once daily for six weeks along with amikacin 400 mg IV every 12 h for the first three weeks. Three weeks after treatment was initiated, both antibody titers remained at 1:640, which was expected as Brucella antibodies may persist for months after conclusion of therapy. His repeated blood and CSF cultures returned negative a few days after treatment. A repeated MRI of the brain showed interval decrease in the number of the previously reported bilateral frontal leptomeningeal enhancing foci. However, small residual abnormal enhancing foci were still noted. Fortunately, no interval development of new lesions was seen (Image 2). Upon completion of the IV regimen (amikacin and ceftriaxone), the patient was discharged on oral doxycycline 100 mg every 12 h and rifampin 300 mg every 8 h to be taken for 6 months. In an outpatient follow up visit three months later, the patient's vision on the right side was slightly improving. While B. melitensis antibody titer slightly decreased to 1:320, B. abortus antibody titer remained at 1:640. Three months later (six months after discharge), a repeated lumbar puncture showed improved CSF analysis with WBC count of 6 cells/mm3, RBC count of 1 cell/mm3, protein level of 0.55 g/L and glucose level of 46.8 mg/dL (serum glucose level was not obtained at the time of this test). Brucella antibody titer in the serum declined from 1:640 to 1:40 for both strains. At this visit, the decision was made to extend the treatment to 3-6 more months to ensure full recovery. Three months later, a repeated brain MRI showed no more meningeal enhancement and CSF analysis was normal; therefore, antibiotic treatment for brucellosis was stopped.

brucella, brucellosis, cases, ceftriaxone, saudi arabia, zoonotic infection

PMC6744365_02

Female

A 54-year-old woman, known case of type 2 diabetes mellitus and hypertension, was admitted to the hospital due to fever, severe neck and back pain, as well as nausea and vomiting for 2 weeks. She admitted drinking a small amount of raw milk several weeks before her presentation. She had no signs of meningitis and her neurological examination was normal. A lumbar puncture revealed no bacterial growth with CSF protein level of 0.7 g/L and glucose level of 126 mg/dL (serum glucose level was 268.2 mg/dL). CSF WBC count was <1 cell/mm3 and RBC count was 8 cells/mm3. AFB stain showed no Mycobacteria, and CSF MTB-PCR did not detect M. tuberculosis. Urine culture came back negative for any bacterial growth. However, a blood culture was positive for Brucella spp. In addition, both B. melitensis and B. abortus antibody titers in the serum exceeded 1:1280. An abdominal ultrasound was unremarkable. A transthoracic echocardiography followed by a transesophageal echocardiography were both normal. The patient was immediately started on ceftriaxone 2 g IV every 12 h, streptomycin 1 g intramuscularly (IM) once daily, doxycycline 100 mg orally every 12 h and rifampin 300 mg orally every 8 h daily for a total duration of 6 weeks. Her nausea and vomiting were treated with metoclopramide and ondansetron. Her back pain appeared to be due to disc prolapse rather than Brucella spondylodiscitis as was concluded from the MRI of her cervical and lumbosacral areas. After the patient completed 12 days of therapy, she was discharged on doxycycline 100 mg orally every 12 h and rifampin 300 mg orally every 8 h for 30 days and to continue her parenteral antibiotics as an outpatient. Upon follow up one month later, both Brucella antibody titers declined to 1:1280 in the serum. CRP level was 6.93 mg/L (no level was obtained at baseline). The patient was advised to continue the oral antibiotics for 6 more weeks while streptomycin and ceftriaxone were stopped. Two months later (three months post discharge), CRP level increased to 31 mg/L; nonetheless, antibody titers of B. melitensis and B. abortus declined to 1:640 and 1:320, respectively. As the patient appeared asymptomatic and clinically well, her antibiotics were stopped; though, she was advised to remain under supervision and to return for follow up in case of a potential relapse.

brucella, brucellosis, cases, ceftriaxone, saudi arabia, zoonotic infection

PMC6744365_03

Male

A 31-years-old man who was otherwise healthy presented to the emergency department with high grade fever that persisted for a week but was manageable with acetaminophen (paracetamol). The patient also suffered from headache for three days which he described as being band-like surrounding his head. He reported regular contact with camels and occasional consumption of their raw milk. Three weeks before presentation, he was on vacation in Turkey where he consumed raw dairy products at a rural farm. He was febrile but his physical examination was normal otherwise. Lab investigations revealed a CRP level of 13.5 mg/L and CSF analysis showing a WBC count of 59 cells/mm3 (polymorphonuclear cells of 23% and lymphocytes of 71%), RBC count of 3 cells/mm3, protein level of 0.43 g/L and glucose level of 54 mg/dL (serum glucose was 100 mg/dL). His blood and CSF cultures were negative for Brucella spp. and so were the AFB satin, culture, and MTB-PCR. Nevertheless, his Brucella serum serology revealed an antibody titer of 1:1280 for both, B. melitensis and B. abortus. He was admitted as a case of neurobrucellosis and was started on ceftriaxone 2 g IV every 12 h, amikacin 720 mg (7.5 mg/kg) IV every 12 h, doxycycline 100 mg orally every 12 h and rifampin 900 mg orally once daily. Ten days later, he stared having spikes of fever reaching 40 C, a thorough physical examination and work up were done and they were negative for any potential infection or reason for fever. Thus, antibiotic-induced fever was suspected due to ceftriaxone, thus, it was discontinued despite the overall improvement of the patient's central nervous system symptoms. Ceftriaxone was replaced with ciprofloxacin 400 mg IV every 8 h. As the fever persisted and liver enzymes were noted to increase, rifampin was stopped as well. In less than a week, rifampin was reintroduced. However, 90 min after the dose, the patient experienced shortness of breath, rash, swelling and redness of skin. His reaction was managed immediately with antihistamine and hydrocortisone. This allergic reaction was presumed to be attributed to rifampin; hence, it was stopped and never introduced again. Moreover, the patient also complained of reduced hearing in his right ear which was suspected to be due to an ototoxic effect of amikacin which resulted in its discontinuation. In order to enhance the management of neurobrucellosis, trimethoprim/sulfamethoxazole (TMP/SMX) double strength was started orally; yet, the patient had an episode of vomiting, so it was switched to IV which was well tolerated. Later on, as the patient was being prepared for discharge, IV TMP/SMX was stepped down to the oral formulation again. A lumbar puncture was repeated before discharge and showed an improvement from baseline with WBC count of 4 cells/mm3 (lymphocytes of 86%), RBC count of 9 cells/mm3, 0.33 g/L of protein and 61.2 mg/dL of glucose (serum glucose was not available at this point of time). Repeated antibody titers for B. melitensis and B. abortus were 1:640 and 1:320, respectively. The patient was discharged on doxycycline 100 mg orally every 12 h, ciprofloxacin 750 mg orally every 12 h and TMP/SMX double strength orally every 12 h. In his first outpatient visit one month after discharge, the patient admitted to voluntarily discontinuing TMP/SMX due to severe episodes of vomiting and refused to take it again; however, he continued taking doxycycline and ciprofloxacin which resulted in clinical success (after a total of 18 weeks on doxycycline and 16 weeks on ciprofloxacin).

brucella, brucellosis, cases, ceftriaxone, saudi arabia, zoonotic infection

PMC6744365_04

Male

A 25-years-old man who was previously healthy came to the hospital complaining of left lower limb pain that progressed to limb weakness with decreased ability to walk. Physical examination revealed moderate lower limb weakness with foot drop. It was worse on the left side with lower motor neuron lesion findings. He had normal sensory exam. He reported drinking raw camel milk three months before the first episode of pain with a family member who was diagnosed with brucellosis recently. There was no tuberculosis contact. Since the patient was suspected to have neurobrucellosis, lumbar puncture was done. CSF analysis showed a WBC count of 420 (polymorphonuclear cells of 4% and lymphocytes of 90%) cells/mm3, RBC count of 18 cells/mm3, elevated protein level at 2.45 g/L and glucose level of 21.6 mg/dL (serum glucose was 81 mg/dL). The CSF culture was positive for Brucella species. The acid fast bacilli stain and culture were negative, as well as the MTB-PCR. Other investigations including tests for hepatitis B and C viruses and human immunodeficiency virus (HIV) 1 and 2 were all negative. Serologically, antibody titers results from the CSF for B. melitensis and B. abortuswere 1:160 and 1:80, respectively. His serum titers were not obtained initially. His CRP level was within normal limits. The patient refused to have a tuberculin skin test. An MRI of lumbosacral spine revealed enhancement of cauda equina nerve roots and surface of thecal sac, as well as L5-S1 degenerative changes with central posterior disc bulge indenting the ventral aspect of the thecal sac with no significant neural compromise associated with intervertebral disc dehydration (Image 3). He was admitted as a case of cauda equina syndrome secondary to neurobrucellosis and was started on ceftriaxone 2 g IV every 12 h, amikacin 500 mg IV every 8 h, doxycycline 100 mg orally every 12 h and rifampin 900 mg orally once daily. The initial plan was to continue the antibiotics with daily physiotherapy then re-evaluate after 6 weeks. However, two weeks into the treatment, the patient's status deteriorated significantly, from difficulty walking to being completely bed bound. Repeated work up showed no other significant findings. Furthermore, after 4 weeks of treatment, the patient started complaining of decreased hearing and pain in both ears resulted in discontinuation of amikacin. Six weeks into therapy, a repeated lumbar puncture did not show a significant improvement with a CSF analysis showing a WBC count of 315 cells/mm3 (polymorphonuclear cells of 41% and lymphocytes of 45%), RBC count of 15 cells/mm3, protein of 3.73 g/L and glucose level of 23.4 mg/dL (serum glucose was 82 mg/dL). Serum antibody titers were 1:320 and 1:80 for B. melitensis and B. abortus, respectively. Since the CSF repeated culture returned negative for Brucella spp., prednisone 1 mg/kg tapering dose was added aiming to reduce further nerve impingement. Luckily, the patient started to show clinical improvement and the IV ceftriaxone was discontinued after completing six weeks of treatment. The patient continued to restore his lower limb power and he was able to transfer to the wheelchair independently. Hence, he was discharged on doxycycline 100 mg orally every 12 h and rifampin 900 mg orally once daily for one year. The patient was scheduled for follow up in both the infectious diseases and neurology clinics. On his outpatient visits, the patient showed remarkable improvement of his lower limb weakness and he restored the ability to walk again using a cane. Serum antibody titers for both Brucella strains were at 1:80 and CRP remained within the normal range.

brucella, brucellosis, cases, ceftriaxone, saudi arabia, zoonotic infection

PMC6744365_06

Male

A 44-year-old man with a history of recurrent epididymo-orchitis presented to the emergency department complaining of an on-and-off scrotal pain for the last 15 days and low grade fever for which he was given ciprofloxacin for 10 days and acetaminophen (paracetamol) from another hospital. This regimen helped managing his symptoms; however, they were not resolved rendering him seeking medical help at our institution. There were no histories of contact with a tuberculosis patient or raw milk consumption. On physical examination, his scrotum was enlarged, swollen and tender. An ultrasound revealed both testes were of normal size; however, there was bilateral significant increased vascularity in both testicles and both epididymal heads. The scrotal skin was not thickened. There was a slightly increased echogenicity of both testes and a small left hydrocele was identified. There were a few (about four) tiny echogenic foci noted within the left testicle likely representing small calcifications. Physical examination findings of regional lymph nodes and skin were not significant. While awaiting other investigations, the patient was started on ciprofloxacin 400 mg IV every 12 h as an empiric therapy. Blood culture came back negative for Brucella spp.; however, antibody titers were positive for B. melitensis and B. abortus at 1:1280 for both strains. CRP level was 6.8 mg/L. The patient was diagnosed with Brucella epididymo-orchitis, but refused to undergo lumbar puncture for further investigation. Due to lack of clinical improvement, ciprofloxacin was discontinued three days later and was replaced by ceftriaxone 1 g IV every 12 h, doxycycline 100 mg orally every 12 h and rifampin 900 mg orally once daily. After two doses of 900 mg rifampin, the dose was decreased to 600 mg orally once daily though nothing in the patient's notes indicated the reason for the dose change nor the liver enzymes were elevated. After ten days of treatment, ceftriaxone was stopped and the patient was discharged on doxycycline 100 mg orally every 12 h and rifampin 600 mg orally once daily for a minimum period of three months. Before discharge, the patient was clinically improving as demonstrated by the decreased swelling and tenderness of his scrotum. On his first visit as an outpatient 2 weeks after discharge, the patient reported no new complications and appeared clinically well. Tests showed no signs of drug-induced hepatotoxicity, so the rifampin dose was increased to 900 mg orally once daily. On examination, his scrotum appeared to be relieved of the swelling and decreased in size. CRP level decreased slightly to 5.21 mg/L. A week later, the patient came again for follow up. While the patient did not show up for the next visit, his Brucella epididymoorchitis was deemed cured based on the improved clinical findings and decreased CRP. No repeated serology was done.

brucella, brucellosis, cases, ceftriaxone, saudi arabia, zoonotic infection

PMC9850095_01

Male

A 12-year-old boy with a one-year history of muscle weakness and gait disturbance that progressed slowly presented to our hospital. He had no remarkable past medical history or family history of metabolic bone disease. Roentgenographic examination revealed a deficiency of mineralization like that seen in rickets patients in the epiphysis of the bilateral proximal tibias and distal femurs ( Figure 1A ), and a radiolucent lesion with endosteal scalloping and marginal sclerosing in the left fibula ( Figure 1B ). Blood examination revealed a low serum phosphorus level of 2.3 mg/dL (reference range: 3.0-4.7 mg/dL), and a markedly high serum FGF23 level of 329 pg/mL (reference range: <50 pg/mL), and so we suspected PMT with TIO caused by the tumor-like lesion in the left fibula. We resected the tumor en bloc by preserving the periosteum of the fibula after confirming its benignity by intraoperative frozen section diagnosis, and the cavity of the tumor was filled with beta-tricalcium phosphate (beta-TCP) ( Figure 1C and Supplemental Figure 1 ). The muscle weakness gradually improved, and the gait disturbance normalized within two months. In the postoperative 21-month follow-up, he had no symptoms, and hypophosphatemia was not detected. Roentgenographic examination revealed absorption of the beta-TCP and bone formation and union of the fibular shaft ( Figure 1D ). Histopathological examination of the resected tumor revealed irregularly deposited osteoid and osteoblast-like tumor cells scattered between the osteoid and reactive osteoclastic giant cells ( Figure 1E and Supplemental Figure 2 ). In immunohistochemistry, expression of FGF23 was shown in the cytoplasm of the osteoblast-like tumor cells ( Figure 1F ), CD56 was diffusely positive on the cell membrane of the tumor cells and SATB2 was diffusely positive on the tumor cells ( Supplemental Figure 2 ). After resecting the tumor, the serum FGF23 level started to decrease immediately and normalized within 3 hours ( Figure 1G ). It was also within the normal range five days after surgery. The increase in serum phosphorus level was slightly delayed as compared with that of the FGF23 level, and was observed 6 days after the operation ( Figure 1H ). We performed RNA sequencing using a resected specimen from the patient and identified a novel in-frame fusion involving NIPBL (encoding Nipped-B gene product and fungal Scc2-type sister chromatid cohesion proteins) and BEND2 (encoding a protein which has two BEN domains in the C-terminus) ( Figure 2A ). The fusion protein contained the phosphorylation site derived from NIPBL and the BEN domain derived from BEND2 ( Figure 2B ). Whole-exome sequencing identified three point mutations (IFT172:NM_015662:exon3:c.A263G:p.N88S; VAF = 0.22, GAB2:NM_080491:exon6:c.A1409G:p.D470G; VAF = 0.15, and PRKCH : NM_006255:exon14:c.A1996T:p.I666F; VAF = 0.17), none of which were reported as driver mutations. In polymerase chain reaction, the amplification of target regions containing breakpoint of the chromosomal structure was confirmed using two primer sets in tumor DNA of the PMT ( Supplemental Figure 3 ). We cloned and transfected the NIPBL-BEND2 fusion gene to HEK293T and MG63 osteoblast lineage cell line. The NIPBL-BEND2 transfected cells showed faster proliferation at 48 hours after transfection (p = 0.001 and 0.003, Student's t-test, respectively). ( Figures 2C, D ). A gene set enrichment analysis of the fusion gene-introduced HEK293T cells identified a significant enrichment of MYC-target genes, consistent with faster proliferation ( Figure 2E ). However, the expression of FGF23 (log2 fold change; 0.031) and FGFR1 (log 2 fold change; 1.59) was not changed significantly by the transfection in addition to the KL/KLB, SPP1, SFRP4, and MEPE ( Supplemental Data 1 ), even though the tumor mRNA showed relatively high FPKM in these genes ( Supplemental Table 3 ).

rna sequencing, bone tumor, fusion gene, phosphaturic mesenchymal tumor, tumor induced osteomalacia, whole exome sequencing

PMC3523579_01

Male

A 28-year-old nonsmoking male was referred for diagnostic evaluation of recurrent mild haemoptysis associated with a right upper lobe solitary pulmonary nodule of 8 weeks duration. Chest radiograph revealed a 1.5 x 2 cm coin lesion in the posterior segment of the right upper lobe of the lung (Figure 1). The medical history was noncontributory. A computed tomographic (CT) scan of the chest confirmed the chest radiograph findings; a solid mass was noted in the posterior segment of the right upper lobe of the lung with an area of central lucency (Figure 2). There was no hilar lymphadenopathy. Sputum microscopy, culture, and cytological examination were noncontributory. The ESR was 14, the haemoglobin 14.6 g/dL, and the leukocyte count of 8.8 x 109/L. The other serum haematological and biochemical results were normal. In view of the patient's ongoing haemoptysis and lack of response to antibiotics he was subjected to an exploratory thoracotomy and wedge resection of the lesion in the right upper lobe. A solid mass in the posterior segment of the right upper lobe was noted and it was excised. No associated lymphadenopathy was noted. Frozen section of the mass revealed no evidence of carcinoma or tuberculosis. The patient developed a right upper lobe lung abscess postoperatively, and underwent a complete right upper lobe lobectomy. Macroscopically, a well-circumscribed tan-coloured nodule measuring 35 x 15 mm was present. The cut surfaces of the tumour revealed a haemorrhagic necrotic centre. Microscopically, the mass consisted of a heavy inflammatory cell infiltrate composed predominantly of lymphocytes, with plasma cells and histiocytes. Foamy histiocytes with macrophages were also seen, as well as occasional eosinophils and neutrophils. Focal areas of micro-abscess formation with necrosis were also noted. A marked degree of fibrosis of the interstitial tissue was present with proliferating myofibroblasts. The histological characteristics were compatible with an inflammatory myofibroblastic pseudotumour (organising pneumonia-like type; Figure 3). The postoperative course was uneventful, the patient was discharged from the hospital one week later, and three years after surgical resection the patient remains well and free of disease.

PMC5723361_01

Female

A 67 year old diabetic lady presented with left groin pain for three weeks off and on associated with fever to the Orthopedic Clinic at the Aga Khan University Hospital, an academic tertiary care hospital in Karachi, Pakistan. She underwent un-cemented unipolar hemiarthoplasty of the left hip 8 years back. On examination, she was unable to elicit active movements at left hip. Personal and family history was negative for tuberculosis and wound infection at the index hip surgery. There was no relevant drug, family and genetic and psychosocial history. Lab workup was done which showed raised serum infective markers. White cell count was 11.9 x 109/L, erythrocyte sedimentation rate was 118 mm/h (0-20) and CRP was 13.45 mg/dl (0-0.5). Urine culture was negative. Chest radiograph was normal. Hip radiographs demonstrated uncemented unipolar left hip arthroplasty with no evidence of any radiolucency or prosthetic loosening (Fig. 1). Moderate degenerative changes were found on radiograph of lumbosacral spine more marked at L4-L5 and L5-S1 level. Ultrasound of hip joint was performed before proceeding with surgery. Two ml pus was aspirated and culture showed growth of E. coli. Due to left groin pain, markedly elevated ESR and CRP and positive culture from hip aspiration, patient was planned for left hip arthrotomy. The surgery was performed by a consultant orthopaedic surgeon. The previous Moore approach was used for left hip arthrotomy. Hip joint appeared normal and implant was noted to be well fixed. Clear fluid was noted in hip joint at the level of psoas muscle. Pus was debrided at the lesser trochanter. Tissue sample was sent for culture and sensitivity which showed E coli and histopathology reported with psoas abscess. Computed tomography scan of abdomen was performed showing bilateral perinephritic fat standing with dilated ureters suggestive of Pyelonephritis (Fig. 2). Patient was seen by infectious disease service. Patient tolerated the procedure well and there were no postoperative complications. Post operatively she was started on antibiotics which were continued for three months. She was mobilized weight bearing as tolerated with support postoperatively.The range of motion was restored with normal gait, initially ambulating with support followed by progressive improvement in her range of motion to 70 flexion, 30 abduction, 10 internal rotation and 15 external rotation within two weeks. ESR and CRP returned to normal limits. Twenty months later, she remains asymptomatic without evidence of infection.

case report, prosthetic hip infection, psoas abscess, pyelonephritis

PMC6010925_01

Male

A 37-year-old Iranian male patient was admitted to the Shohadaye Ashayer Hospital, Khorramabad, Iran, in 2016 with the complaints of weakness, anorexia, fatigue, weight loss along with fever and chills. The fever was dramatically exacerbated at nights and it was accompanied with sweating, dyspnea, and nonbloody sputum. The patient had been bothered by anal pain and discharge. The symptoms had started 7 days prior to his referral to the hospital. The patient added that all of the above-mentioned symptoms emerged a week (2 weeks before his referral to the hospital) after he had undergone anal fistula surgery and pilonidal sinus surgery due to rectal bleeding that had lasted for 9 months. He had also lost weight up to 12 kg over the previous 5 months. He had received antimicrobials and analgesia in the aftermath of his anal surgery, including metronidazole, ciprofloxacin and acetaminophen. The patient had a history of smoking, opium use and IV drug injection. Historically, he was not known to be immunocompromised and had no close contact with a case of tuberculosis. On physical examination, he was fully alert and conscious and could actively participate in a conversation. His vital signs were as follows: temperature: 37.9C, heart rate: 86 beats/min, blood pressure: 100/70 mm/Hg, and respiratory rate: 18 breaths/min. In general, he seemed well. Thoracic and abdominal examinations were completely normal, respiratory and cardiac sound were normal and jugular venous pressure was not raised, nor was any lymphadenopathy detected. On the examination of the anus, anal erythema and swelling as well as discharge near the site of surgery were observed. Standard blood tests are shown in Table 1. A PPD was negative. He was found be HIV antibody positive as well as anti hepatitis C positive. Chest X-ray did not reveal any abnormalities and the CT of the chest was also negative. The CT scan of the abdomen/pelvis with contrast revealed thickening of the rectum (Fig. 1). A colonoscopy revealed grade 2 internal hemorrhoids, many small aphthous ulcers in the rectum and normal sigmoid and descending colon (Fig. 2, Fig. 3). An AFB stain of the ulcers was negative. The biopsy showed chronic granulomatous proctitis (Fig. 4). Staining was positive for acid fast bacilli. The patient was then begun on standard four drug therapy for TB. The cultures for TB were positive and his symptoms and lesions healed.

aids, acquired immunodeficiency syndrome, anal, ct, computed tomography, esr, erythrocyte sedimentation rate, fistula surgery, hb, hemoglobin, hiv, human immunodeficiency virus, iv, intravenous, igg, immunoglobulin g, igm, immunoglobulin m, mtb, mycobacterium tuberculosis, tb, tuberculosis, tuberculosis, vdrl, venereal disease research laboratory

PMC6796728_01

Female

Patient is a 26-year-old female with a past medical history of HIV. She was infected at age 15 and showed poor adherence to antiretroviral medication. She reported the combined use of Tenofovir, Emtricitabine, and Efavirenz intermittently, mostly because she did not seek adequate healthcare due to feelings of shame about being associated with the disease. She also missed most of her follow-ups in the last year, and had no CD4 counts or viral load tests performed in over 6 months. She also suffered from intermittent episodes of coughing, bloody stools, and weight loss during this time; however, she didn't seek any medical attention. She presented to our emergency room with a 10-day history of intermittent lower abdominal pain, nausea, biliary vomits and asthenia. Approximately 24 h prior to admittance, the pain became worse. On clinical examination, a dehydrated, hypotensive and tachycardic patient was encountered. Her abdomen was diffusely tender, and the pain became more intense on touch. Laboratory exams revealed mild leukocytosis and neutrophilia. An arterial gasometry revealed metabolic acidosis with hyperlactatemia. In view of these findings, surgical consultation was requested and a diagnosis of diffuse peritonitis was reached. Aggressive fluid resuscitation with crystalloids was started and an emergency laparotomy was decided. At surgery, the peritoneal cavity was filled with 500 ml of pus and 2 bowel perforations were identified: a 1 x 1 cm perforation in the terminal ileum, 50 cm proximal to the ileocecal valve, and a 3 x 2 cm perforation in the cecum (Fig. 1A-C). A right colectomy was decided, however, the surgical team had doubts about restoring bowel continuity. Nonetheless, since the patient became stable after reanimation and surgery, restoration was considered feasible. Given the context of an HIV patient with poor controls who would be unlikely able to handle an ileostomy, a primary anastomosis with close surveillance was decided. Resection began 10 cm proximal to the ileal perforation and ended near the hepatic flexure of the colon. Then, a side-to-side ileotransverse anastomosis was performed with 75 mm staples (ETHICON Linear Cutter NTLC75, Johnson & Johnson). Extensive washing of the peritoneal cavity was completed and the remainder of the procedure was performed without complications. Based on the historical, clinical, and laboratory data obtained, we initially considered intestinal perforation due to cytomegalovirus (CMV) infection as the probable etiology of peritonitis, and the differentials included, mycobacterial infections, fungal infections, neoplastic disease or Kaposi sarcoma. However, definitive pathology tests for the cause of the perforation were delayed due to the unavailability of an in-house pathologist. Furthermore, other essential tests including CD4 counts and HIV viral loads and antibodies (both IgM and IgG) were not available at our institution. This situation was further complicated by the lack of resources from the patient and our hospital; nonetheless, we managed to send a blood sample to a nearby hospital for testing. Even under these harsh conditions, the patient had a good recovery. She was placed under broad-spectrum antibiotics (Piperacillin/Tazobactam) and was given a 3-day cycle of Ganciclovir. Antiretroviral Therapy (ART) was initiated as well. Meanwhile, sips of liquids were initiated on the second postoperative day without complications. She didn't have any episodes of fever, nausea, vomiting or signs of anastomosis leak. At the 7th postoperative day, the patient requested to leave against medical advice (AMA), she signed the hospital consents and left our facility. Two days after the patient went AMA, CD4 and HIV viral load results arrived along with the pathology report, revealing chronic inflammation of the resected bowel, and multiple ulcers affecting the mucosa of the ileum and the cecum. Also, multiple granulomas surrounded by inflammatory tissue were recognized, as well as some granulomas within the lymph nodes. Bowel perforation due to tuberculosis was confirmed as the final diagnosis, CD4 cell counts were estimated at 94 cells/mm3, and the viral load was estimated at over 106 genome copies (Fig. 2A-C). Since tuberculosis in Ecuador is a mandatory declaration disease, we searched for the patient and found her in the coastal region of the country. Fortunately, she was stable and without complications. She was taken by the national healthcare system and admitted to a tertiary hospital for HIV and tuberculosis treatment.

hiv, hiv/tb coinfection, intestinal tuberculosis, tuberculosis

PMC8573117_01

Unknown

A 4-year old, male-castrated, mixed breed dog was presented to a primary care veterinarian for a routine wellness examination (day 1). The dog was adopted 7-months prior and the previous medical history was unknown. The owner reported that the dog exercised daily without limitation, lived indoors only, and had no history of trauma. The dog was fed a commercial kibble diet and not administered any medications or supplements. The physical examination, which included thorough neurologic, musculoskeletal, and cardiopulmonary evaluations, was unremarkable. A complete blood count, serum biochemistry, symmetric dimethylarginine (SDMA), and urinalysis were performed. Clinically relevant abnormalities on the serum biochemistry performed at that time included a severe hyperCKemia (15,137 IU/L; reference interval 10-200 IU/L), and moderate increases in alanine transaminase (ALT; [432 IU/L; reference interval 180-121 IU/L]) and aspartate aminotransferase (AST; [404 IU/L; reference interval 16-55 IU/L]) enzyme activities. The complete blood count, SDMA, and urinalysis were unremarkable. A serum biochemical profile was repeated 7-days later, which revealed persistently increased serum CK activity (10,301 IU/L) as well as ALT (409 IU/L) and AST (290 IU/L) enzyme activities (Figure 1). Recommendations for additional diagnostic testing were declined by the owner in favor of empirical treatment for potential toxoplasmosis/neosporosis with clindamycin (22.7 mg/kg, PO, q12 h for 14 days). The dog was presented for evaluation on day 55. The owner reported no clinical changes in the dog and the physical examination remained unremarkable. A serum biochemistry was repeated and revealed relatively unchanged serum CK, ALT, and AST enzyme activities (Figure 1). A commercial ELISA-based kit (4DX SNAP Plus Test kit, IDEXX Laboratories Inc., Westbrook, ME) was negative for detection of antibodies for Ehrlichia sp., Anaplasma phagocytophilum, Anaplasma platys, Borrelia burgdorferi C6 peptide, and Dirofilaria immitis antigen. Differential diagnoses considered by the primary care veterinarian at that time included infectious polymyositis (Toxoplasma gondii or Neospora canis [potentially resistant to clindamycin], Hepatozoon canis or americanum), immune-mediated polymyositis, paraneoplastic polymyositis, congenital myopathy, or a hereditary muscular dystrophic disorder. The following diagnostic tests were recommended; skeletal muscle biopsy, electromyogram (EMG), echocardiogram, serum antinuclear antibodies, and additional infectious disease testing. The owner declined these recommendations because the dog was subclinical and instead opted for an additional course of clindamycin (22.7 mg/kg, PO, q12 h for 30 days). The dog was presented for evaluation on day 97. Again, the owner reported no abnormalities and the dog had an unremarkable physical examination. A serum biochemistry revealed relatively unchanged serum CK, ALT, and AST enzyme activities (Figure 1). All additional diagnostic testing recommendations were declined and the dog was discharged without medications. The dog was presented to the primary care veterinarian for a wellness examination on day 602. The owner reported no abnormalities since the dog was last evaluated (day 97). The dog continued to exercise daily without limitation. Physical examination was unremarkable. There was no pain elicited with muscle palpation. A complete blood count, serum biochemistry, and urinalysis were performed. The serum biochemistry revealed persistence in severe hyperCKemia and mild to moderate increases in ALT and AST enzyme activities (Figure 1). The complete blood count and urinalysis were unremarkable. The owner declined additional diagnostic tests or empirical therapies at that time because the dog did not demonstrate any clinical abnormalities. The dog was then presented to the Midwestern University Companion Animal Clinic (MWU-CAC) on day 1,036 for a second opinion regarding the severe hyperCKemia and mild-to-moderate increase in ALT and AST enzyme activities. The dog remained subclinical and exercised daily without limitation. A physical examination performed by a boarded small animal internist (JAJ) was unremarkable. The dog had a normal muscle conditioning score and pain was not elicited with deep palpation of musculature. A neurologic examination performed by a boarded neurologist (JE) revealed the dog was bright, alert and responsive. The dog was ambulatory with no signs of stilted gait, lameness or paresis. There was no overt exercise intolerance after several minutes of walking and trotting. Postural reactions, spinal reflexes and cranial nerves were normal. Serum biochemistry revealed an unchanged severe hyperCKemia and persistent mild-to-moderate derangements in ALT and AST enzyme activities (Figure 1). The dog was negative for detection of antibodies (IgM and IgG) for Toxoplasma gondii or Neospora canis (Protatek Reference Laboratory) and nucleic acids associated with Hepatozoon spp. (Texas A&M Veterinary Medical Diagnostic Laboratory) were not detected. An abdominal ultrasonogram performed by a boarded small animal internist (JAJ) trained in ultrasonography was unremarkable. Differential diagnoses considered at that time in order of likelihood was hereditary muscular dystrophy, and less likely necrotizing myopathy, generalized or focal inflammatory myopathy. Additional diagnostic tests including EMG, echocardiogram, or skeletal muscle biopsies were offered but declined by the owner. The dog was evaluated on day 1,516 at the MWU-CAC for a pre-anesthetic examination for a dental prophylactic procedure. The owner reported no abnormalities since the dog was last evaluated (day 1,036) and the physical examination remained unremarkable. The dog had no muscle loss and remained active at home. A serum biochemistry revealed an improved, but persistent moderate hyperCKemia and mild-to-moderate increase in ALT and AST enzyme activities (Figure 1). A complete blood count and urinalysis were unremarkable. Next, an echocardiogram and electrocardiogram were performed by a boarded cardiologist (CP) in light of the persistent and unknown cause of severe hyperCKemia to ensure the dog did not have clinically relevant heart disease before undergoing anesthesia. Based on the echocardiographic findings, ACVIM Stage B1 degenerative valvular disease was detected, and demonstrated mild mitral and mild tricuspid regurgitation. The global systolic function appeared preserved. During the echocardiogram, Lead II electrocardiographic monitoring revealed a normal sinus rhythm with no evidence of ectopy. The last in-hospital recheck examination took place on day 1,807 (5 years from initial evaluation). The owner reported no clinical abnormalities and the physical examination was unremarkable (Supplementary Video). The neurological examination was again normal. A serum biochemistry revealed a moderate hyperCKemia (4,601 IU/L) and mild-to-moderate increases in ALT (225 IU/L) and AST (165 IU/L) enzyme activity (Figure 1). Electrophoretic identification of serum CK isoenzymes (Antech Diagnostics, Irvine, CA, USA) revealed that CK-MM was the predominant electrophoretic fraction (83.7%), followed by CK-MB (10.3%) and CK-BB (6.0%). No injections were administered to the dog at or near the time serum total CK was measured at any of the examination time-points.

ck, canine, hyperckemia, muscular dystrophy, myopathy

PMC8794318_01

Female

A 67-year-old female patient, complaining a history of poorly responsive bronchitic episodes and atrial fibrillation, underwent radiological work up after detection on January 2018 of a suspicious right upper lobe pulmonary lesion at chest X-ray. CT scan confirmed a right S1 irregular solitary nodule with signs of both mediastinal and parietal pleura involvement with concomitant multiple bilateral lymphadenopaties (stations 3, 4, 5) (February 2018). According to findings, an EBUS-TBNA bronchoscopy was performed on March 2018. The immediate postoperative period was uneventful as no intraoperative injuries, such as vascular or parenchymal ones, were reported. The hospital stay was uneventful and the patient was discharged on POD1. Twenty-four hours later, she was admitted to the Emergency Room Department due to the onset of relapsing episodes of haemoptysis. At admission, no impelling signs of cardiovascular impairment were reported (BP: 145/80 mmHg, HR: 88 beats per minute, T: 36.5 C, SaO2: 95%), as far as neither laboratory nor radiology highlighted any suggestive element for post-procedural complication. At a rapid worsening of patient's clinical conditions requiring emergent oro-tracheal intubation, an urgent fibro-bronchoscopic evaluation showed the presence of an obstructive and non-viable subglottic formation with unsuccessful attempts of disobstruction till the onset of an irreversible cardio-circulatory arrest (Figure 1) due to acute respiratory distress and airway engorgement asphyxia. On autopsy, both lungs presented evident bloody polygonal areas alternating with compensatory emphysema ones. After en-bloc sampling of the airways, esophagus and heart, the section of the tracheal pars membranacea highlighted the presence of a blood clot that extended from the middle third of the tracheal lumen to the terminal bronchioles of both lungs (Figures 2,3). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committees and with the Helsinki Declaration (as revised in 2013). No written informed consent has been obtained as anonymous data have been reported.

endobronchial haemorrhage, bronchoscopy, case report, endobronchial ultrasound transbronchial needle aspiration (ebus-tbna), lung cancer, lung nodule

PMC8046462_01

Female

This was a 9-year-old female patient referred from Kibuye Hospital in the Western province of Rwanda for further investigations and management of the left calcaneal mass suspected to be an osteosarcoma. The condition had persisted for 4 months before consulting our clinic at Kigali University Teaching Hospital CHUK for the left heel pain and swelling. The examination noted a history of fever, weight loss and swelling of the left foot extending to the whole lower limb without cough. Consulted, as structured health system, Birambo Health Centre, then Kirinda district hospital where she received different treatment (that we are unable to get their records for proper identification), without improvement. After 2 weeks, a pus discharging sinus appeared on the heel mass. Two months later, the patient noted right hip swelling with inability to stand and walk. She consulted Kibuye Referral Hospital, from where she was referred at CHUK on December 1, 2017, for further management of possible osteosarcoma of the left calcaneus. No history of trauma nor TB contact. On physical examination: Temperature was 37.6 C, respiratory rate of 20 cycles/min, pulse of 97 beats/min; two ulcerated wounds on the lateral aspect of left ankle and heel, swollen and tender ankle joint, two mobile, non-tender, small inguinal lymph nodes on the left side, limited range of motion of right hip joint with tenderness and mild shortening of right lower limb. COM of the left calcaneum with pus discharging sinuses Left foot synovial sarcoma/Ewing sarcoma TB of the left calcaneum and right hip. As management, she received analgesics, daily wounds care and different clinical pathology tests were requested (Table 1). Imaging studies including computed tomography (CT) scan of the left foot (Fig. 1a, b and d) and pelvic X-ray (Fig. 1c). CT scan results (December 8, 2017): Lytic and sclerotic calcaneal tumor consistent with osteogenic sarcoma, the differential diagnosis is COM. She was admitted on December 14, 2017, on December 18, 2017, curettage and biopsy were performed under general anesthesia and pre-operative chest X-ray was normal. The patient was discharged home on December 20, 2017. On January 10, 2018, microscopic examination of the calcaneal mass curettings (Fig. 2) revealed rare poorly formed granuloma, rare multinucleated giant cells, and mixed acute and chronic inflammatory cell infiltrates in favor of possible extrapulmonary TB. The special auramine-rhodamine stain was positive for acid-fast bacilli (Fig. 2). On February 8, 2018, the patient was referred to pediatric outpatient department (OPD) seen in OPD for TB treatment, as follows: Rifampicin, isoniazid, pyrazinamid, and ethambutol (R75 mg H50 mg Z50 mg E100 mg) 8 tablets per dose for 12 days and then for 48 days. Rifampicin, isoniazid (R75H50) for the remaining period. Pyridoxine 25 mg/day was associated for the two 1st month. On July 9, 2018, she was reviewed in OPD with persistent small sinus on the left heel. Walking with axillary crutches. The X-rays showed sequestrum and sclerosis of calcaneum, distal tibia, and fibula (Fig. 1d). We did a sequestrectomy under general anesthesia at Kibuye Hospital in citizen outreach program. She was discharged and advised to continue anti-TB. On November 29, 2018, she was reviewed and had significantly improved and gained weight; sinuses healed, mild limping with limb length discrepancy of around 1 cm (right being short) and she could stand and walk with the aid of one axillary crutch. Had a limb length discrepancy of around 1 cm (right being short). The liver function test, renal function test, and hemogram test were normal. Control X-rays and morphology picture of the limb were obtained at the same time (Fig. 3).

calcaneus, rwanda, tuberculosis

PMC8639279_01

Male

A 74-year-old male patient with a known case of benign prostatic hyperplasia (BPH) presented on 17 October 2020 to the emergency department (ED) with fever and progressive generalized fatigability for 10 days. He had a history of dysuria for two weeks, in addition to polyuria, mild night sweating, and weight loss of 10 kg in one month. There was no history of upper respiratory tract infections, nausea, vomiting, diarrhea, or abdominal pain. He reported a history of drinking unpasteurized milk and contact with farm animals but denied any history of contact with tuberculosis (TB) patients. There was no history of diabetes mellitus (DM). There was no family history of malignancy or rheumatologic disease. Prior to this presentation, he had frequent visits to the ED due to increased fatigability and joint pain. However, no diagnosis was established, and the treatment was often conservative. On this admission, he was managed empirically with intravenous (IV) tazocin and IV paracetamol, given his history. A septic workup was also performed. Laboratory investigations revealed positive serology for Brucella abortus and Brucella melitensis, elevated erythrocyte sedimentation rate (ESR) (58 mm/hr), C-reactive protein (CRP) (165.08 mg/dl), and leukocytosis (23.32x103/muL). Chest X-ray (CXR) was unremarkable. The patient was diagnosed with brucellosis and, eventually, discharged on doxycycline and rifampin. In addition, he was scheduled for a neurological follow-up to assess his progressive fatigability. After one month, on 17 November 2020, he was seen in the neurology clinic. The diagnosis of Guillain-Barre syndrome (GBS) was suggested as radiculoneuropathy, and axonal sensorimotor polyneuropathy was proven by electromyography (EMG) and nerve conduction study (NCS). Accordingly, the patient was admitted and received immunoglobulin (IVIG) as recommended by the neurologist. After one week of receiving IVIG, his condition was still not improving and he was referred to the outpatient rheumatology clinic to exclude possible vasculitic processes. Later on, the patient was seen in the rheumatology clinic complaining of multiple joint pain and swelling of wrists, fingers, elbows, knees, ankle, and foot, which started four weeks earlier to his visit. The pain and swelling in the knees and elbows almost completely improved after brucellosis therapy. However, he was still complaining of pain and swelling in the other joints, which usually worsened at night and improved with movement. Perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) was strongly positive (131), ESR was 53 mm/1 hr, and CRP was 132.83 mg/dL. Rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA), antinuclear antibodies (ANA), cytoplasmic anti-neutrophil cytoplasmic antibody (C-ANCA), and ferritin were all normal. Despite being on appropriate antibiotics treatment for brucellosis, his fever did not subside. It was recurring in episodes, with each episode lasting 20 minutes per day. The fever was not associated with sweating, shivering, or other constitutional symptoms. Furthermore, based on the constellation of several findings, which include the persisting fever despite appropriate antibiotic therapy, the EMG/NCS finding of axonal sensorimotor polyneuropathy, the persistence of elevated inflammatory markers, the positive P-ANCA, and imaging that did not show any masses or fluid collection, the likelihood of underlying systemic vasculitis was high according to the rheumatology team. Therefore, prednisolone 50 mg PO OD was started. In addition, he was continued on doxycycline and rifampin for another set of 11 days to complete six weeks of the brucellosis treatment course. After one week of being on steroids, his fever totally subsided and other symptoms had significantly improved. Also, his CRP started to decrease, reaching 79.59 mg/dl. However, P-ANCA was still high (119.4). Therefore, the decision was made to continue on prednisolone 50 mg for another week, followed by 40 mg for two weeks and then 30 mg for two weeks. On the next visit after four weeks on 27 December 2020, he reported significant improvement in his symptoms with no more joint pain and resumed his normal activities independently. Also, lab results showed decreased P-ANCA to 57.8 and CRP to 19.36 mg/dL. Azathioprine 50 mg PO twice a day was added while he continued taking steroids with a tapering dose. After four weeks, on 26 January 2021, he reported that he was no longer experiencing fever, fatigue, joint swelling, or pain. However, he could not actively flex or extend his left index finger or right thumb, which was attributed to his peripheral neuropathy. Therefore, azathioprine dose was optimized to 50 mg three times a day. The patient was reevaluated on 7 March 2021. He was found to be asymptomatic, with no active complaints. Subsequently, azathioprine dosage was reduced to 50 mg PO BID.

PMC9263511_01

Male

A 36-year-old Han-Chinese right-handed man (patient III-10, the proband) developed anxiety, depression, sleep disorder, and tremor in his hands after a panic attack but without known medical history. His cognitive state declined, and he was unable to perform job duties due to memory loss. At 11 months after onset, the patient became withdrawn, and more deterioration of his cognitive function was observed, indicated by the difficulty in calculating, being lost at home, and frequently forgetting the names of acquaintances. Besides, the tremors spread to bilateral limbs, which led to difficulty in cake decoration (the patient's profession). After 16 months of onset, he was diagnosed with depression and anxiety and was prescribed sertraline, fluphenazine, and piracetam. At 17 months after onset, he was scored 20 of 30 on the Chinese Mini-Mental Status Examination (MMSE), and 15 of 30 on the Montreal Cognitive Assessment (MoCA Beijing Version). The Hamilton's Depression Scale was 7. At 19 months after onset, he developed hallucinations, which made him see his sons as enemies, and occasionally, he protected himself via aggressive behaviors. In the clinic, the diagnosis of possible behavioral variant Frontotemporal Dementia (bvFTD) was considered because of the abnormal neuropsychological profile, such as early apathy and executive/gene deficits with relative sparing of memory and visuospatial functions. A thorough neurological examination 20 months after the onset revealed a total deterioration of the cognitive state, dysarthria, slight hypermyotonia, and deep tendon hyperreflexias in the bilateral limbs, and the patient presented cogwheel-like rigidity. He had difficulty finishing the finger-to-nose test and heel-knee-tibia test due to tremors in his limbs. The patient was unsteady when walking on a straight line. No involuntary movement was observed. He scored 15 of 30 on the Chinese MMSE, and 9 of 30 on the MoCA Beijing Version. The Hamilton's Depression Scale was 7. To our surprise, the brain MRI demonstrated abnormal intensities in the bilateral caudate nucleus, putamen, and cerebral cortex. A series of laboratory examinations were performed for the rapidly progressive early-onset dementia. The autoimmune screening and tumor marker identification were shown to be unremarkable or negative. An extensive panel for paraneoplastic antibodies including Amphiphysin, CV2, PNMA2 (Ma2/Ta), Ri, Yo, Hu, titin, SOX1, recoverin, zic4, GAD65, and Tr (DNER) were tested, and all were negative. Serology and cerebrospinal fluid (CSF) tests for HIV, cryptococcus, syphilis, tuberculosis, bacteria, fungus, and virus showed no evidence of inflammation. In addition, CSF 14-3-3 protein was tested to be negative. RT-QuIC tests of skin and CSF were also negative (Figure 2). Diffusion-weighted imaging (DWI) sequences displayed restricted diffusion in the bilateral frontal and parietal cortex (Figures 3A-D). DWI hyperintensities were revealed in the bilateral basal ganglia, bilateral pulvinar, and dorsomedial thalamus (Figures 3E-J). Fluorodeoxyglucose PET (FDG-PET) exhibited hypometabolism in the bilateral cerebral cortex and right basal ganglia (Figure 4). An empiric course of pulse IV gamma globulin was tried without notable improvement. At 22 months after onset, the hypermyotonia of the patient in the bilateral limbs became more obvious. He had occasional urinary incontinence, and his ability to study was relatively reserved when he scored 21 of 30 on the Chinese MMSE. The MRC Scale score was 13 of 20. The Hamilton's Depression Scale was 6. EEG showed diffuse slow waves. MRI scanning indicated no obvious change compared to images 2 months earlier. A follow-up study with the MRC Scale revealed gradually developed aphasia, gait disorder, and fecal incontinence 30 months after onset. The patient is still alive, 4 years after the onset, while the MRC Scale score was 2 of 20, and his swallowing function and mobility were still preserved (Table 1). The clinical features indicated that the patient might have prion disease. To determine the etiology of the disease, we extracted genome DNA from peripheral blood leucocytes of the patient and performed a direct DNA sequencing of the PRNP coding sequence. Unexpectedly, a rare mutation of G114V and 1-OPRD of the PrP in the patient was identified (Figure 5). Given that only a few patients with gCJD were reported to carry the G114V PRNP variant, we suspected that the mutation in the patient might be inherited from his parents, and we, thus, enrolled his immediate family members in this study for a genetic investigation. Although the medical record was not available, the maternal grandmother (patient I-2) of the proband was found to have progressive dementia in her 60s, which was within 1 year before her death, and subsequently developed a tremor in her last few months. The proband's mother (carrier II-8) received examination when she was 61 years old, but no neuropsychiatric symptoms were observed. She scored 29 of 30 on the Chinese MMSE and 21 of 30 on the MoCA (Beijing Version). Although the EEG showed slow waves in the left temporal lobe, both cranial MRI (including DWI) and FDG-PET were unremarkable. A follow-up study revealed that she suffered an acute cerebral infarction in the callosum 18 months after the first examination. No cortical ribbon was found by DWI to date (Table 2). Whereas DNA sequencing revealed a G114V mutation and 1-OPRD of PrP in this individual. The elder son of the proband (carrier IV-1) received DNA sequencing at age 10, and G114V mutation and 1-OPRD were also found, although he did not show any clinical symptoms. No further examination was performed due to his age. No autopsy or biopsy were performed on any of the patients.

g114v mutation, prnp, genetic creutzfeldt-jakob disease, one octapeptide repeat deletions, prion

PMC5738199_01

Male

A79-year-old Haitian man with a three-year history of painful oral ulcerations, progressive dysphagia, and weight loss who presented to our medical center directly after arrival from Haiti. On evaluation, the patient complained of acute worsening of oral pain, odynophagia, dysphagia and a two-week history of hoarseness. He also described weight loss, generalized weakness, and an intermittent non-pruritic, non-vesicular rash. The patient's past medical history was significant for hospitalization three years prior for diffuse oral ulcerations, dysphagia, and a wide-spread non-pruritic, keloid-like rash present on his torso and bilateral upper extremities. Nonspecific gastritis and a hiatal hernia were found on endoscopy; no further evaluation was performed and the patient was lost to follow-up. The patient traveled frequently between Haiti and New Jersey and had been a plantation farmer in Haiti since childhood. He worked primarily with vegetable crops, but had exposure to chickens, cows, and pigs. His sexual history was significant for multiple female sexual partners with only occasional condom use. He denied prior history of sexually transmitted diseases. He denied tobacco, alcohol, or illicit drug use. On initial examination the patient was cachectic and appeared chronically ill. Vital signs included a temperature of 37.3 C, heart rate of 84 beats per minute, respiratory rate of 16, and blood pressure of 221/105 mmHg. Oxygen saturation was 100% on room air. His weight was 42.9 kg with a body mass index of 14.8. He had pronounced bitemporal wasting, bilateral erythema of the forehead and cheeks and diffuse left-sided facial swelling. Multiple 3-5 mm ulcerations were present throughout the oral cavity, including on the hard and soft palates, tongue, and buccal mucosa. There was diffuse oropharyngeal edema and mucosal pallor and dryness. He was breathing comfortably with no stridor or wheezing. Additional findings included bilateral anterior cervical chain lymphadenopathy and hypopigmented and hyperpigmented areas of skin on the thorax, abdomen and extremities, including the soles of both feet. Significant laboratory findings included hyperkalemia (potassium 5.2 mg/dL), anemia (hemoglobin 11.6 g/dL) and hypoalbuminemia (albumin 3.3 mg/dL). Chest radiographs demonstrated pronounced airway narrowing and neck radiographs severe oropharyngeal and hypopharyngeal airway narrowing with subepiglottic stenosis. Computed tomography of the neck was performed and revealed diffuse thickening of the mucosal oropharynx, supraglottic larynx, aryepiglottic folds, piriform sinuses, and true/false vocal cords (Fig. 1, Fig. 2). Subsequent evaluation by otolaryngology with laryngoscopy revealed a granular edematous epiglottis, right aryepiglottic fold, and nasal vestibules without evidence of any distinct masses. Malignancy, autoimmune, and infectious etiologies were considered and further diagnostic studies were obtained. HIV antigen/antibody testing, HTLV, HSV, CMV, and RPR antibody tests were negative. His CD4 count was 345 cells/muL (normal 300-1400 cells/muL) with a decreased CD4 percentage of 21.3% (normal 28-57%) and an inverted CD4/CD8 ratio of 0.35 (normal 1.0-3.6). Histoplasma urine antigen and serum complement fixation antibody were negative. Interferon-gamma release assay (QuantiFERON -TB Gold) was negative. Epstein-Barr virus IgM and IgG were both positive. ANA was positive at a low titer (1:160) with a non-specific pattern. C3 and C4 values were within normal limits. Anti-smith, anti-RNP, anti-SSA/SSB, and C1 esterase inhibitor antibodies were negative. Serum protein electrophoresis was notable for an elevated IgG level of 1964 nmg/dL, of which 30.7% was composed of gamma globulin. His sedimentation rate was 59 mm/h and C-reactive protein was 10 mg/L. Blood cultures, including fungal blood cultures, were negative. Throat cultures grew Klebsiella pneumoniae and Serratia marcescens. Oral pharyngeal squamous cell carcinoma was considered the leading diagnosis and a biopsy of a labial mucosal ulcer was performed. Histologic examination of the biopsy revealed granulomatous mucositis with multinucleated giant cells containing multiple budding yeast forms (Fig. 3) that stained with Grocott's methenamine silver (Fig. 4) and were consistent with histoplasma species. Staining for acid-fast organisms was negative. Histoplasma was not recovered from tissue fungal cultures. On histologic identification of yeast consistent with Histoplasma, therapy with daily intravenous liposomal amphotericin B (5 mg/kg daily) was initiated. Despite aggressive intravenous saline hydration, acute kidney injury developed after only three doses of amphotericin, necessitating a change in antifungal therapy to itraconazole suspension. Due to the patient's extensive oropharyngeal inflammation and failed fiberoptic endoscopic swallow evaluations, a percutaneous endoscopic gastrostomy was placed for nutrition and administration of itraconazole. Computed tomography of the chest, abdomen and pelvis obtained to evaluate for disseminated histoplasmosis were unremarkable. The patient had rapid clinical improvement in his symptoms with initiation of antifungal therapy. His serum itraconazole levels were measured and were therapeutic. He was discharged home with a planned 12-month course of itraconazole.

chronic progressive histoplasmosis, disseminated histoplasmosis, histoplasma, oropharyngeal histoplasmosis, urine antigen

PMC10311060_01

Male

A 9-year-old previously healthy Syrian boy was admitted with a 1-day history of epistaxis, hematemesis, hematuria, and melena associated with periumbilical abdominal pain. He also has been complaining of pallor, decreased activity and appetite, and weight loss for a month prior to his presentation. A week before his admission, there was a noticeable increase in his pallor. Upon presentation, he was hypoactive, pale, and jaundiced. He was normothermic and hemodynamically stable. System examination revealed hepatosplenomegaly small palpable lymph node in the supraclavicular and inguinal region. The remainder of his physical examination was unremarkable. His initial Laboratory tests at admission showed a picture of bi-cytopenia in the form of anemia and thrombocytopenia. Platelet 11 x 109/L (normal range: 150-400 x 109/L); hemoglobin 97 mg/L (normal range: 113-150 mg/J); white blood cells 10.2 x 109/L (normal range: 4-12 x 109/L); and reticulocyte counts 2.45% (normal range: 0.5%-1.5%). Peripheral blood smear showed red blood cell fragmentation (Schistocytes) at 1.45%, and white blood cells, mainly neutrophilia, displayed reactive changes in forms of toxic granulation. Lactate dehydrogenase was 1,021 U/L (normal range: 125-220 U/L); aspartate aminotransferase 46 IU/L (normal range: 5-34 U/L); alkaline phosphatase 143 IU/L (normal range: 156-369 U/L); total bilirubin 41.3 micromol/L (normal range: ~20.5 micromol/L); and direct bilirubin 12.7 micromol/L (normal range: ~8.6 micromol/L). Blood urea nitrogen and creatinine were within normal limits. Urinalysis showed hematuria and hemoglobinuria. Coagulation screening tests were within the normal range; fibrinogen level was decreased to 1.72 g/L (normal range: 1.5-4.1 g/L); Coombs test was negative. Initially, the patient was diagnosed with atypical idiopathic thrombocytopenic purpura (ITP) and treated with Intravenous Immunoglobulin (IVIG) 1 g/kg. He received two doses of IVIG without response, and his Hgb and platelet counts declined further. In order to rule out bone marrow infiltration, bone marrow aspirations (BMA) and biopsy were performed. The preliminary report of the BMA did not suggest malignancy; however, it showed megakaryocytes which is suggestive of immune destruction. Therefore the patient was started on a six days trial of pulse steroid therapy (intravenous methylprednisolone 2 mg/kg/day divided twice a day), with no improvement in Hgb or platelet count. The final result of BMA revealed peripheral destruction of blood cells, indicating microangiopathic hemolytic anemia (MAHA), likely TTP, congenital or acquired due to an immune reaction to ADAMTS-13; this diagnosis was supported by repeated peripheral blood smear showing Schistocytes fragments of red blood cells >2.5% (Normal range <1.5%), accordingly a five days trial of fresh frozen plasma transfusion was initiated, in which the patient showed improvement in LDH and platelet levels. In addition, bone marrow biopsy results showed morphologic evidence of frequent small epithelioid non-necrotizing granuloma. Considering that this is a nonspecific finding that could be attributed to various etiologies, including infections (viral, bacterial, and tuberculosis), infiltrating diseases such as sarcoidosis, and malignancies, further investigation has been pursued. Viral surveillance, including EBV, CMV, and HIV were negative. QuantiFERON-TB Gold was negative. Abdominal ultrasound and computerized chest and abdominal tomography (CT) scan showed splenomegaly with no significant lymph node enlargement. Since Brucella is endemic in Saudi Arabia and the patient had recently consumed a significant amount of unpasteurized goat milk and cheese, brucella titers were sent, and the result showed Brucella abortus 1:5,120 (normal range: <1:160), and Brucella melitensis 1:20,480 (normal range: <1:160). A combination of Doxycycline (5 mg/kg/day orally twice a day) and Rifampin (20 mg/kg/day orally twice a day) antimicrobial therapy was commenced for a total of 6 weeks (42 days) to treat brucellosis. Once starting the anti-brucellosis management, the patient did not require further FFP transfusion. The ADAMTS-13 essay result showed: extremely low ADAMTS-13 activity, which was found at 0.02 IU/ml (normal range: 0.40-1.30 IU/ml), with an antigen assay below the detection level of 0.01 IU/ml (normal range: 0.41-1.41 IU/ml); and anti-ADAMTS-13 antibodies were detected at high concentrations of >95 IU/ml (>15 IU/ml is considered positive). All these findings, along with the presentation of thrombocytopenia and hemolysis, are specific to acquired TTP. Several days following the commencement of antibiotic therapy, the platelets count and hemoglobin levels recovered to the normal range (Figure 1), while the lactate dehydrogenase levels decreased substantially to a normal level.

adamts-13 (a disentegrin-like and metalloprotease with thrombospondin type 1 motif), brucella, case report, microangiopathic hemolytic anemia (maha), thrombocytopenia, thrombotic thrombocitopenic purpura

PMC6356047_01

Female

A 75-year-old female patient was admitted with sudden-onset dizziness on April 8, 2017. She had a medical history of hypertension, diabetes mellitus, pulmonary tuberculosis and chronic obstructive pulmonary disease with an FEV1 of 62% of normal predicted (1.39 L). This patient did not report any allergies from the past. Brain magnetic resonance imaging indicated an infarction in the posterior inferior cerebellar artery territory. Atrial fibrillation was also found. Edoxaban and bisoprolol were administered together with amlodipine, gliclazide, metformin, and atorvastatin. The patient became drowsy and dyspneic on May 4, 2017. Her body temperature was 37.6 C with a white blood cell (WBC) count of 7530/mm3 and D-dimer level of 0.89 mug/ml. Enterobacter cloacae was grown on blood and urine cultures. She received ertapenem for 15 days. However, she continued to experience dyspnea until May 18 and the D-dimer level increased to 5.52 mug/ml. Multiple PTEs were found at the segmental pulmonary arteries of the right lower lobe and left lung with focal deep vein thromboses at the infrarenal inferior vena cava, left popliteal vein and calf vein on three-dimensional angiography computed tomography scans. The activated partial thromboplastin time was 38.4 s (29.0-44.0 s); the prothrombin time, 14.5 s (international normalized ratio, 1.17) and WBC count, 7440/mm3. We stopped edoxaban and started intravenous heparin injection. Rivaroxaban 15 mg twice a day was started from May 30. Non-blanching erythematous palpable petechiae and purpura (Fig. 1) were found on both thighs, both arms, and the lower abdomen on June 16. Complete blood count (CBC), erythrocyte sedimentation rate (ESR), and the biochemical profile with liver and renal function, coagulation studies, and urine analysis were within normal limits. Chest X-ray (CXR) showed no active parenchymal lesion. Further studies, including antinuclear antibody (ANA), rheumatoid factor (RF), antineutrophil cytoplasmic antibodies (ANCA) (cytoplasmic and perinuclear), complement levels (C3, C4), serum cryoglobulins, hepatitis B surface antigen, hepatitis C antibody, and human immunodeficiency virus test, yielded normal results. We performed punch biopsies on the abdomen on June 20. The biopsy specimen showed superficial perivascular neutrophilic infiltration with leukocytoclastic debris, and interstitial infiltration of a few eosinophils and melanophages, consistent with LCV. Direct immunofluorescence (DIF) staining demonstrated granular deposition of immunoglobulin A and C3 in dermal blood vessels (Fig. 2). We stopped rivaroxaban on July 12 and started dabigatran 110 mg twice a day instead. The skin lesions improved within 2-3 days. We administered rivaroxaban 20 mg daily again from July 19 to confirm that the skin lesions were caused by it. Similar skin lesions developed again on July 29, and rivaroxaban was stopped on July 31. We started dabigatran 110 mg daily again from August 1. The skin lesions improved within 2-3 days again but they began to reappear on August 13. Dermatological assessment performed at that time indicated that this was the same disease. Since the patient was not receiving any concomitant medication that could be suspected as the cause of LCV, we stopped dabigatran on August 15, and started edoxaban 15 mg daily from August 16. The skin lesions improved over several days. We did not administer rivaroxaban and dabigatran anymore, and the skin lesions also did not develop again subsequently. However, the patient developed hospital-acquired pneumonia and died of it on September 11, 2017.

dabigatran, leukocytoclastic vasculitis, rivaroxaban

PMC2958542_01

Female

A 63-year-old, HIV-negative woman was referred in June 2000 by a general practitioner to the outpatient pulmonary service because she had exhibited a fever and night sweats for 3 months. The patient's medical history included a mild hypertensive cardiovascular disease and a pulmonary tuberculosis episode when she was 16 years old. Her father and brother had pulmonary tuberculosis. She lived in an urban area and had no history of acoholism, smoking, or use of steroids or immunosuppressive drugs. No other pulmonary diseases that could potentially lead to bronchiectasis and further mycobacterial colonization were reported. Physical examination revealed no pathologic findings except a strong positive reaction (24 mm of induration) with tuberculin skin test (5 U of purified protein derivative-standard [PPD-S]). Results of clinical laboratory tests were unremarkable, apart from an elevated erythrocyte sedimentation rate (77 mm/h). A computed tomographic (CT) scan of the chest showed multifocal bronchiectases in the middle right lobe, multiple small nodules in the lower right lobe, and a cavitary lesion in the upper right lobe, which appeared to have thin walls and was surrounded by a scant or absent inflammatory reaction. Bronchoscopy showed no inflammatory mucosal changes on the right side. Smears of bronchial washings were negative for acid-fast bacilli (AFB), and smears of two sputum specimens were positive, while all specimens gave negative results when tested by a ligase chain reaction commercial assay specific for MTB. A reactivation of tuberculosis was assumed, and chemotherapy with isoniazid, rifampin, and ethambutol was begun. Cultures of bronchial washing and sputum specimens produced a slow-growing Mycobacterium, which was identified as M. celatum in July 2000. The isolate was not considered clinically important, and chemotherapy was unchanged. In December 2000, although the general condition of the patient had slightly improved after 6 months of treatment, a control CT scan showed a worsening (enlargement) of the nodular lesions. Smears of two sputum specimens and one bronchial washing specimen were positive for AFB, whereas all specimens were negative when tested by the MTB ligase chain reaction assay. All of these specimens yielded M. celatum. On the basis of susceptibility data obtained from the first M. celatum isolate, chemotherapy was changed to a schedule that included isoniazid, ethambutol, and clarithromycin, which lasted until November 2001. This regimen proved to be well tolerated by the patient. The bacteriologic results (specimens from two additional bronchial washings were negative for AFB by smear and culture) and clinical response were good. In December 2001, chest x-ray examinations and a CT scan showed a considerable reduction of nodular lesions as well as improvement of lung cavitation (Figure). The patient was considered cured after taking medication for approximately 18 months. Clinical, microbiologic, and radiologic data as well, as information on response to treatment and follow-up, were obtained from the patient's records. All material was carefully reviewed to evaluate the clinical significance of the findings according to the criteria proposed by the American Thoracic Society. We examined sputum and bronchoaspirate specimens for acid-fast organisms. They were stained with routine Ziehl-Neelsen stain and cultured by standard procedures by using a combination of radiometric Bactec system (Becton Dickinson Biosciences, Sparks, MD) and Lowenstein-Jensen medium. Amplification for MTB was performed by the LCx-MTB assay (Abbott, Diagnostics Division, Chicago, IL). Conventional identification and growth tests were performed according to standard methods. We tested recovered strains with the Accuprobe system using specific probes for MAC and MTB. Assays were run from liquid culture setting the unbound probe hydrolysis incubation time at 5 and 10 min and temperature at 60 +- 1 C. The amount of chemiluminescence emitted was estimated with a Leader 50 luminometer (Gen-Probe Inc., San Diego, CA, USA) and quantified as relative light units (RLUs). Definitive identification was achieved by mycolic acids high-performance liquid chromatography (HPLC) analysis. Drug susceptibility pattern was determined in 12B liquid medium (Becton Dickinson Biosciences) by using the radiometric macrodilution method developed for MAC. Six isolates were recovered in a 6-month period. M. celatum was isolated from different specimens: two isolates were from bronchial washing and four from sputum. Acid-fast smears were positive in five of the six specimens. Cultures on Lowenstein-Jensen medium yielded multiple colonies, ranging from 100-150 CFU to a confluent growth. No additional microorganisms were isolated during the admission and follow-up period. Amplification tests performed on all respiratory specimens were repeatedly negative for MTB on smear samples positive and negative for M. celatum. M. celatum strains were isolated on both currently used media, radiometric liquid medium (Bactec 12B) and conventional Lowenstein-Jensen solid medium. We used an extended panel of biochemical and cultural tests for conventional identification. On the basis of these test results, the most likely identification, estimated by a program for the computerized identification of mycobacteria, appeared to be M. avium-intracellulare (Table). All strains isolated from this patient produced a weak yellow pigment in the dark, which grew at 45 C and were negative for arylsulfatase activity when tested after 3 days by the method of Kubica and Rigdon. The Bactec NAP test (Becton Dickinson Biosciences) did not demonstrate, as expected, any inhibition by para-nitro-alpha-acetilamino-beta-hydroxypropiophenone (NAP). The hybridization test performed with Accuprobe specific for MAC gave negative results. Weak positive or slightly below the cutoff (30,000 RLUs) results were observed with Accuprobe MTB (mean RLU value 51,170; range 28,219-111,365). When selection reagent (unbound probe hydrolysis) incubation time was set at 10 min, M. celatum strains clearly showed negative results (range 5,721-9,574; mean RLU value 7,210). A reference strain (M. tuberculosis ATCC 25177), run in the hybridization assay as a positive control, gave RLUs of 580,321, about 20 times the cut-off value. Finally, the strains were sent to the Mycobacteria Reference Centre in Florence, Italy (Dr. E. Tortoli), and studied by HPLC analysis of mycolic acids. They showed the same profile that allowed all of our strains to be attributed to M. celatum. MICs (mug/mL) determined for the first isolate were the following: streptomycin, 2.0; isoniazid, 0.5; rifampin, >64.0; ethambutol, 2.5; ciprofloxacin, 1.0; ofloxacin, 1.0; clarithromycin, 1.0; ethionamide, 2.5; and rifabutin, 0.5. Drug susceptibility testing was completed after 6 days. We searched the English-language literature from 1993 to 2001 for all previously reported cases of pulmonary infections with M. celatum in immunocompetent patients. The search yielded two published reports. Descriptions of the clinical signs, radiologic findings, and treatment were not always available, however. Clinical and radiographic features of M. celatum pulmonary infection resemble those of tuberculosis and other nontuberculous mycobacterial infections. Cough and weight loss are the main symptoms, while pulmonary infiltrates and extensive cavitations have been described in all published reports. Patients did not suffer from any underlying diseases when pulmonary infection with M. celatum was diagnosed and had a strongly positive tuberculin skin test, suggesting immunocompetence. Published data and our findings indicate that M. celatum caused pulmonary disease, and not merely colonization, in the affected patients. Indeed, all of these cases met the American Thoracic Society criteria for the diagnosis of nontuberculous mycobacterial disease. The patients displayed radiographic evidence of pulmonary disease that could not be attributed to other causes and that was associated in two of three cases with the repeated isolation of the same mycobacterial strain. By contrast, clinical presentation in immunocompromised patients differs greatly, being characterized by interstitial pulmonary infiltrates or by clinical and micobiologic evidence of disseminated disease. M. celatum strains were isolated on currently used liquid media in all reported cases (radiometric Bactec 12B and MB/BacT [Organon Teknika B.V., Boxtel, the Netherlands]), while samples from one of the published case-patients did not grow on conventional Lowenstein-Jensen solid medium, and growth has not been reported for samples from the second case-patient. Data from an extended panel of biochemical and cultural tests for conventional identification have not been reported; however, the appearance of a scotochromogenic pale yellow pigment with growth at 45 C and a negative 3-day arylsulfatase test are in full agreement with our present and previous findings. All strains showed a partial hybridization with Accuprobe MTB, which disappeared after 10 min of incubation with selection reagent. From a practical standpoint, setting the selection time at 10 min is advisable when the Accuprobe identification is performed on a mycobacterial culture grown in a liquid medium. In this situation, the characteristics of mycobacterial colonies cannot be observed and false-positive reactions may lead to misidentification. However, if the Accuprobe assay is carried out on a mycobacterial culture grown on a solid medium, a 5-min selection time is recommended. In this case, the appearance of mycobacterial colonies and their characteristics of growth may help to evaluate Accuprobe results. Thus, a weak positive reaction when testing nontuberculous mycobacteria with the M. tuberculosis complex Accuprobe strongly suggests that the organism is likely to be M. celatum. In one case, a misleading positive reaction occurred when a clinical sample containing M. celatum was tested for MTB by the Amplified M. tuberculosis direct test (AMTD, Gen-Probe, Inc.). The test amplifies 16S rRNA of Mycobacterium species by transcription-mediated amplification. The resulting amplicons are then detected by a hybridization protection assay by using a probe that targets the same genomic region as the probe of the Accuprobe kit. In our case, when we tested clinical samples by a different amplification system, no false-positive results potentially leading to a delay of appropriate treatment were reported. Patients (including our case-patient) were given different treatment regimens, with three or four antibiotics, mainly ethambutol, rifabutin, clarithromycin, and ciprofloxacin. Clinical improvement, as defined by resolution of symptoms and improved radiographic findings (infiltrates and cavitary lesions), was obtained within 6 months after initiation of therapy in two of three patients. One patient who received antimycobacterial therapy died 10 weeks after admission from complications apparently related to the M. celatum infection. Data from necropsy were not reported. Both cured patients showed a marked improvement when clarithromycin was added the chemotherapy regimen; the patient who later died felt better for 3 weeks when his chemotherapy was changed to a new schedule that included clarithromycin. Despite evidence of clinical and radiologic improvement, one patient was still sputum-positive 1 year after the initiation of therapy. In-vitro susceptibility data (when available) seemed to correlate with patients' clinical improvement as the MICs of tested drugs were below the serum concentrations achievable during therapy. Our findings show that M. celatum is an infrequent cause of potentially treatable pulmonary disease in immunocompetent subjects. Clinical picture and repeated isolation from respiratory specimens enabled us to consider M. celatum strains as clinically relevant in all the patients reported. Treatment with a three- or four-drug combination, including clarithromycin and ethambutol, should result in considerable reduction in the illness associated with this disease. Although at present only 16S rDNA sequencing or mycolic acid HPLC analysis can confirm M. celatum identification, the most practical way to get a preliminary identification relies on a positive DNA hybridization signal for MTB at 5 min but negative hybridization at 10 min with the Accuprobe test. Finally, although no major immunologic disorder could be detected in these patients, the host's defense failure associated with M. celatum infection suggests a possible "hidden immunodeficiency" rather than a true immunocompetence. Recent data on the immunology of nontuberculous mycobacterial infections seem to support this hypothesis.

PMC4217363_01

Female

A 24-year-old unmarried female presented to the outpatient clinic with painful swelling of the right sternoclavicular joint of 2-month duration without any discharging sinus (Figure 1). The swelling was gradually increasing in size and was accompanied with mild pain. The pain was dull, continuous, and limited to the site of the lesion. She also complained of neck stiffness and pain on neck movements. There was no history of any injury. History of cough, weight loss, night cries (severe pain at night), and low grade fever was present for the past 4 months. There was no history of previous tuberculosis or contact with an open case of tuberculosis. She had been prescribed several antibiotics and analgesics at another centre but had no symptomatic improvement. On physical examination the swelling (2 x 3 cm) was present over right sternoclavicular joint and was associated with presence of mild tenderness, erythema, and local rise of temperature. Laboratory tests revealed haemoglobin of 10.4 gm%; total leukocyte count was 10.300/mm3. Her ESR was 34 mm in first hour. She was negative for HIV based on ELISA method. On radiographic evaluation there was destruction with sclerosis on the medial end of the right clavicle along with features of diffuse pulmonary infiltrate (Figure 2). MRI revealed bilateral upper lung lobe infiltrate with arthritis of right sternoclavicular joint, with regional fluid collection. A destruction of the atlanto-axial junction, D7-8 intervertebral disc space along with a pus collection from D5 to D8 region could also be appreciated (Figures 3(a), 3(b), and 3(c)). An early morning sputum sample was sent for Ziehl-Neelsen (ZN) staining and it came out positive suggesting the diagnosis of pulmonary tuberculosis. Fine needle aspiration of the right sternoclavicular lesion was done using a 22-gauge needle and sent for Gram staining, staining for acid-fast bacilli (AFB), histopathology, and cultures including a tubercular culture. The histologic picture was that of chronic inflammation with a caseating granuloma compatible with tuberculosis. The Ziehl-Neelsen stained smear also showed the presence of acid-fast bacilli (AFB), confirming the diagnosis of tuberculosis. The culture for Mycobacterium tuberculosis came out as negative. Antitubercular chemotherapy with four first line antitubercular drugs (rifampicin, isoniazid, ethambutol, and pyrazinamide) was started. The patient had a good clinical response within 6 weeks and was switched to three drugs (rifampicin, isoniazid, and ethambutol) after 3 months of therapy with four drugs. The clinical, haematological, and radiological parameters showed complete healing of the lesion after 1 year of treatment with ATT, which was further continued for a total duration of 18 months. After successfully completing the therapy for 18 months, the patient was followed up for 2 years and showed no recurrence of symptoms.

PMC4789394_01

Female

A fifty-two-year-old, nonsmoker female presented with right-sided severe dull aching chest pain, dry cough, and exertional dyspnoea for four months. Severity of chest pain was gradually increasing and disturbs her sleep at night. Shortness of breath was initially of mMRC grading 2; later it was increased to grade 3. There was no history of hemoptysis, fever, weight loss, and loss of appetite. There was no past history of pulmonary tuberculosis. On examination, general survey revealed no abnormality. Her temperature was 97.2 F, pulse rate, 84 beats/minute, respiratory rate, 24 beats/minute, and blood pressure, 124/80 mmHg. Examination of respiratory system revealed diminished movement of chest wall on right side, tracheal shifting to left, apical impulse in left fifth intercostal space, 1.5 cm lateral to the left midclavicular line, stony dull percussion note over right chest wall, absent vesicular breath sound, and diminished vocal resonance on right side, suggestive of right-sided pleural effusion. Examination of other systems revealed no abnormality. Complete hemogram and blood biochemistry (including serotonin, gastrin, somatostatin, and glucagon) were within normal limit. Chest X-ray posteroanterior view (CXR, PA view) revealed right-sided pleural effusion (Figure 1). Ultrasound of abdomen revealed no abnormality. Pleural fluid was aspirated from right hemithorax and its analysis showed haemorrhagic, exudative, and lymphocyte predominant pleural effusion with adenosine deaminase level 16 U/L. No malignant cell or acid fast bacilli were seen in pleural fluid. Contrast enhanced computed tomography (CECT) of thorax showed only right-sided pleural effusion (Figure 2). No mass lesion or mediastinal lymphadenopathy was detected on CECT thorax. Closed pleural biopsy was done with Abram's needle and histopathological examination of biopsy tissue taken from right parietal pleura showed diffuse sheets of round to oval cells with hyperchromatic nuclei and scant to moderate amount of cytoplasm. Few scattered large cells with abundant eosinophilic cytoplasm were present. Focally spindle cells with hyperchromatic nuclei were seen. Focal micropapillae formation was also noted; features were suggestive of a poorly differentiated malignant tumour (Figure 3). Immunohistochemistry of pleural tissue showed that majority of tumour cells were positive for synaptophysin and a few cells were positive for Ki-67 (2%) and negative for pan-cytokeratin, calretinin, Wilm's tumour protein 1 (WT1), desmin, vimentin, carcinoembryonic antigen (CEA), thyroid transcription factor 1 (TTF1), and CD 56 (Figure 4). Hence, tissue diagnosis was well-differentiated malignant neuroendocrine tumour of pleura. Histopathology and IHC findings were reviewed by another pathologist of different centre, and the diagnosis was confirmed. Fibreoptic bronchoscopy (FOB) was normal. CECT of abdomen and brain revealed no abnormality. No abnormality was detected on endoscopic examination of upper gastrointestinal tract and on colonoscopy. Radionuclide bone scan did not show any metastatic deposit in bones. So, final diagnosis was primary, well-differentiated, malignant neuroendocrine tumour of pleura, presenting as isolated right-sided pleural effusion. Six cycles of cytotoxic chemotherapy comprising of intravenous infusion of carboplatin (at an area under the concentration-time curve 6.0 on day 1, 450 mg in this case) and etoposide (100 mg/m2/day, 130 mg in this case on days 1, 2, and 3) were given. Along with chemotherapy, intercostal tube drainage under water seal was given in right hemithorax through fifth intercostal space at right midaxillary line, as recurrent and rapid collection of massive amount of pleural fluid occurred and repeated aspiration of pleural fluid failed to reduce the volume of pleural fluid. When there was clinicoradiological evidence of complete expansion of right lung parenchyma, chemical pleurodesis with 20 mL of 10% povidone-iodine was done. On one-year follow-up, progressive regression of pleural effusion with alleviation of chest pain was documented.

PMC2778135_01

Male

A previously healthy 9-year-old boy (whose mother was recently found to be HIV-positive) presented to the hospital with 1 week of right-sided hemiplegia and right-sided facial palsy. Past medical history included psoriasis, diagnosed 4 years prior. His only HIV exposure was perinatal. On exam the patient weighed 22 kilograms, and vitals signs were within normal limits. He was alert and oriented with a normal level of consciousness and responded appropriately to questions. His speech was slowed and slurred, but this was his baseline according to his mother. He had right-sided facial palsy and right-sided tongue deviation; otherwise cranial nerves were intact. The boy had 3/5 strength in the right upper extremity and 4/5 strength in the right lower extremity. Left-sided strength was 5/5. The patient was able to walk with limited difficulty. Deep tendon reflexes were 2+ and 3+ throughout. Babinski's sign showed dorsiflexion of the right 1st toe. Sensation was intact throughout. The patient also had clusters of 1-2 mm skin colored papules on his forehead and left cheek in addition to diffuse mild psoriatic scaling. Immunizations were up to date. The patient was admitted for a workup of these symptoms. Laboratory studies showed complete blood count: hematocrit 31.6%, hemoglobin 10.5 g/dL, white blood cell count 5000 cells/muL (N 41%, L 35%, E 12%, M 6%, B 1%, atypical L 1%), and 157 000 platelets/muL. HIV-antibody test was positive with a CD4 T-cell 0.21% (4 cells/muL) and plasma HIV RNA virus of 185 976 copies/mL (log 5.27). Tests for Cryptococcus antigen, Toxoplasmosis antigen, Ebstein Barr virus IgG and IgM, Cytomegalovirus IgG and IgM, Hepes Simplex virus polymerase chain reaction (PCR), Japanese encephalitis as well as cultures for tuberculosis and fungi (plasma and cerebrospinal fluid, CSF) were all negative. Plasma and CSF samples were positive for JCV by real time PCR with a plasma RNA level of 226 copies/mL. Three days after admission a brain computerized tomography (CT) scan was performed and showed frond-like hypodense lesion at the left frontal lobe with mild effacement of the left frontal horn of the lateral ventricle. Highly active antiretroviral therapy (HAART) regimen was subsequently started 10 days after admission, consisting of GPOvir-Z (coformulated zidovudine 250 mg, lamivudine 150 mg, and nevirapine 200 mg). Clinically, the patient deteriorated during the 1st and 2nd weeks of HAART with fever and increased right leg weakness, but immunologic and virologic improvement was seen (CD4 T-cell count 0.8%, 10 cells/muL, and a plasma HIV RNA viral level of 26 532 copies/mL, log 4.42). CT (Figure 1) and brain magnetic resonance imaging (MRI; Figure 2) scans were subsequently performed. The scans showed progressive of white matter lesions with asymmetrical deep and subcortical white matter lesions over the left frontotemporoparietal region and the right frontal lobe. The lesion on the left hemisphere involved internal capsule, lentiform nucleus, thalamus, and genu of corpus callosum and anterior cerebellar hemisphere. There were no enhanced areas after the contrast study. The patient was discharged 7 weeks after the first admission. Upon discharge he was able to walk with assistance, but was unable to speak. The patient was readmitted one day after discharge due to autonomic nervous system dysfunction (nausea, vomiting, and loss of bowel and bladder tone). Deep tendon reflexes were 4+ throughout, and Babinski was positive bilaterally. Continued improvement of immunologic (CD4 T-cell count 2.0%, 30 cells/muL) and virologic (HIV RNA level 3220 copies/mL, log 3.51) measures were seen. Due to progressive neurologic symptoms HAART was ceased. The second MRI (Figure 3) scan was performed and showed a progressive lesion in the same regions as described in the previous MRI, but also found new lesions over the midbrain, pons, and medulla predominantly on the left. The patient was discharged approximately 3 weeks after admission. The patient was readmitted 1 month later (100 days after onset of symptoms). Immune Reconstitution Inflammatory Syndrome (IRIS) was suspected, and the boy was treated with methylprednisolone (2 mg/kg/day) for 5 days. Despite HAART suspension and administration of steroids, his clinical symptoms worsened. The third MRI (Figure 4) scan showed new lesions in the regions of the right brainstem and right hemisphere with gyral enhancement. The patient's mother refused further treatment, he was discharged home, and he subsequently died 1 year later.

PMC5771871_01

Male

A 46-year-old male farmer, presented with a history of multiple, recurrent discharging scrotal ulcers over a period of three (3) years. He had had multiple wound debridements and dressings done, but the ulcers had recurred a few months after complete healing. The discharging wounds occurred after the formation and subsequent rupture of pustules. He was otherwise healthy with no constitutional symptoms, significant comorbidities, and no previous history or contact history of TB. He had received the BCG vaccination during infancy. He was an averagely built male with normal general and systemic examination. Genitourinary examination revealed bilateral craggy, hard epididymes, an enlarged and tender right testis, and multiple, superficial, noninfected scrotal ulcers (Fig. 1A and B). Ultrasonography showed bilateral normal-sized testes. The right epididymis was enlarged and thickened with a 1.4 x 1 cm sized hypoechoic lesion in relation to the head of the right epididymis and a 2 cm x 1.8 cm sized hypoechoic lesion in relation to the lower pole of the right testis. Internal vascularity was noted. The right testis was not identified separately from the lesion. Furthermore, there was a 1.3 x 0.8 cm sized hypoechoic lesion in the left testis and a 0.7 x 0.6 cm sized hypoechoic lesion in relation to the left epididymis. His complete blood count and chest radiograph were normal. Erythrocyte sedimentation rate (ESR) was 90 mm/h, and the Mantoux was strongly positive with a diameter of 20 mm after 72 h. The urine full report (UFR) showed a field full of pus cells, and routine bacterial cultures were negative. He underwent surgical exploration where the right epididymis was noted to be enlarged, irregular, and thickened with mild enlargement of the right testis with an irregular surface lesion, favoring chronic epididymo-orchitis (Fig. 2A and B). A right epididymal and testicular biopsy was performed, and histology revealed evidence of granulomatous inflammation with central caseous necrosis favoring mycobacterial TB infection. There was no evidence of intratubular germ cell neoplasia or malignancy. The Ziehl-Neelsen stain was negative for acid-fast bacilli. Pus from the scrotal discharge, the biopsy specimen, and the urine sent for TB culture returned negative. He was started on category 1 antituberculosis therapy, that is, quadruple antimicrobial therapy for 2 months followed by dual therapy with rifampicin and isoniazid for 4 months, for which there was a good response with healing of the scrotal ulcers. He was compliant, and no significant adverse effects of treatment were noted. However, three (3) months into therapy, he presented with worsening lower urinary tract symptoms, strangury, and acute urinary retention. He required suprapubic catheterization, and subsequent retrograde urethrography revealed a bulbar urethral stricture for which he is under urological care.

case report, chronic epididymo‐orchitis, genitourinary tuberculosis, scrotal ulcers

PMC6679641_01

Female

A 69-year-old woman was admitted to hospital in November 9, 2007 with acute exacerbation of chronic cough and dysphagia with solids and liquids for 2 weeks. She did not have hemoptysis, fever, chills, chest pain, or weight loss. When she was 9 years old, she had worked as a stone crusher for 3 years and was exposed to a large amount of quartz dust for not using any respiratory protective equipment. In 1969, she was diagnosed with silicosis and tuberculosis. She was treated for tuberculosis and was stable. She had no further exposure to dust or other toxic substances, thereafter. On follow-up, her condition had no change. The patient was a life-long nonsmoker and consumed no alcohol. Nor did she receive any medications. On physical examination, the patient looked well, with no palpable peripheral lymph nodes. Occasional wheezing was heard on both lung fields. Laboratory data, including blood tests and serum electrolytes, liver enzymes, and bilirubin, as well as renal function were normal. Skin test for tuberculosis was negative. Three consecutive samples of sputum were negative for acid-fast bacilli by staining and culture. Chest x-ray and computed tomography (CT) of the chest demonstrated eggshell calcification of the hilar and mediastinal lymph nodes in the paratracheal, subcarinal, and aorticopulmonary window regions. Bilateral multiple pulmonary nodules were also visible. The lower lobe of the left lung showed a ground-glass, dense shadow. Barium esophagography revealed two fistulas between the middle esophagus and the left main bronchus, immediately tracking into the left bronchial tree (Fig 1). The diagnosis was silicosis with esophagobronchial fistula and aspiration pneumonitis. The patient received antibiotics. An esophageal stent was placed on December 14, 2007. The symptoms improved. The symptoms however recurred within three days. Gastroesophageal endoscopy demonstrated a small ulcerated lesion above the metallic stent, with a small diverticulum 18 cm from the upper incisor; the esophageal mucosa was inflamed and friable. Biopsy revealed chronic inflammation and an ulcer without granulomas, malignancy, or organisms (Fig 2). Another esophageal stent was placed on December 20, 2007. The symptoms improved and the patient was discharged from hospital. After two months, the patient was admitted to another hospital because of severe cough exacerbated by swallowing liquids and solid foods. Gastroesophageal endoscopy revealed a new small mid-esophageal ulcer. Other examinations, including tests for tumor markers, were normal. A tuberculin skin test gave negative results. Over the next few days, the patient reported expectoration of small grayish coral-like calculi with a stony consistency, measuring 5-10 mm in diameter, as well as episodes of coughing. Bronchoscopic examination showed a free broncholithiasis in the left main bronchus, mucosal thickening, and stenosis with no significant airway obstruction of the main bronchus. The broncholithiasis was extracted with no bleeding. Biopsy of the bronchus revealed chronic inflammation, with no evidence of malignant tumor cells or granulomas. Sputum and bronchoalveolar lavage analyses did not reveal Mycobacterium tuberculosis, fungi, or malignant cells. The diagnosis was silicosis with broncholithiasis and esophagobronchial fistula. The patient continued to have frequent complications and persistent fistula probably related to stasis in the esophagus. Because of her frail condition, we decided to initiate a conservative operative approach and inserted a gastrostomy tube. Two samples of the expectorated materials were analyzed by electron microscopy and energy-dispersive spectrometry (EDS), with a Phenom ProX system (Phenom-world Co, the Netherlands), operating at 15 kV. Without any coating on the sample, with SDD high resolution and a high-sensitivity EDS detector, semiquantitative chemical analyses were performed. Mineralogy analysis revealed the broncholithiasis was composed of calcium and phosphate, with no crystals of silica or silicate (Fig 3). After 16 months, in June 2009, the patient was readmitted because of cough, sputum, dyspnea, fever, and night sweating for 10 days. The admission laboratory data included a white blood cell count of 6.65x103/muL (reference range 4.0-10.0x103/muL), hemoglobin level of 11.4 g/dL (11.0-15.0 g/dL), high-sensitivity C-reactive protein level of 26.38 mg/L (0-3 mg/L), serum albumin level of 4.32 g/dL (35-55 g/dL), serum protein level 7.0 g/dL, erythrocyte sedimentation rate 34.9 mm/h (0-20 mm/h). A skin test for purified protein derivative (5 TU) was strongly positive, with an induration of 25 mm with ulceration. The concentrated sputum test result was positive. The diagnosis was silicotuberculosis relapse. CT revealed an esophageal stent shadow, esophageal wall thickening, multiple small nodule spots, patchy shadows, and mediastinal and lung door multiple calcified lymph nodes (Fig 4). Antituberculous treatment with 450 mg rifapentine, twice a week, 300 mg inhaled isoniazid, once a day, and 750 mg pyrazinamide, once a day, was started. After nine months of antituberculous treatment, the patient did well. We continued to follow the patient until the time we wrote this report; she had no change (Fig 4).

esophagus, fistula, lung diseases, silicosis, tuberculosis

PMC3012841_01

Male

A 32-month-old boy was admitted to our hospital with two days of irritability and fever. He was born with a birth weight of 2.9 kg by normal spontaneous vaginal delivery at 40 weeks gestation to a healthy 28-yr-old G3P2 mother. His delivery was non-eventful, but there was flexion deformity of both his middle fingers, so he was transferred to our hospital and underwent many diagnostic tests and physical therapies in January, 2002. He showed mild general hypotonia in that his cry was weak, and he sucked poorly during early infancy. He had epileptic seizures 6 times since the age of 15 months despite taking anti-epileptic medications. A diagnosis of mental retardation complicated by epilepsy was made, and his development was noted to be markedly delayed. He raised his head at age 7 months, sat up at 26 months, and had not yet acquired the ability to stand. He had a flat and mid-hypoplastic face with prognathism, narrow and upward slanting palpebral fissures with hypertelorism, low-set ears, a small crashed nose, widely spaced incisors, carp-like mouth, and round back (Fig. 1). He demonstrated repeated stereotyped behavior like hitting his chin with his palm; this behavior was often associated with emotional outbursts. Soon after admission, a generalized tonic-clonic type seizure was started and lasted approximately one hour; at that time his vital signs were as follows: blood pressure 100/60 mmHg, pulse rate 138 bpm, respiration rate 32 bpm, and body temperature 38.5C. Mild throat injection was seen, but other systemic examinations were normal. On neurologic exam, mental status was alert, all cranial nerve exams were normal, and muscle tone in both extremities were decreased to grade IV/IV bilaterally but all deep tendon reflexes were physiologic. There was no spasticity or pathologic reflex. Sensory functions were normal and meningeal irritation signs were absent. Initial laboratory investigations revealed: hemoglobin 12.7g/dL, platelet count 374,000/microL and white blood cell count 11,780/microL. The C-reactive protein was slightly elevated at 19.0 mg/dL on the day of admission and returned to normal 3 days later. Urinalysis was normal. All microbiologic studies were negative. A sleep electroencephalogram revealed intermittent high-amplitude slow wave discharges from the temporo-occipital area, representing mild cerebral dysfunction. On radiologic evaluation, spine radiography revealed mild scoliosis. An echocardiogram was normal. The characteristic facial features and mental retardation of the patient led us to consider ATR-X syndrome; thus, peripheral RBCs were screened for hemoglobin H (HbH) inclusion bodies. HbH inclusions were detected under the microscope in 1.1% of brilliant cresyl blue stained RBCs, consistent with the diagnosis of ATR-X syndrome (Fig. 2). The patient's father, mother and two sisters were all given the same test; only his mother and eldest sister had the same findings. We performed gene analysis to confirm the diagnosis of ATR-X syndrome. Genomic DNA from the peripheral blood of our patient and his 4 family members was extracted with the Wizard Genomic DNA Purification Kit (Promega, Madison, WI, USA) and used as a template for amplification of the ATRX gene. Polymerase chain reaction (PCR) was separated into three parts and carried out with sequence-specific oligonucleotide primers containing 20 known major mutation sites (Table 1, Figs. 3, 4). PCR amplification using each primer was conducted with premixture kit (PreMix -Top, Bioneer Inc., Seoul, Korea). Cycling conditions were one cycle at 95C for 5 min, followed by 35 cycles of 95C for 30 sec, at an annealing temperature adjusted to each primer's (Tm) for 30 sec, 72C for 30 sec, followed by one cycle at 72C for 7 min. For direct sequencing, the PCR products were purified using a PCR clean-up system offered by Promega. DNA sequencing was performed using the purified PCR products as template, the same primers as those used for template generation, the BigDye terminator cycle sequencing ready reaction kit (Applied Biosystems, Foster City, CA, USA), and automatic sequencer ABI Prism 3730 XL DNA Analyzer (Applied Biosystems, Foster City, CA, USA). Sequence data were assembled and compared to that of a previously reported ATRX sequence from accession number Z84487 using the DNAstar software (DNASTAR Inc., Madison, WI, USA). Mutation analysis for our patient showed a point mutation on the 9th exon in the ATRX gene of thymine to cytosine so that Trp(C), the 220th amino acid, was replaced by Ser(R) (Fig. 5). This missense mutation was reported by Gibbons in 1997. We investigated the same mutation in his 4 family members, and his mother and two sisters were found to be carriers.

atrx, alpha-thalassemia, hemoglobin h, mental retardation, x-linked

PMC7308213_01

Male

The proband, a Sudanese male born following normal pregnancy and delivery presented at the age of three months with abdominal distension and constipation, in the absence of a goiter or umbilical hernia. Growth was normal for height and weight at the 50th percentile. Written informed consent was obtained from the parents for blood and serum draws and analyses. Serum TSH and free thyroxine (FT4) were initially measured in Khartoum. Serum thyroid function tests (TFTs) after starting treatment including TSH, total thyroxine (TT4), total triiodothyronine (TT3), FT4, thyroxine-binding globulin (TBG), thyroglobulin (TG), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TGAb) were completed (Immulite 1000; Siemens, Munich, Germany and by Elecsys; Roche, Switzerland). Reverse triiodothyronine (TrT3) was measured by radioimmunoassay (Adaltis Italia S.p.A, Bologna, Italy). DNA for sequencing was extracted from peripheral white blood cells using a Qiagen DNA Blood Mini Kit (Hilden, Germany). DNA from the mother and proband were sent for whole exome sequencing (Novogene, Agilent SureSelect Human All Exon V6 Kit). Whole exome sequencing (WES) results were first scanned for mutations in genes known to be related to TH synthesis or function (Supplemental Table 1). Functional prediction scores Sorting Intolerant from Tolerant (SIFT), Polyphen2 HumanDiv (HDIV) MutationTaster and Combined Annotation Dependent Depletion (CADD) were tested in silico, allele frequency, and zygosity were all considered in determining the likely cause of the CCH phenotype. The mutation was confirmed by sanger sequencing of DNA from all available family members in order to determine the mode of inheritance. TFTs at 3 months of age revealed a TSH reported as 0.01 mIU/L (reference range 0.4-4.3 mIU/L) and low FT4 of 1.0 pmol/L (reference range 4-10.6 pmol/L). The proband had no family history of thyroid disease, however, both parents reported being first-degree cousins. The proband was diagnosed with CCH and started on levothyroxine (L-T4) treatment. Now, at eleven-year-old on subtherapeutic L-T4 replacement the TFTs demonstrated undetectable TSH on the Elecsys (<0.01) and on Immulite (<0.03) with Low FT4 (Individual II-1, Figure 1). The proband had normal neurological and psychological development on physical examination. WES found a novel missense mutation located on exon 2 of the TSHbeta, c.T141G p.C47W (numbering includes the 20 amino acid signal peptide). Sanger sequencing confirmed that both parents were heterozygous for the C47W mutation, while the proband was homozygous. The mutation was predicted by several in silico methods to have a deleterious effect (SIFT 0.0, Damaging; Polyphen2_HDIV 0.973, probably damaging; MutationTaster 1, disease causing; and CADD 3.17, 16.62). Analysis of the allele frequency in the African and general populations was not available as this is a novel mutation not located in the Genome Aggregation Database.

central congenital hypothyroidism, secondary hypothyroidism, tsh receptor

PMC8574110_01

Female

A 31-year-old woman was admitted to the hospital for the treatment of newly diagnosed drug-resistant (pre-extensively drug resistant) pulmonary tuberculosis (chest X-ray at time of diagnosis - Fig. 1). She was treated with second-line antituberculosis drugs: moxifloxacin, kanamycin, cycloserine, prothionamide, para-aminosalicylic acid. After 3 weeks of therapy she developed high fever (> 39 C), lymphadenopathy in the cervical and axillary regions and pruritic maculopapular eruption all over the body (Fig. 2). Hematologic abnormalities such as leukocytosis with eosinophilia (1.81 x 109/l) and monocytosis (1.85 x 109/l) were detected in peripheral blood of the patient. Hepatitis was asymptomatic and detected by the evaluation of liver function: serum aspartate aminotransferase (AST) 1379 IU/l and alanine aminotransferase (ALT) 1221 IU/l; levels of liver enzymes were increased by approximately 30-40-fold above the normal limits. The positive diagnosis of Epstein-Barr infection was based on the onset of increase in the anti-Epstein-Barr immunoglobulin (Ig) G titer (> 200 U/ml), implicating Epstein-Barr virus re-activation. Based on the clinic and laboratory findings diagnosis of DiHS/DRESS was suspected, and all the drugs were discontinued. Symptoms and laboratory abnormalities gradually resolved over 4 weeks without additional treatment. A patch test was performed and analyzed according to the recommendations. The results of the patch test are presented in Table 1 and Figure 3. Treatment was adjusted to ethambutol, kanamycin, cycloserine, pyrazinamide, and linezolid, and no new symptoms were observed.

drug reaction with eosinophilia and systemic symptoms, drug-induced hypersensitivity syndrome, second-line treatment for tuberculosis

PMC5498208_01

Female

A 74-year-old woman was referred to our hospital due to steroid-resistant bilateral uveitis persisting for more than 3 years. The patient had no significant medical history and was seronegative for human immunodeficiency virus (HIV). She had undergone vitrectomy of the right eye that was negative for malignant cells. DNA extracted from the vitreous fluid was negative for immunoglobulin heavy locus (IgH) rearrangements, as determined by polymerase chain reaction (PCR). The levels of interleukin (IL)-10 and IL-6 in the vitreous fluid were 51 pg/mL and 712 pg/mL, respectively. The IL-10/IL-6 ratio was <1.0, which was atypical for a diagnosis of vitreoretinal lymphoma. On admission to our hospital, the visual acuity of the right eye was almost lost. The fundoscopic image of the left eye obtained on admission is shown in Fig. 1A. An analysis after diagnostic pars plana vitrectomy of the left eye did not detect any malignant cells. DNA extracted from the vitreous fluid was negative for both IgH and T-cell receptor (TCR) rearrangements, as determined by PCR. These findings did not support that the uveitis occurred because of lymphoma. The concentrations of IL-10 and IL-6 were 53 pg/mL and 430 pg/mL, respectively. The ratio of IL10/IL6 of the left vitreous fluid was <1.0, similar to that in the right vitreous fluid, as indicated above. Screening for infectious diseases by quantitative multiplex PCR of the vitreous fluid DNA was performed for the detection of herpes simplex virus types 1 and 2, varicella-zoster virus, EBV, cytomegalovirus, human herpes viruses 6-8, Toxoplasma gondii, bacterial 16S, fungal 18S/28S, and mycobacterium tuberculosis, according to our previously described method. The PCR results were negative for all tested pathogens, except for EBV DNA, which was detected at 5.47x105 copies/mL. Her anti-EBV antibody titers were 1:80 for anti-viral capsid antigen (VCA)-IgG and 1:10 for anti-EB nuclear antigen (EBNA). Anti-VCA-IgM antibody was undetectable. An otolaryngological examination was negative for nasal lymphoma. EBV DNA was negative in the peripheral blood, and a systemic examination including the nasal cavity with 2-Deoxy-2-[18F] fluoro-D-glucose positron emission tomography (PET)/CT (FDG-PET/CT) did not detect any lesions. We could not determine the diagnosis of lymphoma and injected subtenon triamcinolone acetonide into the left ocular lesion. However, this failed to improve her symptoms. In order to preserve her visual acuity, 400 mug methotrexate (MTX) weekly for 6 weeks, based on the treatment protocol for vitreoretinal lymphoma, was administered into the left vitreous following the approval of the Institutional Review Board. The treatment resulted in a dramatic improvement, and the patient achieved complete response (CR; Fig. 1B). However, two years after the MTX treatment and four years after the onset of symptoms, the uveitis of the right eye rapidly progressed. Because of severe ocular pain and loss of visual acuity that was considered irreversible, the patient underwent enucleation of the right eye. A pathological examination revealed massive necrosis and the absence of lymphoma cells (data not sown). While the symptoms were resolved, the patient subsequently underwent both an ophthalmological examination and magnetic resonance imaging (MRI) for the head and neck. Two years and two months after enucleation, multiple hyperintense lesions were detected on T2-weighted fluid-attenuated inversion recovery (FLAIR) imaging MRI in the right occipital and parietal lobes and the precentral gyrus, and a left visual field defect was detected on an ophthalmological evaluation (Fig. 2). The tumor was suspected to be high-grade glioma and was removed by craniotomy; however, the pathological diagnosis was ENKL. As shown in Fig. 3, the infiltrating cells in the pathological specimen were positive for CD3, CD56, and TIA1. The tumor cells were positive for EBV. EBV DNA was negative in the peripheral blood. The DNA extracted from the right vitreous and brain lesions was amplified for the sequence analysis of LMP1, an EBV gene, to determine homology. The forward and reverse primers were 5'-GCT GTC GAC GCC ACC ATG GAA CAC GAC CTT GAG AGG-3' and 5'-GCT GGA TCC TTA GTC ATA GTA GCT TAG CTG AAC-3', respectively, and their nucleotide positions in EBV variant B95.8 (Genbank No. V01555) were 169474-169454 and 168160-168183, respectively. This lesion had sequence variations in each EBV. The conditions for the PCR reactions were as follows: 94 C for 2 minutes, 98 C for 10 seconds, 62 C for 30 seconds, and 68 C for 90 seconds for 40 cycles. The LMP1 sequence was confirmed after TA cloning with PCR products. As shown in Fig. 4, the repeat regions of LMP1 detected in the vitreous and brain lesion were identical. Based on the clinical, pathological, and genetic findings, the CNS lesion was confirmed to be closely associated with and most likely originated from the uveitis. The patient was treated with intravenous high-dose MTX at 3.5 g/m2, administered 3 times, and has since maintained CR for 24 months without recurrence.

epstein-barr virus, central nervous system, extranodal nk/t-cell lymphoma nasal type, uveitis

PMC5396431_01

Female

A 56-year-old female with a history of pulmonary embolism, myotonic dystrophy, and complete heart block on pacemaker presented to the emergency department (ED) with sudden onset shortness of breath and substernal chest pain radiating to the back. There was no history of fever, chills, cough, sore throat, or chest trauma. Her history was negative for any gastrointestinal, musculoskeletal, or neurological symptoms. She was taking rivaroxaban 20 mg once daily for deep vein thrombosis of the left axillary vein diagnosed 7 weeks ago. There was no prior history of tuberculosis, chest irradiation, or chemotherapy. She had a history of pulmonary embolism in 2007 for which she was on coumadin for a year. She had a biventricular pacemaker placed in 2008 for complete heart block induced nonischemic cardiomyopathy. Complete heart block was diagnosed at the same time and was believed to be secondary to myotonic dystrophy. The pacemaker device reached elective replacement indicator and was replaced with a Medtronic Protecta D314TRG device in 3/2012. She was on Tylenol 500 mg as needed for back pain, levocetirizine 5 mg twice daily for seasonal allergies, and rivaroxaban and zolpidem 5 mg nightly as needed. The above-listed medications do not have p-glycoprotein altering activity or CYP3A4/5 or CYP2J2 inhibiting activity. The past surgical history and family history were unremarkable. In the ED, her blood pressure was 78/48 mm Hg, pulse 106/minute, temperature 36.5 F, and respiratory rate 18/min with saturation of 87%. Her height and weight were 1.7 m and 180 lbs, respectively. Cardiac examination was normal. Chest examination was significant for bibasilar rales. Electrocardiogram revealed ventricular paced rhythm. There was no associated electrical alternans. Lab tests revealed negative troponin, INR of 1.3, and PTT of 28 s. Complete blood count and basic metabolic profile were unremarkable. Computed tomography (CT) on chest showed no pulmonary embolism but revealed a large hyperdense pericardial effusion (Figure 1). Echocardiogram showed moderate-sized circumferential effusion with a swinging heart consistent with pericardial effusion (prior echo 4 years ago showed no pericardial effusion) (Figure 2). Inferior vena cava was dilated with no respiratory collapse and right ventricle outflow tract collapsed in diastole. With the diagnosis of cardiac tamponade, emergency subxiphoid pericardial window was performed and a total of 300 mL of bloody pericardial fluid was drained. Hemostasis was achieved and was satisfactory. Transesophageal echocardiogram confirmed emptying of the collection as well as improved cardiac function. There was immediate improvement in her hemodynamic status. Postprocedure images showed complete resolution of the effusion. Further etiologic workup was unrevealing. Pericardial fluid culture was negative with normal cytology. Pericardial tissue biopsy was negative for malignancy. Thyroid and liver function tests were normal. ANA, rheumatoid factor, anti-saccharomyces cerevisae antibody, anti-mitochondrial antibody, C3, C4, and anti-liver-kidney-muscle antibody were negative making the autoimmune cause unlikely. Myotonic dystrophy was considered to be an unlikely cause of her hemopericardium as pericardial involvement has not been reported with it. In addition, her previous echo was negative for pericardial effusion. There was no temporal relation to the axillary vein DVT and the pacemaker lead implantation as CT scan done in 2013 and echocardiogram done in 2015 mentioned a normal pericardium with appropriately implanted leads. Intraoperatively, there was no mention of pacemaker lead induced pericardial perforation. Further hospital course, unfortunately, was complicated by healthcare associated pneumonia with septic shock and multiorgan failure. The autopsy was not done.

PMC9320325_01

Male

In 2021, a 40-year-old male patient came for consultation. He had chronically recurrent gastrointestinal bleeding for 15 years, developed malignant lesions of the descending part of the duodenum, and then underwent pancreaticoduodenectomy in our hospital. The patient has lost 15 kg of weight since the onset in September 2020. Moreover, he had no notable family medical history. The patient was admitted to the local hospital on March 8, 2019, and operated on a partial enterectomy with a 150 cm intestine because the enteroscopy found bleeding in a part of the intestine. However, the patient was still under anemia after the operation (Figure 1). After then, the patient suffered from jaundice and incomplete ileus with the feeling of ventosity and nausea in October 2020. The local hospital implemented PTCD to improve jaundice and treat fasting, nasogastric drainage, and total parenteral nutrition for incomplete ileus. However, they did not find a solution to handle the bleeding event. Therefore, the patient came to our hospital for further medical consultation. Tracing the history, we found that the patient had anemia before he was 16 and was given blood transfusion therapy. This situation recurred 3-4 times before. We did regular pre-operation examinations after the patient was admitted to our hospital. Enhanced computer tomography showed dilatation of the duodenum and stomach, and there was a space-occupying lesion that tended to be malignant. Magnetic resonance imaging revealed duodenal malignancy, slight dilatation of the bile duct, and fatty liver (Figure 2). Obviously, the gastrointestinal obstruction was caused by the occupying lesion of the descending part of the duodenum. Upper gastrointestinal endoscopy revealed multiple diffused polyps located in the stomach and the duodenum, and colonoscopy showed the same extent polyps of varying sizes localized in the rectosigmoid region. The onset of small intestinal malignant tumors combined with upper and lower gastrointestinal tract polyps might suggest MUTYH-associated polyposis syndrome (MAP) or Lynch syndrome. Nevertheless, further physical examination revealed that the patient had macrocephaly, and dermatologic examination was remarkable (Figure 3). Miliary papules were scattered on the face, especially on the forehead. Also, there was papilloma of the tongue, hyperkeratosis of soles, and melanosis spots on the glans of the penis. Therefore, we considered the possibility of other diseases such as Cowden syndrome and P-J syndrome and performed a radical pancreaticoduodenectomy (classic Whipple) to remove the malignant lesion in the duodenum on March 23, 2021. The gross pathology showed a 6 x 5 x 4 cm cauliflower-like protrusion lesion (Figure 2). The cut surface of the tumor was pale, soft, and fragile and visually infiltrated the muscular layer of the duodenum. Diffuse hyperplastic grayish-brown polyps could be seen in the entire intestinal wall, ranging from 1 to 4 mm. The common bile duct was dilated, and the pancreas was undisturbed. Microscopic pathology (Figure 4) reported that the cauliflower-like elevated tumor of the duodenum was considered a hamartomatous polyp, with malignancy in some areas (80% non-mucinous adenocarcinoma, 20% mucinous adenocarcinoma). Also, the carcinoma tissue had infiltrated into the subserous layer. Other polyps were described as polypoid hyperplasia of mucosal glands. No metastasis was observed in perigastric lymph nodes and peripancreatic lymph nodes. In addition, it is suggested that the mesentery nodules were hemangioma. Immunohistochemical results showed Ki-67(40% positive), CDX2(+), MSH2(+), MSH6(+), PMS2(+), CK20(+), STK11(+/-), PTEN(expression deletion), Her-2(weak +), SATB2(little +), D2-40(no apparent lymphatic tumor thrombus was found), and p52(DO7) (70%+); special staining showed no definite venous invasion of elastic fibers. Immunohistochemical results showed that PTEN protein expression was lost in the tumor and surrounding mucosal tissues, which may be an important factor in tumorigenesis. However, MLH1 and STK11 proteins were normally expressed. Therefore, we believed Cowden syndrome was the most likely diagnosis. At the suggestion of the pathologist, further NGS gene testing was carried out. Gene testing of the tissue samples suggested multiple germline gene mutations. A frameshift mutation was detected in the PTEN gene, leading to amino acid p.E242fs alternation. We refined the localization to position 89717695 of chr10, which might lead to a premature terminator in the new reading frame, resulting in protein dysfunction and having pathogenic significance. According to the large population databases (gnomAD, ExAC, 1,000 genome, ESP6500, etc.), this was a rare mutation that has never been discovered before. Partial genetic mutations of the PTEN gene are related to PTEN hamartoma tumor syndrome/Cowden syndrome. This autosomal dominant genetic disease is associated with an increased risk of breast cancer and thyroid disease and may increase the risk of endometrial cancer and central nervous system tumors. On chr13, missense mutation occurred in two-locus:32906558 and 142274875, causing P.C315S of the BRCA2 gene and p.T729A of ATR change. Missense mutations occurred in PALB2 and MC1R gene on chr16, causing p.Q1114R and p.A166G changes. All mutations of these germline genes were heterozygous mutants, and their clinical significance for CS has not been clarified except for PTEN. Four critical tumor driver gene mutations were detected in the patient. Tumor mutational burden was 2.20 muts/Mb, and microsatellite instability was detected as microsatellite stable. The mutation in exon 2 of KRAS changed P.G12A inactivated GTPase, leading to the accumulation of tumor-associated KRAS in the active GTP-bound conformation. That possibly promoted the development of malignant tumors. Currently, there are drugs targeting KRAS gene mutations in the market. Nevertheless, the detection of KRAS mutation also suggested that patients with colorectal cancer may be resistant to Cetuximab(A) and Panitumumab(A). These discoveries can be expected to guide the follow-up treatment. The other three mutations, resulting in p.R714H, p.A4083P, and p.D351G alternations, were detected in exon 11 of CREBBP, exon 48 of KMT2C, and exon 9 of SMAD4. However, the clinical significance of these mutant genes is unknown. PD-L1 immunohistochemical staining score is as follows: TC >= 1% and IC+:2%; the result was positive. Based on that evidence, the diagnosis of Cowden syndrome is confirmed. Since there were no indications such as regional lymph node metastasis, postoperative adjuvant chemotherapy was not performed. The patient was followed up for 1 year, and there was no postoperative obstruction of bilioenteric anastomotic stenosis. Gastrointestinal bleeding did not recur, and the anemia had been corrected. Repeated reexamination of tumor markers did not suggest recurrence. All these suggest a good prognosis.

asian, cowden syndrome, pten, whipple, duodenal carcinoma

PMC8326275_01

Male

A 73-year-old man with a history of chronic obstructive pulmonary disease (COPD) for more than 10 years, he regularly inhaled salmeterol/fluticasone propionate (50microg/500microg) twice a day. He had 30 pack-years of smoking history and quit smoking for more than 10 years. He was a farmer by profession. He was admitted to hospital with cough and hemoptysis for more than five months. Admission blood tests showed a white cell count of 5.8 x 109/L, C-reactive protein 3.1 mg/L and interleukin-6 16.32pg/mL. All of sputum smear acid-fast staining, tuberculin test and tuberculosis antibody test were negative. Serum biomarkers of lung cancer, such as carcinoembryonic antigen (CEA), Cytokeratin-19-fragment (CYFRA21-1), squamous cell carcinoma antigen (SCC), and neuron-specific enolase (NSE) were negative. The images of computed tomography (CT) scan of the chest revealed large dense shadows and cavity formation in the inferior lobe of the left lung (Figure 1A). The electronic bronchoscopy showed a big and white neoplasm in the lower left lung, with a narrow opening and a lot of white necrotic material in the subsegment (Figure 2). Biopsy revealed chronic inflammation of endobronchial membrane with lymphoid follicular hyperplasia, but without any definite tumor cells (Figure 3). Acid-fast staining and Periodic Acid-Schiff (PAS) staining were both negative. Not only the traditional culture (including aerobic and anaerobic) but also the galactomannan (GM) test of bronchoalveolar lavage fluid were negative. Surprisingly, the mNGS of bronchoalveolar lavage fluid revealed 4415 sequences of Campylobacter rectus and 1091 sequences of Parvimonas micra. Empirical antimicrobial therapy commenced immediately with intravenous tazobactam/piperacillin (4.5g three times daily) and ornidazole (500 mg twice daily) from the first day in the hospital. One week later when we got the result of mNGS, etimicin (300mg one time daily) was used in combination to enhance treatment against Gram-negative bacteria. Another two weeks later, the symptom of diarrhea in the patient was considered to be due to the imbalance of intestinal flora induced by long-term extensive use of broad-spectrum antibiotics. Therefore, the anti-infective treatment regimen was reduced to etimicin only. The patient was hospitalized for one month. The results of CT re-examination suggested that the area of infection in the inferior lobe of the left lung was significantly reduced, and the cavity was smaller (Figure 1B). After he was discharged from hospital, he was treated with oral levofloxacin (0.5g once daily) for four months. The condition of the lung was further improved than before (Figure 1C).

campylobacter rectus, wolinella recta, electronic bronchoscopy, lung abscess, mngs, metagenomic next-generation sequencing

(A) CT revealed large dense shadows and cavity formation in the inferior lobe of the left lung.

PMC8326275_01

Male

A 73-year-old man with a history of chronic obstructive pulmonary disease (COPD) for more than 10 years, he regularly inhaled salmeterol/fluticasone propionate (50microg/500microg) twice a day. He had 30 pack-years of smoking history and quit smoking for more than 10 years. He was a farmer by profession. He was admitted to hospital with cough and hemoptysis for more than five months. Admission blood tests showed a white cell count of 5.8 x 109/L, C-reactive protein 3.1 mg/L and interleukin-6 16.32pg/mL. All of sputum smear acid-fast staining, tuberculin test and tuberculosis antibody test were negative. Serum biomarkers of lung cancer, such as carcinoembryonic antigen (CEA), Cytokeratin-19-fragment (CYFRA21-1), squamous cell carcinoma antigen (SCC), and neuron-specific enolase (NSE) were negative. The images of computed tomography (CT) scan of the chest revealed large dense shadows and cavity formation in the inferior lobe of the left lung (Figure 1A). The electronic bronchoscopy showed a big and white neoplasm in the lower left lung, with a narrow opening and a lot of white necrotic material in the subsegment (Figure 2). Biopsy revealed chronic inflammation of endobronchial membrane with lymphoid follicular hyperplasia, but without any definite tumor cells (Figure 3). Acid-fast staining and Periodic Acid-Schiff (PAS) staining were both negative. Not only the traditional culture (including aerobic and anaerobic) but also the galactomannan (GM) test of bronchoalveolar lavage fluid were negative. Surprisingly, the mNGS of bronchoalveolar lavage fluid revealed 4415 sequences of Campylobacter rectus and 1091 sequences of Parvimonas micra. Empirical antimicrobial therapy commenced immediately with intravenous tazobactam/piperacillin (4.5g three times daily) and ornidazole (500 mg twice daily) from the first day in the hospital. One week later when we got the result of mNGS, etimicin (300mg one time daily) was used in combination to enhance treatment against Gram-negative bacteria. Another two weeks later, the symptom of diarrhea in the patient was considered to be due to the imbalance of intestinal flora induced by long-term extensive use of broad-spectrum antibiotics. Therefore, the anti-infective treatment regimen was reduced to etimicin only. The patient was hospitalized for one month. The results of CT re-examination suggested that the area of infection in the inferior lobe of the left lung was significantly reduced, and the cavity was smaller (Figure 1B). After he was discharged from hospital, he was treated with oral levofloxacin (0.5g once daily) for four months. The condition of the lung was further improved than before (Figure 1C).

campylobacter rectus, wolinella recta, electronic bronchoscopy, lung abscess, mngs, metagenomic next-generation sequencing

(B) The results of CT re-examination suggested that, the area of infection in the inferior lobe of the left lung was significantly reduced and the cavity was smaller.

PMC3567412_01

Female

A 60-year-old woman with no history of tuberculosis, pyothorax or artificial pneumothorax therapy, presented 4 months before her admission an asthenia, fever, chills, and night sweats. Physical examination revealed a mass of 10 cm localised in lateral chest wall (Figure 1). ignificant laboratory findings were as follows: haemoglobin: 9,3g/dL, erythrocyte sedimentation rate: 60 mm/h, LDH rate: 620 UI/ml. Computed tomographic scan confirmed the localisation in chest wall with invasion of the ribs (Figure 2). A biopsy of the chest tumor was performed and revealed a non-Hodgkin lymphoma with null phenotype. Immunohistochemical staining of the specimen was positive for leukocyte common antigen, CD20, and Ki67 and negative for CD3, vimentin, desmin, chromogranin, neuron specific enolase, CD99, and actin. The patient received four cycles of chemotherapy CHOP 21 (Cyclophosphamide 750 mg/m2 Intraveinously (IV) at day1, doxorubicin 50 mg/m2 IV at day1, vincristine 1, 4 mg/m2 with a maximum total dose of 2 mg IV at day1 and prednisone 40 mg/m2/day per os from day 1 to 5) followed by local radiotherapy, total dose was 40 Gy delivered as 2Gy daily fractions, 5 day per week. She had a complete response maintained for more than 7 months.

lymphoma, chest tumor, diagnosis, null phenotype

Computed tomography scan of the chest:Soft tissue mass lesion in posterior chest wall with thorax extension accompanied by pleural thickening.

PMC9253533_01

Male

After obtaining the approval of the local ethics committee (Section Giovanni Paolo II- IRCCS Casa Sollievo della Sofferenza) and written informed consent, we report the case of a 66-year-old man with a history of hypertension and ocular MG. This disorder was diagnosed 2 years before the pandemic onset by electromyography (EMG) and frontal muscle jitter study at the neurology unit of our hospital (Figure 1). AChR antibodies were detected, and and the thymoma ascertainment results were negative. He undertook pharmacology therapy consisting of pyridostigmine at a dosage of 30 mg three times daily, which was efficacious in treating myasthenic symptoms. The strength quantification performed by the Medical Research Council (MRC) was normal before the pandemic. At the beginning of December 2020, he developed fever, cough, myalgia, and dyspnea with progressive severe respiratory failure, which required ICU admission. He underwent chest computer tomography (CT) and nasopharyngeal swab that were positive for COVID-19 and was treated with remdesivir and corticosteroids. The patient underwent mechanical ventilation and tracheotomy. Laboratory tests did not detect an increase in the serum CK level. He also developed infections caused by multi-drug resistant germs, including Klebsiella pneumonia, Acinetobacter baumannii, and Pseudomonas aeruginosa, and underwent multiple antibiotic therapies. The Simplified Acute Physiology Score was 35. During the ICU stay, 15 days after admission, he complained of muscle weakness that evolved into the manifestation of tetraparesis without ocular involvement. Despite this development, pyridostigmine was increased to 60 mg three times daily; the strength remained unchanged. The length of stay (LOS) in ICU was 35 days. After improvement of the clinical conditions, the patient was transferred to our neuro-rehabilitation (NR) unit. At admission, the patient breathed spontaneously but needed 3 L/m oxygen by mask. Capillary oximetry was 97%; he had a central venous catheter, a tracheal tube, and a nasal-gastric tube for nutrition. The neurological picture showed severe tetraparesis that involved predominantly the lower limbs, and he had absent tendinous reflexes. No deficit in ocular or facial muscles was detected, and superficial and deep sensibilities were normal. Given the neurological feature, on day 2 of admission, the patient underwent electroneurography (ENG), electromyography (EMG), and frontal muscle jitter study that confirmed MG and showed overlapping ICUAW. In this respect, the electrophysiological exam revealed signs characteristic of CIP (Table 1). However, a lumbar puncture was performed, and cerebrospinal fluid (CSF) was collected and processed for standard analysis to exclude Guillain-Barre syndrome and polyneuropathies of different etiology. Pressure, cell count, and protein levels (<45 mg/dl) of the CSF were normal without albumin-cytologic disassociation. CSF/serum glucose ratio was normal. The CSF culture results for possible organisms, such as human immunodeficiency virus, hepatitis B virus, hepatitis C virus, bacteria, Mycobacterium tuberculosis, fungi, Borrelia, enteroviruses, Herpes viruses, and CMV, were negative. Similarly, the laboratory test for autoimmune disorders, including lupus anticoagulant, anticardiolipin antibodies, a panel of antiganglioside antibodies, including anti-GM1, -GM2, -GM3, -GD1a, -GD1b, -GT1b, and -GQ1b, and a panel for paraneoplastic syndrome, were negative. Strength and functional evaluation were quantified through the MRC scale sum-score, the Disability Rating scale (DRS), the Barthel scale (BS), and the functional independence measure (FIM) at admission, discharge, and 6 months of follow-up. During NR stay, the patient underwent a personalized and tailored rehabilitation treatment for 3 h daily, 6 days a week. Furthermore, he performed 2 h of daily electrical muscular stimulation on the lower limbs by placing surface electrodes on the quadriceps and anterior tibial muscles bilaterally. The muscular strength improved progressively, and the MRC sum score was 50 at discharge. The anticholinesterase therapy with pyridostigmine at the dosage of 30 mg three times daily, the same that the patient was taking before he had COVID-19, was resumed. His motor abilities recovered and, at discharge, he was able to walk without support but remained with left foot drop, which required the application of an ankle-foot orthosis (AFO). Furthermore, he complained of mild fatigue with reduced endurance, which improved over time. At follow-up, the MRC scale sum score and all functional scale scores resulted to be normal (Table 2). The LOS in neuro-rehabilitation was 42 days.

covid-19, icuaw, myasthenia gravis, neurology, neurorehabilitation, outcome

PMC9139337_01

Male

A 78-year-old man was admitted due to recurrent fever and fatigue for past one year. Two weeks prior to admission, his fatigue intensified, and the highest temperature reached 39.5C. He had lost 5kg over the past year and had a history of cerebral infarction and hypertension. On examination, the patient was febrile at 38C. His C-reactive protein (CRP) (62.49 mg/dl), procalcitonin (0.213ng/mL) and erythrocyte sedimentation rate (84 mm/h) were elevated. Computed tomography (CT) of the chest revealed diffusely distributed nodules in both lungs, bilateral bronchiolitis, and tuberculosis could not be excluded. The aortic arch was thickened and the local calcified plaque moved inward, which indicated further aortic computed tomography angiography (CTA) examination (Figure 1). Echocardiography revealed no vegetation in the mitral and aortic valve areas. The chest CTA confirmed multiple atherosclerosis and ulcers, and intermural hematoma in the aortic arch and thoracic aorta. Combined with the medical history, the involvement of tuberculosis in the aorta should be highly suspected (Figure 2). Re-examination of lung CT revealed bronchiole lesions and multiple miliary foci in both lungs, which were larger than one week prior, with pleural effusion, and slightly thickened pleura, suggestive of miliary tuberculosis (Figure 3). The T cell spot test, sputum culture, and sputum GeneXpert test were positive for Mycobacterium tuberculosis and GeneXpert indicated sensitivity to rifampicin. Since disseminated tuberculosis was definite and the patient's disease potentially involved the major thoracic vessels, anti-tuberculosis and steroids were initiated immediately. Methylprednisolone was administered at 40mg/day for 3 days, 20mg/day for 3 days, 8mg/day for 3 days, 4mg/day for 7 days, and then discontinued. Due to liver dysfunction, with alanine aminotransferase of 161U/L and aspartate aminotransferase of 203U/L, a regimen consisting of meropenem 1 g every 8 h, linezolid 0.6 g once daily, amikacin 0.4 g once daily, and levofloxacin 0.5 g once daily was administered. Surgical consultation concluded that no immediate surgical intervention was needed because the aortic wall was not ruptured. On normalisation of liver function, the anti-tuberculosis regimen was changed to isoniazid 0.3 g once daily, rifapentine 0.45 g twice a week, linezolid 0.6 g once daily, ethambutol 0.75 g once daily, levofloxacin 0.5 g once daily. After two weeks of treatment, the patient's body temperature returned to normal, and a re-examination of the lung CT indicated that the lesion was partially absorbed (Figure 4). The patient was discharged and continued to receive oral medications. We planned the follow-up to be weekly initially, gradually transitioning to every two weeks, and then monthly after stabilisation. Routine blood, liver and kidney functions were examined at each follow-up visit. Sputum smears and cultures were performed monthly. Pulmonary CT was re-examined two months later, and aortic CTA was re-examined four months later. The patient tolerated and was compliant with anti-tuberculosis drugs.

anti-tuberculosis therapy, aortic pseudoaneurysm, endovascular stent implantation, steroids, tuberculosis aortitis

Chest CT showing: diffusely distributed nodules in both lungs, bilateral bronchiolitis, and tuberculosis could not be excluded. The aortic arch was thickened, and the local calcified plaque moved inward, which indicated further aortic CTA examination.

PMC9139337_01

Male

A 78-year-old man was admitted due to recurrent fever and fatigue for past one year. Two weeks prior to admission, his fatigue intensified, and the highest temperature reached 39.5C. He had lost 5kg over the past year and had a history of cerebral infarction and hypertension. On examination, the patient was febrile at 38C. His C-reactive protein (CRP) (62.49 mg/dl), procalcitonin (0.213ng/mL) and erythrocyte sedimentation rate (84 mm/h) were elevated. Computed tomography (CT) of the chest revealed diffusely distributed nodules in both lungs, bilateral bronchiolitis, and tuberculosis could not be excluded. The aortic arch was thickened and the local calcified plaque moved inward, which indicated further aortic computed tomography angiography (CTA) examination (Figure 1). Echocardiography revealed no vegetation in the mitral and aortic valve areas. The chest CTA confirmed multiple atherosclerosis and ulcers, and intermural hematoma in the aortic arch and thoracic aorta. Combined with the medical history, the involvement of tuberculosis in the aorta should be highly suspected (Figure 2). Re-examination of lung CT revealed bronchiole lesions and multiple miliary foci in both lungs, which were larger than one week prior, with pleural effusion, and slightly thickened pleura, suggestive of miliary tuberculosis (Figure 3). The T cell spot test, sputum culture, and sputum GeneXpert test were positive for Mycobacterium tuberculosis and GeneXpert indicated sensitivity to rifampicin. Since disseminated tuberculosis was definite and the patient's disease potentially involved the major thoracic vessels, anti-tuberculosis and steroids were initiated immediately. Methylprednisolone was administered at 40mg/day for 3 days, 20mg/day for 3 days, 8mg/day for 3 days, 4mg/day for 7 days, and then discontinued. Due to liver dysfunction, with alanine aminotransferase of 161U/L and aspartate aminotransferase of 203U/L, a regimen consisting of meropenem 1 g every 8 h, linezolid 0.6 g once daily, amikacin 0.4 g once daily, and levofloxacin 0.5 g once daily was administered. Surgical consultation concluded that no immediate surgical intervention was needed because the aortic wall was not ruptured. On normalisation of liver function, the anti-tuberculosis regimen was changed to isoniazid 0.3 g once daily, rifapentine 0.45 g twice a week, linezolid 0.6 g once daily, ethambutol 0.75 g once daily, levofloxacin 0.5 g once daily. After two weeks of treatment, the patient's body temperature returned to normal, and a re-examination of the lung CT indicated that the lesion was partially absorbed (Figure 4). The patient was discharged and continued to receive oral medications. We planned the follow-up to be weekly initially, gradually transitioning to every two weeks, and then monthly after stabilisation. Routine blood, liver and kidney functions were examined at each follow-up visit. Sputum smears and cultures were performed monthly. Pulmonary CT was re-examined two months later, and aortic CTA was re-examined four months later. The patient tolerated and was compliant with anti-tuberculosis drugs.

anti-tuberculosis therapy, aortic pseudoaneurysm, endovascular stent implantation, steroids, tuberculosis aortitis

Chest CT showing: bronchiole lesions and multiple miliary foci in both lungs with pleural effusion and slightly thickened pleura. This combined with the medical history is consistent with the diagnosis of hematogenous disseminated pulmonary tuberculosis.

PMC9139337_02

Female

A 61-year-old woman presented with intermittent low back pain that persisted for past one month. The pain worsened within one week and became unbearable. Three months previously, the patient was admitted to a local hospital for productive cough. Lung CT showed suspicious TB lesions, and T-SPOT was positive. After excluding other diseases, the local hospital started diagnostic anti-tuberculosis treatment consisting of HRZE. The patient took the medication irregularly because of gastrointestinal reaction. A physical examination revealed no abnormalities. Laboratory results were white blood cells, 7.22x109/L; hemoglobin, 122 g/L; platelets, 216 x109/L; CRP, 32.97 mg/dl; and procalcitonin, 0.213ng/mL. The sputum GeneXpert test result was positive and sensitive to rifampicin. Multiple infections and diffuse miliary nodules in both lungs suggested tuberculosis. Thoracic and abdominal aortic CTA examination showed a 51x28 mm2 pseudoaneurysm arising from the lower abdominal aorta, surrounded by a patchy shadow and lymphadenopathy (Figure 5). Combined with the patient's medical history, tuberculous aortic pseudoaneurysm was considered. Emergency digital subtraction angiography was performed after admission, and two coated stents were implanted in the abdominal aorta and iliac artery. Angiography showed that the stents were well- positioned, blood flow was smooth, and a pseudoaneurysm did not develop. The patient was discharged from the hospital 2 days post-operation and received anti-tuberculosis drug treatment, including isoniazid 0.6 g once daily, rifapentine 0.45 g twice a week, ethambutol 0.75 g once daily, pyrazinamide 0.5 g three times daily, and moxifloxacin 0.4 g once daily. Abdominal aortic CTA performed two weeks later revealed that the aneurysm did not recur (Figure 6). Our follow-up plan was consistent with that of the patient in case 1. The patient tolerated the anti-tuberculosis drugs well.

anti-tuberculosis therapy, aortic pseudoaneurysm, endovascular stent implantation, steroids, tuberculosis aortitis

PMC3606735_01

Male

A 13-year-old previously healthy Iraqi-born unvaccinated immigrant boy presented with a one-year history of worsening vision loss. Over the course of 2 months, he developed myoclonic jerks involving all extremities that increased in frequency over the next few months, occurring every 10 seconds. In addition, he had atonic episodes resulting in him falling to the floor. He had difficulty with fine motor movements, including writing and putting on clothes. Over several months, he progressed to being unable to ambulate independently. He had frequent urinary incontinence. His memory and performance in school began to decline, first gradually and then more rapidly after 6 months. He started to have aggressive outbursts towards his family with behaviors such as hitting and biting. His mother reported a febrile illness associated with a rash as a toddler without confirmation of measles. Initial exam demonstrated decreased visual acuity in the right eye (20/200) and left eye (20/40) and frequent myoclonic jerks. He had evidence of macular retinopathy on fundoscopic evaluation. On mental status examination, he showed progressive impairment with simple multiplication and difficulty with recall and comprehension. He had difficulty with orientation questions. On cranial nerve examination, he had sluggish poorly reactive pupils to direct light bilaterally with normal reactivity on convergence and an oculomotor apraxia. He had diffuse spasticity of both upper and lower extremities with diffuse hyperreflexia. Coordination exam revealed a progressive resting and action tremor bilaterally and an unsteady, wide-based gait. EEG showed significant frontal slowing during the awake state as well as recurrent periodic generalized periodic epileptiform discharges with preservation of his posterior basic rhythm (Figure 1) that raised suspicion for a diagnosis of a progressive myoclonic epilepsy included in the differential diagnosis: baltic myoclonic epilepsy, Lafora body disease, Unverricht-Lundborg disease, neuronal ceroid lipofuscinosis, sialidosis, myoclonic epilepsy with ragged red fibers, and SSPE. Following an extensive negative metabolic and infectious workup of serum and CSF samples, the diagnosis of subacute sclerosing panencephalitis was confirmed by elevated serum measles IgG (22.4) and CSF measles IgG (12.0) titers.

PMC5259602_02

Female

A 3-month-old girl was referred to our hospital with a suspicion of Langerhans cell histiocytosis. She was hospitalized for pneumonia at the fifteenth day of birth followed by recurrent and treatment resistant cervical lymphadenopathies with high CRP levels. She was the first child of a consanguineous family. She had bilateral cervical lymphadenopathies and maculopapular skin eruptions over body and legs on admission. Laboratory investigations revealed anemia, leukocytosis, high CRP level (12 mg/dL), and hypergammaglobulinemia. Histological findings of the skin biopsy and lymph node excision were reported as granulomatous inflammation and necrotizing granulomatous lymphadenitis, respectively. Meanwhile, oxidative burst activity ("Phagoburst" kit, Glycotope, Biotechnology) was insufficient (FMLP 9%, PMA 9%, and opsonized E. Coli 4%; normal values 1-10%, 98-100%, and 97-100%, resp.) leading to a probable diagnosis of CGD later confirmed with mutation analysis disclosing a "homozygous autosomal recessive c.369 + 1G>A mutation" in CYBA gene- p22phox. She was admitted again with tachypnea with coarse lung sounds relevant to acute pneumonia at 30 months of age. She had anemia (Hb: 8.9 g/dL), leukocytosis (16800/mm3), and high CRP (3 mg/dL) and ESR (60 mm/hr) levels. CXR showed bilateral extensive infiltrations especially prominent in left upper lobe (Figure 3). Thorax CT revealed pneumonic consolidations with calcifications (Figure 3). These findings were interpreted in favor of tuberculosis (TB) although objective mycobacterial evidence was absent (PPD 9 mm, gastric fluid acid-fast bacilli and PCR negative). Three-drug combination therapy (isoniazid, rifampicin, and pyrazinamide) was initiated. Echocardiography showed pericardial thickening which was also evaluated as TB sequela. Despite treatment, her clinical condition worsened in a two-month period. Extensive lymph node enlargements in mediastinum and around pericardium reaching to 3 cm in diameter, some showing central necrosis, were recorded in the new thorax CT (Figure 3). During hospitalization, she developed right congestive heart failure signs, fine crackles in lungs, and increased oxygen need. Echocardiography showed findings compatible with pulmonary hypertension, diastolic dysfunction, and constrictive pericarditis (Figure 4). Emergency pericardiectomy was performed. Aspergillus fumigatus was cultured in pericardial fluid and blood Aspergillus antigen was positive for the first time. Parenteral caspofungin and voriconazole infusions were initiated in combination for antifungal therapy. Histological interpretation of the pericardial sample was reported as granulomatous pericarditis. Fever and respiratory distress continued and thorax CT revealed an abscess of 4.5 x 1.7 cm diameter in left lung inferior lobe, two weeks after the pericardiectomy (Figure 5). The abscess was drained and drainage material culture was positive for Aspergillus fumigatus (Figure 5). Granulocyte transfusions were applied for the subsequent days and fever subsided gradually in a few days. She was discharged with oral voriconazole after her condition stabilized with parenteral antifungal therapy for one month. Blood Aspergillus antigen was still positive in low titers. Two weeks later, she was brought to emergency department with left hemiparesis, left central facial paralysis, and fever. Glasgow Coma Scale was 12, motor strength was 2/5 in left upper and lower extremities, and left plantar response was abnormal in neurological examination. A hypodense lesion at the level of right basal ganglia was interpreted as acute ischemic infarction in cranial CT (Figure 6). Diffusional restriction consistent with acute ischemia in right basal ganglia and cerebral, cerebellar millimetric enhancing foci consistent with aspergillosis were reported in cranial and diffusion magnetic resonance imaging (MRI) (Figure 6). In MR angiography, right middle cerebral artery was occluded from M2 segment to end which was also associated with Aspergillus infection (Figure 6). Voriconazole, amphotericin B, vancomycin, and meropenem were started. Intravenous immunoglobulin, 1 gr/kg/day, was given for two days. Fever was controlled and her general condition improved. Acetylsalicylic acid treatment was commenced to prevent further infarction. Neurological findings regressed with decreased facial asymmetry and increased motor strength in the follow-up. Parenteral antifungal treatment was continued for two months and she was discharged with oral voriconazole and negative blood Aspergillus antigen. The ischemic lesion in the right basal ganglia showed chronicity and appeared as cystic encephalomalacia; most of the cerebral/cerebellar foci were smaller than before and some disappeared in the control MRI five months after the initial evaluation (Figure 7). Due to the severe course of her disease, HSCT was planned and due to the lack of full matched relative, an unrelated donor search is initiated.

PMC8264843_01

Male

A 65-year-old male patient with history of keratoconus and penetrating keratoplasty (PK) over 30 years ago developed corneal oedema subsequent to the graft failure in his left eye with best corrected visual acuity (BCVA) of counting fingers. He had an eccentric 7.5 mm penetrating keratoplasty, which made repeat full thickness keratoplasty with a larger donor graft a high risk for rejection. He also had a mild cataract. Therefore, he was offered Descemet membrane endothelial keratoplasty (DMEK) on failed PK combined with cataract surgery using standard keratometry of 43.5D and a hydrophobic acrylic intraocular lens. After inserting the intraocular lens, while the anterior chamber was filled with a cohesive viscoelastic device, we performed a Descematorhexis within the graft-host junction. Care was taken not to expose posterior stromal strands during Descematorhexis. After a thorough washout of the viscoelastic device a 7.25 mm Descemet membrane graft was delivered and secured on the stroma within the old penetrating keratoplasty, using an intracameral injection of 50% Sodium Hexafluoride (SF6) gas. Cyclopentolate 1% eye drops were used immediately after the injection of gas to prevent pupillary block, since he has had no peripheral iridotomies. The patient was advised to comply with supine posture for a minimum of 2 days and was given antibiotic-steroid combination drops qds for a month, G. Cyclopentolate 1% tds for a week and Tb. Acetazolamide 250 mg sustained release for 3 days post-surgery. One week post-operatively the cornea appeared oedematous with inferior detachment of DMEK graft (Figure 1(a)). Re-bubbling with air was performed at the slit lamp via 5 o'clock paracentesis, the patient was started on Acetazolamide 250 mg slow release tablets for 3 days and advised to maintain a supine posture for a minimum of 2 days and ideally as long as the air was present in the anterior chamber. One week later, he was noticed to have persistent inferior graft detachment and corresponding corneal oedema (Figure 1(a)); therefore, the second re-bubbling was performed at the slit lamp in the same fashion. His cornea remained oedematous inferiorly at 4 weeks due to persistent inferior Descemet membrane detachment (Figure 1(a)) despite two subsequent re-bubblings. Careful inspection of his anterior segment OCT (AS-OCT) revealed a ridge on the posterior surface of the graft-host junction infero-nasally (Figure 1(a)), which was the probable cause of his recurrent inferior Descemet membrane detachment. To manage this complication, he underwent DMEK suturing in the theatre under subtenon anaesthesia. The detached graft was repositioned, using intracameral injection of air. Based on the extent of the DMEK detachment three radial full thickness 10-0 nylon interrupted sutures were placed in the inferior cornea to hold the graft in place. The needle passed through the host cornea and exited from the graft cornea. Care was taken not to tear the detached Descemet with unnecessary needle movement in the anterior chamber (Supplemental Video 1) (Figure 1(b)). One week post-operatively, his AS-OCT confirmed complete attachment of the DMEK graft with clear appearance of posterior protuberance (Figure 1(c)). Four weeks later, the corneal sutures were removed at the slit lamp and no further sutures were needed. Following this, his medications switched to G. Dexamethasone 0.1% qds for 2 months followed by bd for long-term. His corneal oedema resolved (Figure 2(a) and (b)) and his visual acuity gradually improved. Eight months from DMEK, his cornea was clear, and his unaided visual acuity was 20/63 with BCVA of 20/32 using rigid gas permeable contact lens (best spectacle corrected vision was 20/60 and best contact lens corrected vision was 20/32 before PK graft failure). The patient provided written informed consent to publish all related medical data, images and videos.

descemet membrane, penetrating keratoplasty, suturing

PMC6136482_01

Female

A 60-year-old woman with arthralgia and back pain lasting for several months and recent metatarsophalangeal luxation of the left toe presented to the ambulatory unit of rehabilitation clinics. She was referred to the clinics as a patient with chronic pain syndrome. The patient had joint hypermobility since childhood, diagnosed as ligament laxity. In adolescence, she is remembered to be called "a clumsy freak" due to joint mobility. At physical evaluation, marfanoid habitus with waxy, sagging skin and varicose veins in the feet was observed. Sclerae were bluish and eyelids dropping. In fingers and toes, spontaneous subluxation in all joints could be elicited. Elbows, knees, and all fingers were overextended. She had flat feet with a bilateral hallux valgus (Figure 1). She had scoliosis with prominent kyphosis. Lungs auscultation was characteristic of chronic obstructive pulmonary disease (COPD); the murmur of mitral valve prolapse was heard over the chest. On the Beighton score, she received all (9) scores: passive apposition of the thumb to forearm and passive dorsal hyperextension of the metacarpophalangeal joint >90 on both sides were done with no strain (Figure 2); she was able to actively hyperextend both elbows and knees on both sides over >10 and flex her spine to the ground with palms placed on the ground without knee flexing. On Five-point Hypermobility Questionnaire, she answered "yes" to all questions. She remembered vividly contorting her body into strange shapes and being called names by other children. Genetic analysis showed a typical mutation consistent with the classical Ehlers-Danlos syndrome. In the ambulatory unit, she received systematic, light, nonweightbearing, and proprioception exercises; she was referred to the occupational therapist for lower limb orthosis; she was taught relaxation techniques including mindfulness-based stress reduction and counselling support, though she was already familiar with cognitive behavioural therapy. She used regular anti-inflammatory drugs. She was referred to the plastic surgeon due to the wound on her foot, since sutures should be applied generously, without tension, in layers, and left in place twice as long as usual. She was already regularly followed by her cardiologist due to mitral valve prolapse.

PMC7652926_05

Female

On April 4, 2020, the US Department of Agriculture (USDA) announced that samples from a 4-year-old female Malayan tiger at the Bronx Zoo in New York City tested positive for SARS-CoV-2 by RT-qPCR. The swab samples were collected and tested after two Malayan tigers, three Siberian tigers, and three African lions showed respiratory signs for a week. On April 17, the OIE confirmed that one of the African lions tested positive for SARS-CoV-2 by RT-qPCR. Later on, all these animals and one asymptomatic Siberian tiger tested positive for SARS-CoV-2 by RT-qPCR of stool samples. The five positive tigers live separately in the same enclosure. The three lions live in an enclosure in another zoo area, and they occasionally interacted. The Bronx Zoo also has one Malayan tiger and two Siberian tigers living in a distant enclosure. These three tigers showed no clinical signs. SARS-CoV-2 was identified and characterized in a Malayan tiger. The seven symptomatic animals have improved and are expected to fully recover. In addition, SARS-CoV-2 characterization has shown distinct viral sources for tigers and lions, with similarities between tiger and zookeeper viruses suggesting human-animal transmission, but no identified viral source was found for the infection in lions. On April 26, 2020, the Dutch Ministry of Agriculture, Nature, and Food Quality communicated SARS-CoV-2 outbreak in two mink (Neovison vison) farms, after respiratory disease and increased mortality. Infection by SARS-CoV-2 has been reported in minks on a farm with 13,000 minks. Additional infections were identified on a second farm with 7,500 adult minks. Three minks with gastrointestinal and respiratory signs were euthanized. Samples of manure, air, and dust collected from the vicinity of the farm are being tested for the presence of the virus. Cats from the farms will also be tested. At least one worker tested positive for SARS-CoV-2 in both farms. It is not surprising that minks are susceptible because they are from the same family (Mustelidae) as ferrets (Mustela putorius furo), and ferrets can be experimentally infected with SARS-CoV-2 and transmit the disease to other ferrets by direct or indirect contact. The infection in minks appears to be a case of human-to-animal infection, once viral sequences of two farms were related to human being sequences, but in separate introductions. In addition, since March 2020, rabbit farms near infected visons have been investigated by the Dutch Ministry of Agriculture, Nature, and Food Quality due to possible susceptibility to SARS-CoV-2. Experimental transmission study has shown that pigs (Sus scrofa) and chickens (Gallus gallus) were not susceptible to SARS-CoV-2, since none of the animals seroconverted and all samples were negative for viral RNA after intranasal inoculation. On the other hand, fruit bats (Rousettus aegyptiacus) have presented virus replication detected by RT-PCR, in situ hybridization (ISH), and immunohistochemistry (IHC) associated with mild rhinitis.

cats, coronavirus, dogs, pets, transmission

PMC3616049_01

Male

A 27 year-old African-American male was brought in by his family for altered mental status and possible seizure activity. The family stated that the patient had been complaining of a headache for one to two months. The family noted some mild behavioral and cognitive changes that had progressed over the last month. The week prior to presentation to our facility, the patient had an episode of slurred speech, facial droop, drooling, and seizure-like activity in the left upper extremity. The patient was taken to outlying emergency department (ED) but on arrival to the outside facility his symptoms had resolved. He was evaluated with basic labs and a non-contrasted computed tomography (CT) of the brain. He was discharged from the outside ED with a prescription for naprosyn and doxycycline. Over the next week, he had further behavior changes and became very lethargic. The family brought the patient to our facility for further evaluation at this time. The patient had no known past medical history and no prior surgeries. Current medications included naprosyn and doxycycline that he had received one week prior, no other home medications. Social history was significant for alcohol misuse for 10 years, tobacco use of 1 pack per day for 10 years and occasional marijuana use. The patient had just recently moved back to Tennessee to seek help from his family in quitting alcohol, after living in Texas and working as a bank teller for 7 years. No known travel outside of the country and no known contact with persons with communicable diseases. On physical exam he was well developed, well nourished, profoundly encephalopathic and diaphoretic. Temperature was 103 F, heart rate 87 beats/min, blood pressure 154/84 mmHg, respiratory rate 16 /min, and oxygen saturation 99% RA. His cardiovascular, pulmonary, and abdominal exams where unremarkable, skin was notable for significant diaphoresis without rash. He was unable to follow commands for a full neurologic exam but was confused and combative, moved all extremities spontaneously and with equal strength, and did exhibit significant photophobia or nuchal rigidity. Initial laboratory data revealed leukocytosis of 11.7 th/mm3 with 92% neutrophils otherwise hemoglobin, hematocrit, and complete metabolic panel where within normal limits. Cerebral spinal fluid evaluation revealed WBC count of 302/mm3 with 98% lymphocytes, glucose 14 mg/dl, protein 144 mg/dl, and was clear in character. Chest x-ray and non-contrast CT of head where without significant pathology. After blood cultures had been obtained and initial CSF studies sent, the patient was place in the neurologic intensive care unit and started on broad spectrum antibiotics with vancomycin and piperacillin/tazobactam. Over the next twelve hours the patient was closely monitored and supportive care was continued as initial results began to return. Gram staining of CSF and blood was negative for bacteria and HIV, RPR, Cryptococcal antigen, HSV PCR where negative. The patient showed minimal mental status improvement within the first 24 hours and an MRI of the brain and Neurologic consult where obtained. MRI with and without contrast revealed right basilar meningeal enhancement with an acute right basil ganglia infarction (Figures 1,2). Given the characteristic finding of the CSF and MRI a PPD was placed and Infectious disease was consulted. PPD was read as negative at 48 hours by nursing staff and re-read as positive at 72 hours by an infectious disease physician. Initial direct smears of two separate samples of CSF where negative for acid fast bacilli, and PCR of the CSF was negative for TB on two different occasions. CT of the chest was obtained to look for possible source of infection and revealed right upper lobe nodules with central cavitations (Figures 3,4). Biopsy of the lung was performed and pathology revealed necrotizing granulomatous inflammation with acid fast bacilli (Figures 5,6). Initial concentrated direct smears for acid fast bacilli from the lung biopsy where negative, but Mycobacterium tuberculosis was isolated and identified by DNA probe with High Performance Liquid Chromatography at 32 days. Treatment should be initiated on the basis of strong clinical suspicion. As mentioned previously it may take several repeated studies before obtaining positive proof of tuberculous infection and delay in treatment often leads to irreversible deficits or death. Recommended treatment is for 9-12 months and is divided into two phases. The intensive phase is four drug therapy with isoniazid (INH), rifampin (RIF), pyrazinamine (PZA), and either ethambutol (EMB) or streptomycin (STM) for two months followed by a continuation phase of INH and RIF for 7-10 months depending on clinical response and sensitivity of the specimen. Once empiric TB coverage was started the patient showed significant clinical response with improvement of his mental status, but at the time of discharge still had prominent personality, memory, and functional impairment.

mycobacterium tuberculosis infection, basilar stroke, extrapulmonary tuberculosis, meningitis, purified protein derivative

CT Thorax findings consist of right upper lobe cluster of nodules with central cavitations.

PMC3616049_01

Male

A 27 year-old African-American male was brought in by his family for altered mental status and possible seizure activity. The family stated that the patient had been complaining of a headache for one to two months. The family noted some mild behavioral and cognitive changes that had progressed over the last month. The week prior to presentation to our facility, the patient had an episode of slurred speech, facial droop, drooling, and seizure-like activity in the left upper extremity. The patient was taken to outlying emergency department (ED) but on arrival to the outside facility his symptoms had resolved. He was evaluated with basic labs and a non-contrasted computed tomography (CT) of the brain. He was discharged from the outside ED with a prescription for naprosyn and doxycycline. Over the next week, he had further behavior changes and became very lethargic. The family brought the patient to our facility for further evaluation at this time. The patient had no known past medical history and no prior surgeries. Current medications included naprosyn and doxycycline that he had received one week prior, no other home medications. Social history was significant for alcohol misuse for 10 years, tobacco use of 1 pack per day for 10 years and occasional marijuana use. The patient had just recently moved back to Tennessee to seek help from his family in quitting alcohol, after living in Texas and working as a bank teller for 7 years. No known travel outside of the country and no known contact with persons with communicable diseases. On physical exam he was well developed, well nourished, profoundly encephalopathic and diaphoretic. Temperature was 103 F, heart rate 87 beats/min, blood pressure 154/84 mmHg, respiratory rate 16 /min, and oxygen saturation 99% RA. His cardiovascular, pulmonary, and abdominal exams where unremarkable, skin was notable for significant diaphoresis without rash. He was unable to follow commands for a full neurologic exam but was confused and combative, moved all extremities spontaneously and with equal strength, and did exhibit significant photophobia or nuchal rigidity. Initial laboratory data revealed leukocytosis of 11.7 th/mm3 with 92% neutrophils otherwise hemoglobin, hematocrit, and complete metabolic panel where within normal limits. Cerebral spinal fluid evaluation revealed WBC count of 302/mm3 with 98% lymphocytes, glucose 14 mg/dl, protein 144 mg/dl, and was clear in character. Chest x-ray and non-contrast CT of head where without significant pathology. After blood cultures had been obtained and initial CSF studies sent, the patient was place in the neurologic intensive care unit and started on broad spectrum antibiotics with vancomycin and piperacillin/tazobactam. Over the next twelve hours the patient was closely monitored and supportive care was continued as initial results began to return. Gram staining of CSF and blood was negative for bacteria and HIV, RPR, Cryptococcal antigen, HSV PCR where negative. The patient showed minimal mental status improvement within the first 24 hours and an MRI of the brain and Neurologic consult where obtained. MRI with and without contrast revealed right basilar meningeal enhancement with an acute right basil ganglia infarction (Figures 1,2). Given the characteristic finding of the CSF and MRI a PPD was placed and Infectious disease was consulted. PPD was read as negative at 48 hours by nursing staff and re-read as positive at 72 hours by an infectious disease physician. Initial direct smears of two separate samples of CSF where negative for acid fast bacilli, and PCR of the CSF was negative for TB on two different occasions. CT of the chest was obtained to look for possible source of infection and revealed right upper lobe nodules with central cavitations (Figures 3,4). Biopsy of the lung was performed and pathology revealed necrotizing granulomatous inflammation with acid fast bacilli (Figures 5,6). Initial concentrated direct smears for acid fast bacilli from the lung biopsy where negative, but Mycobacterium tuberculosis was isolated and identified by DNA probe with High Performance Liquid Chromatography at 32 days. Treatment should be initiated on the basis of strong clinical suspicion. As mentioned previously it may take several repeated studies before obtaining positive proof of tuberculous infection and delay in treatment often leads to irreversible deficits or death. Recommended treatment is for 9-12 months and is divided into two phases. The intensive phase is four drug therapy with isoniazid (INH), rifampin (RIF), pyrazinamine (PZA), and either ethambutol (EMB) or streptomycin (STM) for two months followed by a continuation phase of INH and RIF for 7-10 months depending on clinical response and sensitivity of the specimen. Once empiric TB coverage was started the patient showed significant clinical response with improvement of his mental status, but at the time of discharge still had prominent personality, memory, and functional impairment.

mycobacterium tuberculosis infection, basilar stroke, extrapulmonary tuberculosis, meningitis, purified protein derivative

CT guided biopsy right lung nodule reveals acid fast bacilli (arrows).

PMC5827702_02

Male

In Kosawa's parable, the child's mother appears by contrast as a saintly figure: capable of great patience and gentleness but also possessing a spiritual gift of sorts, able to see into the depths of the child, meet him there, and nurture a 'truly religious state of mind'. Kosawa's own mother, Kon, was a rather more complex figure, and in any case as was common for a family of the Kosawas' standing, the young Heisaku was mostly looked after as a child not by his mother but by a local girl serving as his nanny. 'Ichi' was around ten years old when she began looking after Heisaku, and as one might expect from someone of that age was not entirely committed to the idea of responsible childcare. Missing her friends, she once tied Heisaku to a tree so that he couldn't wander off while she went out to play. Much later in life, Kosawa's thoughts used to return frequently to that moment - a sign, thought one of his students, that his idealization of the maternal possessed deep roots not in satisfaction but in longing and loss (Takeda,). 1 Kosawa was by no means out of the ordinary here. He grew up in a society many of whose men rhapsodized rather than really knew their mothers (Napier,), and who sought to fix the womanly and the maternal as comforting social, emotional and even spiritual categories. She was, nevertheless, a strong presence in his life, ensuring that 'home' offered a reassuring resonance and embrace for Heisaku - powerful enough to surface years later in his free associations. He remembered her joy when he used to return home from boarding at his Higher School in Sendai, in the north of Japan. Mother would make amazake - a sweet rice drink - to welcome him back. She would smile at him as he licked his cup - 'like a baby', he wrote, 'just moving onto solid food'. Heisaku remembered too the vivid sensation of being in the bath with her (Kosawa, yume bunseki). Kosawa's early relationships with his father and mother seem to have shaped his attitudes towards both Buddhism and mental health, and to have inspired his interest in seeing the two placed together in a single, salvific system - albeit with Buddhism and psychoanalysis still retaining separate goals and languages and institutions of their own. Helping to set this emerging conversation in train was a Buddhist monk of the Jodo Shinshu (Shin) sect by the name of Chikazumi Jokan. Kosawa met Chikazumi while he was at Higher School in northern Japan, encountering via him a highly devotional, emotional form of Buddhism in which intra-familial relationships were understood as furnishing the individual with transpersonal salvific opportunity. Chikazumi came to this realization while lying in bed one day, critically ill, and hearing his father by his bedside quietly wishing his son's troubles upon himself. It became a moment of conversion: an encounter with compassion so strong and pure that all at once it broke him out of the small, citadel mentality of a young university intellectual, showing him instead a truer, more vital vision of himself - as weak, vulnerable and loved (Iwata,). The proximate source of this love and compassion was his father. Their ultimate source, for human beings, was the quasi-monotheistic figure of the cosmic Buddha 'Amida' - the Buddha of Infinite Light. The thirteenth-century founder of Shin Buddhism, a man by the name of Shinran, had insisted that the limits of human nature and the boundless compassion of Amida were such that a person needed only to recite a short prayer - Namu-Amida-Butsu: 'Hail to Amida Buddha' - in order to be saved. This wasn't some magical formula. Rather, it was an honest and profoundly generative recognition of weakness, such that the very term 'weakness' lost its typical, negative connotations. The voice with which I call Amida Buddha Is the voice with which Amida Buddha calls to me. Shinran went as far as to say that this prayer could only be truly spoken by Amida Buddha himself, working at the deepest level of a person's subjectivity. As Kai Wariko, a modern Shin poet, put it:For Chikazumi, and soon for Kosawa, the full force of his home life coming into play alongside a new-found devotionalism, modern Japanese family relationships were the means by which Amida's mercy broke into mundane, linear time, and into mundane, human lives (Iwata,). To twenty-first century ears, much of this must already sound like psychotherapy of a sort (Ross,). But for Kosawa, the connection only really came when he encountered the writings of Sigmund Freud while at university. He found in Freud a modern-day Shinran: someone who understood human frailty, and appeared to be on a quest to tease out and treat them, bringing all the tools of modern science to the task. A few months spent in Vienna, with Freud and his circle, failed to change Kosawa's mind about Freud and the purpose of psychoanalysis, although he did write home to his brother to say that he was a little disappointed with the general level of psychoanalytic practice in Vienna - and was looking forward to getting home to start his own clinic in Tokyo (Harding,). 2 This he accomplished in 1933, seeing hundreds of clients from all walks of life over the next few years - students, farmers, civil servants, company employees, even a sushi chef, a politician, and a Buddhist monk. From his client records, and from the testimony of those still alive who were treated by Kosawa, we get a sense of the therapeutic fruits of Kosawa's inner religion-psy dialogue across his early life. Kosawa's impeccably neutral consulting room - Buddhist conversation with interested clients would instead be held next door, once the session had ended. Perhaps most revealing are the records of what Kosawa called 'psychoanalysis by mail'. This involved asking clients who couldn't make it for face-to-face sessions in Tokyo to send him, at regular intervals, two documents. The first was a covering letter, addressed to Kosawa. The second was a written record of a period of solo free association - all that had flashed through their heads when they obeyed the standard psychoanalytic command to allow their thoughts and feelings to go where they will. The first document told Kosawa about the client's own self-understanding. The second was the really interesting one: it revealed something of what lurked in the client's unconscious. As therapy went on, Kosawa would hope to see material move from this second document into the first: unconscious elements making their way into conscious awareness. Covering up the ears symbolizes castration, which in turn suggests your desire to become a girl as a means of securing affection from your father. What's more, your recollection and sharing of that memory now may well be a sign of homosexual feelings towards me ... One client confided in Kosawa that he recalled being embarrassed, as a child, when his parents forced him to wear a girl's rubber swimming cap at the seaside. Kosawa responded that he hadn't been embarrassed at all: he had liked it. Perhaps the client spilled his morning tea as he read this. Maybe he glanced nervously over the top of the letter at his father sitting across the table. Whatever happened, this was part analysis, part carefully calibrated attempt to nudge a client who was beginning to over-intellectualize the process of therapy into precisely the kind of gentle, helpless humiliation that Kosawa believed Shinran and Freud were agreed was central to the success of religious practice and psychotherapy alike. One day, a client of Kosawa's reported to him a vivid experience of being momentarily outside of himself, or at least not quite 'in' himself in the usual way. Kosawa was overjoyed. That, he said, is the real aim of psychoanalysis. Without it, psychoanalysis as a technique can never survive (Harding,). Awareness in the West of the Shin Buddhist sect to which Kosawa belonged has generally been low, despite its considerable size and power in Japan. 3 Buddhism, and especially Japanese Buddhism, has tended to be associated more with Zen. One of the reasons put forward for this is that in Zen, mid-twentieth-century Westerners found a combination they felt Christianity failed any longer to provide: vivid experience, real inner change, minimal theological baggage. Shin Buddhism's emphasis on faith and fundamental human inadequacy, by contrast, was too close for comfort to Protestant, particularly Calvinist Christianity. Why travel thousands of miles to a brand new culture - whether literally or in one's reading - only to find the very thing you were trying to escape? And yet for all the past and on-going interest in how Zen and psychoanalysis might work together, pioneered in the late 1950s and early 1960s by Erich Fromm and Japan's famous Buddhist evangelist D.T. Suzuki (Fromm, Suzuki, & De Martino,), Shin Buddhism and psychotherapy - as Kosawa's experience shows - possess promising commonalities. So it is all the more interesting to see that just five years after Fromm and Suzuki's work was published, Protestant Christianity and psychotherapy were entering into dialogue via a radio and television studio conversation between the German-American theologian Paul Tillich and Carl Rogers - the latter once having spent time in training for the Christian ministry. Carl Rogers in conversation with Paul Tillich, filmed for television in 1965. We may identify four key themes arising in and from Kosawa's inner religion-psy dialogue and the more literal 'dialogue' between Tillich and Rogers: a concern with the damaging social and psychological impact of modernity; a conviction that a profound experience of acceptance lies at the heart of the remedy; a sense that, almost by definition, this cannot be effected by the individual acting alone for his or her own benefit; and a danger - pointed out by critics - that such a remedy, especially where it takes hybrid religion-psy form, risks fostering subjectivities more suited to the totalitarian societies of the recent past in Europe and Japan than their postwar counterparts. It is worth briefly addressing each of these themes in turn. Kosawa Heisaku was a great critic both of what he saw as pathological individualism in early 1930s Japan and the false community and comfort offered by Marxism and by Japan's 'new religions', the latter striking Kosawa as shallow and manipulative. Kosawa was hardly alone in these concerns: commentators from the novelist Natsume Soseki through to journalists and philosophers like Watsuji Tetsuro worried about Japan's social and cultural fabric coming apart under the pressure of successive waves of Western fads and fashions from the late nineteenth century onwards. In the United States, both Paul Tillich and Carl Rogers worried, as Terry Cooper has shown (Cooper,), in similar ways. Tillich wrote about 'estrangement': from the ground of our being (a phrase Tillich used frequently for what other theologians called God), from others, and from ourselves. Rogers coined the term 'incongruence': the result of steadily concealing parts of ourselves from others as we grow up, in the hope of making ourselves more acceptable, the end-point of which is the partial concealment of ourselves from ourselves (Cooper,, pp. 17-21). In all three schemes - Kosawa, Tillich, Rogers - we find that acceptance plays a crucial role in countering all this. Not 'acceptance' in the everyday sense for which 'tolerance' may be the more accurate term, but rather the kind of acceptance that relies on deep knowledge of the person who is being accepted, along with that person's willingness and ability to, as it were, accept the acceptance. One of the reasons why Kosawa chose a little boy, as opposed to an adult, for his parable may be that a little boy, or girl, might still be at the stage where they have not lost their natural ability to accept acceptance. What Rogers called 'conditions of worth', all too clearly communicated in the father's outburst in the parable, have not yet become completely entrenched. But here is an important point of complication: where does this acceptance come from? For Rogers, the human realm is the source. For Tillich, the human realm - including family and therapist - mediates an acceptance that comes from somewhere well beyond us. Though there are obvious perils in seeking to compare Kosawa's with Tillich's cosmologies, the two share something important in common here. They are convinced that anxiety or other forms of distress stem, in part at least, from our very nature, which in turn is a 'given' of existence rather than something we are capable of shaping. Because of this there is always need of what Tillich called grace and what Kosawa understood as the working of Amida's compassion: some salvific force from without, operating in and through the human. This places important limits on religion-psy dialogue, in at least two ways. First, though in entirely secular counselling settings one could talk of moments of 'grace' (where something powerful and unintended arises), and on that basis much fruitful conversation can happen between the religion and psy spheres, Tillich's and Kosawa's cosmologies nevertheless understand the human as something else, or more. So for all their usefulness as bridging concepts between the religious and the psy, ideas like 'grace' should not have distinct meanings folded into them as though such things do not matter. Second, in Kosawa's and Tillich's cosmologies human limitations extend to our ability to formulate any adequate concepts - suggesting an even more fundamental hermeneutic problem for religion-psy dialogue (Hirota,). 4 Critics of particular instances of religion-psy dialogue have been quick to offer related cautions. We need some way of distinguishing in meditation, argues one, between psychological insights (about us, in the past and present) and spiritual insights (relating to the 'divine', for wont of a more appropriately inter-religious term, and our place in it, or relationship with it). We need to avoid religion-psy 'dialogue' devolving into the former simply serving the latter - as a provider of high-sounding, inspirational alternative terminologies for what is basically psychology, effectively masking a slide into agnosticism. 5 Still others wonder how forms of Buddhism and Christianity that resist the idea of ultimate reality having a personal dimension can meaningfully talk about 'acceptance'. Surely acceptance is a process with a person at either end (Cooper,; Harding,). Lastly, there is a concern about what kinds of people some forms of religion-psy dialogue helps to create. Kosawa, in his own day, was accused of literally 'drinking' his clients: thriving on their tales of distress and even playing the saviour to some extent - unable, despite his theorizing to the contrary, to imagine himself rather than Amida Buddha as the source of a person's felt acceptance. An American critic, though not especially well informed about Japan, offered the provocative criticism that whereas psychoanalysis in the United States sought to free the individual from the fetters of society, people like Kosawa actively sought to tighten them. If one stands back and seeks to read, at a purely social level, Kosawa's therapy, then reliant as it was on encouraging an individual to really experience their frailty, inadequacy, and deep need of others it might indeed fit such concerns. Read, however, at a religious or philosophical level, there might seem to have rather more going on: on this reading, everyone is heir to the very same constitutional weaknesses, so there can - or at least should - be no tyranny of 'strong' over 'weak'. In practice, of course, there was the serious risk of a religious reading glossing, even enabling, the harmful effects described in a social reading. Kosawa was criticized on precisely these grounds by some of his young psychoanalytic trainees. For Kosawa Heisaku, the fruits of religion-psy dialogue emerged in two simple questions: what is insight, and what does it cost? Good questions, which seem likely to remain with us for some time yet. And there is much to welcome, from this point of view, in the increasing interaction between the religion and psy professions, institutions, ideas and practices - even orientations within individuals. Finding ways to hold such interaction to account, by understanding its sources, claims, motivations and possible implications, is an important task, in which a range of academic and non-academic specialisms have roles to play. This article has sought to sketch out a social-historical and transcultural approach, as just one of many potential angles on this complex modern and contemporary phenomenon.

carl rogers, kosawa heisaku, kosawa heisaku, paul illich, paul tillich, dialogo religione-psi, dialogue religion-psy, disciplinas psicológicas, discipline psicologiche, disciplines psy, diálogo entre la psicoterapia y la religión, psy disciplines, religion-psy dialogue, διάλογος ανάμεσα στη θρησκεία και στην ψυχολογία, σχολές

PMC3558351_01

Male

A 42-year-old man was hospitalized with sudden-onset weakness in both lower extremities. The patient had been treated with isoniazid 300 mg, rifampin 450 mg, and ethambutol 800 mg daily for pulmonary tuberculosis during the past two months. He had no history of exposure to antituberculosis antibiotics before beginning therapy. His compliance to antibiotics was excellent after the treatment for pulmonary tuberculosis and he denied the interruption on these regimens. He reported no constitutional symptoms, history of hyperthyroidism or paralysis. A physical examination indicated that the muscle strength of the lower extremities was 2/5 of normal. The rest of the physical examination was unremarkable. A chest radiograph revealed reticular opacities on the bilateral upper lung fields, consistent with pulmonary tuberculosis. His laboratory data included hemoglobin 13.0 mg/dL, leukocyte count 9900/muL, and platelet count 290,000/muL. His biochemical data for serum and urine on admission are shown in Table 1. Profound hypokalemia, hypophosphatemia, and hypouricemia were present. Serum pH, bicarbonate level and anion gap indicated hyperchloremic metabolic acidosis with normal anion gap. The urinary anion gap was positive (10.2 mEq/L), suggesting the presence of renal tubular acidosis. Urinalysis showed normoglycemic glucosuria, beta2-microglobulinuria, pH 5.5, 2.5 g/day proteinuria and microscopic hematuria. The fractional excretion of potassium was 29.3% (normal range, 4%-16%); the calculated ratio of the maximal tubular transport of phosphate reabsorption to the glomerular filtration rate (TmP/GFR) was 0.24 mg/dL (normal range, 2.3-4.3 mg/dL); and the fractional excretion of uric acid was 77.4% (normal range, 6%-20%). Generalized hyperaminoaciduria was detected with liquid chromatography-tandem mass spectrometry. These findings suggest generalized proximal tubular dysfunction with wasting of bicarbonate, glucose, protein, potassium, phosphate, and uric acid. Additional blood tests were performed to determine other possible causes of the patient's hypokalemia. His plasma renin activity and serum level of aldosterone were 21.6 ng/mL/h and 30.5 ng/dL, respectively. His thyroid-stimulating hormone and free thyroxine levels were within the normal ranges. Serum and urinary protein immunoelectrophoresis showed no evidence of monoclonal gammopathy, and immunological surveys of autoantibodies were negative. The patient's reticulocyte count, serum lactate dehydrogenase, and liver enzymes levels were within the normal ranges. An ultrasonographic examination showed a normal-sized kidney, with slightly increased echogenicity in the bilateral renal parenchyma. A renal biopsy showed extensive mononuclear cell infiltrates, including epithelioid histiocytes and eosinophils, mild interstitial fibrosis, and tubular atrophy (Figure 1A and B). Ziehl-Neelsen staining for acid-fast bacilli and PCR detection of Mycobacterium tuberculosis in the renal biopsy specimen were negative. Focal granular deposits of immunoglobulin A (IgA) and complement 3 (C3) were demonstrated in the tubules (Figure 1C and D). The same immunofluorescent positivity was also shown in glomerular mesangium, and electron microscopy showed electron-dense deposits in the subendothelial and mesangial spaces (Figure 1E and F). These findings were consistent with IgA nephropathy accompanied by focal immune deposits along the tubules. Half the epithelial foot processes were effaced, and there were no pathological findings in the mitochondria. Potassium chloride supplementation was given to treat the patient's hypokalemic paralysis. His muscle strength increased one day after potassium chloride supplementation. We substituted rifampin with levofloxacin, but his other antituberculosis antibiotics remained the same. Supplementation with potassium chloride and sodium bicarbonate was continued, and the patient was discharged on hospital day 14. The biochemical markers associated with Fanconi syndrome were significantly resolved, and he experienced no paralytic symptoms after discharge. His proteinuria and microscopic hematuria was also improved, and we discontinued supplementation with potassium chloride and sodium bicarbonate at the three-month follow-up. The patient's renal function and proximal tubular function remained stable at the last follow-up.

PMC9353025_01

Male

Mr. A was a 46-year-old single, male. Chronic pain in the left maxillary and right mandibular molar regions (according to him, due to gingival recession caused by periodontal treatment), occlusal discomfort (specific teeth unidentified), extracted teeth, teeth sticking to the lips, occlusal instability, difficulty in opening the mouth, eating, and speaking. None. He began visiting a nearby dental clinic in 2018. On May 7, 2019, he was referred to the clinic of periodontics at the Tokyo Medical and Dental University dental hospital by the nearby dentist due to problems with oral hygiene instructions owing to complaints such as "gingival damage due to tooth brushing" and many other complaints (e.g., occlusal instability, difficulty eating, difficulty speaking). At the clinic, he mentioned that his teeth were sensitive to cold water and did not understand the explanation of the lack of identifiable causes requiring treatment. Thereafter, he had repeated unscheduled visits and phone consultations with the clinic to present with complaints such as "I feel some teeth are missing," "I can no longer chew with the left teeth." In July, periodontal scaling was initiated. However, his complaints increased and worsened (e.g., "gingival recession," a tingling sensation and numbness," and "the lower teeth are damaged by the upper teeth"). He began visiting the clinic approximately once or twice a week. During 3 months after August, he lost 20 kgs due to "hip pain" and "difficulty walking." From October, he was unable to work and took leave. The Department of Psychiatry, to which he was recommended by his younger sister, suspected he had somatic symptom disorder after excluding psychotic disorders, depression, and bipolar disorder. However, the psychiatric treatment was discontinued because he remained highly dissatisfied with the dental treatment. On November 26, 2019, he visited our clinic (Department of Psychosomatic Dentistry) for the first time. However, the examination did not reveal any findings correlated with his complaints (Figure 1). Mr. A was diagnosed with AO, regarding that his pain was limited around his teeth (however, moving beyond nerve distribution), not provoked by jaw movement and failed to respond to every conventional dental treatment. However, based on the previous treatment process and his attitude, underlying developmental disorders were suspected. Hence, effects of amitriptyline and so on were not anticipated. He was referred to the outpatient department of SK, who is familiar with the treatment of developmental disorders in the Department of Anesthesiology, The University of Tokyo Hospital; at this point, the patient declined the referral. However, given his continued complaint calls and letters regarding "incidents at the periodontics clinic" to the chief of periodontics clinic, our dental hospital director issued a treatment refusal document and send it to the patient in April. In response to our letter, the patient made repeated visits and phone consultations with our department, asking "What should I do with my teeth?" Therefore, he was advised to seek treatment at the University of Tokyo Hospital. Despite reluctance, on March 6, he eventually agreed to the referral. He was referred to Dr. SK a psychiatrist at the Department of Anesthesiology and Pain Relief Center, on April 24, 2020 (day 0). The timeline for this patient is shown in Figure 2. During the examination, he was suspicious of the treatment in the primary referral hospital and made unsolicited complaints without listening to the advice of Dr. SK. A structured interview, the Mini-International Neuropsychiatric Interview, was conducted to differentiate comorbid psychiatric disorders. He did not have a major depressive episode with hypochondriac delusions or other melancholy-type features, a manic episode, or psychotic disorder. He displayed gender-atypical gestures and abnormal eye contact and ritualized patterns of verbal or non-verbal behavior (his speech was excessively formal and polite). He was overly particular about Dr. SK's wording and frequently corrected his expressions. He had highly restricted and fixated interests in gingival pain and was hyperreactive to sensory input. Hence, he was diagnosed with ASD according to the diagnostic criteria of the DSM-5. He was highly educated and employed in a highly structured, professional occupation, and did not have severe impairment in social functioning due to ASD prior to the onset of AO. Based on hyperactivity and impulsivity symptoms observed (fidgeting with hands and squirms in seat, blurting out answers, interrupts others), the long version of the Conners' Adult ADHD Rating Scale (CAARS-S) and the observer-rated (CAARS-O) questionnaire were administered to examine the suspected comorbidity of ADHD. Mr A's percentiles of the subscale of the CAARS-S were: E. DSM-IV Inattentive Symptoms, 90; F. DSM-IV Hyperactive-Impulsive Symptoms, 98; G. DSM-IV ADHD Symptoms Total, 96; H. ADHD Index, 88. According to ADHD symptoms in the CAARS, Mr. A's ADHD symptoms were at the clinical level of psychiatry (Table 1). In addition, according to the CAARS-O completed by his younger sister, the percentile of the subscale D. Problems with Self Concept was 99, indicating low self-esteem related to ADHD symptoms. His developmental and life history was obtained and evaluated with the CAARS using the Diagnostic Interview for Adult ADHD. The results indicated inattention: poor listening to others since childhood; avoiding tasks requiring sustained mental effort, poor logical thinking; easily distracted by ambient noise; forgetful in daily activities. Accordingly, he was diagnosed with ADHD, predominantly inattentive type in the DSM-5 (day 26). During each examination, the pain numerical rating scale (NRS), the Hospital Anxiety and Depression Scale (HADS), and Pain Catastrophizing Scale (PCS) were administered. Subjective pain intensity was assessed using the numerical rating scale (NRS). Regarding the changes in NRS scores, the minimum clinically important difference is called MCID, decreases of-2 points (or-33.0%) or more in NRS is considered to be substantial or optimal. The average pain NRS score of Mr. A was high (7 points). Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS). Based on previous studies, the MCID of HADS is set at 1.5. Mr. A's HADS results revealed clinical anxiety and depression symptoms (HADS-A, 15 points; HADS-D, 12 points). Catastrophic thinking related to pain was evaluated using the Pain Catastrophizing Scale (PCS). It has been reported that strong catastrophizing thoughts leads to increased pain and disability possibility, resulting in chronic pain. The MCID of PCS can be improved by 38-44%. Mr. A's PCS results (PCS score 30 points) indicated clinically catastrophic thinking. Changes in pain NRS, HADS, and PCS during treatment course are shown in Figure 2. Mr. A exhibited strong anger and suspicion at the periodontist who performed scaling. Dr. SK identified the uncontrollable temper outbursts and aggression as ASD irritability and prescribed risperidone (1 mg/day) (day 39). In addition, atomoxetine was initiated at 10 mg to treat severe anxiety and fear due to hyperarousal of ADHD that may contribute to irritability. At the subsequent examination (day 69), the patient responded to medication and stated that "pain was reduced." Temper outbursts and frequent suspicions and complaints of scaling in the primary referral hospital were reduced and Mr A was more polite and considerate. To prevent discontinuation of medication due to side effects, atomoxetine was carefully increased to 20 mg. During the examination 2 weeks later (day 83), he was calmer, and his facial expression was less grim, and the amount complaints regarding the symptoms he faced had reduced. Therefore, atomoxetine was increased to 30 mg. During the examination 2 weeks later (day 97) he did not mention anger or suspicion of previous treatments except one mention of oral discomfort. He requested consultation on more practical topics such as the preparation of the document for sickness and injury allowance. Therefore, atomoxetine was increased to 40 mg. During the examination 2 weeks later (day 110), pain and numbness were almost resolved. He stated, "Lately, I have been very stable mentally." Additionally, he wanted to discuss with his boss when he would return to work, so the doctor created a medical certificate permitting him to return to work. Thereafter, atomoxetine was increased by 10 mg at ~2-week intervals, leading to reduced pain and numbness and improved mental health status. He returned to work after the administration of the maximum dose of atomoxetine (120 mg/day) (day 226) with no side effects indicating discontinuation. He stated, "I am able to set up my work better than before because of the medication I have been taking." Re-administration of the CAARS-S at day 324 showed the following percentiles for the subscale of the CAARS-S and improved ADHD symptoms: E. DSM-IV Inattentive Symptoms, 60; F. DSM-IV Hyperactive Impulsive Symptoms, 21; G. DSM-IV ADHD Symptoms Total, 36; and H. ADHD Index, 26 (Table 1). Pain NRS (4 points) improved by 3 points, HADS-A (7 points) improved by 8 points, HADS-D (8 points) improved by 4 points, and PCS (16 points) improved by 14 points (46.7%) from the first visit. Clinically significant improvement was observed exceeding MCID on all scales. Thereafter, he continued to visit the clinic once a month to receive medication. Regardless of the presence of mild pain, he continued his work and achieved social integration. He stated that "the pain has improved, and I am now able to do my hobby of reading, which I had to interrupt because of the pain."

anger, atomoxetine, attention deficit hyperactivity disorder, atypical odontalgia, autism spectrum disorder, chronic primary pain, irritability, risperidone

PMC8822334_01

Male

A 4-month-old male entire indoor-only domestic shorthair cat was referred to the Royal (Dick) School of Veterinary Studies' Neurology Service for acute onset of right thoracic monoparesis following a fall from a chair. Clinical signs progressed rapidly and within 18 h the cat was unable to walk, with right hemiplegia, left hemiparesis and right Horner's syndrome. At this stage the patient was referred. On presentation the cat was quiet, alert and responsive; vitals were within normal limits; and a large, firm bladder was evident on abdominal palpation. Neurological examination revealed anisocoria with a miotic right pupil, cervical hyperaesthesia, right hemiplegia, left hemiparesis, thoracic limb hypotonia, pelvic limb hypertonia, right thoracic limb areflexia, absent deep pain in the right thoracic limb below the elbow and pelvic limb hyperreflexia. Neurolocalisation was to the C6-T2 spinal segments, with lateralisation to the right. Differential diagnoses were trauma, vascular event and infectious/inflammatory disease (feline infectious peritonitis/toxoplasmosis). An emergency CT scan (64-row multi-slice CT scanner; Somatom Definition AS) of the head and spine was performed shortly after admission; no structural abnormalities were identified to explain the clinical signs. Serum biochemistry and haematology identified no significant findings. An echocardiogram revealed trivial tricuspid regurgitation, no left atrial enlargement, no thrombus formation and good contractility. Activated partial thromboplastin time (APTT) and prothrombin time (PT) were within their respective reference intervals (RIs), and serum fibrinogen concentration was not increased: APTT 13.4 s (RI 10-20 s); PT 10.2 s (RI 5-12 s); and fibrinogen 3.2 g/l (RI 2-4 g/l). Testing for serum feline leukaemia virus antigen and feline immunodeficiency virus antibody was negative (SNAP FIV/FeLV Combo Test; IDEXX). Serum IgG and IgM antibody titre testing for Toxoplasma gondii was negative (<50 [Biobest Laboratories, Edinburgh]). Serum analysis for feline coronavirus antibody titre by immunofluorescence assay (<10) and alpha1-acid glycoprotein by radial immunodiffusion assay (0.5 g/l; RI 0.124-0.878 g/l) were both negative (Biobest Laboratories). Analysis of the cerebrospinal fluid (CSF) showed a total cell count of 39.6/microl (RI <5/microl) and a total protein concentration of 1.28 g/l (RI <0.45 g/l). Cytology of the CSF fluid revealed increased red blood cells (RBCs) and scattered platelets. The nucleated cells were approximately 8/1000 RBCs and they comprised 30% non-degenerate neutrophils, 46% small and a few medium lymphocytes, 23% large mononuclear cells (monocytes and macrophages) and 1% eosinophils. One macrophage showed erythrophagocytosis; otherwise, cell morphology was unremarkable. No aetiological agents were seen. These findings were consistent with either local haemorrhage or blood contamination. Based on history, neurological examination and investigations, a presumptive diagnosis of spinal cord trauma was made. Daily physiotherapy was initiated included passive range of motion (PROM) exercises. The patient was managed symptomatically with buprenorphine (20 mug/kg IV q8h), dexamethasone (0.1 mg/kg IV q24h, increased to 0.2 mg/kg on result of negative T gondii), clindamycin (25 mg/kg PO q8h, withdrawn on result of negative toxoplasma), ranitidine (2 mg/kg IV q12h) and prazocin (250 mug/kg PO q8h) to aid frequent bladder expressions. Lactulose and enemas containing sodium citrate (450 mg) and sodium alkylsulfoacetate (45 mg [Micralax; RPH Pharmaceuticals]) were used to manage faecal retention. Seven days after the initial trauma the patient failed to show significant signs of improvement and appeared to have persistent cervical hyperaesthesia, despite analgesia and physiotherapy. Pre- and post-contrast MRI (3Philips Intera 1.5-T Pulsar System; Philips Medical Systems) study of the cervical and thoracic spine and brain was performed. All visible intervertebral discs showed normal T2 fluid intensity (Figure 1a). At C6-C7 the intervertebral disc was protruding into the mid-ventral vertebral canal, causing thinning of the subarachnoid space circumferentially and mild dorsal cord deviation (Figure 1b,c). Extending from C5-C6 to cranial C7, the spinal cord contained a large area of T1, T2 and T2* hyperintensity, with only the left dorsolateral aspect of the cord unaffected. In the same area, there was marked contrast enhancement of the right lateral aspect of the spinal cord (Figure 1d). MRI findings were therefore consistent with a C6-C7 acute non-compressive nucleus pulposus extrusion with secondary C5-C7 spinal cord chronic haemorrhage. The contrast enhancement was considered to be most likely due to vascular damage, inflammation secondary to the trauma and chronic haemorrhage. CSF analysis was repeated 7 days post-trauma and was consistent with normal CSF: total cell count 0 (RI <5/microl) and total protein concentration 0.35 g/l (RI <0.45 g/l), suggesting resolution of the previously suspected subarachnoid haemorrhage. Following MRI, a splint was applied to the right thoracic limb to prevent knuckling and abrasion of the dorsal paw, and to assist ambulation. By 10 days post-trauma the anisocoria, cervical hyperaesthesia, left-sided paresis and postural deficits, pelvic limb hypertonus, and faecal and urinary retention had resolved. The kitten was able to run, jump and climb. However, the distal right thoracic limb was still paralysed, and over the preceding 10 days progressive contracture of the right carpus developed. PROM exercises elicited pain on extension of the carpus and flexion of the elbow, preventing the physiotherapy from being performed effectively. Splints were trialled, but they also elicited discomfort. Radiographs of the thoracic limbs were taken. No soft tissue abnormalities were detected. An 18 lateral deviation of the right carpus was evident, causing narrowing of the radiocarpal joint space affecting primarily the intermedioradial carpal bone. This was consistent with suspected contracture of the triceps and flexor muscles of the carpus and digits. The contracture resulted in the development of a non-weightbearing carpal hyperflexion (Figure 2). Amputation of the limb or a therapeutic trial with BTX were discussed; the owners elected for the latter. Under general anaesthesia, 90 units of BTX type A (BTX-A [Botox Cosmetic; Allergan]) were injected into the flexor muscles of carpus and digits, and 10 units into the triceps. The dose was similar to what has previously been shown to be safe in cats in an experimental study. The aim of the treatment was to alleviate discomfort and reduce the muscle spasticity, allowing the use of a brace and physiotherapy to be performed. The patient was monitored in hospital for 48 h after the treatment; there were no adverse clinical reactions. The cat was discharged with a splint to aid ambulation; the owners were instructed to change the splint daily and perform daily physiotherapy. At a re-check 8 days post-BTX-A treatment the owners perceived the cat to be pain-free and ambulating well with support from the splint. The owners were managing well with the daily splint changes and rehabilitation exercises, although they reported that the cat resented the removal of the tape that kept the splint in place. Examination showed erythema where the tape was applied. The tape was replaced with a custom-made brace made with a spoon splint and Velcro straps. Repeat neurological examination showed that in the right thoracic limb postural reactions were still absent, sensation was decreased but now present at the second and fifth digit, and the muscle contractions had resolved but muscle tone was decreased. The postural reactions and tone in the other limbs were now normal. Mild hyperaesthesia of the cervical, epaxial and shoulder muscles was present, but there was a greatly improved level of comfort on manipulation of neck, right shoulder, elbow and carpus vs before BTX-A treatment. The owners reported that the cat was very active; we suspected that the neck and shoulder muscles were subjected to an increased load secondary to the reduced tone and function of the injected muscles of the right thoracic limb. The cat continued to make a clinical improvement. At 6 months post-BTX-A treatment, sensation was present but still decreased on the distal right thoracic limb. The right triceps brachii muscle was atrophied and a mild increase in muscle tone had returned. However, normal mobility was not impeded and the cat was pain free and able to place its right thoracic paw in a normal position when ambulating, only requiring support from the splint after prolonged periods of exercise (see the video in the supplementary material). The residual clinical signs did not appear to be affecting its quality of life.

botox, spinal cord injury, botulinum toxin, muscle contracture

PMC2738533_01

Male

In September 1998, a 36-year-old male soldier in the French Foreign Legion with hemoptysis was sent back to France from Djibouti. He expectorated bloody sputum after running and on a few other occasions. His medical history was not unusual. When the patient was hospitalized, 2 weeks after the initial symptoms, he began to experience progressive fatigue. He did not experience fever, weight loss, night sweats, anorexia, cough, dyspnea, or chest pain, and did not produce sputum. Results of the clinical examination were normal. The Mantoux test, performed with 10 IU of purified tuberculin (Aventis-Pasteur-MSD, Lyon, France), yielded a maximum transverse diameter of induration of 15 mm. Laboratory values were normal (Table). The chest X-ray showed a triangular consolidation of the left upper lobe with blurred limits and small cavitary lesions. No other contiguous mediastinohilar anomalies were visible. A computed tomographic scan confirmed the cavitary syndrome: three excavated nodular images showed radiating spicules within a micronodular infiltrate. Bronchoscopy showed a moderate inflammation of airway mucosa, especially in the left upper lobe. Biopsy specimens exhibited nonspecific inflammation. A bronchial washing smear from the left upper lobe was positive for acid-fast bacilli. Serologic tests for HIV-1 and HIV-2 were negative. No evidence of disease was found elsewhere; the patient did not experience bone pain. Results of neurologic and ophthalmologic examinations were normal; no lymphadenopathy or hepatosplenomegaly were found and the genitalia were normal. Auscultation revealed no pericardial fremitus; no ascitic fluid was detected. The urinary sediment contained <1,000 red blood cells/L and <5,000 leukocytes/L. Antituberculosis chemotherapy was begun with four drugs: rifampicin, isoniazid, ethambutol, and pyrazinamide. Cultures revealed a strain identified as M. tuberculosis subsp. canetti that was susceptible to all primary antituberculous drugs. Therefore, rifampicin and isoniazid were continued for 3 more months for a total treatment period of 6 months. The patient's response to treatment was favorable, and he remained asymptomatic.

PMC2738533_02

Male

A 55-year-old male soldier in the French Foreign Legion, who returned from Djibouti, was hospitalized in September 1999 after his chest x-ray showed abnormal findings. He was a nurse and had been occasionally in charge at the Djibouti Hospital for 2 years. His medical history was unremarkable. Eight months before he returned to France, he experienced asthenia, anorexia, and a weight loss of 3 kg. The symptoms resolved spontaneously after 2 months, and he had been asymptomatic since then. He had no history of cough, sputum production, hemoptysis, dyspnea, fever, or night sweats. Results of a clinical examination and of laboratory studies were normal (Table), except for hypereosinophilia. Serologic tests for schistosomiasis, hydatidosis, distomiasis, amebiasis, toxocariasis, and trichinosis were negative, and parasites were not found in stool samples. Thoracic radiographs performed when he came back from Djibouti showed parenchymal consolidation of the right upper lobe with small cavities. Sputum was not produced. A gastric aspirate smear was negative for acid-fast bacilli, and a bronchial aspiration smear was positive for acid-fast bacilli. HIV serology was negative, and no other site of the infection was found. Drug therapy was initiated with rifampicin, isoniazid, ethambutol, and pyrazinamide for 2 months. Cultures of bronchial aspirates were positive within 14 days; later, cultures of two gastric aspirates were positive for acid-fast bacilli. An M. tuberculosis subsp. canetti isolate was identified, which was susceptible to all primary antituberculous drugs. The treatment was then extended for 4 months with rifampicin and isoniazid. The patient's response to treatment was favorable. The following methods were used to identify the etiologic agent. First, the samples were decontaminated with N-acetyl-L-cysteine/NaOH. Acid-fast bacilli were detected by auramine staining, the positive smears also were stained with Ziehl-Nielsen stain. The samples were then seeded onto Lowenstein-Jensen and Coletsos slants and also into a liquid system, the BBL Mycobacterial Growth Indicator Tube (MGIT, BD Diagnostic Systems, Sparks, MD). The mycobacteria were identified by using a specific DNA probe (Gen-Probe, Gen-Probe Incorporated, San Diego, CA) and by performing the usual biochemical tests (nitrate reduction, 68 C catalase resistance, niacin production). The Pasteur Institute of Paris used two methods for typing: restriction fragment length polymorphism (RFLP) analysis and spoligotyping. In RFLP analysis, after digestion of the M. tuberculosis strain's genomic DNA with PvuII restriction enzyme and agarose gel migration, the DNA was transferred on a membrane, according to the Southern method, and then hybridized with an insertion sequence IS6110 probe. In the spoligotyping method, after DNA direct repeat amplification, the labeled polymerase chain reaction product was used as a probe to hybridize with 43 synthetic spacer oligonucleotides (DNA sequences derived from the direct repeat [DR] region of M. tuberculosis, H37Rv and M. bovis BCG P3), which were attached to a carrier membrane. The sensitivity to antituberculous drugs was determined by the indirect proportion method. MGIT results were positive for the two cultures in 9 and 12 days, respectively. On Lowenstein-Jensen slants, the cultures were positive in 12 and 14 days, respectively. The white, smooth, and glossy colonies were characteristic of M. tuberculosis subsp. canetti (Figure 1). The two strains had the same phenotypic and genotypic pattern; 68 C catalase was negative, and they reduced nitrate, as do other M. tuberculosis species, but they did not produce niacin. The DNA probe, Gen-Probe, confirmed that these strains belonged to the M. tuberculosis complex. These strains contained two copies of IS6110. Spoligotyping showed that they shared only 2 of the 43 oligonucleotides reproducing the spacer DNA sequences of M. tuberculosis, H37Rv and M. bovis BCG P3. This profile is characteristic of M. tuberculosis subsp. canetti (Figure 2).

PMC9241052_01

Male

A 53-year-old male with a clinical history of nephrolithiasis came to the outside hospital emergency room (ER) with severe pain in the low back, right hip, and thigh, intermittent fever with chills and night sweats, minimally productive intermittent cough spells with whitish phlegm, exertional dyspnea, generalized fatigue for three weeks along with weight loss of 20 pounds in one month. Six days prior, he was seen at the ER for back pain radiating to the right leg for the last two weeks, and x-rays of the right knee and hip with pelvis were within normal limits. He was discharged home with oral prednisone 40 mg daily for five days and as needed diazepam. He was a farmworker, had quit smoking a month back with 30 pack-years of smoking, and was negative for substance and alcohol abuse. He was sexually active with his girlfriend and resided in a trailer. Clinical examination revealed stable vital signs, lack of sensation over the right anterolateral thigh with no point tenderness, painful hip movements with limited motion, and difficulty walking. Labs revealed leukocytosis, thrombocytosis, hypoalbuminemia, and elevated inflammatory markers (Table 1). He received intravenous (IV) ketorolac 30 milligrams (mg) followed by hydromorphone 0.5 mg 1 dose IV, ondansetron 4 mg IV, and oral diazepam 2 mg. Contrasted computed tomography (CT) of the chest, abdomen, and pelvis revealed right upper lobe (RUL) heterogeneous enhancing mass and scattered bilateral nodules < 6 millimeters (Fig. 1), right iliac diffuse permeative appearance, extensive complex septated acute collections within the right iliopsoas region, deep right gluteal region and the right paraspinal musculature from the L4 - S2 levels. Magnetic resonance imaging (MRI) of the pelvis and lumbar spine with and without contrast revealed a large multilobulated cystic mass centered around the right iliac bone with extension medially into portions of the iliopsoas muscle, laterally into the adjacent gluteal musculature, and posterosuperiorly into the posterior paraspinal musculature (Fig. 2). He was admitted and initiated on pain control, IV fluids, and evaluated by the oncology and orthopedics team, who recommended a biopsy or transfer to a tertiary center. On day two, he was febrile at 39.2 Celsius (C) and ordered blood cultures returned negative, whereas procalcitonin and lactic acid were elevated (Table 1). Empirical IV ceftriaxone and azithromycin were started for suspected right upper lobe pneumonia, and his lactic acid improved. Over the next three days, antibiotics were continued, and on day six, he was transferred to our institution for suspected primary bone malignancy with metastasis. On arrival, clinical examination revealed fever (39 C), mild improvement of the right hip movements, and poor oral hygiene. Labs revealed leukocytosis, thrombocytosis, and two sets of blood cultures returned negative (Table 2). IV antibiotics were changed to vancomycin and piperacillin-tazobactam. He then underwent an interventional radiology-guided biopsy of the right ilium and aspiration of 20 mL purulent fluid from the right gluteal mass as recommended by the orthopedic oncology team. He remained intermittently febrile over the next two days, which gradually subsided with his right hip pain improvement. The bone biopsy revealed extensive acute and chronic inflammation with focal granulomatous change and no malignancy. The aspirated purulent fluid showed extensive necroinflammation, bacterial colonies most consistent with Actinomyces (Fig. 3) and no malignant cells. Right pelvic fluid histopath revealed the Splendore-Hoeppli phenomenon (sulfur granules and associated inflammation) (Fig. 4). The infectious disease (ID) team recommended continuing the piperacillin-tazobactam and stopping the vancomycin. Inflammatory markers were still elevated, whereas Quantiferon Gold Tuberculosis testing and serology for human immunodeficiency virus were negative (Table 2). A repeat contrasted CT scan of the chest, abdomen, and pelvis confirmed the prior pulmonary findings, whereas, in the pelvis, there was an interval increase in the size of the complex cystic mass indicative of abscess formation. He then underwent irrigation and debridement of the right hemipelvis and an open right ilium biopsy. Right ilium biopsy returned positive for acute and chronic osteomyelitis and negative for cancer. The right pelvic mass biopsy revealed fibrovascular tissue with acute and chronic inflammation, necrosis, hemorrhage, fibrosis, and negative for malignancy. Intraoperative tissue bacterial, mycobacterial and fungal cultures were negative. The pulmonary team performed the bronchoscopy and obtained an RUL protective specimen brush culture sample, bronchioalveolar lavage (BAL) for analysis, culture, and endemic fungal workup. Endobronchial ultrasound (EBUS) guided fine-needle aspiration on enlarged lymph nodes (stations 11 L,7, and 4 R) returned negative for infection and malignancy. BAL fluid analysis did not suggest any infection; however, the cultures returned positive for A. odontolyticus (Table 2). A. odontolyticus was sensitive to penicillin and resistant to clindamycin. Piperacillin-tazobactam was changed to ceftriaxone 2 g (gm) daily. An oral dental surgeon evaluated his bad oral hygiene (Fig. 4). A transthoracic echocardiogram displayed an ejection fraction of 60% with normal cardiac valves and normal left and right ventricular systolic function. An X-ray Panorex revealed several missing teeth, multilevel caries, significant maxillary and mandibular lamina propria resorption, periapical lucency involving the remaining right maxillary molar, and possible retention cyst/opacification of the left maxillary sinus. He was recommended outpatient follow-up in three weeks to fix his bad teeth. A repeat MRI pelvis with contrast revealed a marked interval decrease in size of the complex multiloculated abscess involving the right retroperitoneum, gluteal muscles, and right paraspinal muscles, abnormal marrow signal, and osseous erosion of the right ilium. He was discharged home on IV ceftriaxone 2 gm daily to complete six weeks of antimicrobial therapy. Four weeks later, he followed up at the ID clinic with a decline in inflammatory markers (Table 2), and he was transitioned to oral amoxicillin 875 mg thrice a day for the next 12 months. Repeat CT chest with contrast at eight weeks post-discharge revealed resolving right upper lobe consolidation with residual linear opacities. A repeat MRI pelvis with and without contrast 12 weeks after discharge revealed markedly improved osteitis of the right innominate bone, surrounding soft tissue infection, and minimal persistent marrow changes within the right iliac bone. At the ninth-month ID clinic follow-up, he had his teeth fixed, recovered weight loss, and resumed daily activities. He completed 12 months of oral amoxicillin with complete recovery. (Fig. 5).

actinomyces odontolyticus, actinomycosis, disseminated, pneumonia, pulmonary nodules

PMC4247007_01

Male

In January 2013, a 65-year-old male presented to Korea University Anam Hospital (Seoul, Republic of Korea), with an intra-abdominal mass that was localized to the right side. The mass had presented one month previously. In addition, the patient had experienced weight loss (5 kg) during the previous four months. The medical history was unremarkable, with the exception of pulmonary tuberculosis 30 years previously, from which the patient had recovered. On physical examination, a round mass was palpated and there was tenderness of the right upper quadrant area. Hematological examination revealed a marginal decrease of hematocrit (35.8%; normal range, 37-51%) and hemoglobin (11.8 g/dl; normal range, 12.6-17.4 g/dl). Liver function tests revealed elevated alkaline phosphatase (423 IU/l; normal range, 30-120 IU/l) and gamma-glutamyl transferase (587 IU/l; normal range, 9-64 IU/l) levels. Aspartate aminotransferase, alanine aminotransferase and bilirubin levels were within the normal ranges of 3-45 IU/l, 3-45 IU/l and 0.0-0.4 mg/dl, respectively. An upper gastrointestinal endoscopy revealed a subepithelial mass with a fistulous hole on the second portion of the duodenum (Fig. 1). A total colonoscopy revealed no abnormalities. A computed tomography (CT) scan, which was acquired from the referring local clinic (Choi Kang Sik Internal Medicine, Seoul, Republic of Korea), demonstrated a large, heterogeneously enhanced lobulated mass (11.5x9.3 cm; longest diameter x greatest perpendicular diameter) with internal necrosis at the pancreaticoduodenal groove (Fig. 2A). The internal cavity of the mass was connected to the second portion of the duodenum, which was consistent with the endoscopic findings. Furthermore, an ill-defined low-attenuation lesion was identified at segment eight of the liver, abutting the bile duct and hepatic artery (Fig. 2B). Significantly enlarged lymph nodes were not observed in the abdominal cavity. In addition, a fludeoxyglucose positron emission tomography (FDG-PET) scan also revealed hypermetabolic masses in the duodenal groove and in segment eight of the liver, which was consistent with the CT scan. Abdominal MRI (magnetic resonance imaging) was also conducted for further characterization of the duodenal and hepatic masses observed on the CT scan, which confirmed the same findings. An ultrasound-guided needle biopsy of the duodenal mass was performed and pathological examination identified whirling sheets of spindle-shaped cells (Fig. 3A). Immunohistochemical staining was positive for c-Kit, but negative for cluster of differentiation 34, S-100 and desmin (Fig. 3B). Mitotic features could not be evaluated, as a surgically excised sample was not obtained. The diagnosis of high-risk GIST with hepatic metastasis was determined and the patient was treated with 400 mg imatinib, daily. The treatment was tolerated well, and the abdominal mass and distension improved significantly. After seven weeks of treatment, the follow-up abdominal CT scan revealed that the duodenal mass had significantly reduced in size (7.9x6.5 cm; longest diameter x greatest perpendicular diameter) and exhibited an increased area of internal necrosis. However, the hepatic mass had increased from 1.7x1.5 cm to 3.9x3.2 cm in diameter (longest diameter x greatest perpendicular diameter) and the right hepatic duct was markedly dilated by the mass (Fig. 4). Various enlarged lymph nodes were observed in the left gastric area, including the porta hepatis and portocaval space. The ultrasound-guided needle biopsy was repeated for the hepatic mass and histopathological examination of the biopsy specimen showed malignant cells with a glandular structure, which was consistent with adenocarcinoma. Immunohistochemical analysis exhibited c-Kit-negative and cytokeratin 19-positive staining (Fig. 5). The final diagnosis was synchronous ICC and GIST. Two weeks after the ultrasound-guided liver biopsy, the patient developed jaundice and a fever, and the total level of bilirubin increased rapidly to 9.4 mg/dl (normal range, 0.0-0.4 mg/dl). Percutaneous transhepatic biliary drainage was conducted along with antibiotic treatment and administration of imatinib was withheld to allow the patient to recover from the condition. An abdominal CT scan following three weeks of conservative treatment revealed an increase in size of the liver mass (5.3x3.9 cm; longest diameter x greatest perpendicular diameter) with portal vein thrombosis, and the size of the duodenal mass had also increased to 9.5x8.7 cm (longest diameter x greatest perpendicular diameter). The treatment regimen became focused towards the ICC, which was associated with a poorer prognosis. Due to the well-known toxicity of combined chemotherapy, administration of imatinib was terminated and the patient was treated with intravenous gemcitabine (100 mg/m2 for 30 min, days 1 and 8) and cisplatin (25 mg/m2 for 1 h, days 1 and 8) every three weeks for four cycles. During chemotherapy, the abdominal mass reappeared, as a follow-up CT scan, performed six weeks following treatment, revealed a prominent increase in the size of the duodenal mass (10.7x10 cm; longest diameter x greatest perpendicular diameter). However, the hepatic mass did not demonstrate a significant change in size during that interval. As the patient had tolerated the initial chemotherapy well, combined chemotherapy (consisting of imatinib, gemcitabine and cisplatin) was initiated for symptom control and treatment of the GIST. The addition of imatinib resulted in the duodenal mass decreasing significantly and the patient exhibited a good response to the treatment. However, certain toxicities are associated with combined chemotherapy, such as grade 1 bone marrow suppression, as observed in the present case. The follow-up CT scan revealed disease progression of the ICC, whereas the size of the GIST mass had decreased. The treatment modality was altered, due to refractory cholangiocarcinoma, from chemotherapy to radiation therapy (daily dose of 180 Gy), whilst maintaining the imatinib treatment. To date, the patient has been undergoing treatment for one year and is tolerating the treatment well.

cholangiocarcinoma, gastrointestinal stromal tumor, multiple primary tumors

PMC6609725_01

Female

A 41-year-old Caucasian woman presented to the emergency department with four day history of intermittent non-specific chest pain on a background of 30 pack years of smoking history. She also had a history of progressive exertional dyspnea for a few months and also loss of appetite during this presentation. She denied fever, cough, hemoptysis, pleurisy or coryzal symptoms. She had no significant past medical history, in particular, there was no history of diabetes and she was not on any regular medications. She had no significant occupational or travel history of significance. There was no history of exposure to tuberculosis. She was an avid gardener, residing in Darwin, Northern Territory of Australia. She usually walked barefoot in her garden and used large amounts of potting mix while gardening. She denied excessive alcohol consumption or recreational drug usage. On clinical examination, vital signs were normal. Respiratory examination was unremarkable, with normal breath sounds bilaterally and there were no crackles or rhonchi or pleural rub in particular. Cardiovascular examination was also normal. Systemic examination showed no evidence of clubbing, oedema, cyanosis or lymphadenopathy. Her ECG showed normal sinus rhythm without ischemic changes. Blood tests showed white cell count of 11.5 x 109/L with neutrophilia 7.9 x 109/L and CRP was 15 Mg/L, Serial troponins were negative. Liver function, electrolytes, renal function were within normal limits. Quantiferon gold test was negative. Pulmonary function showed FVC of 3.88 L, (97% predicted), FEV1 3.05 L (92% predicted), FEV1/FVC ratio 0.787 (96% predicted), DLCO 77% and TLC 4.75L (89% predicted). Chest X-ray showed an opacity in the right mid-zone (Fig. 1a). She underwent a CT scan of the chest, that showed a mass in the right lower lobe measuring approximately 36 x 22mm suspicious of malignancy. There was no endoluminal bronchial lesion nor mediastinal or hilar lymph node enlargement. (Fig. 1b). Due to the high index of suspicion of lung malignancy, a PET-CT was performed, which demonstrated mild to moderate FDG avidity of the mass in the right lower lobe (Fig. 2a) but no other FDG avid nodal or distant metastatic disease. The patient underwent flexible bronchoscopy that showed no endobronchial lesion, then using the Endobrochial radial Ultrasound (EBUS) probe and utilizing the Guide sheath technique, the lesion was localized in the posterior segment of the right lower lobe. The EBUS images (Fig. 2b) demonstrated a heterogeneous lesion with non-compressed blood vessels and scattered air space shadows. Brushings, biopsies and washings were taken from the guide sheath, along with a transbronchial cryobiopsy from the same site identified by the ultrasound probe. The EBUS-guided biopsy of the lesion showed necrotic tissues and malignant cells were not identified. Culture of bronchial brushings on Ashdown's agar medium, however, grew bacterial colonies which were identified microscopically as gram negative bacilli. Bacterial culture from bronchial brushings was subsequently confirmed as Burkholderia pseudomallei, making the diagnosis of pulmonary melioidosis (Fig. 3). She was treated with intravenous ceftazidime 2 g 6 hourly for 4 weeks, followed by oral sulphamethoxazole/trimethoprim (800mg/160mg) 2 tablets twice a day for 3 months with daily folic acid 5mg. During the follow up visits, the patient demonstrated significant improvement both clinically and radiologically. Her CRP was noted to be < 0.1 Mg/L consistently, with normal white cell and neutrophil counts. Her exertional dyspnea was considered to be related to early airway disease secondary to smoking, possibly aggravated in the presence of pulmonary melioidosis and she was provided with support for smoking cessation.

bronchoscopy, burkholderia pseudomallei, ebus, melioidosis, pneumonia

CT chest image showing mass in right lower lobe.

PMC6609725_01

Female

A 41-year-old Caucasian woman presented to the emergency department with four day history of intermittent non-specific chest pain on a background of 30 pack years of smoking history. She also had a history of progressive exertional dyspnea for a few months and also loss of appetite during this presentation. She denied fever, cough, hemoptysis, pleurisy or coryzal symptoms. She had no significant past medical history, in particular, there was no history of diabetes and she was not on any regular medications. She had no significant occupational or travel history of significance. There was no history of exposure to tuberculosis. She was an avid gardener, residing in Darwin, Northern Territory of Australia. She usually walked barefoot in her garden and used large amounts of potting mix while gardening. She denied excessive alcohol consumption or recreational drug usage. On clinical examination, vital signs were normal. Respiratory examination was unremarkable, with normal breath sounds bilaterally and there were no crackles or rhonchi or pleural rub in particular. Cardiovascular examination was also normal. Systemic examination showed no evidence of clubbing, oedema, cyanosis or lymphadenopathy. Her ECG showed normal sinus rhythm without ischemic changes. Blood tests showed white cell count of 11.5 x 109/L with neutrophilia 7.9 x 109/L and CRP was 15 Mg/L, Serial troponins were negative. Liver function, electrolytes, renal function were within normal limits. Quantiferon gold test was negative. Pulmonary function showed FVC of 3.88 L, (97% predicted), FEV1 3.05 L (92% predicted), FEV1/FVC ratio 0.787 (96% predicted), DLCO 77% and TLC 4.75L (89% predicted). Chest X-ray showed an opacity in the right mid-zone (Fig. 1a). She underwent a CT scan of the chest, that showed a mass in the right lower lobe measuring approximately 36 x 22mm suspicious of malignancy. There was no endoluminal bronchial lesion nor mediastinal or hilar lymph node enlargement. (Fig. 1b). Due to the high index of suspicion of lung malignancy, a PET-CT was performed, which demonstrated mild to moderate FDG avidity of the mass in the right lower lobe (Fig. 2a) but no other FDG avid nodal or distant metastatic disease. The patient underwent flexible bronchoscopy that showed no endobronchial lesion, then using the Endobrochial radial Ultrasound (EBUS) probe and utilizing the Guide sheath technique, the lesion was localized in the posterior segment of the right lower lobe. The EBUS images (Fig. 2b) demonstrated a heterogeneous lesion with non-compressed blood vessels and scattered air space shadows. Brushings, biopsies and washings were taken from the guide sheath, along with a transbronchial cryobiopsy from the same site identified by the ultrasound probe. The EBUS-guided biopsy of the lesion showed necrotic tissues and malignant cells were not identified. Culture of bronchial brushings on Ashdown's agar medium, however, grew bacterial colonies which were identified microscopically as gram negative bacilli. Bacterial culture from bronchial brushings was subsequently confirmed as Burkholderia pseudomallei, making the diagnosis of pulmonary melioidosis (Fig. 3). She was treated with intravenous ceftazidime 2 g 6 hourly for 4 weeks, followed by oral sulphamethoxazole/trimethoprim (800mg/160mg) 2 tablets twice a day for 3 months with daily folic acid 5mg. During the follow up visits, the patient demonstrated significant improvement both clinically and radiologically. Her CRP was noted to be < 0.1 Mg/L consistently, with normal white cell and neutrophil counts. Her exertional dyspnea was considered to be related to early airway disease secondary to smoking, possibly aggravated in the presence of pulmonary melioidosis and she was provided with support for smoking cessation.

bronchoscopy, burkholderia pseudomallei, ebus, melioidosis, pneumonia

PET CT - FDG avidity shown in right lower lobe mass.

PMC5966628_01

Male

A 69-year-old man with severe COPD requiring chronic oxygen supplementation (1 L/min) and suspected underlying X-linked granulomatous disease was admitted to the ICU with acute-on-chronic respiratory failure. He had a progressively worsening cough, shortness of breath, increased sputum production and had experienced a 10 kg weight loss with muscle depletion in the preceding three months. The patient had been treated for pulmonary tuberculosis at the age of 23 years, with no subsequent recurrence of infection. Chronic treatment with clomipramine (75 mg/day) was ongoing for a major depressive syndrome which had been diagnosed five years earlier. He was being monitored with monthly seriated electrocardiograms for QT prolongation attributable to clomipramine therapy. At ICU admission, the patient presented with severe dyspnea. Arterial blood-gas analysis showed mixed respiratory failure (pH 7.22, PaO2 58 mmHg, PaCO2 80 mmHg, HCO3- 35 mMol/L) requiring non-invasive ventilation. Chest examination revealed bilateral crackles, with no signs of chronic heart failure. Blood tests showed the white blood cell count to be in the normal range (8000/mm3), with no neutropenia (neutrophil count 1846/mm3), but mild lymphopenia was present (lymphocytes 810/mm3). The patient was anemic (Hb 10.9 g/dL). Platelet count was high (438,000/muL) and C-reactive protein (CRP) was markedly increased (35 mg/L; normal level <5 mg/L). Renal function was normal (serum creatinine 0.9 mg/dL), as were liver function tests (aspartate transaminase [AST] 11 IU/L, alanine transaminase [ALT] 14 IU/L, gamma-glutamyl transpeptidase [GGT] 30 IU/L, total bilirubin 0.15 mg/dL). Baseline electrocardiogram showed a sinus rhythm with a right bundle branch block and prolonged QT interval (453 ms). Chest x-ray showed multiple bilateral lung opacities. CT and [18F] fluorodeoxyglucose (FDG)-PET/CT scans revealed bilateral nodular infiltrates. Due to the patient's critical condition and the multiple potential etiologies for the pulmonary infection, a bronchoscopy was performed, which demonstrated purulent secretions. Broncho-alveolar lavage (BAL) fluid was negative for bacteria, fungi, mycobacteria, Actinomyces spp. and Nocardia, but tested positive for galactomannan (GM; ODI 2.6). According to the European Organisation for Research and Treatment of Cancer (EORTC) criteria for non-neutropenic patients, the diagnosis of probable IPA was made based on the presence of baseline predisposing comorbidities (severe COPD and suspected X-linked granulomatous disease), the presence of bilateral nodular infiltrates, and GM positivity on BAL. Voriconazole was considered unsuitable due to the patient's baseline QT prolongation and the risk of a drug-drug interaction with clomipramine, potentially leading to further QT prolongation and severe cardiac arrhythmias. Isavuconazole therapy was selected, and started with a loading dose of 200 mg every 8 h for six doses, following by 200 mg daily. After starting antifungal treatment with isavuconazole, the patient showed a progressive improvement in his clinical condition. At week 2, the arterial blood-gas analysis showed resolution of the decompensated respiratory acidosis, with normalization of pH (pH 7.40, PaO2 62 mmHg, PaCO2 50 mmHg, HCO3- 30 mMol/L). There was no further need of non-invasive ventilation. On day 17, the patient was moved from the ICU to the infectious diseases ward, and required only low flow oxygen supplementation (1 L/min). He was discharged on day 42. CT scanning and FDG-PET/TC after eight weeks of antifungal treatment confirmed the improvement of pulmonary infiltrates. In total, a three-month course of isavuconazole treatment was completed, and there were no clinical or radiologic signs of infection after six months' follow-up. Isavuconazole was well-tolerated, with no adverse events and no change in liver enzymes. Serial ECG monitoring showed no prolongation of the QT interval.

aspergillosis, drug interactions, isavuconazole, non-neutropenic, qt prolongation

PMC8100614_01

Female

A 71-year-old woman with remitting multi-resistant tender papules with a metameric disposition was initially treated as herpes zoster. She later developed a chronic ulcer on the scalp that, after investigation, was indicative of pyoderma gangrenosum (PG) or pyoderma-like. She had a previous history of pulmonary tuberculosis and PG on both legs in 2003. She was treated with cyclosporine, infliximab, clofazimine, doxycycline, and intralesional triamcinolone injections with varying results for over four years. PG was finally controlled in mid-2007. She remained asymptomatic until March 2020, when intense and sudden pain on the vertex and left parietal region developed. Multiple tender papules with peripheral erythema were present. Although no vesicles were found, a tentative diagnosis of cephalic herpes zoster was suspected. Despite treatment with valacyclovir and pregabalin, symptoms increased, and papules evolved into multiple, deep, ulcerated lesions with a central necrotic scab and undermining border. Expression yielded a significant amount of purulent secretion. Skin biopsy findings were of an ulcer with exuberant granulation tissue. Histology study was performed on the material obtained while curetting one of the large abscesses rather than by a wedge excision of the border. Although the vertex aspect on the scalp suggested an erosive pustular dermatosis of the scalp, histology was more consistent with PG. Attempts to obtain microbiological cultures were twice negative. Previous comorbidities include IgA multiple myeloma in remission for the past seven years and remission of pulmonary tuberculosis treated with triple therapy 18 years ago. In the process of choosing a proper therapy, the Quantiferon test was performed, which was negative. After a short period of use of oral Dapsone, the disease progressed. Due to the previous history of tuberculosis and possible contra-indications for anti-TNF alpha therapy, she was started on baricitinib, a novel Janus kinase (JAK) inhibitor, 4 mg orally daily, taking into consideration the past attempts with more conservative approaches mentioned above. The idea of using JAK inhibitors was considered in the case of failed treatments, which proved helpful. Lesions started to improve, and by seven days, no new lesions were identified. Complete regression was achieved after five weeks, leaving a depressed scar (Fig. 1, Fig. 2). Case 2 A 59-year-old female with rheumatoid arthritis since 2011, controlled with methotrexate 15 mg/week, developed in 2018 a leg skin ulcer for which PG was diagnosed. Healing was obtained with dressings and MTX maintenance. In 2019, another PG occurred on the left leg and ankle; treatment consisted of prednisone 0.7 mg/kg/d associated with MTX 20 mg/week. PG resolved in 4 months; corticotherapy was gradually tapered, and MTX was maintained. Severe Cushing's syndrome signs were noted, impairing quality of life. In 2020, another outbreak of PG compromised the right leg; methotrexate was suspended, and baricitinib 4 mg/day was introduced, with the lesion's healing in 3 months presented in the photos (Fig. 3, Fig. 4).

baricitinib, pyoderma gangrenosum, treatment

PMC2948899_01

Male

A 18-year-old patient with a history of Matched-Unrelated-Donor Peripheral Blood Stem Cell Transplantation (MUD-PBSCT) was admitted to the hospital because of renal failure. In November 2007 the patient was first diagnosed with acute lymphoblastic leukemia of T cells (T-ALL) at another institution, where he was treated with induction therapy according to Hyper-CVAD Protocol (Cyclophosphamide 300 mg/m2 intravenously (IV) over 3 hours every 12 hours for six doses on days 1 through 3, with mesna given by continuous infusion, vincristine 2 mg IV days 4 and 11, doxorubicin 50 mg/m2 IV day 4, and dexamethasone 40 mg daily on days 1 through 4 and 11 through 14) and was refractory when he presented in our department of hematology/oncology. The diagnosis of T-ALL has been confirmed, immunophenotype precursor T-ALL (CD7, CD3, CD2, CD4, and CD8 pos), cytogenetic 46, XY, Fluorescein in sito hybridisation (FISH) analysis 87% deletion of p16 on the chromosome 9 region p21. He was then treated with induction therapy according to the German multicenter ALL protocol (GMALL) achieving only reduction of blasts after Induction II. Briefly, the induction in GMALL protocol was composed of eight cytotoxic drugs administered sequentially in two phases over an 8-week period. During the first 4 weeks (phase I), the patient received 60 mg/m2 prednisolone PO daily (days 1 through 28) plus 45 mg/m2 daunorubicin and 2 mg vincristine IV weekly (days 1, 8, 15, and 22). L-asparaginase (5 000 U/m2) was administered IV daily (days 15 through 28). In the second 4 weeks (phase II), the patient received two doses of 650 mg/m2 cyclophosphamide IV (days 29, 43, and 57) together with 60 mg/m2 6-mercaptopurine PO daily (days 29 through 57) and four courses of 75 mg/m2 cytarabine IV (days 31 through 34, 38 through 41, 45 through 48, and 52 through 55). He was then treated with nelarabine and achieved complete remission (CR1) following MUD-PBSCT. The conditioning consisted of total body irradiation (TBI), 12 Gy, given fractionated 2 times daily for three days, from day -6 to day -4, and cyclophosphamide 60 mg/kg once daily i.v. on days -3 and -2 (total dose 120 mg/kg b.w.). A Human Leukocyte Antigen (HLA) identical unrelated donor peripheral blood stem cells were infused on day 0. Graft-versus-Host Disease (GvHD) prophylaxis consisted of thymoglobulin (2 mg/kg b.w. daily, from day -3 to -1, total dose of 6 mg/kg b.w.), cyclosporine 5 mg/kg starting on day -1, and methotrexate at days +1, +3, +6, and +11 intravenously 15 mg absolute. The bone marrow puncture on day +28 showed a complete hematological remission with 100% donor chimerism. Along with the regeneration of white blood cells the patient developed a methylprednisolone-dependent GvHD of the skin and gastrointestinal, grade II. After 10 days the therapy with corticosteroids could be discontinued by rapid improvement of the GvHD-related symptoms. Under the therapy with corticosteroids the patient developed a herpes simplex related oesophagitis on day 21 post transplant which was treated with 30 g daily over 5 days i.v. immunoglobulin and foscarnet 90 mg/kg b.w. divided in 2 doses. On day +28 after PBSCT the patient developed a hemorrhagic cystitis with high urine titers of BK polyoma virus and CMV infection. A therapy with ganciclovir was initiated for ten days. Under treatment with ganciclovir, CMV infection improved, and the treatment with cidofovir was started (1 mg/kg b.w. for two weeks). The BK Virus viruria and viremia improved, and the patient received ganciclovir treatment for additional two weeks (Figure 1). The cyclosporine level was from 200 to 150 from day 0 to day 30, followed with level of 100 from day 30 to day 40 post transplant, and level of 50 from day 40 to day 50. The cyclosporine has been discontinued on day +70 after MUD-PBSCT in absence of acute GvHD and as recommended in GMALL protocol. On day +48 after PBSCT a cystoscopy with a continuous intravesical saline irrigation was started and discontinued 2 weeks later. The patient symptoms improved, and creatinine levels returned to normal. He was discharged from hospital; his medications at the time of discharge included ciprofloxacin (250 mg twice daily), valacyclovir (500 mg twice daily), fluconazole (200 mg daily), folate, and cotrimoxazole twice weekly for prophylaxis of pneumocystis carinii infection. Over the next year the levels of urea nitrogen and creatinine gradually rose (Table 1), which was attributed to drug toxicity. cotrimoxazole prophylaxis was stopped. Cyclosporine was discontinued since no signs of GvHD were present 6 months after PBSCT. The serum creatinine level was 153 mumol/l (Table 1). Routine urinary diagnostic measures were carried out and showed inconsistent microhematuria. BK viruria was negative in this period. On admission, blood pressure was 130/80 mmHg with 90 heart beats per minute, a temperature of 36.4 C, and an oxygen saturation of 99% when the patient was breathing ambient air. The lungs were clear, the results of the remainder of the examination were normal. The complete blood count and levels of serum electrolytes, liver function tests, and levels of total protein and albumin were normal. The urine sediment was not nephritic but contained a small amount of leukocytes indicating an inflammatory process such as cystitis. Results of other laboratory tests are shown in Table 1. Ultrasonographic examination of the kidneys showed bilateral hydronephrosis stage III-IV (Figure 2(a)). In addition, decreased echotexture bladder tumours were seen (Figure 2(b)). The patient was presented to the urologist. Cystoscopy with urethrography has shown exophytic bladder tumours in both ostii. The extirpation of the tumours was performed and sent off for pathological examination. In addition a double-J catheter was placed. The hydronephrosis of the left kidney improved immediately and improved to grade II in the right kidney. For histological examination tissues were formalin-fixed overnight and embedded in paraffin. Hematoxylin & Eosin staining of 5 micrometer sections was performed following standard procedures. The pathohistology of the specimen showed a chronic cystical urocystitis with bleedings (Figure 3(a)). Tissue probes of both ureters were stained for SV40 large T antigen (clone pAb416, Oncogene Science, Boston, Mass, USA; dilution 1 : 100, antigen retrieval and amplification with catalyzed system amplification, Dako, Carpinteria, CA). The reactions were detected by means of the streptavidin-biotin method and were revealed using diaminobenzidine as a chromogen. In all tissue probes immunohistochemistry for large T antigen was negative (Figure 3(b)). The patient has undergone double-J catheter controls and changes every two months and is doing well 2 years after PBSCT and 1 year after operative extirpation of tumours. The last control was in April 2010 (Table 1). Two different regions of the BKV genome were amplified by PCR, VP2 in serum and urine, and large T antigen from tissue biopsies. Nucleic acids were extracted from 200 microliter blood or urine using magnetic beads (MagNA Pure LC total NA isolation kit, Roche, Mannheim, Germany) according to the manufacturer's instructions while from formalin-fixed, paraffin-embedded material nucleic acids were extracted using the QIAamp DNA FFPE Tissue Kit (Qiagen, Hilden, Germany). VP2 primers lead to amplification of a 131 bp fragment. PCR reaction was carried out in 20 microliter capillaries containing master mix (6 mM MgCl2, 0.1 mg/ml BSA (Sigma, St. Louis, USA)) and 10 picoM of each primer (Metabion, Martinsried, Germany), 3 picoM of each hybridization probe (5'-GGCTGCTGCTGCCACAGGATTTTC-FL (probe 1) and 5'LC Red640-GTAGCTGAAATTGCTGCTGGAGAG-ph (probe 2), 0.25 mM dNTP's (Roche)), and 1U Platinum Taq Polymerase (Invitrogen, Karlsruhe, Germany). Target DNA was added in a volume of 5 microliters. Two negative and 4 positive controls in different concentrations were included into each run performed on a LightCycler 1.0 instrument (Roche, Mannheim, Germany) under the following conditions: initial denaturation and activation of hot-start enzyme at 95 C for 30 s, followed by 45 cycles of denaturation at 95 C for 0 s, annealing of primers at 58 C for 10 s, and primer extension at 72 C for 20 s. Fluorescence was monitored by single acquisition during the annealing phase of each PCR cycle and channel setting F2/F1 (640 nm/530 nm). Differentiation of BK virus amplicons from JC virus depends on the binding of the probe 2, which perfectly matches JC virus but differs at the two underlined positions from BK virus. Thus binding to BK virus results in a shifted melting curve (61.5 C for BK versus 63.8 C for JC). For detection of the viral large T-antigen, a 128 bp long fragment was amplified using modified primers from that match BKV genotypes 1 to 4, forward primer 5'-CAGGCAAGGGTTCTATTACTAAAT-3', reverse primer 5'-GCAACAGCAGATTCYCAACA-3', probe 5'-6FAM-AAACTGGTGTAGATCAGARGGAAAGTCTTTAGGGTCTT-BBQ. PCR conditions were identical to the one described above except TaqMan probe that was used at 4 pico molar, primer annealing was 56 C for 10 s, and fluorescence acquisition was at the end of each primer extension phase at 530 nm.

PMC4236770_01

Male

A 16-year-old man presented with a one month history of fever, pubic pain which irradiates to the genitals and increases when hip is mobilized, and this fact produces gait claudicating. The symptoms started a few days after playing a football match, though the patient denied any history of trauma. He had a temperature of 38.5 C and a normal testicular and abdominal examination. The C reactive protein had risen to 12 mg/l with an erythrocyte sedimentation rate of 25 mm/h and a white blood cell of 16410 per mm3. Echocardiogram was normal and autoimmune screen was negative. The blood culture was negative. The magnetic resonance imagery (MRI) of the pelvis showed a bone oedema of symphysis pubis and abdominal muscles (Figure 1, Figure 2). The puncture guided by computed tomography (CT) of the articulation of pubis returned of Staphylococcus aureus methicillin-susceptible (SAMS). The patient was prescribed intravenous flucloxacillin 1 g six times a day for six weeks and discharged with further four months of oral flucloxacillin at 1g three times a day on microbiologist's advice. A repeat MRI after four months showed a complete resolution.

septic arthritis, osteomyelitis, pubic symphysis

PMC9595572_02

Male

As of now, he was 8 years old and his insulin dosage was 1.1 IU/kg/d. Even under fluconazole therapy, he developed oral mucocutaneous Candida fungi twice every month, but he did not develop recurrent viral or bacterial infections. He was given antituberculosis drugs (isoniazide, rifampicin) for tuberculosis infection. The liver function was normal at the last follow-up, and the HbA1c was 6.5%. Ruxolitinib was recommended to the patient's parents, but they refused because of concerns about side effects.

stat1, case report, chronic mucosal candidiasis, diabetes mellitus, gain-of-function

PMC7370326_01

Male

Written informed consent was obtained from the patient. A 20-year-old man who presented with 2 month history of fever was admitted in our hospital on 8 October 2016. Without obvious cause, the patient had repeated chills and fever 2 months ago and the highest temperature raised to 39 C. He passed bloody stools and got abdominal pain during hospitalization. Physical examination was non-remarkable. Blood examination revealed 10.42 x 109 white blood cells/L, with 69.40% neutrophils and 16.17% lymphocytes. HIV antibody, immunochemistry, dengue antigen, hepatitis B, hepatitis C, influenza A, and influenza B antigen were all unremarkable. Chest and abdominal computed tomography (CT) scan showed ileocecus of ascending colon, and transverse colon showed diffuse thickening of the wall. The most obvious was in the transverse colon, which was considered as inflammation. On 13 October 2016, colonoscopy showed multiple segmental colon ulcers, which was considered as Crohn's disease or tuberculosis (Figure 1(a) and (b)). Pathology showed that there were a lot of acute and chronic inflammatory cells infiltration in lamina propria, submucosa, and muscle layer, and there were multiple granulomatous lesions without obvious caseous necrosis. In addition, the possibility of intestinal bacterial infection, inflammatory bowel disease (IBD), intestinal tuberculosis, lymphoma, histoplasmosis, and other diseases were excluded. It tended to be Crohn's disease, but tuberculosis was not excluded (Figure 2). The CTE of the small intestine showed that ileocecus and distal ileum were thickened and strengthened obviously after injection, so that the patient was conformed to Crohn's disease (Figure 3(c) and (d)). From 8-25 October, we gave him antibiotic treatments. Taking small intestinal computed tomography enterography (CTE), colonoscopy, and pathology into consideration, he was diagnosed as Crohn's disease and given glucocorticoids and immunosuppressant therapy from 20 October. After 5 days of treatment, the patient still had repeated fever, and the anti-infection treatment was upgraded to imipenem. However, his symptoms still have not improved. Therefore, we rechecked the colonoscopy. On 30 October, IBD was considered by colonoscopy, but it was not confirmed (Figure 1(a) and (b)). Meanwhile, tuberculosis was not excluded. Sample of intestinal biopsy was sent to our hospital and the Southern Hospital of Southern Medical University for examination. In the oral report of intestinal pathology in our hospital, the microbes with positive Periodic acid-Schiff (PAS) staining were examined, which were also seen in the intestinal pathology on 13 October. Therefore, we thought that we made a wrong diagnosis. Pathology reported that distal ileum, ascending colon, transverse colon, and sigmoid colon mucosa were infiltrated by a large number of tissue cells that had a large number of blue purple granules. Special staining showed purple blue particles with positive PAS staining and Gomori's Methenamine-Silver (GMS) staining. It was considered to be histoplasmosis. On 7 November, Southern Hospital Pathology Consultation Report described that a large number of tissue cells and multinuclear giant cells were seen in the lamina propria of ileum mucosa, and fungal spores were found in tissue cells, so that he was diagnosed as talaromycosis (Figure 4). On 8 November, immunologic testing showed that CD3 cells accounted for 17.40%, CD4 cells accounted for 11.50%, CD8 cells accounted for 4.10% and a CD4/CD8 ratio of 2.8. According to the pathology consultation report, he was finally diagnosed as talaromycosis. A treatment of itraconazole 0.2 g twice daily for a long term was given to him. The temperature dropped to normal and bloody stools disappeared after anti-fungal treatment for 5 days. We knew that he used to have a history of taking methamphetamine many times between July and August after inquiring about his medical history again. He reviewed colonoscopy in the hospital again on 17 January 2017. The examination results suggested that the intestinal inflammation subsided.

penicilliosis marneffei, histoplasmosis, immunosuppression, methamphetamine, talaromycosis

PMC10400715_01

Female

In April 2020, a 57-year-old female patient initially experienced a sudden onset of a right-sided limb movement disorder and a lack of fluency in speech. The cephalometric CT scan at a local hospital showed thalamic hemorrhages. After conservative treatment, her speech function recovered, but she still felt poor physical strength and had an abnormal gait. She was then admitted to Beijing United Rehabilitation Hospital for further rehabilitation in March 2021. Two months after hospitalization, the patient developed moderate-to-severe pain [visual analog scale (VAS) 6-9] on the right side of her body, including the face, arm, trunk, and limbs, with no apparent cause. The pain was persistent and tightness-like, accompanied by paroxysmal pinprick-like pain occurring 30-50 times per day. The patient felt a painful wandering mass on the right plantar aspect of her foot and was unable to put weight on the right foot due to the pain. She also experienced paroxysmal knife-like pain (VAS 9) in the right upper arm, and moderate-to-severe tearing-like pain (VAS 6-9) in the right axilla and lateral chest wall. The magnetic resonance imaging (MRI) showed a malacic lesion in the left thalamus, and chronic ischemic lesions in the brainstem, bilateral basal ganglia, and periventricular white matter. Multiple white matter lesions in bilateral periventricular and subcortical white matter were observed, and Fazekas 3 was considered (Figure 1). She was prescribed oral medications, including Gabapentin(R) (1,200 mg, three times a day), Duloxetine(R) (60 mg, once a day), Neurotropine(R) (8 u, twice a day), Tylenol(R) (1 tablet, as needed), and received traditional acupuncture, herbal medicine, and physical therapy. However, the pain was not alleviated. The patient frequently woke up at night due to pain outbreaks, which severely influenced her mood, sleep, and her ability to cooperate with rehabilitation treatment. Thus, she sought a consultation from the Division of Pain for further treatment. During the consultation, the patient exhibited slower speech. Her right side of the body was hyperalgesic and could not tolerate cold when wiped with an alcohol swab. The muscle strength of the proximal right limb was grade 4, and the distal limb was grade 4-. The patient's right hand was unable to hold chopsticks or use a pen due to the contracture of the 3rd-5th fingers. Pressing pain was identified in the cervical spinous processes (C2-7), right transverse processes, and coracoid process of the right scapula. Similar symptoms were also detected in the right sternocleidomastoid, trapezius, and pectoralis major muscles. The abdomen was tense with pressing pain in the upper abdomen. The bilateral iliopsoas muscles, upper and lower back, and right hip experienced pressing pain. The patient also reported pressing pain in the posterior leg and on the right plantar. After the first treatment with cheek acupuncture (Figure 2), the patient experienced significant relaxation on the right side of her body and a 60% reduction in spontaneous pain. The painful mass in the right foot shifted to the heel, decreasing in size and pain level. The patient could tolerate the pain in the right foot triggered by touching the ground. The first four sessions were administered once a week, followed by treatments every two weeks. The symptoms continuously improved during the treatments. Eight sessions later, the spontaneous pain in the right limb and trunk was reduced by 70-80%, and paroxysmal pinprick-like pain episodes occurred less than five times a day, lasting 2-3 seconds each time. There were no more nocturnal eruptive pain episodes. The patient only took Gabapentin 900 mg three times a day. The patient could stand only on right leg. The contracture of the right hand significantly improved, and the patient could perform certain fine activities, such as eating with chopsticks and writing. The walking gait was much better than before. Importantly, the patient's mood and sleep improved significantly, which facilitated rehabilitation training.

central nerve system, cheek acupuncture, mechanism of action, nerve compression, pain

PMC4263476_01

Male

Information on outbreak case patients and their contacts is shown in table 1. The index patient (Case 1) was a 9-month-old boy born on November 23, 2010. On August 17, the patient developed fever and cough; on August 20, he developed bilateral weakness of lower extremities. The patient was hospitalized one month later (September 19), and the case was reported as having AFP on September 20. Epidemiologic investigations were conducted, and two inadequate stool specimens were obtained from the patient on September 20 and September 22. Type Pi Sabin-related poliovirus strains were isolated from two specimens with 5 nt VP1 substitutions.

PMC5464578_01

Unknown

Adults (>= 18 years old) with a strong clinical suspicion (solid and/or liquid dysphagia and weight loss) at selected anatomical cancer sites or with confirmed incident primary EC or gastro-esophageal junction cancer according to the International Classification of Diseases for Oncology, 3rd edition, identified at the participating clinics and hospital, were eligible. Patients with a second or relapse EC and those who were mentally, emotionally, or physically unable to give consent were excluded. Eligible topography sites were: cervical esophagus (C15.0), upper third of the esophagus (C15.3), middle third of the esophagus (C15.4), lower third of the esophagus (C15.5), overlapping lesion of esophagus (C15.8), esophagus unspecified (C15.9), and cardia, NOS (cardio-esophageal junction, esogastric junction, gastro-esophageal junction) (C16.0). For patients enrolled at the endoscopy clinics, the initial diagnosis was based on clinical suspicion, but a final diagnosis relied on histological or cytological confirmation. In patients consenting to donate biopsy specimens at endoscopy, three samples were taken and used to generate two formalin-fixed, paraffin-embedded (FFPE) blocks, and diagnosis slides, and the third sample for fresh tissue preservation. A majority of patients recruited at TAH were referred from other hospitals for treatment and did not have tumor tissue archived at TAH. For these patients, the diagnosis was based on histology slides or FFPE blocks, if these materials were available from the referral hospitals and patients consented to release of these specimens, or on a copy of the pathology report from the referral hospitals. A slightly larger proportion of cases (36%) than controls (26%) were ever qat users (S1 Table), whereas duration of use among consumers did not differ much between cases (mean, 30 years) and controls (mean, 31 years). Overall, very few qat users had used qat for less than 10 years. The median retention time of the qat wad in the mouth during a chewing session was 4 hours in both cases and in controls. A higher proportion of cases (11%) than of controls (2.3%) retained the qat wad in the mouth overnight. Smoking during qat chewing sessions was reported in 16.4% of cases and in 11.3% of controls. Reporting of ever alcohol use was slightly higher in controls (41%) than in cases (30%), possibly related to the religious affiliation (S2 Table). Although the overall distribution of reported consumed staple food items did not differ between cases and controls, a slightly higher proportion of cases (21.9%) than controls (12%) specified kocho as the staple food. Kocho (qocho) is a local flatbread made using the starch obtained from the trunk of the false banana plant (Ensete ventricosum), fermented for several months and subsequently cooked in a griddle. Consumption of very salty food was more commonly reported by cases (26%) than by controls (1.5%). A non-significant 2-fold elevation in risk of EC was seen in ever qat chewers compared with never users in unadjusted conditional analysis (odds ratio [OR] = 2.12; 95% confidence interval [CI]: 0.94, 4.74)) (Table 2), although this association disappeared after accounting for differences in tobacco use, consumption of alcohol and green vegetables, education level, and religion (OR = 0.95; 95% CI: 0.22, 4.22). No clear trend was observed between duration of qat use and risk of EC (Table 2). Tobacco use was associated with a more than 2-fold increase in risk of EC (OR = 2.62; 95% CI: 1.16, 5.92), the association in the adjusted model showed a larger magnitude but a lower precision, becoming non-significant (OR = 3.31; 95% CI: 0.53, 20.62) (Table 2). We did not observe a clear trend in EC risk with duration of tobacco use (Table 2). In sensitivity analysis according to control type, we observed a statistically significant elevation in risk of EC associated with ever tobacco use when including healthy visitor-type controls (OR = 3.02; 95% CI: 1.04, 8.77; p = 0.04) but not when limiting to hospital controls (OR = 1.75; 95% CI: 0.56, 5.51; p = 0.34) in fully adjusted unconditional logistic regression models. The association of qat chewing and risk of EC was also evaluated after stratifying by tobacco use. The risk of EC in ever qat users was elevated and statistically significant among never tobacco users (OR = 5.81; 95% CI: 1.21, 27.9) but not among ever tobacco users (OR = 0.76; 95% CI: 0.12, 4.61) (Table 2) in univariate analysis. After adjusting for differences in consumption of alcohol and green vegetables, education level, and religion, the risk of EC in ever qat users remained elevated but with a very wide confidence interval including 1 (OR = 6.75; 95% CI: 0.48, 96). The p-value for the interaction term between ever qat use and ever tobacco use was 0.06. Ever alcohol use was associated with a reduction in risk of EC (OR = 0.45; 95% CI: 0.21, 0.96) according to the unadjusted risk estimate, but the odds ratio increased to 2.3 (95% CI: 0.32, 16.53) after adjusting for tobacco use, consumption of green vegetables, education level, and religion (Table 3). Staple foods reported to have been consumed one year before the interview, or one year before the endoscopy or diagnosis, were suggestive of an elevation in risk of EC. Subjects who specified kocho as the staple food had a statistically significantly elevated EC risk in univariate analysis only (Table 3). Low consumption of green vegetables was associated with an increased risk of EC, with subjects consuming green vegetables less than once a week (OR = 3.57; 95% CI: 1.31, 9.71) or not at all (OR = 12.47; 95% CI: 2.91, 53) having a substantially higher risk of EC compared with those with daily consumption. These results were corroborated after adjusting for confounders (Table 3). Saltiness of food and smokiness inside the home were associated with an increased risk of EC in unadjusted analysis, whereas in adjusted analysis an elevation in risk remained only for saltiness of food (Table 3). Education level and religion were strongly associated with risk of EC (Table 3). More educated people had a lower risk of EC compared with illiterate people, even when the level of education did not reach complete schooling. Christians had a lower risk of EC compared with Muslims. Accounting for differences in tobacco use, alcohol use, and consumption of green vegetables did not affect the statistically significant association of education level and religion with risk of EC (Table 3). Thus, education level and religion were associated with EC independently of these specific lifestyle/dietary factors.

PMC5585683_01

Male

A 24-year-old male presented to our emergency department with worsening cough, fever, and chills of one-day duration. The patient reported cough for one week that progressively worsened, with mucoid phlegm associated with low-grade fever, chills, and shortness of breath of 1-day duration. He denied hemoptysis, gastrointestinal symptoms, and chest pain and reported no bird exposure, skin rash, arthralgia, recent travel, or sick contacts. His medical history was significant for mild persistent asthma and schizophrenia. He had no prior surgeries and had resided in a psychiatric facility for 2 years with no occupational exposure to chemicals or toxins. He was a former polysubstance abuser and was in abstinence for 2 years. He denied smoking cigarettes, using illicit drugs, or abusing alcohol and had no reported allergies. His medications included divalproex sodium, clozapine, zolpidem, albuterol, and fluticasone aerosol inhaler. He had a negative tuberculin skin test 6 months prior to admission for the current complaint. A physical examination revealed a young man of average built, with a temperature of 100.4 F, pulse rate of 78/min, respiratory rate of 20/min, and blood pressure of 110/66 mmHg; he also showed 96% saturation on ambient air. He appeared lethargic, with no conjunctival pallor, cyanosis, nuchal rigidity, skin eruptions, or palpable lymphadenopathy. Bilateral air entry was evident on auscultation of lungs, with fine rales on the right side. A precordial examination revealed normal heart sounds, with no murmur, rub, or gallop. An abdominal exam revealed no organomegaly, and a neurological examination showed no motor or sensory neurological deficits. An initial laboratory examination showed neutrophilic leukocytosis (white blood cell count, 18,000/mm3 with 74% neutrophils) and elevated blood urea nitrogen (25 mg/dL) with lactic acidosis (2.5 mmol/L). He had no anemia (hemoglobin, 13.5 g/dL), thrombocytopenia (157,000/muL), or renal failure (creatinine, 0.6 mg/dL). A urine toxicology screen was negative for any drugs. His initial chest radiograph showed right upper lobe consolidation (Figure 1(a)). He was admitted to the hospital for pneumonia, which was managed with vancomycin, piperacillin-tazobactam, and azithromycin. Further evaluation by chest computed tomography (CT) showed a thick-walled, right upper lobe cavitary lesion (Figure 2(a)). Fiberoptic bronchoscopy (FOB) with bronchoalveolar lavage (BAL) was performed to test for associated infections or noninfectious processes. A transbronchial biopsy of the lung showed diffuse lymphocytic infiltrates. Cultures for common bacteria, Mycobacterium tuberculosis, and fungi were negative, as were cultures for respiratory syncytial virus, influenza viruses, parainfluenza viruses, adenoviruses, and vasculitis workup as shown in Table 1. Serology performed to detect other infections indicated a cold agglutinin titer of 1 : 320 and an M. pneumoniae IgM antibody titer of 1 : 1,280. At this point, antibiotic treatment with oral azithromycin was continued and the remaining antibiotics were discontinued. The patient's condition did not improve clinically, so levofloxacin was started and the patient was discharged to the psychiatric facility on oral medication for 2 weeks. Follow-up chest radiograph two months later showed right upper lobe scarring and improvement in consolidation (Figure 1(b)). Follow-up CT scan two months later showed foci with ground glass opacity in the anterior right upper lobe of the lung surrounding a 9.9 mm nodular density and three months later showed complete resolution of the cavitary lesion without sequelae (Figures 2(b) and 2(c)); the antibody titer for M. pneumoniae IgM was also reduced (1 : 160) 3 months later.

PMC3277043_01

Male

A 31-year-old male, non-smoker, presented to us with a history of attacks of chronic intermittent cough since childhood. These attacks usually last for two to three days. Sometimes initiated and aggravated after heavy meals. It was also associated with recurrent chest infections. No significant history of hemoptysis, shortness of breath, difficulty of swallowing, or chocking was reported. Systemic examination was unremarkable. He used inhalers and cough suppressants as required. Chest X-ray showed bilateral apical pleural thickening with fibroatelectatic changes at the right upper lobe. Barium studies showed significant dilatation of the whole esophagus, more at the proximal 3rd, with free passage of the contrast into the stomach without any stricture or narrowing at the distal end or at gastroesophageal junction; these findings were suggestive of some neurological causes or esophageal motility disorder. For further evaluation, the patient underwent esophageal manometry study and upper gastro-intestinal (GI) endoscopy. Esophageal manometry showed aperistaltic esophagus, but the lower esophageal sphincter could not be assessed. Upper GI endoscopy revealed the presence of smooth tracheoesophageal opening (fistula) in the upper 3rd of the anterior wall of the esophagus at 25 cm from the incisor teeth [Figure 1]; however, biopsy and wash aspiration from this fistula was negative for tuberculosis (TB) culture. Computed tomography (CT) scan of chest confirmed the presence of the TEF at the level of sternoclavicular joint along with dilated esophagus. Also, there was evidence of cystic, cylindrical, and varicose bronchiectatic changes in both the right upper, middle lobes, and in the lingula. There were also subpleural fibroatelectatic changes in the posterior segment of the right upper lobe, most likely due to recurrent aspirations [Figure 2a-b]. Patient explored in the operating room through cervical approach along the anterior border of the left sternocleidomastoid muscle. Fistula was identified between the posterolateral wall of the trachea and the anterior wall of the esophagus. Adhesions separated and the fistula isolated completely and then closed by endo-GI stapler. Esophageal side reinforced with muscular patch to buttress this repair and to minimize the postoperative esophageal leak and to prevent long-term recurrence. Postoperative recovery was uneventful. Patient started oral fluids on the second postoperative day, the drain removed on the third day, and he was discharged home on fourth postoperative day. Patient remained asymptomatic and well at 12-month regular follow-up, as he underwent during this follow-up a barium swallow study which showed normal swallowing process and no hold up of the contrast with no evidence of gastroesophageal reflux and there was no evidence of recurrence of the TEF; however, he remained under regular follow-up with the gastroenterologist team for the esophageal motility disorder which has improved significantly clinically and radiologically.

adult, congenital tracheoesophageal fistula, late presentation

". CT scan chest demonstrating bronchiectatic changes in the right middle lobe, "see arrow".

PMC6487139_01

Female

A 69-year-old lady was admitted to the acute medical unit with a several-month history of progressive, exertional breathlessness and atypical chest pain. Cardiac risk factors were hypertension, hyperlipidaemia, and a positive family history of ischaemic heart disease. Drug therapy on admission was simvastatin and amlodipine. Clinical examination revealed a grade 3 pansystolic murmur radiating to the apex, with no signs of cardiac failure, organomegaly, or lymphadenopathy. The pulse was regular at 81 bpm, BP was 119/90 mmHg, and oxygen saturations were 100% on room air. EKG demonstrated sinus rhythm with fixed, lateral T-wave inversion and ST depression. Serial troponin-Is were 44, 44, and 31 ng/L (normal range: 0-14). Haematology and blood biochemistry were normal including d-dimer, liver function tests, and serum amylase. Chest X-ray demonstrated normal lung fields; however, subtle intracardiac calcification within the cardiac silhouette was visible and comparable to a radiograph in 2015. A transthoracic echocardiogram (echo) demonstrated mobile valve leaflets with an echo-bright structure in the region of the posterior mitral annulus suggestive of calcification. However, views were limited due to poor echogenicity with incomplete visualisation of the myocardium. A transoesophageal echocardiogram (TOE) revealed a heavily calcified mitral annulus but no mitral stenosis. A bidirectional jet of moderate mitral regurgitation (MR) was noted secondary to extensive mitral annular calcification (MAC) with tethering of the leaflet tips, particularly the anterior mitral valve leaflet. No other valvular heart disease was present, and the left ventricle (LV) retained good contractility throughout with overall normal function. A CT coronary angiogram (CTCA) (Siemens' SOMATOM Definition Flash CT) showed extensive MAC which infiltrated the left ventricular myocardium resulting in widespread intramyocardial calcification, predominantly in the septum and anterior wall and also in the apex and apical lateral wall (Figure 1). Maximal septal LV wall thickness measured 28 mm and similarly around the infiltrative lesions. The calcified lesions were heterogenous in appearance and extended from the mitral annulus. The external layer of the lesions was calcific, whilst the internal portion was of a heterogenous lower density signal, suggesting caseation. The myocardium contracted normally around the lesions with the estimated ejection fraction of 57%. Calcification of the coronary arteries was apparent with moderate mid-left anterior descending artery (LAD) disease and moderate stenosis of the proximal first diagonal vessel. Thoracic CT screening for extracardiac calcification and carcinoma was unremarkable. Due to the extent of the intramyocardial calcification, we sought to determine the aetiology and screen for metabolic disease. Serum calcium, phosphate, and eGFR were normal. PTH levels were slightly raised at 8.6 pmol/L (normal range: 1.3-7.3); the vitamin D level was low at 21 nmol/L (normal range: 100-200) indicating vitamin D deficiency. Hb was 119 g/L (normal: 120-160) with negative haemolytic and haematinic screenings. Lipid profile revealed a triglyceride level of 5.0 mmol/L (normal: 0.12-2.10) and HDL of 0.99 mmol/L (normal: 1.2-1.8) with the total cholesterol measuring 5.7 mmol/L. There was an isolated raised bilirubin of 38 microm/L (range: 0-17), but the direct Coombs test and haptoglobin levels did not suggest haemolytic anaemia. Autoantibody screens (immunoglobulins, ANA, ANCA, dsDNA) were negative. Serum iron levels were slightly low; however, the total iron binding capacity was normal. Serum ACE levels were 24 U/L (normal: 8-52). Abdominal ultrasound confirmed fatty liver infiltration. Tuberculosis exposure was excluded through careful history taking and supported with a negative acid-fast bacilli sputum sample. Although still experiencing exertional breathlessness, the patient's symptoms improved with low-dose furosemide, and given the presence of coronary artery disease on CTCA, she was discharged with dual antiplatelet therapy added to her current medication regimen. Cardiac MRI was performed (Figure 2), and similar to the CT, this showed extensive calcification extending into the myocardium from the mitral valve annulus, evidenced by the absent signal on T1- and T2-weighted imaging. The lesions enhanced on late gadolinium imaging suggesting the presence of an extracellular matrix within the calcium, but they were not encased entirely by calcium and were in communication with the surrounding myocardium. The findings were consistent with an aggressive caseating, calcific process extending into the left ventricular myocardium from the mitral valve annulus. The infiltrated myocardium was thickened with reduced contractility, whilst the noninfiltrated myocardium contracted well and compensated to maintain an overall normal left ventricular ejection fraction. Coronary angiography showed moderate mid and distal LAD disease, in addition to severe distal posterior descending artery (PDA) disease (Figure 3); this was not felt sufficient to explain the aetiology of her breathlessness. PET CT was requested to further examine the calcified lesions within the myocardium and evaluate for metastatic calcific phenomenon. This scan demonstrated no abnormal uptake nor metabolic activity outside of the heart, therefore providing reassurance for our patient with exclusion of metastatic infiltrative disease. Interestingly, there was some evidence of metabolic activity around the calcified lesions within the heart; however, it is uncertain whether this represents an active disease process or the chronic inflammatory process described in the caseating tissue. Given her symptomatic improvement and normal left ventricular function, ongoing surveillance was arranged with interval scanning.