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Tuberculosis_Dataset

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PMC6795683_03

Female

Five days later, a 32-year-old, female, Southern rockhopper penguin (case 3) from the same institution began to exhibit weakness, anorexia and dyspnea, and auscultation revealed harsh lung sounds. The bird was treated with ponazuril2 (25 mg/kg PO, once), enrofloxacin3 (15 mg/kg SC, once), meloxicam4 (0.5 mg/kg IM, once), and furosemide5 (0.2 mg/kg IM, once) for presumed pulmonary edema, but died 1 h later. Necropsy examination revealed dark red, wet lungs, and an enlarged, nodular spleen. The caudal aspect of the left lung contained a small, focal, tan to brown, firm area. Cytologic examination of lung tissue imprints from case 3 showed crescent-shaped, 2 x 4-8 mum protozoal zoites (Figure 1B), toxic heterophils and multinucleated giant cells. A complete set of tissues from cases 2 and 3 were fixed in 10% neutral-buffered formalin and submitted to the University of Georgia Zoo and Exotic Animal Pathology Service for histopathology. Fresh spleen from case 2 was submitted to Athens Veterinary Diagnostic Laboratory for aerobic and anaerobic cultures. Fresh lung and liver from Cases 2 and 3 were submitted to the Southeastern Cooperative Wildlife Disease Study (SCWDS, Athens, GA) for molecular testing. Representative sections of all submitted tissues were routinely processed, embedded in paraffin wax, and 4-5-micron-thick sections were stained with Hematoxylin and Eosin (H&E) for light microscopy. For case 1, the only relevant immunohistochemical stain available at the Connecticut Veterinary Medical Diagnostic Laboratory was a rabbit polyclonal antibody against T. gondii (BioGenex, San Ramon, CA). Additional stains for Sarcocystis sp. (rabbit polyclonal antibody) and T. gondii (rabbit polyclonal antibody) were performed at the California Animal Health & Food Safety Laboratory System, Davis, CA as previously described. For cases 2 and 3, immunohistochemistry was performed at the University of Georgia College of Veterinary Medicine Histology Laboratory using antibodies for S. neurona (rabbit polyclonal antibody, 1:500 dilution for 60 min), Neospora caninum (goat polyclonal antibody6, 1:300 dilution for 30 min) and T. gondii (mouse monoclonal antibody6, 1:1,0000 dilution for 10 min). The clinical, histologic, immunohistochemical, and molecular findings for three penguins with fatal S. falcatula infection are summarized in Table 1. All penguins had severe, necrotizing and lymphohistiocytic interstitial pneumonia. Parabronchi were flooded with hemorrhage, edema, and fibrin (Figure 1C). Air capillaries were obscured by foci of necrosis with fibrin exudation, and accumulations of heterophils, hemorrhage, and protozoal schizonts (Figure 1D). Air spaces were multifocally lined by hypertrophied epithelial cells (Figure 1E). In cases 2 and 3, schizonts were numerous and elongate, often conforming to the shape of capillaries (Figure 1D, inset), while schizonts were fewer and this classic serpentine morphology of S. falcatula was not observed in case 1. In all cases, schizonts occasionally exhibited a "sunburst" arrangement, in which merozoites radiated around a centralized clearing (Figure 1E, inset). A full set of tissues, including lung, liver, brain, skeletal muscle, and heart was examined for case 1. No extrapulmonary schizonts or sarcocysts were seen, and additional immunohistochemical stains were not pursued. Cases 2 and 3 exhibited mild lymphohistiocytic myocarditis and myositis and schizonts were observed in multiple tissues in these birds (Table 1). Protozoa stained variably PAS-positive on Periodic acid-Schiff reaction stains, and did not stain with Giemsa. On immunohistochemistry, protozoa exhibited strong immunoreactivity (Figure 1F) for polyclonal S. neurona antibodies and variable immunoreactivity for N. caninum and T. gondii antibodies (Table 1). Cases 2 and 3 had markedly hypercellular spleens with foci of extramedullary granulopoiesis. There were also coalescing foci of coagulative to lytic necrosis, and case 3 had scattered, intraendothelial schizonts (Figure 2A). Under anaerobic conditions, Clostridium perfringens was cultured from the spleen of case 2. Splenic tissue from case 3 was not available for culture. Low numbers of schizonts were present in foci of splenic necrosis for case 3, so sarcosporidiosis is the most likely explanation for this lesion. However, given that low numbers of gram-positive bacilli in one section of skeletal muscle, septicemia cannot entirely be ruled out in case 3. All cases had multifocal lymphohistiocytic portal hepatitis and extramedullary granulopoiesis (Figure 2B); cases 2 and 3 had low numbers of schizonts within sinusoids (Figure 2B, right inset). All cases also had moderate numbers of sinusoidal macrophages containing fragments of erythrocytes and intracytoplasmic hemosiderin (Figure 2B, left inset). In addition to fulminant pulmonary sarcocystosis, case 2 had a small, coelomic fungal granuloma. Aspergillosis is suspected but fungal culture and/or PCR would be required for definitive diagnosis and further testing was not pursued. Case 3 had mild air sacculitis and a focal heterophilic granuloma at the caudal aspect of the left lung lobe. This lesion is believed to be related to a prior aspiration event, given the presence of foreign material and lack of microorganisms on special stains for fungi (Gomori Methenamine Silver), bacteria (modified Brown and Brenn Gram), and acid-fast bacilli (Ziehl-Neelsen). Formalin-fixed lung tissue from case 3 was trimmed into two, 2-mm-thick pieces and transferred to 2% paraformaldehyde, 2% glutaraldehyde in 0.1 M phosphate buffer, pH 7.25. After overnight fixation, tissue was rinsed in 0.1 M phosphate buffer, post-fixed for 1 h with 1% buffered osmium tetroxide (OsO4), then rinsed in deionized water and dehydrated in an ascending ethanol series before infiltration with propylene oxide and Mollenhauer's Epon-Araldite resin mixture. Tissue samples were embedded in fresh resin mixture and allowed to polymerize in a 70 C oven. One-micron-thick sections were stained with Toluidine Blue O to select areas of interest before 60 nm sections were obtained and placed on grids. Grid sections were stained with uranyl acetate and lead citrate before examination with a JEOL JEM 1011 transmission electron microscope at 80 kV. Images were captured with an XR80M wide-angle multi-discipline mid-mount CCD camera7. Transmission electron microscopy revealed protozoa with ultrastructural features compatible with Sarcocystis spp. (Figure 3). Capillary endothelial cells occasionally contained an intracytoplasmic, serpentine schizont, which conformed to the cell shape. One schizont had a multilobulated nucleus with nuclear spindles arranged along the periphery (Figures 3A,B). Merozoites had a round, central nucleus, an anterior conoid and several tear-shaped, electron-dense micronemes at the posterior end (Figures 3C,D). For case 1, formalin-fixed, paraffin-embedded (FFPE) lung tissue was submitted to the Wildlife Conservation Society (Bronx, NY) and DNA was extracted using a QIAamp DNA FFPE Tissue Kit8. Extracts were tested by conventional PCR using both pan-apicomplexan and Sarcocystis-specific assays targeting the 18S rRNA and internal transcribed spacer 1 (ITS-1) regions, respectively. A small portion of the 18S rRNA gene was amplified as previously described. A portion of the ITS-1 region was amplified using primer P-ITSF and a degenerate primer (ShortITSR; 5'-GGGATTCARTKGYYGAAA-3') designed based on publicly available Sarcocystis ITS-1 sequences. Amplicons were bi-directionally sequenced commercially, analyzed using Geneious R7 (Auckland, New Zealand) to generate a consensus sequence, trimmed of their primers, and analyzed by BLASTn. The DNA sequence from the 18S gene was 100% identical to Sarcocystis falcatula in Genbank (MH626537, isolate Lorikeet ID #205850) but also identical to numerous other Sarcocystis isolates in GenBank. The DNA sequence from the ITS-1 region was 100% identical to Sarcocystis falcatula in GenBank (MH626538, isolate Lorikeet ID #205850) and Sarcocystis cf. falcatula in GenBank (AF389339). The next closest match for the ITS-1 region was Sarcocystis speeri and Sarcocystis neurona (98-99% identity). For cases 2 and 3, DNA was extracted from fresh lung and liver using a commercial DNA extraction kit8 at SCWDS. The genus of the organism was determined by screening tissues with primers that amplify a short portion of the 18S rRNA gene of numerous apicomplexan parasites as previously described. Amplification products were visualized in 2% agarose gels stained with GelRed9. Amplicons were gel-purified using a kit8 and bi-directionally sequenced at the University of Georgia Genomics Facility (Athens, Georgia). Chromatograms were analyzed using Geneious R7 and the consensus sequence was compared to other sequences in GenBank. To further characterize the Sarcocystis sp. in cases 2 and 3, partial cytochrome b gene was amplified with primers CYTB-F and CYTB-R, the ITS-1 region was amplified with primers ITS-234F19 and ITS-720R19, and the partial surface antigen 2 gene was amplified with primers SAG2-F1 and SAG2-R1 as previously described. Amplicons were purified, sequenced, and analyzed as described above. To rule out the possibility of Plasmodium and/or Haemoproteus spp. infection in cases 2 and 3, a nested PCR targeting the mitochondrial cytochrome b (cytb) gene was conducted as previously described using primary primers HaemNFI and HaemNR3 and nested primers HaemF and HaemR2. For cases 2 and 3, liver and lung samples from both penguins were positive using the Tg18s58F and Tg18s348R PCR protocol and the resulting sequences (302 bp) were identical to each other and 100% similar to numerous Sarcocystis spp. The cytb gene sequences (580 bp) obtained from liver and spleen of cases 2 and 3 were identical and 100% similar to S. falcatula from captive bare-faced ibis (Phimosus infuscatus) from Brazil (KX265018) and Virginia opossum from California, USA (KP871704). The ITS-1 (287 bp) sequences were identical to each other and contained two polymorphic bases. These sequences were 98-99% similar to numerous S. falcatula strains from Brazil and the U.S.A. with some only differing at those two polymorphic bases. The four SAG2 sequences (402 bp) were identical and were 100% similar to the only S. falcatula (GQ851953) sequence available in GenBank. All four tissues were positive for the rpoB gene. The sequences were identical to each other and 100% similar to one S. falcatula (440 bp, KX265017) strain and >99% similar to several other S. falcatula sequences in GenBank (495 bp, e.g., AY164999).

eudyptes chrysocome, sarcocystis falcatula, spheniscus demersus, apicomplexa, penguin, protozoal pneumonia

PMC5410480_01

Female

An 84-year-old woman presented to a local clinic with dyspnea on exertion and left back pain persisting for a month. She was admitted to our hospital because of left pleural effusion on a chest X-ray. She suffered hypertension and dyslipidemia but had no history of pleural tuberculosis or chronic pyothorax, nor a smoking history or dust exposure. On examination, her vital signs and oxygen saturation were normal (SpO2: 96% ambient air). A chest examination revealed a mass on the left side of her back with pain and decreased breathing sounds in the left lower-lung field. The rest of the examination findings were normal. Laboratory tests revealed elevated levels of C reactive protein, lactate dehydrogenase (LDH), and soluble interleukin-2 receptor (sIL-2R) (Table 1). A chest X-ray (Fig. 1) showed left pleural effusion with mediastinal shift. On the first hospital day, an intercostal drainage tube was inserted, and after drainage, chest computed tomography (CT) (Fig. 2) revealed an irregular pleural mass invading her left chest wall with rib destruction and pleural effusion. The mass was adjacent to the posterior mediastinum, but the lateral side of the mass was thick and invading the chest wall, so we diagnosed this mass as a chest wall tumor. The pleural fluid was serous and not purulent. A fluid analysis showed it to be exudative, and 81% of the white blood cells were lymphocytes. The fluid culture was negative, and cytology did not show any evidence of malignancy (Table 1). CT-guided needle biopsy was performed. The histopathology results supported a diagnosis of diffuse large B-cell lymphoma (DLBCL) that was positive for CD10 and CD20 but negative for CD3 and CD5 (Fig. 3). 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) revealed high FDG uptake in the left chest wall mass without any other uptake (Fig. 4A and B), so we diagnosed her with primary malignant lymphoma originating from the chest wall. We reconfirmed her medical history, and she never had either tuberculous pleurisy or pyothorax. Her performance status (PS) was 3 because of her back pain and fatigue. Owing to her bad PS and age, it was difficult to perform an operation or administer combination chemotherapy with Rituximab, so low-dose oral etoposide (50 mg/day d1-14, q28) was administered. Her pleural effusion disappeared within two weeks, her back pain disappeared, and her PS improved to 1 within a month. Chest CT performed four months later showed complete response (Fig. 4C and D). She continued oral chemotherapy and maintained a good PS for one year after the diagnosis.

PMC6885199_01

Female

In 2016, a 33-year-old female was admitted with fever (40 C) and maculopapular cutaneous lesions involving the face and the trunk. The patient referred that these symptoms had started one month prior. The patient, native to Cuba (Camaguey Region), has been living in Italy for the last decade, and 4 months prior to admission, she had traveled to Cuba for a month. She did not report any past medical conditions, but she did have unprotected sex in the past. HIV serology resulted positive, HIV-RNA 2,150,000 copies/ml, the CD4+ count evidenced 2/muL cells (1%), and the CD4+/CD8+ ratio was zero. Empirical antibiotic therapy was started with piperacillin/tazobactam. Chest tomography (CT) detected a ground-glass pattern involvement of the lung parenchyma, multiple bilateral micronodules, mediastinal, supraclavicular, and lateral cervical lymphadenopathy. Suspecting Pneumocystis jirovecii pneumonia, the patient was referred to our Infectious Diseases Clinic. Physical examination revealed fever (40 C), tachycardia (113 bpm), and tachypnea (40 breaths/min). Blood gas analysis on room air resulted in a pH of 7.49, pO2 of 70 mmHg, and pCO2 of 29 mmHg. Maculopapular cutaneous lesions were present on the face, trunk, and limbs (Figure 1); hepatosplenomegaly, lateral cervical lymphadenopathy, and fine crackles on both basal lung fields were also detected. Laboratory findings showed pancytopenia (white blood cells 1 x 103/muL, platelets 137 x 103/muL, and haemoglobin 7.7 g/dL), alanine aminotransferase (ALT) 67 IU/L (normal value 0-45 IU/L), aspartate aminotransferase (AST) 446 IU/L (normal value 0-45 IU/L), gamma-glutamyl transferase (GGT) 147 IU/L (normal value 7-49 IU/L), alkaline phosphatase (ALP) 500 IU/L (normal value 80-320 IU/L), lactic dehydrogenase (LDH) 6752 IU/L (normal value 225-450 IU/L), gamma-globulin level 21%, C-reactive protein (C-RP) 24 mg/dL (normal value <= 0.5 mg/dL), ferritin >7500 ng/mL (normal value 11-307 ng/mL), and triglycerides 247 mg/dL (40-165 mg/dL). Routine blood and urine cultures, serology for syphilis, toxoplasma, and Leishmania, latex for Cryptococcus neoformans, and smear test for malaria resulted negative. Plasma Cytomegalovirus-DNA was positive with 83087 copies/mL, as well as Cytomegalovirus p65 antigen with 3 cells. Quantiferon-TB gold in the tube (Cellestis, Ltd., Carnegie, Australia) test was undetermined, while the tuberculosis skin test (TST) nonreactive. A broncoalveolar lavage (BAL) was performed, and microbiologic investigations resulted negative for bacteria and fungi including P. jirovecii. The patient was started empirically on sulfamethoxazole-trimethoprim (800/160 mg tid, oral), ceftriaxone 2 g I.V. daily, and foscarnet 90 mg/kg I.V. twice daily without improvement. Three days later, ceftriaxone was substituted with tigecycline. After 3 more days, both a bone marrow biopsy and a bone marrow aspirate were performed. The latter (see Figure 2(a)) revealed inclusion bodies inside the cytoplasm monocytes, suggestive of H. capsulatum yeasts. An identical finding was observed from the peripheral blood smear (see Figure 2(b)). In the following days, from both the peripheral vein blood and bone marrow aspirate, cultures on Sabouraud dextrose agar incubated at 30 C and grew H. capsulatum (Figure 3). Liposomal amphotericin B 3 mg/kg/day was administered, while tigecycline was discontinued and sulfamethoxazole-trimethoprim dosage was reduced to 800/160 mg daily. Over the next 3 days, the skin lesions disappeared. A week after this, the fever persisted at 38 C, platelet count was 19 x 103/muL, haemoglobin was 6.6 g/dL, and the CMV-p65 antigen resulted negative without evidence of CMV organ localization. In light of this, foscarnet was discontinued and voriconazole 200 mg bid orally was added to amphotericin. Two days later, the platelet count dropped to 8 x 103/muL, and at this point, amphotericin B was discontinued. The day after, the fever was resolved, while increases were observed for the platelet count (82 x 103/muL) and the haemoglobin value (10 g/dL) in the following 5 days. Voriconazole was administered for another 3 weeks and then substituted with itraconazole 200 mg tid for 3 days, followed by 200 mg bid as maintenance for 1 year. Antiretroviral therapy, including tenofovir disoproxil fumarate/emtricitabine and dolutegravir, was stared on the third week of antifungal treatment. In 2017, one year after admission, CD4+ cell count was 207 cell/muL (17%) and HIV-RNA was undetectable; itraconazole was discontinued. In 2019, the patient is on the same ART therapy, the CD4+ lymphocytes are 808 cells/muL (33.2%), and HIV-RNA remains undetectable.

PMC9260781_01

Female

A 60-year-old woman presented at our hospital with abnormal liver function tests discovered 2 weeks earlier on physical examination. Enhanced abdominal computed tomography (CT) scans revealed a space-occupying lesion at the hepatic hilum that was presumably considered hilar cholangiocarcinoma. The patient was admitted to our hospital on February 21, 2019. The patient denied any prior abdominal surgery or trauma. No abnormalities were found on physical examination. Laboratory investigations included liver function enzymes and tumor markers: alanine aminotransferase (ALT) 187 U/L (normal: 7-55 U/L), aspartate aminotransferase (AST) 111 U/L (normal: 8-48 U/L), alkaline phosphatase (ALP) 737 U/L (normal: 40-129 U/L), gamma-glutamyltransferase (gamma-GT) 1,074 U/L (normal: 8-61 U/L), total bilirubin (TBil) 28.5 mumol/L (normal: 4-19 mumol/L), direct bilirubin (DBil) 13.7 mumol/L (normal: 0-5 mumol/L), albumin 44.5 g/L (normal: 30-50 g/L), CA19-9 50.01 U/ml (normal: 0-37 U/ml), CA125 12.18 U/ml (normal: 0-35 U/ml), alpha fetoprotein 8.63 ng/ml (normal: <20 ng/mL), and CEA 1.93 ng/ml (normal: 0-2.5 ng/mL). Abdominal enhanced CT scan (Figure 1A) revealed a 10 x 17 mm mass in the hepatic hilum with an unclear boundary. In the arterial phase (Figure 1B), the mass showed obvious enhancement. The intrahepatic bile duct showed obvious dilation, and the mass surrounded the cystic duct. The wall of the gallbladder appeared thickened, but there was no significant enlargement. No enlarged lymph nodes were noted in the retroperitoneum. Furthermore, 3D reconstruction revealed a space-occupying lesion at the hilar bile duct, invading the right branch of the portal vein. Furthermore, the postoperative left residual liver volume (RLV) was estimated to be only 27.6% (Figure 1C). After a multidisciplinary team (MDT) discussion, the location of the tumor was considered unordinary, and, since a biopsy would have been highly risky, the pathological nature of the tumor was difficult to establish preoperatively. Thus, preoperative diagnosis was considered to be hilar cholangiocarcinoma based on enhanced CT scans. However, direct surgical intervention (right hepatectomy) would be inappropriate due to insufficient residual liver volume. The patient thus underwent preoperative percutaneous transhepatic cholangiodrainage (PTCD) on March 1, 2019, followed by percutaneous transhepatic portal vein embolization (PVE) on March 4, 2019, to improve residual liver volume. One month later, the patient was admitted again for surgery. Preoperative laboratory investigations revealed elevated liver function enzymes (ALT 131 U/L, AST 256 U/L, ALP 188 U/L, gamma-GT 209 U/L), while bilirubin and tumor markers were all within the normal range. A contrast-enhanced CT (Figure 2A) of the abdomen revealed improvement in the dilation of the hepatic duct, while the volume of the left hepatic liver had increased by 55.57% (Figure 2B). Magnetic resonance cholangiopancreatography (MRCP) (Figure 2C) indicated an irregular shadow at the porta hepatitis with a vague boundary and involving the cystic duct. The gallbladder was not enlarged, but the walls were significantly thickened. On April 11, 2019, the patient underwent surgery. Intraoperatively, the gallbladder was severely attached to the liver. The gallbladder had atrophied with a hardened texture (Figure 3A). The tumor invaded the hilar bile duct and the right branch of the portal vein. Lymph node enlargement at the hepatoduodenal ligament was observed. Based on the intraoperative findings, gallbladder carcinoma was considered. The surgical intervention included laparoscopic cholecystectomy, laparoscopic right extended hepatectomy, and laparoscopic hepatoduodenal ligament lymph node dissection. A cholangiojejunostomy was then performed. Intraoperative freezing biopsy showed no cancer cells at the level of the resected left bile duct and cystic duct. Postoperative pathological examination revealed that the mucosa of the gallbladder was grayish-white with a hard texture. Fibrous tissue hyperplasia of the gallbladder wall with hyaline degeneration was seen together with chronic interstitial inflammatory cell infiltration and focal multinucleated giant cell aggregation. A nodule, 1.4 x 1.0 cm in size, with a grayish-whitcross-sectionon (Figure 3B), was seen at the neck of the gallbladder. Pathological analysis and immunohistochemistry validated the diagnosis of traumatic neuroma through spindle cells (Figure 3C) and S-100 positivity (Figure 3D). Four resected lymph nodes showed reactive hyperplasia. The final validated diagnosis was traumatic neuroma of the gallbladder, chronic cholecystitis, fibrosis of the gallbladder wall, hyaline degeneration, and gallstones. The patient recovered well after the operation, without complications, and was discharged from the hospital. There was no obvious discomfort in the postoperative follow-up.

case report, cholangiocarcinoma, gallbladder neoplasm, idiopathic, traumatic neuroma

PMC6619743_01

Male

In our study, 22/26 patients had at least one symptom following high dose BCG administration. Most of the patients (57.7%) developed a papule. 11.5% developed a pustule, 7.7% developed skin erythema, and 3.8% developed axillary lymphadenopathy. 1/26 children also developed jaundice, but he was lost-to-follow-up. None of the patients developed fever disseminated TB or osteomyelitis. These findings are in consistent with the literature in which the most common symptoms following a high dose BCG vaccine were adverse local events and few systemic complications. A European report by Lotte et al. in 1984 documented most side effects of BCG overdose following immunization were exaggerated local reactions cases of large, deep ulcers, necrotic lesions or abscesses, and sometimes regional suppurative lymphadenitis were observed and only 8% developed systemic complications including fever, headache, and malaise. A study published in 1996 in Manchester, documented 857 cases of infants between July and November 1994 being injected intradermally with a percutaneous BCG preparation which was 5 times the upper limit of the normal dose. 61 (11%) of these infants had adverse local reactions. 48 infants (8.6%) had axillary lymphadenopathy, 6 infants had papules >10 mm, and 6 of the infants had ulcer >10 mm. One infant had an abscess which was aspirated by a needle. One infant presented at 4 months with severe combined immune deficiency (Omenn syndrome) but she did not have disseminated BCG infection.In the present study, it was observed that majority of the superficial local skin reactions occurred in the first 2 weeks of life which can also be seen normally with a routine BCG vaccination after birth. Almost all routine vaccine recipients experience an injection site reaction characterized by a papule which commences 2 or more weeks after immunization and then may progress to become ulcerated healing after 2-5 months leaving a superficial scar.However, severe local abscess and keloid formation or lymphadenitis following BCG vaccination are rarely reported and are only limited to few case reports.Wei et al. conducted a study in Taiwan about an event that occurred in 2012 in which the vial was diluted with 2mL instead of 3mL. That vaccine was then administered to 20 healthy infants. 3 (15%) of these infants developed injection site abscesses that resolved within 6 weeks. They all recovered without significant complications in the 18 month follow up period. A case report on a 13-year-old boy who mistakenly received intramuscular (IM) intravesical BCG reported that he suffered from fever, anemia, pancytopenia, enlarged spleen, hydronephrosis and fluid around the liver. However, a relationship was not established between the symptoms and IM intravesical BCG administration. At 2 months, he developed cellulitis and swollen lymph nodes were present on sonography. The skin biopsy showed poorly formed granulomas and he was treated with isoniazid, ethambutol, and rifampicin for 6 months. In a 60-year-old man 4 vials of intravesical BCG were administered intramuscularly which caused fever, headache, and sweating. He then developed local indurations and hypogastric pain after 3 days and received prophylactic isoniazid and rifampicin course. The babies were followed up to a mean follow-up time of 252 days which corresponds to around 8.4 months. The median duration of ATT given was 90 days. There is no consensus on how to best manage patients with BCG overdose. Puliyel et al. in 1996 mainly managed patients by observation except for 1 patient who received abscess aspiration and 1 patient with Omenn syndrome who received ATT after diagnosis. Miles and Shaw in 1996 also managed patients using observation. In the study by Ashraf, isoniazid and rifampicin were given for 2 months, another case study by Ritz et al. a surgical excision of the lump was done and then was treated with Isoniazid and Rifampicin for 6 weeks, whereas Wei et al. in their study managed the children by only observing and following them.

PMC6619743_02

Female

There was one patient who suffered an intracranial bleed. This baby had a normal coagulation profile (INR of 1.2), a normal platelet count (427*109/L) and also received vitamin k at birth. 3/26 (11.5%) patients had an INR of >1.0. Two of them had a post circumcision bleed. One had factor X deficiency and another kid had factor VII, IX and X deficiency which are vitamin K dependent factors. These babies responded to vitamin K therapy. This might be because of rifampicin induced coagulopathy due to vitamin K deficiency. Anti-tuberculosis medication can induce thrombocytopenia and coagulopathy which is mostly due to rifampicin. The pathogenesis of rifampicin-induced vitamin K deficiency is most likely to be multifactorial. It can be because of impairment of vitamin K production from gut flora due to intestinal decontamination or may be due to oxidative degradation of vitamin K as a result of hepatic microsomal enzyme stimulation. Chen et al. reported rifampicin induced disseminated intravascular coagulation (DIC) in a 22 year old boy treated for pulmonary Tuberculosis at the West China Hospital. Sampaziotis et al. also revealed rifampicin induced severe coagulopathy in patients with primary sclerosing cholangitis and refractory pruritus. Kang et al. observed a case of a 68-year-old woman developing an acute subdural hemorrhage secondary to rifampicin induced thrombocytopenia. According to the literature, rifampicin-induced thrombocytopenia usually occurs in high dose intermittent treatment because neutralizing antibodies form during continuous daily treatment. It is important to start treatment early in cases of drug-induced thrombocytopenia to prevent morbidity and mortality. In our study we observed coagulopathy however none of the newborns experienced thrombocytopenia. This could suggest that maybe instead of using both rifampicin and isoniazid as chemoprophylaxis; we can use only isoniazid to decrease the chance of thrombocytopenia, coagulopathy and bleeding. However, considering the nature of study and small sample size we can't establish its temporality and causation. There is very little data on BCG vaccination overdose in Pakistan. Moreover, medical errors tend to be underreported. By reporting these medical errors and following-up on the patients we can better understand the consequences of the medical error and their management. It also emphasizes on having checks to prevent medical errors like this in the future by increasing the awareness of health care staff. Small sample size and single centered retrospective nature are the major limitations of our study.

PMC5025916_01

Male

A 55-year-old man with a 10-year history of DM was admitted to our hospital with a 2 months history of dyspnea and cough. The patient was alert and afebrile and complained of chronic nonproductive cough. The patient had no history of immunosuppressive treatment or disease except the history of DM. The patient denied alcohol abuse and smoking. His vital sign was stable. Physical examination was not notable. Cell blood count (CBC) showed hemoglobin (Hgb) 9.9g/dl, white blood cell count (WBC) 6500, with polymorphonuclear dominant (56%). The level of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were 50mg/dl and 105 mm/hour respectively. HIV test was negative. In chest X-ray, nodular pattern was seen. This pattern also was showed in thorax computed tomography (CT) scan [Figure 1]. Considering the course of the disease, clinical manifestations and stable vital signs, the antibiotic was not started. 3 sets of blood cultures and echocardiogram were negative for endocarditis. Examination of the sputum specimen showed C.albicans. As the patient complained of a chronic cough and according to pulmonary lesions, bronchoscopy and bronchoalveolar lavage (BAL) was performed. The specimens evaluated for bacteria, nocardia, actinomyces, fungi and mycobacterium tuberculosis (TB) smear and culture, polymerase chain reaction for TB and also cytology for malignancies. The results were all negative except the culture of BAL fluid which revealed C. albicans. The serum and BAL fluid galactomannan were negative. Hence, CT-guided percutaneous biopsy of the lesion of the lung was performed. The result showed yeast and pseudohyphae that was compatible with the diagnosis of Candida. The tissue culture yielded C. albicans as well. Furthermore, microscopic studies for other microorganism such as acid-fast staining were negative. On special sectioning, no evidence of granuloma or malignancy was reported. Considering diagnosis, antifungal regimen (intravenous fluconazole) was started. Parenteral antifungal therapy continued for 2 weeks and then followed with oral fluconazole. Control chest CT scan was done 5 weeks later, which showed significant regression of pulmonary lesions [Figure 2]. At the completion of treatment, the level of CRP and ESR decrease to 6 mg/dl and 17mm/hr, respectively.

candida, candidiasis, fluconazole, pneumonia

PMC7417347_01

Female

A 40-year-old ethnic Han Chinese female, who used to be healthy and had no history of disorders related to the nervous system, respiratory system, circulatory system, digestive system, rheumatic immune system, and also had no history of mental disorders, from a family without history of genetic disorders, hypertension, coronary heart disease, diabetes, genetic inherited diseases, etc., forming a happy family with her beloved husband and two healthy daughters, initially presented with intractable nausea and dizziness for 9 weeks. She went to local hospital. Full blood count, serum biochemical tests, gastroscopy and head CT examination showed no obvious abnormalities. She felt that her nausea and dizziness did not improve after symptomatic therapy and even followed by dysphagia, limb weakness, blurred vision, ghosting in the right eye, and fatigue. Two weeks later, she went to another local hospital. A blood test was positive for AQP4 antibodies and brain MRI found high-signal lesions (Figures 1a-c). She was diagnosed with NMO and treated with high dose of intravenous methylprednisolone. Two days later, she felt shortness of breath, hard to swallow and difficulty in walking. She was transferred to the ICU and received a tracheotomy and mechanical ventilation due to severe breathing difficulties, and a nasogastric tube feeding due to difficulty swallowing. Her condition did not improve over 2 weeks despite treatment with high-dose intravenous methylprednisolone (0.5 g per day for 3 days, 0.25 g per day for 3 days, 0.12 g per day for 2 days) and immunoglobulin (20 g/day for 5 days) followed by 3 rounds of plasma exchange. She was transferred to our hospital at midnight, and physical examination revealed a temperature and blood pressure of 37.1 C and 96/68 mmHg, respectively. She was conscious on mechanical ventilation, with blurred vision of the right eye, shallow right nasolabial fold, upper limb muscle strength level 1, and lower limb muscle strength level 0. Laboratory tests revealed a white blood cell (WBC) count of 28,240 cells/muL, serum albumin 32.3 g/L, prothrombin time 16 s, activate partial thrombin 38.6 s, and D-dimer 2.24 mug/mL. Rheumatoid, lupus, and vasculitis-related immune indicators, and biochemical indicators related to the heart, liver, and kidney function showed no obvious abnormalities. Tuberculosis-specific enzyme-linked immunospot assay (T-SPOT), hepatitis B virus, hepatitis C virus, HIV, CMV-DNA, CMV-IgM, and Epstein-Barr virus (EBV)-IgM were negative; however, the CMV-IgG antibody was positive. Alpha-fetoprotein, carcinoembryonic antigen, and carbohydrate antigen (CA) 19-9, 125, 153, 50, 724, and 242 were negative. Blood and CSF smears and cultures were negative. On day 2 of admission, the patient developed 150 ml suspicious menstrual blood, accompanied by a high fever, and marked increase in C-reactive protein (CPR) and procalcitonin (PCT); however, WBC count, hemoglobin concentration (1, 3), -beta-D-glucan and galactomannan (GM) tests, and liver and kidney function were not significantly altered. Chest CT showed new glass-like lesions on both upper lungs. Multiple blood, sputum, and urine specimens were taken for pathogenic cultures (all final culture results were negative). Considering the hospital stay and administration of high doses of hormones in the external hospital, the patient was diagnosed with pulmonary infection and underwent an empirical broad-spectrum antibacterial and fungal treatment with meropenem, linezolid, and caspofungin. On day 3 of admission, the patient's body temperature peak began to decline; however, she suddenly passed 640 ml dark red bloody stool painlessly, resulting in shock. Blood transfusion and drug hemostasis treatment were administered to treat the shock. Meanwhile, bedside gastroscopy, colonoscopy, and full abdominal CTA scan were performed to identify the cause of bleeding. Abdominal CTA found a high-density shadow in the colon and rectum, which was considered an accumulation of blood; however, no bleeding vessels were found. Gastroscopy found no lesions in the upper digestive tract. However, colonoscopy revealed a large ulcer-like lesion at 10 cm above the anus and a large amount of feces and dark red bloody fluid (Figure 2a). Biopsy of ulcer-like lesions could not be performed due to coagulation dysfunction. On day 4 post-admission, the patient's body temperature returned to normal. On day 7 post-admission, the WBC count, CRP, PCT, and chest CT were normal; therefore, the anti-infective agents were removed; however, the daily excretion of 200-800 ml dark red bloody stool of this patient continued, and her muscle strength and vision loss did not improve. Based on the patient's bleeding characteristics and lesions found via colonoscopy, it was speculated that the cause of the patient's acute lower gastrointestinal bleeding was most likely AHRU. The pathogenesis of AHRU remains largely unknown. Therefore, we speculated that the presence of AHRU in this patient may be linked with her NMO. To assess this link, we reviewed literatures and only found one reported case of an acute NMO with rhabdomyolysis in an immune-competent patient following CMV infection. Infectious pathogens may trigger and exacerbate NMO by prompting AQP4-IgG production. AQP4-IgG+ NMO is refractory to glucocorticoid treatment. In this case, the patient did not respond to high-dose intravenous methylprednisolone and immunoglobulin followed by plasma exchange. Therefore, we speculated that NMO in this case was caused by the CMV infection. Thereafter, we wondered whether CMV infection could induce AHRU. Enteritis caused by CMV in immune-competent individuals had been reported, although very rarely. Interestingly, no relevant literature about CMV-AHRU was found. However, ARHU may be caused by CMV infection from a monistic point of view. To verify this, on day 23 post-admission, CMV inclusions of pathology of a mucosal tissue specimen from the edge of the patient's rectal ulcer was carried out using routine HE staining and IHC. These results confirmed the presence of CMV infection (Figures 3a,b). In addition, CSF pathogen gene sequencing also detected CMV gene copies on day 25 post-admission (Figure 3c) and serum AQP4-IgG was still positive. After 2 weeks of treatment with ganciclovir and sodium phosphinate, the patient's nausea, dizziness, visual impairment, and limb weakness gradually improved. After 3 weeks of antiviral therapy, her lower gastrointestinal bleeding stopped, and the CMV staining of rectal biopsies (Figures 3d,e), CSF CMV gene sequencing, and serum AQP4 all became negative. Further, high-signals on the brain MRI were significantly reduced (Figures 1d-f). After 4 weeks of antiviral therapy, the colonoscopy revealed a smooth intestinal wall at the original lesion (Figure 2b). In addition, her right eye visual acuity was resumed to counting fingers at 2 m, the muscle strength of her upper and lower limbs recovered to level 4 and 3, respectively. Following this, the antiviral drugs were stopped and the patient was discharged back to her local hospital for further rehabilitation.

acute hemorrhagic rectal ulcer, case report, cytomegalovirus, immunocompetent, neuromyelitis optica

PMC3120280_01

Male

A 75-year-old male belonging to the upper middle class presented with a history of a nonhealing sternal wound following a coronary artery bypass graft (CABG) in June 2010. CABG was done in the early part of May and the patient was discharged with the intact wound with an 8-h dose of amoxicillin and clavulanic acid combination (625 mg). The chest wound gradually progressed in size with a serosanguinous discharge despite the antibiotic cover. The patient was a known case of atherosclerotic heart disease with a history of myocardial infarction and chronic obstructive pulmonary disease. He had undergone percutaneous transluminal coronary angioplasty in March 2010. The patient was normotensive and nondiabetic with a family history of Koch's spine for which his wife was under antitubercular therapy (ATT). The patient at admission was afebrile with a heart rate of 96 beats/min and BP of 120/80 mmHg. The chest was bilaterally clear, and clinically, all the systems were normal. Laboratory investigations revealed the following: hemoglobin: 10.6 gm%; total white blood cell (WBC) count: 10.39 x 103/mm3; differential WBC count: neutrophils 67%, lymphocytes 20%, monocytes 2%, eosinophils 0.2%, and basophils 0.3%; platelet count 4.4 lakhs/mm3. Tests for HbsAg, HCV, and HIV 1 and 2 antibodies were found to be nonreactive. Liver function tests and renal function tests were normal. Blood, pus from the wound, and sputum were sent for aerobic culture. Blood cultures (BacT Alert; bioMeriux) sent in duplicate showed the presence of faint Gram-positive beaded, rod-shaped organisms after 4 days of incubation. Ziehl-Neelsen (ZN) staining of smears from signal positive blood culture bottles showed the presence of beaded acid-fast bacilli in chains. The blood was then inoculated onto blood agar, MacConkey agar, and Lowenstein-Jensen (LJ) medium. Blood and MacConkey agar did not show any growth till 48 h after aerobic incubation. The LJ medium showed the presence of tiny creamish colonies on the third day after incubation. ZN staining of the smears from these colonies showed the presence of acid-fast bacilli. The isolate was provisionally identified as atypical mycobacteria (rapid grower). Gram staining of the pus smear showed plenty of Gram-variable bacilli. No growth was seen on blood and MacConkey agar till 2 days of aerobic incubation. Since the blood culture was positive for atypical mycobacteria, the pus sample was also subjected to ZN staining and mycobacterial culture. ZN staining of the pus smear showed the presence of numerous acid-fast bacilli. The culture on the LJ medium grew tiny creamish colonies on the fourth day of incubation. ZN staining of these colonies also showed the presence of acid-fast bacilli. This isolate was also provisionally identified as atypical mycobacteria (rapid grower). The aerobic culture of the sputum on blood and MacConkey agar did not grow any respiratory pathogen. The sputum culture was negative for Mycobacterium tuberculosis after 6 weeks of incubation in the LJ medium, and PCR for the MTB complex of the sputum sample came negative. The patient was started on second-line ATT comprising IV azithromycin 500 mg every 12 h, IV amikacin 1 g once daily, and tab ciplox 500 mg every 12 h. Sternal wound debridement was done 2 days later under general anaesthesia along with omentoplasty. The tissue was sent for aerobic culture, histopathological examination and MTB complex PCR to rule out M. Tuberculosis presence. The aerobic culture did not show any growth till 3 weeks after incubation and PCR for the MTB complex came negative. The mycobacterial culture grew similar colonies as mentioned above 7 days after incubation. A histopathological examination of the biopsy sample showed chronic necrotizing, granulomatous osteomylitis of the sternum compatible with tuberculosis. The atypical isolates (rapid growers) were later identified as M. abscessus by using the Genotype Mycobacterium CM kit (Hain Lifescience, Germany). This test is based on the DNA strip technology and permits the identification of common atypical mycobacteria along with the M. tuberculosis complex [Figure 1]. Antimicrobial sensitivity testing was done on Mueller-Hinton agar by the Kirby-Bauer disc diffusion method for amikacin, doxycycline, imipenem, ciprofloxacin, sulfonamide, erythromycin, cefoxitin, and clarithromycin. The strains were found to be sensitive to amikacin, erythromycin, ciprofloxacin, and clarithromycin. Repeat blood and swab cultures for mycobacterium from the incision site sent 1 week after starting antibiotic therapy were negative. The sternal wound had completely healed and the patient was discharged on the 18th postoperative day with an advice to continue with the prescribed antibiotics for 6 months with regular follow-up.

bacteremia, mycobacterium abscessus, nontuberculous mycobacteria, sternal osteomyelitis

PMC6431357_01

Female

The patient was initially presented to our clinic at the age of 9 with a chief complaint of limping. Her developmental history was notable for developmental delay without underlying genetic or autoimmune conditions and low infantile weight for which she had a gastric tube. Family history was negative for any neuromuscular disease, hip dysplasia, or autoimmune disease. She had recently moved from Mexico with her family to the United States. Her initial exam revealed a Trendelenburg gait and sign, left hip pain-free range-of-motion with 100 internal rotation, 50 external rotation, 135 flexion, 20 extension, and 70 abduction. Her right hip revealed pain-free range-of-motion with 90 internal rotation, 50 external rotation, 135 flexion, and 60 abduction. The comparison of both hips revealed a positive Galeazzi sign with a leg-length difference of 2 cm and normal bilateral reflexes. Imaging demonstrated bilateral hip dysplasia with left hip dislocation with pseudoacetabuli (Figures 1 and 2). At this time, the working diagnosis was untreated bilateral hip dysplasia, and we discussed surgical options including fusion, pelvic and femoral osteotomies, and total hip arthroplasty (THA). Given the chronicity of her dislocation and severity of her dysplasia, it was determined that any surgical treatment on the unilateral left hip dislocation was unlikely to provide a significant benefit and may make her worse. We recommended proceeding with a possible THA versus fusion in her teenage years when pain warranted treatment. For the right hip, we recommended a future periacetabular osteotomy (PAO) once her triradiate cartilage closed and her hip became symptomatic, possibly in a few years. She was unfortunately lost to follow-up and did not receive additional treatment during this time but represented to our clinic 1.5 years later with progressive decrease in ambulation requiring a wheelchair and walker and bilateral left greater than right hip pain. On exam, both hips had painful range-of-motion with the development of a 5 hip flexion contracture on the left and increased flexion, abduction, and internal rotation on the right. Her limp was significantly worse, but her leg-length discrepancy decreased to 0.5 cm. Imaging demonstrated erosive changes of the bilateral femoral heads with infiltrative destructive patterns to the bilateral acetabula, hip effusions, and synovial thickening (Figures 3 and 4). In addition, she developed a new dislocation of the right hip. She was directly admitted from clinic for further work-up. On the day of admission, she had bilateral hip aspirations which showed unremarkable inflammatory fluid changes (left hip: 20 mL of cloudy, turbid, straw-colored fluid, cell count 908, polymorphonuclear cells 2%; right hip: 80 mL of bloody, cloudy fluid, cell count 359, polymorphonuclear cells 49%). Crystal exam, gram stain, and cultures were negative. Synovial fluid cytology demonstrated numerous benign reactive synovial cells without identification of malignant cells. Given the severity of the destruction, a possible spinal etiology including tumor syrinx resulting in Charcot joint was suspected. Magnetic resonance imaging of the brain and cervical/thoracic/lumbar spine was within normal limits. Other etiologies including bacterial, fungal, and viral infection were considered. Coccidioidomycosis and histoplasmosis titers and Lyme disease antibodies were negative. To evaluate for tuberculosis, a chest X-ray was obtained within normal limit while CT demonstrated a 4 mm nodule in the right middle lobe that was noncalcifying and believed to be postinfectious. AqQuantiFERON-TB gold test was negative. A complete blood count, basic metabolic panel, CRP (0.3 mg/dL), and ESR (7 mm/hr) were within normal limits with the exception of elevated platelets (550). Compliment fixation serum and immunodiffusion serum tests were negative. Autoimmune etiologies were also considered. Extensive serologic testing was performed including dilute Russel's viper venom time, lupus anticoagulant, anti-CCP, anticentromere, antimitochondrial, anti-double-stranded DNA, antinuclear antibody, anti-SSA, SSB antibody panel, rheumatoid factor (RF), and HLA-B27 which were all negative. Because of the unusual and severe presentation of the disease and the lack of a diagnosis, on hospital day 10, she was taken to the operating room for bilateral hip arthrocentesis and bilateral hip arthroscopy for biopsy of the bone and synovium. A synovial biopsy was obtained to examine the tissue visually and histologically to confirm the diagnosis of an inflammatory arthritis. Intraoperative findings demonstrated right capsular destruction with unusual appearing and inflamed and reddened synovium with erosive destruction of the articular surface of the femoral head and acetabulum. On the left, there was a free-floating femoral head with multiple moderate-sized osteochondral loose bodies grossly inflamed synovium, intact labrum, no clearly discernable joint capsule, and near-complete absence of cartilage within the acetabulum and overlying the femoral head (Figure 5). Following the diagnostic component of the arthroscopy, she underwent a left femoral head arthroscopic resection, bilateral synovial and bone biopsies, and bilateral Kenalog intra-articular injections for pain relief. Biopsy results demonstrated synovial hyperplasia with chronic inflammatory changes. Postoperative X-rays showed left femoral head resection (Figure 6). Given the results of the arthroscopic findings and synovial biopsy, we subsequently referred the patient to a board-certified pediatric rheumatologist for further evaluation. Additionally, she was found to have moderate arthropathy of her right calcaneocuboid and bilateral 1st metatarsophalangeal joints. Given these clinical findings, she was given the diagnosis of Persistent Oligoarticular JIA characterized by negative RF, CCP, and HLA-B27 and was subsequently started on methotrexate and folic acid. At 3-year postoperatively, she has continued erosion of the right femoral head (Figure 7). A genetics consult was obtained, and comprehensive screening was negative. She remains nonweight bearing with the plan for bilateral THAs once she becomes a teenager. However, this could result in multiple challenges if the patient becomes nonambulatory, has limited acetabular bone stock, if the hip dysplasia requires femoral shortening, or if custom implants are needed due to the small size and deformity.

PMC9880049_01

Male

A 23-year-old man with no known co-morbidities presented in the Emergency Department at a Tertiary Care Hospital in Karachi with multiple complaints of neck swelling for 1 year, fever for 1 month, and generalized weakness for 1 week. He was a resident of Khuzdar, unmarried, and a final-year student of Doctor of Veterinary Medicine. On detailed history, the single neck swelling presented anteriorly and was not associated with any joint swelling, morning stiffness, or tenderness in small joints. It also regressed with time. However, he then noticed another static swelling on the right side of the neck in close proximity to the previous one. Fever was reported as intermittent and documented up to 104 F. It was associated with rigors and chills but subsided after oral paracetamol. It was associated with severe body aches and joint pain involving the wrists, elbows, and knees bilaterally. No diurnal variation or night sweats were accounted for, nor was any rash or oral ulcer. There was no history of Raynaud's phenomenon, burning micturition, cough, or loose stools. On further inquiry, it was revealed that he had a pet cat for a duration of 1 year in 2020 and is a student of Doctor of Veterinary Medicine (DVM), reports positive for exposure to various animals. His personal history revealed no addictions, but there was a history of sexual contact. On examination, three to four swellings were accounted for in the right posterior cervical region, the largest one having dimensions of ~2.0 x 1.0 cm. They were non-tender, non-erythematous, firm, and immobile, with no discharging sinus. Two small swellings were also noted bilaterally in the inguinal region. These were also found to be non-tender, non-erythematous, firm, and immobile with no discharging sinus. They measured ~1.0 x 1.0 cm. Blood pressure was recorded as 80/40 mm Hg, pulse 92 beats/min, oxygen saturation 98% on room air, and temperature as afebrile in the Emergency Department. On systemic examination, the abdomen was found to be soft and non-tender, with no visceromegaly noted; the chest, cardiovascular system, and central nervous system were also found to be unremarkable. The hospital course was initiated by giving IV fluids and commencing ionotropic drugs (noradrenaline) to raise his blood pressure, and he was hospitalized. Meropenem 1 g was started IV three times a day (TDS) secondary to high total leukocyte count (TLC = 49) and procalcitonin (PCT = 8.17). As the diagnosis was uncertain and the patient presented with fever, to rule out infective endocarditis and vegetation, echocardiography was scheduled, which was found to be unremarkable. Next, the general surgery team was consulted for an excisional biopsy of the right cervical lymph node. He was then stepped down to a private room as blood pressure started to show improvement, and ionotropic support was eventually tapered off. Azithromycin 500 mg was added to the treatment regime as there was no improvement in fever. The Infectious Diseases Department next advised VDRL and HIV serology (which came out to be negative), and azithromycin was switched to an injection of ciprofloxacin 500 mg IV twice daily. Histopathology ruled out tuberculosis and malignancy, and as fever started to space out, meropenem and ciprofloxacin were continued. After about 5-6 days, the histopathology department came up with the diagnosis of cat-scratch disease. The patient was fever-free for 2 days, clinically and vitally stable, and discharged on doxycycline 100 mg and rifampicin 300 mg twice daily for 6 weeks. Figure 1 shows a section of a lymph node showing areas of necrosis and abscess surrounded by palisading histiocytes along with capsular and subcapsular granulomas. Table 1 highlights results of important laboratory investigations to reach a diagnosis.

bartonella henselae, cat scratch disease, fever, infection, lymphadenopathy

PMC10288649_01

Female

In this case, a 31-year-old female presented with progressive pain and decreased range of motion of her left hip over 2 months, and the pain had increased progressively and worsened with activity. During the 2 months, the patient reported fever and had self-administered cephalosporin antibiotics. She had no history of chills, fatigue, weight loss, or other systemic symptoms. However, she mentioned her husband was being treated for "tuberculosis". Physical examination revealed pain in flexion, adduction, and external rotation of the left acetabulum, but no swelling, local skin damage, ecchymosis, or obvious local deformity. It showed no respiratory and neurologic symptoms or signs. Laboratory investigations showed a serum C-reactive protein level of 67.51 mg/L, total white blood cell count of 7700/mm3 with 86.8% neutrophils, and erythrocyte sedimentation rate of 64 mm/h. The viral serology tests for hepatitis B yielded positive results and suggested chronic hepatitis B. The HIV screening, Mycobacterium tuberculosis antibody, and Mycobacterium tuberculosis DNA tests were all negative. Radiographs demonstrated a 3 cm purely lytic lesion in the left acetabulum without sclerosis or periosteal reaction. The continuity of the local cortical bone was interrupted, and the adjacent soft tissues were inflamed (Fig. 1a). Computed tomography (CT) scan showed osteolytic bone destruction of the left acetabulum with clear borders and no sclerosed margins, and a soft tissue mass measuring 3.5 cm by 2.0 cm by 3.3 cm in the left acetabulum. The average CT value was approximately 44HU (Fig. 1b, c). The wall was strengthened with a CT value of 76HU, and there was a liquid low-density shadow in the mass with a CT value of 23HU, and no enhancement was seen (Fig. 1d, e). Three-dimensional reconstruction showed bone destruction in the left acetabulum (Fig. 1f). Chest CT showed bullae at the apical segment of the right upper lobe, with the remainder of the chest showing no obvious abnormalities. Magnetic resonance imaging (MRI) showed irregular bone destruction and abscess formation in the left acetabulum, with the abscess measuring 3.6 cm by 1.9 cm by 3.5 cm, cortex erosion and significant bone and soft tissue edema were also observed (Fig. 2a-c). The presence of enhancement at the edge of the lesion and an area of liquefaction necrosis without enhancement in the center indicate abscess formation (Fig. 2d-f). Imaging diagnosis of infectious disease with abscess formation. The mass was sampled by fine-needle aspiration biopsy under ultrasound guidance. Histopathological examination of the specimen showed granulomatous inflammation surrounded by a large number of multinuclear giant cells, some lymphocytes, and plasma cells (Fig. 3a, b), and the presence of Cryptococcus was confirmed by periodic acid-Schiff's reaction (Fig. 3c). The resulting histopathological diagnosis was granuloma with Cryptococcus. After one month of antifungal treatment with fluconazole and flucytosine, a fungal culture from diseased tissue secretions produced a negative result. Upon discharge, the left leg was placed under traction and immobilized to prevent hip dislocation and relieve the pain, and we continued the antifungal treatment. A follow-up of MRI after 10 months confirmed a decrease in the lesion's size (from 3.6 cm by 1.9 cm by 3.5 cm to approximately 2.7 cm by 1.6 cm by 3.1 cm), but there was still some bone defect in the left acetabulum (Fig. 4).

cryptococcus, acetabulum, case report, osteoarticular cryptococcosis, osteomyelitis, skeletal infection

PMC7298554_01

Female

Our patient is a 35-year-old female. She was the restrained front seat passenger in a car vs. tree RTA at 80 km/h. Her seatbelt was worn with the shoulder strap sitting under her left axilla. The car had no airbags and was right hand drive. The accident occurred in urban South Australia. The 2 other occupants sustained minor injuries. She had a past surgical history of only bilateral breast implants, took no regular medications and had no pre-existing medical conditions. She was heavily intoxicated at the time of the RTA. She denied any previous drug use. She has no significant family or psychiatric history. She was retrieved from the scene to a tertiary trauma centre via ambulance. Primary survey showed a patent airway, equal air entry, tachycardia of 110 bpm and blood pressure of 130/60. She had multiple superficial abrasions, a generally tender abdomen, an unremarkable chest X-ray, and a negative Focused Assessment of Sonography in Trauma (FAST) scan. She was taken immediately for Computer Tomography (CT) imaging from the trauma bay. Imaging showed a moderate volume of free intra-abdominal fluid (Image 1), a distended stomach with transection of the gastroduodenal junction (Image 2, Image 3, Image 4), and splenic injury (Image 5). Upon transfer from CT machine to barouche the patient became haemodynamically unstable with a blood pressure of 80/40 and tachycardia at 130. She was transfused with red blood cells and taken immediately to the operating theatre for exploratory laparotomy. The patient underwent Rapid Sequence Induction (RSI) and midline laparotomy was performed. The on-call Trauma Surgical Consultant performed the procedure with the on-call Surgical Registrar assisting. She required 10 min of supracoeliac aortic compression until haemodynamic stability was secured. Subcapsular splenic injury with uncontrollable bleeding was identified and managed with splenectomy. Bleeding from a posterior paracaval liver laceration was controlled with packing. Once rapid bleeding was controlled systematic examination of the abdominal viscera revealed a complete shearing transection of the gastroduodenal junction. The pyloric sphincter was seen periodically relaxing and spurting alcohol smelling gastric contents into the abdomen. Pylorus and duodenum were stapled off and an orogastric tube was placed. Further examination showed a 13 cm seromuscular injury of the transverse colon with associated contusion. This was repaired primarily. Systematic examination incorporating all viscera including retroperitoneal structures did not demonstrate further injury. Extensive washout was performed, and the patient's abdomen was packed with a negative pressure dressing. She was transferred to the Intensive Care Unit (ICU) still intubated and sedated with a view to re-look laparotomy in 48 h. Secondary survey and imaging identified an L3 chance fracture, multiple lower left sided rib fractures and a humeral fracture. She remained stable in the ICU and was managed with intravenous broad-spectrum antibiotics and received a total of 8 units of red blood cells intra and post operatively. Re-look laparotomy was performed 48 h following the initial injury. This was performed by the same Trauma Surgeon with assistance from Senior Hepatobiliary and Colorectal Surgeons. Packing was removed and there was no bleeding identified. The gastric and duodenal stumps were healthy and gastro-jejunal anastomosis was performed. The transverse colonic contusion had worsened, middle colic vascular injury was identified and resection with stapled anastomosis was undertaken with defunctioning loop ileostomy. Her liver laceration was no longer bleeding and repeat systematic examination did not demonstrate further injury. After further washout her abdomen was closed. After several days in ICU she was transferred to the ward where she remained for a period of 4 weeks. Her admission was complicated by a post-operative ileus. The humeral fracture was managed by open reduction and internal fixation. The patient was unable to recall the events of her initial trauma and multiple operations. She was an active participant in her rehabilitation and maintained good spirits throughout her admission. She received formal trauma counselling, stomal therapy education and was discharged home once deemed safe by a multidisciplinary team. She did not appear to be suffering from any long term physical or psychological disabilities as a result of her injuries. While she struggled initially with stoma management, she learned to manage this independently after several days of education. Her stoma was reversed 6 months after discharge. Written consent was obtained from the patient prior to the creation of this report. This work has been reported in line with SCARE 2018 criteria.

emergency surgery, road traffic accident, seatbelt, trauma, upper gastrointestinal injury

PMC6147815_01

Female

A 49-year-old, nonsmoking female was admitted to our clinic on 20 June 2001 with a one-year history of progressive dyspnea and dry cough. She denied sputum production, hemoptysis, night sweats and fever. At the time of her evaluation, she had been taking antituberculous drugs for two months. She had been noted to have abnormal shadows on a chest radiograph in 1990, but she had not been treated for it due to her good clinical status. She was treated for tuberculosis for about one year in 1993. Her family history was negative for any lung disease. Vital signs were within normal limits. Examination of the chest indicated bibasilar end-inspiratory fine rales. Extremities showed digital clubbing of grade V with slight cyanosis. Although the patient appeared well at rest, she became dyspneic after walking about twenty to thirty meters. Laboratory findings are shown in the table. Plain chest x-ray and thorax CT are shown in Figures 1 and 2, respectively. (see )

PMC10064912_01

Unknown

This is also termed 'periodic vestibulocerebellar ataxia' and 'North Carolina autosomal dominant ataxia'. It is reported in 2 families from North Carolina, suggesting a common single founder. It is characterized by ataxia, vertigo, episodic impaired smooth pursuit, gaze-evoked nystagmus, and diplopia. The onset is between 30-60 years, and symptoms worsen over time. It resembles EA2 but without interictal nystagmus, and it does not respond to acetazolamide. Gabapentin may relieve vertigo symptoms in EA4. Linkage studies in 1996 excluded autosomal dominant ataxias with known chromosomal localization at that time, including KCNA1, CACNA1A, SCAs 1-5 and DRPLA. Autopsy findings in a 91-year old EA4 patient showed polyglutamine repeats in Purkinje and granule cells, without intranuclear inclusions, similar to SCA6 brains. This was of interest as SCA6 can present as a fluctuating ataxia. This was reported in a single French-Canadian family 20 years ago, with a mutation in CACNB4 gene, coding for the beta4 auxiliary subunit of voltage-gated calcium channels (Cav2.1). It is late onset and responds to acetazolamide. There were attacks of vertigo and ataxia lasting for several hours, although 1 family member had a single attack lasting for weeks. Interictal examination revealed spontaneous downbeat and gaze-evoked nystagmus, mild dysarthria and truncal ataxia. However no additional cases have subsequently been identified, despite frequent screening of CACNB4 mutation in EA patients. Meanwhile, the same mutation was reported in a family with epilepsy. Other CACNB4 mutations have been associated with epilepsies. Some researchers have questioned whether there is sufficient data to support EA5. EA6 has been reported in several Caucasian and Korean families to date, and associated with SLC1A3 mutations in all cases. The phenotype resembles EA2 with long duration attacks, interictal nystagmus, similar triggers, and acetazolamide response. Migraine, alternating hemiplegia, progressive ataxia and epilepsy may co-occur. Childhood and adult onset is reported, and it appears to have reduced penetrance. The SLC1A3 gene codes for EAAT1 (excitatory amino acid transporter), a glial Na+-dependent glutamate transporter and ion channel. Functional studies suggest SLC1A3 mutations impair EAAT1 by altering transport function in various ways via reduced or enhanced glutamate uptake and/or anion currents. There are differing clinical phenotypes, according to the glutamate reuptake capability. A SLC1A3 mutation underlying EA6 has also been reported in a family with adult-onset progressive ataxia. SCL1A3 mutations have also been found in migraine, ADHD, autism and Tourette syndrome. In a patient with familial migraine, the mutation impaired K+ binding to the EAAT1 channel and completely disrupted glutamate transport. This was reported in 7 members of a 4-generation family in 2007. It is similar to EA2 but without interictal nystagmus. This was mapped to 19q13 with a LOD score slightly above significance cutoff. Sequencing of 2 candidate genes in this region (KCNC3, SLC17A7) did not identify a mutation. This was first reported in 2016 in an Irish 3-generation family. This presented by age 2, much earlier than EAs 1-7. There are episodic attacks with impaired balance, dysarthria, and generalized weakness. Attacks can be triggered by physical fatigue or stress. Interictal examination can show intention tremor, eyelid myokymia, and impaired tandem gait. Attacks vary in duration from minutes to hours, and frequency ranges from daily to every few months. Migraine with aura may co-occur. Attacks respond to clonazepam and are not improved with acetazolamide. The gene has been mapped to a large region on 1p36.13-p34.3 with a LOD score near to cutoff. Exome sequencing revealed variants in 2 genes, SPG2 and UBR4. UBR4 had a greater likelihood of pathogenicity than SPG2, as UBR4 is ubiquitin ligase protein that interacts with calmodulin and may potentially disrupt calcium sensor in neurons as hypothesis for ataxia. A Korean study reported 2 patients with mutations in both UBR4 and CACNA1A, and suggested UBR4 may act as a genetic modifier with synergic effects on abnormal CACNA1A activity. No functional analysis studies have been performed as yet for UBR4. There are a growing number of genetic disorders that can present with EA either alone or embedded in a complex syndrome. These include chronic ataxia disorders (SCA-14, SCA-27, SCA-35, SCA-42, AOA2, CAPOS,), genetic epilepsy syndromes (KCNA2, SCN2A, PRRT2, TBC1D24), GLUT-1, mitochondrial disorders (PDHA1, PDHX, TPK1, DARS2, ACO2), metabolic disorders [aminoacidopathies (Maple syrup urine disease: BCKDHA, BCKDHB, DBT; Hartnup disease: SLC6A19), urea cycle defects (type I citrullinemia: ASS1), thiamine metabolism defects (thiamine pyrophosphate deficiency: TPK1) biotin metabolism (biotinidase deficiency: BTD),] and others (KCND3, NALCN, FHM2/ATP1A2, PACS1, CEP290). Some of these might explain prior classical familial EA cases that were negative for EA1 and EA2 and genetic loci of other EAs. Three of them (SCA-27/FGF14, SCA-42/CACNA1G, and SCN2A) have been proposed to be categorized as EA9 or EA10. SCA-14 is a dominantly inherited slowly progressive ataxia, sometimes accompanied by parkinsonism, dystonia, myoclonus and cognitive impairment. It is caused by mutations in PRKCG gene encoding protein kinase C gamma (PRKgamma). PRKCG mutations may also present with adult-onset episodic ataxia, with a frequency of 1/14 PRKCG-positive patients. SCA-27 is a late-onset progressive ataxia with parkinsonism, postural tremor and titubation; 20% have coexistent episodic ataxia. It is caused by mutations in FGF14 gene which encodes Fibroblast Growth Factor 14. This protein is highly expressed in the brain, especially Purkinje cells, where it interacts with voltage-gated Na+ channels to regulate neuronal excitability. Isolated EA is also reported to be caused by heterozygous FGF14 gene mutations. Onset age ranges widely from early childhood to adulthood. Attacks may be accompanied by vertigo, dizziness, unsteadiness, with interictal nystagmus and tremor. Attacks are highly variable, lasting seconds up to several days. There are a variety of triggers; a fever trigger with a prolonged attack in a young child can mimic febrile cerebellitis. Attacks may respond to acetazolamide, and may improve with age. Developmental delay and paroxysmal dyskinesia have also been observed. Some authors suggested designating this EA9. CACNA1G encodes the pore-forming alpha1G subunit of T-type voltage gated calcium channel (VGCC). Mutations in CACNA1G cause generalized absence epilepsy and SCA42. A single family is reported with episodic vestibulocerebellar ataxia associated with a mutation in the CACNA1G gene. There were attacks of dizziness, unsteadiness, headache and facial numbness, and head-movement induced vertigo. Attacks lasted up to several months in duration. Interictal examination showed cerebellar findings and bilateral vestibulopathy. The attack duration and absence of myokymia or tinnitus distinguishes this from EA3. Attacks were worsened by acetazolamide, and suppressed by carbamazepine. The authors proposed this be designated EA10.

ataxia, cerebellum, episodic, genetic, paroxysmal, primary, secondary, treatment

PMC10064912_02

Male

Mutations in SETX (senataxin) account for two separate clinical syndromes. Oculomotor apraxia type 2 (AOA2), an autosomal recessive spinocerebellar ataxia, with adolescent or early adult onset progressive ataxia, oculomotor apraxia, neuropathy, cerebellar atrophy, and elevated alpha-fetoprotein levels. Autosomal dominant juvenile-onset motor neuron disease (ALS4) is also characterized. There is a single case report of a 4 year old boy presenting with isolated severe EA attacks lasting 20-30 minutes, and intermittent mild impaired tandem gait between attacks. Genetic testing excluded EAs 1,2,5,6. Whole exome sequencing (WES) identified a heterozygous deletion in SETX gene, possibly explaining the milder phenotype compared to homozygous mutations in AOA2. Mutations in the ATP1A3 gene mutation cause a broad spectrum of neurologic disorders. These include the clinical syndrome of cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS), rapid-onset dystonia parkinsonism (RODP), and alternating hemiplegia of childhood (AHM). It may also present with paroxysmal ataxia triggered by fever, with attacks responsive to acetazolamide. Dystonia, hypotonia, neuropsychiatric symptoms, cognitive impairment, and microcephaly may also be observed. The SLC2A1 gene encodes glucose transporter protein type 1 (GLUT1) which facilitates glucose transport across the blood-brain barrier, and is critical for brain energy. The GLUT-1 deficiency syndrome is a result of inadequate brain glucose transport. The main phenotype is a severe chronic neurologic disorder (microcephaly, developmental delay, early infantile seizures, ataxia). About 10% do not have this phenotype, and instead have milder paroxysmal variants often provoked by fasting or exercise, such as EA or paroxysmal exercise-induced dyskinesia (PED). Amongst 25 SLC2A1 carriers, 1 had EA. The GLUT-1 spectrum disorder has grown to encompass other paroxysmal dyskinesias (PKD, PNKD), myotonia, migraine, hemiplegic migraine and episodic eye movements. EA may be pure or with additional neurological findings. A diagnostic test to assess for GLUT1 deficiency is spinal tap showing a low CSF to serum glucose ratio (hypoglycorrhachia). Treatment for GLUT1 deficiency is avoidance of triggers, or ketogenic diet to provide an alternative energy substrate for brain energy metabolism. However EA attacks may also respond to acetazolamide, which may lead to misdiagnosis as EA2. A spectrum of neurological disorders may be caused by mutations in the KCNA2 gene, which encodes voltage-gated potassium channel Kv1.2. Early onset developmental and epileptic encephalopathy, intellectual disability, and ataxia are recognized. A milder phenotype of episodic ataxia, epilepsy, and complicated hereditary spastic paraplegia is reported. Mutations in SCN2A are associated with a spectrum of neurological disorders from benign to severe epilepsies, autism spectrum disorder and intellectual disability. SCN2A encodes the alpha subunit of voltage gated neuronal Nav1.2 channel. Loss-of-function mutations result in severe epilepsy, intellectual disability and autism, whereas gain-of-function mutations cause benign familial neonate infantile seizures (BFNIS) with or without EA. Patients with BFNIS have seizures before age 3 months which resolve in early life, and may later develop EA between age 10 months to age 14 years. Cognitive outcome is mostly favorable in these cases. Amongst cases with a more severe intellectual disability phenotype, EA appears to be uncommon. Phenotypes may vary in family members, e.g. EA in infant and episodic hemiplegia in parent. EA may be triggered by vaccinations, minor head trauma, and sleep deprivation. Some but not all have a favorable response to acetazolamide. Seizures, but not EA attacks, respond to Na-channel blockers (phenytoin, carbamazepine) suggesting different pathophysiologic mechanisms. Some authors have designated this EA9. PRRT2 (proline-rich transmembrane protein 2) mutations are responsible for a spectrum of paroxysmal neurological disorders. The 3 main phenotypes are paroxysmal kinesogenic dyskinesia (PKD), benign familial infantile convulsions (BFIC) and infantile convulsions and choreoathosis (ICCA). Other phenotypes include migraine, FHM and epilepsy. EA appears to be a rare manifestation of PPRT2 mutations. In 1 large study of 374 PRRT2-positive patients, episodic ataxia was only occasionally reported. In another study of 182 EA patients, only one case was attributed to a PRRT2 gene mutation. MRI brain imaging performed in a PRRT2 patient during an EA attack showed cerebellar diffusion restriction. Most PRRT2 mutations respond exquisitely to carbamazepine so EA attacks due to PRRT2 may cause diagnostic confusion with EA1. The PRRT2 protein interacts with SNAP-25 and may play a role in synaptic transmission. Most mutations are loss-of-function, which may result in disrupted synaptic transmission and neuronal hyperexcitability. This does not explain phenotype variation, and no specific phenotype-genotype correlation is identified. A handful of cases are reported with homozygous PRRT2 mutations and a severe phenotype with episodic ataxia, intellectual disability, and infantile seizures. Mutations in the TBC1D24 presynaptic protein are associated with a neurological spectrum of epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation and seizures), hearing loss, and myoclonus. Biallelic mutations of TBC1D24 were found in an infant with EA and myoclonus, with a later finding of cerebellar atrophy in adolescence. EA cases are reported in mitochondrial disorders, such as pyruvate dehydrogenase complex deficiency, (PDHx, PDHA1), TPK1, DARS2, MTATP6, ACO2 genes. EA can be isolated or occur with other neurological abnormalities. Diagnostic clues are the presence of serum and CSF lactic acidosis. A mild presentation of fever-triggered EA attacks lasting 2 to 7 days, and a normal interictal exam, was observed in a young child with PDH deficiency. Tests showed elevated serum and CSF lactate, and MRI brain showed dentate nucleus hyperintensity. Attacks responded to thiamine, levocarnitine, and alpha-lipoic acid. In comparison, homozygous or compound heterozygous mutations in ACO2 (encodes mitochondrial aconitase 2 that catalyzes citrate to isocitrate) can cause a spectrum of disorders with often severe neurologic impairment. A recent report of 2 siblings with ACO2 mutations had EA plus mild developmental delay and neuropsychiatric symptoms. A "late-onset EA" was reported in 2009 of 4 cases in a single 2-generation family but the gene is not known. Onset was in the fifth or sixth decade. Phenotype severity was variable, with more severe cases exhibiting daily attacks with slowly progressive ataxia and poor acetazolamide response. Screening excluded KCNA1 (EA1), CACNA1A, (EA2), and locus for EA2, EA5, EA6 and EA7. There is a broad differential diagnosis for acute-onset recurring ataxia. (Table 2). Secondary or acquired EA may resemble primary EA with regards to onset-age, attack variability, and interictal cerebellar findings, but are more likely to have abnormal laboratory and MRI imaging. Many secondary causes are treatable, and collectively more common that primary EAs, so they are important to consider. The most common secondary disorders are transient ischemic attacks or stroke, multiple sclerosis or other immune-mediated disorders. "Paroxysmal dysarthria and ataxia" (PDA) is a well-recognized phenomenon in multiple sclerosis, with stereotyped multiple daily episodes of sudden ataxia lasting seconds to minutes, attributed to ephaptic transmission. This PDA syndrome can mimic genetic EA, and is also reported in immune-mediated diseases such as antiphospholipid syndrome, Bickerstaff's/Bickerstaff-like encephalitis, certain autoimmune ataxias, and ischemic stroke. This has been attributed to a lesion in the midbrain, near or in the red nucleus. Other inflammatory disorders (postinfectious cerebellitis, Miller-Fisher syndrome) and vascular disorders (Behcet's disease with brainstem and red nuclei involvement, Kawasaki disease) can present with prolonged attacks of acute ataxia. Structural lesions in the posterior fossa or cerebellum such as a tumor or occult neuroblastoma can present with recurrent ataxia. Epileptic pseudoataxia may transiently occur after a seizure. Hypothyroidism can present with recurrent ataxic episodes, and responds to thyroxine. Toxins (e.g. alcohol, antiseizure medications, lead) can present with reversible acute ataxia. Metabolic disorders (e.g. maple syrup urine disease, pyruvate dehydrogenase deficiency, ornithine transcarbamylase deficiency, biotinidase deficiency, Hartnup disease, argininosuccinic aciduria, citrullinemia, thiamine pyrophosphate deficiency) causing EA usually present in childhood with severe neurologic symptoms, but may present in adults with much milder features. Thiamine pyrophosphate deficiency has been reported in a small number of patients with EA, delayed development and dystonia, and may respond to thiamine supplementation. Maple syrup urine disease may also have significant clinical or biochemical improvement with thiamine supplementation. Citrullinemia is a rare recessive urea cycle disorder due to mutations in the ASS1 (type I citrullinemia) gene which cause deficiency of arginosuccinate synthetase enzyme, necessary for catalyzing the formation of arginosuccinic acid from citrulline and aspartic acid. A typical presentation is a neonate with toxic hyperammonemia and progressive encephalopathy. Mild late-onset childhood or adult-onset forms with intermittent symptoms (ataxia, headache, stroke, intellectual disability, or encephalopathy) are reported. A case of citrullinemia presented in late childhood with brief EA attacks with fever, a normal interictal neurological exam, cerebellar atrophy, and elevated citrulline and ammonia blood levels. Autoimmune ataxias are usually chronic, but three types to date may manifest with EA. CASPR2 (VGKC complex) can present with episodic ataxia and dysarthria, seizures and cognitive dysfunction. MRI brain may be normal or show medial temporal hyperintensity, with elevated CSF protein and positive CASPR2-IgG in serum and CSF. It responds to immunotherapy. Anti-NMDA receptor autoimmunity can present with paroxysmal dysarthria-ataxia syndrome. Anti-Hu (ANNA-1)-associated paraneoplastic limbic encephalitis presented in a child as episodic ataxia and progressive behavioral changes evolving to intractable epilepsy. Iatrogenic intermittent ataxia may be provoked during deep brain stimulation programming. Finally, functional ataxia may be suggested by incongruent examination findings, distractibility, and the presence of other functional signs. EA can be mimicked by other paroxysmal disorders with stereotyped attacks of central or peripheral origin (e.g. vestibular migraine, migraine with brainstem aura, seizures, paroxysmal dyskinesias or benign paroxysmal positional vertigo). Patients with EA have been misdiagnosed with migraine, seizures, functional or anxiety disorders, resulting in premature diagnostic closure. A personal or family history of epilepsy or migraine may have suggested these alternative more common diagnoses, rather than EA. It may also be difficult to distinguish chronic ataxia with stepwise exacerbations or stepwise decline (e.g. SCA 6), from EA with persistent cerebellar dysfunction. Suspicion for EA should be heightened with acetazolamide-responsive attacks. EA can be readily misdiagnosed or overlooked. In order to recognize, it is important to routinely include it in the differential diagnosis of spells, whether these are movement or non-movement based. A detailed history should include: onset age, triggers, duration, frequency, aura, baseline between spells, and response to treatment trials. Patient descriptors may pose challenges (e.g. episodic stiffening due to EA1 versus PKD attack, or EA with episodic cognitive impairment due to EA2 versus seizure). Events during early childhood development (e.g. infantile paroxysmal torticollis, episodic oculomotor dysfunction, BFNIS) may provide diagnostic clues for EA2. The interictal examination can offer clues to primary EAs when findings are present (e.g. nystagmus EA2, myokymia EA1). Ictal examination or a video of the attack can help reconstruct the phenomenology. A 3-generation family history is important to look for other paroxysmal neurologic disorders because of considerable phenotypic variability in families. Family history may appear negative with de novo mutations, false paternity, early death, or estrangement from biological family, deceptively pointing away from a genetic cause. Secondary EAs or mimicking conditions can be suggested by history, examination, and imaging findings. While functional features may suggest a non-genetic EA, functional embellishment of primary EA may lead to diagnostic uncertainty regarding the predominant etiology. Diagnostic delay or misdiagnosis include patient factors (young children cannot give a history, atypical features) or clinician factors (bias towards alternative diagnosis, atypical or evolving phenotype). Diagnostic challenges may also arise where attack duration or triggers overlap between categories. For example, EA1 and EA2 attacks may both last hours and have permanent cerebellar signs, so one needs to look for interictal myokymia or nystagmus or ancillary tests to distinguish them. Brain imaging looking carefully for cerebellar atrophy or other structural brain lesions can provide diagnostic clues for primary or secondary EA. Electroencephalography during a triggered attack can help differentiate EA from an epileptic event. However, baseline EEG abnormalities may be encountered in both EA2 and genetic epilepsies with EA. Laboratory testing (e.g. serum and CSF lactate or glucose can assist diagnosis of mitochondrial disorders or GLUT-1 syndromes respectively). For secondary cases, blood tests for metabolic disorders and toxins may be necessary. If one suspects a primary EA that is fairly classical for either EA1 or EA2, proceeding to single gene testing for KCNA1 or CACANA1A may be an appropriate choice. In uncertain cases, a multigene EA panel could be used. For atypical or complex cases, where other investigations have failed, next generation sequencing or whole exome sequencing has diagnostic utility to detect a causal gene mutation. Reaching a specific genetic diagnosis can provide clinical value: guide treatment, reduce unnecessary investigative tests, aid genetic counselling, and further refine phenotype-genotype profiles. For cases that resemble EA1 or EA2, one may proceed directly to first-line treatment (antiseizure medication or acetazolamide, respectively), without requiring genetic confirmation. If unsuccessful, consider second-line treatment trials. Ultimately, genetic testing is gold-standard for the diagnosis to guide appropriate treatment and long-term management. Many of the primary EAs, other genetic causes of EA, and secondary forms of EA are treatable. (See Table 4).

ataxia, cerebellum, episodic, genetic, paroxysmal, primary, secondary, treatment

PMC4690819_01

Female

Here was a 55-year-old female patient with episodic stabbing pain on the right superior eyelid for 2 years. The VAS score was eight. The onset time was about 1 minute and the remission period was completely pain free. The pain could be triggered by daily activities like smiling, washing face, speaking and eating. Any contact with the upper eyelid could lead to pain outbreak. Apart from the allodynia on the skin of upper eyelid, no abnormality was found in neurological examinations. Also, the ophthalmologic exams including funduscopy, intraocular pressure, visual field testing was normal. The head CT and MRI scan were also normal. The patient had no history of surgical operation and trauma, no history of diabetes mellitus, high blood pressure, chronic heart diseases, hepatitis, and some other relevant chronic diseases. The patient was diagnosed as primary TN. The treatment was initiated by oral carbamazepine. The pain could be relieved by carbamazepine 200 mg daily at first. Gradually increasing dose of carbamazepine was reported during the medication period. About 2 weeks prior to the treatment, the pain could not be controlled by carbamazepine 800 mg daily, and dizziness and vertigo developed simultaneously. Peripheral branch neurolysis was planned. Firstly, right supraorbital nerve block was implemented as a diagnostic test. After identifying the supraorbital notch through palpation, a 25-gauge needle was inserted at the level of supraorbital notch. 0.5 ml 1 % lidocaine was injected slowly. Ten minutes later, hypoaesthesia in the skin of the forehead instead of the upper eyelid was observed, and the pain continues. This result indicated that supraorbital nerve was not involved. Then, diagnostic blocks to lacrimal, infratrochlear and supratrochlear nerves were successively performed. The puncture point slightly above the lateral canthus along outer border of the orbit was selected for the lacrimal nerve block. As infratrochlear and supratrochlear exiting points were located closely together, we chose the point where the bridge of the nose abuts the supraorbital ridge as the single puncture point (Fig. 1). The patient was put in supine position while eyes firmly closed. After disinfection, a 25-gauge needle was punctured at the lacrimal nerve point described above. The needle was slid over the edge of the orbit, and advanced about 4 mm along the lateral wall of the orbit. With no aspiration of blood, 0.3 ml 1 % lidocaine was injected slowly. Five minutes later, hypoesthesia was found on the lateral part of the upper eyelid, while the medial part remained allodynic. Then the infratrochlear and supratrochlear nerve blocks were performed. The needle was inserted in the previously mentioned point, just slid over the edge, with the same depth along the medial wall. The same amount of lidocaine was injected slowly. The whole upper eyelid and adjacent areas were found hypoesthetic. The patient was completely pain free for the whole day. Then lacrimal, infratrochlear and supratrochlear nerves radiofrequency thermocoagulation (RT) was planned the next day. With supine position, the skin of upper eyelid and adjacent areas was disinfected. From the two puncture points above-mentioned, a 22 G radiofrequency needle with a working tip of 4 mm was slowly inserted successively. Slide over the edge of the orbit and advance about 4 mm. Repositioning the needle slightly to the point where sensory test stimulation at 0.3 mA and 50 Hz could evoke obvious paresthesia in the periocular region. As for infratrochlear and supratrochlear nerves RT, with the aim to ablate both the two nerves, redirect the needle tip superiorly and inferiorly along the medial wall of the orbit to make additional ablation. After local anaesthesia, RT with tip temperature of 80 C and duration of 80 s was performed. The patient was discharged after 2 h observation. There were no complications, except for hypoesthesia in the upper eyelid and eyelid swelling for 2 days. The pain was completely relieved within the follow-up period of 6 months without any medication.

ophthalmic branch, radiofrequency thermocoagulation, trigeminal neuralgia, upper eyelid

PMC3530757_01

Male

The patient was a 30-year-old, 60 kg male who presented several days after sustaining blunt trauma to the left side of his jaw. The patient was playing football and was elbowed in this area. He immediately had swelling and pain in the left mandibular area adjacent to his ear. He had limited jaw mobility, which greatly exacerbated his pain and was only able to tolerate eating soft foods. On admission, the patient had obvious facial swelling to the left side of his face and dental misalignment was noted. A maxillofacial CT scan was obtained which showed an acute left mandibular fracture just inferior to the condyles. The remaining facial bones were intact without acute fracture. Also observed on the CT scan were narrow nasal passages and a leftward deviated nasal septum. Otolaryngology scheduled surgical intervention for fracture reduction and maxillomandibular fixation. Evaluation preoperatively showed poor mouth opening secondary to pain. He was appointed a Mallampati score of II and was estimated to have a thyromental distance greater than 6 cm. Nasotracheal intubation was the proposed means of airway control due to the necessity of maxillomandibular fixation thus precluding orotracheal intubation. The patient demonstrated patency of both nares and provided no history of nasal trauma or knowledge of any nasal septal deviation. The patient was premedicated with midazolam 2 mg intravenously and fentanyl 100 mcg intravenously. All standard monitors were applied. The patient received 3 sprays of oxymetazoline to each naris. Anesthesia was induced with propofol 200 mg intravenously and fentanyl 150 mcg intravenously. After successful mask ventilation, succinylcholine 100 mg was administered intravenously. Easy mask ventilation was achieved with confirmation of end-tidal CO2 and adequate oxygenation. A nasal RAE endotracheal tube was then introduced into the right naris with immediate resistance. Repositioning of the angle of entry did not overcome the difficult passage, nor did downsizing to a smaller nasal RAE endotracheal tube. Intubation via the right naris was aborted and intubation through the left naris was attempted. However, immediate resistance was again experienced and it was felt at this time that nasotracheal intubation was not going to be possible. The patient was mask ventilated again and was then intubated orally with an 8.0 endotracheal tube. On direct laryngoscopy, miniscule amounts of blood were noted in the patient's pharynx from the nasal trauma sustained during the initial intubation attempts. Bilateral breath sounds and end-tidal CO2 were confirmed. The surgeon then made a small, approximately 2 cm incision in the right submental region and bluntly dissected through the floor of the mouth with Kelly forceps. The ventilator was then briefly disconnected and the endotracheal tube and pilot balloon were pulled through the submental tunnel via the Kelly forceps. The circuit was reconnected, end-tidal CO2 and bilateral breath sounds were confirmed, and direct laryngoscopy was repeated to confirm tube placement. The supraglottic and oropharyngeal areas were adequately suctioned and the surgeons proceeded with the case. Anesthesia was successfully maintained with inhaled isoflurane. The patient's initial airway pressures while orotracheally intubated were consistently 15-16 cm H2O. However, after tunneling the endotracheal tube through the floor of the mouth, peak pressures increased to 25-30 cm H2O. These increased pressures were felt to be secondary to the acute bend that the tube was required to make in the oropharynx. No other issues with ventilation or oxygenation were encountered throughout the case. The surgical team inserted four, 8 mm self-drilling screws into the patient's maxilla and mandible and used 26-gauge wire to achieve properly aligned dental occlusion. The submental incision was then infiltrated with lidocaine and epinephrine. A soft suction catheter was used to attempt to remove as much secretions as possible from the patient's pharynx. The inhalational agent was turned off and the patient awakened. The surgical team was standing by with wire cutters in hand should airway compromise had been encountered. It was felt that the patient was adequately awake when he was able to generate sufficient and consistent tidal volumes, follow commands to squeeze fingers and maintain a head lift when asked. At this time the cuff was deflated and the endotracheal tube was slowly removed through the submental tunnel. The surgical team closed the submental incision, first with 4-0 Vicryl for the subcutaneous plane and a 5-0 fast absorbable suture for the skin. The patient maintained excellent ventilation and oxygenation and at no time experienced any airway compromise or oxygen desaturation. He was taken to the postanesthesia care unit in excellent condition.

PMC9157441_01

Female

A 7-year-old child patient, from the central Andes of Peru, with a history of multiple trips to the tropical region in the last 4 years, without other significant medical history presented to the emergency department with 3-month illness characterized by general malaise, weight loss, and in the last month, respiratory distress was added to physical effort, difficulty walking, sensation of unquantified thermal rise and presence of diffuse adenopathy throughout the lymphatic tract. His physical examination was remarkable decrease in subcutaneous cellular tissue, generalized joint pain that intensifies on movement, the presence of multiple lymphadenopathy in the cervical, axillary, thoracic, and inguinal region of different diameters of indurated consistency and painful on mobilization, presence of crackless in the base of both lungs and respiratory distress, distended abdomen painful on deep palpation, the patient is in an uncooperative state of alert and responds adequately to questioning. Laboratory tests showed; white blood cell count 8.67 x 103 / uL, eosinophils 1.75 x 103/uL (17.1%), hemoglobin 10.2 g/dL(Table 1). Ultrasound showed markedly enlarged liver and spleen with presence of multiple mesenteric nodes and 180 mL free fluid in the peritoneal cavity; Chest tomography showed lung consolidation at the bases and bilateral pleural effusion of 130 mL. The patient underwent a cervical lymphadenopathy biopsy showing multinucleated giant cells and the presence of positive acid fast bacilli in the Zielh Nielsen stain (Fig. 1), for which he began anti-tuberculosis treatment with rifampicin, isoniazid, ethambutol and pyrazinamide with clinical improvement and a decrease in fever for which he was discharged from the hospital. Three weeks after starting treatment for tuberculosis, the patient returned with generalized lymphadenopathy, fever, abdominal distension, lethargy, poor oral intake, cough with whitish sputum and dyspnea at rest, was noted to be tachycardic (heart rate of 119 beats per minute), tachypnoeic (respiratory rate of 28 breaths per minute) (Fig. 2), and had an oxygen saturation of 88% under room air. Arterial blood gas taken under room air revealed type 1 respiratory failure (pH 7.45, PO2 69 mmHg, PCO2 32 mmHg, HCO3 27 mmol/L). The patient was screened for HIV, HTLV1-2, with results negatives; and serologies were negative for antinuclear antibodies, antidouble-stranded DNA and anticardiolipin antibodies. Outpatient HIV testing was repeated five days later, this time including an HIV RNA, with results negatives. Auscultation of lungs revealed reduced air entry over the lower area on both sides and chest radiograph of patient on admission revealed nodular and air space opacities bilaterally, no cavity, or pleural effusion was seen. Sputum smear examination showed multi-gemant yeasts and was negative for acid fast bacilli. Biopsy of the right cervical lymph node and of the thoracic region was performed, the histological study revealed presence of yeasts with multiple budding in ship's rudder compatible with paracoccidioidomycosis in both lymph node tissues (Fig. 2), therefore, the patient was treated as a case of disseminated CPM with secondary TB. Amphotericin b deoxycholate and hydrocortisone were administered as per local Disseminated paracoccidioidomycosis treatment guidelines. He received amphotericin b deoxycholate 1 mg per kg of weight for 14 days through a central vein, with daily corrections of serum potassium for hypokalaemia, the patient presented clinical improvement from day 7 of receiving the medication. The patient stayed in the hospital for almost two months. Upon discharge, her laboratory results are shown in Table 1. He showed significant improvement on the itraconazole regimen 200 mg daily and treatment for tuberculosis without any significant adverse effects. He has not had a recurrence of symptoms since.

acid-alcohol-resistant bacillus, amphotericin b, itraconazole, paracoccidioidomycosis, tuberculosis

PMC10272371_01

Female

A 17-year-old girl with major depression for 3 years was involuntarily admitted for severe depressed mood with suicide attempts (neck cutting; tranquilizer overdose) and paranoid state in the last 2 weeks without any precipitating factors. She experienced depressed and irritable mood in the last 3 years, and her condition had not improved although several adequate trials of antidepressants were used with satisfactory compliance (sertraline 200 mg/d; escitalopram oxalate 20 mg/d). Over the 2 weeks prior to admission, her depression continued to worsen with increasing irritability, she committed several suicide attempts, and once stated that she was unsafe at home. On admission, her heart rate was 116 bpm with blood pressure 139/81 mmHg and normal temperature; physical examination showed a cushingoid and virilising appearance (central obesity, swollen and hirsute face with acne, purple striae on the abdomen and bruises on the arms). No other abnormal signs were noted. She seemed drowsy but arousable, and she walked slowly, with bent shoulders and an inclined head. Mental state examination was hard to continue because she was passive and reluctant to answer our questions. Venlafaxine 150 mg/d has been used for more than 3 months with poor effects at that time. Besides, weight gain (25 kg), irregular menstrual cycles and numbness of the hands and feet in the last half year were reported by her parents. Otherwise, No episodes of elevated mood and hyperactivity were found during the history taking. She does not have remarkable family history of serious physical or psychiatric illness; she was healthy, had an extroverted personality and had never used substances. Her premorbid social function and academic performance were good. Several clinical characteristics found during the following mental state examinations were listed as follows: Prominent cognitive impairment without clouding of consciousness: Forgetfulness was frequently noted; she easily forgot important personal information such as her school and grade; she could not recall the suicide attempt committed recently and perfunctorily ascribed it to a casual event; and it was hard for her to recall her medical history (as it is for other depressive patients). The serial seven subtraction task could not be finished, and the interpretation of the proverb was superficial. Difficulty was found in attention maintenance; an effective conversation was hard to perform because she was mind-wandering (we needed to call her name to get her immediate attention) and often interrupted our conversations by introducing irrelevant topics or leaving without apparent reasons. Decreased language function that did not match her educational background: The patient could not find the proper words to articulate her feelings; instead, many simple, obscure and contradictory words were used, which made her response seem perfunctory. For example, she responded with "I do not know," "I forgot," or kept silent in response to our questions, which made the conversations hard to perform. Psychotic outbursts: Once she left the psychological therapy group, ranted about being persecuted and shook in fearfulness, stated "call the police" repeatedly, negative of explanations and comforts from others, but she cannot give any explanation about her behavior when calmed down. Sometimes she worried about being killed by the doctors but the worries were transient and fleeting. Depressed mood and negative thoughts (self-blame, worthlessness, and hopelessness) that were not persistent and profound: During most of her hospitalization, the patient seemed confused and apathetic, with intermittent anxiety, but she could not clearly express what made her anxious. Her crying and sadness happened suddenly, without obvious reasons, and she even denied low mood sometimes and said she had come to the hospital for cardiac disease treatment (she did not have any cardiac disease). Her description of her depressed mood was uncertain when specifically questioned, and she rarely reported her depressed feeling spontaneously as other depressed patients would. She did not even have the desire to get rid of her "depression". Her suicidal ideation was transient and impulsive, and she could not provide a comprehensive explanation for her suicide attempts, such as emptiness, worthlessness or guilt. She was impatient and restless when interacting with others or when a more in-depth conversation was performed. She seemed apathetic, gave little response to emotional support from others and did not care about relevant important issues, such as hospital discharge or future plans. Elevated mood and motor activity were not found during the admission period. Social withdrawal and inappropriate behaviors: The patient often walked or stayed alone for long periods of time before speaking to other patients suddenly, which seemed improper or even odd in normal social interactions. During most hospitalization periods, lethargy and withdrawal were obvious. Basic laboratory tests reported abnormal results (Table 1), and the circulating cortisol level was far beyond the upper limit of normal, with a loss of circadian rhythm (Table 2); 24-h urinary free cortisol : >2897 nmol/24 h (69-345 nmol/24 h); serum ACTH (8 AM, 4 PM, 12 PM): 1.2 pg/ml, 1.3 pg/ml, < 1 pg/ml (normal range: 1-46 pg/ml); low-dose dexamethasone suppression test (1 mg) (cortisol value): 1010.1 nmol/l (not suppressed; normal range: <50 nmol/L); high dose dexamethasone inhibition test (cortisol value): 879.0 nmol/l (not suppressed); OGTT and glycosylated hemoglobin; both normal. Other results used to rule out hyperaldosteronism and pheochromocytoma, such as the aldosterone/renin rate (ARR) and the vanillylmandelic acid, dopamine, norepinephrine and epinephrine levels, were reported to be within normal limits; ECG suggested sinus tachycardia; dual-energy X-ray bone density screening values were lower than the normal range; B-mode ultrasound showed a right adrenal tumor and fatty liver. The abdominal CT scan showed a tumor in her right adrenal gland. Brain MRI showed no abnormalities. Psychometric tests including HAMD (Hamilton depression scale), MADRS (Montgomery-Asberg Depression Rating Scale), WAIS (Wechsler Intelligence Scale) and MMSE (Mini-mental State Examination) were hard to perform due to her poor attention and non-cooperation presentation. The patient had little response to adequate antidepressants in our hospital, including fluoxetine 20-60 mg/d and aripiprazole 5-30 mg/d combined with 3 sessions of MECT (modified electroconvulsive therapy), which was stopped because of her poor cognitive function and poor response. Her last diagnosis was right adrenal adenoma and non-ACTH-dependent Cushing's syndrome. The adrenal adenoma was excised through laparoscopic resection in a general hospital. Hydrocortisone, amlodipine besylate, potassium chloride, metoprolol and escitalopram were used for treatment. Escitalopram 10 mg/d has been used until 2 weeks after her discharge. At the follow-up visit about 1 month after the surgery, her depressive mood had significantly improved, with no self-injury behaviors or psychiatric symptoms found. The patient was calm but still reacted slowly, and cognitive impairment was still found at the last visit.

cushing's syndrome (cs), acute psychosis, adolescent girl, adrenal adenoma (aa), treatment-resistant depression

PMC8885599_01

Male

A 30-year-old male suffered an intermittent fever with a maximum temperature of 39 C since July 2017. He had a history of type 1 diabetes mellitus for 8 years. He was admitted to a local hospital and received cephalosporin therapy for a week, and then his temperature returned to normal. A CT scan of the chest showed lymphadenopathy in the mediastinum and hilar regions and multiple small nodules in both lungs. His white blood cell count was 2.9 x 109/L with severe lymphopenia of 0.5 x 109/L, and hemoglobin was 107 g/L, while the platelet count was average at 331 x 109/L. He received a positron emission tomography-CT scan to identify whether it was benign or malignant, which revealed multiple enlarged lymph nodes with hypermetabolism in the bilateral hilum, mediastinum, axilla, and clavicle, and lymphoma could not be excluded (Figure 1). Subsequently, the patient underwent a biopsy of mediastinal lymph nodes performed by thoracoscopy, and the pathologic result was granulomatous lesions; thus, type II sarcoidosis was diagnosed. However, he did not receive glucocorticoid therapy with the consideration of his diabetes history and the early stage of sarcoidosis, and then he was told to recheck every 6 months. In the following 2 years, the patient suffered from intermittent fever (T max 37.7 C), which could be alleviated by oral antibiotics, accompanied by dyspnoea, fatigue, occasional cough, less sputum, and significant weight loss (lost 50 pounds). It is unfortunate that the patient was not regularly rechecked as prescribed. Last month, he complained that he had experienced progressive abdominal distention and dyspnoea, so he came to our hospital. The patient was sane without nausea and vomiting, and no positive signs were found on neurological examination. Abnormal physical findings consisted of a few scattered skin ulcers on the legs and splenomegaly extending 5 cm below the left costal margin. Abdominal ultrasonography revealed enhanced hepatic parenchyma echo, gallbladder (8.13 x 3.29 cm) and spleen enlargement (17.29 x 5.48 cm), and peritoneal effusion (depth of ~7.34 cm). An abdominal contrast-enhanced CT scan also revealed multiple retroperitoneal lymph nodes. A CT scan of the chest showed lymphadenopathy in the mediastinum and hilar regions with multiple nodules, patchy shadows, ground-glass opacities, and emerging bilateral pleural effusion as well as right atelectasis. Cardiac ultrasound reported that there were no abnormalities in cardiac structure, blood flow, or left ventricular systolic function, with an ejection fraction of 69%. No abnormal finding was seen in ECG. Ophthalmic tests including vision and fundus oculi were both normal. Superior lymph node ultrasound revealed enlargement throughout the left supraclavicular lymph nodes, bilateral inguinal nodes, popliteal lymph nodes, left neck lymph nodes, and bilateral axillary lymph nodes (Grade 3). Blood cell count was a remarkable abnormality with marked leucopenia and anemia. The liver function test suggested liver damage and hypoproteinemia. In addition, the patient also had severely impaired immune function. Laboratory test results are shown in Table 1. In summary, the patient had multiple organ involvement, and the disease progressed rapidly during these 2 years. During hospitalization, he took thoracentesis. As shown in Table 2, the pleural effusion was a yellow exudate. Cytopathologic examination of the pleural fluid was negative for malignant cells. In addition, both M. tuberculosis strains (acid-fast) and tuberculosis RT-PCR were negative. Subsequently, a biopsy of the left supraclavicular lymph node revealed the non-caseating granulomas with negative results for acid-fast staining and tuberculosis PCR. This result was in accordance with sarcoidosis (Figure 2). Histological analysis of the pleura obtained by thoracoscopy also revealed granulomas (Figure 3). A bone marrow aspirate and biopsy showed partial hypoplasia and no evidence of a lymphoproliferative disorder was found. In addition, a biopsy was taken from the left leg ulceration also revealed granulomas with a negative mycobacterium genetic test and culture results of fungi and bacteria (Figure 4). Abdominocentesis was not performed due to intestinal bloating and fewer ascites. Based on the above pathological results, the diagnosis of sarcoidosis was strongly suspected. Because of severe conditions and multiorgan involvement, 40 mg methylprednisolone was given intravenously once daily for seven consecutive days, followed by oral methylprednisolone 24 mg once daily. After 1 month of methylprednisolone therapy for 24 mg once daily, there was no reduction in pleural effusion on high-resolution CT (HRCT), and the spleen was larger than before; thus, we continued to maintain the current dosage (24 mg once daily). After another months' treatment, the right pleural effusion was decreased slightly, then the dose of methylprednisolone was reduced to 16 mg once daily. Six months later, a follow-up HRCT showed that the bilateral pleural effusion was significantly less than before (Figure 5). Hepatic function (Figure 6) and superficial lymph nodes and spleen were reduced. After methylprednisolone administration (the dosage was still 16 mg/day) for 9 months, the patient became asymptomatic with a normal blood cell count (Figure 7), and the CD4+ T cell count increased from 82 to 162. Ascites were negative, and the spleen and gallbladder were both reduced. In addition, the leg skin ulcers and scabs completely disappeared (Figure 8). We then focused on the patient's side effects of glucocorticoids. The patient had no psychiatric symptoms or gastrointestinal discomfort. Blood glucose levels were reasonably controlled by subcutaneous injection of insulin (fasting blood glucose and postprandial blood glucose levels were maintained at 6-8 and 8-10 mmol/l, respectively).

case report, glucocorticoid, pancytopenia, sarcoidosis, splenomegaly

(A-C) Partial images of positron emission tomography-CT scan in 2017. (B) Hilar lymph nodes enlargement.

PMC4501506_01

Male

A 63 year old farmer, a known smoker and beetle nut chewer for over thirty five years, presented to our hospital with three month old complaints: (i) pain in the left side of the mouth, which was aggravated whenever he opened his mouth to talk and chew food. Pain was secondary to an ulcerative lesion present in the left buccal mucosa, which gradually increased in size to involve the left angle of the mouth; (ii) progressive trismus for over a month; (iii) productive cough with scanty, white, mucoid, non-foul smelling, non-blood stained sputum; (iv) fever was intermittent, low-grade not associated with chills, rigors, or night sweats. He had no significant past, family or allergy history. He denied losing weight and having reduced appetite. The differentials considered were: (I) malignancy (II) infection. On examination, he was found to be moderately built, poorly nourished, pale, with digital clubbing, and a fever of 101 F associated with night sweats. His respiratory system examination revealed bilateral scattered crepitations on auscultation. He was immunocompetent. Local examination revealed: a solitary, non-healing ulcer in the left oral cavity, irregularly shaped, measuring 2 5 cm x 3 cm. From its location in the left buccal mucosa, it extended anteriorly to involve the left commissure, left mucocutaneous junction of both lower and upper lip. Its posterior extent was 3 cm from the commissure. Medially extending to the left labial mucosa and laterally extending to the left commissure. Yellowish slough was present over the ulcer's floor. Palpation elicited firmness in the middle, due to fibrosis, with tenderness and bleeding spots in the left commissure and left lower lip region. Oral examination revealed: teeth numbers 14, 16, 23, 24, 28; 34 to 38; 43 to 46, 48 were periodontally involved with local factors like calculus, stains, gingival recession, furcation involvement, mobility, with dental attrition. He was partially edentulous in relation to the other teeth. Physiological melanin pigmentation was observed in the residual alveolar ridges, buccal and labial mucosa. The tongue was coated and fissured. The remaining quadrants too showed poor dental hygiene as described above. No other ulceration, fissure, growth or swelling was seen in oral cavity. Routine investigations were normal except for his chest x-ray, which showed bilateral patchy opacities with scarring. (a) Punch biopsy of the buccal ulcer showed caseating granuloma surrounded by epitheloid cells, giant cells with acid-fast bacilli. (b) Wedge biopsy of the ulcer involving the left angle of the mouth showed chronic inflammation. His (c) sputum was positive for acid-fast bacilli. He was immunocompetent. Diagnosis made was intraoral tuberculosis involving the left buccal mucosa, commissure, lower and upper lips secondary to pulmonary tuberculosis. He was treated with antitubercular therapy under RNTCP DOTS Category-I intermittent regimen [2H3R3Z3E3 & 4H3R3] (see Figs. 1 and 2). Follow-up examination of his oral cavity, after three months of treatment, revealed a completely healed ulcer with profound fibrosis of the left buccal mucosa with persistence of trismus, while his chest x-ray and labs were within normal limits. His findings remained unchanged when he followed up after completing the entire six month course. This cancerous looking lesion was neither malignant nor benign. Instead, it proved to be an atypical presentation of a common infectious process of Mycobacterium tuberculosis. Intraoral tuberculosis is rare, accounting for 0 05-5 0% of all tuberculosis cases with the tongue most commonly affected. Primary oral tuberculous lesions are extremely rare, usually observed in young adults with cervical lymphadenopathy. Secondary oral tuberculosis, cited here, comprises 0.05-1.5% of all tuberculosis cases and affects older patients. With the rising frequency of co-morbidities and immunocompromised states globally, this case highlights the benefits that accrue from a multidisciplinary approach to patient evaluation and management.

invasive oral ulcer, non-traumatic aggressive solitary oral ulcer, tuberculosis of buccal mucosa, tuberculous ulcer

PMC3124992_01

Male

An 84-year-old gentleman was admitted with complaints of swelling over the right side of scrotum for the past 2 months. The swelling was progressive in nature and was also associated with pain. It was not reducing on lying down. No history of fever or trauma. Patient gave a history of hemorrhoids and angioplasty done 8 years ago. Patient gives no other history of comorbid illness such as tuberculosis, diabetes mellitus, or hypertension. On examination, performance status according to Eastern Cooperative Oncological Group , Scoring was 2; all the vital parameters were normal. Local examination revealed a 10x15 cm tense, firm, and tender swelling involving the right scrotum. On palpation, the swelling was not reducible. One could get above the swelling. Testicular sensation was lost on the left side. The opposite side testis was normal. A computed tomography scan of the abdomen and pelvis showed heterogeneous soft tissue right testicular mass, which was measuring 10x6x5 cm in size with some evidence of necrosis within the right testicles and there were right inguinal lymph nodes [Figure 1]. At this time, the differential diagnosis was infected hydrocele/pyocele or organized hematoma was entertained. Preoperatively complete blood count, serum biochemistry, and thyroid function tests were normal; viral serology (retroviral and Epstein bar virus) was negative. Beta human chorionic gonadotropin and alpha-fetoprotein values were normal. Hence, he was taken up for surgery. Per-operatively, he seemed to have tumor testes infiltrating the scrotal wall. Therefore, high orchidectomy with excision of hemiscrotum was done. The opinions from four different pathologists were sought. The histopathology gave a differential diagnosis of testicular tumor with scrotal sac wall infiltration/diffuse large cell non-Hodgkins immunoblastic/anaplastic lymphoma; poorly differentiated carcinoma in favor of embryonal carcinoma; poorly differentiated malignant tumor most consistent with plasmacytoma. Immunohistochemistry showed Vimentin, CD30, CD 138 Lambda chains positive, increased Ki 67, EMA, CD79a, S100P positive, in favor of anaplastic plasmacytoma [Figures 2 (a-k) and 3 (a-i)]. EBER, cyclin D1, MiB1, and CD 56 were not done due to logistic reasons. In the meanwhile, workup for MM was done, which showed normal serum electrophoresis and beta2 microglobulin level. Urine was negative for Bence Jones protein. Tc99m Bone scan and bone marrow reports were normal. After a lapse of 2 months due to the diagnostic dilemma, treatment was started for plasmacytoma with daily tab - thalidomide 100 mg weekly tab, dexamethasone 40 mg daily tab, melphalan 5 mg twice daily for 5 days. The patient has completed six cycles of chemotherapy and is in remission.

primary testicular plasmacytoma, anaplastic plasmacytoma, extramedullary plasmacytoma

PMC2873635_01

Male

KG, a 42-year-old Indian male, presented in 1995 with abdominal pain exacerbated by eating, anorexia, and weight loss. He had travelled to India 5 years previously, and he was known to have beta thalassaemia trait. There was no history of fevers or diarrhoea. He remained afebrile during his inpatient stay. Gastroscopy, colonoscopy, small bowel meal, and barium enema were normal. Early morning urine samples, and Mantoux test, did not demonstrate evidence of tuberculosis. Furthermore, bone marrow biopsy showed leukopenia and thrombocytosis, with no organisms present on culture. His initial blood tests confirmed a thrombocytosis with a platelet count of 645 x 109/L. His haemoglobin was 12.0 g/dL, and his ESR was elevated at 64 mm/hr. In our experience, the diagnosis of tuberculous enteritis frequently remains challenging despite the investigations described above. Several authorities recommend initiating antituberculous therapy if there is a strong clinical suspicion of tuberculosis despite nondiagnostic histological or bacteriological studies. Whilst laparoscopy and mesenteric sampling have a higher sensitivity, these patients frequently respond rapidly to medical therapy and, thus, laparoscopy is usually considered if improvement is not seen after two weeks. In this case, due to the patient's marked systemic inflammation, Indian origin, and lack of evidence for alternative diagnoses such as lymphoma or inflammatory bowel disease, he was commenced on empirical antituberculous treatment with rifampicin, isoniazid, ethambutol, and pyrazinamide. He gained weight rapidly, and his blood tests returned to normal. He received eight and a half months of treatment. He relapsed the following year with abdominal pain, vomiting, and fever. CT of the abdomen demonstrated an abnormal terminal ileum and caecum, suggestive of tuberculosis, inflammatory bowel disease, or lymphoma. A small bowel meal confirmed an irregular thickening in the terminal ileum. However bone marrow aspirate and peripheral cultures proved unremarkable, with no evidence of mycobacteria. A diagnostic laparoscopy was recommended, but the patient declined this procedure. A further course of antituberculous therapy with the same regimen again provided a dramatic therapeutic response. He received a year of treatment. Five years later, a further recurrence of symptoms occurred. He was worked up in an identical fashion with colonoscopy, abdominal CT, and barium meal and follow-through. The only positive finding was on CT, which demonstrated a featureless terminal ileum, despite the wall being of normal thickness with no fat stranding. On this occasion the patient again declined diagnostic laparoscopy. Again, he responded to empirical antituberculous therapy, although a laparoscopy was not performed. A further three years later, he again presented with a recurrence of his symptoms, CT showed thickening of the terminal ileum (Figure 1), and colonoscopy demonstrated multiple erosions in the terminal ileum (Figure 2). Biopsies did not demonstrate granulomata but highlighted patchy acute and chronic inflammation with inflammatory cell infiltrate consistent with Crohn's disease. Prolonged microbiological culture of ileal specimens was also negative. On this occasion, a course of steroids for Crohn's disease was prescribed and, again, he made a dramatic recovery.

PMC9829975_03

Male

A 35 years old male patient presented with a one-month history of abdominal discomfort. Upon evaluation, he has a mildly pale conjunctiva. Abdominal examination revealed an enlarged spleen measuring 6 cm from the left lower costal margin along the line of growth. Serological and hematological investigations were all in the normal range except for raised bilirubin (TB -1.9 mg/dl, DB-0.4 mg/dl). On ultrasound examination, the liver was normal-sized with normal homogenous echotexture. Spleen was enlarged (20.3cm) with periportal collaterals. The endoscopic evaluation revealed grade III EV with a red color sign and white nipple sign. Prophylactic Esophageal Variceal Ligation (EVL) was done; the patient was admitted for close follow-up. Upon discharge, he was started on propranolol and linked to a hematology clinic. He was found to have JAK 2 mutation and was started on anticoagulation (warfarin). He was admitted once for upper gastrointestinal bleeding (UGIB) 5 months after the commencement of warfarin, for which emergency EVL was done. The patient was discharged upon improvement. On his last follow-up, the patient was relatively well and his vitals are all in the normal range.

ethiopia, jak 2 mutation, mpn, cholangiopathy, portal cavernoma, sub-sahara

PMC9829975_05

Female

A 53-year-old female patient presented to the emergency department with a history of vomiting of ingested matter and passage of dark tarry stool of one-day duration with associated abdominal pain. At presentation, her vital signs were stable. Physical examination revealed mild pallor and an enlarged spleen (5cm below the left costal margin). Her investigations revealed a leukocytosis of 17, 500/l (neutrophil - 85.5%), moderate anemia (10.5 gm/dl) with a platelet count of 325,000/l and raised bilirubin (TB-2.9mg/dL DB-0.98mg/dL). Otherwise, laboratory studies were all in the normal range. Abdominal ultrasound identified normal-sized liver and normal liver echo pattern with splenomegaly (23.4cm) secondary to portal hypertension secondary to chronic portal vein thrombosis. The endoscopic evaluation revealed grade three esophageal varices without red spots and PHG. EVL was done and the patient was started on propranolol. On follow-up visits, the patient had consistent leukocytosis ranging from 16,300/l-26,200/l without any sign of infection. Her hemoglobin ranged from 11.8 gm/dl - 13.8 gm/dl, while her platelet count ranged 183,000/l-243,000/l. Thus, the patient was linked to a hematologist for further workup and management. Peripheral morphology revealed leukocytosis mainly of band cells and neutrophils and a few basophils. The patient refused BM examination. Jak 2 mutation screening turned out to be positive, BCR-ABL was not done for financial reasons. Hence, with diagnosis of JAK2-positive MPN, the patient was started on Hydroxyurea and warfarin. She, later on, had a smooth course except that she discontinued medications for social reasons two times and experienced episodes of UGIB which required EVL. She currently is adherent to her medications and her symptoms are well controlled.

ethiopia, jak 2 mutation, mpn, cholangiopathy, portal cavernoma, sub-sahara

PMC9829975_07

Female

A 32-year-old female patient presented to our OPD with a history of left-side abdominal discomfort and bloating sensation of 3 months duration. Physical examination was unremarkable. On further history, she claimed that she was told to have an intraabdominal blood clot elsewhere around 2 years back after presenting with a similar complaint. She was by then started on anticoagulation with warfarin, discontinued it after 6 months (physicians' decision), and was off anticoagulation for the last 1 year. Laboratory investigation revealed raised Bilirubin (TB-1.6 mg/dl and DB-0.9 mg/dl). Other investigations were in the normal range. Ultrasound evaluation revealed liver has a normal echo pattern, while the Portal vein cavernous transformation with splenomegaly (16.5cm). Abdominal CT revealed chronic portal and spleno-mesenteric vein thrombosis with a cavernous transformation of PV and portal biliopathy. Three columns of distended tortuous esophageal varices (Grade III) with PHG were seen upon endoscopy. On our evaluation for the underlying cause, JAK 2 mutation turned positive. Prophylactic EVL was done. Propranolol and warfarin were resumed. She currently is stable with INR in the target.

ethiopia, jak 2 mutation, mpn, cholangiopathy, portal cavernoma, sub-sahara

PMC9829975_08

Male

A 46 years old male patient, who is a known T2 diabetes mellitus (DM) (poorly controlled) patient over the last 5 years on glimepiride and metformin, was referred to our OPD after he presented with abdominal pain of one-week duration. Physical examination was unremarkable. Laboratory studies revealed ALP was four times raised (1143 IU), hypoalbuminemia (3.1 gm), and thrombocytosis (548, 000/l-684,000/l). His fasting blood level was in the range of 199-234 gm/dl. Otherwise, laboratory studies were in the normal range. On abdominal ultrasound, the liver has a homogenous echo pattern with smooth contours, the portal vein is obliterated with periportal collaterals, and the spleen is enlarged (15.8 cm). The endoscopic evaluation revealed multiple tense tortuous lower third varices with diffuse gastric mucosal congestion, for which EVL was done. The patient was admitted and glycemic control was optimized. Warfarin, propranolol, and diuretics were commenced upon discharge. Seven months after initiation of anticoagulation the patient presented with hematemesis and melena (last INR- not known then). At presentation, his vitals were stable. Physical examination was unremarkable. CBC was normal (WBC -9200/l (74.4%) Hgb -15.7gm/dl, PLT - 578,000/l). ALP was two times raised (84 IU). Warfarin was discontinued. Therapeutic EVL was done and the patient was discharged. Upon further evaluation abroad, JAK 2 mutation was identified. However, anticoagulation was not resumed. Updated abdominal ultrasound revealed worsening of splenomegaly (16.7 cm). Abdominal CT identified chronic portal and spleno-mesenteric vein thrombosis (Figure 5) with cavernous transformation and splenomegaly with Portal hypertensive biliopathy (Figure 6). TB was raised (1.5 mg/dl -2.2 mg/dl). PLT was persistently elevated. Peripheral morphology revealed thrombocytosis. He has taken several sessions of prophylactic EVL. With the diagnosis of non-cirrhotic portal hypertension secondary to portal vein thrombosis secondary to high-risk PV, he was put on propranolol, hydroxyurea, and aspirin, with intermittent prophylactic sessions of EVL. During the course of his treatment, he had several admissions for prophylactic and therapeutic EVL. Upon follow up his hematocrit level was significantly raised (52.9%) which necessitated two sessions of 1-unit phlebotomy, one month apart. His post-phlebotomy hematocrit level dropped to 48.1%. Currently, his symptoms are well controlled.

ethiopia, jak 2 mutation, mpn, cholangiopathy, portal cavernoma, sub-sahara

PMC2276602_01

Female

A 21-year-old Hispanic female with a 32-week twin pregnancy presented in preterm labor. She had immigrated to the United States two years prior, and her pregnancy course was uncomplicated except for complaints of an occasional nonproductive cough. She was a nonsmoker, denied any history of TB exposure, and was HBsAg and HIV negative. On general exam, she was tachypneic and anxious but in no apparent respiratory distress. She was found to have a low oxygen saturation of 89% on room air with a respiratory rate of 30/min and her blood pressure was 127/76 mmHg. Lung exam was clear to auscultation. Her uterine fundal height corresponded to 32-week twin pregnancy and she had bilateral pedal edema. She was also noted to have uterine contractions every 1-3 minutes. She was initially admitted to the labor and delivery unit in our hospital and subsequently transferred to the medical ICU. ABG showed pH of 7.41, PaCO2 of 29, PaO2 of 64, bicarbonate of 18, and the base excess of -6, saturating at 93% on 21% FiO2. CBC showed WBC 9.9 th/mm3, Hb, and Hct 10.8 g/dl and 32.8%, respectively, Platelets 432 th/mm3. The chest X-ray demonstrated a right paratracheal soft tissue opacity measuring approximately 4 x 4 cm with a slight elevation of the right hemidiaphragm with a linear density in the right lower lung consistent with atelectasis (see Figure 1). No prior X-ray was available for comparison. Patient was put in respiratory isolation early on and the pulmonary team was consulted. CT showed a large extensive mediastinal soft tissue mass in the right paratracheal region extending into the hilar and subcarinal region. An associated atelectasis on the right upper and lower lobe with questionable alveolar infiltrate in the right lower lobe was also found. An abdominal ultrasound showed twin-twin transfusion with reversed end-diastolic flow on umbilical artery doppler in twin B and the patient had an emergent low transverse cesarean section the next day with delivery of two male infants. Infant A had Apgars of 7 and 9, and infant B had Apgars of 0, 4, and 5, respectively. Both infants went to the NICU, and the patient returned to the MICU. A PPD was placed which was positive at 10 mm after 72 hours. Successful samples of sputum could not be obtained but a bronchoscopy with endobronchial biopsy and bronchoalveolar lavage (BAL) was done. Bronchoscopy showed a trachea with diffuse mucosal swelling and the mucosal abnormalities persisted throughout the right bronchial tree. She also had irregular tumor growth from the anterior wall of the proximal bronchus intermedius and the base of the proximal right upper lobe bronchus. These two growths were sampled and the infectious disease team was consulted. There was an abundant growth of Staphylococcus aureus but no acid-fast bacilli (AFB), fungus, or hyphae from the BAL. The patient was started on Vancomycin and Clindamycin to cover Methicillin-resistant Staphylococcus aureus (MRSA) which was later changed to Moxifloxacin based on sensitivities. Transbronchial biopsy of the right bronchus intermedius showed inflammatory and squamous debris with ulceration, reactive squamous epithelium, and colonizing coccal bacteria. Endobronchial biopsy of the proximal bronchus wall showed caseating granulomatous inflammation. The treatment of this young Hispanic immigrant female with an occasional cough, positive PPD, questionable alveolar infiltrate, caseating granulomatous inflammation and no significant evidence of TB infection posed a definite challenge. Given her high risk for TB, she was empirically started on INH, Rifampin, Ethambutol, and Pyrazinamide. It was only on Day 26 that Mycobacterium tuberculosis was isolated by DNA probe from her right lung tissue which was subsequently confirmed on culture. The infants were started on INH prophylaxis after placental pathology did not demonstrate evidence of TB. Patient was discharged to home in a stable condition to be followed up at the local TB center for direct observation therapy.

PMC2910500_01

Male

A 21-year-old male presented with a 2-year history of progressive shortness of breath on exertion and dry cough. At physical examination, auscultation of the lungs has revealed random wheezes and coarse crackles. Cardiac auscultation was normal, and no cyanosis or peripheral edema was observed. There was no history of smoking or previous known pulmonary disease. On routine blood examination, blood counts and serum chemistries were found to be normal. Arterial blood gas analysis and echocardiography showed no important abnormalities. Pulmonary function tests (PFT) showed a mild restrictive ventilatory defect, with a reduced total lung capacity of 79% (5.94 L), forced vital capacity of 80% (4.18 L) and a forced expiratory volume in one second of 83% (3.72 L). The sputum was negative for acid-alcohol resistant bacillus and human immunodeficiency virus testing was negative as well. The chest plain films revealed a diffuse symmetric dense bilateral micronodular pattern (Figure 1). Based on this finding, HRCT scan was obtained, revealing diffuse ground glass attenuation and septal thickening, more pronounced in lower pulmonary regions, with calcifications along the interlobar septa and subpleural regions. Subpleural cysts were also noticed (Figure 2). The patient underwent a fiberoptic bronchoscopy with bronchoalveolar lavage and transbronchial lung biopsy. The lavage fluid was negative for tuberculosis or fungi. Microliths were not found. Histology revealed round, concentrically laminated microliths in the alveoli associated with slightly thickened interstitial septa, consistent with the diagnosis of PAM.

PMC4150118_01

Male

A 59-year-old male patient was admitted to our university hospital (Botucatu, SP, Brazil) complaining of a perianal suppurative ulcer developed two months before the first medical consultation. He was under therapy with prednisone 40 mg/day for six months due to a presumed diagnosis of a drug reaction. On physical examination, a clean 10-cm diameter phagedenic perianal ulcer (Figure 1) and two longitudinal suppurative ulcers on the inguino-crural region were observed. During investigation, and soon after reducing the corticosteroid dose, disseminated erythematous papules and nodules were observed in the upper limbs (Figure 2).Histopathology of the perianal ulcer revealed a dense histiocytic dermal infiltrate and a granulomatous inflammatory response with central caseous necrosis (Figure 3). Fite-Faraco staining showed a few acid-fast bacilli and the hypothesis of cutaneous tuberculosis was raised. The histopathology of upper limbs papular and nodular lesions showed foamy macrophages with globi of bacilli, suggesting lepromatous leprosy (Figure 4). The perianal and inguinal ulcers were considered uncommon manifestations of type 2 leprosy developed when corticosteroid was gradually diminished. The patient was treated as for multibacillary leprosy with multidrug therapy and thalidomide. Four weeks later, the patient had fever, weight loss, asthenia and worsening of the perianal ulcer (Figure 5), but without erythema nodosum leprosum. With this clinical picture, new investigation was developed. The tuberculin skin test was positive (20 x 20 mm) and culture of M. tuberculosis - using a biopsy sample from the perianal ulcer - on Lowenstein-Jensen medium was positive (Figure 6). Polymerase chain reaction (PCR) and DNA analysis from upper limb skin samples were positive for M. leprae (Figure 7). With the new information the patient was finally diagnosed as presenting simultaneously lepromatous leprosy - type 2 reaction - and cutaneous tuberculosis expressed by the perianal ulcer. Screening for HIV, HBV or HCV infection as well as lung, renal or colon compromising were negative. Hence, the patient was treated with isoniazid, ethambutol and rifampin for nine months with complete healing of the perianal and inguinal lesions after two months (Figure 8). After the tuberculosis treatment, the patient was submitted to additional multidrug therapy for 12 months with dapsone, rifampin and clofazimine with complete cure of leprosy.

erythema nodosum leprosum, leprosy, mycobacteria, tuberculosis

PMC9905231_01

Male

A 29-year-old man presented to the hospital with progressively worsening dyspnea and palpitations for 7 years, and intermittent lower extremity edema and abdominal distension for 12 years. He denied chest pain, had no history of hypertension and diabetes, and no family history of heart disease. Personal habits included a small amount of alcohol intake and no smoking. He was diagnosed with bilharziasis, a nephrotic syndrome, approximately 10 years previously, and AF 3 years previously at a local hospital. On admission, he was hypotensive [blood pressure (BP), 95/60 mmHg] and weak. A physical examination revealed distended jugular veins, abdominal distension, pitting edema of both lower extremities (Figure 1A), decreased breath sounds in the right lower lung, and a grade II/VI systolic murmur at the apex of the heart. Routine blood, renal function, plasma electrolyte concentration, troponin, and inflammatory and tumor marker tests were normal. He had mild liver dysfunction and elevated D-dimer (19.20 g/ml) and plasma B-type natriuretic peptide (NT-proBNP, 1,987 pg/ml). Chest radiology revealed a right-sided pleural effusion and cardiac enlargement (Figure 1B). AF [heart rate (HR), 154 bpm] without ST-segment and T-wave changes was confirmed on electrocardiography (ECG) (Figure 1C). Transthoracic echocardiography (TTE) revealed left atrial (LA) and right atrial (RA) enlargement (LA, 51 mm; RA, 53 mm), mild mitral and tricuspid regurgitation, decreased LV systolic function (LVEF, 45%), diastolic dysfunction, and a normal LV size (42 mm) (Figures 1D, E). Abdominal ultrasonography revealed a large amount of abdominal fluid, liver congestion, and inferior vena cava (IVC) distention. Pleural and abdominal effusion analyses indicated transudative fluid. Tuberculosis and rheumatism were excluded based on laboratory test results and effusion fluid analysis. Pulmonary embolism was excluded using computed tomography angiogram (CTA) (Figure 1F). Chemical cardioversion was attempted unsuccessfully using several antiarrhythmic medications (amiodarone and nifekalant). A repeat TTE revealed mitral lateral annulus e' velocity (14.4 cm/s) < mitral medial annulus e' velocity (18.4 cm/s) using tissue Doppler imaging (TDI) (Figures 2A, B). We were unable to determine significant respiratory variation of mitral and tricuspid peak E velocity due to the AF (Figure 2C). Paradoxical septal motion during respiration was not observed (Figure 2D). The IVC was dilated without inspiratory collapse (Figure 2E). The pulmonary artery pressure (~30 mmHg) was elevated according to the velocity of the tricuspid regurgitation (Figure 2F). Careful review of the echocardiographic images showed nodular thickening of the pericardium in the AV groove, without significant thickening of the whole pericardium. We then measured the peripheral venous pressure, which was elevated (43 cm H2O). These findings supported but did not confirm the diagnosis of CP. ACP was diagnosed using further CT scan analysis, which showed a thickened and calcified pericardial ring around each AV groove with minimal pericardial calcification; however, radiological pericardial thickening and calcification were not observed on chest X-ray (CXR) (Figures 3A, B). Intraoperatively, a calcified pericardial ring encircling the RV and LV cavities at the level of the AV groove was revealed. As the calcified pericardial ring was severed, spontaneous conversion to sinus rhythm was observed (Figure 3C). Pathological examination of the pericardial tissue revealed pericardial thickening, fibrous tissue hyperplasia, and hyaline degeneration, in which a large number of capillaries and few inflammatory cells were observed. A large amount of fat was observed on the surface, confirming the diagnosis of ACP (Figures 3D, E). Post-operatively, the patient's symptoms and vital signs improved significantly. The lower extremity edema, pleural effusion, and ascites subsequently subsided, and the pulmonary congestion and cardiac enlargement mitigated, indirectly indicating a reduced constrictive pattern. The patient was followed up on an outpatient basis and remained in good clinical condition. The echocardiographic assessment at the 1-month follow-up showed that the enlarged atria became smaller (LA, 39 mm; RA, 38 mm) and LV ejection fraction (LVEF) significantly improved (from 45% pre-operation to 57%). The patient management timeline during hospitalization is summarized in Table 1. This study was approved by the local Ethics Committee, and written informed consent was obtained from the patient for the publication of any potentially identifiable images or data included in this article.

annular constrictive pericarditis, atrial fibrillation, atrioventricular groove, mechanical-electric feedback, predisposing factors

PMC9530803_01

Male

A 34-year-old otherwise healthy male presented with asymptomatic, greenish discoloration of the nail plate that had set in over a period of 4 weeks. The discoloration began at the distal margin extending to the middle of the nail plate. The patient did not report any history of trauma or onychosis. Before the lesions appeared, he was an epidemic prevention volunteer who wore PPE (Figure 1A) for at least 10 h daily. He washed his feet for an average of two to three times per shift during the outbreak of the Omicron variant of severe acute respiratory syndrome coronavirus (SARS-CoV-2) in Shanghai. Physical examination revealed greenish black discoloration from the middle to distal parts of the first and third toenails of the left foot (Figure 1B). A white scale was observed on the distal part of the big toenail plate on the left foot (Figure 1C). Neither onycholysis nor paronychia was observed around the affected nails. Direct fluorescence microscopy and fungal culture of nail scrapings were negative; however, bacterial culture of the nail scrapings was positive for P. aeruginosa. Subsequently, drug sensitivity tests were performed, which revealed sensitivity to fluoroquinolones including ciprofloxacin and levofloxacin. GNS was diagnosed based on these findings, and the patient was instructed to stop wearing PPE, to wash his feet daily, and to keep his feet dry. Based on previous literature and drug sensitivity tests, he was prescribed treatment that included the application of topical nadifloxacin in combination with acetic acid twice daily. At the 2-month follow-up, discoloration of the nail was significantly reduced (Figures 1D,E).

omicron, pseudomonas aeruginosa, epidemic prevention volunteer, green nail syndrome, protective clothing

PMC9204206_01

Male

A 54-year-old male was diagnosed as having lung cancer. He underwent video-assisted thoracoscopic surgery for left upper lung cancer in the Second Affiliated Hospital of the University of South China, and his postoperative diagnosis was polymorphic adenocarcinoma of the left upper lung (T2aN2M0 stage IIIA). Immunohistochemical staining showed the following: CK (+), CK7 (+), TTF1 (+), Napsin A (part+), Vim (+), Syn (-), CgA (-), CD56 (-), P40 (-), CK5/6 (-), and Ki67 (50%+). After the surgery, he was started on the TP chemotherapy regimen, which included the administration of carboplatin (40 mg, days 1-3) + paclitaxel (400 mg, day 1). Four cycles of this TP chemotherapy regimen were administered, with each cycle lasting about 21 days. However, about 178 days postoperatively, he was diagnosed with brain metastases [pT2N2M1 stage IV, epidermal growth factor receptor/anaplastic large-cell lymphoma kinase/ROS1 negative, Kirsten rat sarcoma virus (KRAS) mutation 71.8%, KRAS amplification 2.4, cyclin D1 gene amplification 2.6, cyclin-dependent kinase inhibitor 2A mutation 9.1%, and PD-L1 tumor proportion score 60%], after which he received eight courses (approximately 21 days per course) of bevacizumab (1,100 mg) + sintilimab (200 mg) from 2020 to 2021. In April 2021, he was started on sintilimab maintenance therapy. Bevacizumab was discontinued. About 10 days later, he soon visited our hospital for epigastric pain. He underwent gastroscopy on day 419, which showed squamocolumnar junction (SCJ) blurred, local mucosal hyperemia edema with erosion and opaque white mucus covering the mucosal surface, and localized hemorrhage. A large amount of opaque white mucus was attached to the mucosal surface of the gastric antrum and body, and the gastric mucosa was diffusely hyperemic with spontaneous hemorrhage ( Supplementary Figure 1). Colonoscopy showed no abnormalities. The patient was treated with oral ilaprazole (5 mg, once daily) and gastric protection with sucralfate oral suspension (1 packet, twice daily). Repeat esophagogastroduodenoscopy (EGD) performed in May showed improvements, and repeat colonoscopy still showed no abnormalities. Then, he stopped the oral drug treatment without permission from the doctors after the symptoms subsided ( Supplementary Figure 2). After treatment with three courses of sintilimab alone, he had recurrent epigastric pain and black tarry stools, which were worse than before. Repeat EGD showed that the entire gastric mucosa was evidently edematous and hyperemic and showed adhesion of opaque mucus, diffuse erosion of the white moss, and active localized hemorrhaging was extensively observed. The gastric antrum was found to have a necrotic mucosa with exfoliation of large flakes ( Figure 1 ). The Carbon 14 breath test was negative, and tests for cytomegalovirus and Epstein-Barr virus revealed a previous infection, but not a current infection. The patient was also negative for tuberculosis immunoglobulin G (IgG) antibodies, HBV, HCV, syphilis antibodies, and HIV ( Supplementary Table 1 ). Initially, he was treated with esomeprazole (40 mg every 6 h via an intravenous pump), oral rebamipide (100 mg, thrice daily), sucralfate oral suspension (10 ml, twice daily), and rehabilitative new liquid (10 ml, thrice daily, taken orally). However, the symptoms of the patient did not subside and were aggravated even with consuming a small amount of water or other fluids. After regular treatment for acute erosive hemorrhagic gastritis, his fecal occult blood test was still positive, indicating that the upper GI lesion still existed. After three days of the abovementioned regular treatment for acute gastritis, his EGD revealed that the whole gastric mucosa was hyperemic and edematous, with erosion of the attached diffuse white moss and active oozing of blood. Small flaps of mucosal necrosis and stripping could be visualized at the posterior wall of the gastric antrum, indicating a relatively healed mucosa compared with previous EGD findings ( Figure 2 ). Pathologic findings of the biopsy specimens from the gastric antrum showed severe atrophic gastritis with erosion, atrophy, and loss of intrinsic glands; focal aggregation of lymphocytes in the lamina propria and mucosal muscular layer; multiple neutrophil infiltration; and the formation of small abscesses ( Figure 3 ). Considering that bevacizumab has already been discontinued for almost 2 months, it can be concluded that the current presentation was not an effect of bevacizumab; we confirmed that his gastritis was associated with the immune checkpoint inhibitor sintilimab. We suspended sintilimab administration and simultaneously changed the regimen to steroid therapy as follows: intravenous methylprednisolone sodium succinate drip (100 mg, once daily for 4 days; 70 mg, once daily for 3 days; and 40 mg, once daily for 3 days), followed by oral methylprednisolone tablets as maintenance therapy (32 mg once daily for a week; Supplementary Figure 3 ). His symptoms gradually subsided after this treatment. Re-examination of EGD on day 526 showed markedly relieved edematous and hyperemic gastric mucosa and no signs of active oozing of blood compared to previous EGD findings ( Figure 4 ). The patient began to resume the next course of sintilimab treatment (200 mg, 42 days per cycle) starting in October (day 598). Approximately half a month later (day 613), his EGD revealed that the entire gastric mucosa was hyperemic and edematous with white opaque mucus attachment; however, no erosion, ulcer, or mass was identified ( Supplementary Figure 5 ).

acute erosive hemorrhagic gastritis, immune checkpoint inhibitor, immune-related adverse event, sintilimab, upper gastrointestinal tract irae

PMC6914985_01

Male

A 41-year-old man presented to the HIV clinic for a follow-up after a recent visit to the Emergency Department at another hospital for dysphagia. His medical history was significant for HIV infection with last known CD4+ count 1,271 cells/muL and undetectable viral load within the previous month. The patient was on HAART with EVG/c/FTC/TAF with adequate adherence for the past two years. He stated that his dysphagia progressed over 2 weeks, and it was initially associated with hiccups and then odynophagia and white pharyngeal plaques. In the Emergency Department, his laboratory exams showed a white blood cell count of 18 x 103/muL with monocyte predominance, and a chest X-ray revealed a new 2 cm right upper lobe infiltrate with nodular characteristics (Figure 1). The patient had normal vital signs and lacked respiratory symptoms. He was diagnosed with esophageal candidiasis, prescribed oral fluconazole, and was discharged home with pending outpatient follow-up of the abovementioned radiological findings. Of note, the patient did not disclose his HIV status during the encounter. The next day, upon evaluation at the clinic, the patient denied cough, night sweats, fever or chills, but reported noticing a 5-pound unintentional weight loss, which he attributed to decreased appetite and swallowing difficulties. In addition, he reported using a self-initiated over-the-counter fluticasone nasal spray 2-3 times per day for at least 2 weeks prior to presentation. Other past medical history included essential hypertension and dyslipidemia. The patient had a documented history of positive tuberculin skin test and had completed 6 months of treatment with isoniazid 21 years prior to this presentation. He had a negative chest X-ray within the past year. He had a family history of type-2 diabetes. Social history was significant for trips to visit his family in Philippines and Mexico during the previous year and daily tobacco smoking for 17 years. On exam, he was not in respiratory distress and had mild posterior pharyngeal and nasal erythema. The rest of the physical examination was noncontributory. Given the abnormal X-ray findings and the suspicion for immunosuppression based on the presence of esophageal candidiasis, the patient was immediately placed on airborne precautions and a chest computed tomography (CT) scan was ordered, which revealed a new thick-walled right upper lobe cavitary nodule measuring 19 x 14 mm (Figure 2). The patient was admitted to the inpatient ward for further evaluation. Bronchoalveolar lavage (BAL), acid-fast bacillary (AFB) smear, and cultures were all negative. Serology for Aspergillus, Blastomyces, Histoplasma, and Cryptococcus were negative. Polymerase chain reaction in serum for cytomegalovirus was negative. A CT-guided lung biopsy of the nodular lesion was performed, and the AFB culture yielded Mycobacterium tuberculosis. Therefore, the decision was made to start antituberculosis therapy with rifabutin, isoniazid, pyrazinamide, and ethambutol, and the HAART regimen was switched to efavirenz/emtricitabine/tenofovir disoproxil fumarate for a better drug interaction profile. Rifabutin was prescribed at an oral daily dose of 450 mg due to interaction with efavirenz. The patient was discharged in stable condition and currently has regular follow-ups in our HIV clinic.

PMC7796835_01

Male

A 54-year-old male who is a known hypertensive compliant on medications, was admitted at the HIIU as a case of COVID-19 pneumonia (positive SARS-CoV-2 polymerase chain reaction analysis on a nasopharyngeal swab sample). He had a 3-week history of fever, cough productive of yellowish, non-bloody sputum and pleuritic chest pain. He also had a week s history of progressively worsening breathlessness. There was associated sore throat, headache and myalgia. He had no contact with a confirmed COVID-19 patient. Initial chest computer tomography (CT) scan at the onset of symptoms showed features suggestive of mild COVID-19 pneumonia. At presentation his symptoms had worsened. His temperature was 36.4 C, pulse rate was 58 beats/min, respiratory rate 30cycles/min, blood pressure 145/96mmHg and oxygen saturation (SpO2) 93% on oxygen delivered via non-renon-rebreather mask at 15Liters/min. His full blood count showed leukocytosis with neutrophilia (Table 1). Sinus bradycardia and a corrected QT interval (QTc) of 0.446s was seen on initial ECG with a repeat QTc on completion of hydroxychloroquine being 0.426s. Cultures for blood and urine were negative. Sputum gene Xpert was negative for Mycobacterium tuberculosis. He was initiated on empiric intravenous ceftriaxone 2g twice daily for 72 hours, intravenous dexamethasone 6mg daily for 10 days and subcutaneous enoxaparin 80mg twice daily. He was also given oral hydroxychloroquine 200mg three times daily for 10 days, oral azithromycin 500mg stat, then 250mg daily x 4; zinc 20mg daily (according to Ghana s Standard Treatment Guidelines for COVID-19) oral zinc 20mg daily x 21 and oral multivitamins 1 daily x 30. On day 7 of admission, 15 days after the initial chest CT scan was taken, his symptoms had worsened further with marked breathlessness on minimal exertion and easy fatiguability. His respiratory rate was 40 cycles/min. SpO2on oxygen given via non-rebreather mask at 15L/min was 94% and 85% in room air. CT pulmonary angiogram (CTPA) was requested due to suspicion of pulmonary embolism. It showed severe worsening of bilateral consolidation and ground glass densities with fibrotic changes in the lung bases on both sides. There was no evidence of pulmonary embolism (Figure 1). On day 11 of admission, his C-reactive protein (CRP) came out as 80.59mg/L (Table 1). A single dose of 400mg of tocilizumab reconstituted with 80mls of 0.9% of normal saline solution was administered via a perfuser over 60 minutes on day 12; on account of deteriorating respiratory symptoms, hypoxia, an elevated CRP (all indicators of CRS) and worsening chest CT scan findings. His respiratory symptoms gradually improved. CRP done on day 15 was 4.57mg/L and a repeat chest CTPA done on day 16 showed marked improvement with significant loosening of the bilateral consolidations and improvement in bilateral ground glass densities (Figure 2). There was however a bilateral base of fibrotic changes for which oral pirfenidone was initiated for 3 weeks. His lymphocyte count also increased from 2.06 x103/microliter to 2.78 x103/microliter. On day 21 of admission he was weaned off oxygen. His SpO2in room air was 96%. He was discharged on day 23 for review at the outpatient clinic and is presently doing very well clinically.

covid-19, tocilizumab, case report, interleukin-6, sub-saharan africa

PMC7723478_01

Male

The first case was of a 72-year-old male whose somatic anamnesis was unremarkable and no prior intake of medications. He was hospitalized for localized zoster in the right groin and front thigh for 23 days. Eight days after tooth extraction, the patient developed a local rash with pinching pain and was diagnosed with extensive HZ of dermatomes T12 to L2 by a dermatologist. The oral medication was initially 200 mg celecoxib twice a day, 75 mg pregabalin, and 250 mg of famciclovir three times a day, for 7 days, respectively. The patient-reported visual analogue scale (VAS) score was controlled, no more than 6. On the 19th day after the appearance of the rash, the patient developed severe breakthrough pain, with more than ten attacks per day (about 5-6 outbreaks at night), each episode lasting 5-8 minutes, accompanied by a tremor of the right lower limb. The VAS pain score was 10 in the onset of breakthrough pain and 0 in the resting. The initial dermatologist tried to increase the dosage of pregabalin, but the patient reported intolerable dizzy and lethargy without any alleviation of his breakthrough pain. Therefore, the patient was admitted and prescribed 75 mg pregabalin three times a day, as well as 100 mg tramadol hydrochloride every 12 hours. Two days after hospitalization, the patient reported no reduction of the intensity and number of episodes of breakthrough pain, after which epidural blockade was performed to resolve the pain. However, during the process, breakthrough pain recurred and the patient was unable to keep his lateral position and switched to a supine position; therefore, the treatment was suspended. The patient received repetitive infusions of 4 g of vitamin C in 250 ml of physiological saline solution, without adjusting the dosage of pregabalin and tramadol hydrochloride. On the second night, there were still 5 episodes of breakthrough pain, but the duration of each attack did not exceed 3 minutes, and the VAS dropped to 8. On the fourth day, although the daily attack frequency did not decrease markedly, the duration had dropped to about 1 minute and the VAS was 6. On the seventh day, the second attempt of epidural blockade using 10 ml 1% lidocaine with 40 mg methylprednisolone was performed successfully. Although the patient suffered an attack of breakthrough pain after lying in the lateral position, the pain intensity was tolerable and lasted for merely 1.5 minutes. During the first 24 hours after the epidural blockade, there were 5 times of attacks, each time lasting for no more than 1 minute and the pain intensity remaining, with a VAS of 3-4. On the tenth day after intravenous administration of vitamin C, the patient had only one attack in the daytime, lasting for half a minute, with a VAS of 1-2. The next day, he was totally pain-free and was discharged from the hospital with an oral prescription for 75 mg pregabalin three times a day for two days. At 1-week and 3-month follow-up, there was no pain recurrence.

PMC6592672_02

Unknown

By 2002 it was established that for subjects over 50 years old going under their first screening colonoscopy it should be a minimum of 25% for men and 15% for women adenoma detection rate. Later, the value was risen by 30%for men and 20% for women, by The American Society for Gastrointestinal Endoscopy/American College of Gastroenterology Task Force Quality in Endoscopy. Still, there are studies suggesting that ADR should have higher values by even reaching 40% and 50%. The growth in ADR values is due to factors such as smocking, obesity, race but most important, patients gender and age. Only by performing a high number of procedures can assure a correct calculated value of ADR. Do et al. might be necessary at least 500 colonoscopies. Screening intervals are also established based on ADR, such as endoscopists with high ADR usually have shorter time intervals between two colonoscopies because of the large number of preneoplastic lesions detected. On the contrary, endoscopists with low ADR recommend colonoscopic re-evaluation for a bigger time interval. Between 2000-2004 a Polish study was carried on approximately 45 000 patients to evaluate the risk of interval CRC development and it concluded that edoscopists with ADR<20% exposed patients on a number 10 times higher than those with ADR>20%. Also, Kaminski et al. implies that endoscopists with ADR under 11% expose patients to a 11 times higher risk of interval CRC development than tose with ADR>20%. The correct ADR calculation has its limitations regarding an ultimate strong bond needed with the histopathology department which is translated into supplementary work taken by the endoscopists. Addition to that, it was shown that edoscopists fail to carefully examine the rest of the mucosa after the discovery of a possible adenoma lesion. As an alternative there were introduced Polyp Dtetection Rate (PDR) and Adenomas Per Colonoscopy (APC) into calculations. In hindsight PDR sums up the percentage of patients older than 50 years to whom at least one polyp was resected during a screening colonoscopy without further histopatology history database requirement. Multiple studies have forwarded a correlation coefficient bigger than 0.8, along with conversion as a result of the best suited correlation between PDR and ADR [60,64-67]. But nonetheless, we should take into consideration a recent retrospective study that emphasizes the better correlation of ADR and PDR for the proximal colon. Based on a retrospective analyses of 3367 colonoscopies carried by 20 different endoscopists, Francis et al. had figured a 0.64 correlation coefficient, while Baxter et al. figured the link between low prevalent interval CRC and a high rate of PDR. Arguably the main setback of PDR is that endoscopists can artificially raise the index number by performing biopsies on normal tissue or by resecting small hyperplastic lesions which were in no need for that. Total number of documented adenomas in reference to the entire number of colonoscopies are shown through APC quality indicator, which gradually became used in clinical practice. By offering pertinent information on the correlation with interval cancers, APC can be used complementary to ADR, or even replace it. Also, APC has a lower tendency of artificially being influenced, contrary to ADR and PDR. Thus, as an alternative to APC, it was introduced the numbering of documented adenomas after the first lesion visualization or resected, leading to a continuously attention of the endoscopists while avoinding the first lesion mirage. Along with this improvement, there is an effort put into introducing the advanced ADR in current evaluation, which quantifies lesions bigger than 10mm with adenoma histology or high-grade dysplasia, also the serrated detection rate and ADR based on colon segment. Future aims propose higher quality of endoscopic images, implying a polyp management through "resect and discard" approach, that will allow endoscopists to anticipate the histology type relying on the macroscopic aspect of the masses, without the need for submission of the resected tissue to anatomic pathology department. Throughout many studies it was demonstrated that gastroenterologists obtain by far higher quality indicators in comparison with doctors from other specialties that practice colonoscopy. 8. Medium time of withdraw and measurement of its frequency by endoscopists. The importance in quality monitoring of colonoscopy is likewise represented by the withdraw time as second indicator and consists in the time spent by the endoscopists in the withdrawal of the endoscope from caecum up to the anorectal junction. It is to no value for endoscopists with ADR above average, mostly aiming to correct those with index below standard. Regardless of the prior demonstrated link between the withdraw time and endoscopy quality there are multiple studies suggesting a lack of correlation of ADR value and withdrawal time. Barclay et al. assessed through their study that colonoscopies with medium time of withdraw of six minutes had significantly a higher rate of neoplastic lesions detection in contrast to those performed in less than six minutes, 28.3% vs. 11.8%. Lately, a research on 8000 colonoscopies brought up that for a 9 minutes withdrawal time the ADR value was 33.6%, while for a less than 6 minutes withdrawal time the ADR value was 23.8%. As long as there is an understanding and willingness for improvement in preneoplastic lesions discovery the results can become even more spectacular following peculiar educational and training sessions. One study prone to improve the overall outcome is the Barclay et al. research, imposing a two minute withdrawal time for each segment of the colon which showed a direct effect on the increase of ADR rate, up to 50% for endoscopists participating in the study, unlike the ADR of those not partaking. On the other hand, another research conducted in Peru was unable to prove a growth of PDR after setting a withdrawal time higher than six minutes. Besides the Peru study, two more studies failed to conclude the relation between withdrawal time and endoscopy quality. 9. Frequency of the attempt of endoscopic polypectomy for polyps bigger than 2cm. All gastroenterologists must be qualified to perform endoscopic polypectomy along with biopsy sampling, therefore any step taking into recommending another gastroenterologist to the patient, due to incapacity of polyp visualization should be frown upon. Exceptions must made in case of large sized polyps or when it comes to slim accessible positions, for which polypectomy should not be encouraged to be realized by not well trained edoscopists. 10. Incidence of perforation and postpolypectomy bleeding Although it has a slim occurrence (less than 1:1000 in screening colonoscopies), perforation is known as a severe colonoscopy complication with a 5% fatal rate. Amid the factors implied in perforation, most common are as it follows: poor bowel preparation, severe diverticular disease, severe intestinal inflammatory diseases and ischemia. Plus, whenever a resistance occurs against advancing with the procedure it is upon the endoscopist to stop the investigation. Discovered perforations during the colonoscopy could be mended by using metallic clips. Unlike cold resection techniques, polyp resection is generally undertaken with electrocautery with risk perforation implications. For postpolypectomy most frequent complication is the bleeding, yet its occurrence rate is just at 1%. This 1% bleeding occurrence rate can rise up to 10% for polyp resection bigger than 2cm. The internal bleeding might happen throughout the investigation or afterwards, [ , ] and in most cases can be solved with the help of the electrocautery. Submucosa infiltration reduces the possible bleeding risks emerging during EMR performance and also evaluates the degree of lesions infiltration because of its utility of sessile polyp raise. In prophylaxis adrenalin administration in dilution is preferred at the base of sessile or pedunculated polyps and detachable loops implantation for gross pedunculated polyps. 11. Postpolypectomy fbleeding frequency in need of chirurgical intervention In 90% of the cases postpolypectomy bleedings can be resolved within the endoscopy by adrenalin administration, electro-coagulation or hemostatic clip. Among adverse events related with the examination it is excluded the bleeding surfaced during the entire period of hospital admission. Lastly, in terms of a long distance bleeding, colonoscopy can be taken into consideration without any further preparation, but in most cases the bleedings stop spontaneously. 12. Proper recommendations for repeated colonoscopy dependent on histopathology results of samples obtained by previous colonoscopy. Current guidelines suggest patients confronted with medium risk CRC development should undergo colonoscopy screening every 10 years. Grounded on the number, size and histological structure of the detected polyps in prior colonoscopies, the monitoring intervals should be applied as it follows: 5-10 years for 1-2 tubular adenomas, smaller than 1cm, 5 years for history of advanced adenomas, 3 years for patients with three small adenomas, large adenomas, villous adenoma or even with high-grade dysplasia. Inexperienced endoscopists with low ADR should be aware of the possibility of missing lesions during colonoscopy, especially the non non polypoid ones. Numerous reviews brought into attention stronger links between non polypoid lesions and interval CRC placed in proximal colon, with the mention that this link remains arguable. Nonetheless, colonoscopy abuse must be avoided, particularly colonoscopies conducted for polypectomies that can arise bigger issues. Accordingly to Robertson et al. assessment, incomplete polyp resection constitutes 26% of the total interval CRC documented, mainly within colon segments who went under polypectomies. Emergence of interval CRC at 5 years has a rate of 0.17% for colonoscopies without polypectomy and 1.5% for those with polypectomy, as demonstrated in Liberman et al. research. A brief synthesis of the main types of ADR enhancing techniques and devices is presented in Fig. 1. The wrong focusing of edoscopists, known as "inattention blindness" phenomena, refers to lesion missing even if the lesion is in the visual spectrum of the edoscopist. The mentioned issue can be solved with the help of an additional observer such as an experienced assistant, another gastroenterologist etc. The improvement of colonoscopy quality with additional observers was the main subject for various studies, one of which pointed out a significantly higher ADR (37%) in colonoscopies performed with additional observers than those performed only by gastroenterologists (23%). Furthermore, other studies carried on 500 patients have shown PDR and APC enhancement when assistants were involved during the procedure. But the effect of additional observers is exclusively and strongly marked at inexperienced endoscopists. On account of critical preparation, different tumor biology for right colon tumors, prominent falds and numerous lesions with risk of malignant development, there must be a peculiar attention towards ascending colon examination. Following the sole purpose of improving examination quality and diminishing interval CRC risk development, ascending colon retroflexion was recommended complementary to colonoscopy examination. Hewett and Rex attained a lesion missing rate of 9.8% subsequently to the colonoscopy completion with retroflexion examination of right colon, this result was contingent upon 1000 patients referred for screening. Same outcomes are testified in other two studies but with the use of a second examination called forward view of right colon. Whether is the retroflexion or the forward view examination, it is implied a second procedure for the right colon for previous lesions detected. Older research, relying on ADR, consider the colon examination carried in specific positions for each segment a more accurate assessment than the one in left lateral decubitus (ADR 37% vs 23%). On the other hand, recent research found no significant difference between the two examination methods, having 41.8% ADR for patients with positioning change and 37.9% ADR for those examined in left lateral decubitus. However, if high rigor is considered then this factor should be taken into account. Due to colon peristalsis, certain lesions can be overlooked while performing the colonoscopy. Although past data affirmed no ADR improvement following antispasmodic medications, new data from a Japanese study affirm an ADR enhancement in patients who were administrated L-menthol spray in the caecum, in contrast to the ADR of patients in group control (69.2-42.6%). Thus, double-blind studies, obtaining similar results, are required for an accurate result confirmation. a)High-definition and Enhanced Imaging Technologies In spite of the high quality images obtained in high-definition (HD), reviews show only a 3.5% ADR improvement for HD examination in comparison with the classic one. Enhanced Imaging Technologies were developed by endoscopic equipment producers in order to upgrade the polyp rate of detection, as well to facilitate neoplastic lesion differentiation. Nowadays there are three such systems. Olympus offers NBI (narrow-band imaging), a virtual technique of chromoendoscopy which was recently introduced in the clinical practice. NBI relies on a basic light examination using a short wavelength (blue and green light) facilitating a softer tissue penetrating, together with a better evaluation of mucosa and vascular patterns. Both I-scan (Pentax) and FICE (Fujinon), are real time chromoendoscopy virtual techniques that were developed based on processing algorithms applied on images obtained under white light. Up to this point, the results of chromoendoscopy techniques efficiency evaluated in recent studies are highly arguable. In addition, studies that have proven a superior ADR for examinations made through these techniques, were subject of a series of limitations such as prolonged withdrawal time in contrast to the control group examined in HD or low ADR in control group Still, chromoendoscopy has certified its efficiency in neoplasia detection occurred on the basis of intestinal inflammatory diseases. The third eye retroscope is a system developed by Avantis Medical Systems and is a mini endoscope that is inserted into the colonoscope's working channel and allows retrograde visualization of the colon. Although there are few studies certifying its efficiency, a new study sampled on 300 patients exposed to Third Eye exam has identified up to 16% more colon adenomatous lesions than the standard colonoscopy. A further study sapling a bigger number of subjects resulted in a higher ADR value of 22.6% after the Third eye procedure. The setbacks this technique implies are related to the cost, aspiration drop and the constant need of removal whenever a polyp must be resected. Full Spectrum endoscopy represents a new edoscopic system that allows a 330 degree mucosa evaluation throughout three lenses placed in front and on both sides. Gralnek et al concluded that adenoma miss rate is only at 7.6% in FUSE exam, while in standard colonoscopy it is at 41.7%. It is to be mentioned that the withdrawal time for FUSE examination was significantly longer. Cap assisted colonoscopy is a method that stands in attaching a translucent cap that creates a better visualizing of the colonic lumen by colon fold flattening. Thus, a suggestive higher ADR for cap assisted exam is differentiating from the ADR group control (69% vs 56%) in a research conducted on 420 patients. On the contrary, a study conducted on 1000 patients highlights a superior ADR standard colonoscopy to the cap assisted exam (37.5% vs 30.5%). Endocuff is a rubber accessory attached to the top of the endoscope, having a set of flexible wings that contribute to fold flattening, therefore making possible the mucosa visualizing from their back during the endoscope withdraw. In previous studies the endocuff using appears to improve ADR only for inexperienced edoscopists with a low ADR. Moreover, EndoRings (EndoAid, Israel) and balloon assisted colonoscopy function based on a similar principle. When it comes to the balloon assisted colonoscopy remarkable differences were noted for PDR values in contrast with classic colonoscopy (91.7% vs 45.8%). This study is limited in terms of being realized on a colonic model with stimutaed polyps. Correction of poor performance 1. Identification of endoscopists with low levels of performance combined with further training followed by the cut of the right of colonoscopy practice if there is no improvement after retraining. 2. Implementing the split-dose preparation model. 3. Informing and educating the endoscopists on the large spectrum of precancerous lesions as well as the importance of their detection. 4. Imposed withdraw time, longer than six minutes, associated with an adequate colonic distension. 5. Proximal colon intrubation performed two times. 6. Usage of additional observers and fold flattening devices for inexperienced endoscopists with low ADR. 7. Purchase of last generation edoscopic equipment that allow HD visualizing. The emergence of interval cancers or postprocedure complication might lead to legal actions taken against medical personnel. This stresses the importance of well informing patients on the colonoscopy limitations, the complications they are exposed to, even more when we refer to interventional procedures. All procedures should be performed only after the informed consent is signed by the patient. Furthermore, data processing regarding the colonoscopy quality, caecum intubation, colon preparation, the withdrawal time and registration/photography of possible abnormality registration, should also be considered.

adr, apc, pdr, colonoscopy, interval cancer, quality indicators

PMC7327586_01

Female

An 18-year-old female patient with a past medical history significant for iron deficiency anemia presented four-week postpartum (first pregnancy) with a one-week history of chest pain and shortness of breath. The patient described a left-sided chest pain as not radiating, constant and stabbing in nature, moderate to severe, pleuritic, and not related to physical activity. The pain was associated with worsening shortness of breath and palpitations. The patient reported associated exertional dyspnea, dizziness, and fatigue that restricted her ability to take care of her baby. She denied fever, orthopnoea, paroxysmal nocturnal dyspnea, or lower limb swelling. The patient had recently returned from a twenty-eight-hour car journey. Apart from anemia, her pregnancy and delivery were both uneventful. The patient has no allergies, no family history of cardiovascular, or clotting disorders. On examination, the patient was distressed, tachycardic, and tachypneic and had normal blood pressure. She required FiO2 of 44% to maintain normal saturation. Heartbeat was regular: soft heart sounds without murmurs, gallops, or rubs. There was no parasternal heave and no clinical signs of fluid overload. Moreover, there were no clinical features of endocarditis. She had normal vesicular breath sounds bilateral, with no crackles or wheezes. Lower limb examination was normal without signs of deep vein thrombosis. Her EKG showed sinus tachycardia with T wave inversion in leads V1-3 (Figure 1). Biochemical investigations showed a D-dimer of 3331 ng/ml (<500 ng/ml), BNP of 1034 pg/ml (<125 pg/ml), mildly elevated troponin I, and microcytic anemia. Otherwise, renal function, electrolytes, liver function tests, and thyroid hormones were within normal limits. Transthoracic echocardiogram showed a severely dilated right ventricle with globally reduced right ventricular systolic function and a left ventricular ejection fraction of 45-50% (Figure 2). CT pulmonary angiogram showed a dilated pulmonary trunk with no evidence of pulmonary embolism (Figure 3). An extensive venous thromboembolic workup including ultrasound Doppler of both lower limbs, CT venogram of the pelvis and lower limbs, and V/Q scan was negative. Cardiac MRI showed a severely dilated right ventricle with a strain pattern with significant global reduced right ventricular systolic function, no signs of dysplasia or myocarditis, normal coronary anatomy, and no septal defects. Coronary angiography showed no coronary artery disease or dissection. Right heart catheterization (RHC) revealed the following: right atrial pressure = 12 mmHg (normal range 1-8 mmHg), right systolic ventricular pressure = 45 mmHg (normal range 15-30 mmHg), mean pulmonary artery pressure = 31 mmHg (normal range 10-22), pulmonary capillary wedge pressure = 7 mmHg (normal range 6-15), cardiac output = 2.97 L/min (normal range00204-8 mmHg), and cardiac index of 1.74/min/m2 (normal range 2.8-4.2), respectively. Eventually, the patient was diagnosed with postpartum pulmonary hypertension. She was admitted and treated in the intensive care unit under the direct care of a pulmonary hypertension team. Her management was guided by a close follow-up of her hemodynamics. Given the high risk of sudden deterioration at any given point, inotropic support was considered and planned. Luckily, the patient's blood pressure remained normal. Good perfusion pressure was supported by normal lactate measures and absence of end-organ damage. Intravenous furosemide infusion was initiated with close monitoring of volume status, which was well tolerated without the need for inotropic support along with parenteral iron. The patient was discharged on torsemide and spironolactone. On review three weeks postdischarge, her functional status was back to premorbid levels with improved exercise tolerance. Repeated transthoracic echocardiogram revealed no significant interval changes. Repeat right heart catheterization showed mild pulmonary hypertension, normal right and left ventricular filling pressures, and normalization of the cardiac output and index. The patient was counseled about the importance of contraception and the risks of pregnancy, given the associated mortality risk. However, a few months later, the patient became pregnant, and after a multidisciplinary meeting and recounseling, she underwent a therapeutic abortion. She remains to follow in the pulmonology clinic and is doing well.

PMC8406155_01

Male

A 30-year-old male presented acutely to our medical service with a petechial rash over his body of 2-day duration. He had no chronic medical conditions and works as a waiter. Further evaluation revealed a diagnosis of refractory TTP and received plasma exchange, steroid, Rituximab, and Caplacizumab with excellent recovery. Through this admission, he developed a seizure with suggestive MRI of neurocysticercosis and received Albendazole with steroids. Furthermore, he developed MSSA bacteremia likely lines related and started on Cefazolin with the fever subsided and no evidence of endocarditis on the Echocardiogram. Toward the end of the two weeks course of Cefazolin and 4 weeks of hospitalization, the fever recurred with left hip pain. On examination, the left hip was held in flexion, externally rotated, and exquisitely painful with minimal movement in all directions. Laboratory findings revealed a white cell count of 16.4 109 /L (4-11) with 88% neutrophils and a C-reactive level of 220 mg/L (0-5). MRI showed evidence of left hip septic arthritis with iliopsoas collection (Fig. 1). A provisional diagnosis of disseminated MSSA infection was made. Cefazolin continued, arthrotomy and washout of the joint followed by CT- guided aspiration of the iliopsoas abscess was performed on days 7 and 9 respectively from the first joint symptoms. Cloudy yellow synovial fluid containing white blood cell count 74,000/mm3 (86% polymorphonuclear neutrophils) was obtained from the aspirates. Subsequently, all cultures were taken back sterile. Tuberculosis and fungal infection were subsequently considered and ruled out in the aspirated samples. However, at week 3 from the first joint symptoms, fever recurred, and CRP increased to 305(0-5). Repeated MRI of the left hip showed increased joint effusion and multiple collections of the muscles around the left hip joint, mainly in the obturator internus and sartorius muscle. Hence, radiology-guided aspiration (at day 27 from the first joint symptoms) for the sartorius muscle and obturator internus was performed but persistently the cultures were negative. A second incision, drainage, and washout of the joint (at day 34 from the first joint symptoms) were performed; however, this time the MALDI-TOF isolated the organism, and specific PCR targeting the yidC gene in M. hominis confirmed the diagnosis . Cefazolin was switched to Tigecycline and Moxifloxacin. Repeated MRI of the hip after three weeks revealed a significant reduction in all described abscesses coupled with improvement in clinical status in terms of fever, range of movement, and inflammatory markers (Fig. 2). Tigecycline was switched to Doxycycline, and Moxifloaxcin continued with a plan to continue therapy for 6-8 weeks. Unfortunately, the patient traveled back to his home and was lost to follow-up.

mycoplasma hominis, pcr, doxycycline, rituximab, septic arthritis

PMC5513951_01

Male

A 64-year-old man presented to the emergency department with diplopia, vertigo, unstable gait, and dysarthria. He reported to have had headaches during the preceding 3 weeks. Apart from a type II diabetes mellitus, which was reasonably controlled by metformin (HbA1c 6.4%), his medical history was unremarkable. Upon physical examination, the patient had a slurred speech, slight right-sided brachiofacial hemiparesis, and partial oculomotor paresis on the left, but no nuchal rigidity. Body temperature was 38.1 C. On the day of admission, a cranial CT was performed and showed a small hypodensity in the left thalamic region, compatible with focal ischemia. Subsequent lumbar puncture and CSF analysis revealed a mixed pleocytosis (700 cells/muL), elevated protein and lactate (3.5 mmol/L), and slightly reduced glucose (53 mg/dL). No microorganisms were detected in the Gram stain of the CSF. Latex agglutination tests for cell wall polysaccharides of typical bacteria causing meningitis (S. pneumoniae, N. meningitidis, group B streptococci, H. influenzae) were all negative. Empiric therapy for meningitis was started with a combination of ceftriaxone, ampicillin/sulbactam, and aciclovir. The initial and repeated CSF cultures taken on days 4 and 10 after hospitalization remained sterile, and PCR for 16S bacterial rRNA genes as well as specific PCRs for Tropheryma whipplei, Mycobacterium tuberculosis, non-tuberculous mycobacteria, and the herpes viruses HSV and VZV were all negative. No evidence for infection with Borrelia burgdorferi, Treponema pallidum, FSME, or HIV was found by serology. NMR imaging on day 3 revealed infarction in the left thalamus, based on diffusion-weighted imaging and hyperintensity in the FLAIR sequence (Figure 1A), as well as an enlargement of the sellar region consistent with an adenoma of the pituitary gland. Despite an initial clinical response to the treatment with antibiotics and corticosteroids, which was accompanied by a drop of the CSF cell count to 280/muL on day 3, the patient continued to have fever. As he deteriorated clinically and the pleocytosis of the CSF persisted, the antibiotic regimen was changed to a combination of ampicillin, levofloxacin, and doxcycline because anamnestic exposure to sheep and excretions of wild birds during cleaning of nesting boxes suggested the possibility of a zoonotic pathogen. However, serological tests for antibodies to Coxiella burnetii, Rickettsia spp., Brucella spp., Mycoplasma pneumoniae, Leptospira spp., and Francisella tularensis were all negative; Toxoplasma gondii- and Chlamydia-specific antibodies were detected at low titers, consistent with past infections. Analysis of the CSF for cryptococcal antigen was repeatedly negative. On day 8, NMR imaging was repeated and suggested vasculitis of the basilar artery with a small infarction of the brain stem. The cCT scan obtained on day 10 revealed sinusitis sphenoidalis and an increase in the space-occupying sellar process was observed, leading us to consider a fungal infection (Figure 1B). Therefore, additional treatment with the antimycotic agent voriconazole was initiated (200 mg every 12 h). On day 12 after initial hospitalization, the patient was transferred to the neurosurgical department of the university hospital to obtain a tissue biopsy and histology of the sellar process. Within 2 h after transfer, the patient deteriorated dramatically, developed a respiratory arrest and absent pupillary reflexes. Emergency cCT showed a massive subarachnoidal hemorrhage (Figure 2A), caused by active bleeding from a fusiform aneurysm of the basilar artery tip as revealed by digital subtraction angiography (Figure 2B). Bleeding could be stopped by insertion of a flow diverting stent (Figures 2C,D). However, the patient did not improve clinically during the following days but was comatose without reaction to nociceptive stimuli yet with intact corneal reflexes. The EEG showed a burst-suppression pattern. On day 17, large demarcated infarction areas were seen by NMR in the mesencephalon, the cerebellum, and brain areas supplied by the A. cerebri anterior and posterior (Figure 2E). Given the poor prognosis at this stage, a decision was made to limit therapy after consultation with the family of the patient. The patient died on day 18 after admission. Although cultures of repeated CSF samples did not yield growth of bacteria or fungi, the development of a presumptive mycotic aneurysm of the basilar artery despite broad and high-dose antibiotic therapy, along with the radiologic suspicion for a possible infectious process in the sellar region, prompted us to re-consider a fungal infection in this patient. Therefore, remaining CSF samples from days 4, 10, and 13 after admission were analyzed for the presence of Aspergillus galactomannan antigen using the Platelia assay (Bio-Rad, Marnes la Coquette, France) (Table 1). The index values were positive in all three samples (4.2, 10.2, and 1.4, respectively, cutoff 0.5); serum was only tested for Aspergillus galactomannan on day 13 and was negative. CSF samples taken at day 4 and day 10 were weakly positive for fungal 5S-28S rRNA spacer DNA using PCR amplification and identified as derived from A. fumigatus by sequencing (Table 1). Brain autopsy revealed generalized brain edema with uncal/transtentorial as well as tonsillar/cerebellar herniation. At the sites of herniation, there were foci of necrosis and hemorrhage including the midbrain and pons region. There was prominent subarachnoid hemorrhage within the basal cisterns and intraventricular extension of the hemorrhage. In addition, widespread hypoxic-ischemic damage in supra as well as infratentorial areas was observed. The cause of death was a rupture of an aneurysm of the basilar artery (Figures 3A-C). Microscopic analysis of the aneurysmatic vessel wall revealed inflammation and foci of hyphal structures with septae and dichotomous ramifications, which were best visualized by Grocott histochemical staining (Figures 3D-F), arguing for a mycotic aneurysm due to a hyphomycetal infection. The sellar region showed a pituitary adenoma with immunohistochemical expression of adrenocorticotrophic hormone (ACTH) in terms of a corticotroph adenoma (Figures 3G,H) with invasiveness concerning the adjacent bone and dura. There was also invasion of hyphae into the dura surrounding the sphenoid sinus (Figure 3I). Furthermore, one of the autopsy samples (taken from the right thalamus) was culture-positive for A. fumigatus (Table 1). Thus, invasion and destruction of adjacent tissue by the pituitary adenoma may have facilitated the intracranial invasion of A. fumigatus and subsequent vasotropic infection of the basilar artery.

pcr aspergillosis, fungal infection, galactomannan antigen, meningitis, β-d-glucan antigen

PMC7476685_01

Male

Our patient was 16 years old and he was a student with no particular medical history. The patient and his parents gave their informed consent to report this case. He presented a left upper limb trauma when he was 12 years old that was orthopedically treated by a cast during 3 weeks. Since then, he presented pain in his wrist, especially at sport and when he was leaning on his left hand. His pain was quoted at 7/10 (visual analog scale) and he reported a severe handicap at sport. Clinical examination showed a normal range of motion of his wrist with a normal but painful pronosupination motion. It revealed distal radioulnar instability with a protrusion of the ulnar head (Fig. 1) without instability of the extensor carpi ulnaris tendon. The radioulnar ballottement test of the radioulnar joint, the fovea sign, and the chair test were positive. The clunk test was negative. The symptomatology was marked by a severe functional concern when leaning on his hand during gym classes or when playing basketball. The patient-rated wrist evaluation (PRWE) score was at 51/100 (pain = 31, function = 20), the QuickDASH score was at 43/100. The pain was specifically localized on the ulnar side of the wrist by the patient. No nerve compression or vascular signs were detected. X-rays of the wrist revealed a shortening of the radius with a high radioulnar index (11mm on the anteroposterior view) and an ulnocarpal impingement (Fig. 2). This was highlighted on the magnetic resonance imaging T1sequence of the wrist that revealed overpressure cysts of the triquetrum (Fig. 3). The radioulnar joint surface on the radial side was flat. A lengthening of the radius with an iliac crest autograft was indicated as a reconstructive surgery to recover the normal length of the radius. A bilateral wrist computed tomographyscan was performed with a 3D reconstruction to evaluate the needed lengthening according to the contralateral side. The position and the orientation of the metaphyseal osteotomy were also calculated. A lengthening of 10mm in the longitudinal axis was calculated. The final position of the plate, the length of its screws, and the dimensions of the graft were also generated (Fig. 4). A patient-specific guide was 3Dprinted (Allians Radius , Newclip) to guide the osteotomy during the surgery. The 3D-printed material of the guide was done in PA2200 uspcl6 (polyamide). Under locoregional anesthesia and with a tourniquet, a volar Henry approach was performed to expose the distal radius. The distal part of the brachioradialis tendon was released at its radial insertion. The guide was applied on the metaphysis of the radius; a K-wire was positioned to evaluate the good position of the guide on the metaphysis with a fluoroscopy control. The holes of the plate were drilled previously. The osteotomy was performed with a 0.8mm saw blade and completed with an osteotome. A specific distractor with 1.8 pins was used to spread the two fragments. To avoid the buckling of the wire and the rotation of the fragment under the distraction stress, a Meary distractor was used and left in place. This allowed the stretching of the soft tissues during the iliac crest taking and it facilitated the insertion of the graft. A tricortical iliac crest bone graft of 10mm length was then taken on the homolateral side. The tricortical graft was then positioned into the osteotomy site flush to the anterior radial surface. The plate was screwed on the radius using the previously drilled holes (Fig. 5). The tourniquet was deflated (50 min). A cautious hemostasis was done and the approach was closed as usual. A removable sling was used to immobilize the patient during 1 month and a passive mobilization of the wrist was started the day after surgery. At 6-month post-operative(Fig. 6), the radius was consolidated with no more clinical deformation. The radioulnar index was improved (5mm on the anteroposterior view) with no more ulnocarpal impingement. The extension was symmetric at 65 , the flexion was at 80 versus 90 on the contralateral side, the radial and ulnar inclinations were at 5 and 40 , respectively, on both sides. The PRWE was at 2/100 (pain = 2/50, function = 0/50), the Quick DASH score was at 2/100. The patient presented no more pain on the ulnar side and was back to sport. No neurologic symptoms were found.

patient-specific instrumentation, epiphysiodesis sequelae wrist disorders, pre-operative planning

PMC3891083_01

Male

A 64-year-old man was admitted with a history of severe right pleuritic chest pain of a few days duration. He had been treated for diabetes mellitus and hypertension for twenty years, which were well controlled, without any complications. He also had a history of pulmonary tuberculosis, but denied alcoholism and drug abuse. On admission, he had respiratory symptoms, including a mild cough, yellowish sputum and severe right pleuritic chest pain. He also had mild fever, with a body temperature of 37.3C, pulse rate 103/min, respiratory rate 18/min and blood pressure 150/80 mmHg. A chest examination revealed decreased breathing sound in the right lower lung. Laboratory studies revealed the following values: leukocytes 21,500/cu mm with 84% segmental neutrophil, 3% band forms, 10% lymphocyte and 4% monocytes; arterial pH 7.41, PCO2 37.5 mmHg, PO2 60.7 mmHg on room air. The chest radiography taken on admission revealed a loculated pleural effusion, with suspicious consolidation in the right lower lung. A blood culture was obtained and treatment was started with intravenous antibiotics (cefpiramide 1 g every 12 hours and amikacin 500 mg every 24 hours). Sono-guided thoracentesis was performed. The pleural fluid contained a pus-like material: WBC > 1,000/mm3 almost PMNL; glucose 346 mg/dL; protein 4.3 mg/dL; LDH 2211 u/L. Bacteria, fungi and tuberculosis cultures were all negative, as were the blood and sputum cultures. On the fifth day of hospitalization, chest radiography revealed an air cyst and air fluid level in the right lower lung (Figure 1). On the ninth day, the size of the air-cyst had rapidly increased to about 9x11 cm in size; the air fluid level had also increased (Figure 2A). Computed tomography of the chest was performed, and the enhanced chest CT scan showed a 9x11 cm-sized thin-walled cavitary lesion, with an air fluid level, pleural effusion and consolidation in the right lower lung (Figure 2B). A percutaneous pig-tail catheter was inserted into the pneumatocele with the air fluid level, and foul-odored pus drained. The bacterial culture was positive for Bacteroid species, Peptostreptococcus asaccharolyticus and Fusobacterium species. On the same day, antibiotics were changed to intravenous clindamycin, 600 mg every 8 hours. On the next day, after percutaneous catheter drainage, the patient became afebrile, and the size and amount of the air fluid level of the pneumatocele progressively decreased. On the twenty-seventh day, there was no further drainage and the catheter was removed. Eventually, the patient was discharged on the thirty-sixth day of hospitalization.

(B) Enhanced chest CT scan showed a 9x11 cm sized, thin-walled cavitary lesion, with an air-fluid level, pleural effusion and consolidation in the right lower lung.

PMC4821329_01

Female

A 45 year old non-smoker female presented with complaints of dyspnea, dry cough and left sided chest pain for the past one and a half years. She gave history of recurrent refilling and multiple thoracentesis over this period. There was no past history of tuberculosis. There was no history of fever, joint pains and weight loss. There was no history suggestive of chronic use of any medications. She was housewife by occupation. On examination, her vitals were normal. Respiratory system examination showed findings suggestive of left sided bulging with decreased movements of left side, stony dull note on percussion and decreased vocal resonance suggesting left sided effusion. Her chest radiograph was suggestive of massive left pleural effusion with left upper zone rounded opacity (Fig 1). Pleural fluid aspiration was done which was straw colored and had a cell count of 150 cells/cubic mm, 60%polymorphonuclear cells and 40% mononuclear cells, glucose-131 mg/dl, protein-4400 mg/dl, ADA-7.72U/L, LDH-98U/L. Gram's and ZN stains were negative for bacteria and acid fast bacilli. Cytology for malignant cells was negative. Computed tomography revealed a well defined heterogeneously enhancing mass lesion along the posterior chest wall in left upper hemithorax with massive left sided effusion (Fig 2) MRI was done to rule out chest wall origin or invasion and it suggested a well defined lesion in the D4, D5 paravertebral region?neurogenic tumor with massive left side pleural effusion with left lower lobe collapse. Thoracoscopy was done using a rigid thoracoscope (Karl Storz). A large tumor arising from the posterior chest wall of the apical region was seen. The tumor was highly vascular and bled on touch. (Fig. 3) Biopsy from the tumor was taken with electrocautery assistance to prevent excessive bleeding. Biopsy was suggestive of pleural hemangioma. (Fig. 4). Patient was referred for surgical management. Left posterolateral thoracotomy with excision of the tumor was done and intercostal drain was placed. The drain was removed after 4 days of surgery when any fluid ceased to drain through it. There was no re-accumulation of pleural fluid on follow-up chest skiagram after 14 days (Fig. 5). Patient is in our regular follow up and she is absolutely normal.

effusion, pleural hemangioma, thoracoscopy

Chest computed tomogram showing heterogeneously enhancing mass lesion along posterior chest wall in left upper lobe and left sided moderate pleural effusion.

PMC8711735_01

Male

An 83-year-old man was admitted to the Respiratory Department of the Affiliated Kunshan Hospital of Jiangsu University on October 30, 2019, due to cough and expectoration accompanying hemoptysis for 1 week. The patient had a history of tuberculosis for more than 30 years and chronic bronchitis and emphysema for 10 years. Chest computed tomography (CT) revealed an irregular mass (5.3x2.6 cm) in the upper lobe of his left lung (Figure 1A). Furthermore, positron emission tomography/computed tomography (PET/CT) showed multiple lymph node and bone metastases (Figure 1B). The patient underwent a transthoracic core needle biopsy of the lung mass. Histological staining of lung tissue showed obvious tumor cell characteristics with adenoid and stratified structures and visible nuclear division (Figure 1C). Immunohistochemistry analysis revealed positivity for thyroid transcription factor 1(TTF-1), CK7, SPA, napsin-A and Ki-67 (about 10%), but negativity for villin, P63 and P40. Taken together, he was diagnosed with stage IV (T4aN2M1) invasive lung adenocarcinoma. On December 6, 2019, a novel PTH2R-ALK fusion was identified in the patient's tumor tissue by NGS (Figure 2A), which was composed of exon 1 of PTH2R (parathyroid hormone second receptor) gene and exon 20-29 of ALK gene (Figure 2B). Fluorescence in situ hybridization further confirmed the ALK positive (Figure 2C). It contained the entire kinase domain of ALK and may activate ALK signaling to play a role in tumor genesis and development. Based on the results of NGS test, the patient started oral crizotinib 250 mg BID from December 12, 2019. After taking crizotinib for 10 days, the patient developed mild nausea without vomiting. Reexamination of liver function revealed that the level of alanine transaminase (ALT) and aspartate transaminase (AST) was 3-4 times higher than baseline (Table 1), suggesting mild liver function impairment. Thus, the patient was treated with polyene phosphatidylcholine for liver protection. The irregular mass shadow of the upper lobe of the left lung shrank significantly to 1.47x0.89 cm when reexamined by CT on January 18, 2020, indicating that this patient achieved a partial response. However, considering the intolerable hepatotoxicity, the patient switched to take alectinib 1200 mg BID from January 20, 2020. After 1 week, the clinician reduced the dosage to 600 mg BID, but the patient still had swelling in his legs and felt fatigued. His uncomfortable symptoms were slightly eased after symptomatic treatment of spironolactone. Carcinoembryonic antigen decreased obviously after treatment for a month. However, the total bilirubin of this patient reached up to three times of reference range (Table 1). Furthermore, he did not respond to symptomatic treatment of liver protection. On June 20, 2020, the patient started ceritinib orally 450 mg QD with food. He suffered from diarrhea and antidiarrheal drugs were ineffective. Then, the clinician reduced the dosage of ceritinib to 300 mg QD. During treatment with dose reduction of ceritinib, the patient's blood routine tests and liver function tests were normal, and chest CT scan demonstrated stable disease. The patients were followed up several times, with the last follow-up on June 13, 2021. The tumor lesion in the left lung remained stable and PFS was nearly 12 months.

pth2r-alk, adverse events, ceritinib, non-small cell lung cancer

Diagnosis results by CT scan and pathology. (A) CT diagnosis of lung tissue.

PMC3323271_01

Male

On January 26, 2003, a 22-year-old shepherd was treated at a health post in the Popenguine District, 60 km south of Dakar, Senegal; he reported fever, epistaxis, arthralgia, myalgia of the lower limbs, and dark urine for the past 2 days. Without biologic confirmation of the infection, he was treated for malaria with two intravenous injections of quinine, followed by oral administration of chloroquine. On January 31, the patient had a temperature of 39 C, conjunctival jaundice, bleeding gums, and was vomiting blood. He was seen again at the health post and was given antimicrobial drugs, intravenous quinine, and vitamin K; the next day, the bleeding stopped and the fever subsided. A serum sample was sent to the World Health Organization Collaborative Centre for Arboviruses and Viral Hemorrhagic Fevers at the Institut Pasteur, Dakar. Tests for anti-CCHF specific immunoglobulin (Ig) M antibody by enzyme-linked immunosorbent assay (ELISA) were positive, and CCHF virus by isolation on cell cultures (AP61 and Vero cells) and reverse transcriptase-polymerase chain reaction (RT-PCR) were negative. From January 31 to February 10, the IgM titer increased from 1/3,200 to >1/12,800 and IgG titer increased from 1/200 to 1/6,400. Examination of the patient on February 10 showed he had recovered without sequelae, and no trace of tick bites was found. The patient stated that he had not traveled, noticed any tick bites, slaughtered any animals, or been in contact with people with fever for several weeks before his illness. He lived in close proximity to goats and cattle, but no blood samples were taken from these animals. Although no ticks were found on nearby goats, 10 Amblyomma and Hyalomma ticks were collected from three cattle. Ticks were negative for CCHF virus isolation on suckling mice and RT-PCR amplification. No other case of fever accompanied by hemorrhage was reported in the area, and none of the patient's 14 close contacts became ill. Of the four close contacts from whom blood samples were taken, analyses for IgM and IgG antibodies against CCHF virus were negative by ELISA. While no clinical case of CCHF has ever been reported in Senegal, studies dating from 1969 indicate that CCHF virus had been found in various locations in the country (,). In the village of Bandia, in the same district where the reported case was observed, a study conducted from 1986 to 1988 showed a prevalence of anti-CCHF IgG of 3.2% in the human population. Another study, conducted in the same area from 1989 to 1992, showed seroconversions for several ruminants and isolated the virus from ticks. During CCHF outbreaks, an average of 30% of people who had the disease died (case-fatality ratio). It is often discovered during nosocomial outbreaks, as was the case in Mauritania, a country on Senegal's northern border, in 2003 (P. Nabeth, unpub. data). To prevent outbreaks of CCHF, public awareness campaigns aimed at the populations most at risk:livestock farmers, butchers, and health personnel:must be conducted, and the epidemiologic alert systems must be strengthened. In addition, conditions that enhance maintenance of the virus in nature and its transmission to humans must be better understood so adequate control measures can be developed.

PMC8416635_01

Male

The patient was a 23-year-old man who was living in a village in his private small livestock farm and was an owner of a cat. His past medical history was unremarkable. He presented to the Clinic of Infectious diseases of the University hospital, Stara Zagora with a 3-week history of asthenia, fever - up to 39 C, cough and loose stools, lethargy, confusion, slurred speech and unsteady gait. On admission he complained of a progressively worsening headache, photophobia and dizziness. Signs of meningoradicular irritation - severe neck stiffness, positive Brudzinski's neck sign and positive Kernig's sign. VI, central VII and XII cranial nerve lesions on the right side Right hemiparesis Static and locomotor ataxia Brisk tendon reflexes and clonus on the left foot Dysarthria The patient was admitted in a generally bad condition, toxic appearing but conscious with a fever -39,6 C, dry pharyngeal and oral mucoses, whitish coated tongue. There was no skin rash. Cardiovascular and pulmonary exams were unremarkable - heart rate 78 bpm, blood pressure- 110/70 mm Hg, respiratory rate - 22/min and oxygen saturation - 94% on room air. There were enlarged liver -3-3, 5-4 cm and spleen - 1-1,5 cm. The neurological examination revealed: Laboratory investigations showed anemia, mild leukocytosis with left shift. Renal and liver function tests were unremarkable. There were no hemostatic disorders. There were high levels of C-reactive protein (CRP). CSF changes were consistent with those of viral meningoencephalitis. Table 1. Based on clinical presentation and laboratory findings a provisional diagnosis of serous meningoencephalitis was considered. Treatment with Ceftriaxone, Amikacin, Mannitol, Dexamethasone, fluids, and multivitamins was started. The patient was treated symptomatically as well. Despite the negative results of pulmonary X-ray and screening tests for tuberculosis (Mantoux test and QuantiFERON -TB Gold test), tuberculostatic drugs were included in the therapy. On the first hospital week the patient continued to spike fevers - up to 38 C (despite of antipyretics). On the 10-th day his condition deteriorated. He had severe headache, bradypsichia, bradylalia, sensory-motor aphasia and III cranial nerve lesion on the right side were demonstrated. On the third hospital week he was clinically improved. The temperature was subfebrile, symptoms of meningoradicular irritation and VI and VII cranial nerve were reduced. Right hemiparesis regressed to monoparesis on the lower limb. On the 21-st hospital day a new febrile peak up to 39,8 C was registered. The patient appeared anxious and irritable and experienced communication difficulties. During his hospital stay, the patient underwent several brain imaging tests (CT and MRI) - on the day of admission and thereafter. Figs. 1, 2A, 2B and 3 show some of the most pronounced pathological lesions. Brain CT and MRI images arose a high index of suspicion of a parasitic infection, especially of Toxoplasma infection. A combination of Clindamycin and TMP/SMX was included in the therapy. Toxoplasma CSF serological tests both IgM and IgG were requested for the patient at the Nacional Reference Laboratory for diagnosis of Parasitic diseases, Sofia. Both tests were positive and this confirmed the diagnosis. To assess the patient's immune status, 4 classes of immunoglobulins (A, G, M, E) and complement factors (C3, C4) as well as the CD panel parameters were tested. All of them were in the lower reference range. Due to evidence for slight immunological suppression (Table 2) the patient underwent 3 HIV tests with ELISA and 1 with Western blot following nationally validated testing algorithm. The recommended by Ministry of Health in Republic of Bulgaria laboratory HIV testing algorithm follows these steps: The ELISA test is done first. If the ELISA is positive, a Western blot test is performed. If the ELISA and Western blot test are positive, the viral load must be determined. If ELISA is negative, the Western blot test is performed only in high-risk persons. The testing algorithm is validated by the National Reference Laboratory for HIV/ AIDS in Sofia. On the day of admission - ELISA negative result. On the 10-th day, when the diagnosis of cerebral toxoplasmosis was confirmed and high index of suspicion for HIV infection arose - ELISA negative, Western blot test negative, too. On the 41-st hospital day - ELISA negative result. The our patient HIV testing was as follows: The patient's wife underwent 2 ELISA HIV tests, too. They were all negative. The patient and his family requested for discharge. He left the clinic with a slight improvement after a 45 hospital stay regardless of a possible risk. The discontinuation of the treatment against medical advice resulted in a lethal outcome.

hiv-negative status, toxoplasma gondii meningoencephalitis

PMC9296300_01

Female

The present study reports the case of a retired 59-year-old female, overweight (BMI 29.3 kg/m2), with decompensated type two diabetes mellitus (DM) and hypercholesterolaemia, under drug therapy (ezetimibe with simvastatin 1 tbt/day and metformin hydrochloride 1000 mg 1 tbt twice a day), no coronary artery disease or herpetic virus liver disease, previous appendectomy surgery under general anaesthesia, and common childhood rashes. The patient was treated during the COVID-19 period, and all indicated measures according to the scientific literature were taken to protect all medical workers and the patient. Seven days prior to emergency room (ER) admission, she reported swelling in the right mandibular region which showed progressive volumetric increase with spontaneous and on-palpation pain. She started a nonbetter-specified antibiotic therapy with no benefits at all so that a subsequent dysphonia and liquid and solid dysphagia developed. On ER physical examination, the patient presented a voluminous right half-face abscess, inability to speak correctly due to trismus, and oedema of the tongue and mouth floor (Figure 1). Optical fiber video exploration of the upper respiratory tract showed mucosal oedema and hyperaemia of both the hypopharynx and the larynx. Complete blood count and laboratory tests (the most relevant values are reported in Table 1), Sars-CoV2 swab (negative), orthopantomography (OPG) X-ray (Figure 2), computed tomographies (CT) of the head-neck (Figures 3 and 4), and chest (Figure 5) were performed. Skull CT underlined the presence of gas bubbles in both the cavernous sinuses, possible odontogenic focus on tooth 4.7, part of a prosthetic bridge (4.7-4.5); neck CT was positive for huge phlegmon and gas bubbles affecting the right half of the face and platysma, the right parotid gland posteriorly, extending up to the contralateral parotid capsule and sternocleidomastoid muscle medially and the thyroid space inferiorly; chest CT showed no pathological findings. Emergency surgical laterocervical abscess drainage appeared to be mandatory and was performed together with the homolateral submandibular gland sialoadenectomy. The patient also underwent a surgical tracheostomy, according to the previous optic fibre video evaluation, in order to secure the airways and ensure proper ventilation (Figure 6). Antibiotic therapy with Teicoplanin 400 mg and Levofloxacin 500 mg was prescribed (Targosid 400 (Teicoplanina) mg Endovein at 12 : 00 and 22 : 00 with Rocefin (Ceftriaxone) 2 g Endovein at 8 : 00 and 20 : 00, and Desometasone 8 MG at 8 : 00 and 22 : 00 + gastroprotectives.) The day after the emergency surgery, neurosurgical signs (negative) and infectious disease (new antibiotic therapy: piperacillin/tazobactam 4.5 g and linezolid 600 mg) consultations were requested. Urgent head and neck-chest computed tomography (CT) scans were performed. Presence of bilateral gas bubbles in correspondence to the cavernous sinuses was revealed. At the level of the neck, a large phlegmonous collection was present with a considerable contextual air share located mainly in the right half of the face, the platysma, and the ipsilateral parotid gland capsule. Medially, it extended to the buccal floor to the left submandibular lodge and the sternocleidomastoid fascia. C-reactive protein value was reduced but still high. On the third day of hospitalization, the patient was admitted to the intensive care unit because septic shock had developed due to the patient requiring vasopressors to maintain a mean arterial pressure higher than 65 mmHg and presenting a serum lactate level greater than 2 mmol/L. SOFA score was 9, and fever was present (38.2 degrees C). Neck-chest CT showed increased phlegmonous collection, especially on the left side (extended to the left parotid gland), on the anterior region of the neck, and down to the superior mediastinal region in the retrosternal site. Head CT revealed almost complete reabsorption of the gaseous collections at the level of the cavernous sinuses on both sides; only a small gas bubble remained in the right cavernous sinus. Emphysema in the neck was also moderately reabsorbed. There were no signs of venous thrombosis of the cerebral vessels or neck. Thoracic surgery consultation revealed no need for emergency surgery and neck-thorax CT with contrast medium after 48 hours and revaluation. The patient proceeded to surgery (Figure 7). After local anaesthesia (mepivacaine 3%) without vasoconstrictor, tooth 1.7 was removed because of a periapical lesion with necrosis; afterwards, the prosthetic bridge 4.5-4.7 was sectioned with rotating instruments in order to save the 4.5. Tooth 4.7 was extracted together with the pontic 4.6. Since a radiopacity spot in area 4.8 was seen on the skull-CT, a surgical revision in this site was also carried out. Alveolar curettage was performed using Volkmann spoons, and two specimens of exudate, collected in the postextraction site (4.7) and in 4.8 area, were sent for histological and microbiological examination; after washing with physiological solution and rifamicine topic antibiotic, haemostis with oxidized regenerated cellulose gauzes (Tabotamp ) was performed. The day after surgery, the patient was kept sedated and under controlled mechanical ventilation; SOFA score dropped from 9 to 8, and haemodynamic stability was achieved through vasopressors (noradrenaline). Fever was still present. In the following days, as the SOFA score dropped to 0 and discontinuation from amine support transpired, fever resolved, and the patient initiated successful weaning that resulted in disconnection from the ventilator on the 9th day of hospitalization. ENT (ear, nose, and throat) consultation revealed a thorough surgical treatment and suggested surgical wound dressing, washing with H2O2 and physiological solution through the drains. In addition, dentistry and thoracic surgery consultations were required. A new neck-thorax CT with contrast medium showed unchanged bilateral neck abscess and involvement of the anterior part of the neck down to the superior mediastinal region in the retrosternal site that did not require surgical treatment. After 10 days of hospitalization, chest X-ray did not show any variation compared to the previous evaluation, and the patient's condition was stable, being neurologically well oriented, hemodynamically stable, and with good gas exchange. On the 12th day, the patient was moved to the ENT ward. Patient discharge took place approximately 1 month after performing neck and chest CTs (Table 2 and Figure 8). Check-up 3 months after discharge revealed no externally visible swelling (Figure 9) and a good intraoral tissues healing (Figure 10). Control OPG (Figure 11); CTs of head-neck and chest were requested and checked. Neck-chest CT (13/02/2021): presence of bilateral gas bubbles in correspondence to the cavernous sinuses. At the level of the neck, a large phlegmonous collection with a considerable contextual air share located mainly in the right half face, the platysma, and the ipsilateral parotid gland capsule. Medially, it extended to the buccal floor to the left submandibular lodge and the sternocleidomastoid fascia. Chest X-ray (bedridden) (14/02/2021): presence of tracheostomy tube with distal end in place; raised right hemidiaphragm with ipsilateral basal dysventilation; heart substantially within the limits. CT neck-chest (15/02/2021): increase of the known phlegmon, especially on the left side (where it also extends to the left parotid gland) and also to the anterior region of the neck and down to the superior mediastinal region in the retrosternal site. Cranial CT (15/02/2021): almost complete reabsorption of the gaseous collections at the level of the cavernous sinuses on both sides; currently, only a small gas box remains in the right cavernous sinus. Emphysema in the neck is also moderately reabsorbed; no signs of venous thrombosis of the cerebral vessels and neck. Ct neck and thorax with contrast medium (17/02/2021): the known abscess collection in the neck bilaterally unchanged, especially on the left. It also extends to the anterior region of the neck and down to the superior mediastinal region in the retrosternal site; filiform the lumen of the pharynx and larynx. The pharyngolaryngeal spaces are obliterated. The remaining finds unchanged. Chest X-ray bedridden (22/02/2021): no variation compared to the previous. The written informed consent for the study and case publishing was obtained from the patient recruited.

PMC6522838_01

Female

A 46-year-old African American female presented to an outside hospital in late November 2017 due to altered mentation and flu-like symptoms. Her past medical history was significant for bipolar disorder, 1 seizure episode at age 17, and psoriatic arthritis treated with rituximab infusions since 2014. Her last known rituximab infusion was July 2017. Prior to seeking medical care, the patient tried multiple doses of Theraflu (acetaminophen, dextromethorphan, and phenylephrine) because she attributed her symptomatology to influenza. She complained of a subjective tactile fever, myalgias, and cough. Initial physical exam revealed the patient to be normotensive and afebrile, but she did have nuchal rigidity, was obtunded and showed generalized stiffness with her arms flexed and legs extended. Initial emergency department workup included a CT scan of the brain without contrast that showed no mass effect or hemorrhages and normal gray-white differentiation. Complete blood count (CBC) on admission showed a leukocytosis of 18,000/uL with an absolute neutrophil count of 15,600/uL. C-reactive protein (CRP) was elevated at 156.8 mg/L. A lumbar puncture showed a high WBC count of 161/uL with 70% lymphocytes, 25% PMNs, 98 mg/dL protein, and 55 mg/dL glucose. The patient was placed on isolation precautions and empirically started on ceftriaxone, vancomycin, and acyclovir. A CSF BioFire Meningitis/Encephalitis Panel revealed the presence of enterovirus. As a result, empiric antimicrobials were discontinued. On subsequent hospital days, the patient continued to have generalized stiffness, was unable to follow commands, and remained nonverbal. She experienced recurrent febrile episodes as well as multiple witnessed generalized tonic-clonic seizures. An EEG showed abnormal bihemispheric slowing suggestive of nonspecific diffuse encephalopathy. Attempted brain MRI on hospital day 5 was not successful. The patient did not improve, had recurrent febrile episodes with leukocytosis, and frequent seizures. A brain MRI under sedation revealed restricted diffusion in the bilateral cortical and subcortical regions of the parietal and posterior temporal lobes, splenium of the corpus callosum, and bilaterally in the posterior thalamus (Fig. 1). These findings raised concern for posterior reversible encephalopathy syndrome (PRES) at the outside facility. The patient was transferred to our tertiary care facility. On arrival, the patient remained altered with disorientation to person, place, and time. She showed left gaze preference and was unable to follow simple one-step commands. Her reflexes, muscle tone, and sensorium were normal. CRP was elevated at 64.2 mg/L. Her liver function studies and pancreatic studies were unremarkable. Intracranial and extracranial CT angiography showed no abnormalities. Brain MRI showed restricted diffusion in the splenium of the corpus callosum. Left greater than right restricted diffusion in the temporoparietal cortex was present. Subtle leptomeningeal enhancement on the left was also observed. Folate, vitamin B12, vitamin B1, and TSH levels were all within the normal reference ranges. The patient improved clinically and was able to follow one-step commands. However, she had intermittent episodes of agitation requiring four-point restraints. She was placed on olanzapine as needed with haloperidol for breakthrough agitation. Follow-up brain MRI two weeks later showed stable FLAIR and T2 signal abnormalities within the splenium of the corpus callosum and thalami with no residual hypointensity on ADC map images, indicating no persisting restricted diffusion in these locations. Previous temporoparietal diffusion hyperintensities also had returned to normal and no new areas of signal abnormalities were identified (Fig. 2). At this point, the patient was awaiting placement in a skilled nursing facility. Her mentation and orientation continued to improve. Her episodes of aggression and agitation lessened. A month after admission, the patient complained of decreased visual acuity. She was found to have decreased bilateral blink-to-threat reflexes with left-gaze preference. However, she was able to distinguish colors and track around the room. As a result, a repeat brain MRI was done on January 10, 2018. New cortical-restricted diffusion was present in the bilateral parietal and occipital lobes. Stable abnormal diffusion abnormality within the splenium of the corpus callosum and thalami remained (Fig. 3). These findings were concerning for Creutzfeldt-Jakob Disease but a 14-3-3 protein analysis was found to be within the normal reference range and real-time quaking-induced conversion failed to detect abnormal prion proteins. Repeat CSF PCR for enterovirus was negative as well as a swab of the oropharynx. Cerebrospinal fluid testing for California (La Crosse) encephalitis, John Cunningham virus, Mycobacterium tuberculosis, Eastern equine encephalitis virus, Cryptococcus neoformans, VZV, HSV-1, HSV-2, CMV, VDRL for neurosyphilis, and angiotensin converting enzyme for neurosarcoidosis all proved to be negative. An India ink stain was performed and proved to be negative. Serum and plasma testing for hepatitis B virus, hepatitis C virus, HIV-1, HIV-2, John Cunningham virus, Borrelia burgdorferi, Borrelia mayonii, Borrelia Garinii, and Borrelia afzelii were all negative. The prior hospital had tested a CSF sample for West Nile virus and Streptococcus pneumoniae antigen, both of which were negative. Blood and CSF cultures showed no growth for bacteria or fungi. The patient did have a positive QuantiFERON-TB Gold test. However, a follow-up chest X-ray was negative, AFB sputum culture ultimately showed no growth for 42 days, and sputum PCR for Mycobaterium tuberculosis was negative. A serum Epilepsy Autoimmune Evaluation (Mayo Clinic Laboratories) failed to reveal any of the 19 autoantibodies tested. A serum NeoCerebellar Degeneration Paraneoplastic Profile with Recombx (Quest Diagnostics) was unremarkable for any autoantibodies indicative of cerebellar degeneration. CSF and serum paraneoplastic autoantibody evaluations were negative. The patient's IgM, IgG, and IgA levels were all within the normal reference ranges. She ultimately received a five-day course of 400 mg/kg/day IVIG. Although the patient was not at baseline, she was discharged in an improved clinical condition with decreased visual acuity. She was instructed to follow-up as an outpatient with neurology, psychiatry, and infectious disease.

enteroviral meningoencephalitis, enterovirus, psoriatic arthritis, rituximab, viral encephalopathy

PMC4785710_01

Female

A 46-year-old female patient presented with chief complaints of painful, sudden diminution of vision in right eye, following trauma by a wooden stick 3 days prior. On presentation, visual acuity in the affected eye was the only perception of light with an inaccurate projection of light rays whereas visual acuity in the left eye was +0.2 LogMAR. Ocular examination showed purulent conjunctival discharge with matting of eyelashes, sealed corneal perforation with corneal infiltrates, and the anterior chamber was full of the exudates [Figure 1a]. The ultrasonography of the right eye showed dense vitreous exudates and retina was in suggesting the diagnosis of endophthalmitis. Corneal scrapings and conjunctival swabs sent for bacterial and fungal smears were negative. Diagnostic vitreous tap for bacterial and fungal smears was also done, and intravitreal antibiotics (vancomycin 1 mg in 0.1 ml and ceftazidime 2 mg in 0.1 ml) were administered. The patient was started on fortified vancomycin (50 mg/ml) eye drops 1 hourly; cefazolin (50 mg/ml) eye drops 1 hourly along with natamycin 5% eye drops 1 hourly in the right eye. The vitreous tap was also negative for bacterial and fungal smears. However, the patient developed panophthalmitis in 24 h with positive t-sign and thickened retinochoroid on ultrasonography [Figure 1b] that led to the painful blind eye. Considering the diagnosis of panophthalmitis and painful blind eye, the patient was counseled for evisceration. After obtaining informed written consent, evisceration was done, and the excised ocular tissue was sent for histopathological examination. Histopathological examination showed the presence of lymphocytic infiltrate with caseous necrosis suggesting granulomatous inflammation [Figure 1c]. Staining for acid-fast bacilli was positive [Figure 1d]. Polymerase chain reaction (PCR) of the corneal tissue also showed positivity for the tubercular antigen. The patient was investigated for any systemic focus of tubercular infection, but the results were negative. There was no past history of tubercular infection or contact. The patient was started on anti-tubercular therapy. After follow-up of 6 months, the patient was asymptomatic, and there was no systemic manifestation of tuberculosis.

panophthalmitis, posttraumatic, tuberculosis

PMC4379639_01

Female

A 32-years old female has presented with history of recurrent chest discomfort and left shoulder pain for 2 days. She has an acute stress at home regarding the health of her child and the symptoms started following this emotional outburst. The pain was not associated with sweating, shortness of breath or syncope. There was no past history of heart disease nor other conventional risk factors for ischemic heart disease like diabetes mellitus (DM), hypertension smoking, or illicit drug use. She has a history of gestational DM during her last pregnancy and has amenorrhea for 6 months. She was on diet and exercise regimen to lose weight since 6 months. On physical examination she was obese with a BMI of 34 kg/sqm2. Her physical examination showed normal heart sounds and normal blood pressure. An electrocardiogram (ECG) was taken and it showed sinus rhythm with symmetrical T wave inversions in leads V1 to V6. [Figure 1] Cardiac troponin I which was 0.62 ng/ml (normal < 0.04ng/mL) at presentation peaked to 6.38 ng/mL subsequently normalized after 1 week suggestive of MI. She was treated with aspirin, clopidogrel and enoxaparin injection in the emergency room. Her echocardiography was done and it showed hypokinesia of the mid and apical anterior septum and anterior wall with moderate left ventricular systolic dysfunction. She was taken up for coronary angiography on the next day. Her coronary angiography showed 75- % stenosis of the proximal left anterior descending coronary artery (LAD) and 50% lesion in the left circumflex coronary artery.(LCX) [Figure 2] She has undergone angioplasty and stenting to LAD with good result. [Figure 3] She remained pain free after the procedure. Serial ECGs showed normalization of the anterior wall ischemic changes [Figure 4] and normalization of the left ventricular function on follow up. Routine blood investigation showed anemia with hemoglobin of 11g/dL with microcytic and macrocytic red blood cells (RBS) with hypochromia. She was evaluated for cause of anemia and it revealed both iron deficiency and vitamin B12 deficiency. As she has no conventional risk factors for atherosclerosis and young age of presentation, her serum homocysteine and lipoprotein A (Lp (a)) levels were assessed. Serum Lp (a) was normal and serum homocysteine levels were elevated at 28.48 micromoles/L. She received vitamin B12 and iron supplementation and was started on folic acid for the hyperhomocysteinemia. The patient made a good recovery of her cardiac condition and improvement in anemia with normalization of the hemoglobin, blood pictures and vitamin B12. Her homocysteine level after 6 months of followup showed normal values suggesting that elevated homocystiene level was acquired due to nutritional deficiency of vitamin co -factors. She was advised to continue the started medication and to do lifestyle measures and she was followedup in the cardiology OPD and is doing well on follow up at 9 months.

myocardial infarction, hyperhomocyteinemia, risk factors, vitamin b12 deficiency

PMC7089917_01

Male

A 59-year-old male presented with a 3-month history of flu-like illness, palpitations, and atypical chest pain irradiating to the shoulders. The patient also noted also a decrease in his appetite with progressive weight loss of 4 kilos in 1 month. 1 month before admission, he had an exacerbation of his symptoms, with a new onset of cough, dyspnea increasing with inspiration, and chest pain improving when bending forward. In addition, he had some rare episodes of low-grade fever with night sweats. The patient's past medical history revealed asthma, chronic sinusitis, and acute intoxication with paracetamol. When he first consulted his physician, he was diagnosed with pericarditis and a right pleural effusion treated with colchicine (1 mg, 1 tablet daily), and steroids (0.25 mg/lg, then 0.5 mg/kg). An EKG showed a slow atrial fibrillation of 50 beats per minute, with low voltage QRS. A chest X-ray revealed a bilateral pleural effusion with cardio mediastinal enlargement. A CT scan showed a moderate bilateral pleural effusion, with a pericardial thickening of 5 mm and mild pericardial effusion. A pseudo-intrapericardial mass in the right anterior mediastinum and centered on the right coronary artery with multiple mediastinal adenopathy was also described. This presentation encouraged the physician to search for granulomatous lesions or tuberculosis or even to think about Wegener's disease, but malignancy was also an option. An additional abdominal ultrasound was suggestive of hepatomegaly. An ultrasound-guided thoracentesis of the pleural effusion was done, suggesting an exudative effusion indicating malignancy, especially lymphoma. Transthoracic echocardiography showed an effusive-constrictive pericarditis pattern. A decrease of >25% in the peak E wave velocity by pulsed wave doppler, due to a respiratory variation of the mitral inflow velocity was noticed, in addition to a visually respiratory phasic shift of the interventricular septum toward the left ventricle cavity during inspiration with an early diastolic mitral septal annulus velocity. Furthermore, an expiratory diastolic flow reversal of the hepatic vein is seen with a mild to moderate circumferential pericardial effusion. These findings encouraged the physician to perform more investigations with a transesophageal echocardiography. A transesophageal echocardiography revealed a mild circumferential effusion with a thick pericardium. An infiltrating mass in the right atrioventricular groove involved the right atrium and the right ventricular free wall, extending to the posterior free wall of the right atrium and probably the interatrial septum. The superior vena cava appeared thick also and probably infiltrated, as for the right pulmonary artery. A decrease in the emptying velocity <25 cm/s of the left atrial appendage with a suspicious thrombus was noticed. A pattern in favor of a primary cardiac tumor was most likely (Figures 1A-C). MRI may be used for evaluation of cardiac masses, extracardiac structures, involvement, and characterization of masses in the differentiation of tumors from intracavitary mural thrombi. It also helps in discriminating between benign versus malignant cardiac masses, emphasizing infiltration, invasion, and other signs of metastasis; but in our case, we opted for PET scan, being the gold standard in this area. Primary cardiac lymphoma can be hypointense on T1-weighted imaging and hyperintense on T2-weighted imaging, but it can demonstrate heterogeneous signal intensity. Contrast enhancement is frequent and may be homogenous or heterogeneous. A PET scan was done to study the extension of the tumor. A high-fatty diet with low carbohydrates 24 h before PET (no cereals, pasta, dry beans, fruits, sugar, honey, candy, desserts, starchy vegetables, alcohol, bread, rice, gravies, jams, milk, or caffeine) was initiated. The patient fasted for 6 h. There was no need to suppress the physiological myocardial uptake. The patient was positioned ~60 min after the intravenous administration of 8.3 mCi of FDG (fluorodeoxyglucose uptake). A non-contrast CT scan was acquired from the skull base to the mid thighs. A 3D emission scan of the same area was acquired. The patient's fasting glucose level was 94 mg/dl. The PET scan showed a cardiac mass infiltrating the right heart cavities and the interatrial septum, involving the pericardium. Diffuse metastatic mediastinal adenopathy with bilateral pleural effusion and metastatic pleural implants was observed. Two nodules in the upper lobes with bilateral cervical adenopathy and a right supraclavicular adenopathy and a retroperitoneal adenopathy with omental thickening and peritoneal implants in the pelvis were observed. It also revealed bilateral adrenal lesions with right renal mass. These findings were suggestive of cardiac sarcoma or cardiac lymphoma of the heart (Figure 1D) (Supplementary Video 1). For a definitive diagnosis, a percutaneous biopsy of the right supraclavicular adenopathy was performed (Figure 2). Pathology confirmed the diagnosis of a non-Hodgkin's cardiac lymphoma. The patient was treated with high doses of dexamethasone to relieve symptoms. He developed a severe symptomatic bradycardia and long pauses suddenly. A single chamber pacemaker VVI was implanted as a backup because the patient was in atrial fibrillation and no need for atrial lead in this case. Even with symptomatic treatments, he complained of severe shortness of breath, due to his severe bilateral pleural effusion. Bilateral pleural chest drainage was done as a salvage procedure because the patient was in severe respiratory distress. After the procedure, he experienced a rare complication: a re-expansion pulmonary edema. He was moved to the intensive care unit (ICU) and supportive therapy was given for stabilization and symptoms relief. After recovery, he complained of a new onset of diplopia. Brain CT was done to rule out cerebral metastasis with a lumbar puncture. These exams didn't reveal any abnormalities. Eight cycles of chemotherapy with the R-CHOP protocol. Rituximab, Cyclophosphamide, doxorubicin, vincristine, and prednisolone were initiated. After these cures, a new PET CT was performed. Complete metabolic treatment response was noted with a persistent focal prostatic uptake at the right base. An echocardiography declared a complete remission. There were no more infiltrated tissues, and the right ventricle regained its function (Figure 3). Few months later, the patient came to the hospital complaining of an external chest pain with palpation and no dyspnea or any other symptoms. On physical examination, a palpable subcutaneous thoracic mass was noticed. A total body CT scan revealed some new large left supra- and retro-clavicular, mediastinal, and pleuropericardic masses. The largest one was 6 cm. A PET scan confirmed a recurrence of his lymphoma. Three large hypermetabolic mediastinal masses with cervical, mediastinal, axillar, and hilar lymphadenopathy were observed. An invasion of the subpleura with a pulmonary parenchymal focus was also noticed. Two subcutaneous nodules were detected in front of the right pectoral muscle with a left pleural effusion and a markedly increased uptake at any site including new site of disease (Deauville score 5). A new cycle of chemotherapy began. Two months later, a PET scan for control was done with complete remission. Two weeks after, the patient was sent for bone marrow transplant to prevent further recurrences. The patient remained actually stable.

cardiac tumors, case report, lymphoma, pleuropericarditis, primary, right heart

PMC10427233_01

Female

The patient is a 20-year-old single man. He is unemployed and has a history of polysubstance abuse and family problems. For the past 2 years, he has used alcohol, cocaine, and medical substance (Lyrica and other medications). He has a history of social anxiety with biological symptoms, which are unresponsive to medication. He expressed low self esteem and feelings of worthlessness. He was pessimistic about the future, saying, "I don't see anything ahead for me." He described a passive death wish, but denied having any active suicidal thoughts. He described feeling fast heartbeats, blushing, trembling, sweating, trouble catching his breath, dizziness, and panic complaints, especially when talking to people and women in specific. He also described being unable to carry out a conversation with others, feelings of being watched and laughed at, and believing that he is ugly looking. He described having these complaints since adolescence. The patient has been an addict for the past 2 years. He started with Marijuana and alcohol, and then he tried several medical drugs. The patient talked about various upsetting memories of instances that took place during his childhood and up to his late teenage years. This included memories, such as not being given a choice or participating in decision making, his father's absence from the house due to travel, followed by the discovery of his marriage to another woman and the presence of children. His family's upbringing style is firm, authoritarian on the part of the mother, and permissive on the part of the father.

PMC9326303_01

Male

Case 1 involved a 62-year-old man with mild COVID-19 combined with hypertension, diabetes, and bronchiectasis. He had symptoms of a sore throat. After admission to the hospital on February 7 2020, he was administered with interferon alpha, arbidol, lopinavir, and other antivirals, and cefuroxime, cefoperazone, two antibiotics, and glucocorticoids. But the symptoms of sore throat were not relieved significantly. Three days after admission, several TCM doctors were invited to participate in the consultation of this patient, and then he was treated with one dose of QFPDD three times a day. Five days after admission, his sore throat improved. The nucleic acid test result turned negative. Computed tomography (CT) results of the lungs showed no exudation or signs of pneumonia, and no serious adverse events were observed. Nine days after administration, his condition further improved, and he was discharged from the hospital on February 16 2020. Case 2 was a 66-year-old woman with moderate COVID-19, hypertension, coronary heart disease, and diabetes. She visited the hospital because of cough, sputum, blood in the sputum, and fever. After admission on February 5 2020, as the patient's symptoms of cough did not improve, it was thought suitable to administer QFPDD through a joint consultation including TCM doctors. Therefore, in addition to taking lopinavir-ritonavir and arbidol, she was administered one dose of QFPDD three times a day. After one course of the treatment (3 days), symptoms of fever, anorexia, and nasal obstruction improved. After 7 days of QFPDD treatment, her cough was completely cured. After administering QFPDD for 23 days, the nucleic acid test result became negative. No serious adverse events occurred during the treatment, and the patient was discharged on March 10 2020. Case 3 was a 67-year-old woman with moderate COVID-19 and tuberculosis. She was admitted to the hospital on February 2 2020 with symptoms of cough. After group consultations with doctors practicing Chinese and Western medicine, she was treated with one dose of QFPDD three times a day. In addition, we administered interferon alpha and arbidol. After taking QFPDD for 2 days, her symptoms of cough significantly improved, and the nucleic acid test result turned negative after admission. Furthermore, serious adverse events were not observed. She recovered and was discharged on February 19 2020. Case 4 involved a 72-year-old man with moderate COVID-19 and tuberculosis. He was admitted to the hospital on January 22 2020, and presented with fever and cough. The symptoms were recurrent after conventional treatment and there was no significant improvement. After inviting doctors of TCM to participate in the consultation, he was advised to be treated with one dose of QFPDD three times a day. After taking QFPDD, the fever was quickly relieved. The cough was completely cured after 4 days of TCM treatment. Sixteen days after admission, the symptoms significantly improved and the nucleic acid test result was negative. Serious adverse events were not observed. The patient recovered and was discharged on February 14 2020. Case 5 involved a 60-year-old man with severe COVID-19 who also had type I respiratory failure and community-acquired pneumonia. He was admitted on February 15 2020 and presented with fever, fatigue, cough, and asthma. Once he was admitted, doctors held a group consultation with doctors practicing Chinese and Western medicine to decide whether to use QFPDD. After the evaluation by TCM doctors, he was treated with one dose of QFPDD three times a day. Seven days after admission, the symptoms significantly improved, and the nucleic acid test result was negative. On February 24, chest CT showed improvement in the lung lesions. No serious adverse events occurred during the treatment. The patient was cured and discharged on February 26 2020. Case 6 involved a 66-year-old man with severe COVID-19 and lobar pneumonia. He was admitted to the hospital on February 16 2020 and presented with fatigue, anorexia, and asthma. The doctors held a group consultation with doctors practicing Chinese and Western medicine to decide whether to use QFPDD. This patient was treated with one dose of QFPDD three times a day after admission. After taking two courses of QFPDD, the symptoms were quickly relieved; scattered ground glass, strip, and dot film shadows appeared on both sides of the lung, and the absorption of lung lesions was reduced compared with that measured on the day of admission. Serious adverse events were not observed. We compared chest CT images before and after taking QFPDD (Figure 1). After 29 days of treatment, the symptoms significantly improved and the nucleic acid test result became negative. The patient was discharged on March 18. Case 7 involved a 65-year-old man in critically ill condition. The patient exhibited a fever of unknown origin, accompanied by cough, paroxysmal dry cough, fatigue, and asthma. On February 16 2020, he was transferred to the hospital because of fever and cough for more than 20 days. No significant improvement was observed after conventional treatment. On February 21, relevant experts and TCM doctors were organized for joint consultation and decided to administer QFPDD. After QFPDD administration, the symptoms rapidly improved, and chest CT showed partial absorption on February 25. Serious adverse events were not observed. The patient was cured and discharged on March 8 2020. Case 8 was an 82-year-old man who was critically ill. On February 8 2020, he was admitted to the hospital because of a cough for 8 days and fever for 7 days, accompanied by chills, sore throat, muscle soreness, fatigue, and other discomforts. Respiratory diseases, including respiratory failure, chronic bronchitis with emphysema, and electrolyte disorders, were observed. Chest CT showed scattered ground glass and mesh shadows in lungs, subpleural distribution, interstitial involvement, and scattered strip shadows in both lungs, mainly in the lower lobe. He was considered critically ill on February 11. After treatment, his airtightness was relieved and his blood oxygen saturation was approximately 97%. Interferon and acetylcysteine were administered, and the 13-day treatment had no significant effect on chest CT. On February 21, relevant experts and TCM doctors were organized for a consultation and decided to administer QFPDD after discussion. After two courses (February 27, 19 days after admission), symptoms such as cough and asthma were significantly reduced, and the nucleic acid test result turned negative. Before being discharged, chest CT showed scattered spots, plaques, ground glass, and cable shadows in the multi-lobar segments of both lungs, which were much better than those measured before admission. No serious adverse events occurred during QFPDD administration, and the patient was discharged on March 10 2020. Detailed information of the aforementioned eight cases is shown in Figure 2, Figure 3, Table 2, and Table 3.

covid-19, qingfei paidu decoction, tcm, case series, respiratory diseases

PMC9359940_01

Male

The patient was a 10-year-old boy who presented with eyelid edema on awaking the day before admission. He attended a local hospital, which confirmed proteinuria 3+, and he was referred to our hospital for admission. Based on the patient's weight gain of approximately 3 kg, mild anorexia, and clinical examination, he was diagnosed with primary nephrotic syndrome and was admitted to the hospital. He had no medical history and was on no medication. Before admission, he lived with his mother and sister, and his father worked away. He played basketball three times a week as a club activity. Written consent was obtained from the patient and his parents for publication of this case report. Physical examination revealed the following: height 134.6 cm, weight 27.2. kg; blood pressure (BP) 122/66 mmHg; heart rate (HR) 93/min, and oxygen saturation 99%. Blood chemistry showed total protein 4.0 g/dl, serum albumin (Alb) 1.2 g/dl, blood urea nitrogen (BUN) 16 mg/dl, creatinine (Cr) 0.46 mg/dl, Na 139 mEq/l, white blood cell count 4460/mul, C-reactive protein 0.1 mg/dL, and hematocrit 38.7%. Urine testing showed a urine protein level of 1189 mg/dL and a urine creatinine level of 185.8 mg/dL, resulting in a urine protein/creatinine ratio (UP/Cr) of 6.4. A cardiothoracic ratio of 48.7 was assessed on chest radiography, with no iliopsoas image. Abdominal ultrasonography showed slight renal hyperintensity and ascites. Prednisolone (PSL) was started at 50 mg (2 mg/kg/day) on the 3rd day. After admission, weight and edema decreased, whereas systolic BP remained in the 120-130 mmHg range, and 2 mg enalapril maleate was started on the 5th day. UP/Cr was below 2.0,) the definition of nephrotic syndrome in pediatric patients, after the 12th day. Therefore, the effects of PSL treatment were evident, and renal function was expected to improve, so rehabilitation was started on the 15th day. The patient was independent in all activities of daily living at the start of rehabilitation. Physical function was evaluated on days 15, 29, and 51 of hospitalization. Measurements included grip strength, knee extension strength, the sit-up test, side-step test, sit-and-reach test, and 6-min walk test (6 MWT). Grip strength was measured using a Smedley digital hand dynamometer with the patient in a standing posture. Measurements were made twice, alternately on the right and left sides, and the average of the highest value on each side was used. Knee extension strength was measured using a hand-held dynamometer (mu-tas F1, ANIMA, Tokyo, Japan) in a sitting square, with the hip and knee at 90 flexion.) The sit-up, side-step, and sit-and-reach tests were performed according to the method described in the new fitness test recommended by the Ministry of Education of Japan.) In the sit-up test, a test of trunk muscle strength, the number of times both elbows touched both thighs in 30 s was counted with the patient starting from a supine position with both arms folded in front of the chest and both knees held at 90 . The side-step test, an agility test, was measured using three lines drawn at intervals of 100 cm as the measurement area; the patient stands straddling the center line and, at the "start" signal, side-steps until crossing or touching one sideline, then returns to the center line and side-steps again until crossing or touching the opposite line. The measurement time was 20 s, and the number of times the center line was crossed was recorded. The sit-and-reach test, as a flexibility test, was measured by placing both legs in the flexibility box, and with both arms stretched out at shoulder width, the box was pulled forward with both hands to assume a long-sitting posture. The patient slowly bends forward and moves the slider on the box straight ahead as far as possible, taking care to keep the hands one above the other and not to bend the knees. The distance the slider was moved by the outstretched clasped hands when bending forward was measured. The 6 MWT was measured by walking as fast as possible along a marked indoor corridor and recording the total distance traveled after 6 min according to the methodology of the American Thoracic Society.) Alb, BUN, eGFR, and UP/Cr were obtained from medical records. UP/Cr was examined to evaluate the safety of rehabilitation. The measurement period was from the 19th day, just after the start of weekly rehabilitation, to the 54th day, the day of discharge. Resistance training, balance exercise, and aerobic exercise therapy were administered for 40 min, five times a week. For resistance exercise, calf raises and squats were performed as 2-3 sets of 20 repetitions, and for balance exercise, 2-3 sets of standing on one leg for 1 min on each side were performed. Aerobic exercise was performed on a bicycle ergometer for 20 min at an intensity of 60% of the peak work rate (peak WR) calculated in the exercise tolerance test, and the Borg scale and heart rate were monitored and adjusted accordingly. Systolic BP, diastolic BP, and HR before and after rehabilitation during hospitalization were measured, and the average values were calculated. Karvonen's formula determined the percentage of the HR during aerobic exercise to the maximum HR measured in the exercise tolerance test. The exercise tolerance test was performed only once as an initial evaluation using a bicycle ergometer to measure peak WR. The protocol of the exercise load test was a 3-min warm up followed by a multistep incremental load of 10 W/min at 50 rpm. Improving balance, muscle strength, and exercise tolerance are important for maintaining athletic performance in basketball, the patient's preferred sport. Therefore, balance training was included in the exercise program for this patient. After the start of exercise therapy, the patient was steroid resistant. A renal biopsy was performed on the 34th day, and the patient was diagnosed with minimal change nephrotic syndrome. Subsequently, steroid pulse therapy was administered twice for three days, from 41st to 43rd and 48th to 50th day. No adverse events were observed before or after renal biopsy or steroid pulse therapy. The PSL dose was reduced to 25 mg on the 43rd day. The blood glucose level before breakfast was 142 mg/dl on day 49, indicating steroidal hyperglycemia, but this had decreased to normal levels on day 54. The patient was discharged home on the 54th day, and PSL 25 mg and an angiotensin-converting enzyme inhibitor 2 mg were administered. After discharge from the hospital, the patient was treated with pulse steroid therapy once a month, and cyclosporine A was considered after 4-6 months, depending on the response to pulse steroid therapy. The amount of energy provided by the patient's diet was increased from 2000 to 2300 kcal from the 25th day. From the 15th to the 33rd day, resistance exercise, balance exercise, and aerobic exercise were performed on the lower limbs. Bed rest was ordered until a renal biopsy was performed on the 34th; on the 35th day, based on the biopsy findings, the patient was released from bed rest. From the 36th day onward, bedside exercises for the lower limbs and gait training in the ward were performed. The amount of exercise was gradually increased. During steroid pulse therapy, exercise therapy was administered in the afternoon after the steroid pulse. During the 43rd-53rd day, lower limb resistance exercise, balance exercise, and aerobic exercise were resumed.

acute phase, exercise therapy, pediatric nephrotic syndrome, physical function

PMC5312194_01

Female

Pigmented Bowen's disease is a rare subtype of Bowen's disease, accounting for 2% to 5% of all cases. It manifests as a slow-growing, well-defined, hyperpigmented plaque, and should be included as a differential diagnosis of pigmented lesions. The present case stands out for the lack of dermoscopic criteria suggestive of pigmented Bowen's disease and the presence of streaks. Thus, it was not possible to set it apart from a melanocytic lesion by dermoscopy. Our patient was a 67-year old female, skin type IV, with no prior diseases, with a history of progressively growing dark lesion on her left buttock that had been present for the past five years. Clinical examination revealed a 1 cm hyperpimented (half dark brown and half light brown) macule with relatively regular borders (Figure 1). Dermoscopy showed an amorphous lightbrown areaadjacent to a dark brown area, containing irregularly distributed globules, streaks and grayished-black portions (Figure 2). Seborrheic keratosis and melanoma were the postulated as working diagnoses. An excisional showed loss of polarity, atypias in all layers of the epidermis, mitoses, dyskeratosis and dyskaryosis (Figure 3). The Fontana-Masson stain showed a heavy accumulation of melanin in the epidermis and melanophages in the upper dermis (Figure 4). Bowen's disease, or squamous cell carcinoma in situ , is an epithelial neoplasm that may rarely manifest as a pigmented disorder. It has been more frequently described in patients with high skin types and in sun-protected areas such as lower limbs and intertriginous areas. Clinically, it is a slow growing, well-defined, unevenly pigmented plaque, with a scaling, velvety, verrucous or flat surface. The differential diagnoses include - melanocytic lesions (nevi or cutaneous melanoma), solar lentigo, seborrheic keratosis, lichen planus-like keratosis, pigmented actinic keratosis and pigmented basal cell carcinoma. Since 2004, several dermoscopic findings have been described, and dermoscopy has proved to be an important diagnostic tool. Zalaudek et al. reported the following findings in a series of 10 cases: desquamative surface (90%), small brown globules grouped and irregularly distributed in the lesion (90%), glomerular vessels (80%), greyish homogeneous pigmentation, as well as pigmented network (10%), and streaks (10%). In the largest case series of cases thus far published Cameron et al. described the dermoscopic features of 52 cases of pigmented Bowen's disease. The most common pattern (48%) was amorphous (with no structures), followed by the association of amorphous pattern and dots (35%). Hypopigmented areas ( pink, normochromic or white) without structures were seen in 67% of the lesions. Vessels were detected in 67% of the lesions, and the glomerular vessels were the most frequent (44%). Dotted or glomerular vessels in linear arrangement were detected in 12% of the cases. The presence vessels and brown or gray dots in arrangened in linear fashion in the periphery of the lesion was considered by the authors to be the most suggestive, and perhaps the most specific, finding of pigmented Bowen's disease. These changes have not been described in other lesion and were present in 21% of the cases. The predominant dermoscopic finding in our case was the amorphous pattern . The presence of sreaks turned the diagnosis even more challenging since since this finding is higly suggestive of a melanocytic lesion. However, pigment network and streaks are relatively common in pigmented Bowen's disease and have already been reported with an incidence ranging from 4% to 10%. The differential diagnosis with other pigmented diseases continues, therefore, to be challenging. Albeit rare, pigmented Bowen's disease should be suspected especially if glomerular vessels or brownish dots are found to be linearly arranged in the lesion, or if there are no clear criteria of melanocytic lesion in the dermoscopy, given that the brownish amorphous pattern seems to be the most frequent one. Some lesions may show streaks, making it even more difficult to tell them apart from melanocytic lesions. Dermoscopy is not always diagnostic, but leads to a proper approach. In this case, surgical removal was chosen due to dermoscopic features.

PMC4129850_01

Male

A 30-year-old man presented with fever for seven days and generalized abdominal pain for one day. On examination, he was febrile, and had signs of peritonitis. X-ray examination of the chest showed free air under both the domes of the diaphragm. He was taken up for exploratory laparotomy after adequate resuscitation. Laparotomy was performed by a midline incision and revealed purulent peritoneal fluid, mainly in the pelvis. The terminal ileum had a small perforation along the anti- mesenteric border, about one foot proximal to the ileocaecal junction. There were no other significant findings on laparotomy. After thorough peritoneal lavage, the ileal perforation was freshened along the margins and closed primarily using interrupted sutures. The edges of the perforation were sent for histopathological examination. The post-operative period was uneventful. The histopathological report of the perforation margins that were sent intra-operatively revealed caseating epithelioid cell granulomas with Langhans' giant cells and a dense mixed inflammatory cell infiltrate within the mucosa and submucosa (Figure 1). On receiving this report, the patient was started on anti-tubercular treatment and remained well on follow up. Efforts were made to detect a primary focus of tuberculosis, but were unsuccessful.

ileum, perforation, peritonitis, tuberculosis

PMC5846957_01

Male

A 3-month-old male intact Somali cat weighing 0.63 kg presented to the Small Animal Hospital of the University of Bern for evaluation of seizures. Approximately 4 weeks previously, the cat had been bitten in the head by a dog. Immediately after, the cat had one generalised seizure and was ataxic for 24 h. Two weeks later, the cat began having intermittent tonic-clonic seizures on a daily basis. It also showed opisthotonus and tremors. Upon evaluation by its primary veterinarian, blood sampling revealed hypoglycaemia as the only abnormality. The cat received subcutaneous fluid therapy, including glucose supplementation, and was discharged with no additional treatment. The cat did not have any more seizures; however, its mental dullness persisted and, according to the owner, it was blind. The cat lived indoors in an apartment with one dog and 10 other cats, four of which were littermates. It was up to date on vaccinations and had been recently dewormed. Upon evaluation at the University Hospital, 4 weeks after the dog bite, physical examination showed a small-statured cat with proportional appearance. It was moderately apathic. Apart from mild hypothermia (37.6 C), clinical parameters were all within normal limits. On neurological examination, the cat was severely obtunded and showed mild-to-moderate ataxia. Postural reactions were absent on all four limbs. Menace response and nasal sensation were absent bilaterally. The evaluation of the remaining cranial nerves proved normal. The neuroanatomical location was forebrain and cerebellum. At that time point, differential diagnoses included metabolic disorders such as portosystemic shunt or hypoglycaemia, viral encephalitis, TBI, storage disorders and congenital malformation of the brain or the heart. Emergency blood work revealed normoglycaemia (4.2 mmol/l; reference interval [RI] 3.2-5.7 mmol/l). Complete blood count (CBC) was unremarkable. A serum biochemistry panel showed a slightly elevated urea (15.4 mmol/l; RI 6.5-12.2 mmol/l) with normal creatinine (112 mumol/l; RI 52-138 mumol/l) and mild hyperkalaemia (5.3 mmol/l; RI 3.1-4.9 mmol/l). Pre- and post-prandial bile acids were within the RI (1.7 mumol/l and 1.5 mumol/l, respectively; RI 0-15 mumol/l). A faecal examination, including direct examination and centrifugation flotation, was negative. Four hours after admission, repeat blood sampling revealed marked hypoglycaemia (<1.5 mmol/l) using a portable glucose meter (AlphaTRAK; Abbott Animal Health). Hypoglycaemia was confirmed in the laboratory using a biochemistry analyser. An intravenous (IV) bolus of 50% glucose (0.5 ml diluted 1:3 in 0.9% sodium chloride solution) resulted in clinical improvement. The cat was more alert and ambulatory. An IV 5% glucose continuous rate infusion (sodium chloride 0.9% w/v and glucose 5% w/v solution for injection [G25; B Braun Medical]) was commenced. Given the history of head trauma a few weeks prior, MRI of the brain and a cerebrospinal fluid analysis were undertaken, both of which were unremarkable. General anaesthesia was uneventful. However, 12 h later, the cat's general condition suddenly deteriorated and it was found in lateral recumbency, stuporous, hypothermic (36 C) and hypoglycaemic (<1.5 mmol/l). Following the administration of an IV bolus of 0.5 ml 50% glucose, the cat's stupor and hypothermia rapidly resolved. It was more alert and started eating. Frequent feedings every 2-3 h were instituted, and the cat's glycaemia was monitored every 4 h. Over the next 48 h, glucose substitution was slowly decreased and finally stopped. The cat's condition was good, with no neurological deficits, and its blood glucose remained stable, between 3.2 and 6.5 mmol/l. Four days after initial presentation, the cat was discharged with instructions to feed the cat frequent meals throughout the day, and to contact us if the cat showed any clinical signs. Two weeks after discharge, the cat was presented again with stupor, hypothermia and with severe hypoglycaemia (<1.5 mmol/l). For the first time, the owner recognised that the cat was smaller and lighter than his littermates. Also, the cat was more lethargic and not as active as the others. On physical examination, it was noted that the cat's haircoat was woolly and contained fewer primary guard hairs. CBC showed a mild anaemia (haematocrit 22%; RI 27-47%), mild leukopenia (3.8 x 109/l; RI 6.5-15.4 x 109/l) with neutropenia (1.6 x 109/l; RI 2.5-12.5 x 109/l) without left shift or toxic changes. Serum biochemistry panel revealed slightly elevated urea (14.1 mmol/l; RI 6.5-12.2 mmol/l) with normal creatinine (81 mumol/l; RI 52-138 mumol/l). Both fasting serum cortisol (2.18 microg/dl; RI 0.50-8.80 microg/dl) and post-ACTH stimulation (6.72 microg/dl; RI 0.50-8.80 microg/dl) were within the RIs. Total thyroxine concentration was also normal (19.8 mmol/l; RI 16-46 mmol/l). Insulin concentrations were unmeasurably low (<1 mU/l; RI 5-30 mU/l). As before, the cat's condition responded rapidly to IV glucose substitution and was discharged 3 days later. The serum IGF-I concentration was significantly low (<25 ng/ml; RI >50 ng/ml). Blood sampling and measurements were repeated twice and the results verified, confirming a presumptive diagnosis of juvenile pituitary hyposomatotropism. Concentrations of IGF-1 from four other Somali cats, (two littermates of the same age, one adult half-sister and one adult unrelated cat) were also determined and were all within normal limits: 394 ng/ml (sibling 1), 614 ng/ml (sibling 2), 406 ng/ml (half-sister) and 561 ng/ml (unrelated Somali cat). When the owner brought the other siblings for blood sampling, the small stature, mental dullness and haircoat abnormalities of the cat became obvious (Figures 1 and 2). Given that porcine GH is not available in Europe, no hormonal replacement therapy was offered to the owner. The owner was recommended to check the cat's glycaemia at home, using a portable glucose meter, once daily for 1 week, and then once weekly for 4 weeks, and whenever the cat showed neurological signs. The glucose concentration was always normal and the cat did not show neurological signs. However, the cat's physical retardation and woolly haircoat with secondary hair retention persisted. One year after initial presentation, the owner reported that the cat showed polyuria and polydipsia. The cat was found to be mildly azotaemic (creatinine 178 mumol/l [RI 52-138 mumol/l] and urea 19.6 mmol/l [RI 6.5-12.2 mmol/l]) and urinalysis showed isosthenuria Specific Gravity (SG 1.010) and alkalinuria (pH 7.9) without proteinuria. Arterial blood pressure was normal. An abdominal ultrasound showed normal renal size, shape and internal architecture. There was very mild bilateral pyelectasia (left renal pelvis: 2 mm; right renal pelvis: 1.7 mm; RI <1 mm). Urine culture was negative. Ten days later, alkalinuria and renal pyelectasia persisted. Given the suspicion of a pyelonephritis, treatment with amoxicillin-clavulanate (20 mg/kg orally q12h) was prescribed. Two weeks after starting antibiotic therapy, kidney values, urinalysis and ultrasound findings were re-checked, all of which remained unchanged. Antibiotic therapy was then discontinued. Kidney values stayed stable for the following 6 weeks. The cat was diagnosed with chronic kidney disease (CKD) IRIS stage 2 without proteinuria and hypertension.

PMC7784608_01

Male

Patient 1: A 22-year-old male patient admitted to our hospital on May 1, 2000, with 92% TBSA burns (87% deep burns and 5% superficial), sparing the groin and both feet (Fig. 2A). This patient developed a severe inhalation injury subsequent to an explosion while working on a fuel tank and he was intubated on site. The first days after the patient admission were marked by a severe hypovolemic shock requiring a resuscitation with 45 l of fluid within the first 24 h, which led to an abdominal compartment syndrome (ACS) followed by emergency decompressive laparotomy. He was also treated with large escharotomies on the whole body; the escharotomy on the abdominal wall was closed at day 3. Over the first month, the patient developed many episodes of systemic infection and septic shock (n = 11) with secondary acute respiratory distress syndrome (ARDS). Mechanical ventilation was maintained for 4.5 months and an open lung biopsy showed interstitial lung disease with bronchiolitis obliterans organizing pneumonia (BOOP). Deep burns of the hand necessitated secondary reconstruction, but distal phalangeal amputations were inevitable. The equivalent of 198% TBSA was debrided and we used temporary cover with 100% TBSA cadaver skin (glycerol preserved). Several reconstructive surgeries and skin grafts were performed on the body and face (nose, eyelids, ears, and lips). Overall, he had the equivalent of 101% TBSA grafted, including 75% TBSA of CEA, 18% of CDEA, and the rest with autologous skin grafting: total of 30 surgical interventions. After spending 162 days in the intensive care unit (ICU), he was then transferred to the plastic surgery floor, where he received intensive physio- and ergo-therapy, and was finally discharged after a total of 18-month hospitalization.

biological bandages, burn, cell therapy, cultured epithelial autograft, skin tissue engineering, wound care

PMC7784608_02

Male

Patient 2: A 39-year-old male patient admitted to our hospital on July 27, 2017 with 90% TBSA deep and intermediate burns after an explosion of solvents in his workshop. The burns were mainly of the face and neck sparing the groin and both feet as for patient 1 (Fig. 2B). On site, he was stable with no signs of respiratory distress but was intubated because of perioral burns. For resuscitation, he received 16 l of fluid within the first 24 h. Multiple escharotomies were performed on the trunk and the four limbs; closure of the escharotomies on the trunk occurred on days 17 and 24. At day 8, the patient developed an acute renal failure KDIGO III with a normal intrabdominal pressure and no finding on the computed tomographic scan. Continuous renal replacement therapy was needed until day 46, followed by intermittent dialysis until day 63. Although there was no inhalation injury on bronchoscopy, the patient remained intubated for 30 days. He had five infection events (three cutaneous and two pneumonia). His wounds were debrided, followed by skin grafting without requiring any amputation. The same surgical debridement technique was used as for patient 1, using a Weck's blade, a Watson's blade, and curettage. As often as possible, a tourniquet for the limbs was employed. Wounds were injected with saline adrenalized solution before debridement, to minimize blood loss (as a standard procedure). As for patient 1, timing of debridement started at day 3 post traumatism, with a maximum of 15% to 20% TBSA debridement per surgery, and the mean interval between debridement was 48 h until the burned tissues were fully accomplished. The equivalent of 110% TBSA was debrided, 189% TBSA was covered with Biological Bandages based on progenitor cells and used as temporary cover, and 7% TBSA was covered with glycerol-preserved cadaver skin. Overall, the patient had 85% TBSA grafted (80% TBSA of CEA and the rest with autologous skin graft), with a total of 15 surgical interventions. The final evaluation of deep burns was evaluated at 75% TBSA versus 81% TBSA at admission (Fig. 2B), because several body zones of second intermediate burns (chest, abdomen, back, thighs, and legs) healed by themselves. These zones received the application of Biological Bandages (Fig. 3), which when compared to past experience were thought to stimulate these intermediate-degree burns toward a spontaneous healing of particular body regions (Fig. 4). After spending 76 days in the ICU, he was transferred to the Plastic Surgery floor, then to a rehabilitation center, where he received intensive physio- and ergo-therapy. He was finally discharged after a total of 9.5-month hospitalization. The data for both patients regarding their burn injury and the received medical treatments are summarized in Table 1. A summary over time of the main surgical interventions and the corresponding body regions is shown for both patients in Fig. 3.

biological bandages, burn, cell therapy, cultured epithelial autograft, skin tissue engineering, wound care

PMC9848806_01

Female

A 19-year-old female sought medical attention at the primary care clinic for dyspnea on exertion (DOE) and a cough productive of blood-tinged sputum. The patient was diagnosed with pneumonia and was prescribed oral antibiotics as an outpatient. Approximately two weeks later, her hemoptysis progressed to daily episodes of 1-2 teaspoons of fresh blood and her DOE also increased to a point where she was feeling tired while performing her activities of daily living (ADL). She was then admitted to the local emergency department for further workup. Her associated symptoms included weight loss of 30 lbs, subjective low-grade nocturnal fever and drenching night sweats. She also had a past history of menorrhagia and her social history included incarceration for a year approximately 6 months ago. She denied any history of smoking, multiple sexual partners, or drug abuse. Blood workup at the hospital indicated severe anemia with hemoglobin (Hb) of 4.6 g/dL and the chest X-ray showed bilateral infiltrates. With her history of menorrhagia, she was diagnosed with chronic blood loss anemia, transfused packed red blood cells, and advised to follow-up with gynecologist. The chest X-ray was interpreted as bacterial pneumonia and the patient was discharged with oral antibiotics to follow-up in an outpatient clinic. Approximately one week later, her symptoms worsened to severe dyspnea at rest along with substernal chest pain and persistent hemoptysis and she was eventually brought to the emergency department at our hospital. On arrival, her vital signs were significant with temperature of 36.5 C, blood pressure of 126/84 mmHg, pulse 115 beats/minute, respiratory rate of 15 breaths/minute, and oxygen saturations of 90% on room air corrected to 96% with a 2-liter nasal cannula. Upon physical examination; the patient was anxious; coarse crackles were heard in bilateral lung fields; tachycardia with a regular rhythm; and 1+ pitting edema in bilateral lower extremities were noted. Initial laboratory work was notable for hemoglobin (Hbg) 8.5 g/dl, hematocrit (Hct) 28.6%, mean corpuscular volume (MCV) 91 fl, platelets 198 x 103 mul, serum sodium 140 mEq/L, potassium 3.5 mEq/L, chloride 110 mEq/L, bicarbonate 21 mEq/L, serum creatinine 0.66 mg/dl, blood urea nitrogen (BUN) 5 mg/dl, blood glucose 83 mg/dl, prothrombin time (PT) 14.2 second, partial thromboplastin time of 24 seconds, international normalization ratio of 1.1 and a negative respiratory viral panel. Urine analysis was remarkable for hematuria (176 RBCs/HPF) without red blood cell cast, 7 WBCs/HPF, 100 mg/dl proteinuria, and the absence of glucose or ketones. Chest X-ray revealed patchy bilateral infiltrates, as shown in Figure 1. The patient also underwent computed tomography (CT) of the chest with a contrast pulmonary embolism protocol, which revealed diffuse bilateral pulmonary infiltrates with ground glass and diffuse mediastinal lymphadenopathy (Figures 2(a)-2(d)). Based on the clinical and radiological findings, the patient was diagnosed with pneumonia and admitted to the medicine floor. She was started on intravenous (IV) azithromycin and ceftriaxone. However, her hypoxemia worsened in the next 12 hours with an increased oxygen requirement to 5-liter nasal cannula. Pulmonology was consulted, and the patient was moved to the intensive care unit (ICU). Given the high index of suspicion for alveolar hemorrhage, her heparin drip was stopped. Patient's oxygen requirements continued to worsen, and she was eventually intubated. Follow-up chest X-ray is shown in Figure 3. To establish a diagnosis, flexible bronchoscopy was performed, which revealed a gross bloody return with gradual darkening on three subsequent bronchoalveolar lavages (BAL) consistent with diffuse alveolar hemorrhage (DAH). The BAL cell count was remarkable for 743,000 mm3 RBCs and a total WBC count of 3233 mm3 with 78% neutrophils and 20% lymphocytes. BAL cultures were reported negative for bacterial growth. Autoimmune workup revealed positive antinuclear antibody (ANA), high antidouble stranded DNA titer of 48 IU/ml, high antismith antibodies titers of 4.3 AU/ml, normal rheumatoid factor titers (<20 mu/ml), negative antibasement membrane antibody (anti-GBM), negative cytoplasmic antinuclear antibody (cANCA) and negative perinuclear antinuclear antibody (pANCA). A diagnosis of diffuse alveolar hemorrhage secondary to systemic lupus erythematosus (SLE) was made. Patient was started on pulse dose of Methylprednisolone, 1 gm IV for 5 days oral mycophenolate mofetil (MMF) for maintenance immunosuppression therapy. She also underwent 3 sessions of plasmapheresis. Her condition improved in a week, she was extubated to nasal cannula and subsequently discharged home on stable doses of prednisone and MMF. Six weeks later, the laboratory reported that her BAL cultures grew Mycobacterium tuberculosis (MTB). The patient was informed about the recent finding of tuberculosis and was setup in outpatient TB clinic for antituberculous therapy (ATT). She is currently finishing her 6 months of ATT with reduced dosing of MMF with close monitoring without any further complications in her condition.

PMC9148264_01

Female

A 44-year-old female farmer presented with erythematous blisters with paroxysmal tingling on the left side of the lower back and abdomen for 8 days and the same rash with pain on the right side of the chest, armpit and back for 7 days. After the onset of the disease, the patient was diagnosed with a "snake pan sore" by a local village doctor. The patient refused the treatment of Western Medicine and believed in alternative methods. In brief, patient used the "circling method" handed down by folklore, asking a so-called experienced person to dip a brush in ink and make circles around the skin lesions in an attempt to stop the rash from progressing. The lesions did not improve but continued to develop, and the pain became significantly worse, so she came to our department. Before the acute episode of HZ, the individual was in good health and denied any history of chronic illnesses, such as hepatitis, tuberculosis, diabetes, tumors, or connective tissue disease, or hormone or immunosuppressant medications. Further inquiry into the medical history revealed that the patient had become angry with her husband for some reason one month before the onset and that both parties were noisy and intended to divorce. Since then, she had been feeling depressed, desperate, and fatigued all over her body. The patient's physical examination showed no systemic abnormalities. Dermatological conditions included the following: lesions on the left side of the waist and abdomen (Figure 1A) and posterior back (Figure 1B), on the right side of the chest (Figure 1C), axillae (Figure 1D), and posterior back, with clusters of red papules and small blisters the size of small rice grain on a base of flaky erythema, with the rash distributed in strips along the intercostal nerves. Part of the blisters burst, and there were small decayed surfaces and black scabs stained with the exudate of ink. After further discussion, the patient stated that she had chickenpox caused by a primary VZV infection in childhood. The patient denies close contact with someone who had chickenpox or shingles before suffering from HZ and has not received the varicella zoster vaccine. Lab results (Supplementary Tables 1-3) showed an abnormal count of lymphocytes at 0.94*109/L, and other values in the complete blood count test are normal. Routine urinalysis (-), liver and kidney function tests (-), blood glucose (-), human immunodeficiency virus (HIV) (-), hepatitis (-), and tuberculosis antibodies (-), normal chest X-rays, ECG, and abdominal ultrasound. Thus, we diagnosed the patient as HZ duplex bilateralis. (References: 1. Chinese diagnostic standard) Similar diagnostic procedures were also reported by other studies. (References: 2. Other papers used the same protocols. (may be more than one paper)) 5 papers published in good journals. Acyclovir 0.25g q8h IV, gabapentin capsules 10 mg/day orally, vitamin B1 10 mg/day orally, and mecobalamin tablets 0.5 mg/day orally were prescribed for treatment. After 10 days of treatment, the original erythema and rash basically disappeared. All the papules and blisters dried up and crusted over, with a small amount of hyperpigmentation in some of the rash areas. Patients still had paroxysmal pain and we prescribed mecobalamin tablets, vitamin B1, and gabapentin capsules orally for maintenance treatment, and the pain disappeared after three weeks.

bad mood, duplex bilateralis, herpes zoster, immunological tests, viral infections

PMC9206550_01

Female

A 4-year-old female alpaca introduced from China was subcutaneously injected with 100 mug purified human TIM-3 protein (Sino Biological, Inc.) plus adjuvant FAMA (Gerbu, Germany) once a week. Peripheral blood was collected from jugular vein before the first injection and 7 days after the last injection, and serum was isolated by Sepmate tubes for comparison of the antibody titer by ELISA. A 96-well microplate well (Nunc, Danmark) was coated with 100 muL 1 mug/mL TIM-3 protein, and blank wells were coated with PBS. After washing and blocking, the preimmunization and postimmunization serum was added at serial dilutions. HRP-conjugated goat against Llama antibody (Thermo) was added as the II antibody, followed by the addition of ABTS reagent for the development of reaction. The measurement of OD (405 nm) was performed with the use of a microplate reader (Bio-Rad). All animal experiments were carried out with the approval of the relevant ethics committee and in strict accordance with the relevant regulations on the care and use of experimental animals in the international code of ethics and national health guidelines. Using Sepmate tubes (STEMCELL) and Lymphoprep (STEMCELL), 100 mL peripheral blood was drawn to isolate peripheral blood mononuclear cells (PBMCs) 7 days after the last immunization. Trizol (Invitrogen)-separated total RNA from PBMCs was subjected to cDNA synthesis by SuperScript II reverse transcriptase (TAKARA) using random 6 primer. Then, via nested PCR, VHH gene amplification was done using primers CALL001 (5'-GTCCTGGCTGCTCTT CTACAAGG-3') and CALL002 (5'-GGTACGTGCTGTTGAACTGTTCC-3'). The heavy chain antibody fragments (700 bp) were subjected to agarose gel (1%) electrophoresis and extraction via Quick Gel Extraction (Thermo) and then used as the template for the second PCR via primer VHH-sense (5'-CTAGTGCGGCCGCTGGAGACGGTGACCTGGGT-3') and VHH-antisense (5'-GATGTGCAGCTGCAGGAGTCTGGRGGAGG-3'). These primers, designed for framework regions 1 and 4, involved restriction sites Pst 1 and Eco91I. The second PCR product was electrophoresed and purified by PCR Purification Combo Kit (Thermo). The phagemid vector pMES4 was digested with Pst 1, XbaI, and Eco91I restriction enzyme, while purified PCR product was digested with Pst 1 and Eco91I. The triple-digested pMES4 and double-digested PCR product was ligased with T4 DNA ligase enzyme (Invitrogen). After transfecting with the recombinant vector, chemically competent E. coli TG1 cells were subcultured on ampicilin-containing LB agar plates. Twenty colonies were randomly picked, and colony PCR was perform by vector primers GIII (5'-CCACAGACAGCCCTCATAG-3') and MP57 (5'-TTATGCTTCCGGCTCGTATG-3') to ensure that VHH was inserted into most of the transformants. Following infection of transformed TG1 with M13K07 helper phage (Invitrogen), the VHH library was displayed on phage. Infected bacteria were cultured overnight in 2x TY medium comprising ampicillin (AMP; 100 mug/mL) and kanamycin (50 mug/mL) while shaking (200 rpm). The medium was centrifuged for 15 min at 3200 g in 4 C. The supernatant was mixed with 20% ice cold PEG6000/NaCl and incubated for 30 min on ice. After centrifuged for 10 min at 3200 g in 4 C, such resuspended the phage pellet in ice cold PBS for biopanning. Three rounds of biopanning were performed on microplate wells coated with 100 muL 1 mug/mL TIM-3 protein in PBS to screen anti-TIM-3 phage displaying nanobodies. After blocking with 5% milk in PBS and 5 PBST rinses (250 muL; 0.05% (V/V) Tween 20 in PBS), over 1011 p.f.u phage library preincubated in 0.1% milk in PBS was added into both well coated with TIM3 protein and PBS. Wells were washed with PBST for 15 times and eluted by adding 100 muL 0.25 mg/mL trypsin solution per well for 30 min. The eluted phage was transferred into 100 muL 10%BSA-PBS to stop protease reaction. The infecting log phase E. coli TG1 cells were obtained by serial dilution of 10 muL phage eluted from wells coated with TIM-3 and PBS. 5 muL drops of TG1 infected by dilutions of phage were pipetted on LB agar plate comprising AMP. The enrichment of phages carrying TIM-3-specific VHHs was identified by comparing the titers between phages eluted from antigen-coated wells and those from PBS wells. The rest of the eluted phages were applied to infecting log phage E. coli TG1 and cultured overnight to amplificate phage library as mentioned above for next round of biopanning. E. coli TG1 cells infected by second and third round of phage sublibrary were subjected to overnight cultivation (37 C) on AMP-containing LB agar plates. 66 colonies from second rounds and 132 colonies from third-round sublibrary were picked randomly and cultured in TB medium containing AMP at 200 rpm in 37 C. Log phase E. coli TG1 were induced with 1 mM IPTG (Thermo) overnight (28 C). Via osmotic shock, the periplasmic proteins were extracted for ELISA using anti-HIS antibody (1 : 1000, Thermo), following by HRP-conjugated anti-mouse antibody(1 : 2000, Thermo) and TMB reagent. Anti-TIM3 (1 : 1000, Cell Signaling Technology) and HRP-conjugated anti-rabbit (1 : 2000, Cell Signaling Technology) antibodies were also added successively as the positive control. Positive clones were indicated if the OD450 in antigen-coated wells was three times higher than OD450 in PBS-coated wells. Clones considered positive were chosen for fragment sequencing and were classified according to CDR3 region. The TIM3-specific nanobody gene sequence was inserted into pHEN6c plasmid and transfected into E. coli WK6. His-tagged recombinant nanobodies were expressed in 1 L TB medium through 1 mM IPTG inducement and extracted via osmotic shock, followed by immobilized metal affinity chromatography (IMAC) purification with the use of a Ni-NTA column. The buffer of nanobody was exchanged from imidazole elution buffer to PBS by dialyzing. Measurements of nanobody expression and purity were made by Coomassie brilliant blue stained 4%-20% SDS-PAGE and Western blot. The nitrocellulose membranes were transferred and blocked with 5% milk in TBST, and detected using anti-HIS (1 : 1000, Cell Signaling Technology) and HRP-conjugated anti-mouse (1 : 2000, Cell Signaling Technology) antibodies. Affinity of TIM3-specific nanobody was firstly determined by ELISA. Briefly, a 96-well plate coated by TIM3 protein or PBS overnight in 4 C and blocked with 5% milk PBS. A serial 10-fold dilution of nanobodies in 0.1% milk PBS was added. Antibodies anti-HIS (1 : 1000, Cell Signaling Technology) and HRP-conjugated anti-mouse (1 : 2000, Cell Signaling Technology) as well as TMB reagent were added into wells after washing, successively. The OD450 was measured, and the combination curve was drawn by GraphPad prism. All statistical analysis was performed with SPSS 23.0 software (SPSS Inc., Chicago, IL, USA). All data are reported as the mean +- standard deviation (SD). Paired t test was used to compare the results in two matched groups. One-way ANOVA were applied to compare the differences between groups. P < 0.05 was considered as statistically significant.

PMC8378054_01

Female

We report a case of a 39-year-old female, who presented to casualty with a 1-week history of right iliac fossa pain, associated vomiting and fever and no haematuria. She was HIV-positive, on highly active anti-retroviral therapy (HAART) for 3 years. Current treatment regimen was second-line therapy, including lopinarvir and ritonavir, and abacavir and lamivudine. Her T cell lymphocytes (CD4) cell count and HIV viral load were not known. She had completed treatment for pulmonary tuberculosis (PTB) 2 years prior. The only surgical history of note was an appendectomy 10 years prior. There was no history of intravenous drug or steroid use. On clinical examination, the patient had a low-grade fever of approximately 37.5 C, generalised abdominal painwith right angle tenderness. She was admitted to the gynaecology ward and later transferred to the urology ward. On admission, a urine dipstick test showed 1+ leukocytes without blood. Glucose, protein and ketones were not recorded. She was anaemic with haemoglobin of 10.2 grams per decilitre (g/dL) (n = 11.6 - 16.4), with a normal white cell count of 9.83 x 109/L and elevated C-reactive protein of 168 milligrams per litre (mg/L). Blood cultures were negative. Beta-(1,3)-d-glucan (B-D) assay, cryptococcal antigen test and glycated haemoglobin (haemoglobin A1c [HBA1c]) were not performed. These findings prompted for further investigation including radiological imaging. The computed tomography (CT) scan showed enhancing heterogeneously iso-dense right renal mass (Figure 1a), and magnetic resonance imaging (MRI) showed heterogeneously iso-intense right renal mass with solid and cystic areas (Figure 1b). On review of these findings, the revised differential diagnosis included a renal cell carcinoma, urothelial carcinoma or tuberculosis. A chest x-ray (CXR) showed bilateral nodular infiltrates. Ultrasound-guided renal biopsy tissue was submitted for histological assessment. Broad, irregular, right-angled branching aseptate fungal hyphae were identified within a necrotic background. Angioinvasion was not seen. Morphologically, these features favoured a diagnosis of renal mucormycosis. Fungal culture and susceptibility testing were not performed. The patient was treated with deoxycholate amphotericin B 50 mg intravenously daily. On day 13 of treatment, the patient had deranged renal function with urea of 7.9 millimoles (mmol)/L; creatinine of 140 micromoles per litre (micromol/L). The treatment was stopped at day 14. Once the patient's condition had stabilised, a nephrectomy was planned for definitive management. Patient expressed reluctance to undergo the procedure and requested discharge from hospital to discuss it with family. She was discharged with analgesia and itraconazole 200 mg oral daily for 2 weeks. She was reviewed 2 weeks after discharge without any complain. She was then to be reviewed in 2 weeks time or once the decision had been made with regard to the nephrectomy. Six weeks later, she presented to the urology outpatient department with excruciating pain. Follow-up CT scan did not show any improvement. She agreed to undergo nephrectomy and the surgical procedure was uneventful. The kidney specimen was submitted for histopathological assessment. Gross assessment was that of an enlarged kidney with an intact capsule. The cut surface showed pale resident kidney with cystic degeneration, central necrosis with pus (Figure 2a). The haematoxylin and eosin (H&E) stained sections of this specimen were similar to the initial renal biopsy finding (Figure 2b) with angioinvasion now noted (Figure 2e, f). There was no co-infection or features of diabetes mellitus. Malignancy was not seen.

aids, disseminated, human immunodeficiency virus, mucormycosis, renal mass

PMC5971316_01

Female

A 32-year-old Caucasian woman, with no relevant medical history, was admitted to the Emergency Department due to generalized abdominal pain, nausea, postprandial infarction, diarrhea, and enlargement of abdominal perimeter, lasting 3 weeks. She reported an aggravation in the last 3 days. She denied other symptoms, including fever, night sweats, weight loss, arthralgia, or skin rash, as well as history of atopic diseases, food allergies, raw fishing eating, or recent medication intake. On examination she had painful and distended abdomen. The cardiopulmonary examination was normal. Blood tests revealed leukocytosis [13360/microliter (mul)] with 36.5% of eosinophils (4880/mul). The abdomen X-ray showed levels in the upper right quadrant (Figure 1). Abdominal CT scan revealed diffuse and concentric parietal thickening of the distal two-thirds of esophagus, moderate volume ascites, and small bowel wall thickening with distension on the left quadrants (Figure 2) The gastroscopy showed a "peptic ring at 40 cm and hyperemia of the body and antrum mucosa"; no biopsies were taken (Figures 3 and 4). She was admitted to the Internal Medicine Department for complementary study. The abdominal ultrasound showed several dilated loops in the small bowel, with significant reduction of their peristalsis, compatible with intestinal subocclusion. The parasitological stool exam was negative for eggs, cysts, and parasites. Serum IgE level was normal (83.8 KU/L). The patient underwent an ultrasound-guided paracentesis. Results showed 6912 leukocytes/mm3, of which 93.3% were eosinophils (6450/mul), without malignancy; laboratory testing of the ascitic fluid for bacterial culture and tuberculosis was negative. Colonoscopy showed a congestive and petechial ileocecal valve and hypotrophic mucosa with evidence of submucosal circulation, suspected of microscopic colitis. Colon biopsies showed mucosa with nodular lymphoid hyperplasia and increased number of eosinophils/high power microscopic fields in left colon (20-24/high power microscopic fields) (Figure 5). The constellation of clinical, analytical, and histopathological results suggested the diagnosis of eosinophilic gastroenteritis. The patient was started on 40 mg of oral prednisolone/day, with clinical and analytical rapid improvement (decrease of 5130 eosinophils/uL to 100 eosinophils/uL with 2 doses of prednisolone). To date, the patient stopped taking corticosteroids and remains asymptomatic.

PMC5530449_01

Male

A 64-year-old man presented to the emergency department with a one-day history of lower extremities distal numbness, rapidly progressing to four-limb weakness, back pain, dysarthria, facial weakness, and diplopia. He had received influenza vaccination 18 days before. Five days after vaccination, the patient developed productive cough and diarrhea lasting 3 days. Initial neurological evaluation disclosed marked leg (1/5 grade) and mild arm weakness (4/5 grade), hypoactive deep tendon reflexes, normal plantar reflexes, decreased pinprick, and vibration sensation in all limbs, without a well-defined sensory level, as well as bilateral facial weakness, dysphonia, dysphagia, and restricted eye movements in all directions. The patient quickly developed urinary retention, labile blood pressure, and respiratory distress, ultimately requiring ventilatory support. Brain computed tomography results were normal. Cerebrospinal fluid (CSF) analysis revealed 1 leukocyte/mm3, high protein content (763 g/dl), normal glucose level, and negative bacteriological testing. Guillain-Barre syndrome was suspected, and the patient was treated with intravenous immunoglobulin (0.4 mg/kg/d) for 5 days. Electrodiagnostic studies showed decreased motor and sensory potentials, mild slowing of nerve conduction, and denervation signs in all limbs, consistent with an acute axonal motor sensory polyneuropathy, with a markedly predominant motor impairment. Upper limb strength, facial weakness, and eye movements gradually improved. On hospital day 55, the patient no longer required ventilatory support but still experienced urinary retention and bilateral leg anesthesia. A defined T8 sensory level became apparent. A spinal cord MRI showed a longitudinally tumefactive spinal lesion extending from T6 to the cone (Figure 1). Repeat CSF analysis showed increased cell count (31 leukocytes/mm3), elevated protein levels (1,722 g/dl), and high gamma globulin levels (29.9%, range 7-14%). CSF polymerase chain reactions (PCR) for Mycobacterium tuberculosis, Herpes simplex (HSV) I/II, cytomegalovirus, Epstein-Barr (EBV), and varicella-zoster viruses were negative. Serological testing did not indicate recent or active Borrelia, Bartonella, EBV, HSV I/II, HIV, HTLV, syphilis, hepatitis, or Mycoplasma pneumoniae infection. Serum anti-aquaporin-4 and rheumatological tests were negative. The patient was treated with a 5-day methylprednisolone course (1 g/day), 1 g cyclophosphamide, and six plasma exchange sessions, without lower limb strength or sensation improvement. Additionally, the patient received a 14-day doxycycline course, due to positive Mycoplasma serum IgG titers and the history of productive cough. The patient was discharged to long-term rehabilitation on hospital day 170, still unable to walk, on intermittent bladder catheterization.

PMC3265990_01

Female

A 57-year-old woman presented in the emergency department complaining of progressive dyspnea for the previous 5 days. On clinical examination she had productive cough with clear sputum and intermittent fever. She was a lifelong nonsmoker but with multiple hospitalizations due to respiratory infections and asthma-like episodes from the age of 8 years. During the past 15 years the patient was treated symptomatically with antibiotics, nebulizer bronchodilators, and long-term oxygen therapy (2 L/min/24 hours). She had daily exposure to gases from a brazier used at home since childhood. Her family past medical history included her 30-year-old sister's sudden death from unknown reasons and her mother's infection from tuberculosis. At the time of admission her axillary temperature was 38 C and blood pressure 120/70 mmHg. The patient was in respiratory insufficiency with an arterial pH of 7.46, PCO2 of 56 mmHg, PO2 of 72 mmHg, and HCO3 of 30 mmol/L on air. Lung auscultation revealed widespread bilateral crepitating and crackles over the lower part of both lungs. No lymphadenopathy was found and examination of other systems was unremarkable. The electrocardiogram was normal with a heart rate of 69 beats per minute. Laboratory data showed an elevated erythrocyte sedimentation rate of 100 mm/h and a white blood count of 9000/muL without peripheral blood eosinophilia, and C-reactive protein was 9.3 mg/dL. Biochemical values were normal. Her sputum sample for acid-fast bacilli was negative on multiple occasions. Sputum sent for fungal culture did not grow any organisms. Screening for Aspergillus in sputum cultivation was also negative. Pseudomonas aeruginosa was isolated from her sputum culture. Urine antigen for Legionella and Streptococcus was negative. Her chest X-ray demonstrated increased lung volumes and revealed multiple ring shadows in lungs that were almost symmetrical in distribution and more apparent in the mid and lower zones. There was the sense of air-fluid levels in some of them corresponding to cystic bronchiectasis. Also, there was thickening of the interstitial network. The trachea and main bronchi were normal (Figure 1). A laboratory investigation was performed for alpha-1 antitrypsin level and was normal. Total serum immunoglobulin (Ig)E concentration was elevated at 2500 U/mL (normal range 0-165 U/mL). Immediate cutaneous reaction to Aspergillus fumigates was not available at the time of the patient's hospitalization; nevertheless, A. fumigatus-specific serum IgE levels were 1.37 U/mL. This is essential for the diagnosis of allergic bronchopulmonary aspergillosis. Total serum IgG, IgA, and IgM levels were quantified to rule out hypogammaglobulinemia and did not reveal any deficiencies. Antinuclear and antineutrophilic cytoplasmic antibody tests were performed to exclude Churg-Strauss syndrome, and the results were negative. A pulmonary function test demonstrated a mixed obstructive and restrictive pattern. There was a reduced forced vital capacity of 1200 mL (43.35% pred), reduced expiratory volume in 1 second of 720 mL (30.7% pred) with Tiffeneau index, reduced expiratory volume in 1 second/forced vital capacity of 76.29, and carbon monoxide-diffusing capacity of 28%. A contrast-enhanced computed tomography (CT) scan of the chest demonstrated central cylindrical/cystic bronchiectasis involving segmental/subsegmental bronchi, bronchial wall thickening with air-fluid levels, and mucus plugging with predominant localization in the lower lobes. There was ground glass and tree-in-bud scattered in all lobes, a finding consistent with pneumonitis and acute bronchiolitis. Chest CT also revealed a mosaic picture, which also emerges in all lobe findings consistent with bronchiolitis obliterans. Collapse of bronchi with distal air trapping, the result of an excessively compliant bronchial wall, particularly in the left and right lower lobe, was also present (Figure 2). We also performed fiberbronchoscopy on the patient. The findings were unremarkable. The bronchoalveolar lavage fluid obtained from the patient for an acid-fast bacillus was negative on multiple occasions, but the same P. aeruginosa was again isolated. The bronchoalveolar lavage fluid was negative for Aspergillus antibodies (IgG and IgM). A diagnosis of saccular bronchiectasis due to Williams- Campbell syndrome was made based on clinicoradiological findings, laboratory testing, and past medical history. Genetic testing was planned, but the patient refused further investigations due to financial constraints. The patient was treated with intravenous antibiotics; third-generation cephalosporins, ciprofloxacin, and acetylcysteine; and chest physiotherapy, and was discharged after 1 month. Written informed consent was obtained from the patient upon discharge for publication of this case report and all accompanying images.

williams-campbell syndrome, bronchietasis, bronchomalacia

Sequential axial high-resolution computed tomography images of the upper, middle, and lower lung fields demonstrate multiple large and coalescent cystic bronchiectases, associated with volume loss. Some of the bronchiectases have air-fluid levels that are due to brochial secretions.

PMC8007360_02

Female

Patient 2: a 24-year-old female was diagnosed with CBF-AML (inv16, corresponding CBFB-MYH11 fusion gene). Pulmonary tuberculosis had been cured with nine months of four-drug therapy one and a half years ago, but otherwise her medical history was unremarkable. We initiated a course of 7 + 3 combined with a single dose of GO (Table 1). Wide-spread cytarabine-related cutaneous reaction and mucositis and high fever were observed from day 4 onwards. Blood cultures and virus samples remained negative. Because of suspected hyperinflammation (P-ferritin >16500 mug/L, P-IL2R 5509 kU/L), we administered corticosteroid from day 16: fever responded but P-LD was rapidly increasing. P-Hb rose (410 mg/L at highest), and the color of patient's plasma slightly darkened while P-Haptog and P-Bil stayed normal. Hypertension and bradycardia were observed. We did not see any other sign of target-organ damage caused by the toxic reaction. We conducted preemptive TPEs daily on days 20-22. No more TPEs were needed, as P-LD and P-Hb declined after day 22 together with recovering hematopoiesis. CR with low MRD-positivity (CBFB-MYH11 0.02%) was detected in the BM on day 29.

PMC2853045_01

Female

A 27 year old female patient came to our department with discharging sinus from proximal part of third metacarpal of left hand and pain. Detailed history revealed that she got minor abrasions by some trivial injury over left hand about 2 months back. These abrasions resolved spontaneously but small nodular swelling developed over the proximal part of third metacarpal bone of left hand. During this period she also had pain at local area and low grade pyrexia. She was given antibiotics and other supportive treatment for one month. After one month there was no improvement and sinus formed with discharging pus in that swelling. There was no past history of antitubercular treatment as well as no history of contact to a known case of tuberculosis. General examination revealed average built of patient with no significant peripheral lymphadenopathy. Examination of left hand revealed retraction of overlying skin over the proximal part of third metacarpal bone of left hand and pus discharging sinus (figure: 1). Her resting pulse rate was 92/min and blood pressure was 112/68mmHg. Respiratory system examination was within normal limit. Examination of others system was unremarkable. Her Haemoglobin was 14 gm%; Total Leucocyte count was 8,900/cmm; Differential Leucocyte count was Neutrophils 72%, Lymphocytes 17% and Monocytes 7%, eosinophil 4% and Erythrocyte sedimentation rate was 58 mm/hour. Her blood culture was sterile. She was HIV seronegative. Her chest x-ray was normal (Figure: 2). X-ray left hand AP and lateral view revealed osteolytic lesions over neck of third metacarpal bone (fig 3). Her Ultrasonography abdomen revealed no abnormality. Her mantoux test showed 34 mm indurations at 72 hours. Pus from discharging sinus was negative for acid fast bacilli on three occasions. Pus culture was positive for Mycobacterium Tuberculosis by Bactec method. So the diagnosis of tubercular dactylitis was established and her treatment was began with 4 drugs (Rifampicin, Ethambutol, Isoniazid and Pyrazinamide) for 2 months, followed by 2 drugs (Rifampicin, Isoniazid) for 4 months. Swelling disappeared and sinus healed after six months of institution of antitubercular treatment along with decrement of shadow in radiology (Figure: 4).

PMC9097713_01

Male

A 55-year-old man was admitted to our institution for the assessment of abnormal chest shadows. He had non-alcoholic fatty liver disease and visited the gastroenterologist regularly. He complained of dry cough, dyspnea on exertion, and anorexia for the preceding 2 months. A chest radiograph revealed bilateral central consolidation (Fig. 1A). On admission, his vital signs were as follows: blood pressure, 115/96 mmHg; pulse rate, 94 beats/min; respiratory rate, 18 breaths/min; SpO2, 93% in room air; and body temperature, 36.4 C. Auscultation revealed fine crackles in the right upper chest at the end of inspiration. Blood examination results revealed that the lymphocyte and serum immunoglobulins were nearly normal, and the anti-HIV antigen/antibody test was negative. Serum Krebs von den Lungen-6 (KL-6) and (1-3)-beta-D-glucan levels were elevated (4007 U/mL and 217.1 pg/mL, respectively) (Table 1). Chest computed tomography (CT) revealed bilateral central consolidation with peripheral sparing, some accompanied by cysts and traction bronchiectasis (Fig. 1B and C). Bronchoscopy performed under mild sedation using midazolam and pethidine without intubation revealed normal endobronchial airways. The bronchial alveolar lavage fluid comprised histiocytes, 96%; neutrophils, 1%; and lymphocytes, 3%; the polymerase chain reaction for P. jirovecii was positive. Pathologically, a transbronchial lung biopsy (TBLB) specimen of the right upper and lower lobes showed granulomatous inflammation highly infiltrated with inflammatory cells, mainly macrophages, obscuring the alveolar structure. Furthermore, in the alveolar spaces, accumulation of periodic acid-Schiff-positive foamy eosinophilic materials was observed, while Grocott methenamine silver (GMS) stain revealed cystic forms of P. jirovecii (Fig. 2A-C). The peripheral blood CD4+ lymphocyte count was 508/muL. No signs of neoplastic disease were detected during full-body contrast-enhanced CT, 18Fluorodeoxyglucose-positron emission tomography/CT, upper gastrointestinal endoscopy, and bone marrow puncture. In addition, the patient had no history of recurrent infections or family history of immunodeficiency. Thus, there was no suspicion of primary immunodeficiency or secondary immunodeficiency such as malignancy, HIV infection, or drug-induced immunodeficiency. Therefore, the patient was diagnosed as an immunocompetent patient with PCP. Trimethoprim (960 mg/day) and sulfamethoxazole (4800 mg/day) were administered for 3 weeks without steroids. The patient's symptoms and chest radiograph findings improved with treatment (Fig. 3). His serum KL-6 and (1-3)-beta-D-glucan levels, which were elevated at diagnosis, continued to decrease to normal ranges after treatment; no recurrence occurred during the 18 months following the discontinuation of trimethoprim and sulfamethoxazole.

aids, acquired immunodeficiency syndrome, ct, computed tomography, central consolidation, ggo, ground-glass opacity, hiv, human immunodeficiency virus, immunocompetent, kl-6, krebs von den lungen-6, pcp, pneumocystis pneumonia, pneumocystis jirovecii, pneumocystis pneumonia, tblb, transbronchial lung biopsy

PMC9639239_01

Male

Patient 1 was a 22-year old male involved in a motor vehicle accident 8 months prior to participation. He sustained a severe TBI [initial GCS score 3, increased to 7 in the emergency department, loss of consciousness (LOC) 10 days, post-traumatic amnesia (PTA) 1 month]. A Computed Tomography (CT) scan showed subdural hematoma, haemorrhagic contusions in the right frontal and left temporal lobes, a significant right to left midline shift and mild hydrocephalus. Prior to participation in this study he had completed rehabilitation for mobility and personal activities of daily living.

eye movement, antisaccades, attention, convergence, eye tracking, microsaccades, saccades, scanpath, smooth pursuit

PMC9639239_02

Female

Patient 2 was a 45-year old female involved in a motor vehicle accident 10 years prior to participation. She sustained a severe TBI (GCS score 4, LOC 2 months, PTA 2 months), fractured pelvis, fractured right tibia and fibula and a dislocated left knee. She spent several weeks in intensive care and was subsequently transferred to a rehabilitation center, where she spent several months to improve her cognitive and physical functioning. At the time of participating in this study, her ongoing problems included discomfort in her legs, slowed thought processing and poor balance and co-ordination affecting her gait, which was slow, wide-based and generally unsteady. She was living with her father who assisted her in all aspects of her daily life. As her accident occurred overseas, medical reports were not available, but she reported damage primarily involved frontal and temporal lobe regions.

eye movement, antisaccades, attention, convergence, eye tracking, microsaccades, saccades, scanpath, smooth pursuit

PMC9639239_03

Female

Patient 3 was a 19-year old female with a complicated history. Her TBI was not diagnosed at the time of her first hospitalization at age 14. According to her mother, she had vomited and had a severe occipital headache before falling asleep. She was unarousable in the morning and was taken to the hospital. A CT scan showed posterior fossa hematoma. She underwent occipital craniotomy with evacuation of a fourth intraventricular hemorrhage and inter-parenchymal hemorrhage. She developed hydrocephalus post-operation which required an external ventricular drain. She was unconscious for 3 days following the craniotomy. It took several days until she was able to remember the incident resulting in her TBI and communicated that she had received a hard blow with a soccer ball to the back of her head after school. At the time she felt dizzy. After she became medically stable, she began speech therapy. She also complained of diplopia and was given an eye patch. After all vascular investigations were negative; she was referred for comprehensive rehabilitation for mobility, activities of daily living, balance and vision. She also reported a second head trauma 4 years after the first accident. At this time, she suffered a blow to the head as a result of falling downstairs. She had headache, double vision and ataxia following this incident. Her medical report recorded a GCS score of 15 and no other systemic abnormalities. A CT scan and magnetic resonance imaging (MRI) revealed stable postoperative changes from occipital craniotomy associated with cerebral encephalomalacia and gliosis. At the time of participation in this study, she was attending University and living independently in dormitory accommodation. Self-paced saccades were recorded using a SensoMotoric Instruments (SMI) monocular infrared video-based eye tracker (SensoMotoric Instruments, Berlin, Germany), that recorded left eye at 200 Hz with a spatial resolution of less than 1 . Stimuli were presented on a 20 inch LCD monitor (SAMSUNG, 2043BW, with a refresh rate 60 Hz and resolution of 1050x680 pixels) with patient sitting 67 cm from it with head stabilized using a chinrest. A 5-point calibration was conducted before recording eye movements and if the x-coordinate spatial accuracy was < 1 , eye movement recording (left eye) began. A fixation cross was presented in the center of the monitor. While recording, the fixation cross was substituted with two 1o black dots at 10o to the left and right side of the center for 30 seconds. Patient was asked to make volitional saccades between the two dots as fast and accurately as possible. The number of primary saccades was counted. Eye movements throughout the abstract conjunctive search were recorded using an Eyelink II head-mounted eye tracker (SR Research). Viewing was binocular, but the left eye only was tracked as there was no disconjucacy of the eyes in any subject. Eye position was sampled at 500 Hz with spatial accuracy of 0.5 . The search task was presented using a short-throw projector (NEC, WT610) on a screen at a viewing distance of 130 cm, resolution of 1024 x 768 and subtended 62.8 x 38.2 of visual angle on the screen. Task presentation and eye tracking were controlled with SR Research Experiment Builder software. The task trials were created by R statistical software (A language and environment for statistical computing, R Foundation for Statistical Computing, Vienna, Austria, http://www.R-project.org). Each trial contained 59 red and green letter "d"s with green "b"s as distractors and one red letter "b" as the target, randomly positioned on a white background (Figure 1). Each letter subtended approximately 0.6 x 1 degrees of visual angle. A 9-point calibration and validation were performed before starting the task and calibration was repeated if the spatial accuracy fell above 0.5 . Patient was required to locate a red letter "b" and press the button box as fast and accurately as possible. Each trial stayed on the screen until the subject reached his/her decision, indicated by pressing a button on a gamepad to end the trial or until an automatic time-out of 20 seconds. Ten trials were shown to the participant in every day of testing and training. Eligible participants read the study information sheet and signed the consent form. They were reimbursed $10 per session for their participation as well as their public travel costs and parking fees. The study was approved by the University of Melbourne Human Research Ethics Committee (approval number: 1238522.1). Participants had normal or corrected-to-normal visual acuity as tested with a LogMAR chart at 3 meters and normal color vision as tested by the Ishihara test. Each participant was tested five times on five consecutive days on the self-paced and abstract search task to record baseline data. They subsequently began training, using the game Call of Duty, Modern Warfare II (Infinity Ward) for a total of 10 hours (1 hour per day for ten days), over a two-week period. Before each training session, participants were tested on the saccade and the abstract search tasks. Each session took 1 hour and 20 minutes to complete. Participants were also tested on the saccade and the abstract search tasks on two other occasions during the training period, once after 5 hours of training and once after finishing the training. Overall, the study included at least 17 sessions: 5 baseline testing sessions, 10 testing plus training sessions, 1 mid-training testing session, and 1 post-training testing session). These took at least 4 weeks for each participant to complete and did not include weekends. On the first day of testing, tasks were explained to the patient and the experimenter ensured that the patient had learned the task by performing practice trials (five in each test) before recording. The testing procedure commenced with the self-paced saccade task. Following a variable rest period, the visual search task was presented to the patient. Game training was performed using a 15.5-inch laptop (Dell, Latitude E6520) with 1920 x 1080 resolution. The monitor subtended 35.3 x 19.6 visual angle, when the participant sat 55 cm from the laptop. In the first training session, the content and aim of the game, different movements and weapons were explained to the trainee, who started playing the game by completing the first level or 'mission', which served as a tutorial. The participants subsequently played the game for 1 hour, taking breaks when required. The experimenter sat in the testing room and was available to assist and give feedback if needed. Participants played the single-player mode of the game, which comprised 17 missions. If a participant finished the single player mode, they played the advanced Special Ops section which consisted of five new levels with new objectives. After finishing the daily training, the participant's achieved level (mission) was recorded. If a mission was not completed, the participant started from that uncompleted mission the following day. To investigate the influence of training on self-paced saccade rate and duration of fixation and visual search time in abstract search task, we used a procedure called percentage of non-overlapping data (PND) . PND is used in single-case analysis studies as one of the alternatives to visual trend analysis . For this technique, the percentage of data points during the treatment period which exceeds the best performance data within the baseline phase is used to index the effectiveness of an intervention. Here, effect size is based on the percentage of non-overlapping data between baseline and treatment phases of the single-case intervention trial: highly effective >= 90%, moderately effective 70-90%, minimally effective 50-70%, ineffective < 50% .

eye movement, antisaccades, attention, convergence, eye tracking, microsaccades, saccades, scanpath, smooth pursuit

PMC9575662_01

Female

Dear Editor, Infliximab, a chimeric mAb against TNF-alpha, is approved for PsA treatment. Infliximab is available as an originator (Remicade) and as biosimilars (CT-P13, Remsima, Inflectra; SB2, Flixabi). We present the case of a 38-year-old Caucasian female physician, who was diagnosed with PsA in 2009, with skin and peripheral joint involvement. She received treatment with MTX, which was not tolerated, before receiving adalimumab, ultimately controlling her disease. In 2010, she developed lymph node tuberculosis and was treated successfully with standard tuberculostatic treatment. After her tuberculosis was treated, she started on etanercept, which was maintained until 2013. Treatment with etanercept was stopped owing to sustained absence of symptoms related to psoriatic arthritis (PsA). In 2018, after a long drug-free phase because of sustained minimal disease activity, the patient presented with a relapse of PsA, with severe arthritis and dactylitis involving the hand, feet and knee joints, in addition to exacerbation of skin disease. Sequential attempts at treatment of PsA with etanercept, certolizumab pegol and secukinumab failed. The patient was therefore started on infliximab (Flixabi), which led to a status of minimal disease activity. However, after 6 months the symptoms recurred and the patient was switched to infliximab (Remsima), which worsened skin and joint symptoms. Therefore, treatment with infliximab (Remicade) was started, but led to an allergic reaction, with flushing, dizziness, shortness of breath, nausea and shivering. The infusion was stopped, and prednisolone controlled the symptoms. Based on the initial response to infliximab (Flixabi) and after discussion with the patient, who was well aware of the potential harms and benefits, treatment with infliximab (Flixabi) was reintroduced. Other therapeutic options, such as apremilast, ustekinumab or a Janus kinase inhibitor, were rejected because of possible side effects. The patient did not develop any allergic reaction and responded in an excellent manner, reaching controlled disease after 8 weeks, with ongoing improvement of symptoms thereafter. Our patient has been treated based on her preferences and experiences, which she brought to the decision-making process, which goes against normal clinical advice to switch back to an agent that had previously been ineffective or had caused an adverse reaction. She had no concomitant MTX treatment because it was not well tolerated. Infliximab levels were found to be sub-therapeutic before the infusions/injections (<3 microg/ml) and supra-therapeutic (>60 microg/ml) after the infusions/injections, while anti-infliximab antibodies were persistently positive from the commencement of the infliximab therapies. To date, our patient has been treated with Flixabi for 24 months at 4-week intervals, achieving minimal disease activity, occasionally presenting with recurrent hand and finger joint tenosynovitis. Subjectively, she is satisfied with her status quo and therapy. This case is interesting for two reasons. First, the patient developed an allergic reaction to one of the three different infliximab products and tolerated re-exposure with another infliximab product. Allergic reactions occur in ~5-20% of patients treated with infliximab. Those occurring during administration and within 24 h of infusion are categorized as acute. Their symptoms include headache, hypotension/hypertension, dizziness, shortness of breath, shivering, sweating, increase in temperature and rash/urticaria. The explanations for the differential response to different infliximab products are unclear and might not necessarily be related to the antibody itself. Although switching between bio-originator and bio-similar is widely practised, we could not find another documented case of an allergic reaction to one infliximab product, with subsequent exposure to another infliximab product. The second interesting finding is that the patient became responsive to infliximab (Flixabi), once again, after the allergic reaction against infliximab (Remicade). Hence, the patient experienced a good response, although the first course of infliximab (Flixabi) before the allergic reaction resulted in only a spurious response with rather rapid secondary failure. The reason for this is also unclear. However, a possible explanation is the fact that allergic reaction is associated with type 2 immunity, and recently, eosinophils have been shown to be important for resolution of arthritis. Hypothetically, the combined activation of pro-resolving pathways in conjunction with eosinophils and TNF inhibition might have shown added efficacy in controlling PsA. Further work is planned to evaluate this possible mechanism of action.

PMC1334206_01

Male

This twenty-seven years old male presented with complaints of fever with rigor and chills and sore throat for ten days. It was associated with myalgia and recurrent vomiting followed by diffuse maculopapular rash all over the body with sparing of mucous membranes and periorbital tissues. On examination, he had conjunctival congestion with toxic facies. He had a past history of gout for which he received allolpurinol for twenty days and phenytoin for sudden loss of consciousness in another institution. There was no past history of tuberculosis, diabetes or hypertension. Bilateral hard indurated cervical lymphadenopathy and bilateral inguinal lymphadenopathy was also observed along with bilateral parotid and submandibular gland enlargement. Hepatosplenomegaly was detected on ultrasonography. Hemogram on several occasions from admission revealed normal hemoglobin and red blood cell morphology. There was transient neutrophilic leukocytosis, whereas platelet counts and erythrocyte sedimentation rate were normal throughout. During his treatment with ceftriaxone, he suddenly developed shock, cyanosis and acute renal failure for which he was given inotropic support, amoxicillin, ceftazidine and steroids. He gradually responded and recovered in due course of time. A clinical diagnosis of shock syndrome due to Dengue fever or Epstein Barr virus (EBV) or streptococcus or phenytoin induced hypersensitivity syndrome was made. The Dengue virus IgM antibody Elisa was positive and serum D-dimer levels were positive (>200 ng/ml). Anti EBV IgG antibody test was positive but EBV IgM antibody test was negative. The serology tests for anti- cytomegalovirus antibody, anti leptospira antibody, Widal test, brucella (abortus and melitensis), and HIV were negative. The blood, throat swab and urine cultures were sterile. Paul-Bunnel and Weil-Felix tests were negative. Cervical lymph node biopsy was undertaken for histopathology. Gross examination revealed four lymph nodes, the largest one measuring 1.5 cm and the rest below 1 cm. On microscopy, two of the lymph nodes (including the largest one) showed near total infarction of the parenchyma with preservation of cellular outlines of the lymphocytes (Fig 1). A thin rim of viable subcapsular normal mature lymphocytes along with neutrophils and plasma cells were identified. The medullary vessels showed vascular congestion however the blood vessels in the perinodal adipose tissue showed multiple fibrin thrombi with congestion in some of the vessels (Fig 2). Multiple deeper sections revealed perinodal granulation tissue with viable subcapsular lymphoid tissue but no atypical cells, histiocytes or granulomas were seen. Stains for fungi and acid-fast bacilli were negative. The adjacent two uninvolved lymph nodes showed features of reactive change. Immunohistochemistry with B- cell (CD20) and T- cell (CD3) markers was performed. The viable lymphoid tissue showed an admixture of both B and T-cells. The infarcted tissue showed variable positivity and these markers highlighted few reactive follicles (Fig 3). The uninvolved lymph nodes also showed a normal positivity pattern. The patient was asymptomatic thereafter and had complete regression of the lymph nodes. He was lost to follow up after two months of discharge from the hospital. Lymph node infarction is a rare phenomenon reported in literature in association with various neoplastic and non-neoplastic conditions. The non-neoplastic conditions associated with infarction are namely polyarteritis nodosa, viral infections (Parvovirus B19, Infectious mononucleosis), cholesterol atheromatous embolism, thrombosis, gold injections, intestinal volvulus, postmediastinoscopy, mononeuritis multiplex, fine needle aspiration cytology and finally may be idiopathic. Hemorrhagic infarction of hilar lymph nodes has also been reported recently in association with heart lung transplantation. The neoplastic lesions most commonly associated with infarction are malignant lymphoma and metastatic melanoma. The differential diagnosis pertaining to the present case would be the above mentioned two conditions along with necrotizing lymphadenitis (Kikuchi's lymphadenitis), mucocutaneous lymph node syndrome, and necrotizing granulomatous inflammation. Serial deeper sections failed to reveal any evidence of either lymphoma or melanoma, any granulomatous inflammation, and vasculitis or monocytoid histiocytes, thus ruling out the above mentioned conditions. Drug induced hypersensitivity reactions in a lymph node especially due to phenytoin are known in the form of inter follicular expansion by a mixed infiltrate of immunoblasts, plasma cells and eosinophils with varying degrees of vascular proliferation. Focal necrosis has also been observed. Other drugs have been reported to show reactive change. These changes were not seen in the present case in the non-infarcted lymph nodes. In the present case it appears that infarction of the lymph node occurred before the DIC became clinically evident. A completely infarcted lymph node should alert the pathologist to the high possibility of malignant lymphoma, as it is the most common cause of spontaneous lymph node infarction. Further investigation can be carried out by taking multiple deeper sections of the infarcted lymph node to visualize the viable subcapsular tissue for any clue of malignancy. Immunohistochemistry has been done on the infarcted lymph node sections to establish the underlying pathology. Although it is widely believed that necrotic tissue is not suitable for immunohistochemical study, this view may be inaccurate. The detection of spontaneous lymph node infarction should alert the pathologist and the clinician alike for an associated or underlying impending pathology. In a multicentre study of 51 cases of lymph-node infarction seen in the 30-year period, Maurer et al identified 14 cases of malignant lymphoma synchronously with the infarct. Of the remaining 37 patients, six showed manifestations of malignant lymphoma in the follow-up period within 2 years of the lymph-node infarction. On analyzing other cases in the literature these authors also confirmed that a minority (26 of 81) have developed malignant lymphoma, which appeared within 2 years of infarction. Therefore, a thorough examination of both the infarcted lymph nodes and others resected at the same time is mandatory in order to exclude concomitant or underlying malignant lymphoma. The risk of development of malignant lymphoma after infarction was found to be negligible after two years.

PMC6195938_01

Male

A 29-year-old male presented to the emergency room with sudden onset of dyspnoea and cough that started while travelling in a hilly region. He reported a history of asthma since childhood, requiring the intermittent use of inhalers. There were no other co-morbidities, history of prior tuberculosis or prior severe exacerbations of asthma. He rapidly went into respiratory failure, requiring intubation and high FiO2. Chest radiographs revealed left-sided pneumonia and an unexplained right lung volume loss, for which he was treated with antibiotics. He recovered within 3 days and was discharged. He returned for follow-up to understand the cause for his sudden and severe respiratory deterioration at high altitude. Physical examination was unremarkable apart from the right lung volume loss and a few scattered crepitations on the right side. Laboratory reports showed normal haemogram, and normal renal and liver function tests. D-dimer screening and venous Doppler of both lower limbs were negative for deep vein thrombosis. Echocardiogram did not show evidence of elevated pulmonary artery (PA) pressures. All prior serial chest radiographs demonstrated a consistent right lung volume loss with transmediastinal herniation of the left lung. High-resolution CT chest, performed the previous year, confirmed right lung volume loss and revealed a subtle reticulation that had been attributed to tubercular sequelae. However, the patient did not know of any prior tubercular illness or antitubercular therapy. He did, however, report that, while in utero, his mother had unsuccessfully attempted to medically terminate the pregnancy. The current chest radiograph demonstrated a small volume right lung, mild elevation of the right hemidiaphragm, ipsilateral mediastinal shift, absence of the right PA, dilated left PA and a hyperinflated left lung that had herniated to the right side, as indicated by a displaced anterior junction line. Within the small right lung, there was a subtle reticulation, most obvious in the periphery of the upper zone. The intrapulmonary vasculature of the left lung was normal (Figure 1). Contrast-enhanced CT (CECT) of the chest revealed dilatation of the left PA and its divisions with complete absence of the mediastinal segment of the right PA (Figures 2 and 3). In addition, branches of the dilated intercostal collateral arteries were present in the right epicardial fat (Figure 2b) and a dilated right internal mammary artery was identified in the anterior chest wall (Figure 2a,b). The small right lung demonstrated fine reticular opacification consistent with transpleural collateral arteries (Figure 4a,b). Although the right lung was small, the bronchial airway branching pattern was normal with no evidence of bronchiectasis, fibrosis or cavitation. Herniation of the hyperinflated left lung into the right hemithorax was evident.

PMC5881438_01

Male

A 49 year old Afro-Cuban male with a history of chronic alcoholism and hypertension presented with a three day history of fever (106 F), change in mental status, and body aches in August, 2016. On admission, he was febrile 103.1 F, with a heart rate of 137 beats per minutes, blood pressure of 156/79 mm of Hg, and respiration rate of 32 breaths per minute. The patient's laboratory results on admission included white cell count 9.2 x 103/microL, platelets 71 x 103/microL, PT 28 s, PTT 43 s, INR 2.62, albumin 3.1, Tblb (total bilirubin) 13.6 mg/dl, AST (aspartate transaminase) 133, and ALT (alanine transaminase) 56. Lactic acid was 6.2 mmol/L, and blood alcohol level checked the next day was less than 10 mg/dl. In addition, he showed left lower extremity cellulitis, left great toe ulceration, and 2nd right toe dark discoloration. Five days prior to admission, the patient ruptured a lesion on his left great toe which caused blistering and limping when he walked. Two days later, he walked outside without footwear in soil contaminated by chickens and hens. The animals are unrestrained in the yard, and the patient's spouse reports that the area is not cleaned or sanitized. It happened as well that his backyard was flooded earlier that week, after a recent hurricane hit this area. The patient has a history of poor hygiene and self-care, and was only brought to the hospital by insistence of the spouse. During the first day of his hospital stay, the patient went into septic shock and intravenous vancomycin and piperacillin/tazobactam were started empirically. Blood cultures were collected and sent to the microbiology laboratory. Head CT showed no abnormalities and chest X-ray showed no cardiopulmonary disease. Ultrasound of the lower extremities showed indurations at the left pretibial regions about 4 cm-5 cm. X-ray of the left foot showed soft tissue swelling over the dorsum of the foot without osseous or joint pathology. The next day preliminary blood culture results revealed gram positive rods. Given patient's critical condition and encephalopathic state, the piperacillin/tazobactam treatment was changed to meropenem out of concern of central nervous system infection - mainly listeria given newly diagnosed liver cirrhosis this admission. However, on the third hospital day blood cultures grew the more infrequently seen Erysipelothrix Rhusiopathiae. The patient was evaluated by cardiology and a 2D transthoracic echocardiogram was negative for endocarditis. Susceptibility testing was done so that the antibiotic coverage could be adjusted for the most effective treatment (Table 1). The susceptibility profile showed susceptibility to ceftriaxone but resistance to penicillin. Ceftriaxone was then added to the patient's regimen at 2 g intravenously daily. Patient's clinical condition dramatically improved on day two antibiotics, and his repeat blood cultures on day two of antibiotics were negative. Patient completed four weeks of intravenous ceftriaxone. He was evaluated by our team two months later for extended spectrum E. coli urinary tract infection, and his blood cultures were negative.

alt, alanine transaminase, ast, aspartate transaminase, ct, computed tomography, e coli, escherichia coli, e rhusiopathiae, erysipelothrix rhusiopathiae, edil, edil, eint, eint, tblb, total bilirubin

PMC4413521_01

Female

A previously healthy 40-year-old African American G2 P1 female with a 23-week twin gestation complicated by an incompetent cervix requiring a cervical cerclage presented to the emergency department with intermittent palpitations and shortness of breath for the past two months. The patient arrived via EMS complaining of persistent shortness of breath and palpitations for the past six hours. She was noted by EMS to have a tachydysrhythmia, atrial fibrillation with rapid ventricular response (RVR), and received two doses of diltiazem en route: 20 mg and then another 25 mg without rate control. Upon arrival, the patient's shortness of breath had resolved but she continued to have palpitations. The patient denied dehydration, alcohol or caffeine use, lack of sleep, recent illness, or any other precipitating factors. Her past medical history was significant only for a previous preterm delivery at 20 weeks due to an incompetent cervix. She denied any cardiomyopathies, prior arrhythmias, or other structural heart diseases. On physical exam, the patient was afebrile, normotensive, with a heart rate in the 130s-140s, and a respiratory rate of 25-42. Abnormal physical exam findings included bilateral crackles in the lung bases and an irregularly irregular heartbeat. Fetal heart tones were observed in both fetuses. Initial work-up included an EKG, CBC, CMP, UA with microscopy, chest X-ray, cardiac enzymes, D-Dimer, BNP, and thyroid studies. On EKG, rate was 142 and rhythm was atrial fibrillation with rapid ventricular response. The chest radiograph revealed cardiac hypertrophy and right greater than left perihilar opacities suggestive of pulmonary edema. Laboratory examination revealed mild leukocytosis and mild elevation of D-Dimer, with the remainder of the results within normal limits. The patient was placed on a diltiazem drip, which was titrated to 15 mg/hr without successful rate control. Her heart rate remained in the 130s and the rhythm continued to be atrial fibrillation with RVR. Digoxin was then added as a second agent, and discussions about the potential risks of cardioversion in pregnancy ensued. Fortunately, the patient converted to sinus rhythm before cardioversion became necessary. The digoxin was discontinued; the diltiazem was also discontinued after the patient subsequently developed hypotension. The patient was admitted to hospital and was followed closely in an intermediate care unit by cardiology and OB/GYN. An ECHO was completed during her hospital admission that showed moderate left ventricular hypertrophy (LVH), and on further laboratory examination she appeared to likely have gestational diabetes. Due to her LVH, flecainide was not recommended, and due to her pregnancy it was decided that aspirin would be used for anticoagulation. The patient was discharged with follow-up with cardiology, high-risk obstetrics, and maternal fetal monitoring for the remainder of her pregnancy.

PMC6441490_01

Female

A 46-year-old white woman was referred to our physicians for symptom related to biliary tract injury (pruritus, abdominal pain, and fatigue), without jaundice. With a history of smoking, no other clinical information has been noted to this patient. Baseline laboratory data obtained from blood sampling revealed alkaline phosphatase (ALP) elevation together with g-glutamyl transferase (gGT), aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Bilirubin level was normal (Table 1). The differential diagnosis will go through the evidence of specific etiological agent that cause disease. For this reason, we take into consideration three clinical hypothesis: viral, pharmacological and autoimmune aetiology. Viral serologies, summarized in table 1, was considered exhaustive to exclude viral aetiology. Many drugs can cause cholestasis or cholestatic hepatitis, including sulfamethoxazole/ trimethoprim, amoxicillin/clavulanate, antiepileptic medication, and antituberculosis drugs. Histologic findings are variable but usually include mild portal inflammation, ductular reaction, and cholestasis. Clinical history is important, because a patient's medication list should be reviewed for potentially offending substances, and the length of symptoms is important as well. Patient not referred the use of these and others pharmacological therapy, included "homemade" herbal substances. Immunological evidences A two distinct cytoplasmic pattern were identified in a routine ANA test using HEp-2 cell slides from Euroimmun, at end dilution of 1:1280 (Figure 1, table 2). Mitochondrial-like cytoplasmic pattern IIF- pattern were characterized by the presence of larger irregular granules extending from the nucleus throughout the cytoplasm in a reticular network. Cytoplasm of dividing cells was strongly positive (Figure 2, Panel A). IIF on a commercial rat liver, kidney and stomach tissue with the use of polyclonal IgG antibodies confirmed the presence of AMAs, with a characteristic staining pattern: granular diffuse cytoplasmic staining of the Kupffer cells and hepatocytes, of the renal tubules (strongest staining is noted in distal which is mitochondria-rich) and parietal gastric cells (Figure 2, panel B). Line immunoassay Euroline profile autoimmune liver diseases (IgG; LIA, Euroimmun Lubeck) revealed antibodies against AMA-M2. M2-E3 (BPO) but not against Sp100, PML, gp210, LKM-1, LC-1 and SLA/LP (Figure 2, panel C). Rods and rings cytoplasmic pattern The structures recognized by patient serum were distinct cytoplasmic rods and rings (figure 1 and 3). We observed one to two rods and/or rings per cell including some intermediate structures such as a figure ''8'' (Figure 3, B1; B2), elongated rings (Figure 3, A2 ), twisted rings (Figure 3, C2), rods with pin loops (Figure 3). Some rods often align adjacent to the nucleus or perpendicular to the nucleus, and rings may be found in the cytoplasm (Figure 3, A3; B3; C1). Histological evidences The typical findings of PBC on hematoxylin-eosin stain were appeared, as described below: moderate lymphoplasmacytic portal inflammation with moderate interface hepatitis and bile ductular reaction along the periphery of the portal tracts, typical for early disease stages (Figure 4 panel A and B). Diagnosis Following the American Association for the Study of Liver Diseases Guideline, PCB diagnosis was made: 1) Biochemical evidence of cholestasis based on alkaline phosphatase (ALP) elevation; 2) The presence of anti-mitochondrial antibodies (AMAs); 3) Histological evidence of intrahepatic destructive cholangitis of interlobular bile ducts.

anti-mitochondrial autoantibodies, primary biliary cholangitis, the rods and rings (r&r) autoantibodies

PMC8320545_01

Male

A 44-year-old otherwise healthy Sri Lankan male presented with left ankle joint swelling of 6 months duration. He had progressive ankle swelling with restricted movement and pain while weight-bearing. He denied any respiratory symptoms, pyrexia and constitutional symptoms. Patient did not have a history of previous trauma or surgery. On examination, his left ankle joint was swollen without tenderness or warmth (Figure 1). There was global restriction of movements at the ankle joint. Apart from this, the general physical examination was unremarkable. His basic haematological tests were normal; however, his erythrocyte sedimentation rate (ESR) was 35 mm in the first hour. A Mantoux test was performed and it was positive with an induration of 18 mm. However, Ziehl-Neelsen stain for acid-fast bacilli was negative and the chest X-ray was unremarkable. Arthritis workup with rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP), and antinuclear antibody (ANA) was negative. His fasting blood sugar level was normal and retroviral screening was negative. X-ray of the ankle region showed irregular outline at ankle mortise and loss of joint space with an irregular articular outline at subtalar joint (Figure 2). The magnetic resonance imaging (MRI) showed a marked loss of articular cartilage with associated bone marrow oedema in the subarticular region of distal tibia extending to distal metaphyseal region (Figure 3). The subtalar joint also showed evidence of chronic inflammation. Aspiration was not possible due to minimal effusion. Since initial workup, including MRI, was inconclusive, the patient underwent open synovial biopsy which showed granulomatous type of inflammation without any Langhans type of giant cells or associated caseating granulomas. Xpert MTB/RIF test was negative; however, culture for mycobacteria was positive for Mycobacterium tuberculosis. The ankle was splinted with a back slab and was kept non-weight-bearing for the initial 2 months, followed by gradual mobilisation. Anti-tuberculosis treatment was initiated immediately after the synovial biopsy result, that is, 7 weeks after the initial presentation. Patient was treated for 2 months with isoniazid 300 mg, rifampicin 600 mg, pyrazinamide 1500 mg, and ethambutol 800 mg once daily (intensive phase), followed by 7 more months with isoniazid 300 mg and rifampicin 600 mg once daily (continuation phase). With anti-tuberculosis treatment and physiotherapy, his pain and swelling improved dramatically and he was able to bear weight by 3 months of treatment. Patient completed anti-tuberculosis treatment at 9 months and remains asymptomatic after 1-year follow-up. A repeat MRI was not performed since patient clinically improved.

tuberculosis, ankle joint, arthritis, monoarticular

PMC6469271_01

Female

A 32-year-old female presented with dyspnea and constant, non-radiating chest pressure along the left sternal border associated with palpitations that started at the gym during her routine workout, with ongoing racing heartbeat after exercise. She had no medical history. She had been taking oral contraceptives for birth control since age 18 (ethinyl estradiol/desogestrel) with no recent changes, and had traveled one-week prior on a flight of 6 h with breaks. On presentation, she had tachypnea and decreased breath sounds in the right lower lobe. Laboratory results demonstrated a mildly elevated troponin I of 0.18 ng/mL (ref <0.03 ng/mL). CT angiogram chest showed a large embolus in the distal main right pulmonary artery straddling the right upper and lower lobe pulmonary artery divisions; almost completely occluding flow to the segmental arteries (Figure 1). The patient was started on a therapeutic unfractionated heparin. Lower extremity venous Doppler ultrasound was negative for deep vein thrombosis (DVT). Transthoracic echocardiogram (TTE) showed a large, highly mobile mass attached to the right inter-atrial septum (Figure 2) prolapsing through the tricuspid valve in diastole highly suggestive of a cardiac myxoma (Supplemental Video 1). The patient underwent median sternotomy, right atrial mass resection, repair of atrial septal defect with pericardium, and pulmonary embolectomy (Figure 3). Histologic evaluation of specimens confirmed benign myxoma. The patient was discharged home in stable condition after her surgical procedure and uneventful post-operative course.

myxoma, pulmonary embolism, transthoracic echocardiogram

PMC6446216_01

Female

A 35-year-old Caucasian female with a past medical history of hepatitis C virus, thalassemia minor and ankylosing spondylitis presented to the hospital with worsening dyspnea on exertion accompanied by occasional wheezing for the past month. Her symptoms included substernal pleuritic chest pain, heartburn, recurrent epigastric pain, night sweats, and subjective fevers. She also reported weight loss of 30 pounds over the past 4 months. Review of systems was positive for fatigue, headaches, back pain, recurrent sinusitis, and lower extremity weakness. Complete blood count (CBC) showed hemoglobin 10.5 g/dL with mean corpuscular volume (MCV) 63, white blood cell (WBC) count 24.4 K/mm3, 75% eosinophils, absolute eosinophil count 18.3 K/mm3, platelets 256 K/mm3. Basic metabolic panel showed sodium 135 mmol/L (136-145 mmol/L), potassium 4.2 mmol/L (3.5-5.1 mmol/L), chloride 99 mmol/L (98-107 mmol/L), bicarbonate 27 mmol/L (21-31 mmol/L), blood urea nitrogen (BUN) 5 mg/dL (7-25 mg/dL), creatinine 0.5 mg/dL (0.6-1.3 mg/dL), glucose 87 mg/dL (70-110 mg/dL). Liver function tests were within normal limits. Urinalysis was unremarkable. Procalcitonin was normal at 0.07 ng/mL (<0.49 ng/mL). Erythrocyte sedimentation rate was elevated at 34 mm/hr (0-20 mm/hr). Serum antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies (ANCA) panel, serum fungal and parasite serologies were all negative as well. Computed tomography (CT) with angiography of the chest revealed ground-glass tree-in-bud opacities within the upper lobes bilaterally, concerning for respiratory bronchiolitis, interstitial lung disease, or atypical pneumonia. Bone marrow biopsy confirmed hypercellular marrow with trilineage hyperplasia and associated moderate eosinophilia. Pulmonary function testing (PFT) revealed FEV1 1.97 L (63% of predicted), FVC 3.77 L (74% of predicted), FEV1/FVC 85% of predicted; methacholine challenge test was positive. A follow-up high-resolution CT chest showed subtle centrilobular ground-glass nodules along the bronchovascular structures most pronounced within the bilateral mid and upper lungs (Fig. 1). Bronchoscopy with bronchoalveolar lavage showed marked eosinophilia (47%) on cytology, however, bacterial and fungal cultures were negative. Transthoracic lung biopsy was pursued and subsequent histopathological analysis showed prominent eosinophilic infiltrate, granulomatous reaction around small arterioles with occasional multinucleated giant cells and eosinophilic microabscesses, consistent with granulomatosis with polyangiitis and eosinophilia (Fig. 2A and B). She was started on prednisone 60 mg daily for 8 weeks and was found to have improvement in her symptoms.

PMC4138934_01

Male

A 46-year-old man presented to his physician with a 3-month history of generalized weakness and 15-pound unintentional weight loss. He also reported mild dyspnea on exertion and decreased appetite. His past medical history was significant for hypertriglyceridemia, primary hypothyroidism, and vitamin D deficiency. He had emigrated from the Philippines 6 years prior and had been working as a nurse at a skilled nursing facility. He had not left the country since his initial arrival. He denied sick contacts, specifically exposure to tuberculosis, smoking, alcohol consumption, or the use of illicit substances. A tuberculin skin test performed in 2007 resulted in induration (diameter unknown) and it was attributed to prior BCG vaccine. There was no evidence of pulmonary tuberculosis on a chest radiograph. Physical examination revealed abdominal distension and free fluid but was otherwise unremarkable. A diagnostic paracentesis revealed an exudative effusion with a positive Ziehl Neelsen stain for acid fast bacilli. The patient was started on treatment (Isoniazid, rifampicin, pyrazinamide, and ethambutol) for presumed extrapulmonary tuberculosis which was later confirmed by culture. One month after starting antitubercular therapy he presented to the hospital with worsening fatigue, salt craving, vomiting, loss of libido, and erectile dysfunction. On examination, he had low blood pressure and appeared cachectic. In addition he had bitemporal muscle wasting and hyperpigmentation of skin, oral mucosa, and nails. Laboratory evaluation was significant for hyponatremia, hyperkalemia, and mild hypercalcemia. A random cortisol was 2.5 mcg/dL with an ACTH of 531.2 pcg/mL. The basal and cosyntropin stimulated serum cortisol were, respectively 1.8 mcg/dL and 2.0 mcg/dL, which was consistent with the diagnosis of primary adrenal insufficiency most likely due to tuberculosis. A computed tomography scan of the abdomen with intravenous contrast revealed bilaterally enlarged adrenal glands (4 cm x 3.3 cm on the right, 2.3 cm x 2.1 cm on the left) (Figure 1). On review of his prior CT scan of the abdomen, the patient had bilaterally enlarged adrenal glands at the time of his initial presentation as well. With the background of tuberculosis and acute adrenal insufficiency diagnosed by laboratory test, bilateral enlargement of adrenal glands was considered most consistent with tuberculosis in our patient. Deterioration of his clinical status following antitubercular treatment could be attributed to accelerated cortisol metabolism by induction of CYP 3A4 by rifampicin. He was initially treated with intravenous hydrocortisone and was subsequently discharged on hydrocortisone and fludrocortisone. His symptoms have improved significantly. However, he is requiring slightly higher dose of hydrocortisone, which could be due to CYP 3A4 induction by rifampicin. He is likely to require lifelong treatment for adrenal insufficiency. A study that looked at tuberculosis patients with bilaterally enlarged adrenal glands found that treatment with antituberculosis drugs does not improve or help recover adrenal functionality. Adrenal biopsy was not performed because the presentation was strongly suggestive of adrenal tuberculosis with active extra-adrenal tuberculosis. Comment. It is to be noted that BCG vaccine received at birth has no impact on PPD test result 10 years later. The presumption made by the other hospital that this patient's positive TST is secondary to a vaccination at birth was incorrect. Positive PPD in this patient should have prompted further investigations. It is interesting to note that Thomas Addison was in fact seeking an anatomic basis for pernicious anemia rather than the biochemical effects of adrenal insufficiency when he published his seminal paper on the subject. The eleven patients he described in his report all had tuberculosis of the adrenal glands. This consumption has since receded to the background of ailments that afflict the Western world and today is generally considered a disease of immigrants from endemic areas, the immunocompromised or the destitute. In the developing world, however, tuberculosis continues to account for about 20-30% of cases of Addison's disease. The clinical presentation of primary adrenal insufficiency is protean, and an underlying infectious etiology can further obscure the manifestations. The most frequent manifestations are weakness, fatigue, anorexia, weight loss, nausea, vomiting, hypotension, and skin hyperpigmentation (present in 60-100% of patients). Understandably any of the above symptoms or signs could be easily missed or attributed to the primary infectious process itself. In the developed world, about 10% of cases of Addison's disease have an infectious etiology; however there are few data available regarding the frequency of organisms that cause clinical adrenal insufficiency. HIV/AIDS and opportunistic infections like cytomegalovirus are the most commonly cited causes following tuberculosis. Various fungi like Cryptococcus, Histoplasma, Coccidioides, Paracoccidioides are also described to involve the adrenal glands in several case reports (Table 1). Mycobacterium tuberculosis complex spreads to the adrenal glands hematogenously. Clinical manifestations may take years to become apparent, and asymptomatic infection is not uncommon. Adrenal involvement was found in 6% of patients with active tuberculosis in an autopsy series. More than 90% of the gland must be destroyed before insufficiency appears. The widespread use of computed tomography has improved our understanding of the patterns of involvement of the adrenal gland in tuberculosis. The majority of patients with active or recently acquired disease (<2 years) have bilateral adrenal enlargement, while calcification and atrophy are the norm with more remote infection or inactive disease. That the adrenals can be enlarged in patients with pulmonary tuberculosis without active involvement of the glands has been demonstrated in various studies. Stress and inflammation could be potential reasons. The activity of the hypothalamic pituitary axis (HPA) has been the subject of numerous studies. The lack of a uniform definition of a "normal cortisol response" to ACTH stimulation has perhaps contributed to some of the heterogeneity in the results. Kelestimur et al. studied the HPA axis in 27 patients with active pulmonary tuberculosis. They also compared responses to 1 mcg and 250 mcg ACTH stimulation. Cortisol responses were consistently higher in the cases when compared to controls. A more recent study by Laway et al. found significantly lower basal and stimulated cortisol levels in active pulmonary tuberculosis when compared to controls, as well as enlarged adrenal glands. None of the patients had clinical adrenal insufficiency. Both of these findings improved after successful antituberculous treatment. However, the absence of serum albumin levels and the lack of adrenal biopsies in the cases limit the interpretation of the results. Other studies have also demonstrated a reduction in adrenal gland size after successful treatment of pulmonary tuberculosis. When tuberculosis results in overt adrenal insufficiency, antituberculous chemotherapy does not appear to restore function. One must also be cognizant of the effect of rifampin, a potent hepatic enzyme inducer on the metabolism of glucocorticoids. Failure to increase the dose of steroid replacement therapy may result in the development of adrenal crisis. Adrenal biopsy is not necessary for primary adrenal insufficiency with bilateral adrenal enlargement in a patient with proven extra-adrenal tuberculosis. However, about 12% of patients with adrenal tuberculosis have no evidence of active extra-adrenal tuberculosis. Adrenal biopsy is generally necessary in these patients to prove adrenal involvement by tuberculosis. HIV infection affects the adrenal gland in multiple ways. Apart from direct infection, opportunistic infections and antiretroviral medications also have a significant effect on the adrenal glands. Adrenal insufficiency is prevalent in 17% of patients admitted with AIDS. Due to its high prevalence, recommendations have been made to screen for adrenal insufficiency in HIV patients with symptoms. Most common causes of adrenal insufficiency are infections like CMV, Mycobacterium tuberculosis and MAI, Cryptococcus neoformans, Histoplasma capsulatum, Pneumocystis jirovecii, and Toxoplasma gondii, neoplastic diseases (Kaposi's sarcoma and lymphoma), and bilateral adrenal hemorrhage. Few drugs used for the treatment of HIV infection (protease inhibitors) and drugs used to treat opportunistic infections like rifampicin, ketoconazole, and cotrimoxazole may exacerbate manifestations of primary adrenal insufficiency. Studies have shown decreased level of cortisol, adrenal androgens, and mineralocorticoids in patients infected with HIV. HIV infection can also lead to secondary adrenal insufficiency in advanced stages of the disease by decreasing pituitary and adrenal responses to CRH. Opportunistic infections like CMV, Mycobacterium tuberculosis, Toxoplasma gondii, Cryptococcus neoformans, and Pneumocystis jirovecii can also infiltrate the pituitary leading to multiple endocrinopathies. Treatment of adrenal insufficiency in HIV infection includes hydrocortisone and fludrocortisone (if there is evidence of mineralocorticoid insufficiency). There are cases of Cushing's like phenotype in patients treated with antiretroviral drugs (protease inhibitors and NNRTIs) often referred to as "pseudo-Cushing's". A normal cortisol response to the dexamethasone suppression test differentiates pseudo-Cushing's from Cushing's syndrome. Studies have also shown elevated levels of basal plasma cortisol in untreated HIV patients when compared to healthy individuals. The postulated mechanisms include stress due to HIV infection, increased cytokines resulting in stimulation of HPA axis, and reduction in cortisol catabolism. Adrenal tumors found almost exclusively in HIV patients include Kaposi's sarcoma which is secondary to coinfection with the oncogenic human herpes virus type 8 (HHV8) and non-Hodgkin's lymphoma (high-grade malignant B phenotype) which could be secondary to Epstein-Barr virus (EBV). Human cytomegalovirus (HCMV) has been frequently identified as a cause of adrenal insufficiency, especially in patients with HIV/AIDS. The virus has been shown by Trevisan et al. to infect normal human adrenocortical cells and induce cytopathic changes. It also acts as an inducer of steroidogenesis which may explain the discordance between the high rates of CMV adrenalitis in immune suppressed patients in autopsy studies and the relatively rare diagnosis of adrenal insufficiency ante mortem. The virus causes the greatest damage at the cortex-medulla junction. While adrenalitis may be the sole manifestation, the disease is usually disseminated. There have been case reports of exacerbation of CMV infection in patients of adrenal insufficiency after starting glucocorticoids most likely due to the immunosuppressive effect. Adrenal involvement is typically seen with disseminated chronic histoplasmosis. In one report, primary adrenal insufficiency occurred in 41.3% of adrenal histoplasmosis cases. Histoplasmosis often coexists with HIV-AIDS and is more commonly seen in the immunocompromised, posttransplant and elderly populations. Histoplasmosis presents with similar constellation of clinical features as tuberculosis and is often missed. Furthermore, it also shares pathological characteristics of necrotizing granulomas and caseous necrosis with tuberculosis. Adrenal glands have bilaterally enlarged radiographic appearance and CT guided biopsy often confirms the diagnosis of adrenal histoplasmosis. In addition to tuberculosis, it can also be often mistaken for a lymphoma, underlining the importance of biopsy in these cases. Management includes treatment with amphotericin B followed by itraconazole (for disseminated disease) and replacement of glucocorticoid and mineralocorticoid if there is evidence of adrenal insufficiency. Paracoccidioides, a thermal dimorphic fungus, causes infection through the inhalation of infectious conidia. It is endemic in several South American countries. Two species, P. braziliensis and P. lutzi, are pathogenic in humans. While the acute form usually appears as progressive lymphadenopathy, the chronic form affects the skin, lungs, mucous membranes, and the adrenal glands. Adrenal insufficiency occurs in a large number of patients (2.9%-48.2%) and has even been reported as the initial presenting feature. Autopsy series have demonstrated adrenal involvement in 85-90% of cases. Clinical manifestations range from the asymptomatic to frank Addisonian crisis. This correlates with the extent of granulomatous involvement of the adrenal glands. Similar to tuberculosis, adrenal insufficiency typically persists even after treatment of the infection. Many of the herpes viruses infect the adrenal gland including herpes simplex virus types 1 and 2, Epstein-Barr virus, and HCMV. This occurs usually in the setting of disseminated disease and may appear as adrenalitis. Disseminated HSV type 1 and 2 infections in neonates can be fulminant. Murine models suggest the possibility of the adrenals being the initial seat of multiplication of these viruses. EBV, HCMV, and Polyoma BK virus have been identified in resected adrenocortical tumors; the former has also been associated with lymphoma of the adrenal gland. Other commonly occurring viruses that can infect the adrenal glands include echoviruses which can lead to adrenal hemorrhage and necrosis in neonates. The hemorrhagic fever viruses, although rare, can cause devastating damage to the adrenal glands. The Ebola virus, a filovirus, has been shown to cause liquefaction of the adrenals. Other filoviruses and arenaviruses can also damage the adrenals by direct infection. Adrenal cryptococcosis occurs in disseminated cryptococcal infection, usually in the immunocompromised; however, there are case reports of adrenal cryptococcosis in healthy individuals as well. Pneumonia and meningitis are the most common presentations. Like any other fungal infection, the adrenal glands are enlarged on CT scan and the diagnosis is confirmed by a CT guided biopsy. Cryptococcal antigen titers are invariably high and can be used as a biomarker for disease resolution on follow-up. A 6-month course of fluconazole appears to be effective. In contrast to tuberculosis and histoplasmosis, adrenal insufficiency is often improved with resolution of the disease. Adrenal cryptococcal infection resistant to antifungal therapy may respond to adrenalectomy. Pneumocystis jirovecii is an infrequent cause of adrenal insufficiency even in patients with defective cell mediated immunity such as patients with HIV/AIDS. However, it has been known to cause fatal adrenal crisis in the apparently immunocompetent host as well. Blastomyces dermatitidis is a thermal dimorphic fungus that is the North American counterpart of Paracoccidioides in terms of its pathogenesis and propensity for establishing chronic systemic infection. Although pulmonary infection is the most common presentation, it frequently affects the skin, bones, adrenal glands, and the genitourinary system. Almost any organ system may be involved. It appears that subclinical infection of the adrenal glands is more common than overt insufficiency. About 10% of cases in autopsy series revealed adrenal gland infection. Amphotericin B and itraconazole are the drugs of choice in disseminated disease. Atypical mycobacteria have been isolated from adrenal glands in patients with HIV/AIDS, however, given the multiple etiologies for adrenal insufficiency and frequent coinfection with other organisms that are known to cause destruction of the adrenal glands; however, it is difficult to establish a causal relationship. The Waterhouse-Friedrichsen syndrome deserves special mention. It is a form of acute adrenal insufficiency that occurs in the setting of bacterial sepsis resulting in adrenal hemorrhage. A number of bacteria are associated with this entity including N. meningitidis, H. influenza, pneumococcus, P. multocida, K. oxytoca, S. aureus, Capnocytophaga canimorsus, Ewingella, and group A streptococcal infections. The organisms are rarely isolated from the adrenal glands at autopsy. Of all the organisms mentioned in this review, parasites are perhaps the least commonly reported causes of adrenal infection in the United States. Microsporidia have been reported to cause necrotic lesions in the adrenal glands, particularly in patients with AIDS. Echinococcosis (hydatid disease) is responsible for about 7% of all adrenal cysts. Treatment is surgical excision followed by several months of chemotherapy with oral albendazole to prevent recurrence. Visceral leishmaniasis is another cause of cystic adrenal disease. Trypanosoma cruzi, the causative agent of Chagas' disease, has been shown to infect the adrenal gland. Studies have postulated that the adrenals may serve as a reservoir for T. cruzi and parasitemia in the central adrenal vein has been correlated with the development of chronic chagasic cardiomyopathy. African trypanosomiasis has been associated with polyendocrinopathies including hypogonadism, hypothyroidism, and adrenal insufficiency. This can result from a primary glandular or secondary (central) involvement. In one case series of 137 Ugandan patients, treatment of the infection resulted in recovery of adrenal and thyroid function, but hypogonadism tended to persist for years.

PMC3320293_01

Female

The patient, a healthy, 38-year-old woman in the 7th week of pregnancy, traveled with her husband to Hong Kong. From March 1 to March 6, 2003, they stayed at the Hong Kong hotel where it is believed a physician from China spread SARS-CoV to several guests. These guests were the index case-patients for subsequent outbreaks in Hong Kong, Vietnam, Singapore, and Toronto, Canada. The woman and her husband returned to the United States on March 6; the husband had onset of SARS illness on March 13. On March 19, the patient had onset of an illness with fever (temperature 37.8-40 C), muscle aches, chills, headache, runny nose, productive cough, wheezing, and shortness of breath. A chest radiograph showed a diffuse infiltrate in the left lung. The patient was hospitalized for 9 days and given broad-spectrum antimicrobial drugs. She recovered from her illness, and enzyme immunoassay and immunofluorescent assays conducted on serum samples on days 28 and 64 after illness onset were positive for antibodies to SARS-CoV. The patient had an uneventful pregnancy until the last trimester, when her blood glucose levels were elevated. Early spontaneous rupture of membranes initiated preterm labor, and a cesarean section was performed at 36 weeks' gestation because of fetal distress. A 5-pound, 7-ounce, healthy boy was delivered without complications. Apgar scores were 7 at 1 minute and 8 at 5 minutes. The newborn had no illness, abnormalities, or congenital malformations. Serum samples from the patient at delivery were positive for antibodies to SARS-CoV, but cord blood and placenta samples were negative. Breast milk samples on postpartum days 12 and 30 were also negative for SARS-CoV antibodies. Blood, stool, and nasopharyngeal swab samples from the patient and cord-blood samples showed no viral RNA by reverse transcription-polymerase chain reaction. Stool samples from the newborn, collected on days 12 and 30 after delivery, were also negative for viral RNA. Although other countries have reported cases of severe illness and poor outcome associated with SARS-CoV infection during pregnancy (-), neither of the two pregnant SARS case-patients in the United States had serious adverse outcomes. The presence of antibodies to SARS-CoV in breast milk might be influenced by the time of infection in relation to gestation. Robertson et al. reported that antibodies to SARS-CoV were detected in the breast milk of a patient who was infected at 19 weeks' gestation; however, the patient in this case was infected at 7 weeks' gestation, and antibodies to the virus were not detected in her breast milk. No reports have indicated vertical transmission of SARS-CoV, a finding that is supported by our data. However, too few cases have been studied to clearly define the risks and provide guidance for treating pregnant women infected with SARS CoV.