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Tuberculosis_Dataset

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PMC4617009_01

Male

A 42-year-old man without any previously known medical history contacted his general physician due to complaints of cough and dyspnea. He was predisposed toward pulmonary illness through daily smoking of tobacco and inhaled illicit drugs of poor quality. Furthermore, the patient had a chronic occupational exposure to concrete and limestone, two known sources of silica dust. He was prescribed general antibiotics, but was admitted at Shariati Hospital, Isfahan 3 months later due to the persistence of his symptoms. During admission, x-ray and computerized tomography (CT)-scan of the thorax were performed, which were suggestive of pneumonia; then the patient was represcribed antibiotics and discharged. One month later the patient's condition worsened, now presenting with fever (39.8 C), daily headache, and vomiting. Brain magnetic resonance imaging (MRI)-scan with contrast was performed, which revealed multiple bilateral brain abscesses [Figure 1a] causing his immediate transfer to Arad Hospital, Tehran for stereotactic brain biopsy. The biopsy material was cultivated and examined by smear microscopy, which indicated long 1 microm-wide, branching, filamentous, gram-positive elements suggestive of Nocardia, or less likely fungi, which at that point could not be confirmed by culture. The patient was referred to Alzahra Hospital, Isfahan and the treatment was expanded to consist of vancomycine, meropenem, trimetroprime/sulfametoxazol (TMP/SMX), amphotericin B, and dexamethasone. In the search for a primary focus of infection, and with cancer as the differential diagnose, the patient was systematically examined. At first an echocardiogram following blood cultivation of three independent blood samples was performed in order to rule out endocarditis, all of which turned out negative. The chest CT-scan was inconclusive showing diffuse alveolar infiltrations [Figure 2]. Further smear microscopy and culture were performed on sputum and bronchoalveolar lavage (BAL) but they showed negative for Actinomyces, Nocardia, Mycobacterium Tuberculosis, and other bacteria and fungi. Cytopathology analysis for malignancy was also performed but turned out negative. The abdomen and pelvic were assessed using CT-scan with contrast and ultrasonography but revealed no abnormalities. Neither did the urine analysis nor did the culture show any sign of infection. When assessing the patient's immunocompetence the patient was tested negative three times for HIV type 1 and 2, and a complete blood and bone marrow analysis was performed including CD8+ and CD4+ T-cell count, which revealed no immunodeficiency, malignancy, or sign of tuberculosis. Finally, an open lung biopsy was performed. This revealed PAP, but was negative for malignancies, Actinomyces, Nocardia, Mycobacterium Tuberculosis and other bacteria, confirming the negative results of sputum and BAL analysis. 3 weeks after the brain biopsy the result of the brain abscess culture was completed and turned out positive for Nocardia Asteroides, confirming the results of the smear. Based on these results, a 2 months intravenous drug regime was started consisting of TMP/SMX, meropenem, and amikacine. Neurosurgical intervention was also considered due to the large size of the abscesses, but was not found to be possible because of the high number of abscesses and the profound location. Dexamethasone was also prescribed and it showed a beneficial effect on the headache but its tapering was complicated due to the return of headaches. After 3 weeks of treatment the fever began to diminish, and after 2 months the patient was discharged with a body temperature of 37.2 C and a reduction in the frequency of vomiting and headaches from a daily basis to a weekly basis. The treatment was continued with oral TMP/SMX antibiotics. Four months after discharge the patient returned to the hospital with newly-emerged neurological and psychological symptoms such as diplopia, headaches, and breakdowns despite continuous oral antibiotic treatment and brain MRI-scan with contrast that on the contrary was showing diminished cerebral abscesses [Figure 1b]. Because of the worsening condition and the increasing neurological character of the symptoms, the patient was discontinued treatment at the infectious disease department and transferred to the neurology department for further treatment.

brain abscess, nocardia, immunosuppression, pulmonary alveolar proteinosis, silica dust

PMC4677800_01

Male

The first example is based on a study that examined the effects of providing praise and preferred edible items based on variable-time schedule in order to reduce problem behavior. In addition, effects of variable-time schedule on compliance were also evaluated. The study was based on a reversal design (ABAB) and included three participants. In the current example, data for one of the participants is provided. Sam was an 8-year-old boy diagnosed with Asperger syndrome and attention deficit hyperactivity disorder. Data displaying frequency of problem behavior and percentage of compliance in each phase of the design are presented in Figure 4 and Figure 5, respectively. Conclusions based on VA of the data suggested that the variable-time schedule reduced problem behavior, but did not increase compliance for Sam. stated that "levels of compliance were only slightly higher during treatment with VT food and praise for Sam ..." and that "variable-time delivery of food and praise superimposed on a demand baseline (in which problem behavior continued to produce escape) greatly reduced problem behavior ..." (p. 431). ITSA was implemented to evaluate the effect of variable-time delivery on problem behavior and compliance. The ARIMA (1, 0, 0) was applied to both behaviors to estimate 4 parameters: level, change in level, slope and change in slope. For problem behavior, lag-1 autocorrelation was .40. The analysis for slope and change in slope yielded non-significant findings, whereas change in level in the variable-time delivery phase indicated significant decrease in problem behavior (t (18) = -2.39, p < .05) with medium effect size (d = 1.85) based on tertile distribution. The findings based on statistical analysis confirm conclusions drawn from VA, indicating decrease in problem behavior due to variable-time delivery of preferred food and praise. For compliance, lag-1 autocorrelation was .13. The analysis for slope and change in slope yielded non-significant findings, whereas change in level in the variable-time delivery phase indicated significant increase in compliance (t (18) = 2.43, p < .05) with medium effect size (d = 1.76). The findings based on statistical analysis did not confirm the conclusions drawn from VA, which indicated only slight increases in compliance, while statistical findings show significant increases with large effect sizes. ITSA details are presented in Table 1. The second example is based on a study that examined the effectiveness of a device that prevents drivers from changing gears for up to 8 seconds unless the seatbelt is buckled. The study was based on an ABA reversal design and included 101 commercial drivers. Data for one driver is displayed in Figure 6. Based on the VA of the data presented in the top panel, concluded "... an increase in seat belt use following the 8-s delay and a decline when the delay was removed" (p. 377). ITSA was implemented to evaluate the effect of the 8-s gearshift delay on seatbelt use. Two ARIMA (5, 0, 0) models were applied to test increases in seatbelt use following the 8-s delay (AB) and to test a decline in seatbelt use when the delay was removed (BA). Each model estimated 4 parameters: level, change in level, slope and change in slope. For AB phase of the design, lag-1 autocorrelation was significant (ar1 = .56). The analysis for slope and change in slope yielded non-significant findings, whereas change in level in the 8-s delay phase indicated significant increase in seatbelt use (t (79) = 8.59, p < .05) with large effect size (d = 2.78). The findings based on statistical analysis confirm conclusions drawn from VA, indicating an increase in seatbelt use due to 8-s gearshift delay. For the BA phase of the design, lag-1 autocorrelation was significant (ar1 = .76). The analysis for slope yielded non-significant findings, however change in slope and change in level were significant and indicated a decrease in seatbelt use due to removal of the gearshift delay (t (87) = -2.19, p < .05; t (87) = -8.58, p < .05 for change in slope and change in level respectively). The findings based on statistical analysis confirm conclusions drawn from VA, indicating a decrease in seatbelt use following removal of the 8-s gearshift delay.

PMC7330058_01

Female

A 35-year-old woman was admitted at our hospital for pleural empyema. Primary antibiotic treatment was followed by surgical removal of the affected lung sub-segment. Histology showed a fibrosing reaction with histological pattern of non-specific interstitial pneumonia (NSIP), as well as typical infectious features. Since adolescence, the patient suffered from recurring respiratory infections. At the age of 15, she developed immune thrombocytopenia, which was successfully treated with several cycles of intravenous immunoglobulins. In her early 30s, she twice suffered from herpes zoster reactivation. Further examination revealed splenomegaly, abdominal lymphadenopathy, and decreased serum immunoglobulin levels. According to the guidelines of the European Society for Immunodeficiencies (ESID), diagnosis of CVID could be made. Total immunoglobulin values at diagnosis were IgG 598 mg/dl, IgA < 5 mg/dl, IgM 27 mg/dl. The lymphocyte count was reduced (760/mul) with low levels of CD4+ T-helper cells (234/mul), reduced naive CD4+ T-helper cells (11,2% of all CD4+ T-cells), but immunophenotyping showed a normal percentage of NK cells, T-cells and B-lymphocytes with disturbed maturation and reduction of switched memory B-cells and an increase in CD21 low B-cells, which according to the classification for immunodeficiencies (EUROclass) corresponds to the following subgroup: smB- TRhigh CD21low. Due to the low T-cell count, classification as a combined Immunodeficiency (CID) would also have been possible. Furthermore the patient displayed a decreased frequency of regulatory T cells (Treg) which also indicated a dysfunctional phenotype with low expression of CTLA4 (cytotoxic T-lymphocyte-associated Protein 4) as well as FOXP3 (Supplemental Figure 1). Molecular genetic testing for typical genetic defects in CVID such as LRBA, CD3G, IL2RA, LAT, LCK, PIK3CD, PIK3R1, PTEN, STAT3, ZAP70, or CTLA4 deficiency, yielded no results. Other causes of secondary hypogammaglobulinemia, such as HIV, were excluded. No lymphoma was found by bone marrow trephine biopsy or total body CT scan. The patient recovered well under antibiotic therapy. Immunoglobulin replacement therapy (IgRT) with subcutaneous immunoglubulins (0.5 g/kg body weight every 4 weeks combined with hyaluronidase, target trough level of 6 g/l) was initiated. Despite stable clinical representation, a chest CT scan 2 months later showed progressive infiltrates of the lung parenchyma, as well as bronchiectasis. To rule out a new infection, a bronchoscopy was performed, which showed no evidence of bacterial or mycotic infection, including TB. Virus PCR for EBV, CMV, and common respiratory tract infections was negative. We therefore considered the infiltrates a manifestation of CVID, most likely as granulomatous-lymphocytic interstitial lung disease (GLILD), and started immunosuppressive therapy with prednisolone (1 mg/kg) and subsequent taper, and azathioprine (2.5 mg/kg/day). A CT scan 6 months later showed a significant improvement of the pulmonary infiltrates, the patient had no relevant infections since starting IgG substitution. 4 months later the patient suffered a generalized epileptic seizure. Cerebral MRI showed several periventricular, subependymal, and leptomeningeal lesions with intensive contrast medium uptake. The criteria for multiple sclerosis were not met on the basis of the distribution pattern and a pattern of different ages of lesions. The largest lesion was located in the left posterior lobe with a diameter of 4.4 cm (Figure 1). CSF analysis showed a mild pleocytosis with a normal protein content. Oligoclonal bands were not detectable. A eubacterial 16S rRNA PCR was negative, as were PCRs for HSV, VZV, EBV, CMV, HHV6, HHV7, HHV8, adenovirus, enterovirus, BK virus, and JC virus. We proceeded to biopsy the occipital lesion by stereotactic puncture. The histological examination showed an inflammation with predominantly perivascular accumulation of T-lymphocytes and an increase in plasma cells without kappa/lambda light chain restriction. Malignant cells, granulomas, or demyelinating plaques were not detected. Hence, the etiology remained unclear. Another whole-body CT scan as well as a further bone marrow trephine biopsy did not show any pathological findings. Due to the lack of clarity and the therapeutic relevance, a second stereotactic biopsy was performed. This second tissue sample was sent to the German Reference Laboratory for Neuropathology. Again, no signs of malignancy were found, as well as no evidence of infection or demyelination, the pattern of T-cell predominant perivascular lymphocytic infiltration was confirmed. Thus, the histological findings as well as the other previous findings were compatible with an autoimmune encephalitis. Important differential diagnoses like lymphoma or multiple sclerosis were excluded. In addition to IgRT, we started a more intensive immunosuppressive therapy with 2 cycles of rituximab 1,000 mg i.v. and high-dose steroids (prednisolone ~1.5 mg/kg/day) with subsequent taper. An MRI control of the CNS a few weeks later showed receding lesions. The patient's condition was stable with additional administration of an anticonvulsant and azathioprine as maintenance therapy. However, under the dose of azathioprine 2.5 mg/kg/day and prednisolone 15 mg/day, another MRI control 2 months later showed a renewed increase in intracerebral inflammatory activity with progressing lesions. Immunosuppressive therapy was escalated using cyclophosphamide (750 mg/m2 iv every 3 weeks), with additional trimethoprim/sulfamethoxazole prophylaxis. Azathioprine was discontinued. A staging MRI 3 cycles of cyclophosphamide showed a mixed response. New lesions were found in the medulla oblongata and in the posterolateral cervical medulla. MRI of the entire spinal cord showed focal lesions in the cervical and thoracic myelon extending to the Th2 segment (Figure 2). The clinical examination was inconspicuous, with no evidence of neurological symptoms. We initiated therapy with abatacept, a T cell activation modulator 14 mg/kg bw i.v. (week 0, 2, then every 4 weeks), also due to the known Treg CTLA4 deficiency. In addition, a high-dose therapy with steroids (prednisolone 1,000 mg for 3 days) with subsequent dose reduction to 1 mg/kg body weight and then further tapering was performed. Again, MRI control of the CNS and spinal cord after initial improvement showed progression 3 months after starting abatacept. Up to this point, no treatment regime had led to a sustained improvement in cerebral or spinal inflammation. The diagnosis underwent a critical review, including renewed CT, CSF analysis, and infection screening. No new findings were made. A further biopsy was not performed. Due to the organ-threatening character of the inflammatory activity, which could not be controlled despite the previous intensive immunosuppression, we saw an autologous stem cell transplantation as the best possibility to intensify the therapy. Other therapy options did not seem promising in this situation. We used a well-established protocol according to the guidelines of European Group for Blood and Marrow Transplantation (EBMT). For mobilization of autologous hematopoietic stem cells, the patient received cyclophosphamide 2 g/m2 together with a daily dose of 105 mug G-CSF, starting on the second day after cyclophosphamide administration. Leukapharesis was performed on day 10. The autologous hematopoietic stem cells underwent CD34+-selection using immunomagnetic separation (CliniMACS CD34 Complete Kit, Miltenyi Biotec, Bergisch Gladbach, Germany). 8 weeks after apheresis, conditioning with cyclophosphamide (4 x 50 mg/kg body weight) and rabbit antithymocyte globulin (rATG) (3 x 5 mg/kg body weight) was administered over 5 days. On day 1 after conditioning, the autologous graft was transplanted (2.6 x 106 CD34+ cells/kg body weight). During the subsequent aplasia phase until engraftment, the patient had several typical adverse events. Due to thrombocytopenia a small, non-significant subdural hematoma occurred. Substitution of 2 platelet concentrates stabilized hemostasis sufficiently. In addition, 2 red cell concentrates were given due to severe anemia. Apart from sinusitis, which was treated with antibiotics, no relevant infectious complications occurred. The patient received oral acyclovir and posaconazole prophylaxis. IgRT was continued unchanged to keep immunoglobulin levels stable within target range (6 g/l). Recovery of neutrophils above 500/mul occurred on day 14 after transplantation. Lymphocyte counts remained low at 700/mul on day 30. However, rather low values had already been measured before transplantation, probably because of the CVID itself, or due to immunosuppressive therapy. As was to be expected, the number of CD4+ T-helper cells was significantly reduced after transplantation (52/mul on day). On the day of discharge a low dose of prednisolone (10 mg/day) was maintained, as well as prophylactic oral therapy with trimethoprim/sulfamethoxazole, oral amphotericin B, and acyclovir. A CNS-MRI 3 weeks after discharge showed a significant decrease in intracerebral and intraspinal inflammation. Further controls after 3, 7, and 12 months showed a complete disappearance of the lesions. The health condition of the patient improved steadily. Regular controls of the immune reconstitution by immunophenotyping showed a gradual increase of T cells and B cells in the following months. After 11 months the CD4+ T helper cells reached 200/mul, so that acyclovir and amphotericin B were discontinued, trimethoprim/sulfamethoxazole was continued. As a sign of increased plasma cell activity during reconstitution there was an increase in polyclonal IgM. We decided to administer rituximab as B cell depleting maintenance therapy (1,000 mg, day 0, 15). The first cycle was given 9 months after transplantation, a second cycle 6 months later, resulting in a complete depletion of B cells and a decrease in IgM. Prednisolone was reduced to a minimal dose of 2.5 mg/day. 18 months after transplantation the patient is in good health without autoimmune symptoms, regular MRI controls show a sustained remission. Under persistent IgRT no severe infection has occurred since transplantation. The patient resumed her daily activities and her former profession.

autoimmune encephalitis, autoimmunity, autologous stem cell transplantation, common variable immunodeficiency, primary immunodeficiencies

PMC4976608_01

Male

A 25-year-old man was referred to our hospital with a 10-year history of bilateral upper lung fibrosis. He had had asthma since the age of 2 years. He never smoked and had no occupational or environmental exposure. At the age of 19 years, he underwent a fiber-optic bronchoscopy examination at another hospital. However, at that time, TBLB specimens stained with hematoxylin and eosin (HE) did not allow any specific diagnosis. Since then, he has visited the hospital once a year for a medical check-up. Although he was asymptomatic, the lung fibrosis progressed gradually. He was then referred to our hospital. On physical examination, he was slender with a body mass index (BMI) of 15.1 kg/m2 and had no clubbed fingers. Respiratory sounds were normal. A chest radiograph at the age of 15 years showed upper lung-dominant fibrotic opacities with elevated hilar opacities. Ten years later, upper lung fibrosis had worsened with markedly increased hilar opacities (Fig. 1a). A chest computed tomography (CT) taken at our hospital showed a flattened chest cage and subpleural consolidations with traction bronchiectasis located in the bilateral upper lung fields (Fig. 1b). By contrast, the lower lung fields were almost normal. Spirometry showed markedly restrictive impairment: forced vital capacity (FVC) was 1820 mL (43.5% pred.). Serum Krebs von den Lungen-6 (KL-6) concentration was near the upper limit of the normal range (470 U/mL), and Surfactant protein-D (SP-D) concentration was markedly increased (531 ng/mL). The slender constitution with flattened chest cage and the long history of upper lung lesions with restrictive impairment raised the possibility that the disease was PPFE. We obtained the previous biopsy specimens stained with HE and the paraffin blocks, and additional histological specimens stained with Elastica van Gieson (EVG) were prepared to identify elastofibrosis. The EVG specimen revealed dense elastosis just beneath the subepithelial reticular basement membrane of the peripheral airway (Fig. 1c, d). Another specimen showed that alveoli were filled with collagen in association with septal elastosis. All of these histological findings are consistent with those of PPFE.

idiopathic interstitial pneumonia, pleuroparenchymal fibroelastosis, surgical lung biopsy, transbronchial lung biopsy

b. Upper lung fields of chest CT in case 1.

PMC4976608_02

Male

A 64-year-old man was referred to our hospital with a diagnosis of pulmonary upper lobe fibrosis. He had experienced repeated pneumothorax since the age of 18 years. In his 30s, he noticed cough and mild fever. He received antituberculous medical therapy under the diagnosis of suspected pulmonary tuberculosis, but the cough remained. A few years ago, he noticed exertional dyspnea. Since then, cough and dyspnea have been gradually worsening and he has experienced repeated episodes of fever. He had smoked 20 to 30 cigarettes a day for about 20 years and had quit smoking in his late 30s. His mother had rheumatoid arthritis and systemic sclerosis. On admission, he was slender with a BMI of 17.9 kg/m2 and had no clubbed fingers. Respiratory sounds were normal. A chest radiograph showed upper lobe-dominant fibrotic opacities with elevated hilar opacities (Fig. 2a). Chest CT showed subpleural consolidations with traction bronchiectasis and bilateral apical cysts (Fig. 2b). However, the lower lung fields were almost free from fibrotic lesions. FVC and total lung capacity (TLC) were decreased: 2220 mL (59.4% pred.) and 4970 mL (87.0% pred.), respectively. However, residual volume (RV) was increased (2850 mL, 142.5% pred.), which resulted in an increased RV/TLC ratio (154.6% pred.). He underwent fiber-optic bronchoscopy examination. TBLB specimens obtained from the left upper lobe showed fibrosis, but there was no specific diagnosis. However, the histological specimen stained with EVG revealed dense aggregates of elastic fibers that were associated with intra-alveolar fibrosis (Fig. 2c, d). These histological findings are consistent with those of PPFE.

idiopathic interstitial pneumonia, pleuroparenchymal fibroelastosis, surgical lung biopsy, transbronchial lung biopsy

b. Upper lung fields of chest CT in case 2.

PMC4434166_02

Female

Case 2: A 54 year old post-menopausal female was referred following the removal of a 4 cm endocervical polyp with final histopathology demonstrating a malignant melanoma with positive margins. Immunostains for S100, HMB-45, and Mart-1 were positive (See Fig. 2). A staging PET/CT scan was negative for metastatic disease, and a pelvic MRI demonstrated a 23 x 22 x 49 mm cervical lesion with concern for parametrial extension. The patient underwent a type-III radical hysterectomy, bilateral salpingooophorectomy and pelvic lymphadenectomy with residual amelanocytic melanoma involving the full thickness of the cervix and extending to the vagina with extensive angiolymphatic invasion. All margins were negative, as were 26 pelvic lymph nodes. Her post operative course was complicated by a small bowel obstruction that resolved with conservative management as well as a pelvic abscess which required percutaneous drainage and antbiotics. A multidisciplinary team recommended high-dose rate brachytherapy given the high-risk features, which was completed 8 weeks after surgery, followed by systemic therapy with ipilimumab. Unfortunately, she was hospitalized for nausea and vomiting post-radiation, and imaging revealed metastatic disease with innumerable new liver and pulmonary metastases that were not present on imaging 6 weeks earlier. She was lost to follow-up and died of disease 2 months later (7 months from initial diagnosis) without receiving systemic therapy.

cervical melanoma, immunotherapy, multidisciplinary treatment, ovarian melanoma

PMC2637836_01

Male

A 30 year old non-smoking male patient presented with intermittent, high-grade nocturnal fever with night sweats of one year. He also had low back ache over his right hip. Prior to hospitalization, he had received four-drug anti-tubercular therapy (ATT) based on right sacro-ileitis seen on magnetic resonance imaging (MRI). No change in symptoms was observed during one year of therapy and he lost 10 kg weight. He also developed a tender swelling over sternum about a month before presenting to us. We found him febrile, pale and his long bones, ribs and pelvis were tender. He had a 3 x 4 cm tender and hard swelling over the upper part of his sternum. Another firm, non-tender swelling about 4 x 5 cm was seen in the right iliac region. He had mild anaemia with normal liver/renal functions, serum calcium and alkaline phosphatase. Radiographs of the skull (Fig 1a and 1b), spine (Fig 1c) and pelvis (Fig 1d) revealed multiple variable sized lytic lesions affecting all visualized bones. T1 weighted MRI images of pelvis (Fig 2a) revealed a hypointense mass lesion involving the right iliac bone extending into the sacrum (arrow). T2 weighted MRI images (Fig 2b) revealed that the lesion in right iliac bone was hyperintense (double arrows). Plain chest radiograph (Fig 3a) of the patient revealed an ill-defined mass in the left mid and lower zones, along with multiple patches of consolidation in the right lung. Multiple lytic bony lesions were also seen (arrows). CT scan of chest (Fig 3b and 3c) showed the lung masses (solid arrows) and lytic lesions were observed in the sternum and the vertebra (double arrows). A metastatic malignancy or disseminated tuberculosis was considered. His anti-tubercular therapy was intensified by addition of a quinolone and aminoglycoside to the existing regimen. Pain was controlled with NSAIDs. Fine needle aspiration performed from sternal lesion showed inflammatory cells. A bone marrow biopsy was taken from iliac crest and this showed infiltration of marrow spaces by tumor cells as shown in figure 4. The tumor was present in acinar architecture. The cells were polygonal in shape. The nuclei were hyperchromatic and showed moderate degree of nuclear pleomorphism. They had moderate amount of cytoplasm. The section also showed areas of procedural haemorrhage. These features are suggestive of metastatic adenocarcinoma. Patient's condition continued to deteriorate and he died within a fortnight of his hospitalization.

PMC9482418_01

Male

A 37-year-old male patient was admitted to the Second Hospital of Lanzhou University on 23rd July 2019 due to "fever accompanied by progressively deteriorating headache for 3 days and paroxysmal unconsciousness for 1 day." The patient had a history of "herpes zoster" 6 months ago. He developed fever without obvious predisposing factors 3 days before admission. His body temperature was 38.4-39.4 C, accompanied by a headache, mainly a mild intermittent throbbing pain in the temporal region. The symptoms aggravated the next day. The headache spread to the occipital region and the back of the neck and lasted longer. Meanwhile, the patient experienced mild fatigue and sore muscles that were unresponsive to ibuprofen sustained-release capsules. On the morning of 22nd July, the headache became significantly aggravated and more persistent, accompanied by nausea and vomiting of stomach contents two times. The patient suddenly lost consciousness that night, accompanied by involuntary movement of the left limbs, and regained consciousness 0.5 min later. When visiting our hospital on 23rd July, the patient lost consciousness again, accompanied by involuntary movement of the left limbs, and regained consciousness 1 min later. Physical examination on admission showed a body temperature of 38.2 C, a pulse-93 beats/min, a respiratory rate of 23 times/min, and a blood pressure of 124/82 mmHg. Scattered rice-like scabs caused by previous herpes zoster were observed in the sixth left intercostal space, with old skin lesions and fusion, but without redness or ulceration. The nervous system examination showed consciousness and a poor mental state without obvious abnormalities involving high-level cortical functions or cranial nerves. The muscle strength of the four limbs was graded as 4+. The muscle tension was normal, and tendon reflexes were present without any pathological signs. The neck was rigid, and the mentosternal distance was four fingers. Kernig sign+ and Brudzirnki sign+ were observed. Blood routine on admission plus C-reactive protein (CRP) showed white blood cell (WBC) counts at 9.5 x 109/L, neutrophil ratio (NE%) of 0.51, lymphocyte ratio (LY%) of 0.49, and CRP of 21 mg/L. The rest of the laboratory tests showed no abnormalities (Table 1). Electroencephalography (EEG) showed rhythmic emission of focal slow waves in the right frontal and temporal regions at 2-6 cycles per second, spreading to all leads. Preliminary diagnosis on admission indicated central nervous system infection of suspected viral meningoencephalitis and secondary epilepsy. Acyclovir 0.5 g/8 h, intravenously guttae (ivgtt), dexamethasone 10 mg, ivgtt, and carbamazepine 200 mg orally twice daily. were administered. Lumbar puncture was subsequently performed with the cerebrospinal fluid (CSF) intracranial pressure of 210 mmH2O, WBC counts of 145 x 106/L, mononuclear cell ratio (MN%) of 97.7, and proteins of 0.84 g/L. The rest examinations showed no abnormalities. In addition, 4 mL of CSF was collected for Pathogen Capture Engine Sequence (PACEseq) mNGS (Hugobiotech, Beijing, China) to determine the pathogen. In the meantime, autoimmune encephalitis antibody, infectious disease (including Toxoplasma, rubella virus, cytomegalovirus, herpes simplex virus, and other pathogenic microorganisms), rheumatism, respiratory tract 9-items, and tuberculosis antibody were all tested but showed negative. Brain magnetic resonance imaging (MRI) on July 25th showed patchy long T1 signal and slightly longer T2 signal in the right frontal, temporal, and insular lobes. While on diffusion-weighted imaging (DWI) and fluid-attenuated inversion recovery (FLAIR) sequences, high signals and patchy enhanced shadows in the lesion areas were also observed, and the dura mater adjacent to the lesion areas was enhanced and thickened (Figure 1). On July 26th, the mNGS result came out, and a total of 12,024 unique sequences of HHV-2, with a coverage of 95.44% were detected (Table 1, Figure 2), indicating HHV-2 meningoencephalitis. On 28th July, the patient's autoimmune encephalitis-related antibody was reported negative. After 21 days of antiviral treatment, the re-examination of the CSF showed intracranial pressure of 120 mmH2O, WBC counts of 4 x 106/L, and MN% of 100. No abnormalities were found for the rest items. The patient was discharged and given acyclovir and carbamazepine. One month later, an EEG re-examination on 15th September showed normal results. Head MRI showed irregular long T1 and T2 signal shadows in the right temporal pole. Low signals in FLAIR lesions and patchy high signals in the periphery were also detected by DWI. When compared with previous findings, temporal lobe and hippocampus atrophy adjacent to the lesions were observed. Local necrosis and softening foci were formed, and the right temporal horn was widened (Figure 1). After discharge from the hospital, the patient felt significant memory loss, without other obvious discomforts.

case report, cerebrospinal fluid, human herpesvirus 2, metagenomic next-generation sequencing, necrotizing meningoencephalitis

PMC9116532_01

Male

For this proof-of-concept study the 4D cardiac-gated CT scan from a 55 year-old male patient suffering from VT was used. The CT data of this VT patient has been previously used for other purposes in a work published by Gianni et al.. The treatment target for this patient had a size of 45 cm3 and it was located on the left ventricular free wall. This clinical target volume (CTV) was determined by electrophysiological mapping and contoured prior to the treatment by a medical doctor from the Texas Heart Arrhythmia Institute in Austin, USA. The left anterior descending coronary artery, the circumflex coronary arteries and the non-involved left ventricle were OARs near the target. First, the 4D CT scan of the VT patient was loaded into the Raysearch Raystation treatment planning system (version 10B, Raysearch Laboratories AB, Stockholm, Sweden). Subsequently, a virtual representation of the prototype version of the proprietary US probe system of EBAMed (Geneva, Switzerland) was manually inserted as volume of interest (VOI) in two locations representing the estimated position of the apical and parasternal US viewing windows. A separate study has already verified that these US viewing windows provide US images of sufficient quality for VT patients in supine position. The US probe was simulated as a cube of 2 x 2 x 2 cm. It is equipped with infra-red markers such that the probe can be localized by an optical camera (see Figure 1) and it is attached to a holder such that it can be fixed on the chest of the patient allowing for hands-free imaging during the treatment. To account for uncertainties in repositioning of the US probe during the treatment, including probe position uncertainties due to respiration and breath-hold differences, an isotropic safety margin of 10 mm has been added to the union of the US probe, holder, and optical marker. The parasternal US probe position allowed entrance of the treatment beams from optimal directions with respect to dosimetry for this particular patient. After selection of this virtual US probe position, a pencil-beam scanned proton therapy treatment plan was generated with the treatment planning system using the CNAO (Pavia, Italy) synchrotron proton beam model adapted to the Hitachi PROBEAT gantry system with 360 range of beam angles. During planning, the solid angle was restricted to take into account the US probe, the probe holder and the localization marker. Two fields were applied both with a gantry angle of 25 and a couch rotation of 0 and 90 for beam 1 and 2, respectively. The treatment volume was planned with an internal target volume (ITV) approach in order to compensate for shape and position changes of the target due to the heartbeat. It was assumed that the motion of the heart due to respiration would be mitigated using a breath-hold technique or respiratory gating. The envisioned role of the US imaging during this treatment was real-time cardiac motion monitoring and sending an alert to the operator in case the measured motion was outside of predefined limits. For the generation of the ITV, the heartbeat motion envelope was extracted from the 4D CT scan by deformable registration of each phase of the 4D CT scan to the planning CT scan. The resulting ITV is the union of the CTVs at all phases of the 4D CT. Finally, the planning target volume (PTV) was generated by adding a 5 mm margin to the ITV based on typical patient set-up errors which are expected when no image guidance tool like US imaging is used. Dose constraints on dose-volume tolerances (Table 1) in agreement with prior investigators were set as planning objectives. All doses are reported in Cobalt Gray Equivalent Dose (CGyE). The plan required the ITV to be covered by the 25 CGyE isodose, which is a dose level used in prior clinical studies to achieve safe, efficacious radioablation. To achieve this, the plan was normalized so that PTV D92% = 25 CGyE. Also, in order to arrive at a satisfactory treatment plan, robust optimization with 2 mm set-up error in all directions and 2% range uncertainty was used during planning. To verify the clinical acceptability of the generated plan, evaluation of standard target dose-volume metrics D98, D95 D50 and D2 was performed. In addition, the dose to OARs and the target dose conformity and homogeneity were evaluated.

cardiac motion monitoring, protons, stereotactic radioablation, ultrasound, ventricular tachycardia

PMC4797127_01

Female

We report a 55 year old female, who was diagnosed to have chronic autoimmune hypothyroidism for past 5 years on thyroxine, presented with insidious onset of constitutional symptoms for 6 months duration. Her thyroid function tests showed satisfactory control. Despite satisfactory control of thyroid function tests, she experienced a gradual but profound loss of weight of thirty six (36 kg) kilograms with loss of appetite for the same duration. She did not have any past or contact history of tuberculosis or a past history of malignant disease. She is not on any medication too. Over the last few months, she was complaining of a worsening generalized malaise, which affected her activities of daily living. There was no muscle pain but complained that her walking has become clumsy and it was difficult for her to stand from the seated position. On examination, she was cachectic with BMI of 19 kg/m2 and was found to be pale, without icterus or palpable lymph nodes or organomegaly. Neurological examination revealed reduced muscle power in lower limbs with diminished reflexes without any sensory deficit. Her fundoscopic examination was normal. Her initial investigations revealed normocytic normochromic anaemia (8.9 g/dl) with rouleaux formation. She had elevated ESR of 120 mm/1st hour and hypokalemia (2.9 mmol/l). Liver function tests showed reversed albumin to globulin ratio (Albumin - 29 g/l, Globulin - 50 g/l). On further investigation, serum protein electrophoresis revealed a monoclonal band in the gamma region. However, her skeletal survey and urinary Bence Jones protein were negative. In bone marrow aspiration, there were 15 % clonal plasma cells and immunofixation revealed IgG myeloma. After confirming the low potassium, we detected her urinary excretion of potassium to be increased. Furthermore, her arterial blood gas showed a marked hyperchloraemic metabolic acidosis (pH 7.2, HCO3- 8.2 mmol/l) with normal anion gap (15 mmol/l). Her urine pH was 7.5 and was high despite systemic acidosis and the fractionated bicarbonate excretion was 3 %. Her non-contrast CT of kidneys revealed bilateral non-obstructing renal calculi (Fig. 1). Her autoimmune markers namely ANA, Rheumatoid factor, Complement levels were all normal. Her serum ionized calcium level (1.1 mmol/l) and urinary excretion of oxalate, phosphate, uric acid, calcium and citrate levels were within normal range. Contrast CT scan of chest and abdomen did not show evidence of sarcoidosis or malignancy. The summary of the investigations is depicted in Table 1.

distal renal tubular acidosis, multiple myeloma, nephrolithiasis

PMC10272489_01

Female

A 31-year-old Nigerian woman with a history of endometriosis and primary infertility was referred to the hospital after an abnormal chest X-ray, which was performed for immigration purposes, showed a large right-sided pleural effusion. Despite having no respiratory or constitutional symptoms, an examination revealed dullness to percussion and absent breath sounds on the right lower and middle lung zones. The patient had a history of endometriosis four years prior, which was characterized by severe dysmenorrhea. Hormonal therapy was prescribed for three months, and an excisional biopsy was taken from an umbilical mass (Fig. 1) that occasionally bled during menses. The mass was later proven to be of endometrial origin. Upon admission, a complete blood count was unremarkable except for mildly reduced hemoglobin and low albumin. C-reactive protein was normal, and initial work-up for Mycobacterium tuberculosis was negative. A chest X-ray (Fig. 2a) revealed pleural effusion, and pleural tapping yielded bloody fluid that was sent for analysis and microscopy. The analysis revealed glucose of 5.3 mmol/L, LDH 314 U/L, and protein of 47.7 gm/L. The total nucleated cells were 250/muL, and red blood cells (RBCs) were 104,062/muL (Table 1). Thoracoscopy showed extensively inflamed parietal pleura (Fig. 3), and a large bore chest tube was placed afterward. The tissue biopsy confirmed endometriosis. An abdominal ultrasound revealed fluid in the right and left iliac fossae and a trace of fluid in the subcutaneous fat plane of the irregular umbilical mass. Chest computed tomography (CT) (Fig. 4) showed right pleural effusion with subtle pleural thickening and bilateral apical thickening, as well as mildly enlarged axillary lymph nodes mainly on the right. During the patient's follow-up, re-accumulation of pleural fluid was discovered by an X-ray with her menstruation (Fig. 2d). A therapeutic thoracocentesis was done to prevent possible complications of the bloody effusion. After considering the patient's desire for using assisted reproductive technology, a multidisciplinary approach recommended right-side pleurodesis prior to any conception attempts and avoiding hormone suppressive therapy. Fig. 5 demonstrates the timeline order of events from the initial evaluation until the final treatment.

asymptomatic, catamenial, endometriosis, hemothorax, pleural effusion

PMC9851858_01

Female

A 72-year-old female presents with left flank pain of two months duration, attenuated with position changes, accompanied by fever and polyuria. She is hospitalized and antibiotic treatment is started under the clinical suspicion of complicated pyelonephritis. During the approach, a computed tomography (CT) scan with intravenous contrast was performed. It revealed a left renal abscess, hydronephrosis, and a staghorn calculus, for which percutaneous drainage was placed (Fig. 1A). As there was no clinical improvement, coupled with the formation of a cutaneous fistula draining purulent fluid, a simple nephrectomy was performed, but was complicated due to the presence of multiple peritoneal adhesions at the level of the splenic flexure of the colon, so during the procedure it was decided to perform splenectomy and partial colectomy as well. Gross examination revealed a terminal kidney, a staghorn calculus occupying the renal pelvis, purulent fluid, and multiple exophytic lesions with a papillary appearance, which extended close to the ureteral surgical border (Fig. 1 B). Histopathological findings were villoglandular fronds lined by pseudostratified columnar epithelium, in addition to intestinal metaplasia in the renal pelvis and ureter with involvement of the ureteral surgical border. Another finding was of intestinal-type adenocarcinoma with microinvasion to the lamina propria (Fig. 2). Immunohistochemistry (IHC) stains were performed for CK20, CDX2, and SATB2, all of which were positive and corroborated the intestinal differentiation of the tumor (Fig. 3). After five days of favorable clinical evolution during the patient's postoperative period, hospital discharge was decided. After one year of follow-up, the patient is asymptomatic, in good general condition, and with no evidence of distant metastasis.

intestinal-type adenocarcinoma, renal pelvis, villous adenoma

PMC7607749_01

Female

A 14-year-old Caucasian female presented with a 3-month history of progressively worsening lower back pain. Her back pain quality was sharp, with 9/10 pain at its worst. The pain would sometimes radiate to her hips and down her legs and worsen with prolonged walking or activity. She was an otherwise healthy, competitive volleyball player. She had no fevers but did recall some occasional night sweats. There was no appreciable weight loss, no abdominal pain, no urinary or fecal incontinence. She had no recent diarrhea; in contrast, she reported experiencing more constipation in the weeks preceding her diagnosis. She had no significant past medical history and no known medication allergies. She was a freshman in high school and lived on a farm in southeast Michigan, raising chickens, turkeys, and cattle. Her only travel was to Key West, Florida, 3 months earlier. She had no specific risk factors and no known contacts with possible exposure to tuberculosis. Her symptoms were initially attributed to a musculoskeletal injury secondary to playing volleyball. Anti-inflammatory treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and physical therapy (PT) only provided moderate relief. Her back pain continued to worsen to the point that she was unable to walk without assistance. X-ray imaging of the spine was obtained by her primary care physician and was interpreted as normal, with no abnormalities of the vertebral bodies or disk spaces identified. A chest X-ray showed no pulmonary infiltrates and no masses concerning tuberculosis or other invasive infection. An orthopedic surgeon obtained a magnetic resonance imaging (MRI; Figure 1) of her spine to screen for possible musculoskeletal injury with nerve involvement. Surprisingly, the imaging demonstrated lesions consistent with pre- and para-vertebral phlegmon with associated osteomyelitis of the L4 vertebra and L4-L5 discitis. Blood work was obtained and showed a normal complete blood cell count but elevated inflammatory markers with erythrocyte sedimentation rate (ESR) of 43 mm (normal < 20) and C-reactive protein (CRP) of 1.7 mg/dL (normal < 0.6). She was subsequently referred to a quaternary care children's hospital for further evaluation. She was admitted to the pediatric general medicine service for presumed vertebral osteomyelitis, and pediatric orthopedic surgery and pediatric infectious diseases were consulted. Upon admission, she was afebrile, and her physical exam was notable for tenderness to palpation over her lower back about the area of L4. She hyperextended her spine with ambulation and was unable to flex her spine without significant pain. Laboratory studies showed a white blood cell (WBC) count of 11.9 K/mcL with 63% neutrophils, hemoglobin of 10.6 g/dL, and platelet count of 370 K/mcL. A procalcitonin level was obtained at 0.1 ng/mL (normal < 0.25 ng/mL). Her inflammatory markers were repeated with ESR 41 mm/Hr and CRP 1.4 mg/dL. Lactate dehydrogenase (LDH) and uric acid (UA) were within normal limits, reducing the likelihood of malignancy. Blood culture was obtained; note that she had not received antibiotics before her arrival. Given the prolonged duration of symptoms, her osteomyelitis was categorized as subacute to chronic, necessitating a longer course of antibiotic therapy of likely 6-12 weeks. A biopsy was requested to obtain specimens for microbiologic cultures to assist with organism identification and susceptibility testing. A computed tomography (CT)-guided tissue biopsy of the vertebral lesion was performed to obtain culture specimens for aerobic, fungal, and acid-fast bacilli (AFB). She was subsequently started on IV cefazolin for empiric treatment of typical organisms causing vertebral osteomyelitis in healthy children, including methicillin-susceptible Staphylococcal aureus (MSSA) and Streptococcus species. Cefazolin was chosen for empiric MSSA coverage, as our institution, as have many medical centers across the United States, has noted an increased incidence of MSSA as opposed to methicillin-resistant S. aureus (MRSA) in pediatric bone and joint infections. Surprisingly, the tissue biopsy culture resulted in the pure growth of a gram-negative rod, initially identified as Salmonella species, with subsequent identification by the Michigan State Health Department Microbiology Laboratory as Salmonella enterica subsp. enterica serovar Poona (S. Poona). Given the recovery of Salmonella species and unknown susceptibilities initially, cefazolin was transitioned to ceftriaxone for more reliable empiric coverage. A stool specimen was sent for nucleic acid testing. It was negative for the detection of Salmonella, suggesting she was not an active carrier. However, we cannot exclude the possibility that antibiotic treatment for 2 days before the stool specimen submission may have eradicated the infection. The isolate was susceptible to ampicillin, ceftriaxone, trimethoprim-sulfamethoxazole (TMP-SMX), and ciprofloxacin. All other biopsy and blood cultures remained negative for growth. After 5 days of IV antibiotics as an inpatient, she was clinically stable, afebrile, and had adequate oral intake. Given her clinical course and her known isolate susceptibilities, she was an appropriate candidate for an early transition to oral therapy with a highly bioavailable antibiotic. She was discharged home to continue treatment with oral TMP-SMX. One week after hospital discharge, she developed a pruritic rash worrisome for possible sulfa allergy, and she was transitioned to ciprofloxacin. Her rash resolved, and she completed a 10-week course of antibiotics in total. She wore a supportive back brace for approximately 2 months. With PT, she underwent a gradual build-up of core strength-building and flexibility exercises. By 3 months after the initiation of antibiotics and PT, she resumed limited physical activity and some volleyball practice participation. At the 3-month clinic visit, her lower back pain was entirely resolved, she had a full range of motion on physical exam, and her ESR and CRP had normalized. By 6 months post-treatment, she had completed all PT sessions, and she had resumed full volleyball activity. As of 12 months post-treatment, she remains asymptomatic with normal inflammatory markers.

pediatrics, salmonella poona, adolescent, infectious disease, vertebral osteomyelitis

PMC10481813_01

Female

A 34-year-old female presented to the surgery department with persistent nodular left axillary swelling and pain for 15 days. A fine needle aspiration biopsy was performed from the left axilla and image of the smear is depicted below. Q1. What is the interpretation/diagnosis? Breast carcinoma Granulomatous mastitis (GM) in accessory axillary breast Fibrocystic change Phyllodes tumor. b- GM in accessory axillary breast. Cytological findings showed cellular aspirate with sheets of benign ductal epithelial cells, few non-necrotizing epithelioid cell granulomas, numerous foamy macrophages, neutrophils, and multinucleated giant cells showing emperipolesis [Figures 1a-c]. Ziehl-Neelsen stain and TrueNat for acid-fast bacilli were also performed which was negative, excluding Tuberculosis. Based on cytological findings, the diagnosis of GM in the accessory axillary breast was considered. Methicillin-resistant Staphylococcus aureus was later isolated in the bacterial culture performed on aspirate sample. Following the administration of antibiotics, the lesion significantly improved. Q2. Which of the following is true about GM? Usually occurs in women of reproductive age, and most cases occur around 2 years after breastfeeding Malignant disease of the breast It is an untreatable condition None. Q3. Which of the following disease is reported in the accessory breast? Phyllodes Mastitis Fibroadenoma All of the above. Q4. What are the other granulomatous diseases of the breast? Tuberculous mastitis Sarcoidosis Both Galactocele. Answers: Q2-a, Q3-d, Q4-c. GM is an unusual chronic inflammatory condition of the breast that is characterized by breast masses, erythema, abscesses, indurations, and tenderness. It usually occurs in pregnant women within 5 years of giving birth. GM was described as a distinct entity in 1972 by Kessler and Wolloch. In general, accessory breast tissue extends from the axilla to the pubic area along the embryonic mammary ridge. The disease processes that affect accessory breast tissue are similar to those that affect normal breast tissue. The most frequent diseases reported in the accessory breasts are cancers followed by mastitis, fibroadenoma, phyllodes tumors, and fibrocystic change. The majority of cases of GM occur within the first 2 years after breastfeeding, while GM during pregnancy is rare. Idiopathic GM manifests histologically as non-caseating granulomas and is chronic, rare, and inflammatory. Typically, it presents as an inflamed, tender mass on the breast. In our case, the patient had given birth to her first child 3 years ago, and there was no history of breast trauma/use of oral contraceptives/any family history of breast cancer. Clinical examination revealed a tender swelling of approximately 1.5 cm in size with redness in the left axilla. Ultrasonography findings were suggestive of left axillary lymphadenitis. The patient was exposed to a number of risk factors, including delivery and breastfeeding, which both contribute to GM and accessory breast tissue formation. The diagnosis of GM remains challenging for clinicians. Cytological examination of fine-needle aspiration biopsy can ensure the diagnosis of this disease, despite the fact that it often mimics breast cancer. Patients with GM are often subject to prolonged disease courses with substantial negative impacts on quality of life during diagnosis and treatment. Therefore, diagnosing and treating them remain a challenge for clinicians as well as patients. To the best of our knowledge, till date, only two other cases of GM in accessory breast tissue have been reported in the literature. At present, there is no consensus regarding the etiology and management of GM. In our case, the patient was treated with oral antibiotics and the patient's condition improved.

PMC4469512_01

Male

Dislocation of revision Total Knee Arthroplasty (TKA) is a very rare, serious and difficult complication. Incidence of significant instability and dislocation following primary TKA ranged from 1% to 2% in the past ten years. This incidence has been lowered to 0.15% to 0.5% with the development of modern surgical techniques and posterior stabilized implants. It is very few reports have been published but it is not usually described in textbooks. A 72-year-old man underwent primary TKA for osteoarthritis on the left side at a private hospital 5 years ago. He had aseptic loosening and the revision was performed. He was referred with a painful locked left knee without any history of trauma (5 months post revision surgery). On clinical examination the left knee was deformity and painful and locked in 40 degree flexion (A). His radiographs taken. Radiographs showed the left knee in flexion and a posterior dislocation of the knee (B). A lower extremity CT angiography showed intact vascular structures. The patient was taken to the operation theatre for exploration and if necessary, revision. We attempted closed reduction of the dislocated knee but this was unsuccessful. Paramedian arthrotomy was performed via the previous longitudinal incision, and the knee was exposed. The mobile components were removed and replaced with a large-size tibial insert (C). The patient was doing well on his 3-month and 1-year follow up, ambulating with no assistive devices with good range of motion and no further instability and complications (D).

revision knee arthroplasty, arthroplasty complications, knee dislocation

PMC9886229_01

Female

In this study, the S. clavata strain was isolated from the blood culture and urine (>100.00 CFU mL- ) of an immunosuppressed patient with B-cell acute lymphoblastic leukemia. In general, such cases are the usual profile and exhibit the risk factors of those who develop S. clavata-related infections. In Brazil, S. clavata had only been previously reported in 2016, isolated from a 6-year-old female patient with hemophagocytic lymphohistiocytosis. This case exhibited neutropenia and was treated with amphotericin B deoxycholate and voriconazole, but the outcome was death . In our study, S. clavata was identified using MALDI-TOF and SARAMIS from blood cultures and isolated colonies, and then confirmed with NGS of gDNA using bioinformatics tools. Our case was restricted to only one patient and any other cases or outbreaks were reported after his/her death.

PMC111192_02

Female

Other than skin changes consistent with wasting, her examination was benign. There was no abnormal flatus or bloating, but there had been intermittent blood in the stool with some mucous. Laboratory studies are shown in Table 1. The intact parathyroid hormone (PTH) was appropriately suppressed to 6 pg/mL with concomitant serum calcium of 13.8 mg/dL and ionized calcium (Ca2+) 1.98 mmol/L (normal 1.20-1.38); other pertinent laboratory values included: phosphorus 5.7 mg/dL; magnesium 2.6 mg/dL; alkaline phosphatase 79 IU/L; PTH-related peptide (PTH-rp) appropriately undetectable at <0.2 pmol/L (normal < 2.8); 25-hydroxy Vitamin D 16 ng/mL (reference lab normal range for age 3-17 years = 13-67); and 1,25-dihydroxy Vitamin D level 32 pg/mL (reference lab normal range for age 3-17 years = 27-71). The urine calcium was 11.9 mg/dL with urine creatinine < 10 mg/dL. Renal ultrasound demonstrated nephrocalcinosis. The hemi-skeletal bone age was interpreted to be delayed to that of a 3-6 month old. Stools were positive for leukocytes and trace reducing substances. Normal karyotype and normal fluorescent in-situ hybridization (FISH) for the elastin gene locus on chromosome 7 (46, XX, negative ELN 7q11.23) along with a negative echocardiogram helped exclude Williams syndrome. She initially was treated with intravenous normal saline followed by furosemide with only transient improvement. Recurrent hypercalcemia prompted a 3-day course of intravenous pamidronate (0.5 mg/kg per dose) leading to sustained high-normal serum calcium (Figure 1). She was discharged home. She was empirically treated with Polycitra for the persistent metabolic acidosis, but on-going FTT prompted reevaluation. At time of second admission the infant was taking Neocate supplemented with 5 jars of baby food fruits per day plus Polycitra . Gross motor development was delayed but other developmental axes were intact. Family history was significant for Hashimoto's thyroiditis in the mother, maternal aunt, and maternal grandfather. The parents were both of European ethnic origin and there was no consanguinity. Physical examination showed an alert, nondysmorphic infant with severe reduction in muscle mass and subcutaneous fat. Frequent loose watery stools were noted. A skeletal survey showed striking linear bone density increase in the epiphyses in an area adjacent to the growth plate (Figure 2A). Follow up admission laboratory studies are shown in Table 1. Specifically, the calcitonin was 9.9 pg/mL (normal < 12) and the Vitamin A concentration was 33 mug/dL (20-43). The urine calcium was 11.1 mg/dL and calcium/creatinine ratio of 2.8. EKG showed a normal QTc. Renal ultrasound confirmed nephrocalcinosis (Figure 2B). Upper endoscopy with biopsy revealed areas of mild focal chronic inflammatory cells in the stomach. Colonoscopy showed no bowel wall inflammation but copious watery stool. Stool sodium was 17 mmol/L. The persistence of hypercalcemia with diarrhea prompted a nuclear medicine scan with 1.5 mCi of 111indium pentetreotide to pursue a possible paraneoplastic process which showed uptake in the right orbital region. A head CT and MRI demonstrated an infiltrating lesion in the right orbit along the inferior and lateral compartment of the orbit involving the intra- and extra-coronal space. There was no obvious lytic change or periostosis; however, there were flow voids consistent with a vascular malformation. No abnormalities in extraocular movements, globe, or retina were observed. These findings were interpreted as consistent with a benign orbital hemangioma. Serial follow up studies confirm that the lesion is not growing; indeed there is evidence of fatty involution. Small bowel biopsies taken at the time of endoscopy revealed: lactase 34.6 muM/min/g (24.5 +/- 18, abnormal less than 15), sucrase 0 muM/min/g (54.4 +/- 25.4, abnormal less than 25), maltase 22.7 muM/min/g (160.8 +/- 52.8, abnormal less than 100) leading to the diagnosis of sucrase-isomaltase deficiency. Sucrose free diet with Sucraid enzyme replacement was prescribed followed by changing feeds to 3232A base formula with supplemental anhydrous dextrose (Ca 94 mg/100 mL) resulting in a prompt cessation of diarrhea. Urine calcium/creatinine ratio decreased to 0.58. Her weight has steadily improved (Figure 3). Residual muscle weakness in the lower extremities is being treated with physical therapy. An extensive evaluation of our patient failed to identify any abnormality in calcium regulation. It should be emphasized that our patient demonstrated nephrocalcinosis prior to alkalinization with Polycitra to combat her metabolic acidosis. Urine alkalinization is a common strategy to treat urate and cysteine renal stones. Animal and preliminary human studies suggest acid-phosphate replacement (vs. neutral-phosphate therapy) is of equal benefit and does not perturb calcium/phosphorus metabolism in children with phosphate-wasting rickets. Infants with hypercalcemia may have no obvious symptoms, but constitutional symptoms such as poor appetite, irritability, vomiting, FTT, or occasionally seizures may occur. Classically, hypercalcemia leads to increased urine output and diminished stool frequency. Physical signs may include hypotonia, dehydration, and bradycardia. Laboratory abnormalities can include short QTc and elevated creatinine. Increased urinary calcium is an expected compensatory response with associated increased risk of renal calculi. The differential diagnosis of hypercalcemia in infants includes hyperparathyroidism, familial hypocalciuric hypercalcemia, hypervitaminosis, paraneoplastic processes, and Williams syndrome. Hyperparathyroidism may be either sporadic or familial arising from either adenoma or parathyroid hyperplasia. Familial hyperparathyroidism may be confined to parathyroid adenoma (HRPT1 #145000) or may involve the broader endocrine disturbances of multiple endocrine neoplasia Types I (#131100) and IIA (#171400). MENI results from mutations in menin, a regulator of TGFbeta signaling in a variety of tissues. MENIIA results form mutations in RET a cell surface growth factor receptor with intrinsic tyrosine kinase activity. Familial hypocalciuric hypercalcemia (#145980), generally autosomal dominant and caused by mutations in the renal calcium sensing receptor, is excluded rather easily based on urinary calcium levels of the patient and parents. Both hypervitaminoses D and A are potential causes of hypercalcemia. Prolonged feeding with over fortified milk or vitamin preparations has been reported as sources of excess intake of vitamin D. Abnormal vitamin D metabolism resulting from inflammatory diseases such as sarcoidosis or tuberculosis or as seen in neonatal fat necrosis are additional potential causes, albeit highly unlikely in young infants. The mechanism is thought to be due to increased 1a-hydroxylase activity leading to increased production of 1,25-dihydroxy Vitamin D. While neoplasia with osseous metastasis is a potential cause of hypercalcemia, tumors may also secrete materials such as PTH-rp or other osteoclast-activating factors, cytokines, or other growth factors that modulate bone remodeling leading to calcium adsorption from bone. Chronic immobilization can also lead to enhanced bone resorption. Williams syndrome is a well described birth defect complex characterized by FTT, branch pulmonary artery stenosis, supravalvular aortic stenosis, dysmorphic facies, mental retardation, and infantile hypercalcemia. Williams syndrome results from a constitutional deletion in chromosome 7q11.23. The cause of hypercalcemia associated with Williams syndrome is not well understood but has been postulated to be associated with enhanced intestinal absorption of calcium. The presence or absence of significant hypercalcemia does not correlate with the deletion size. Sucrase-isomaltase deficiency is a rare autosomal recessive disorder in which there is complete absence of sucrase and most of the maltase digestive activity. The usual presentation generally is at weaning from breast milk when infants are first exposed to the offending carbohydrates. Upon ingestion of disaccharides and oligosaccharides, the failure to breakdown sucrose into fructose and glucose results in an osmotic-fermentative diarrhea. Occasional patients may come to attention in late childhood or adulthood but careful history often indicates that symptoms have appeared earlier. The mainstay of treatment is dietary restriction of sucrose-containing foods. Effective enzyme replacement with whole yeast cells has been reported. Purified yeast enzyme, sacrosidase, is a highly effective adjunct to dietary restriction. The enzyme itself is composed of 1827 amino acids encoded by a 3364 bp mRNA. The gene locus has 30 exons spanning 106.6 kB. Pro-SI is anchored in the membrane by a 20 amino acid membrane-spanning segment. This is followed by a 22 amino acid stalk on which sit the 2 globular catalytic domains. The catalytic domains are similar to one another (41% amino acid identity) indicating that they have arisen by duplication and divergence. One estimate indicated a 2% mutant heterozygote frequency in European Americans but, given the rarity of diagnosed SI deficiency, this seems high. Sucrase deficiency may be especially common in indigenous Greenlanders (estimated 5%) and is accompanied most often by lactase deficiency. Initial studies demonstrated that most SI mutations result in lack of enzyme protein (i.e. null mutation). Mutation may alter the post-translational processing of the enzyme only for the asparagines-linked high-mannose groups but not the mature oligosaccharides. The resulting enzyme is both mislocalized and unstable. Another mutation, Q1098P, was found to cause retention of SI in the transport pathway between the endoplasmic reticulum and Golgi apparatus. An unusual mutation, Q117R, that alters the structure close to the O-glycosylated stalk domain, leads to random distribution of the enzyme to both the apical and basolateral cell membranes. An unusual human mutation that causes SI to be secreted rather than retained in the plasma membrane demonstrates that the enzyme is required to be at the enterocyte cell surface. A single case report potentially relates SI deficiency with disturbance of calcium metabolism. In that study, two adults presented with renal calculi and nephrocalcinosis. Lactase deficiency may give rise to metabolic bone disease. More pertinently, Saarela et al described 7 of 10 infants with congenital lactase deficiency who had hypercalcemia at the time of initial presentation. Five of these 7 infants had medullary nephrocalcinosis. The mechanism by which congenital lactase deficiency induces hypercalcemia is uncertain. There may be roles for chronic metabolic acidosis and dehydration in promoting both increased bone mobilization of calcium and thus increasing the risk of renal deposition. Non-hydrolyzed lactose may also exert a direct enhancing effect on calcium absorption in the ileum. In other conditions with chronic diarrhea, such as inflammatory bowel disease, renal stones have been composed of calcium phosphate or oxalate. Alternatively, it is possible that both SI and lactase are connected mechanistically to intestinal calcium homeostasis through molecular interactions with calcium transporters. In this regard, SI, lactase, and the receptor for 1,25 OH-VitD3 (VDR) share transcriptional regulation through the homeodomain transcription factor CDX2. The possibility that SI or lactase deficiency could cause secondary up-regulation of VDR awaits exploration in cell culture or animal models.

PMC4531549_01

Male

A 50-year-old man was transferred to our hospital from a local clinic due to fever and weight loss. The patient had been healthy until 15 days prior to his admission, when, at that time, he began to feel febrile, lost his sense of taste, and developed a poor appetite. The symptoms continued until the admission. Upon examination at the originating clinic, adrenal masses had been found on CT. On admission the patient's temperature was 37.7 C, pulse 80 beats/min, respiration rate 20 breaths/min, and blood pressure 120/80 mmHg. On examination, the patient appeared ill and prostrated. Liver was palpable in 1 finger-breadth on the epigastric area and a 1.5x1.0 cm sized firm and nontender right supraclavicular lymph node was palpated, but otherwise unremarkable. His leukocyte count was 1,700/muL with 65% neutrophils, hemoglobin 10.6 g/dL, and platelet 142,000/L. His blood chemistry revealed total serum protein was 6.3 g/dL, albumin 3.6 g/dL, aspartate transaminase 52 IU/L, alanine transaminase 29 IU/L, alkaline phosphatase 183 IU/L, sodium 129 mmol/L, potassium 4.0 mmol/L, lactate dehydrogenase (LDH) 1415 IU/L, and serum ferritin >2000 ng/mL. The renal function was normal. Cortisol in the morning and evening was 17.8/20 mug/dL (normal range: 5 - 25 mug/dL) and ACTH in the morning and evening 726/265 pg/dL (normal range: 10-56.7 pg/dL). Serologic test for Epstein-Barr virus and cytomegalovirus were normal. Chest radiographs obtained on admission revealed normal findings, but a CT scan of the abdomen revealed bilateral adrenal masses and hepatosplenomegaly (Figure 1). Right adrenal mass measured 6x1.7 cm and the left was 8x3 cm in size. CT-guided adrenal gland biopsy was done and showed numerous epithelioid cells and caseous necrosis consistent with tuberculosis (Figure 2). But, an AFB stain of the tissue and polymerase chain reaction for Mycobacterium tuberculosis were negative. On subsequent bone marrow aspiration and biopsy, hemophagocytic histiocytes had increased in proportion (4.6%) without accompanying evidence of malignancy (Figure 3), hence HPS associated with adrenal gland tuberculosis was diagnosed. Biopsy of the supraclavicular lymph node revealed necrosis, but no evidence of malignancy. Treatment with isoniazid, rifampin, ethambutol, and pyrazinamide was started immediately. On treatment day 4, the patient developed jaundice and elevated levels of transaminases. We discontinued hepatotoxic drugs (isoniazid, rifampin, pyrazinamide, and acetaminophen) and changed his medications to ethambutol, cycloserine, streptomycin, and ciprofloxacin. During the anti-tuberculous treatment the patient showed recurrent hypoglycemia and hypotension. Rapid ACTH stimulation test revealed adrenal insufficiency. Corticosteroid treatment was added. After supplementation with corticosteroid, the hypotension and hypoglycemia were corrected. After normalization of liver function, isoniazid was restarted with a gradual increase in dose. But pancytopenia progressed during the anti-tuberculous treatment. On treatment day 30, repeated bone marrow aspiration was performed and showed that numerous hemophagocytic histiocytes persisted (5.0%). On treatment day 41, the patient expired due to multiple organ failure (including disseminated intravascular coagulation, hepatic failure, and renal failure).

PMC3447256_01

Female

The six-year-old girl has been evaluated due to hyperactivity, social interaction impairment, with little social initiative and lack of social or emotional reciprocity, stereotypic and repetitive use of language with echolalia, failure to follow parents/caretakers orders, inconsolable outbursts, and persistent preoccupation with parts of objects. The girl has normal cognitive function. She is the only daughter of a nonconsanguineous young and healthy couple. There are no other similar cases in the family. She was born at term (caesarean delivery), weighing 3800 g and measuring 50.5 cm. She started to walk at 1 year and 4 months, and to speak at 2 years and 6 months. The patient has improved with language and educational therapies. She was examined when she was 6 years and 4 months old, 123 cm (p 50-75) tall, weighing 23,000 g (p 50-75), and had 50.5 cm of head circumference (p 2-50) (Figure 1). The clinical examination showed no physical, neurological, or dysmorphological abnormalities. Hematologic and hormonal test results were normal. The EEG displayed a normal pattern. Bone age was 8 years and 10 months (chronological age was 6 years and 4 months). Brain magnetic resonance imaging was normal. PCR-based assay for sizing CGG repeats at the FRAXA locus showed two normal alleles. Metaphase chromosome spreads were obtained after lymphocyte temporary cultures, and the slides were subjected to GTG, CBG, and replication bandings. FISH was performed only for verification of the X chromosome with total chromosome digoxigenin-labeled probe obtained commercially (Oncorr, Gaithersburg, MD, USA:catalogue no. P5222-DG.5). Hybridization was performed according to manufacturer's instructions, followed by detection with FITC-labeled antidigoxigenin and count stain with propidium iodide (final concentration 0.3 mug/mL in antifade). A SKY KIT from Applied Spectral Imaging (ASI, Carlsbad, CA, USA) was used for SKY. The slide treatment, posthybridization detection and washes, was performed as per standard protocols and manufacturer's instructions. The slides were mounted with 20 mM Tris-HCl pH 8.0, 90% glycerol containing 2.3% antifade, 1,4,diazabicyclo-(2.2.2)octane (ONCOR Inc., Gaithersburg, MD, USA). Spectral images were acquired and analyzed with a SD 200 spectral bioimaging system (ASI Ltd., MigdalHaemek, Israel) attached to a Zeiss microscope (Axioplan 2) by means of a C-mount consisting of an optical head with a special Fourier transformed spectrophotometer (SAGNAC common path interferometer) to measure the spectrum, and a refrigerated CCD-camera for imaging. Excitation through the custom filter set (Chroma Technology, Brattleboro, VT, USA) allows all dyes to be excited and measured simultaneously, without any image shift. The generation of a spectral image is achieved by acquiring ~100 frames of the same image. Each two frames differ from each other only in the optical path difference (OPD) created by the scanner controller in the interferometer. The images were stored in a computer for further analysis using the SKYVIEW (ASI, Carlsbad, CA, USA) software. Based on the measurement of the spectrum for each chromosome, a spectral classification algorithm was applied. DAPI images were acquired from all metaphases analyzed using a DAPI-specific optical filter.

PMC8361508_01

Male

A 56-year-old man who was previously healthy presented with a history of episodic pain and numbness over the left cheek for a month followed by inability to open mouth fully for a week. He also complained of left eye swelling with drooping of eyelid and reduced vision for 1 week. He initially visited a general practitioner for his pain and later consulted a neurosurgeon as his symptoms got worsened. He was treated for left trigeminal neuralgia by the neurosurgeon and then referred to us to evaluate further for his cheek pain and numbness. He did not have nasal blockage, rhinorrhoea, epistaxis, anosmia or constitutional symptoms like fever, loss of appetite and loss of weight. He did not have a previous infection with tuberculosis and could not recall any contact history. There was no history of nasal or sinus surgery. On examination, he had severe trismus with just a finger breadth of mouth opening. Perception to light touch was impaired on his left cheek at V2 (maxillary division) region. There was mild proptosis and ptosis of his left eye; however, eye movements were normal and full range. Other cranial nerve examinations were normal. There was no obvious swelling on his left cheek or facial asymmetry except for the mild proptosis and ptosis. Neck examination revealed no palpable lymph nodes. Anterior and posterior rhinoscopic examinations did not reveal any sinus pathology and other physical examinations were normal. Blood investigation showed white blood cell (WBC) 10.9 x 103/dL, and differential counts were normal. Erythrocyte sedimentation rate (ESR) was 9 mm in the first hour. Blood for anti-HIV was non-reactive. Sputum for AFB x 3 was negative. Chest X-ray did not reveal any lung pathology. CT (computed tomography) scan of the paranasal sinuses showed soft tissue lesion in the left anterior ethmoid sinus and maxillary antrum (Figure 1) with erosions of the medial and lateral walls of the maxillary sinus. The lesion was extending into the inferomedial aspect of the left orbit displacing the orbit anteriorly (Figure 2). Malignancy in the maxillary antrum involving the anterior ethmoid and orbit was our initial impression. Endoscopic left medial maxillectomy and anterior ethmoidectomy was performed which revealed soft fluffy and necrotic mass at the left maxillary antrum and ethmoidal cells with a bit of pus. The mass was cleared off and sent for histopathological examination and acid-fast bacilli. Histopathological examination was reported as necrotic tissue composed of reactive multinucleated giant cells, many of Langhan's type and aggregates of epithelioid histiocytes admixed with a predominantly chronic inflammatory infiltrate forming coalescent granuloma compatible with tuberculous granuloma (Figure 3(a)-(c)). No AFB or fungi were detected on special stains and no malignant cells were seen. We diagnosed him as a case of tuberculous granuloma of left maxillary and ethmoid sinus involving the orbit. The patient was started on a 6-month course of standard antituberculous treatment (ATT), that is, isoniazid, rifampicin, pyrazinamide and ethambutol for 2 months in the intensive phase and isoniazid and rifampicin for 4 months in the continuation phase. His trismus improved to two fingers breath on post-operative day 3 and almost normal by 2 weeks. His left eye vision also improved from 6/30 preoperatively to 6/18 on post-operative day 7. He was doing well on follow-up at 6 months and nasal endoscopy was clear.

tuberculous granuloma, maxillary antrum, paranasal sinuses, trigeminal neuralgia

PMC7603567_01

Female

A 14-year-old intact female mixed-breed dog (body weight of 8.5 kg) was presented with dyspnoea. This condition had persisted for eight days and was treated by the referring veterinarian with antibiotics, prednisolone, and vitamins. On the following day, prednisolone was substituted by a single dose of dexamethasone. Six days before presentation in our clinic, benazepril (0.3 mg/kg, PO, SID) and furosemide (1.2 mg/kg, PO, BID) were prescribed additionally. The bitch was regularly vaccinated and dewormed, with the last deworming dating three months back. The dog had never been abroad. For three years, a generalized alopecia was apparent without any known cause because the owners had declined a thorough dermatological examination; only the head and the distal limbs showed hair growth. The last period of heat was observed three years ago by the owners. For around eleven months, the dog showed polyuria und polydipsia. Food intake and defecation were reduced during the last days prior to presentation. On physical examination, the dog showed a calm and attentive general condition in upright posture. Rectal temperature was 36.8 C; mucous membranes were pink and moist with a capillary refill time of one second. Palpation of the peripheral lymph nodes revealed slightly enlarged, relocatable, and unpainful mandibular lymph nodes. In addition, a senile cataract on both eyes was diagnosed. Heart rate was 120 beats/min, and during auscultation, the volume of the heart sounds was unequal in every heartbeat. The femoral pulse was palpable on both sides, and no pulse deficit was found. The respiratory rate was 24 breaths/min and abdominally intensified. During lung auscultation, slightly amplified breathing sounds were noticed. The abdomen was prominent and indolent. Based on anamnesis and clinical examination, the preliminary diagnosis of a hyperadrenocorticism was assumed. A chest X-ray in two planes was performed (Figure 1). The transthoracic echocardiography (LOGIQ S8, General Electric, Munich, Germany) showed a moderate dilated left atrium (left atrium (LA): 2.66 cm, aorta (AO): 1.39 cm, LA/AO: 1.91, normal range: <1.6). A round, hyperechoic mass with a maximum diameter of 1.63 cm was floating from the left atrium into the mitral valve leaflets (Figure 2). At that time, an obstruction of the mitral valve was apparent. A notable connection between this mass and the atrial wall could not be depicted. Hence, a left atrial thrombus was suspected. A neoplasia was considered as a differential diagnosis. In addition to the mass in the left atrium, also a moderate mitral regurgitation, a low-grade pulmonary insufficiency, and a minimal aortic and tricuspid insufficiency were observed. Systolic blood pressure was measured by a Doppler device (Eickemeyer Doppler, Tuttlingen, Germany) and was 80 mmHg. An ACTH stimulation test was performed. The basal serum cortisol level was 9.1 mug/dL (normal range: <0.9-4.5 mug/dL), and the post-ACTH serum cortisol level was 61.6 mug/dL. Cortisol levels after stimulation of >20 mug/dL indicate a hyperadrenocorticism. Additional diagnostics like hematology and chemistry panels, an abdominal ultrasonography, and follow-up blood pressure and echocardiographic control were refused by the owners. The prescribed therapy with benazepril (0.3 mg/kg, PO, SID) and furosemide (1.2 mg/kg, PO, BID) was supplemented with clopidogrel (2 mg/kg, PO, SID). After 19 days, the owner reported the sudden death of their dog.

PMC9113034_01

Female

A 5-year-old female child was transferred from a local hospital for further management after 5 weeks of inpatient treatment with oxygen, parenteral broad-spectrum antibiotics, and anti-tuberculous (TB) drugs for non-resolving pneumonia and suspected pulmonary tuberculosis. Her symptoms started acutely with high fever, cough, and difficulty of breathing 8 weeks before admission. After 4 weeks of treatment, the fever subsided but the respiratory distress and hypoxemia persisted for which treatment for pulmonary tuberculosis was initiated empirically without strong clinical or laboratory/imaging evidence. Finally, the child was referred for better workup and management after she failed to respond to the anti-TB. Physical examination at presentation demonstrated an acutely sick and emaciated child who had significantly increased work of breathing (WOB) and was hypoxemic (SPO2 = <70% at room air and 90-94% on 6-7 L/min facemask). She had crackles and decreased aeration over the left lower posterior chest with significantly decreased air entry over the right hemithorax and the remaining part of the systemic exam was unremarkable except for presenting as a grossly emaciated child. PA chest X-ray (CXR) revealed a significant right pneumothorax (Figure 1); other investigations including CBC, COVID-19 and HIV test were unremarkable except for a mildly elevated ESR (30 mm/hr) but negative C-reactive protein. Her antibiotics and anti-TB treatment were continued, and a chest tube was inserted for pneumothorax. Within the first hour of drainage, she started to have worsening cough and increased WOB with worsening hypoxemia. A repeat CXR 4 hours after her clinical deterioration showed an expanding but opacified right lung and worsening opacity of the left lung suggestive of bilateral pulmonary edema (Figure 2). The patient was then started on treatment for severe pulmonary edema with diuretics, and noninvasive ventilation (NIV) without success for >12 hours, subsequently requiring admission to the PICU. She was put on mechanical ventilation with PRVC mode and prior management was continued but she failed to respond and died after 16 hours of PICU stay from therapy-resistant and worsening pulmonary edema. To the best of our knowledge, this is the first case of RPE reported from Ethiopia. This case report aims to alert clinicians to this rare but potentially fatal complication following drainage of significant pleural effusions and pneumothorax, both of which are fairly common for the practicing pediatrician, especially in low- and middle-income countries (LMICs).

ethiopia, chest tube, pleural effusion, pneumothorax, pulmonary edema, re-expansion

PMC8203063_01

Female

A 55-year-old female was referred to the pulmonology outpatient department with a history of a persistent productive cough of 'pink' sputum for the preceding 12 months. During this time, she also developed progressively worsening dyspnoea and had grade 3 dyspnoea on the modified Medical Research Council scale at the time of presentation to the clinic. No other respiratory symptoms such as wheezing or chest pain were reported and she did not have any constitutional symptoms of fever, night sweats or weight loss. She had no history of any childhood respiratory illnesses nor did she have any history of previous tuberculosis. The patient never smoked and maintained sober habits. Her family history was non-contributory, and she was employed as a domestic worker with no significant exposures that she could recall. She had hypertension and was on chronic medication that included spironolactone, furosemide, amlodipine, aspirin, simvastatin and oestrogen replacement therapy. She previously underwent hysterectomy for abnormal uterine bleeding and no malignancy was detected at the time. She was treated with a 7-day course of amoxicillin-clavulanic acid for supposed community-acquired pneumonia at a local hospital prior to referral. Sputum for microscopy, culture and sensitivity during this time did not yield any pathogens. The result of a tuberculosis GeneXpert test was negative, but Mycobacterium tuberculosis culture or investigations for atypical pathogens were not done. Blood tests showed a white cell count of 7.3 x 109 /L, haemoglobin level of 13.6 g/dL, platelet count of 267 x 109 /L, C-reactive protein level of 21 mg/L and she tested negative for HIV. Although a chest radiograph performed at the local hospital was described as revealing 'extensive opacification of the left lung', the image was not presented at the clinic and thus could not be reviewed. In view of her poor response to treatment and blood results that were not in keeping with infection, she was referred to us for further evaluation On clinical examination, she was obese with a body mass index of 48.24 kg/m2 . Her blood pressure was 120/80 mmHg, pulse rate was 72 beats per minute (bpm), respiratory rate was 15 breaths per minute and oxygen saturation was 93% measured by pulse oximetry while breathing room air at rest. Arterial blood gas testing was not performed. On respiratory examination, her trachea was centrally situated, but she had dullness to percussion and bronchial breathing of the whole of the left hemithorax, while she had normal percussion and vesicular breath sounds on the right. The rest of the clinical examination was within normal limits. A chest X-ray image at the time of initial assessment revealed complete opacification of the left lung with associated air bronchogrammes noted in the left perihilar region (Fig. 1). Chest computed tomography analysis confirmed dense consolidation of the left lung with no evidence of atelectasis or pleural effusion (Fig. 2). In view of the clinical problem of a non-resolving pneumonia, the differential diagnoses included atypical pneumonia, non-tuberculous mycobacterial disease, primary lymphoma of the lung and slow-growing primary lung neoplasms. Flexible bronchoscopy was therefore performed to obtain respiratory specimens for further analysis. Inspection of the tracheobronchial tree revealed an excessive amount of watery sputum in the airways in keeping with bronchorrhea. Bronchoalveolar lavage specimens from the left upper lobe were sent for microscopy, culture and polymerase chain reaction (PCR) tests for Mycobacterium tuberculosis, Pneumocystis jirovecii, Mycoplasma pneumoniae and Chlamydia pneumoniae. All PCR tests were negative. Flow cytometry of bronchoalveolar lavage fluid found a normal ratio of CD4:CD8 cells, in keeping with a reactive T-cell response. Transbronchial lung biopsies, however, revealed tumour tissue with the appearance of a well-differentiated mucus-secreting adenocarcinoma with lepidic features (Fig. 3). Immunohistochemical staining for cytokeratin 7 (CK7), thyroid transcription factor-1 (TTF-1) and napsin A were positive, while staining for CK20 was negative. A final diagnosis of invasive mucinous adenocarcinoma (previously known as bronchioloalveolar carcinoma) was therefore established.

adenocarcinoma, bronchioloalveolar carcinoma, lung cancer, non-resolving pneumonia

Chest computed tomography image confirming consolidation of the left lung.

PMC8558582_01

Male

A 64 year old Vietnamese male with no past medical history presented for evaluation of fevers which started in April 2020. The fevers occurred at least once daily and were associated with sweating and weight loss. Over several weeks he unintentionally lost 4 kg. After a week of fevers the patient sought care. He was a smoker but otherwise healthy and on no medications. He worked as a shrimper but had not worked since November 2019 when the season closed. Physical examination was unrevealing. Serologic testing demonstrated a mild transaminitis, elevated erythrocyte sedimentation rate, and negative viral hepatitis screen. Initial imaging with right upper quadrant ultrasonography demonstrated multiple hypoechoic lesions (Figure 1). Computer tomography (CT) of the abdomen demonstrated a 6 cm multi-cystic partially enhancing mass within the right hepatic lobe (Figure 2). He was hospitalized and a drain was percutaneously placed. Purulent debris drained which grew methicillin sensitive Staphylococcus aureus (MSSA). The patient was tested for a variety of organisms and tested negative (ie, no TB, malaria, etc.) Tissue samples obtained from the hepatic lesion also demonstrated fibro-inflammatory lesions with focally increased IgG4 positive plasma cells (Figure 3). He started intravenous antibiotics and a serum IgG4 level was elevated at 322 mg/dL (normal range: 4-86 mg/dL). He was treated with 2 months of intravenous antibiotics and monitored clinically but not placed on immunosuppressive therapy. In accordance with the comprehensive diagnostic criteria of IgG4 related disease, patient fulfilled all 3 criteria to include clinical, hematological, and histopathological. Unfortunately, patient was lost to follow up during the covid pandemic and did not follow up for repeat evaluation and proper treatment.

immunoglobulin allotypes, autoimmune lymphoproliferative syndrome, immunosuppressive agents

PMC7178486_01

Female

A 13-month-old female with no pertinent medical history was admitted with a one-week history of left temporal swelling. The patient's mother reported no previous trauma to the area and a lack of apparent tenderness on palpation. The mother also stated that the patient experienced a short viral illness approximately one to two months previous to presentation with apparent trismus. The patient had no residual symptoms of the viral illness and no longer appeared to demonstrate decreased range of motion of the jaw or decreased oral intake. The patient was up to date on all immunizations and had a normal birth and developmental history. All questions on review of systems were negative except for a temperature of 37.7 C. On examination there was boggy, non-tender, non-erythematous swelling of the left temporal region. The patient was otherwise normocephalic with no other positive findings. Investigations revealed a white blood cell count of 17.6 K/uL (normal range 6-17.5 K/uL) with neutrophilia and C-reactive protein of 17.0 mg/dL (normal range 0.0-0.5 mg/dL). CT of the maxillofacial region and sinuses with contrast showed an indeterminate process centered over the left temporalis muscle with considerations including vascular or lymphatic malformation, myositis, or injury (Fig. 1). Magnetic resonance angiography and venography of the brain without contrast showed normal venous and arterial anatomy. MRI of the brain with and without contrast showed the enhancing mass overlying the left temporalis muscle with no cranial involvement and was otherwise normal. Infection was suspected from the clinical picture and the patient was discharged with a one-week course of amoxicillin-clavulanic acid and scheduled for follow-up with otolaryngology. On follow-up one week later, the patient had finished the antimicrobial with no reduction in temporal swelling. The mother reported no further complications or developments with the exception of a mild cough and rhinorrhea. The patient was scheduled for ultrasound-guided fine needle aspiration of the mass in order to further evaluate. However, the patient was readmitted six days after being seen in the clinic due to further enlargement of the mass. The mother stated that the swelling had nearly tripled in size, had become tender to touch, and the patient had decreased jaw opening. Repeat laboratory investigation showed a normal white count, but elevated erythrocyte sedimentation rate of 84 mm/hr (normal range 0-20 mm/hr) and C-reactive protein of 2.2 mg/dL (normal range 0.0-0.5 mg/dL). Repeat imaging with CT of the head with contrast showed enhancing soft tissue masses in the left frontal scalp, left masticator space, and left parotid space. MRI of the face and sinuses with and without contrast showed an infiltrative lesion in the left temporalis region with extension along the lateral aspect of left orbit and inferiorly into the infratemporal fossa. Differential considerations included cranial fasciitis or neoplastic processes such as rhabdomyosarcoma or fibrosarcoma. Infection was considered unlikely due to the stability in size compared to the previous admission's imaging (Fig. 2). On day 2 of admission, excisional biopsy with incision and drainage of the left temporal region was performed. A 1 cm incision was marked over the most edematous region hidden in the hairline. Sharp incision was created through the skin down to temporal muscle. A wedge of temporalis muscle was removed and sent for histopathological evaluation. Blunt dissection was then taken down to the calvarium and down to the lateral orbital rim. Keratin debris with hair follicles were encountered and sent for histopathological evaluation. Cavity walls were also biopsied and sent for histopathological evaluation. The wound cavity was then copiously irrigated and suctioned and closed in layers. All aerobic, anaerobic, and fungal cultures showed no growth. Histopathologic examination of the temporalis muscle and debris showed granulation tissue with nonspecific acute inflammation, lymphocytes, and macrophages. The patient was discharged with clindamycin 30 mg PO three times daily for seven days and scheduled for follow-up in otolaryngology clinic again. During the next two clinic visits for follow-up, the course of antimicrobials were completed and the mother reported reduction in swelling and improvement in jaw opening. However, approximately one month later the patient presented to a follow-up visit with recurrence of left temporal swelling, this time with erythema and edema of the area. A seven-day course of amoxicillin-clavulanic acid was started and CT of the maxillofacial region with contrast and 3D reconstruction was performed in preparation for surgical removal. The imaging showed a stable size of the infiltrative lesion in the left temporalis muscle extending into the infratemporal fossa with underlying bony hyperostosis. There were enlarged lymph nodes in the left anterior parotid region. Differential considerations again included cranial fasciitis versus a neoplastic process (Fig. 3). The patient was admitted one month later for excision of the left temporoparietal lesion. A 4 cm extended incision was performed at the site of the previous incision. At this point, sharp dissection was carried through the skin, subcutaneous tissue, and loose connective tissue until encountering the temporalis muscle. The muscle was noted to be very inflammatory with exudative material and some purulence. Samples of the exudate were sent for culture. Exudative tissue overlying the temporalis muscle was curetted off of the muscle and skin. This dissection was carried medially to the point of the epicenter of the lesion. There was noted to be a tract extending from the deeper tissue to the overlying skin. The tract was followed and removed. All tissue was sent for permanent pathology. Due to a small amount of bleeding, a TLS drain was placed during the postoperative period. Pathology of the left temporal lesion showed granulation tissue with nonspecific acute and chronic inflammation. Cultures of the region returned showing 3+ beta lactamase negative Aggregatibacter aphrophilus colonies. Sensitivities of the organism were not available, so empiric intravenous azithromycin 94 mg once daily was begun. Bartonellosis and coccidioidomycosis serologies as well as a tuberculosis interferon- release assay were done at this time. The patient was discharged on day three of admission after removal of the TLS drain and transitioned to oral azithromycin 100 mg daily for seven days and cefixime 100 mg daily for ten days. Upon follow-up with both pediatric infectious disease and otolaryngology, the patient had improved with no complications. The incision healed appropriately, antimicrobials were finished and discontinued, and bartonella, coccidioidomycosis, and tuberculosis testing was negative. The most recent laboratory investigations approximately one month after the final hospital admission showed a white count of 7.3 K/uL (normal range 6-17.5 K/uL), erythrocyte sedimentation rate of 13 mm/hr (normal range 0-20 mm/hr), and C-reactive protein of 0.1 mg/dL (normal range 0.0-0.5 mg/dL). The mother stated that swelling, trismus, fevers, and other symptoms have not recurred.

PMC7275215_01

Male

Mister X, a 20-year-old male college student, living in Hefei, Anhui Province, China. Mister X traveled in Wuhan from January 15 to 18, 2020, and returned to his home in Hefei on January 18, 2020. The COVID-19 epidemic began to break out around January 20. Because he felt feverish and suspected that he was infected with COVID-19, Mister X suddenly went insane at the evening of January 29. Mister X stayed up all night, talking nonsense, sometimes dancing, crying, and laughing. His family sent him to a designated COVID-19 hospital in Hefei on January 29. His body temperature was 37.2 C. The pharynx swab was taken for novel coronavirus nucleic acid test. The chest computed tomography (CT) results showed "left lung nodule". Outpatient doctors diagnosed "upper respiratory tract infection" without considering COVID-19's diagnosis. But Mister X firmly believed that he had got the COVID-19 and did not believe the doctor's diagnosis. At noon on the same day, he went with his family to a fever clinic of another hospital. During the queuing period at the outpatient clinic, the patient suddenly got emotional and gibberish, saying, "he has been hurt by others", "Why does someone else not get pneumonia, only he has it? Someone must be trying to hurt him." The patient used Wechat to tell all his friends that he had COVID-19. On the morning of the 31st, the patient and his family went to the hospital to get the nucleic acid test report. The patient's nucleic acid test result was negative, but he still cried and laughed, and the family went to the pharmacy to buy antipyretic drugs and azithromycin and other drugs for the patients to take, the symptoms did not improve. At noon on February 1, the patient began not to talk to his family, did not eat or drink, and his expression was painful. Sometimes he yelled and cursed and kept spitting things out of his mouth. The patient suddenly jumped from the sixth floor of his home at around 17 : 00. Luckily, because of the canopy below, he suffered no serious injuries. He was sent to another designated hospital in Hefei for treatment. The CT examination of Mister X showed that "there were no traumatic lesions in the skull, chest and abdomen", and no obvious fracture was found in the whole body. The patient had a skin wound on the inside of his right ankle that had been sutured, and a skin scratch on his left chest, which was disinfected by iodophor. On the morning of February 2nd, according to the admission procedure of the psychiatric department of our hospital during the epidemic situation of novel coronavirus, the patient was admitted to a hospital. The results of the peripheral blood test showed that creatine kinase (CK) 1236 U/L was higher than normal, but no obvious abnormality was found in the rest. Both novel coronavirus nucleic acid tests showed negative results. The results of chest CT showed "nodular foci of the left lung". The diagnosis of novel coronavirus pneumonia was excluded after consultation in the respiratory and infection department. The patient was later admitted to the psychiatric isolation ward of our hospital. ATPD was diagnosed by psychiatric consultation, and quetiapine fumarate was given with an oral rehydration solution of 0.1 g bid per day. After entering the psychiatric department, the blood biochemical examination showed (CK) 1236 U/L, total bilirubin (TB) 46.8 mmol/L, and aspartate aminotransferase (AST) 62 U/L. Routine blood test showed that the percentage of lymphocytes was 18.10%, the percentage of monocytes was 12.10%, the ratio of eosinophils was 7.10%, and the rest was normal. Electrocardiogram (ECG), electroencephalogram (EEG), and cranial CT were normal. The score of Positive and Negative Syndrome Scale (PANSS) was 76, Hamilton Depression Rating Scale (HAMD) was 29, and Hamilton Anxiety Rating Scale (HAMA) was 19. No previous family psychiatric history and no history of drugs. Later, quetiapine gradually increased to 0.4 g per day for oral treatment, supplemented by cognitive therapy. After a week of medication and psychotherapy, the patient's condition was improved, the diet was normal, and the sleep was better than before. Psychiatric symptoms also improved markedly. The score reduction rate of PANSS was more than 50%. The patient is exposed to cooperation and occasionally shows signs of tension, hallucinations, and delusions were not elicited. The patient was discharged from the hospital on February 9.

PMC10448513_01

Male

A 6-year-old boy, previously experiencing normal development and without any significant medical, family, or social history, suffered severe traumatic brain injury (TBI), diffuse axonal injury (DAI), and atlanto-occipital dislocation with accompanying severe cervical (C1)-level spinal cord and bulbo-medullary injury (as depicted in Figures 2, 3), which is often considered fatal. Furthermore, the patient experienced cardiac arrest. Upon admission, he was in a state of acute flaccid coma with closed eyes and showed no response to stimuli, exhibiting only sluggish reactivity in one pupil. This condition was observed on the first day of hospitalization. Although the initial prognosis indicated a futile and terminal state, for which it was expected that he may progress to brain death, the decision to continue life support was made as the parents were undergoing their hospitalization. Consequently, a comprehensive assessment of multimodal brain networks was conducted, leading to therapy and further testing. Miraculously, the patient survived and now possesses communication and cognitive abilities comparable to his chronological age, despite being quadriplegic. On day 2 (d2), antiseizure medication treatment was initiated based on rs-fMRI findings, which detected rs-SOZ suggestive of epileptogenic activity in deep brain regions that were not observed on cvEEG monitoring conducted during that period. Task-fMRI performed on d2 showed no reactivity initially but demonstrated activation in response to commands on d10, indicating command-following (CMD), despite the patient being in a coma according to bedside examinations. Consequently, network improvement was first detected through rs-fMRI and task-fMRI, a significant 17 days prior to the patient regaining consciousness, which became evident on day 27 when he exhibited facial and eye movements in response to commands, despite his quadriplegia. Before d10, the option of WLST was presented to the family, but they declined following the discovery of CMD, as described in a recently published interview. During further hospital care, amantadine was administered from d11 to d19. However, it was discontinued due to family concerns regarding its unclear benefits, particularly considering the patient's covert consciousness. Unfortunately, on d72, newly developing hydrocephalus was identified and likely contributed to deterioration in consciousness. The patient experienced subsequent recovery following the emergent placement of an external ventricular drain (EVD). Later, at 8 years of age, the patient is attending grade-appropriate academic classes, able to communicate orally, and has intermittent recovery of urinary continence. However, there has been only mild improvement in quadriplegia. The primary conclusion drawn from this case is that rs-fMRI can detect potential epileptogenic signals that may be suppressing brain network activity. Following treatment and repeated testing, confirmed command-following (CMD) can be identified, as initially suggested by rs-fMRI and confirmed by task-fMRI. These findings have significant implications for the consideration of WLST, representing unique advancements in the field of pediatrics with ABI.

acute brain injury, case report, cognitive motor dissociation, coma, disorders of consciousness, pediatric, resting state functional mri

PMC8592857_01

Male

A 55-year-old Honduran man with a past medical history of non-ischemic cardiomyopathy due to valvular heart disease with associated combined heart failure (ejection fraction 40%, stage III diastolic dysfunction), a recent bioprosthetic mitral valve replacement with tricuspid valve repair (2 months prior to admission), and paroxysmal atrial fibrillation presented to our hospital with 3 weeks of subjective fevers, night sweats, 30-pound weight loss, fatigue, and anorexia. One month prior to this presentation, the patient was briefly admitted following his valve replacement surgery with a day of watery diarrhea and was found to be in septic shock due to E. coli bacteremia of uncertain source. Evaluation during this admission included an unremarkable urinalysis and urine cultures and CT imaging only notable for distention and mild dilation of the small bowel suggestive of possible enteritis. Stool studies were not obtained given the self-limited nature of his antecedent diarrheal illness, but serum Strongyloides serologic testing was notably negative at the time. After a brief parenteral antimicrobials course, he was instructed to complete a two-week course of oral cefpodoxime 200 mg q12h upon discharge for transient bacteremia from a presumed self-limited gastrointestinal source. He did well clinically for one week after discharge before developing subjective fevers with generalized myalgias despite his outpatient cefpodoxime course. Over the following 3 weeks the patient progressively declined with more frequent subjective fevers, night sweats, malaise, anorexia with weight loss, and abdominal fullness further prompting another presentation to the emergency department. He denied sternal wound pain or drainage and a thorough review of systems for other localizing infectious symptoms was otherwise negative. On admission, vital signs were notable for a temperature of 38.8 C (101.8 F), blood pressure 91/62 mm Hg, heart rate 84 beats per minute, respiratory rate 21 breaths per minute, and oxygen saturation 100% on room air. Physical examination revealed an irregularly irregular heartbeat without murmur and an unremarkable lung exam. His abdomen was soft, nondistended, nontender to palpation, and no organomegaly was noted. No distal extremity edema or distal embolic phenomena were noted on skin exam. Notably, a stage 2 sacral wound that had developed following his valve surgery had healed completely since his prior admission. Laboratory tests were significant for a leukocytosis with a white blood cell count of 14000 (normal 4500-11000 cells/mul), anemia with a hemoglobin of 9.4 (normal 13.5-17.5 gm/dL), and normal kidney and liver function on complete metabolic panel. Inflammatory markers were elevated with a sedimentation rate of 119 mm/hour (normal 0-20 mm/hr). Urinalysis and culture were again unremarkable. Chest radiograph showed no evidence of acute cardiopulmonary disease, and an initial transthoracic echocardiogram showed no obvious vegetations or compromise of his prosthetic valve. The patient was started on broad spectrum antimicrobials with intravenous vancomycin 1 g q12h and cefepime 2 g IV q8h at the time of admission. Antibiotics were quickly narrowed to cefepime alone after admission blood cultures ultimately grew gram-negative rods in 4/4 collection tubes which later speciated as Escherichia coli. He was transitioned to ceftriaxone 2 g IV q24 based on sensitivity data, but blood cultures remained persistently positive on hospital day 2 and 3 raising concern for an endovascular nidus of infection. Transesophageal echocardiogram was obtained on hospital day 5 which revealed a small 3 mm mobile, filamentous vegetation on the anterior cusp of the prosthetic mitral valve without significant valvular compromise. As a result, he met Duke criteria for diagnosis of infective endocarditis by fulfilling one major criterion (TEE demonstrating a vegetation) and three minor clinical criteria (persistent fevers, predisposing cardiac condition, and persistently positive cultures.). Antimicrobial therapy was tailored to combination therapy with ongoing ceftriaxone 2 g IV q24h and gentamicin 5 mg/kg IV q24h which was adjusted continually based on levels of accumulation and changes in renal function. He continued to improve clinically, and blood cultures demonstrated complete clearance on hospital day 5. Given that the patient lacked evidence of an antecedent urinary tract infection as the source of his recurrent bacteremia, additional imaging was obtained to exclude a secondary source or nidus of infection. This included CT of the chest, abdomen, and pelvis to exclude an indolent abscess and doppler ultrasounds of the extremities and portal vasculature to exclude septic thrombophlebitis. An MRI of the full spine was also performed to exclude osteomyelitis/discitis given his prior sacral wound during his previous hospitalization. Imaging studies were only notable for mild periappendiceal stranding concerning for a possible site of antecedent inflammation as the source of his recurrent E.coli bacteremia. Given a benign abdominal exam, surgical consultants did not feel he met criteria for acute appendicitis and declined intervention. Neither a colonoscopy nor capsule endoscopy were performed during his inpatient stay owing to limitations on endoscopic procedures performed during a concurrent coronavirus pandemic surge. Given the patient's rapid clinical improvement on tailored antimicrobial coverage, cardiothoracic surgery concluded that the risks of redo-valve replacement outweighed the benefits as there were no significant valvular defects noted on echocardiogram. The patient subsequently completed a six-week course of combination antimicrobial therapy with appropriate levels of gentamicin and no adverse sequelae of therapy. Repeat echocardiogram showed a largely unchanged small mobile vegetation on the anterior cusp of the prosthetic mitral valve without valvular compromise. He was reassessed by cardiothoracic surgery who again recommended conservative management with chronic oral suppression and additional echocardiographic follow-up given his overall clinical improvement without significant valvular compromise on serial echocardiograms. He was subsequently transitioned to suppressive therapy with trimethoprim-sulfamethoxazole given the presence of continued vegetation on his prosthetic valve with plans for withdrawal after a distant repeat echocardiogram at 6 months of follow-up. The patient was reevaluated several weeks post-discharge and remained clinically well. Unfortunately, he was not seen again in follow-up at our clinic since he returned to his home country of Honduras for continuity of care.

ai, aortic insufficiency, ami, acute myocardial infarction, amk, amikacin, amp, ampicillin, av, aortic valve, avr, aoritc valve replacement, cef, cefalexin, cip, ciprofloxacin, ctx, ceftriaxone, e coli, escherichia coli, ef, ejection fraction, escherichia coli, gent, gentamicin, gi, gastrointestinal, gu, genitourinary, hacek, haemophilus species, aggregatibacter actinomycetemcomitans, cardiobacterium hominis, eikenella corrodens, kingella kingae, ie, infective endocarditis, imp, imipenem, infective endocarditis, m, man, mr, mitral regurgitation, mv, mitral valve, mvr, mitral valve replacement, ofl, oflofloxacin, pve, prosthetic valve endocarditis, prosthetic valve, sd, standard deviation, sul, sulbactam, tv, tricuspid valve, uti, urinary tract infections, unk, unknown, w, woman, wma, wall motion abnormalities infective endocarditis

PMC4242059_01

Female

A 32-year-old Tunisian woman presented with 2 years history of headaches. The patient's past medical history was no significant. She did not have a history of sinusitis, nasal deformity, or oral ulcers. she was not on any regular medications. Routine laboratory tests including renal function were normal. Chest x-ray showed neither lung lesions, nor mediastinal lymphadenopathy. After an initial CT scan showed a left temporal lobe mass, he was referred to neurosurgery. A follow-up Magnetic resonance neuro-imaging studies (MRI), with and without contrast, identified a left temporal globular mass involving the lenticular nucleus and the internal capsule with edema and signal intensities suggestive of glial neoplasm (Figure 1, Figure 2). Administration of gadolinium resulted in significant enhancement in clods. The patient underwent a left subtemporal craniotomy with complete resection of the mass. Pathological examination revealed neuroglial tissue heavily involved with multiple granulomas (Figure 3). These lesions consisted of focal areas of fibrinoid necrosis, surrounded by a rim of mononuclear cells (Figure 4). The latter often had either oval-shaped or elongated irregular and indented nuclei. Most cells also had a generous amount of pink cytoplasm (epithelioid cells) (Figure 5). Intermixed with the epithelioid histiocytes were a modest number of lymphocytes and plasma cells, although acute inflammatory infiltrates including segmented neutrophils or eosinophils were not seen. Fibrosis surrouding granulomas was highlighted with Masson Trichrome staining (Figure 6). There was no definitive vasculitis, although some vessels had inflammatory cells around them. Sections were stained with periodic acid-Schiff and did not reveal any fungal organisms. Stain for mycobacteria (Zeihl-Neilsen) was negative. Based upon the histopathology of the resected mass lesion, the two main differential diagnostic considerations were a mycobacterial infection (likely tuberculosis) and sarcoidosis. However, negative special stains, negative skin test for tuberculosis and normal Chest x-ray, nearly ruled out an infectious aetiology. Postoperatively, the patient underwent corticotherapy. She had a partial motor deficiency of the right hemibody due to the achievement of the internal capsule. She is currently being retraining and she will have a fruther control.

sarcoidosis, nervous system, pathology

PMC5350300_01

Female

35-year-old female presented with a hyperkeratotic plaque on the left side of forehead. Lesion started as a small papule after 3 months following a roadside fall 2 years back, gradually increased in size, and spread in an annular fashion to form a plaque with warty surface [Figure 1], which started showing ulceration in last 3 months. Lupus vulgaris and leprosy were kept as the differential diagnosis. A detailed history and clinical examination were not in favour of leprosy. She had no history of visit to/residence in known endemic areas for leprosy, no family history of leprosy, no hypo/anaesthesia, tingling, or numbness of hands or feet, and no reduced sweating, loss of hair, dryness of eyes, or epistaxis. On clinical examination an erythematous annular hyperkeratotic plaque with a warty surface measuring 4 x 5 cm was present on the left side of forehead. The lesion showed some crusting and a small scar at the periphery. There was no lymphadenopathy. On clinical examination there were no hypopigmented lesions on body, there was no loss of sensations, and there was no nerve enlargement. Systemic examination also did not reveal any abnormalities. Routine investigations and X-ray chest were normal. Tuberculin skin test was positive with an induration of 20 mm. A punch biopsy from the lesion showed pseudoepitheliomatous hyperplasia with hyperkeratosis, acanthosis [Figure 2(a), H and E (40x), and Figure 2(b), H and E (400x)], and dense inflammatory infiltrates with epithelioid cells and giant cells in the dermis with few acid fast bacilli (AFB) [Figure 2(c), H and E (400x), and Figure 2(d), ZN Staining (1000x)]. PAS staining was not performed. A small scar was evident in the plaque, possibly secondary to an earlier biopsy. Also the histopathology was more in favour of TBVC than lupus vulgaris. A diagnosis of tuberculosis verrucosa cutis was made, and the patient was started on category 1 treatment as per Revised National TB Control Programme (RNTCP) with which the lesions improved.

PMC5350300_02

Female

A 16-year-old girl presented to our OPD with a lesion in left axilla [Figure 3] which started 10 years back as a small papule in axilla which turned into a pustule within a week which crusted and spread slowly over years. Patient did not give any history of trauma, prolonged cough, sputum production, fever, night sweats, and weight loss. No family member had cough or sputum production or history of treatment for tuberculosis. On examination the lesion was sharply demarcated 10 x 6 cm erythematous scaly annular plaque showing peripheral extension and central clearing with atrophic scarring. The plaque extended up to upper inner arm. On diascopy apple jelly nodules were appreciated. No BCG scar was present. There was no axillary or peripheral lymphadenopathy. Tinea corporis was considered as a differential diagnosis, but the lesion was asymptomatic and other flexures and nails were normal. PAS staining was not performed. Routine investigations and X-ray chest were normal. Tuberculin skin test was positive with an induration of 18 mm. Biopsy revealed well-formed granulomas with epithelioid cells and Langhans giant cells surrounded by chronic inflammatory cells and central necrosis without AFB [Figure 4, H and E (400x)]. PAS staining was not performed. Diagnosis of lupus vulgaris was made and she was put on category 1 treatment as per Revised National TB Control Programme (RNTCP) with which the lesions improved.

PMC5368710_01

Female

A 13-month-old, female, mixed-breed cat weighing 4.0 kg was referred to the Animal Medical Center at the Tokyo University of Agriculture and Technology with chronic decreased appetite, loss of vigour and intermittent vomiting from 7 months of age. Physical examination revealed no cyanosis or wasting, and no heart murmur was auscultated. Arterial blood pressure was within the normal range (139/98 mmHg [mean arterial pressure 113 mmHg]). Complete blood count revealed mild anaemia with haematocrit (Hct) 22.5%, and serum biochem-istry revealed elevated levels of aspartate aminotrans-ferase (114 U/l), alanine aminotransferase (366 U/l) and preprandial serum ammonia (109 microg/dl). Levels of albumin (3.1 g/dl) and total bile acid (TBA) (preprandial, 3.3 micromol/l; postprandial, 3.6 micromol/l levels) were within normal limits. Abdominal ultrasonography revealed dilation of an intrahepatic portal vein branch and an intrahepatic saccular dilation (maximum diameter 10.3 mm) showing pulsatile mosaic perfusion. Contrast-enhanced (4 ml iodine contrast agent; Iopamidol injection [Konica Minolta Health Care]) CT confirmed dilation of a portal vein branch (diameter 6.7 mm) in the left lateral hepatic lobe with several tortuous vessels that appeared continuous with the hepatic artery and a nidus visible around the associated portal vein branch (Figure 1). CT also confirmed the presence of multiple shunt vessels. Moderate splenomegaly and ascites were also present. Based on these findings, hepatic arteriovenous fistula/hepatic artery-portal vein fistula with multiple acquired portosystemic shunts was strongly suspected. The cat was medically controlled using antibiotics (ampicillin sodium, 15 mg/kg q12h), liver-protecting agent (ursodeoxycholic acid, 50 mg q12h) and a low-protein diet with blood transfusions. However, because medical treatment proved ineffective, coil embolisation was performed on day 11 using a hybrid approach via the mesenteric vein. Intravenous (IV) ampicillin sodium was administered at 30 mg/kg (ampicillin Na injection; Kyoritsu Seiyaku) to prevent infection, with IV buprenorphine hydro-chloride at 0.01 mg/kg (Lepetan 0.2 mg; Otsuka Pharmaceutical) as pain relief. Following preadministration of a subcutaneous injection of atropine sulfate at 0.02 mg/kg, general anaesthesia was induced using 5% isoflurane (Isoflurane for Animal Use; Intervet). Coil embolisation was performed via a transperitoneal approach under general anaesthesia maintained with isoflurane inhalation (3.5-4.0%). For the midline transperitoneal approach, the mesenteric vein was cannulated with an IV catheter, and portal venous pressure was 26/24 mmHg (mean pressure 24 mmHg) (portal venous pressure in anaesthetised cats is 8.9 +- 0.35 mmHg, with a mean of 7.38 +- 2.7 mmHg). A wide area of greater omentum was pale and the colour of the intestines suggested congestion. Anterograde angiography with iodine contrast agent (4 ml) showed that the contrast medium injected into the portal vein branch immediately diverted into the mesenteric vein, and multiple shunts were visible in the abdominal cavity. Congestion, dark-red colouration and varicose projections were apparent in part of the right medial hepatic lobe, which presented an extremely irregular texture. However, no abnormalities in external appearance were observed in the quadrate or left medial lobes. A small amount of pale-yellow ascites fluid was accumulated in the abdominal cavity. The splenic head was enlarged and dark red, and splenectomy to improve anaemia was performed using a vessel-sealing system (LigaSure; Covidien). After splenectomy, a 3 Fr sheath was inserted in the proximal mesenteric vein and a 0.018 inch guidewire was introduced. A microcatheter (Virtus 2Marker microcatheter; Boston Scientific Japan) was then inserted under fluoroscopic guidance as far as the region of the arterioportal fistula. A detachable coil (interlocking detachable coil, 12 mm, 20 cm x 1 coil; Boston Scientific Japan) was deployed inside the portal vein branch under fluoroscopic guidance. Portal venous pressure was measured and peristaltic movements and colour of the intestines were checked, then five push-up coils (Cook push-up coils: 10 mm, 14.2 cm; Cook Japan) were added in order to embolise the intrahepatic portal vein (Figures 2 and 3). Portal venous pressure after coil embolisation was 27/23 mmHg (mean pressure 25mmHg). Recovery from anaesthesia was uneventful, and appetite was evident 3 h postoperatively. Postoperative condition was improved, with no diarrhoea or vomiting. The day after the operation (day 12), pulsatile mosaic perfusion on abdominal ultrasonography was decreased in the intrahepatic branches of the portal vein. The animal was discharged on day 15. On day 92, the animal was vigorous and showed a good appetite, with no sign of diarrhoea or ascites. Postprandial serum ammonia (197 microg/dl) showed no decrease and remained medically controlled using ursodeoxycholic acid, but no sign of hepatic encephalopathy was identified and the cat exhibited good levels of activity and a stable condition. In addition, anaemia was improved (Hct 30.9%). On day 113, abdominal ultrasonography revealed that the mosaic pattern around the site of coil placement was nearly undetectable.

PMC7289761_01

Female

A 43-year old previously healthy woman visited her doctor due to exercise-induced pain in her right knee, which showed up to be a spontaneously transient symptom. Otherwise, she was completely asymptomatic, had never had tuberculosis or had episodes of erythema nodosum, arthralgias, eye pain or fatigue. The lung function and all blood test were normal. She had been smoking corresponding to 15 pack years. Two years earlier (2016) bilateral breast implants placed of cosmetic reasons had been removed since leak was demonstrated by breast magnetic resonance imaging (MRI) and ultrasound, which also revealed enlarged silicone-containing right axillary lymph nodes. The patient was referred for a routine chest X ray (no symptoms but former smoker) that lead to CT of the chest. This showed non-calcified asymmetrical lymphadenopathy of stations 2R, 7, 10R and 11R (short axis diameter: 10-15 mm), and multiple bilateral lung nodules (diameter 5-10 mm) with no pleural, subpleural or perivascular preference. Furhermore, a prosthesis residue was demonstrated laterally in the right breast. C-reactive protein, renal function tests and ionized calcium were all normal. The patient was referred to our unit for workup of suspected malignancy. PET-CT revealed increased metabolic activity in the lymph nodes and lung nodules mentioned (Fig. 1, Fig. 2). We performed bronchoscopy (bronchial wash for cytology and culture) and endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA). The patient had difficulties cooperating during the first procedure performed under conscious sedation because she was coughing. To ensure sufficient biopsies from as many lymph nodes as possible, we performed a second procedure under general anesthesia. At 12-month follow up, she was consistently asymptomatic, but the patient refused the planned chest CT due to fear of long-term consequences of irradiation.

endosonography, granulomatous disease, mediastinal lymph node, silicone implants

CT (2018) showed bilateral pulmonary infiltrates and enlarged lymph nodes in all mediastinal stations.

PMC9691950_01

Male

A 14-year-old male patient had swelling in his right leg with intermittent pain for 1 year. The swelling of the lower leg was severe after exercise and could be relieved by rest. The previous month, he was treated at an external hospital, and the plain film radiography showed a lesion of the right tibia, so he came to our hospital for treatment. Physical examination: both lower limbs were equal in length, and obvious swelling or tenderness was not palpated in the right lower leg. The movement of both lower limbs and the muscle strength were normal. Plain radiography: the cortical expansive bone destruction of the anterior edge of the right upper tibia was irregular and lobulated, and the sclerotic edge could be seen. The long axis of the lesion was consistent with the tibia, with a maximum cross-sectional area of 2.1 x 1.9 cm and a length of approximately 7.5 cm, with no obvious periosteal reaction and no definite soft tissue mass. Computed tomography (CT): the lesion showed an eccentric polycystic expansive lucency area, and the bone cortex was expanded and thinned. Cortical interruption could be seen on some levels, and a small local lamellar periosteal reaction was observed in some parts. The lesion was associated with pathological fracture. Magnetic resonance imaging (MRI): the lesion of the upper right tibia showed a low signal on T1-weighted imaging (T1WI), a high signal on T2-weighted imaging (T2WI), and a high signal on diffusion-weighted imaging (DWI). The lesion showed significant enhancement on the postcontrast MRI scan. The preoperative imaging diagnosis was OFD of the upper right tibia with pathological fracture. After admission, the patient underwent tumor resection of the right tibia, free transplantation of the left fibula, and internal fixation. During the operation, the lesion was found to be located in the anterolateral bone cortex of the right tibia, and the tumor was white, flexible, and bleeding. The patient had good tolerance to the surgery with stable intraoperative condition. After resection of the tumor, the wound recovered well, the vital signs were stable, and activity was normal. Pathological examination showed a small amount of hyperplastic fibrous tissue and irregular woven bone and osteoblasts, in which scattered nest-like epithelial cells were seen. The immunohistochemistry results showed Ki-67 (+1%), SATB2 (+), CK19 (1+), AE1/AE3 (1+), CK18 (-), EMA (-), P63 (1+), S-100 (-), MDM2 (2+), SMA (-), and beta-catenin (2+, cytoplasm) ( Figure 1 ). The patient was recommended to be closely followed up and observed after the operation, avoiding weight bearing to prevent the aggravation of pathological fracture. The patient has been followed up for more than a year with no recurrence or distant metastasis.

bone tumor, computed tomography, magnetic resonance imaging, osteofibrous dysplasia-like adamantinoma, plain radiography

PMC5941974_01

Male

In April 2013, a 61-year-old man suffering from early RA [2-10 small joints, increased erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP), positivity of anticyclic citrullinated peptide antibodies (ACPA)/rheumatoid factor (RF), symptoms lasting 1 year] came to our attention for the worsening of morning stiffness, pain and symmetrical swelling of proximal interphalangeal (PIP), metacarpophalangeal (MCP) joints and wrists. The patient presented several comorbidities: high blood pressure, type 2 diabetes mellitus, dyslipidemia, class I obesity [body mass index (BMI) = 33.2], prostatic enlargement and depressive mood. In addition, he was a smoker [60 pack-years (PY)]. He was receiving treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids (CCS) in the medium/high doses (up to 15 mg/day prednisone). During the first visit at our division, the patient exhibited laboratory investigation that showed ESR 37 mm/h, CRP 10 mg/l, RF 122 IU/ml, ACPAs 233 IU/ml; quantiferon-TB gold test, antinuclear antibody (ANA) and extractable nuclear antigen (ENA) screening as well as complete hepatitis B and C markers were negative; blood count [white blood cells (WBC) 6.5 x 103/microl, granulocytes 55%, lymphocytes 35%], transaminases, creatinine and serum protein electrophoresis were normal. He did not present other clinical signs and symptoms suggestive of connective tissue disorders such as: Raynaud's phenomenon, skin thickening, dysphagia and acid reflux, rashes, sicca syndrome, myalgia and proximal muscle weakness, nor constitutional symptoms of fever and sweats. X-ray of November 2012 documented a mild increase of the plot in the absence of clinical signs; hands and wrists X-ray reported diffuse arthropathic manifestations with initial erosions of ulnar styloid. Ultrasound of hands and wrists bilaterally demonstrated moderate proliferative, erosive and active synovitis [power Doppler (PD) III] of radiocarpal joints, moderate active (PD II) proliferative tenosynovitis of the flexor tendons of the fingers, mild proliferative synovitis of the II MCP joint (Figure 1(a,b)). On examination, he presented four tender and four swollen joints (radiocarpal and II MCP joints bilaterally). Clinimetric data showed moderate activity with disease activity score in 28 Joints (DAS28) of 4.8 and moderate disability with Health Assessment Questionnaire (HAQ) of 1.5. We also performed the Short Form Questionnaire for general well being (SF-36) to gain a deep insight of his mental and physical quality of life. He presented a severe reduction (>2 standard deviations from the mean) in all the SF-36 subscales with a Physical Component Summary (PCS) of 22 and a Mental Component Summary (MCS) of 26. MTX 15 mg/week was, therefore, introduced and progressive CCS decrease (up to 5 mg/day) started. After 2 months of therapy with MTX, the patient showed significant improvement of RA signs and symptoms. However, he began to complain of persistent dry cough and dyspnea without fever. The objective examination of the chest documented bilateral basal crackles. In suspicion of ILD, the patient was submitted to lung function tests that documented mild restrictive defect with mild reduction of CO single-breath diffusing capacity (DLCO SB 60%) and CO divided by the alveolar volume (DLCO/VA 87%; forced vital capacity 67%). High-resolution computed tomography (HRCT) showed one micronodule (5 mm) with smooth margins in subpleural parenchymal right upper lobe and notes of bilateral interstitial fibrotic striae type 'ground glass' more evident on the left (Figure 2(a)). MTX was interrupted and therapy with Sulphasalazine 2 g/day was introduced. The consultant pneumologist proposed to also perform a bronchoalveolar lavage (BAL) which excluded concomitant infections and showed an increased cellularity with raised granulocytes (10%) and lymphocytes (20%), eosinophils and macrophages were within the normal range; the CD4/CD8 ratio was 1.3. The CCS dose was not increased; however, after 3 months the patient presented marked arthritic worsening with six tender and six swollen joints and a DAS28 of 5.8 (severe activity), accompanied by a deterioration of its depressive mood. Consequently, treatment with tocilizumab at recommended standard dose (8 mg/kg, total 760 mg ev/monthly) was introduced. After 3 months of treatment with tocilizumab, the clinical condition of the patient visibly improved. The clinimetric data showed low disease activity (DAS28 = 3) and a reduced disability (HAQ = 1) confirmed by the marked amelioration in all the SF-36 subscales (PCS from 22 to 33 and MCS from 26 to 43). The patient presented only one tender and swollen joint (left radiocarpic joint). Ultrasonography of hands and wrists documented a mild synovitis (PD grade I) of radiocarpic joints bilaterally (Figure 1(c)). He no longer complained of cough and dyspnea and bilateral basal crackles were no more present. After 6 months of therapy with tocilizumab, the clinical conditions of the patient were still stable (DAS28 = 3); the tests of lung function showed persistence of mild restrictive defect with normal CO diffusion (DLCO/VA 102%). At 1-year follow up the patient showed a clinical remission (DAS28 = 2), further improvement in disability (HAQ = 0.5) and SF-36 (PCS 35; MCS 45). The objective examination of the chest was normal and the tests of lung function were stable. HRCT was repeated and it documented the reduction in size and density of ground glass area (Figure 2). Informed consent was obtained from the patient for his information and images to be included in this article, as well as for diagnostic and therapeutic interventions. Our institution does not require ethics approval for reporting individual cases.

anti-tnfα agents, interstitial lung disease, rheumatoid arthritis, tocilizumab

PMC8247726_01

Male

A 47-year-old hepatitis B positive male underwent L4-L5 microdiscectomy 45 days ago. He newly presented with low back and bilateral gluteal pain (i.e., VAS score 8 and 5 respectively) and swelling under the surgical scar. The lumbar ultrasound showed a deep dorsal paraspinal collection extending from L3 to L5 in the subcutaneous and intramuscular region. The MRI additionally revealed diffused vertebral body edema with a large intraspinal/ paraspinal and anterior epidural fluid collection from L4 to S1 [Figure 1]. First, 5 cc of whitish pus was aspirated under ultrasound guidance and it was sent for RT-PCR MTB, culture/sensitivity(C/S), Gram staining, and ZN staining for acid-fast bacilli (AFB). The results of all samples came back negative. However, as the ESR (erythrocyte sedimentation count) and C-reactive protein (CRP) levels were elevated, the patient was presumptively treated for bacterial spondylitis with cefepime and amikacin. Surgically, the entire abscess was drained and the wound was debrided. Samples were sent for histopathological and RT-PCR evaluations. The patient's clinical symptoms fully resolved postoperatively. The histopathological report showed epithelioid cell granulomas with central caseation surrounded by Langhans type giant cells [Figure 2]. ZN stain for AFB was also positive [Figure 3]. The RT-PCR for MTB was again negative. Antitubercular drug therapy (ATT) of four drugs (HRZE) was started. One month later, both CRP and ESR decreased [Table 1]. The plan was to continue the four drugs for 2 months followed by a three drugs (HRE) regimen for another 10 months.

antitubercular drugs, microdiscectomy, spine, tuberculosis

PMC5122815_01

Female

A 53-year-old woman presented with severe left retro-orbital pain and diplopia for 1 month [Figure 1]. Neurological examination performed on admission in a local hospital revealed left abducens nerve palsy. A magnetic resonance image (MRI) revealed an enlargement of the bilateral CS, in which the left side was dominant [Figure 2a]. Biochemical analysis of the blood and cerebrospinal fluid revealed no systemic or neuronal inflammation. A presumptive diagnosis of THS was made. Neurological symptoms were relieved by two sessions of steroid pulse therapy with methylprednisolone (mPSL, 1000 mg/day for 3 days). She began receiving regular corticosteroid therapy with 30 mg/day of oral mPSL. However, right retro-orbital pain and right abducens nerve palsy developed over a period of 3 weeks in spite of the steroid administration. Therefore, the oral mPSL was increased to 60 mg/day. Her symptoms worsened, and she was transferred to the neurological department in our hospital for further examination and treatment. There were leukocytosis, a slightly high level of C-reactive protein, and an increased erythrocyte sedimentation rate. The blood coagulation function, autoimmune test, infection examinations, and tumor markers were normal. The patient had bilateral retro-orbital pain and right oculomotor and bilateral abducens nerve palsy. An MRI showed noticeable enlargement of the right CS [Figure 2b]. The serum level of the pituitary hormones was within normal limits. Additional mPSL pulse therapies were introduced twice. The left abducens nerve palsy disappeared, and the right oculomotor and abducens nerve palsy were ameliorated. A gadolinium-enhanced T1-weighted MRI revealed multiple low-intensity lesions in the pituitary gland and the bilateral CS. Mucosal thickening and fluid collection in the sphenoid sinus were also seen [Figure 2c]. The amount of steroid was gradually decreased, and her orbital pain became worse. An MRI taken 1 month later showed that the inner membrane of the bilateral CS had become unclear. Hypertrophic dura mater around the sellae was also observed, and the sphenoid sinusitis had worsened [Figure 2d]. A tiny aneurysm was discovered to have arisen from the C4 portion of the right ICA as revealed by MR angiography (MRA) [Figure 3b]. This aneurysm was not apparent on the initial MRA [Figure 3a]. The follow-up hormonal examinations indicated total anterior hypopituitarism. Clarithromycin and carbocisteine (400 mg/day and 1500 mg/day, respectively) were administered for the diagnosis of bacterial sinusitis. An endoscopic endonasal transsphenoidal surgery was performed to exclude a CS tumor, such as a lymphoma, or a specific granuloma, as well as the possibility of an infectious disease; during the procedure, the sphenoid sinus and intrasellar contents were drained. A cream-like purulent content was discharged at the opening of the anterior wall of the sphenoid sinus. Mucosal thickening of the sphenoid sinus was also observed. The sellar floor was partially destroyed, and the dura mater was thick and hard. A biopsy of the hypophysis was performed. The pituitary gland was fragile, and the purulent discharge was similar to that from the sphenoid sinus. The dead space was irrigated with copious amounts of saline. Specimens were extracted from the left CS because the aneurysm was in the right CS. Histological examination of the CS showed granulomatous inflammation. This lesion consisted of eosinophilic foamy histiocyte-like cells that were positive for CD68 and negative for S100, CD1a, and inflammatory cells. The sphenoid sinus mucosa suffered from infiltration of lymphocyte and plasma cells in the edematous stroma. Inflammation was also seen in the hemorrhagic and necrotic pituitary gland. Neoplasms such as lymphoma, tuberculosis, and sarcoidosis were excluded. No bacterial growth was observed in the cultures of the drained contents. The severe painful ophthalmoplegia subsided immediately after the operation. She was diagnosed as having a steroid-resistant THS, and methotrexate (MTX, 4-8 mg/week) was administered. Clarithromycin and carbocisteine were continued for 3 months after the operation, at which time, decreased swelling of the bilateral CSs and no effusion in the sphenoid sinus were noted on the follow-up MRI [Figure 2e]. However, the aneurysm had slightly enlarged. Right ophthalmoplegia did not recur, and the aneurysm was carefully observed without any treatment. The mPSL was gradually decreased. MTX was maintained for 6 months, and the ophthalmoplegia disappeared. An MRI revealed the decreased size of the CS and pituitary lesions [Figure 2f]. However, the intracavernous aneurysm remained without change as revealed by MRA [Figure 3c]. Hormonal examination 3 months after the operation revealed still total anterior pituitary dysfunction. Hormone replacement therapy was started with hydrocortisone and levothyroxine sodium hydrate. Somatropin was also administered approximately 1 year after the operation.

aneurysm, tolosa–hunt syndrome, cavernous sinus, pituitary abscess, sphenoid sinusitis, steroid

PMC5661833_01

Male

A 44-year-old Hispanic male was brought in with the chief complaints of progressive neurologic deterioration such as paranoid behavior, complete loss of memory, generalized weakness, and urine incontinence for 2 months. The patient was an active smoker, a heavy drinker, an intravenous drug abuser, and was sexually active. He used to work in a restaurant 2 months ago with completely normal mental status. His physical examination showed low-grade fevers and gait ataxia; his level of consciousness was always proper, but the content was altered. Laboratory testing showed he was human immunodeficiency virus (HIV) positive (CD4 count- 348 cells/mm3) with normal complete blood count (white blood cell count 5.4 M/muL, hemoglobin 12 g/dL, and platelet count 176x109/L). His kidney function was persistently normal; urinalysis was normal as well. Lumbar puncture was done and cerebrospinal fluid showed normal white blood cell count with normal glucose and protein levels. The entire HIV-related opportunistic infections including herpes simplex, cytomegalovirus, toxoplasma, tuberculosis, progressive multifocal leukoencephalopathy, and John Cunningham virus were negative, except EBV, which was followed as shown in Table 1. Imaging studies including magnetic resonance imaging and computed tomography scans were performed, which showed lucencies at different levels of brain and around the ventricles (Figure 1). This patient was started on antiviral therapy acyclovir 10 mg/kg and his symptoms started resolving day by day. Patient was followed in infectious disease clinic and after 6 months, he was again completely functional. Written informed consent has been provided by the patient to have his case details and any accompanying images published.

epstein–barr virus, hiv, human immune deficiency virus, intravenous

PMC4488084_01

Male

A 61-year-old immune-competent male with history of coronary artery disease preserved ejection fraction, and osteoarthritis of the knee was admitted with a 5-month history of increasing dyspnea, cough, lower extremity edema, and persistent atrial fibrillation. He was diagnosed with bilateral pleural effusions and loculated pericardial effusions (Figures 1(a) and 1(b)). Pericardiocentesis and bilateral thoracentesis were performed: pericardial and pleural fluid revealed lymphocytic predominance (white blood cell count was 302 with 245 lymphocytes). Pleural fluid was transudate (pH was 7.5, LDH ratio was 0.35, and protein ratio was 0.3). Blood cultures were negative for P. acnes and peripheral blood smear showed rare atypical lymphocytes. Hence, the patient underwent a whole body 18FDG-PET scan to rule out malignancy. Quantiferon Gold (to rule out tuberculosis) and rheumatologic workup were negative. P. acnes was considered contaminant, but since it was isolated from both pleural and pericardial fluids, he was started on oral amoxicillin 1000 mg three times daily, with plans for a 21-day course. The patient was readmitted 2 weeks later with recurrent pericardial and pleural effusions and New York Heart Association (NYHA) class III symptoms. On exam, he did not have evidence of pulsus paradoxus. Jugular venous pressure was 7 cm and systolic blood pressure was in the 110-130 range. He underwent repeat pericardiocentesis and thoracentesis for relief of symptoms. Cultures of pericardial and pleural fluid were negative for P. acnes on oral amoxicillin therapy. Echocardiography after pericardiocentesis revealed evidence of constrictive physiology (Figure 1(c)) and MRI demonstrated pericardial thickening with delayed enhancement (following administration of gadolinium), suggesting the presence of active inflammation and/or fibrosis (Figure 1(d)). Intravenous Penicillin G (3 million units every 4 hours) and colchicine 0.6 mg twice daily were initiated for treatment of presumed P. acnes pericardial/pleural effusions, with significant improvement in symptoms within a few days. He received a six-week course of intravenous Penicillin G and was subsequently switched to oral doxycycline 100 mg twice daily for 6 weeks. The patient's exercise capacity progressively improved to the point that he was able to participate in an international competitive sporting event several months following discharge. On follow-up, the patient had no recurrence of effusions (Figures 2(a) and 2(b)). Repeat echocardiography performed 10 weeks after initiation of intravenous antibiotics confirmed resolution of constrictive physiology (Figure 2(c)).

PMC5899771_01

Female

Case 1: A 71-yr-old woman presented with postmenopausal bleeding. Gynecological examination revealed endometrial thickening. There was no history of contact with TB patient. Histopathological examination of the endometrial biopsy specimen revealed granulomatous endometritis and endometrial polyps. After homogenization and decontamination procedure, biopsy material was stained with EZN and no AFB was seen. M. tuberculosis culture was performed with LJ medium and MGIT. Only MGIT liquid medium was positive. According to the identification with conventional biochemical methods and PCR-RFLP, the strain was identified as MTC. Anti-TB susceptibility was performed and the strain was sensitive to all first-line anti-TB drugs.

female genital tuberculosis, infertility, mycobacterium tuberculosis

PMC5899771_02

Female

Case 2: A 31-year-old woman with primary infertility presented with a complaint of vaginal discharge and secondary amenorrhea for the past three years. Like case 1, there was no history of contact with TB patient. Endometrial biopsy was performed. Histopathological examination revealed chronic granulomatous inflammation. No AFB was seen after homogenization and decontamination procedure. In this case, both LJ and MGIT mediums were positive. The strain was identified as MTC and anti-TB susceptibility was performed. Only INH resistance was detected in this strain.

female genital tuberculosis, infertility, mycobacterium tuberculosis

PMC5899771_03

Female

Case 3: A 22-yr-old virgin female presented with lower abdominal pain with menstrual irregularities. She took non-specific antibiotics for 15 days. Family history was negative for TB. There was a complex mass of 7 cm with solid and cystic components in the right adnexa. CA125 level was 167 mg/dL. A peritoneal biopsy was obtained via laparotomy. AFB was not seen with EZN stain. In culture, both LJ and MGIT mediums were positive. After the identification of strain as MTC, anti-TB susceptibility was performed and SM resistance was detected solely.

female genital tuberculosis, infertility, mycobacterium tuberculosis

PMC5899771_04

Female

Case 4: A 44-yr-old gravidity 5, primiparous female with four abortions in the first trimester and with a post-neonatal death of her child presented with irregular menstrual bleeding and abdominal pain. There was no history of contact with a TB patient. Pelvic examination revealed a pelvic mass of 10 cm and abdominal fluid collection. CA125 was 1000 mg/dL, and CA19-9 was 139 mg/dL. Endometrial biopsy was reported to be granulomatous endometritis. Four liters of serohemorrhagic fluid and miliary spread of small foci of nodules in all peritoneal surfaces including bilateral tubal structures and ovaries were encountered in explorative laparotomy. Examination of frozen sections demonstrated necrotizing granulomatous inflammation. Samplings of the peritoneal lesions and ascites were performed for microbiological evaluation. After homogenization and decontamination procedure, no AFB was seen from peritoneal fluid. In peritoneal fluid culture, both LJ and MGIT mediums were positive. The strain was identified as MTC. Anti-TB susceptibility was performed and the strain was sensitive to all first-line anti-TB drugs.

female genital tuberculosis, infertility, mycobacterium tuberculosis

PMC10148083_01

Female

A 40-year-old woman, Acehnese civil servant, presented to the Dr Zaionel Abidin Hospital in Banda Aceh Indonesia with shortness of breath. One week before the admission, the patient's skin was peeling; red blotches and rashes emerged all over the body. The patient also reported that their eyes were itchy. The patient was coughing up phlegm for three days before admission. There was no fever and no documented allergy history. The patient had the same complaints in 2011 and 2013 and was diagnosed with allergic contact dermatitis and Steven Johnson Syndrome (SJS). However, the patient was unable to recall the drug(s) that was associated with it. The patient had type 2 diabetes mellitus, and tuberculosis and was routinely treated with insulin Novorapid 12-12-12, Levemir 0-0-0-12 and tuberculosis drugs. The patient's condition worsened since the patient took tuberculosis drugs for one month. On physical examination, eyelid edema, bulbar conjunctiva, and tarsal superior and inferior hyperemia were observed; the mouth was excoriated and fissured. The genital area was within normal limits. On pulmonary examination, there was a decreased tactile fremitus, decreased breath sound and ronchi over the left lung suggesting pleural effusion. Resonant percussion and auscultation were vesicular in the right lung field. On the dermatological status, macules, erythematous plaques, multiple brownish crusts, and nummular-size plaques were observed on regio of facialis, superior and inferior thoracic, and superior and inferior extremities with epidermolysis > 90% of body surface area, and Nikolsky sign (+) ( Figure 1). The SCORTEN score was used to calculate the prognostic score and yielded a score of 2 with a possible mortality rate of 12.1%. The blood test showed hemoglobin 13.6 g/dL, platelets 302.000/mm 3, leukocytes increased by 16.000/mm 3. Kidney and liver function, as well as blood sugar levels within normal limits. Blood gas analysis showed pH 7.497 mmHg, pCO 2 29.00 mmHg, pO 2 61 mmHg, bicarbonate 22.7 mmHg, total CO 2 23.6 mmHg, BE 0.3 mmol/L, and oxygen saturation 93.5%. Histopathological examination showed mild acanthosis, vacuolar changes, and scattered apoptotic keratinocytes in the epidermis, consistent with TEN. The dermis has a perivascular infiltrate consisting of lymphocytes, eosinophils, and neutrophils. There were no subcorneal spongiform and/or intraepidermal pustules. Based on the physical examination and histopathology test result, the patient was diagnosed to have toxic epidermal necrolysis. The tuberculosis drug was discontinued because it was suspected the drug was the cause. Furthermore, the patient was taking oral prednisone and loratadine. After consultation to Department of Dermato-Venereology, the therapies were replaced by methylprednisolone injection 62.5 mg, oral mebhydrolin napadisylate 50 mg and combination of salicylic acid 3% and desoximethasone 0.25%, and vaseline album. Because there was no improvement observed, the patient was planned to undergo plasmapheresis with 5% albumin using the prismaflex machine. On the fourth day of plasmapheresis, the patient was given desoximethasone ointment as additional therapy. Methylprednisolone started to be tapped into 31.25 mg per day, fluconazole drip therapy200 mg/day and sun protection factor (SPF) 50 PA+ sunscreen was added on the fifth day. After a week of therapy, the skin lesions improved, and the itchy skin complaints decreased. Purplish red macules with hypopigmented macules in the middle begin to diminish. Methylprednisolone injection therapy was replaced by oral treatment ( Figure 2). Re-epithelialization was observed after three days, and the patient was discharged on day eight.

scorten score, ten, plasmapheresis, steroid, toxic epidermal necrolysis

PMC4242703_01

Female

A 17-year-old Caucasian female came under our observation with a history of full-term precipitous delivery. At birth, the Apgar score was 7 at minute 1 and 9 at minute 5, and she showed postnatal hepatosplenomegaly, jaundice, and a petechial rash on her face, limbs, and trunk. Motor development was delayed: she gained head control at 4 months, the ability to sit at 12 months, the ability to stand unassisted at 13 months, and learned to walk, albeit precariously, at 20 months. By this time, no verbal language had developed nor had she gained adequate voluntary control over chewing and tongue movements. When she was one year old, clinical examination showed bilateral sensorineural hearing loss and mild mental retardation. An auditory prosthesis was implanted, and logopedistic rehabilitation was suggested. Transfontanellar ultrasonography, made possible by persistent opening of the fontanelle over 12 months, showed mild dilatation of the ventricular system, more prominent in the left lateral ventricle than in the right, in association with bilateral parenchymal calcifications. A diagnosis of congenital cytomegalovirus (CMV) infection with intracranial calcifications was made. Clinical examination at admission to our institution when she was 17 years old showed myopathic facies with amimia, bilateral hyposthenia of the facial muscles, an elongated and partially protruded tongue, an ogival palate, and bilateral claw hands. Neurologic examination showed a lack of speech with emission of inarticulate sounds and severe deafness. She was able to understand spoken language and communicate using international sign language. There was salivary incontinence due to facial muscle hyposthenia, tongue protrusion and lateral movements were impossible, chewing was inadequate, a bilateral eyelash sign was present, and automatic-voluntary dissociation was also recognized. Reflexes were normal, except for an indifferent plantar response bilaterally. The patient did not require assistance for activities of daily living, such as eating, bathing, and dressing. She was described by one of her parents as stubborn, immature for her age, and prone to aggressive outbursts when frustrated; she showed a narrow range of interests and preferred to spend her time alone. During neuropsychologic evaluation, the patient appeared wakeful and sufficiently compliant, although easily distracted and intolerant of errors. General cognitive abilities were found to be borderline impaired (intelligence quotient 77) when measured with Raven's Progressive Matrices. There was also evidence of impaired visuomotor coordination and severe deficits in attention and executive function.

foix-chavany-marie syndrome, cortical dysplasia, cytomegalovirus, opercular syndrome, polymicrogyria

PMC3278523_01

Female

A 25-year-old female with a prior history of syncope (lightheadedness, followed by LOC for a few seconds, and no ictal or post ictal phenomena) presented with a witnessed generalized tonic clonic (GTC) seizure. She had recently returned from Switzerland and was otherwise well. She had eaten. She was walking, followed by running on a treadmill, felt a little faint for a second or so and then lost consciousness. She was unable to brace herself, fell backwards and sustained a head laceration on the posterior, right back of her head. The event was witnessed by a physician, and she was noted to have rhythmic shaking for 30 to 45 s. She bit her tongue, had post-ictal confusion, but no bowel or bladder incontinence. The head and cervical spine CT scans were unremarkable. Her brain MRI with contrast was notable for 2 enhancing lesions in the left frontal and temporal lobes (Fig. 1A, B). It was unclear whether these lesions were intra-axial or extra-axial given their small size and peripheral location. Differential of prior infection/granulomatous disease including tuberculosis and sarcoid, small meningiomas, and neoplastic seeding was raised. Her electroencephalogram (EEG) was notable for left temporal slowing with some sharp features (Fig. 1C). Lumbar puncture showed zero red blood cells and white blood cells. Tests for cerebrospinal fluid protein, glucose, gram stain and culture, acid-fast bacilli, cytologic examination, angiotensin-converting enzyme (ACE), and cysticercosis antibody were all negative. Blood erythrocyte sedimentation rate, C-reactive protein, ACE, anti-nuclear antibody (ANA) and antineutrophil cytoplasmic antibodies (ANCA) were only notable for positive ANA of 1:320. EKG showed no PR shortening, ST wave abnormalities or QTC prolongation. The patient underwent repeat imaging and testing 1 month post event. Her head CT was notable for a small region of encephalomalacia in the left frontal region (Fig. 2A). No enhancement was seen on axial T1-weighted MRI following contrast administration (Fig. 2B, C). Her sleep-deprived EEG was normal. The patient was not initiated on anti-convulsant medication and has done well since.

PMC3856474_02

Female

Myrtle (not her real name) was an 80-year-old retired nurse. Prior to her stroke, Myrtle was an active lady who socialised regularly and used public transport independently. Myrtle described herself as always having been "a worrier". She also saw herself as a very independent lady who did not like to rely on others for help. Myrtle suffered a left middle cerebral artery infarct a year prior to the psychology referral. An MRI scan showed that the infarct involved the insular regions and the left temporal lobe, sparing the corpus striatum structures. The MRI scan also showed an old infarct in the right parietal region. At the time of the stroke, Myrtle presented with right-sided weakness including right-sided facial weakness, dysphagia and no speech. She was admitted to hospital and thrombolysed. Sixteen days post-stroke, Myrtle was transferred to a rehabilitation ward. By this time, Myrtle had little residual physical disability and her main difficultly was dysphasia. She remained on the stroke rehabilitation ward, where she received physiotherapy, occupational therapy, speech and language therapy and medical care, for one month. Myrtle did not appear to have long-term cognitive difficulties following the stroke: the Lowenstein Occupational Therapy Cognitive Assessment completed by occupational therapists during her time on the rehabilitation ward demonstrated intact orientation, perception of objects and self, praxis and memory. Myrtle was seen by a speech and language therapist (SALT) at acute and rehabilitation hospitals and subsequently as an outpatient. She received input for expressive dysphasia, which was described as "mild" by the time she was discharged from hospital. The SALT intervention focused on adopting a total communication approach (communicating in any way possible, including writing, drawing, gesturing, etc.) and reducing anxiety about her speech. After six sessions of outpatient SALT, Myrtle was referred to the psychology service for further work on anxiety about her speech. At the time of the psychology referral, Myrtle had episodes of speech that were appropriate and intelligible, but at other times displayed disorganised language, reduced volume and "jargonistic" output. The SALT felt that this variability was directly related to anxiety and confidence. During a SALT session 11 months post-stroke, Myrtle rated her confidence as 1 out of 10 and reported avoiding situations that she used to enjoy, for example talking to friends and going to town. Initial psychological assessment identified significant levels of anxiety. She reported worry about a stroke happening again, about finding it hard to communicate with others and about being a burden to family and friends. She scored 14 out of 20 on the Geriatric Anxiety Inventory (GAI), which is well above the cut off of 9 or more. Myrtle reported often feeling tearful and having a reduced appetite. She did not, however, report any difficulties with sleeping, nor did she report suicidal ideation. Her score on the Brief Assessment Schedule for Depression Cards (BASDEC) was below the cutoff (7 or more), indicating that Myrtle's main difficulties were principally related to anxiety. She believed that these difficulties had been triggered by the stroke and the resulting speech difficulties that this had left her with. Myrtle's goals of therapy were to: "Have more contact with family and friends," "Visit sisters who lived between 30 and 60 miles away, using public transport independently," "Visit family in her country of origin," "Spend less time sitting on her own thinking about the things she worried about," and "Return to hobbies she had previously enjoyed but currently avoided". Myrtle appeared to be experiencing a high level of anxiety, including worry that she would have another stroke and that she was a burden to friends and family. She was also finding it hard and embarrassing to communicate with others and worrying on this account. The anxiety had resulted in Myrtle avoiding activities that she previously enjoyed, such as meeting friends, going bowling and going into town. The avoidance of these activities appeared to maintain her feelings of anxiety. Additionally, avoiding social activities resulted in a decrease in social contact, something which she had thoroughly enjoyed before her stroke and which was contributing to feelings of low mood and tearfulness. Due to her difficulties with communication, Myrtle relied more upon her family to help her with day-to-day activities. This decrease in control over her own life led to feelings of frustration and served to further maintain her high levels of anxiety. Myrtle avoided talking to family members when she felt worried or upset, as in these emotional states she found it harder to speak coherently. This meant that at any time when she started to feel upset or worried, she would go upstairs and spend time on her own. This seemed to result in Myrtle's children worrying more about their mother. Myrtle's reluctance to discuss her anxieties with her family was also likely influenced by her independent nature and her reluctance to be "a burden" or to rely on others for help. Spending time on her own also resulted in increased time thinking about the possibility of having another stroke and what that might mean for her independence, thereby maintaining her difficulties. There is currently no anxiety measure validated for use with older people after stroke. Given Myrtle's age and cognitive and communication difficulties it was considered inappropriate to administer the HADS-A which requires a choice of four response levels against a descriptive statement. Instead the GAI was used. This scale requires simpler Yes/No responses to statements. The GAI has been specifically developed for use with older people and research has shown it is reliable and valid in older people with another neurological condition, Parkinson's disease. The standard cut off (a score of 9 or more) was used to consider the presence of significant anxiety symptoms. To confirm the presence/absence of significant depressive symptoms, the BASDEC was used. The BASDEC was developed specifically for use with older people and has demonstrated good reliability and validity at its recommended cut off (7 or more) in sample with older people who have had a stroke. In addition to the standardised measures, one of Myrtle's major presenting concerns, the belief she would have another stroke that would render her completely unable to communicate, was also rated over the course of the intervention using a scale of 0 to 10 ("0" meaning believing this would definitely not happen, "10" meaning believing that this would certainly happen). Following the assessment session, eight sessions were held over an approximate four month period, followed by a one- and three-month follow up session. Sessions were 50-60 minutes in duration and administered by a trainee clinical psychologist, supervised by a consultant clinical psychologist as described under Participant 1. Initial components of intervention included psycho-education about anxiety and the basis for cognitive-behavioural intervention. Following this, the focus was on relaxation training. This involved teaching breathing for relaxation and an autogenic relaxation exercise, the script for which was recorded on a CD for Myrtle to take away and use at home. Work then moved towards developing a hierarchy of situations that Myrtle was avoiding and working her way through confronting these situations. This was modified to accommodate Myrtle's difficulties with reading and writing. Hierarchies were not formally written down but noted by the therapist and discussed and updated in sessions. This style also served to maintain a collaborative therapeutic relationship and to avoid the therapist appearing didactic. Throughout the intervention, the therapist was careful to allow Myrtle to take the lead in sessions due to the lack of control that she found frustrating in other areas of her life. Cognitive disputation was undertaken while working through the hierarchy. Negative predictions associated with certain activities were challenged. For example, Myrtle avoided going to meet friends for coffee because she was concerned that she would have difficulty speaking and that this would result in her becoming extremely embarrassed and her friends becoming either impatient or pitying towards her. Once she had tested this out by going to meet friends, the evidence for these thoughts was revisited and updated. Myrtle was then able to identify strategies to use when she found it hard to speak clearly, for example taking a deep breath or asking for a moment to think. The cognitive component of the work also involved disputing some of the beliefs that were contributing towards Myrtle's anxiety. One belief that was causing her a significant amount of distress was that she would definitely have another stroke and that this would render her completely unable to speak. This part of the intervention included psycho-education about stroke recurrence, the wide range of effects strokes can have, and risk factors for stroke. The risk of Myrtle having another stroke was real and acknowledged. However, discussions highlighted those things that Myrtle was already doing to minimise this risk (for example, not drinking alcohol, taking more exercise and using relaxation exercises and prescribed medication to lower blood pressure). The costs and benefits of worrying about something that she only had limited control over were also discussed. In order to support communication, discussions were summarised more frequently than might have been the case for a patient without deficits in this area. Additionally, discussions were revisited across sessions and important points summarised at the end of the session by the therapist when appropriate. Cognitive disputes were also kept as concrete as practical in light of Myrtle's communication problems, and behavioural components of the intervention emphasised. The therapist also wrote things down and slowed the pace of conversations to assist Myrtle's understanding. The sixth session was used as a review session. At this point Myrtle had made progress towards her goals, including re-commencing a hobby, visiting family more frequently, using public transport to meet friends independently and finding that her speech was less frequently "muddled". Following the review, sessions focused on relapse prevention. This involved revisiting what Myrtle felt she had learnt over the course of therapy and what strategies she had used that would be helpful in future. These included continuing to practise relaxation and maintaining her current level of social activity. It was acknowledged that setbacks might occur, following which future challenges were identified and strategies to deal with these challenges were discussed. The cognitive-behavioural model was revisited, with specific focus on avoidance and its role in maintaining anxiety. Two follow-up sessions were held after one and then three months. Figure 2 summarises the changes on the GAI, and the belief rating over the course of the intervention and at the two subsequent follow-up sessions. The positive change in scores was maintained over the course of therapy and at both follow up sessions. Myrtle's rating of her belief about having another stroke remained at 5 out of 10 from the review session onwards. When this was discussed, she explained that she was happy with this rating as she felt that it was "realistic" and reflected the real risk of stroke recurrence. Further, she felt that the anxiety associated with this belief had reduced significantly. Other indicators of change included Myrtle's reports that she felt more confident going out on her own and more confident in her ability to communicate with other people and feeling "more like herself again". She had also achieved many of her original therapy goals. Myrtle had re-engaged with previously enjoyed activities and more regularly met with friends. She made independent trips to see family members, including booking a holiday to see family in her country of origin who lived some distance away. Myrtle also reported that she felt she spent much less time "worrying about things" and was getting better at "taking each day as it comes". Two follow-up sessions were held after one and then three months. Myrtle was offered a six month follow up session but declined the offer as she reported that she did not feel that another session was needed.

PMC8529157_04

Male

Case #4: A 56-year-old male patient was diagnosed with AITL. Standard chemotherapy was consolidated with auto HSCT. Five months after transplantation, enlarged pulmonary LN were noted on routine chest CT, and histopathologic examination showed granulomas consistent with pulmonary sarcoidosis. Oral GC therapy was initiated leading to a remission of pulmonary nodules and LN. After tapering of GC, an increase in size of mediastinal and infradiaphragmal LN was noted, and a repeat biopsy was performed leading to the diagnosis of a relapse of the AITL. An allo HSCT from a MRD with no known history of sarcoidosis was performed. Post allo HSCT, the patient suffered from GC-sensitive cutaneous and intestinal GvHD; no relapse of sarcoidosis was noted. Overall, we observed symptomatic sarcoidosis in a total of 4 out of 1,065 and 957 patients, who had received allogeneic and autologous stem cell transplantations in the UMG transplantation program, respectively. The disease emerged within a median follow-up observation period of 22 months, resulting in an estimated incidence of 156/100,000 and 58/100,000 for patients at risk after allo and auto HSCT, respectively. An additional 15 cases of sarcoidosis following HSCT have been reported in the literature, with 5 patients having received an auto HSCT, while 10 had received an allo HSCT. Together with our patients, this translates into a total number of 19 reported cases. Although the total populations of the previously published case reports are unknown, the overall low incidences in the allogeneic transplantation group appear consistent between our cohort and the published data. The patient characteristics are shown in Tables 1 and 2. At our center, we also identified 11 patients with a previous history of clinically apparent sarcoidosis prior to HSCT. None of these patients developed histologically proven symptomatic sarcoidosis following HSCT. Of note, only four patients with sarcoidosis prior to HSCT could be observed beyond the median time of disease emergence of 22 months, with a median post-transplantation observation period of 52 months. The most frequently reported underlying disease leading to treatment with allo HSCT was lymphoma (n = 7) followed by leukemia (n = 4) and myelodysplastic syndrome (MDS)/myelofibrosis (MF) (n = 3). The reported underlying diseases leading to auto HSCT were breast or testicular cancer (n = 4), as well as polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes (POEMS) syndrome in one patient. Of the 13 patients who received an allo HSCT, 6 patients were transplanted from a MUD, 6 from a MRD, and in 1 case, the donor status was not reported. Five patients received peripheral blood stem cell donations, five received bone marrow transplant donations, and in three patients, the mode of transplantation was not specified. None of the three donors of our cohort had a history of sarcoidosis, while this was the case in 3 of 10 donors in the cohort of published case studies. The most frequently applied chemotherapeutic agents in the allo HSCT cohort were busulfan (BU) (n = 8), fludarabine (FLU) (n = 7), and cyclophosphamide (CYC) (n = 5). Two patients each also received alemtuzumab (ALM) or antithymocyte globulin (ATG) as part of the conditioning regimen, respectively. In five patients, chemotherapy had been combined with total body irradiation (TBI). In the autologous cohort carboplatin, etoposide, BEAM, and melphalan were the most frequently applied cytostatic drugs. All patients had pulmonary sarcoidosis. Most patients showed changes on CT/chest radiographs (15/19; n = 3 unknown [UKN], n = 1 no changes). Involvement of extrapulmonary organs was present in 11/19 patients; the most common organ manifestation was skin followed by liver. Seven of the 13 allo HSCT also had evidence of GvHD; in two patients, the GvHD status was not reported. A response to GC was noted in all patients where they were given (12/19; 2 UKN, 4 asymptomatic, 1 resolution of symptoms after donor lymphocyte infusion [DLI]). No additional immunosuppressive therapies were used. The characteristics of the patients in both groups (allo vs. auto HSCT) are summarized in Table 3. The HLA status was reported in eight cases. Four of these patients expressed the DRB1*03:01 HLA allele, already known for a strong association with sarcoidosis. Similarly, all other patients also exhibited HLA types known to be associated with sarcoidosis (Tables 1 and 2). Specifically, the allele frequencies of DRB1*03:01 and DQB1*02:01 were higher in our cohort compared to the respective allele frequency in the cohort of all reported patients with sarcoidosis following HSCT (our cohort and published case reports). The allele frequencies for the respective genotypes in this cohort were, in turn, higher than the allele frequency reported in a German and European reference population (Figure 2). The median age of patients with sarcoidosis after HSCT was 50 years (range 25 to 69 years). The median time to onset of sarcoidosis post HSCT overall was 17 months (range 3 to 120 months), with patients developing sarcoidosis after allo HSCT at a median time of 20 months (range 3 to 30 months) and 7 months (range 3 to 120 months) after auto HSCT (p = 0.5422) (Figure 3A). In patients over 50 years of age, the median time to sarcoidosis after HSCT was 12 months, while it was 21 months in patients younger than 50 years (p = 0.1438) (Figure 3B). Overall, patients were more often female (11 vs. 8) and of Caucasian ethnicity. There were no statistically significant differences between groups. Furthermore, we analyzed the cumulative incidence of sarcoidosis depending on gender, donor status (MRD/MUD), solid vs. hematological neoplasia, and lymphoma vs. leukemia/MDS/MF (Figures 4A-E). Due to the low overall numbers, no statistically significant differences were detected.

hla, allo and autologous transplantation, hematopoietic stem cell transplantation, immunology, sarcoidosis

PMC6249401_01

Male

A 74-year-old Japanese man sought care at a previous hospital with a 2-month history of general fatigue and lymphadenopathy. The findings at physical examination were unremarkable except for cervical and axillary lymphadenopathy. A chest computed tomography revealed right supraclavicular, mandibular and bilateral axillary lymphadenopathy and bilateral psoas abscess. Culture of biopsy samples of his right supraclavicular and axillary lymph nodes was positive for Mycobacterium avium, indicating disseminated M. avium disease. He was treated by antimycobacterial therapy with rifampicin (450 mg per day), ethambutol (750 mg per day) and clarithromycin (800 mg per day). Standard antimycobacterial therapy for over 2 years improved his clinical symptoms and lesions. One month later, he was admitted to our hospital with portal hepatic and right axillary lymphadenopathy, which were positive for M. avium. Total bilirubin level was 6.1 mg/dL, and direct-reacting bilirubin level was 3.9 mg/dL. Immunoglobulin levels were within the normal range (IgG, 1555 mg/dL; IgM, 126 mg/dL; IgA, 348 mg/dL). HIV antibody testing was negative, and his CD4/CD8 lymphocyte counts were within normal ranges. Epstein-Barr virus nuclear antigen, viral capsid antigen IgG 2.6 and viral capsid antigen IgM 0.9 were detected by the enzyme immunoassay method. The positive control for QuantiFERON-TB Gold (QFT-3G) was undetectable. We detected a high titre of serum neutralizing anti-IFN-gamma autoantibodies by enzyme-linked immunosorbent assay (patient, 50.85 EU; control, 25.49 EU). These antibodies are also potent inhibitors of IFN-gamma-stimulated signal transducer and activator of transcription 1 (STAT1) phosphorylation in leukocytes using a previously described method (Fig. 1(A)). Briefly, recombinant human IFN-gamma was added to Jurkat cells inoculated with serum. After the cells were permeabilized, anti-phospho-STAT1 antibodies were conjugated, and the cells were subsequently analysed by flow cytometry. According to the results of this assay, anti-IFN-gamma autoantibodies were proved to have a neutralizing effect in this patient. After the detection of anti-IFN-gamma autoantibodies, we continued antimycobacterial chemotherapy. After 1 year of therapy, he sought care for jaundice and systemic pruritus. Contrast-enhanced abdominal computed tomography and magnetic resonance cholangiopancreatography (Fig. 1(B)) and hilar bile duct stricture by endoscopic retrograde cholangiopancreatography (ERCP) (Fig. 1(C)) revealed intrahepatic bile duct dilation. PCR and culture from bile was positive for M. avium, whereas sputum, blood and bone marrow results were negative, resulting in a diagnosis of hepatobiliary M. avium infection. In addition to continuing the same antimycobacterial regimen, a stent was placed in the bile duct after insertion of an endoscopic nasobiliary drainage tube. His symptoms and laboratory findings improved, with no relapse observed during 2 years of treatment. HIV-associated cholangiopathy due to biliary obstruction resulting from a benign stricture of the biliary tract has been reported. Patients with HIV-associated cholangiopathy showed near-normal bilirubin concentrations, with only a few patients requiring a procedure to resolve the biliary obstruction, suggesting the pathogenesis of cholangiopathy in our patient was likely not HIV associated, while neutralizing anti-IFN-gamma autoantibodies could cause similar immunodeficiency in advanced HIV infection. To our knowledge, non-HIV-associated hepatobiliary NTM infection has never been reported. Although adjunct therapy with rituximab was considered in our patient, stent placement during ERCP had successfully improved patient outcome without disease relapse. Hepatobiliary M. avium infection should be considered in the differential diagnosis of jaundiced patients with neutralizing anti-IFN-gamma autoantibodies, even those receiving antimycobacterial therapy for disseminated M. avium disease. In addition to antimycobacterial therapy, biliary decompression by stent placement using the ERCP procedure may be an effective treatment option.

anti–interferon gamma (ifn-γ) autoantibody, mycobacterium aviumcomplex (mac), disseminated mycobacterium aviumcomplex infection, hepatobiliary infection, jaundice

PMC10130679_01

Female

A 47-year-old woman presented with crescendo chest pain, palpitations, and shortness of breath on exertion for two days. She was hypotensive, tachycardic and tachypneic at the emergency department. Physical examination showed bilateral fine basal crepitation, a grade 2 decrescendo diastolic murmur, and bilateral pitting lower limb edema. She was an active smoker and worked as warehouse logistic worker. She had no history of substance or alcohol misuse. There was no family history of cardiovascular disease or sudden death. Chest X-ray showed congested basal lung fields with mild bilateral pleural effusion. Electrocardiography showed ST-segment depression in inferior leads. The clinical findings were suggestive of acute pulmonary oedema. Transthoracic echocardiography (TTE) showed hypokinesia in the anterior wall as well as moderate-to-severe aortic insufficiency. An astute attending cardiologist noted immobile echogenic shadows in the ascending aorta on echocardiography obscuring the aortic valve, and thus arranged a computed tomography aortogram which excluded aortic dissection. Urgent cardiac catheterization showed an unusual picture of a slit-like left main coronary artery ostium, with the rest of the coronaries free from atherosclerotic plaque (Figure 1). The atypical imaging findings prompted investigations for etiologies of infectious and inflammatory aortitis. Potential causative organisms of infectious aortitis included Treponema pallidum, Mycobacterium tuberculosis, Salmonella sp., Staphylococcus sp. and Campylobacter jejuni. Musculoskeletal examination and immunological assays were not suggestive of rheumatoid arthritis, systemic lupus erythematous, and Behcet disease. Ten days after hospitalization, the results of the Venereal Disease Research Laboratory (VDRL) test came back to be positive, which was further confirmed by a positive enzyme immunoassay for Treponema pallidum antibodies. Screening for co-infection of other sexually transmitted diseases including human immunodeficiency virus was negative. While investigations for aortitis were ongoing, the case was discussed in a multidisciplinary team meeting. The decision was made to proceed with inpatient surgery for the critical left main stenosis and severe aortic regurgitation, after a brief period of medical optimization. To facilitate operative planning, an electrocardiogram (ECG)-gated CT of the aortic root was performed, which demonstrated thickened and calcified circumferential plaque at the level of the sinotubular junction, causing subtotal obstruction of the left coronary ostium and partial obstruction of the right (Figure 2). Trans-esophageal echocardiography showed that the aortic valve was trileaflet. The leaflets were mildly calcified and thickened but free from vegetations. However, closure of the left coronary cusp was delayed, causing severe aortic insufficiency (Video 1). The operation was performed two weeks after admission and commencement of guideline-directed heart failure and antimicrobial pharmacotherapy. Through a median sternotomy, aortic valve replacement, coronary ostioplasty and bypass grafting of the left anterior descending and obtuse marginal arteries was performed. After institution of cardiopulmonary bypass and aortic cross-clamping, cold blood cardioplegia at 4 C was administered via an aortic root cannula. Although the heart initially achieved electrical quiescence, it recovered a slow junctional rhythm shortly after aortotomy. Ice slush was applied and cold fibrillatory arrest was achieved. After excision of valve leaflets and brief period of debridement lasting a few minutes, antegrade cardioplegia can be delivered smoothly to both coronary ostia (Video 2). Coronary ostioplasty was then attempted. The right coronary ostium was exposed, revealing a normal calibre orifice surrounded by healthy intima. Although cardioplegia can be given via the left coronary ostium, the ostium appeared atretic and the surrounding intima was thickened and fibrotic. This necessitated bypass grafting to the left coronary circulation, sparing the right. The left internal mammary artery was anastomosed to the anterior descending; a great saphenous vein graft, harvested endoscopically, was anastomosed to an obtuse marginal branch. A size 19 On-X mechanical aortic valve was used (CryoLife, Kennesaw, GA, USA). We elected not to perform a root enlargement or replacement because her body surface area was only 1.44 m2. Given the presence of aortitis and the poor tissue quality, a more aggressive operation may be hazardous. The crossclamp time was 97 min and she came off bypass without inotropes. Her postoperative course was unremarkable. She completed an additional four-week course of oral doxycycline at a dose of 100 mg twice daily. Histopathological examination confirmed the diagnosis of syphilitic aortitis (Figures 3,4). Seroreversion was confirmed at 6 months. TTE 6 months postoperatively showed a mean gradient of 8 mmHg. She expressed satisfaction with her treatment as her recovery was swift and she is now asymptomatic. An overview of the patient's course was presented in a timeline in Figure 5.

cardiovascular syphilis, case report, ostial coronary stenosis, ostioplasty

PMC9081798_01

Male

In July 2018, a 21-year-old man was hospitalized after a road accident with open comminuted proximal right femoral and acetabular fractures, laceration of the right lower hand, and hemorrhagic shock. Wound debridement, fasciotomy, femur fracture stabilization with gamma nail, and tissue reconstruction were performed on the 14th of July. On consecutive days, the patient developed secondary MDR P. aeruginosa, carbapenem-resistant Acinetobacter baumannii, and vancomycin-resistant Enterococcus faecium (VRE) wound infections and multiple organ dysfunction syndrome. The patient underwent five debridement procedures and therapy using a wound vacuum system. Broad-spectrum IV antimicrobial treatment with meropenem, colistin, piperacillin-tazobactam, linezolid, and fluconazole was administered, and renal replacement therapy was initiated. Regardless of the treatment, the patient developed an osteosynthesis-associated infection and osteomyelitis, and repeatedly positive wound cultures grew with VRE, MDR P. aeruginosa, and MDR A. baumannii. On the 13th of August, the gamma nail was removed, and proximal femoral segment resection was performed, followed by tissue reconstruction and lower leg external fixation. Based on the antibiogram, the antimicrobial regimen was changed to intravenous fosfomycin, meropenem, and colistin. On the 13th of September, the right thigh wound was closed using a scapular flap. The patient's condition improved gradually, and there were no signs of systemic or local inflammation. Repeated cultures of the wound were negative. The patient was discharged on the 15th of October with IV meropenem and colistin treatment, which was discontinued after two weeks due to acute kidney injury, presumably colistin-induced nephrotoxicity. In November, purulent discharge from the right upper tight appeared. Computed tomography with contrast injection in the cutaneous wound opening revealed a fistula that connects femoral head and skin on the right upper third of the lateral femur surface (Figure 1A). The patient underwent fistulotomy, and MDR P. aeruginosa and VRE were isolated from the wound. With a presumptive diagnosis of recurrent femoral osteomyelitis, two-stage surgery was planned to preserve hip replacement surgery in the future. Local bacteriophage therapy was planned using the bacteriophage cocktail BFC 1.10 produced at Queen Astrid Military Hospital in Brussels, Belgium, consisting of phages active against P. aeruginosa and S. aureus. The treatment was performed according to Paragraph 37 of the Declaration of Helsinki. The patient provided written informed consent for the use of the bacteriophages. On the 5th of December, a right femoral head excision was performed and replaced with colistin-impregnated cement spacer. The proximal femoral culture was positive for MDR P. aeruginosa, VRE, and Staphylococcus epidermidis. The pathology and intraoperative findings confirmed femoral head osteomyelitis with fistula (Figures 1B,C). After surgery, the patient was treated with IV colistin for 7 days and linezolid for 23 days. On the 7th of December, 2,000 mL of BFC 1.10 cocktail with 107 plaque-forming units (PFU) per mL of each phage were shipped to Latvia. Prefilled sterile containers containing 30, 40 or 50 mL of phage solution were prepared under sterile conditions. Three days before the procedure, the patient was treated with IV ceftazidime-avibactam, which was continued for 15 days. On the 13th of December, bone cement was removed; wound and acetabular cultures were taken, and were positive for MDR P. aeruginosa. Next, wound rinsing with 50 mL BFC 1.10 bacteriophage suspension was performed intraoperatively, tissue damage was replaced with a serratus muscle flap, and an irrigation system for local bacteriophage application was installed (Figure 1D). For the first 7 days, the patient was treated with 40 mL (1 ml/min) of BFC 1.10 three times daily and then with 30 mL (1 ml/min) of BFC 1.10 two times daily via an irrigation catheter for another 7 days. The wound was rinsed with 50 ml of 4.2% sodium bicarbonate solution before the phage application using syringe. Together with the local phage treatment, linezolid and ceftazidime-avibactam were continued. During and after phage treatment on days 1, 3, 4, 7, 10, and 15, no bacterial cultures from the wound grew. Phages were isolated from the wound in the morning buffer sample before phage administration on days 1, 3, 4, 7, 10, and 15. At the end of treatment, the wound healed with no local or systemic signs of infection. When the irrigation catheter was removed, the tip of the catheter was positive for Candida tropicalis, which was not treated (Figure 2). No adverse effects, such as fever, local rash, itchiness, or other symptoms, were noted during phage therapy. Patient was discharged with lower leg external fixation until hip replacement surgery. Two months later, the wound healed and there were no signs of inflammation (Figure 1E) that was reassured with magnetic resonance imaging (MRI) of the right hip. Three months after phage treatment, computed tomography of the right hip and femur revealed no fluid collection or signs of osteomyelitis. In the following six months, two punctures from the right femur were performed and were culture negative, three months before hip replacement lower leg external fixation was removed. On the 3rd of September 2019, a hip replacement with a silver-coated implant was performed. During the surgery bacterial cultures were taken, the distal part of the femur was positive for MDR P. aeruginosa and VRE (fosfomycin susceptible), but acetabular bone and proximal part muscular tissue were culture negative. Patient received one dose of IV vancomycin for perioperative prophylaxis and IV colistin that was continued until microbiology results. Once the cultures came back positive patient was kept on IV colistin and IV fosfomycin. Sixteen days later DAIR (debridement, antibiotics and implant retention) was performed because of hematoma development and possible prosthesis infection, swabs taken during the surgery from periprosthetic tissue in distal segment were positive for MDR P. aeruginosa. On 4th of October punctures from periprosthetic tissue were performed and were culture negative. Three days later patient was discharged and continued antimicrobial therapy in outpatient setting with colistin and fosfomycin. For this episode patient received colistin for six weeks and fosfomycin for five months. During the follow-up period a year later, there were no local signs of infection, and the patient noted limited mobility in the right leg; however, he could continue to play basketball. Radiography of the right hip and femur 15 months later did not reveal any signs of inflammation (Supplementary Figure 1).

p aeruginosa, bacteriophage, biofilm, multidrug resistance, osteomyelitis, phage therapy

PMC3879513_01

Female

A 57-year-old African American woman presented with a 1-day history of atypical substernal chest pain which was intermittent, non-pleuritic, and non-exertional. She also reported a 3-month history of dysphagia (predominantly for solids) which she described as 'food stuck in my throat'. In addition, our patient reported a 20-pound weight loss over 3 months. She had occasional nausea and heartburn, however she denied any vomiting, odynophagia, abdominal pain, or regurgitation of food. Her medical history was significant only for gastroesophageal reflux disease. She denied any tobacco, alcohol, or drug use. She was not on any prescribed medications. Physical examination revealed cachexia but was otherwise unremarkable. Vital signs were within normal limits. Initial evaluation showed non-specific electrocardiographic (ECG) abnormalities in the form of T-wave inversions in the lateral leads; however, she had two negative troponin assays. Her chest X-ray was unremarkable. The rest of her laboratory tests including complete blood count (CBC), basic metabolic profile (BMP), and liver function tests (LFTs) were within normal limits. The patient underwent an esophagogastroduodenoscopy (EGD), which revealed a non-bleeding gastric ulcer. Campylobacter-like Organism (CLO) test was positive for Helicobacter pylori, for which she received standard triple therapy. Her dysphagia was further evaluated with a barium swallow, which showed smooth extrinsic compression on the posterolateral aspect of the esophagus (Fig. 1). As the patient continued to have chest pain, she underwent a nuclear pharmacological stress test, which was high probability for ischemia. She was then taken for cardiac catheterization. Cardiac catheterization revealed non-obstructive coronary artery disease. Due to the presence of extrinsic compression of the esophagus on the barium esophagogram, an aortogram was performed which showed an anomalous take-off of the right subclavian artery distal to the left subclavian artery (Fig. 2). This condition is known as dysphagia lusoria. In pursuing the workup of her chest pain, a computerized tomography (CT) angiogram was performed which confirmed the anomalous right subclavian artery coursing posteriorly resulting in smooth extrinsic compression of the esophagus (Fig. 3). There was no evidence of pulmonary embolism.

aberrant right subclavian artery, barium esophagogram, chest pain, congenital anomaly, dysphagia, extrinsic esophageal compression

PMC4767725_01

Female

In January 2011, a 62-year-old female patient was admitted to the Hospital da Luz, Lisbon, Portugal, complaining of lower back pain and a left lumbar mass for two months with subsequent development of skin lesions and bilateral knee arthritis for two weeks that worsened over four days, with night sweats episodes without quantified fever. The patient had traveled to Thailand on October 2010, during a heavy rain period. One month after arriving home, the patient developed a left sciatic pain resistant to analgesic therapy with a normal lumbar spine CT scan. Three weeks before admission to Hospital da Luz, the patient noticed a left lumbar mass and pustular lesion in the chin. One week later, the patient went to a dermatology consultation, after noticing ulcerated lesions on the outer side of the right arm and leg, and was treated with amoxicillin/clavulanic acid and mupirocin for five days, with partial resolution of the ulcerated lesions. Four days before admission, the patient started feeling pain in both knee and ankle joints, with edema and inflammatory signs. With continuing complaints of left sciatic pain and left lumbar palpable mass, the patient went to the hospital Emergency Service (in Hospital Luz) in January 2011. On examination the patient had a left palpable lumbar mass with 15 cm in greater diameter, arthritis of both knees and two skin lesions on the right leg suggestive of erythema nodosum. Laboratory results showed a mild anemia and elevated inflammatory parameters. Abdominopelvic CT scan showed a left gluteal abscess (14 x 11 cm) with left ilium bone osteomyelitis and a smaller contralateral gluteal abscess (5 cm). B. pseudomallei was isolated from the patient's blood as well as from the left gluteal abscess. Identification was made in Vitek 2 system (bioMerieux) and species identity was subsequently confirmed by a probe-based real time PCR assay. The patient was treated with intravenous meropenem for 14 days, as recommended for treatment of patients with complications during the acute phase, and regression of the knee and ankle arthritis and skin lesions. Considering the finding of resistance of the patient's B. pseudomallei strain (here designated as PtBps01) to the first-line eradication-phase therapy trimethroprim/sulfamethoxazole (SXT), which is infrequently described, the patient was discharged with the recommended alternate oral antimicrobial therapy with amoxicillin/clavulanic acid. Right gluteal abscess was drained after two months of treatment and eradication therapy was maintained for a total period of seven months, until full resolution of the infectious process. To perform the full genome characterization, the strain PtBps01 was subject to whole genome sequencing on a MiSeq Ilumina platform (Illumina Inc., San Diego, CA, USA), and comparative genomics against fully-sequenced B. pseudomallei strains available in GenBank representative of several genome groups was performed. Globally, the draft genome of PtBps01 harbors 7,117,230 bp with an average GC-content of 68.2%. Both core- and pan-genome phylogenetic analyses grouped PtBps01 with isolates from Southeast Asia, suggesting the Thai origin of this Portuguese isolate. It appears to be most genetic relatedness to the previously characterized Thai 1106a isolate, exhibiting >99% of similarity in the core genome. PtBps01 accessory genome revealed two putative intact prophages of 40.7Kb (%GC 64.6) and 25.1Kb (%GC 66.0), both comprising 30 predicted CDSs revealing homology with other Burkholderia phage sequences. No putative plasmids were found in PtBps01. The putative genetic basis for the observed unusual STX resistance was also investigated, in particular those involving the BpeEF-OprC efflux pump as it was already shown to confer resistance to STX. However, only three synonymous changes (one in bpeE at 1014 bp and two in bpeF at 120 bp and 153 bp) in PtBs01 isolate were found, suggesting that antimicrobial resistance is governed by unidentified regulatory mechanism(s). Full-genome sequence was also used to extract loci sequences for MLST analysis, revealing the allelic profile 1-4-2-3-8-4-3, which corresponds to sequence type (ST) 376. Based on public B. pseudomallei MLST databases, no European isolate reported so far displayed such ST profile. The ST376 seems to be restricted to Southeast Asia, as it was previously observed in water samples collected in the 1960s in Thailand, as well as in human isolates obtained in 2012 from a Laotian melioidosis patient with suppurative parotitis and two Malay patients with bacteremia.

burkholderia pseudomallei, melioidosis, whole genome sequencing

PMC7530217_01

Male

A 39-year-old male, chronic alcoholic presented to surgical outpatient department (OPD) with the chief complaints of pain in the left upper abdomen along with difficulty breathing for seven days. Pain was insidious in onset, dull aching type with no any relieving factors. Breathing difficulty was associated with productive cough, whitish in color, non-foul smelling and not mixed with blood. Cough was followed by lower chest pain in the left side. Also, there was a history of loose motion for four days, 3-4 times/day not mixed with blood or mucus. There was no history of fever, burning micturition, headache, dizziness, orthopnea or paroxysmal nocturnal dyspnea (PND). On examination, the patient looked ill. Icterus was present. Vitals were within normal limit except for respiratory rate (RR) which was 24 breaths/min. Spo2 was 92% in room air. Chest examination showed decreased air entry on left lung field with dullness appreciated while on percussion. Abdominal examination revealed tenderness on left hypochondriac region with splenomegaly around 3 cm below left subcoastal area along with enlarged liver around 7 cm below right subcoastal margin. Laboratory parameters showed hemoglobin (Hb) 10 gm/dl, Erythrocyte Sedimentation Rate (ESR)- 25 mm/1 st hour, Total Leucocyte Count (TLC)- 35,800/mm3 with neutrophilia (88%), prothrombin time (PT): 30 s with International Normalized Ratio (INR)- 2.07. Renal Function Test (RFT) was normal. HIV, HBSAG, HCV serology were negative. Stool examination along with WIDAL test was normal. Liver Function Test (LFT) showed total bilirubin 3.4 mg/dl, direct bilirubin 2.1 mg/dl, Alanine Amino Transferase (ALT) -15 U/L, Aspartate Amino Transferase (AST)- 40 U/L and Alkaline Phosphatase (ALP)- 216 U/L. Ultrasonography abdomen and pelvis showed enlarged liver and spleen with echogenic fluid noted in peri splenic region with no vascularity and low-level echoes floating within it. Free fluid was noted in the peritoneal cavity along with echogenic free fluid in left pleural space. Chest X ray showed complete white out lung field on left side (Fig. 1). Chest tube drain was inserted on the left chest, which drained around 1500 ml of pus. Contrast enhanced computed tomography (CECT) abdomen showed splenomegaly (14 cm) with non-enhancing hypodense collection of mean HU 14 measuring 6.3 x 3.3 x 5 cm (approx. 54 ml) in the inferior pole of the spleen with peri splenic extension along with irregularity at lower pole suggesting parenchymal origin of the abscess. Liver was enlarged (19 cm), portal vein diameter of 16 mm with left sided pleural effusion with collapse of posterior basal segment of left lung along with mild right sided pleural effusion and minimal pericardial effusion (Fig. 2a and b). Pleural aspirate analysis showed total cell count of 120,000/mm3 including leucocytes of 1,10,000/mm3 and red blood cells (RBC) 10,000/mm3 with polymorphs 85%, lymphocytes 15%, sugar 20 mg/dl, protein 3.2 gm/dl, albumin 2.3 gm/dl and fluid adenosine deaminase (ADA) of 90. Pleural fluid gram stain revealed few gram-positive cocci in pairs and chains whilst culture analysis showed Streptococcus pyogenes sensitive to ampicillin, azithromycin, cefotaxime and ceftriaxone. Tuberculosis workout including Mantoux, sputum acid fast bacilli (AFB) and gene expert from pleural fluid was negative. USG guided splenic abscess was aspirated, that revealed around 30 ml of pus initially followed by second aspiration of 10 ml the next day. Splenic abscess culture was sterile. The patient was managed with Ceftriaxone/Sulbactam along with Vancomycin and azithromycin according to culture sensitivity reports. Chest X ray gradually improved along with the condition of the patient (Fig. 3). Chest tube removal was done on 5th day of insertion. The patient got discharged on 8th day of admission.

empyema thoracis, splenic abscess, streptococcus pyogenes

PMC5838848_01

Female

A 47-year-old female presented to our outpatient department with complaints of drooping of the right eyelid and painless swelling of the right cheek for 1 year. She also complained of difficulty in mouth opening for the past 6 months. The swelling had been progressively increasing and showed no postural variation or pulsatility. The mouth opening was restricted to less than 1 finger, and the patient could drink only liquids using a straw. At the time of presentation, she did not give any history of fever or past medical history of diabetes, high-risk behavior, heart problems, or any other conditions that would predispose her to an intracranial infection. On examination, the swelling was nontender, hard diffuse without any clear margins or defined edges. It was arising from the maxilla and was not independently mobile off the same. The right eye proptosis was axial and nonpulsatile with no extraocular movement restriction. The vision was 6/24 in both eyes on Snellen's chart. Rinne's test showed that the right ear had no air or bone conduction while on the left side air conduction was more than bone conduction. Weber test was lateralized to the left side. Rest of the examination was unremarkable. Laboratory investigations were normal. After clinical evaluation, a large lesion involving the maxilla, orbit, and temporal base with extension to the middle ear was suspected of the possibility of slow-growing neoplasm being a possibility. She underwent a computed tomography (CT) scan, which showed diffuse hyperostosis of the right frontal, squamous temporal, sphenoid and zygomatic bones, and an en-plaque ground glass lesion, involving the basitemporal bone [Figure 1a and b]. On magnetic resonance imaging (MRI), lesion showed a T1 hypointense and T2 hyperintense contrast-enhancing extra-axial lesion located in the right frontotemporal bone with dural thickening and possible brain parenchymal involvement [Figure 1c and d]. Extension was also noted into the right temporomandibular joint and maxillary sinus and orbit, explaining her clinical presentation. Diagnosis of an en-plaque meningioma was suspected and she underwent a right frontotemporal craniotomy and complete excision of the intracranial lesion and partial decompression of involved areas of bone [Figure 1e], with areas of dural involvement [Figure 1f] being reconstructed with a Fascia lata graft taken from the right thigh. Intraoperative frozen section revealed a granulomatous lesion, and hence, aggressive resection was avoided. Postoperatively, the patient was conscious and without any fresh neurological deficits. Due to the endemic nature of tuberculosis in India and squash report of pathology, diagnosis of tubercular granulomatous inflammation was made and the patient was started on antitubercular drug therapy and discharged on antitubercular therapy with a hospital stay of 5 days. She was also put on antiepileptic drugs (Phenytoin) for prevention of postoperative seizures and steroids to counteract tubercular arteritis. Human immunodeficiency virus (HIV) was negative on repeated testing from two different centers. However, she reported back to the emergency 3 days after discharge in an unconscious state. According to the relatives, patient was complaining of mild headache since the time of discharge, and on the 3rd day after discharge, in the morning patient was found unconscious in her bed. At the time of presentation, patient vitals were not recordable, her GCS was 3/15, with bilateral pupils nonreactive and fixed. She was immediately given cardiopulmonary resuscitation, but could not be revived despite aggressive resuscitative measures. The exact cause of death could not be ascertained, but could be flare up of the primary disease as later seen in brain autopsy. Subsequent histopathological analysis revealed a suppurative granulomatous inflammatory pathology with dense fibrosis of the stroma. The thickened fibrotic dura showed multiple discrete and confluent suppurative microabscess rimmed by histiocytes and granulomatous inflammatory cells along with multinucleate giant cells (foreign body type). Many of the microabscesses showed colonies and collections of slender filamentous bacteria with evidence of neutrophilic reaction. Rest of the stroma showed dense fibrosis with scattered lymphoplasmacytic infiltrate and reactive blood vessels. The adjacent brain parenchyma included showed cerebritis. The colonies were highlighted on Grams stain and Gomori methenamine silver stain. Staining for acid-fast bacilli was negative for tubercular and Nocardia species. These findings on histopathological examination resulted in the final diagnosis of a chronic necrotizing granulomatous inflammation with Actinomyces-like organisms [Figure 2]. Partial autopsy limited to the removal of brain revealed presence of bacterial colonies with a suppurative granulomatous inflammation, as seen in the biopsied tissue. There were no other lesions on the external examination at autopsy.

abscess, actinomycosis, cranial infection, en-plaque, pachymeningitis

PMC9709338_01

Male

A 79-year-old male patient was admitted to the Respiratory Department of our hospital on August 15, 2022, because of fever, cough, sputum production and dyspnea after cold. On July 8, 2022, the patient underwent coronary angiography in the Cardiology Department of our hospital due to coronary artery disease, and a stent was implanted in the right coronary artery. The patient regularly took aspirin enteric-coated tablets, clopidogrel bisulfate tablets and atorvastatin calcium tablets. Other past medical conditions included hypertension, atrial fibrillation, and tuberculosis. The patient's allergic history included iodine (allergic reaction was local skin erythema papules) and "cephalosporins" (allergic reaction was urticaria in the limbs), but the patient had been repeatedly infused with cefazoxime, cefpilamine, ceftazidime and other drugs, no allergic reaction occurred. On the morning of August 23, 28 minutes after the injection of cefoperazone-sulbactam, the patient developed numbness in the extremities, chest tightness, palpitations, flushing of the skin in the extremities and body, progressive loss of consciousness, wheezing, sweating, and cyanosis of the lips. The bedside ECG monitor showed: heart rate of 80 beats per minute, with blood pressure and oxygen saturation being undetectable. The respiratory physician considered that the patient had developed severe anaphylactic shock. Then, them immediately stopped the suspicious fluid infusion, opened the airway, administered epinephrine 1 mg (again 1 mg after 5 minutes), with rapid infusion of sodium chloride injection 1,000 ml and methylprednisolone sodium succinate 40 mg. ICU physicians immediately established central venous access and tracheal intubation upon arrival, maintained blood pressure with norepinephrine and epinephrine, and assisted the patient's breathing with an invasive ventilator. The patient was then transferred to the ICU on advanced life support. Her blood pressure on arrival at the ICU was 92/52 mmHg (at this point the norepinephrine and epinephrine doses were 1.25 and 0.83 mug/kg/min, respectively), but the patient was extremely hemodynamically unstable, and bedside cardiac ultrasound suggested poor cardiac contractile function and left ventricular ejection fraction only 25% (Figure 1). What's worse, the patient's norepinephrine dose was increased to 3.5 mug/kg/min, and ventricular fibrillation occurred frequently. The ICU physician immediately treated the patient with veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and intra-aortic balloon pump (IABP). After admission to ICU, 18-lead electrocardiogram (ECG) showed a new left anterior fascicular block, the ST segment of lead I, aVL, V2-V6 depression 0.1-0.3 mV, and the ST segment of lead II, III, avF, V3R-V5R elevation 0.10-0.20 mV (Figure 2). Serum cardiac troponin I was 22.35 ng/mL (normal range 0-0.05). Upon completion of our consultation with the cardiologist, the patient was considered to have had an acute myocardial infarction, which required urgent percutaneous coronary angiography (the right coronary angiography results 1 months earlier was shown in Figure 3A). The results showed stent shadow in the proximal and middle segments of the right coronary artery, mild intimal hyperplasia in the stent, complete occlusion in the middle, and myocardial infarction (TIMI) flow of grade 0 (Figure 3B). Right coronary artery lesions were pretreated with 2.0 mm x 20 mm pre-dilated balloon and 3.0 mm x 10 mm open balloon, and then percutaneous transluminal coronary angioplasty was performed with 3.5 mm x 30 mm balloon into the stent. Re-angiography showed no stenosis in the right coronary stent and TIMI flow of grade 3 (Figure 3C). The patient was sent back to ICU after completion of surgery. By then, the postoperative ECG showed that ST-segment elevation of lead III and avF was 0.05-0.1 MV (Figure 4). Laboratory tests suggested a serum immunoglobulin E concentration of 290 IU/ml (normal range 0-165). The diagnosis of type III Kounis syndrome with cardiogenic shock was made, and the condition manifested as acute ST-segment elevation myocardial infarction caused by allergic stent thrombosis. After from percutaneous coronary intervention, the patient continued to receive ECMO combined with IABP, norepinephrine, epinephrine and other drugs. However, the patient's heart function did not recover and he died seven days later. Cause of death: cardiogenic shock.

kounis syndrome, allergy, cardiogenic shock, case report, cefoperazone-sulbactam, intra-stent thrombosis

PMC3959392_01

Female

A 65-year-old female presented to our clinic with a two-month history of painless progressive jaundice with pruritus and clay colored stools, anorexia and weight loss. On examination she had icterus and a palpable gallbladder which was cystic in consistency. She had normal hematological parameters. Serum bilirubin was 16.9 mg/dL (0.2-1.1 mg/dL) with a conjugated fraction of 13.3 mg/dL, serum alkaline phosphatase was 678 IU/mL (<128 IU/mL), serum aspartate aminotransferase (AST) was 76 IU/mL (<35 IU/mL) and serum alanine aminotransferase (ALT) was 57 IU/mL (<40 IU/mL). She had normal coagulation parameters. Transabdominal ultrasound showed hugely distended gallbladder, dilated common bile duct up to its lower end along with dilated intrahepatic biliary radicles (IHBR). CECT of the abdomen showed dilated pancreatic duct and biliary system. However, a definite cause of the distal obstruction could not be identified. Side viewing endoscopy showed a bulky ulcerated papilla. Biopsies from the papilla showed adenocarcinoma of the ampulla. PET-CT scan was done to look for metastatic disease before surgery. It showed increased [18F]-Fluoro-Deoxy-Glucose (FDG) tracer uptake in the periampullary region (SUV max 4.1) (Fig. 1) as well as in the enlarged subcarinal nodes (SUV max 14.7) (Fig. 2). There were no positive loco-regional lymph nodes on PET-CT scan. Endoscopic ultrasound (EUS) showed a small hypoechoic lesion in the ampullary region with dilated common bile duct and IHBR (Fig. 3). Also large hypoechoic subcarinal nodes with echogenic foci were noted (Fig. 4, 5) and fine needle aspiration of the node was done using a 22 Gauge needle (EchoTip, Wilson-Cook, Winston-Salem, North Carolina, USA) was performed (Fig. 5). Cytological examination of the aspirate showed granulomatous inflammation consistent with tuberculosis. Stain for AFB was negative but PCR (polymerase chain reaction) was positive for Mycobacterium tuberculosis. She underwent pancreatioco-duodenectomy and achieved complete resection. Following six months of tuberculosis treatment she improved and is asymptomatic after 1 year of follow up.

adenocarcinoma, endoscopic ultrasound, lymph node, pancreas, tuberculosis

PMC4061443_01

Male

A 44 year-old male former heavy smoker was referred to our hospital for an abnormal chest radiograph and cough. He reported productive cough, fevers and night sweats for three weeks. On review of systems he had an unintentional weight loss of 40 lbs over the previous four months. He never had a tuberculin skin test (TST) and denied tuberculosis contacts or wheezing. He was originally from Ecuador and had a history of right lower lobe pneumonia in the previous two years. A TST placed on admission was positive (20 mm). Decreased breath sounds on auscultation and dullness on percussion were appreciated at the right base. Blood tests revealed only mild leukocytosis (13,300 cells/uL) without bandemia. His basic metabolic panel and liver function panel results were unremarkable. The patient's posteroanterior and lateral chest radiographs are shown in Fig. 1A-B. Chest CT images (axial and coronal views) are shown in Fig. 2A-B. Pulmonary function tests were normal. Flexible bronchoscopy showed a smooth round white polypoid lesion with wide base at the distal end of bronchus intermedius almost completely occluding the lumen (Fig. 3). White thick mucoid substance could be seen exuding from the right middle lobe bronchus. Our patient underwent bilobectomy and a biopsy of the polypoid lesion is shown in Fig. 4A-B. The diagnosis of an endobronchial leiomyoma causing complete obstruction of bronchus intermedius was made.

endobronchial tumor, leiomyoma

Chest CT scan reveals an endobronchial lesion (asterisk) in the bronchus intermedius with complete atelectasis of right lower lobe and a small pleural effusion. A, Axial window.

PMC4061443_01

Male

A 44 year-old male former heavy smoker was referred to our hospital for an abnormal chest radiograph and cough. He reported productive cough, fevers and night sweats for three weeks. On review of systems he had an unintentional weight loss of 40 lbs over the previous four months. He never had a tuberculin skin test (TST) and denied tuberculosis contacts or wheezing. He was originally from Ecuador and had a history of right lower lobe pneumonia in the previous two years. A TST placed on admission was positive (20 mm). Decreased breath sounds on auscultation and dullness on percussion were appreciated at the right base. Blood tests revealed only mild leukocytosis (13,300 cells/uL) without bandemia. His basic metabolic panel and liver function panel results were unremarkable. The patient's posteroanterior and lateral chest radiographs are shown in Fig. 1A-B. Chest CT images (axial and coronal views) are shown in Fig. 2A-B. Pulmonary function tests were normal. Flexible bronchoscopy showed a smooth round white polypoid lesion with wide base at the distal end of bronchus intermedius almost completely occluding the lumen (Fig. 3). White thick mucoid substance could be seen exuding from the right middle lobe bronchus. Our patient underwent bilobectomy and a biopsy of the polypoid lesion is shown in Fig. 4A-B. The diagnosis of an endobronchial leiomyoma causing complete obstruction of bronchus intermedius was made.

endobronchial tumor, leiomyoma

Chest CT scan reveals an endobronchial lesion (asterisk) in the bronchus intermedius with complete atelectasis of right lower lobe and a small pleural effusion. B, Coronal lung window.

PMC10102933_01

Male

A 35-year-old man with uncomplicated well-controlled HIV on bictegravir, emtricitabine, and tenofovir alafenamide presented to the emergency department with multiple facial lesions for 7 days. The first lesion was a small pustular "bump" on his lip. He subsequently developed 4 more lesions on his lips and chin before seeking an evaluation by a physician. Lesions were flesh-colored with a central concavity and small pustular discharge (Image 1). They were non-pruritic and non-tender. Concurrent with the onset of these lesions, he also developed mild right-sided submandibular pain associated with lymphadenopathy. The patient identifies as bisexual with a history of oral and anal intercourse. The last sexual contact was 2 months prior. He then traveled to Hawaii 3 weeks prior to the index presentation and attended a large public gathering. Lesions were swabbed for mpox virus using viral culture media and sent to a contracted commercial reference lab for qualitative PCR testing. He returned home to self-isolate. Results were available after 4 days. The reference lab notified the local public health department per Laboratory Response Network protocol. Public health officials informed the patient's infectious disease physician who arranged a clinic visit following infection control precautions as recommended by the CDC. At the clinic visit, his original facial lesions had increased in size and central crusting (Image 2). He had also developed a new diffuse maculopapular rash on the neck, chest, and torso with a herald patch on the right chest (Image 3). Early eczema versus secondary syphilis was the concern at this time. His lymphocyte CD4 count was 588 per cubic millimeter (reference range, 500-1500), and his HIV viral load was undetectable. After the patient was provided informed consent for use of tecovirimat for treatment of non-variola orthopox virus infection under CDC Expanded Access Investigational New Drug Protocol No. 116 039 (IRB No. 6402), he was started on tecovirimat 600 mg twice a day for 14 days. A small supply had already been arranged by the pharmacy department in coordination with the CDC, California Department of Public Health, and Kern County Public Health Department a few weeks in advance for possible local outbreaks. Co-infection testing eventually revealed reactive syphilis antibody, reactive Fluorescent Treponemal Antibody Absorption test, and reactive Rapid Plasma Reagin test (RPR) with titer 1:1. Through California Reportable Disease Information Exchange, no prior treatment history for syphilis was found. Syphilis was staged as secondary syphilis. He was treated with 2.4 million units of benzathine penicillin G intramuscularly once. Urine gonorrhea and chlamydia nucleic acid amplification testing was negative. At follow-up 1 week (Images 4 and 5) and 3 weeks (Images 6 and 7) after treatment initiation, he showed improvement and subsequent resolution of all symptoms. Isolation was lifted after all lesions had resolved, 4 weeks after symptom onset.

hiv, mpox, non-variola orthopoxvirus, syphilis

PMC6057304_01

Male

The patient in this case was a 25-year-old obese male with a past medical history of borderline hypertension and diabetes well controlled with medication and a moderate level of physical activity that heard a pop in his knee after playing basketball. The patient ignored his knee injury until 5 months later when he presented to a clinic with instability in his knee, inability to fully straighten his leg, and anterior knee pain with flexion. On physical exam, the patient's preoperative range of motion was 10 to 100 degrees. The patient began experiencing anterior knee pain and tightness after 90 degrees of flexion. The patient is brought to the operative suite and positioned supine on the operating room table, and general anesthesia is induced. Prior to draping, the contralateral knee is placed in 60 degrees of flexion, and the length of the native patellar tendon is measured (4.5 cm in the case pictured). The operative extremity is prepped and draped to the proximal thigh. A sterile triangle is placed to hold the knee in 60 degrees of flexion. The distance between the inferior pole of the patella and the tibial tubercle is then measured on the injured extremity (8.0 cm). A sterile tourniquet is applied to the thigh but will only be inflated if needed. A midline longitudinal incision is made from the superior pole of the patella to the tibial tubercle through the skin and subcutaneous tissue. The underlying fascia is identified and incised longitudinally. The peritenon is identified superiorly, and the peritendonous flaps are elevated to reveal the chronic, scarred patellar tendon rupture (approximately 3.5 cm in the midsubstance of the tendon) (Figure 1(a)). The scarred portion of the tendon is debrided along with any redundancy of the medial and lateral retinacula. A Cobb elevator is used to release the superficial and deep aspects of the quadriceps tendon from the surrounding tissues (Figure 1(b)). The vastus medialis is left intact, and the surgeon ensures that the patella can be reduced to its native position at 60 degrees of flexion as measured on the contralateral knee preoperatively. A four-stranded end-to-end repair is then undertaken using a #5 FiberWire (Arthrex, Naples, FL) in a Krackow fashion (Figure 2(a)). A #2 FiberWire (Arthrex, Naples, FL) is used in a running-locking fashion to imbricate the elongated medial and lateral retinacula and oversew the tendon repair (Figure 2(b)). Next, the semitendinosus autograft is harvested. The insertion of the pes anserine is visualized through the same incision, and the semitendinosus tendon is identified and detached from its insertion. Once rid of adhesions, the tendon is harvested in standard fashion with a closed tendon harvester. The graft is prepared on the back table with both ends tied in a Krackow manner using #2 FiberWire sutures and then sized when doubled (6.5 mm). A tibial bone tunnel is created using an appropriately sized (6.5 mm) cannulated reamer (Arthrex, Naples, FL), 3 cm distal to the tibial tubercle and 2 cm posterior from the anterior tibial crest (6.5 x 40 mm). The graft is passed through the bone tunnel from medial to lateral and courses along the lateral aspect of the native patellar tendon. Small rents are created in the medial and lateral retinacula at the level of the superior pole of the patella, and the graft is woven transversely through the distal quadriceps tendon from lateral to medial. The graft is then brought down along the medial border of the native patellar tendon and passed through the bone tunnel from lateral to medial. The free ends cross in opposite directions within the tibial bone tunnel and are secured using interference screws (Tenodesis Screw, BioComposite, 6.25 x 15 mm; Arthrex, Naples, FL):one from medial to lateral and one from lateral to medial (Figure 3(a)). Finally, an InternalBrace (Arthrex, Naples, FL) is used to augment and protect the reconstruction. Two 4.75 x 15 mm SwiveLock BioComposite suture anchors (Arthrex, Naples, FL) are placed into the distal pole of the patella securing the midpoint of one 2 mm FiberTape suture tape (Arthrex, Naples, FL) each. The free limbs of the FiberTape cross the repair site:one limb straight inferior and the other in an "X" fashion:and are then secured to the tibial tubercle using two 4.75 x 15 mm SwiveLock BioComposite suture anchors (Figure 3(b)). The tension of the InternalBrace is set such that the knee can be passively flexed to 90 degrees. The wounds are thoroughly irrigated, closed, and dressed in the surgeon's usual sterile fashion. The patient was placed in a locked hinged knee brace and instructed to bear weight as tolerated with crutches in extension for 6 weeks. A supervised physical therapy program lasting 4 months was recommended. At 6 weeks, the patient was able to perform passive and active flexion to 90 degrees. At 12 weeks, the patient discontinued the brace and began zero-resistance straight leg raise exercises, as recommended. The patient began quadriceps strengthening at 12 weeks and ultimately should return to impact cardiovascular activity after 20-24 weeks. This current patient has had a six-month follow-up. He has active range of motion from 0-120 degrees with no extensor lag and has returned to sporting activity.

PMC8203073_01

Female

A 7-year-old girl with Noonan syndrome (NS) presented with a history of recurrent haemoptysis. She was diagnosed with pulmonary stenosis at the Paediatric Cardiology Department at Chris Hani Baragwanath Academic Hospital (CHBAH) and was treated with a transannular patch at the age of 6. She had severe pulmonary regurgitation following the surgery and was on treatment with furosemide, potassium chloride and digoxin. She presented to her local hospital with a history of coughing up fresh red blood a year after undergoing surgery. The parents could not quantify the amount of blood; however, it was thought to be significant because she had a haemoglobin level of 7.5 g/dL and required a transfusion of packed red blood cells. It was reported that she had two other episodes of haemoptysis 11 months prior but did not seek medical attention. She was airlifted to CHBAH for further management. On arrival, she was noted to be in respiratory distress and was put on 60% O2 via a rebreathing mask. She was pink and well perfused. She had an early diastolic murmur of pulmonary regurgitation. Detailed echocardiography excluded pulmonary hypertension and pulmonary vein stenosis. Laboratory investigations showed haemoglobin (11 g/dL), platelets (235 x 109 cells/L), international normalised ratio (1.02) and prothrombin time (34). She was HIV-negative and had normal urea and creatinine levels. She had a von Willebrand factor antigen of 34% (normal range 50 - 160%) and activity of 88% (normal range 66 - 99%) and her Factor VIII level was 52 IU/dL. Her sputum showed no acid-fast bacilli, a Mycobacterium tuberculosis culture was negative and no other pathogenic bacteria were isolated. A computed tomography (CT) scan of the chest showed a right lower-lobe dense consolidation, which was thought to be due to lobar pneumonia (Fig. 1). She had a rigid bronchoscopy, which also showed an inflammatory polyp at the entrance to the posterior basal segment of the right lower-lobe bronchus (Fig. 2). The inflammatory polyp and lobar pneumonia were thought to be the cause of the haemoptysis, which was exacerbated by her underlying haematological abnormalities. She was treated with antibiotics and discharged home. A repeat bronchoscopy 3 months later showed that the polyp had significantly decreased in size. She presented to the local hospital 2 weeks after the repeat bronchoscopy with another episode of massive haemoptysis, where she was resuscitated with fresh frozen plasma and a platelet transfusion. She was airlifted to CHBAH after stabilisation. A repeat bronchoscopy was done, but the patient had massive haemoptysis during the procedure and required resuscitation and intensive care admission for mechanical ventilation. She was referred to the cardiothoracic team for lobectomy to control the haemoptysis. She continued to have more episodes of haemoptysis while awaiting surgery. Rigid bronchoscopy was done and did not reveal a polyp. She had a cardiac catheterisation for further investigation of the haemoptysis and an angiogram showed a torturous right bronchial artery, with extravasation of blood into the right lower lobe. The patient was referred for embolisation of the torturous bronchial artery. A descending aorta angiogram in the anterior-posterior view confirmed the findings (Fig. 3). The prominent bronchial artery formed a confluence with an abnormal vessel that arises from the right common carotid artery She had a right bronchial artery embolisation and was stable post procedure. That evening she bled again during rigid bronchoscopy. The decision was taken to do a lobectomy to control the bleeding. The histology of the resected lobe showed normal lung parenchyma, with patchy bronchopneumonia, alveolar haemorrhage and fibrointimal hyperplasia of the hilar vessels. The bronchus at the resection margin was normal and patent. There was no granulomatous inflammation or malignant neoplasm. The patient had an uneventful course post lobectomy, and after 6 months follow-up there was no further bleeding reported.

noonan syndrome, bronchial artery, haemoptysis, polyps

PMC8044568_01

Male

A 7-year-old neutered male Siamese cat was presented to a university referral hospital in Scotland for weight loss and hyporexia of 1 month's duration, as well as hypercalcaemia (3.3 mmol/l; reference interval [RI] 2-3 mmol/l) detected by the referring veterinarian. Defaecation, thirst and urination were normal. The cat was fed a good-quality commercial diet, and routine vaccinations and prevention against external and internal parasites were up to date. It was an indoor/outdoor cat and an avid hunter (Figure 1), with no travel history outside of Scotland. On physical examination, the cat had harsh lung sounds with a normal respiratory rate (25 breaths/min) and effort; the remainder of the physical examination, including a retinal examination, was unremarkable. Differential diagnoses for hypercalcemia included granulomatous disease, neoplasia, hypervitaminosis D, renal disease, primary hyperparathyroidism, idiopathic hypercalcaemia, osteolysis or hypoadrenocorticism. Weight loss could be caused by hyporexia, maldigestion, malabsorption, chronic infection or inflammation, renal or hepatic disease, neoplasia, cardiac or - less likely - endocrine disease, including hyperthyroidism (the cat was relatively young for this), diabetes mellitus (polyuria, polydipsia and polyphagia would be expected) or hypoadrenocorticism (rare in cats); underfeeding, poor-quality diet and oral disease had been excluded. Harsh lung sounds could indicate pneumonia, primary or metastatic neoplasia or - less likely - idiopathic pulmonary fibrosis, pulmonary oedema or contusions. Hyporexia is a non-specific clinical sign; in the absence of oral/nasal disease or environmental stress, hyporexia could indicate systemic disease, nausea or pain. Haematology, serum biochemistry (including thyroxine) and urine analysis were unremarkable, except for hypercalcaemia (ionised calcium [iCa] 1.75 mmol/l [RI 1.1-1.35 mmol/l]; Table 1). Ionised hypercalcaemia was confirmed with a repeated blood sample, and there was no haemolysis or lipolysis. Feline immunodeficiency virus antibody and feline leukaemia virus antigen were negative, and blood pressure was normal. Further investigations of hypercalcaemia (Table 2) included plasma parathyroid hormone concentration (<10 pg/ml [RI <40 pg/ml]; not supporting hyperparathyroidism), plasma parathyroid hormone-related protein (<0.1 pmol/ml [RI <0.5 pmol/ml]; not supporting neoplasia, although there are other mechanisms by which neoplasia could result in hypercalcaemia), 25-hydroxyvitamin D (95 nmol/l [RI 127-335 nmol/l]; not supporting most types of hypervitaminosis D) and serum toxoplasma IgG and IgM titres (<50 and <20 [RI <50 and <20, respectively]). Abdominal ultrasound and radiographs were unremarkable. Thoracic radiographs (Figure 2) revealed a diffuse, interstitial-alveolar pattern, most marked on the caudal lung lobes. Differential diagnoses included infectious pneumonia (bacterial, parasitic, protozoal, viral or fungal), primary or metastatic neoplasia or, less likely, idiopathic pulmonary fibrosis. The spine and vertebrae were carefully examined in all radiographs for the presence of osteolytic lesions, and none were found. The patient received treatment for possible lungworms (Advocate; Bayer) and underwent bronchoscopy. The airways appeared macroscopically normal; bronchoalveolar lavage fluid (BALF) was sent for routine bacterial and fungal culture (which were negative), Mycoplasma felis PCR (this was negative) and cytology (which showed severe pyogranulomatous inflammation). In addition to routine haematoxylin and eosin staining, the BALF was stained with Grocott methenamine silver to evaluate the presence of fungi (negative) and Ziehl-Neelsen (ZN), which showed acid-fast bacilli morphologically consistent with mycobacterial infection. The interferon gamma release assay (IGRA) was performed, and the results were compatible with infection by the less pathogenic member of the Mycobacterium tuberculosis complex (MTBC); that is, Mycobacterium microti ('the vole bacillus') (Figure 3). Combining clinical signs and results, the patient was diagnosed with pneumonia and hypercalcaemia caused by M microti; that is, the cat had a form of tuberculosis commonly seen in cats in certain UK regions, including Scotland. The patient was treated with rifampicin (Rifadin [Sanofi]; 10 mg/kg PO q24h), azithromycin (Zithromax [Pfizer]; 15 mg/kg PO q24h) and marbofloxacin (Marbocyl P [Vetoquinol]; 3 mg/kg PO q24h) for 2 months initially. A month after starting treatment, the cat's body weight and appetite had improved, and iCa was normal. After 2 months of triple antibiotic therapy, haematology, serum biochemistry and thoracic radiographs were unremarkable, and rifampicin was stopped. After an additional 4 months, iCa and thoracic radiographs were unremarkable, IGRA was negative and serum vitamin D concentration was now normal, and so azithromycin and marbofloxacin were stopped. The patient remained asymptomatic for 1 year but was infected with tuberculous pneumonia five more times - a total of six episodes over one decade (Figure 4). The cat was tested for retroviruses on several occasions and the results were always negative. The longest the cat was asymptomatic while not receiving treatment between episodes of tuberculous pneumonia was 2 years 4 months. The cat always presented with weight loss, pneumonia, hypercalcaemia and an IGRA result compatible with M microti. In the initial infections, the cat was treated with triple antibiotic therapy (rifampicin, azithromycin and a fluoroquinolone - marbofloxacin or pradofloxacin) for a minimum of 2 months, then double therapy (azithromycin and a fluoroquinolone) for a minimum of 4 months. The last two episodes of tuberculous pneumonia were treated with triple antibiotic therapy for 6 and 11 months, including pradofloxacin (Veraflox [Bayer], 5 mg/kg PO q24h) and combined rifampicin/azithromycin capsules (Rifampicin 35 mg/Azithromycin 30 mg Capsules [Bova Laboratories]; rifampicin 12 mg/kg PO q24h and azithromycin 10 mg/kg PO q24h). All six episodes were treated for at least 2 months beyond clinical resolution. The cat was monitored throughout using an awake CT scan using the VetMouseTrap (University of Illinois). In addition to the six episodes of tuberculous pneumonia, the cat has had two episodes of presumptive M felis pneumonia (based on a negative IGRA and deep pharyngeal swab positive for M felis by PCR with a low cycle threshold number, hence significant infection; treated with pradofloxacin, dosed as above, for 2 months); at the time of writing, the cat has developed pulmonary fibrosis.

m microti, mycobacteria, mycobacteriumtuberculosis complex, hypercalcaemia, pyogranulomatous, tuberculosis

PMC3579686_01

Female

A 17 year old Greek female was hospitalised in the ICU because of acute respiratory failure requiring mechanical ventilation. A degenerative central nervous system (CNS) disease, possibly post infectious encephalomyelitis (ADEM) was the underlying condition. Upon hospital admission the patient complained of headache, low back pain and fever. Within days, the patient progressively deteriorated with muscle weakness in the upper and lower extremities. The MRI of the brain was normal (Figure 1A), but the cervical and upper thoracic MRI revealed intramedullary inflammatory lesions extending from C3 to Th5 (Figure 1B). The patient was treated with high doses of corticosteroids (methylprednisolone 1gr per day for 4 days), with no response. Gradually, visual disturbances developed and the patient complained of dyspnea. An oxygen saturation of 85% was observed by pulse oxymetry, and oxygen administration (Venturi mask 50%) followed. Her condition rapidly deteriorated. The patient was intubated immediately, supported with mechanical ventilation and transferred to the ICU. (No spirometric evaluation or blood gas analysis was performed). Intravenous immune globulin (IVIG) treatment was administered (30 grams per day for 4 days). An MRI of the brain revealed diffused extensive lesions, mainly in brain stem and cerebellum, with a high T2 signal compatible with myelitis (Figure 2A). The MRI of the spine revealed extensive confluent lesions extending cranially up to the medulla oblongata and caudally to the middle of the thoracic spine (Figure 2B). CSF was abnormal (WBC = 240/ml, mainly lymphocytes, total protein = 750 mg/dl, glucose ratio CSF/serum = 45/92 mg/dl and no oligoclonal bands of IgG). CSF PCR examination was negative for HSV1,2, enteroviruses, n. meningitis, streptococcus pneumonia, listeria, haemophilus influenza, TBC. In the ICU no additional data was found by repeated cerebral MRI. Neutropenia developed and bone marrow examination was performed, which disclosed a normal bone marrow. The neutropenia probably was due to neutrophil's peripheral destruction, as the patient suffered from severe sepsis, due to ventilator associated pneumonia. All attempts to liberate the patient from the ventilator failed, as the patient could not use the intercostal muscles. A new CSF examination showed normal, serum NMO-IgG, ANA and ACE were negative. The patient underwent tracheostomy and gastrostomy. A month later, the patient's condition gradually improved, allowing her exemption from the ventilator. A new MRI of the brain was normal (Figure 3A) and most of the intramedullary lesions had vanished (Figure 3B). Her consciousness level improved. Some motion was observed in her arms. Although blindness remained in her right eye, gradual improvement allowed closure of tracheostomy and gastrostomy. However she could not move her lower extremities and had no sense of touch. During the last weeks of hospitalisation she had a persistent bacteriuria by multidrug resistant gram(-) bacteria. She also experienced a right pneumothorax, conservatively treated with success. Three years after discharge the patient is still paraplegic despite the resolution of the lesions in MRI. She complains of a bilateral loss in her senses of heat and touch at the level of the thighs.

PMC8459367_01

Male

An 18 year old male was presented after a high speed motor vehicle accident. The primary and secondary surveys revealed a Glasgow Coma Scale (GCS) of 15, abrasions on the chest and abdomen consistent with the seatbelt sign, and abdominal tenderness. Initial vital signs showed haemodynamic stability. A computed tomography scan (CT) of the chest, abdomen, and pelvis revealed an infrarenal abdominal aortic dissection, a peri-aortic retroperitoneal haematoma, and free fluid in the abdomen. Additionally, he also had a sternal fracture and three column fracture of the third lumbar vertebral body (L3) with bony retropulsion into the spinal canal, correlating with the level of the aortic injury. The initial CT also revealed focal narrowing of the coeliac artery (CA) at its origin, with opacification of the vessel distally, and patent superior and inferior mesenteric arteries. An emergency aortogram in the operating room confirmed an infrarenal aortic injury with active extravasation. A 23 mm x 70 mm long Endurant aortic cuff (Medtronic, Minneapolis, MN, USA) was placed, with resolution of the aortic extravasation. However, the patient continued to be hypotensive with no other obvious source of bleeding, which prompted an exploratory laparotomy. This revealed multiple small intestinal mesenteric tears and a 20 cm length of devascularised jejunum that was resected. The intra-operative examination and mesenteric Doppler evaluation confirmed adequate perfusion of the remaining small bowel. The patient improved haemodynamically, a primary bowel repair was performed, and he was transferred to the intensive care unit (ICU) for further care. By post-operative day six, the patient's laboratory values revealed an elevated aspartate transaminase (AST; 488 U/L [normal range 4-35 U/L]) and alanine transaminase (ALT; 1 174 U/L [normal range 6-55 U/L]). Total and direct bilirubin levels were 16.5 and 11.5 mg/dL, respectively, and the international normalised ratio was 1.4. His white blood cell count (WBC) and serum lactic acid level were normal. A CT angiogram (CTA) of the abdomen and pelvis showed severe focal stenosis of the proximal CA and superior mesenteric artery (SMA) with small bowel dilation, inflammation, and evidence of liver hypoperfusion. With a diagnosis of post-traumatic dissection of visceral arteries the patient was brought to the hybrid operating room for emergency revascularisation. On table bilateral saphenous vein mapping was done with a low threshold for conversion to open bypass surgery. A mesenteric angiogram via left brachial artery access confirmed severe stenosis in the proximal SMA (Fig. 1A) and CA (Fig. 2A). A 7 x 22 mm iCAST (Atrium, Hudson, NH, USA) covered balloon expandable stent was placed in the SMA and the CA stenosis was treated with two 8 x 20 mm and 9 x 20 mm self expanding non-covered Epic nitinol stents (Boston Scientific, Marlborough, MA, USA) accommodating the tortuosity of the CA at the dissection site. Completion angiography showed an excellent radiographic result with brisk flow in the SMA and CA (Figure 1, Figure 2B). For the remainder of his hospitalisation, the patient required decompression of the lumbar spine with vertebral fusion for spinal injuries resulting from the initial accident, and a right hemicolectomy and ileostomy for a presumed iatrogenic injury at the index abdominal exploration. Sixty-nine days after presentation, he was discharged to a rehabilitation centre with normalised gut function.

blunt mesenteric artery injury, coeliac artery injury, endovascular mesenteric injury repair, endovascular trauma management, vascular trauma

PMC4940980_01

Female

A 24-year-old Japanese woman with no notable past medical history presented with complaints of fever and nausea while she was traveling in Australia; within the previous 2 months, she had also traveled to India and Africa. She visited a local hospital in Australia, and the laboratory tests showed significantly elevated levels of transaminase, so she was checked for viral hepatitis. After excluding hepatitis A, B, and C, as well as other causes of hepatitis, it was revealed that the patient was positive for HEV-IgM. Since she was a visitor to Australia, she was sent back to Japan and was transferred to our hospital. During her stay in India and Africa, she ate most of her meals at local restaurants, and she sometimes drank tap water. Her initial vital signs revealed a blood pressure of 103/64 mmHg, heart rate of 84 beats/min, and body temperature of 36.4 C. Physical examination revealed jaundice with no tenderness over the right upper quadrant. The chest, extremities, and other systemic examinations were unremarkable. Laboratory investigations revealed an aspartate aminotransferase (AST) level of 1382 U/L, alanine aminotransferase (ALT) level of 2842 U/L, total bilirubin level of 4.8 mg/dL, and direct bilirubin level of 3.9 mg/dL. The test results were all negative for anti-nuclear antibody, anti-mitochondrial antibody, cytomegalovirus IgG and IgM, Epstein-Barr virus, and hepatitis A, B, and C antibodies; but the test for HEV-IgM was positive (Table 1). Her initial ultrasonography of the abdomen revealed splenomegaly (108 x 39 mm) and a small amount of ascites, but no signs of hepatomegaly or an enlarged gallbladder. According to the data above, HEV infection was diagnosed. She was treated with intravenous fluids with normal saline. On day 4, the patient complained of right upper quadrant pain. Ultrasonography of the abdomen showed 3 mm of a gallbladder wall; moreover, a physical examination detected tenderness over the right upper quadrant and positive Murphy's sign. Since the levels of transaminase and total bilirubin were gradually declining at that time, the enlarged gallbladder was left untreated, but closely followed up. However, the level of AST was elevated again at 980 U/L on day 7. In addition to the ultrasonographic findings, perivesical fluid accumulation and an edematous gallbladder wall (4 mm) had appeared (Fig. 1). There were no stones in the gallbladder. In addition, there were no other causes of acalculous cholecystitis. Pneumonia, acute pancreatitis, hepatic or subphrenic abscess, and right pyelonephritis were considered for the possible causes but were excluded from the diagnosis due to the fact that no evidence was shown on ultrasonographic findings, urinalysis, and chest X-ray. No antibiotics were administered for the cholecystitis. From day 9, the levels of transaminase and bilirubin began to decline even without the use of antibiotics. Blood culture was negative, and the procalcitonin level was within the normal range. Based on these findings, we assessed the cholecystitis was not caused by bacterial infection and decided not to administer any antibiotics. The edematous wall showed significant improvement on day 11 and had returned to normal by day 14. Since the patient did not complain of abdominal pain and the findings were gradually being recovered, it was not necessary to intervene surgically. The patient was discharged on day 16 because all of the symptoms had disappeared. The serum of the patient was tested to identify the genotype of the HEV at the Osaka Prefectural Institute of Public Health, and it was identified to be HEV genotype 1, OSN2015-5 (Fig. 2). It was confirmed by using SuperScript III-one step RT-PCR system with Platinum Taq (Invitrogen). From this case, two important clinical discoveries were made: (1) HEV can cause acalculous cholecystitis as an extrahepatic manifestation, and (2) it can recover without any antibiotics. First, HEV can cause acalculous cholecystitis as an extrahepatic symptom. It has been reported that HEV can cause pancreatitis, arthropathy, aplastic anemia, and Guillain-Barre syndrome as extrahepatic symptoms; however, acalculous cholecystitis has not been previously reported as a symptom of HEV. We performed a search of the MEDLINE database for the terms 'cholecystitis' and 'viral hepatitis E'. Three hits were found, but the contexts were unrelated to cholecystitis due to HEV. Hepatitis A virus infection is known to cause acalculous cholecystitis as a rare complication. Although further investigations of a larger number of cases are needed to clarify the matter, it is presumed that hepatitis A virus invades the endothelial cells of the gallbladder and bile duct and induces cell-mediated immunity. However, this is the first case report of acalculous cholecystitis as an extrahepatic manifestation of HEV. Second, the acalculous cholecystitis due to HEV infection could recover without any antibiotics. On the seventh day after admission, the level of serum AST was increased, and ultrasonography of the abdomen detected a thickened gallbladder wall without calculi and perivesical fluid accumulation; these met the criteria for acalculous cholecystitis. In general, the treatment options for acalculous cholecystitis are antibiotics, drainage, and/or operation. However, none of them were necessary in this case, and the patient recovered completely. According to the clinical course, the cholecystitis was secondary to HEV infection and recovered as the HEV infection resolved. Humans can be infected by four different genotypes of HEV: genotypes 1, 2, 3, and 4. HEV genotypes 1 and 2 are common and restricted to human. Individuals may become infected with HEV genotypes 1 and 2 from drinking contaminated water, so it was suspected that this patient became infected with HEV from drinking tap water in India. Genotype 1 is prevalent in the Indian subcontinent, Asia, the Middle East, and Africa. The latent period of HEV infection is approximately 6 to 8 weeks. Based on the travel history of the patient, it is possible that she became infected with HEV while she was in India. HEV infection does not affect only developing countries. HEV genotypes 3 and 4 are found in some industrialized countries. In addition, zoonotic transmission to humans is possible with HEV genotypes 3 and 4. Occasional foodborne outbreaks from the consumption of undercooked meat contaminated with HEV have occurred in Europe, North America, Japan, and New Zealand. Among the different genotypes, genotype 1 HEV infection can cause the most serious disease. As such, it is important to determine the genotype of the HEV infecting a patient to know the prognosis and to identify the source of the infection. We found that HEV can cause acalculous cholecystitis as an extrahepatic manifestation. In addition, the cholecystitis could be resolved without any antibiotics. As such, it is necessary to check for the presence of cholecystitis by using abdominal ultrasonography when a patient complains of upper abdominal pain, and laboratory tests show an elevated level of transaminase. In general, the treatment options for acute cholecystitis include antibiotics and operation; however, if the cholecystitis is induced by viral hepatitis, none of these options may be necessary. Further studies are needed to determine how often HEV infection causes cholecystitis.

acalculous cholecystitis, case report, genotype 1, hepatitis e virus

PMC5581851_01

Male

A 53 year old man with a history of substance abuse initially presented to an emergency room with complaints of progressive dyspnea. He was diagnosed with an acute exacerbation of chronic obstructive pulmonary disease (COPD) and discharged home. With worsening dyspnea, dry cough, and weight loss, he was hospitalized and started on levofloxacin along with corticosteroids. Due to a history of high risk behaviour, an HIV test was obtained which returned positive. Given the patient's hypoxia and demonstration of diffuse ground glass opacities on computed tomography (CT) of the chest [Fig. 1], a clinical diagnosis of PCP was made, and the patient was switched to intravenous (IV) trimethoprim-sulfamethoxazole (TMP-SMX) and corticosteroids. He remained in the hospital for about 3 weeks, continuing to require supplemental oxygen as well as non-invasive ventilation in the form of BiPAP (Bilevel Positive Airway Pressure). This prompted transfer to our institution, a tertiary care university hospital, for a possible need for an open lung biopsy. Upon presentation at our institution, he had no fever or hemodynamic instability. He appeared to be in moderate respiratory distress requiring BiPAP support. He had diffuse, coarse crackles on lung auscultation bilaterally. The rest of his examination was unremarkable except for the presence of skin tattoos and oral thrush. He reported a 37-pack-year smoking history and denied any alcohol abuse. He denied international travel or known exposure to anyone with tuberculosis. He reported that he had sex with men and prior history of IV methamphetamine use. He denied any known exposure to chemicals or toxic fumes. Differential diagnoses in this case included atypical infections such as Mycoplasma, Legionella, mycobacteria such as Mycobacterium avium complex (MAC), Mycobacterium tuberculosis, fungal etiology such as Cryptococcus or Histoplasma, and viral pneumonia including CMV, adenovirus, respiratory syncytial virus, or influenza virus. Drug-resistant Pneumocystis was also possible given the non-response to treatment. Non-infectious causes such as acute eosinophilic pneumonia, acute interstitial pneumonia, cryptogenic organizing pneumonia as well as immune reconstitution syndrome were possibilities. Considering the patient's immunocompromised status, infectious causes were, however, more likely. A complete blood count revealed a normal white count of 6500/mm3 (normal: 4000-10,000/mm3). Hemoglobin was 10.5 g/dL (normal: 13.0-16.5 g/dL) with a normal platelet count. Chemistry panel showed normal renal and hepatic function with a low albumin of 2.9 g/dL (normal: 3.5-5.0 g/dL). Arterial blood gases (ABG) analyses showed a PaO2 of 64.7 mmHg on supplemental oxygen. HIV RNA PCR showed a viral load of 194,901 copies/mL. His CD4 count was 44 cells/mm3 with CD4% of 8.5%. 1,3-beta-d-glucan assay was strongly positive with a value >500 pg/mL (>80 pg/mL is considered positive). Routine blood cultures showed no growth at 5 days, fungal and AFB (acid fast bacilli) blood cultures also remained negative. Urinary Histoplasma antigen and serum Cryptococcal antigen were both negative. Serum rapid plasma reagin (RPR) was non-reactive. A repeat CT scan of the chest showed progression of bilateral ground glass opacities with development of mild interlobular septal thickening resulting in a characteristic "crazy-paving" pattern [Fig. 2]. On day 3 of admission, he underwent a bronchoscopy and bronchoalveolar lavage (BAL). BAL Gram stain and culture showed no organisms. BAL fungal and AFB stains along with cultures remained no growth. BAL galactomannan was negative. BAL cytology showed enlarged cells with a large intranuclear inclusion surrounded by a halo, creating an "owl's eye" appearance which is characteristic for Cytomegalovirus. Also present were alveolar casts which stained weakly with Gomori methenamine silver (GMS) and revealed structures morphologically consistent with Pneumocystis organisms [Fig. 3]. Plasma CMV DNA PCR was also positive with 17,424 copies/mL.

ab, garterial blood gas, afb, acid fast bacilli, bal, broncho-alveolar lavage, bipap, bilevel positive airway pressure, cmv, cytomegalovirus, copd, chronic obstructive pulmonary disease, ct, computed tomography, coinfection, cytomegalovirus, dphs, dihydropteroate synthetase, gms, gömöri methenamine silver, hiv, hiv, human immunodeficiency virus, iv, intravenous, pcp, pneumocystis jiroveci pneumonia, pcr, polymerase chain reaction, pneumocystis jiroveci pneumonia, rpr, rapid plasma reagin, tmp-smx, trimethoprim-sulfamethoxazole

PMC2779313_01

Female

The patient was a 30-yr-old, non-smoking female housewife. She had been in excellent health. However, 2 months ago, she began to experience shortness of breath, coughing, and febrile sense at night and her symptoms were progressively aggravated. She has lived at old house for 8 months and the ceilings and walls of her bedroom, living room, and bathroom had been covered with moulds since 3 months ago. Initial physical examination showed inspiratory crackles in both basal lung fields. Her leukocyte count was 6,300/microL (neutrophil: 52.6%, lymphocyte: 33.8%, monocyte: 8.6%, eosinophil: 5%). On the chest radiograph, there were diffuse small nodular densities with increased haziness on both lower lung fields. High-resolution computed tomography (HRCT) revealed wide disseminated poorly defined nodules and ground glass opacities in both lung fields. Arterial blood gas analysis were pH of 7.43, PCO2 of 33 mmHg, PaO2 of 84.6 mmHg, HCO3 of 22.6 mM/L, and O2 saturation of 95.7%. Spirometry showed FVC of 2.2 L (60% predicted), FEV1 of 1.87 L (60 % predicted), FEV1/FVC of 85%, and DLCO of 7.23 mL per min/mmHg (28% predicted). Erythrocyte sedimentation rate (ESR) was 44 mm/hr and complement C3 and C4 levels were normal. Serum IgG (872 mg/dL), IgA (297 mg/dL), and IgM (372 mg/dL) levels were normal. Skin prick tests with 80 common inhalant and food allergens showed all negative responses and total IgE by UniCap (Pharmacia, Upsala, Sweden) was 110 IU/mL. Sputum stainings for Mycobacterium tuberculosis were negative. Bronchoalveolar lavage fluid analysis revealed that lymphocytes were increased up to 89% of collected cells and CD4+/CD8+ ratio was reversed (0.19). The pathologic findings of specimens obtained by transbronchial lung biopsy demonstrated lymphocytic infiltration within alveolar wall and interstitium without an evidence of granuloma. At 5 day's admission, her symptoms were improved with corticosteroid therapy. Under the diagnosis of HP, she was advised to move to another house and take oral corticosteroid for 3 weeks. Her clinical symptoms, chest radiograph, and spirometry were normalized after 2 months. Saboraud glucose agar (Difco, Detroit, MI, U.S.A.) plates containing 0.06 g/L of chloramphenicol were left open for 2 hr on floor in the patient's bedroom, living room and bathroom, and then incubated at 28C and 37C for 10 days. Colonies appearing on the plates were subcultured and identified morphologically. Penicillium species was the predominant isolate (70-80 colonies per plate) from all sites of the air in the patient's home. A few colonies of Alternaria sp., Cladosporium sp., and Scopulariopsis sp. were noted. Each fungal isolate was cultured in Saboraud glucose agar for 3 days and incubated in Czapek-Dox broth media (Sigma, St Louis, MO, U.S.A.). Incubated broth media were kept at 37C for 4 days on a gyratory shaker. Fungal mycelia were separated from the broth media by passing through Whatmann filter paper. Mycelial extract was separated in liquid nitrogen containing sea sand. After shaking for 12 hr at 4C in phosphate-buffered saline containing 0.1% Triton X-100, the extract was separated again ultrasonically. The supernatant obtained through centrifugation and dialysis against distilled water was lyophilized. SDS-PAGE was performed by the method of Laemmli. Mycelial extract antigens were dissolved in a sample buffer (Novex, San Diego, CA, U.S.A.) and boiled for 5 min. Standard markers (3-185 kDa) (Novex, San Diego, CA, U.S.A.) and antigens were applied to a Novex precast NuBis-Tris gel (4-12%) for the separation of fungal antigens. Electrophoresis was performed with a Novex X cell II mini-cell for 40 min at 200 constant voltage. The gel was fixed and stained with 0.1% Coomassie brilliant blue. By the method previously described by Tsang et al., electroblotting was carried out for 60 min at 30V in Tris-glycine transfer buffer with 10% MeOH with a Novex X cell II blot module. After transfer, the nitrocellulose membrane was blocked with Tris-buffered saline (TBS) containing 5% skim milk. The patient and control sera were diluted to 1:100 v/v with 5% skim milk/TBS. The membrane was then incubated with the patient and control sera for 1 hr at room temperature. It was then washed with TBS. Peroxidase-conjugated goat antihuman IgG was diluted to 1:1,000 with 5% skim milk/TBS and used as a secondary antibody solution. The membrane was then incubated with the secondary antibody for 1 hr at room temperature and washed again as above. To detect immobilized specific antibodies, enhanced chemiluminescence detection kit (ECL, Amersham) was applied according to the instruction manual. Mixed an equal volume of detection solution 1 with detection solution 2, added to the protein site of the membrane and incubated for one min at room temperature. And then the membrane was exposed to the film in the film cassette for 10 sec and developed. To determine the protein components of a fungal extract, the extract was analyzed by a 4-12% gradient SDS-PAGE. Fig. 1 demonstrates the binding of specific IgG in patient and control sera on the blotted nitrocellulose membrane. Only a band of 43 kDa was bound to Penicillium species extracts, while no specific binding was found in other fungal extract and sera from control subject.

PMC6260442_01

Male

A 74-year-old man was referred to our hospital with abnormal chest X-ray findings in February 2015. He complained of dry cough, dyspnea on exertion (DOE) of modified Medical Research Council (mMRC) grade 1, and intermittent arthralgia. Initial significant findings were fine crackles in bilateral lower lung fields and tenderness of the metacarpophalangeal joint of the left second digit. Initial laboratory findings were as follows: rheumatoid factor 7.2 IU/ml, anti-cyclic citrullinated peptide antigen 818.9 IU/mL, and erythrocyte sedimentation rate (1 hour) 92 mm. Initial high-resolution computed tomography (HRCT) images showed typical UIP pattern with basal and subpleural lung dominant reticular opacities, interlobular septal thickness associated with honeycombing and traction bronchiectasis. Since the morphologic pattern showed UIP with no apparent cause, the diagnosis was IPF. His symptoms gradually worsened over 2 years until January 2017; his dry cough increased, and DOE gradually worsened to mMRC grade 2. Chest HRCT images showed extended reticulation (Fig. 1B). Pulmonary function test findings, especially FVC, also declined (Fig. 2). In February 2017, bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBLB) were performed. BALF cytology showed total cell counts of 2.71 x 105/mL, lymphocytes of 12%, and a CD4/CD8 ratio of 0.4. Histopathology showed old fibrosis and aggregated alveolar walls accompanying fibroblastic foci. At that time he had no arthralgia. Treatment was initiated with nintedanib 300 mg/day. It was generally well tolerated except for slight diarrhea. His dry cough improved gradually and diminished 8 months after he started treatment. Pulmonary function testing also improved; the gradual FVC decline in February recovered 60 mL 3 months after treatment initiation, followed by milder decline. FVC decreased by 490 ml 13 months after the initial visit (-12.6%/13 months) and by 90 ml after 6 months of treatment (-2.6%/6 months) (Fig. 2). In October 2017, his metacarpophalangeal joint of the left second digit developed swelling. At this time, he met the criteria of RA with a DAS 28 score of 3.61, showing moderate disease activity.

PMC9445417_01

Male

A 42-year-old male patient with 161 cm height was admitted for ankylosing spondylitis and atlantoaxial dislocation. The patient presented pain and restricted movement in the lower back 15 years ago. He was definitely diagnosed with ankylosing spondylitis. Because of no specific and effective treatment, his sign of hunchback developed worse and worse. Three years ago, he presented neck stiffness with limited movement and pain in the occipital and nape region; meanwhile, his head leaned and fixed rightward. Because of the progressive condition, his trunk deformity developed into a more curve magnitude company with physical pain, which led to reduced quality of life and social and psychological distress. Therefore, he was admitted for spinal fusion and instrumentation surgery to restore the spine without neurological deficit. The patient's previous medical history was negative. He did not smoke and had no pets at home. There was no family history of any congenital, lung, or infectious conditions. After admission, he accepted a detailed assessment of neuromuscular spinal deformity, including clinical examination, cardiac and respiratory evaluation, and digestive and urinary assessment. Although there was thoracic deformity and motor disorder caused by ankylosing spondylitis, he did not present an obvious reduction in respiration and cardiac function. Also, there were no other apparent signs, for instance, abnormal chest auscultation. The preoperative thoracic computer tomography (CT) of the patient demonstrated multiple subpleural pulmonary bullae on the upper lobes of bilateral pulmonary. Preoperative spirometry showed a forced expiratory volume in 1 s (FEV1) of 2.46 L (67.55% predicted), forced vital capacity (FVC) of 2.60 L (59.02% predicted), FEV1/FVC ratio of 113.07%, and a peak expiratory flow rate of 7.85 L/s (88.87% predicted). After 1 month halo traction treatment, the patient was sent to the operating room for osteotomy orthopedics. Because his head was fixed rightward in the anterior flexion position, there was difficulty in rapid sequential induction; thus, awake nasotracheal intubation was implemented according to the preoperative anesthesia plan. After the standard monitoring was utilized and venous access was secured with an 18G cannula, the patient was administrated with 1 mg of midazolam and 5 microg of sufentanil, followed by ephedrine contracting vessel of the nasal mucosa and tetracaine nasopharynx mucosa surface anesthesia. During the process, the patient breathed with 5 L/min 100% oxygen under a mask covering his mouth and nose slightly. Meanwhile, he was administrated cricothyroid puncture with 5 ml of 1% tetracaine. After perfect surface anesthesia, a 6.0-size endotracheal tube (ETT) was inserted into the main trachea smoothly by a fiber bronchoscope guidance at 28 cm scale from the tip of the nose. Inflating cuff of ETT and connecting with breathing circuits. After the wave of end expiratory carbon dioxide was confirmed, the patient was administrated with 2 mg of midazolam, 20 microg of sufentanil, 100 mg of propofol, and 50 mg of rocuronium. When mechanism ventilation was used instead of spontaneous breathing completely, significant peritubular leakage happened accompanied by a sonorous sound from his mouth. At the same time, there was no distinct movement of the chest. An adequate seal was unable to achieve around the ETT cuff despite inflation with an increasing amount of air. Mechanism ventilation was quickly switched to manual ventilation to increase the volume of ventilation. There was still a sonorous sound of air leakage, but the movement of the chest and saturated pulse oxygen could be maintained. Bilateral respiration sounds were acquired by chest auscultation when manual ventilation. The ETT cuff was checked and injected with more air to stiff intensity. Fibrobronchoscope examination demonstrated the ETT located in the main airway again. Because of continuous air leakage and inability to maintain ventilation, the previous 6.0-size ETT was replaced by a 6.5-size ETT, and the cuff was inflated to stiff intensity. The situation made everyone disappointed due to uncorrected serious peri-cuff leakage. The patient's preoperative chest digital radiography image and CT had to be reviewed further. His chest digital radiography image showed that a part of the main trachea was seemingly wider than normal (Figure 1). However, the widened main trachea was unable to be confirmed by chest CT because the images were not the standard due to his scoliosis profile. Meanwhile, fibrobronchoscopy examination had to be done again, and it demonstrated the tip of ETT close to the carina of the trachea; thus, the ETT was withdrawn 3 cm distance. The air leakage was corrected suddenly whenever manual or mechanical ventilation. Finally, the ETT was fixed at 25 cm from the tip of the nose, and the ETT cuff pressure was regulated suitably. There was no peri-cuff leakage until the end of the operation. After recovery from the operation, the patient accepted a thoracic CT scan again and a three-dimensional airway reconstruction. Meanwhile, the result of the postoperative X-ray tracheomalacia test was negative. TBM was considered by these standard radiological images (Figures 2, 3).

mounier-kuhn syndrome, difficult airway, endotracheal intubation, orthopedic, scoliosis, tracheobronchomegaly

PMC9573961_02

Male

A 58-year-old man who had been experiencing chills, fatigue, and recurring fever for 10 days visited our hospital. He had been diagnosed to have AIDS, non-tuberculous mycobacteria (NTM) infection, and infection with Talaromyces marneffei 3 months ago. Since then, he had received highly active antiretroviral therapy, anti-NTM therapy, and antifungal medication. Furthermore, he had a 10-year history of diabetes and had no personal or family history of HLH. The patient claimed to have lost 10 kg in the previous 6 months. After being admitted, the patient experienced frequent episodes of high fever, with a maximum temperature of 39.8 C, ongoing chest pressure, and low mental well-being. He was found to have neutropenia (neutrophil count: 0.84 x 109/L), anemia (hemoglobin level: 78 g/L), and severe thrombocytopenia (platelet count: 7 x 109/L) ( Figure 1A-C ). The levels of IL-6, IL-10, and IFN-gamma were markedly high ( Figure 2B-D ). His triglyceride, fibrinogen, ferritin and D-dimer levels were 3.63 mmol/L, 0.91 g/L,6070 ng/mL, and 32960 microg/L, respectively ( Figures 1D, E and Figure 2A ). Moreover, he had severe hypoalbuminemia, a CD4+ lymphocyte count of just 8/microl, and renal failure ( Table 1 ). Hepatosplenomegaly was detected on an abdominal CT. Importantly, bone marrow aspiration testing revealed hemophagocytosis. Based on HLH-2004 diagnostic criteria, the patient's symptoms were compatible with those of HLH. We were unable to determine the cause of the infection at first because the blood bacterial culture was negative. However, the next-generation sequencing (NGS) revealed the herpes virus 4 (EBV)as a culprit. EBV-DNA was 835000 copies/ml. We believe that the patient had an outbreak of HLH due to EBV activation on the basis of poor immune reconstitution. In light of the patient's extremely poor immune status and renal failure, ruxolitinib 15 mg PO bid was started, and empiric antibiotics were started to manage any potential pathogen infections along with continuous administration of cART, anti-NTM therapy, and antifungal medication. After 3 days of ruxolitinib treatment, he no longer had a fever, and his strength and appetite had started to return. His neutrophil and platelet counts improved to 2.34 x 109/L and 27 x 109/L ( Figure 1A, C ), respectively, and CRP level decreased to 34.3 mg/ml. His ferritin level dropped to 3062 ng/mL, fibrinogen level was 2.24 g/L, and D-dimer level was 7350 microg/L after 6 days of treatment. After therapy for 14 days, his hemoglobin level and platelet count increased to 108 g/l and 66 x 109/L, respectively, and neutrophil count, kidney function, and triglyceride level normalized ( Figure 1 ). The levels of HLH-related cytokines IL-6, IL-10, and IFN-gamma decreased to 29.85, 10.7, and 29.85 pg/ml, respectively ( Figure 2 ). Furthermore, ultrasound showed that hepatosplenomegaly resolved (thickness of 3.5cm). After the cART regimen was modified and the patient's indicators markedly improved, the patient was discharged in a stable condition 21 days after being admitted ( Table 1 ). Antifungal and anti-NTM medications were continued while ruxolitinib was gradual tapered and discontinued after 4 weeks. No signs of recurrence were observed at 3 months after discharge from the hospital.

acquired immune deficiency syndrome, cytokines, hemophagocytic lymphohistiocytosis, inflammation, ruxolitinib, therapeutics

PMC7500472_01

Female

A 73-year-old female presented at the outpatient department with a 2-day history of upper abdominal pain after a meal. She has no pre-existing conditions or major past medical history. Before admission, she went through the mandatory pre-screening assessment (Figure 1), which has been implemented at our hospital through the COVID-19 outbreak, including inquiry of potential contact history (whether contacted with a suspected or laboratory-confirmed COVID-19 patient in the last 2 weeks); patient's symptom check (body temperature >=37.3 C, coughing or shortness of breath and/or other symptoms of acute respiratory symptom are highly suspected); laboratory test (a nasopharyngeal swab specimen for COVID-19 RNA test and serological tests for COVID-19 antibody); and a chest computed tomography (CT) scan (a typical "ground glass opacity" image is highly suspected), respectively. The patient was categorized as having a "low risk" of COVID-19 infection and was subsequently admitted to the GI unit. During routine physical examination, her vital signs were stable, whereas moderate rebound tenderness appeared at the upper abdominal region. The blood chemistry panel showed prominently elevated amylase (5,082 IU/L) and lipase (>3,000 IU/L) levels, suggesting pancreatitis. Bilirubin level and the lipid profile were normal, with the mild increase of gamma-glutamyl transpeptidase (GGT, 59 U/L), alamine amino transferase (ALT, 95U/L), and aspartate amino transferase (AST, 95U/L), respectively. In addition, complete blood count showed severe inflammation with increased white blood cell (20.5 x 109/L) and neutrophil (19.1 x 109/L) counts. An abdominal CT scan indicated inflammation and swelling of the pancreas, a mildly enlarged gallbladder, as well as a slightly dilated common biliary duct (CBD) (Figure 2A). Notably a diverticular pouch was present at the junction of second and third with no obvious stone identified at that time portions of duodenum. To further rule out the possible biliary or extrabiliary obstructive pathology, the patient was referred to MR cholangiopancreaticography (MRCP) examination. MRCP coronal haste thin slice image confirmed the presence of duodenal diverticular partially compressing the distal end of CBD and resulting in dilation of its proximal part (Figure 2B). The maximal diameter of the diverticula was 2.67 cm. An ERCP may be sufficient to identify the presence of small stones (and subsequently remove them) or, alternatively, to place a stent inside the duct to restore bile flow. The patient was informed of management options and agreed to endoscopic interventions. She was also acknowledged to have potential exposure risks to COVID-19 in the hospital environment. Surgical mask and gloves were provided to the patient and the relative who was responsible for transfer her to the ERCP unit. In addition, the patient was also provided with a disposable medical hair net and gown. They were further advised to minimize movement while waiting for the procedure to minimize the risk of contamination. Prior to the ERCP procedure, the patient's status of COVID-19 was verified among the ERCP team. To limit the exposure risk for HCW, general anesthesia with tracheal intubation or deep sedation, which normally requires the anesthesia personnel to stay in the procedure room, was not applied in the current setting. Pre-ERCP screening was therefore critical to assess the patient's suitability to undergo conscious sedation. With regards to this, the patient had no cardio-pulmonary disease, no difficulties related to the airway, no morbid obesity, and, furthermore, no significant gastroesophageal reflux disease (GERD), which will probably cause an increased risk of developing complications during and after the ERCP procedure. Ten minutes before the procedure, intravenous administration of diazepam (5 mg) and dezocine (2.5 mg) was used to generate effects of anesthesia for the patient. In addition, antispasmodic (phloroglucinol, 20 mg) was given to reduce duodenal motility for the procedure. The vital parameters [heart rate (HR), blood pressure (BP), and respiration rate, (SpO2)] were monitored throughout the procedure. Although performing endoscopic procedures in a negative-pressure room during the COVID-19 outbreak was recommended among several gastroenterological endoscopy societies, this is not available in most endoscopy facilities around the world. We equipped an operative room with a negative-pressure system in a separate unit to be used for all patients with respiratory symptoms. Given that the current patient was categorized as being at a low risk of infection, she was not transferred to the negative-pressure room. All HCW at the hospital have received appropriate training on hand hygiene and use of PPE prior to procedures. The endoscopists and assistance wore PPE by reviewing the Asian Pacific Society for Digestive Endoscopy (APSDE) guidelines, American Society for Gastrointestinal Endoscopy (ASGE) guidelines, and CDC recommendations for ERCP. Washing hands with soap and water or alcohol-based hand rub were mandatory before and after patient interaction, contact with potentially infectious sources, and before putting on and removing PPE. The step-by-step approach for wearing PPE is as follows (Figures 3A-C): wear a respirator [either N95, the US standards for respirator masks, or NK95, the Chinese standards for respirator masks, or the equivalent, which are rated to capture 95% of tiny particles (0.3 micron particles, to be exact)]; wear an impermeable gown; wear the first pair of gloves so they cover the impermeable gown, which cover the wrist; wear lead aprons, thyroid shields, and dosimeters; wear boot covers; wear goggles and a face shield; wear a disposable isolation gown; wear a second pair of gloves over the isolation gown so they cover the wrist. At ERCP, JPDD was observed, and a duodenoscopy identified the papilla located on the edge of diverticular fundus (Figure 2C). ERCP was performed in the usual fashion with selective biliary cannulation and injection of contrast material into common bile. A small stone was visualized in the distal CBD where it was juxtaposed against the diverticulum. To remove the stone, the endoscopist performed a small sphincterotomy in conjunction with balloon dilation, and subsequent removal of the stone was achieved with balloon extraction (Figure 2D). A 6F endoscopic nasobiliary drainage (ENBD) tube was placed to drain remnant stone. After the procedure, the patient's respiratory and cardiac signs were carefully monitored in the GI ward. Physical distancing was emphasized; we permitted only one relative or guardian per patient, and they were given masks and a separate room to other patients. All the nurses and healthcare providers were tested for COVID-19 and had to show negative results prior to returning work; we had mandatory education and training on infection measures, including hand hygiene and use of PPE. A total of 2 days later, the patient's amylase and lipase levels returned to normal, and the EBD tube was thus withdrawn. In addition, a sample of bile collected during ERCP procedure was tested for COVID-19 serology; it showed negative results. The possible ERCP-related complications, including pancreatitis, infection of the bile ducts or gallbladder, hemorrhage, and perforation in the bile or pancreatic ducts, were not observed. The patient was discharged afterwards and followed up 2 weeks later to assess whether she developed any respiratory symptoms and to further assess her progress after the procedure. A total of 2 months later, she was further followed up at an outpatient department. There was no retaining stone detected in CBD by CT scan, and no evidence of post-ERCP pancreatitis or other ERCP-related complications developed during the follow-up.

covid-19, ercp (endoscopic retrograde cholangiopancreatography), healthcare workers (hcw), personal protection equipment (ppe), post-coronavirus outbreak

PMC8437625_02

Female

A 61-year-old woman presented with inflammatory thoracic and back pain. Clinical examination showed a stiffness of the lumbar spine. She had no fever. The CRP and ESR were elevated to 14 mg/L and 83 mm, respectively. Conventional radiography showed a narrowing of the intervertebral discs of D5-D6 and D6-D7. Spine MRI showed spondylodiscitis in D3-D4, D4-D5, D5-D6, D6-D7, and L1-L2 and soft tissue involvement, simulating infectious spondylodiscitis (Figure 3). All infectious investigations were negative: chest X-ray, cytobacteriological urinalysis, tuberculin skin test, test for mycobacterium tuberculosis in sputum and urine, and Wright's serological test. The discovertebral biopsy showed unspecific inflammation. Despite the negativity of the infectious investigation and given MRI findings and the notion of unpasteurized milk consumption, the diagnosis of brucellar spondylodiscitis was first evoked, and treatment with Rifadin and doxycycline was decided upon. After six months of treatment, no clinical improvement was noted. CRP and ESR remained elevated. No bone reconstruction was noticed in the X-rays. So, a second MRI was performed and showed the stabilization of the original lesions and the appearance of a new lesion in L4-L5. A second infectious investigation was performed but was negative. A discovertebral biopsy was indicated and was sterile. The diagnosis of SAPHO was then suspected, and bone scintigraphy was performed showing uptake in the chondrosternal articulations and D4 to D7 vertebrae, supporting the diagnosis of SAPHO (Figure 4). Treatment with NSAIDs associated with brace wearing was indicated. The patient did not respond to four classes of NSAIDs, so the decision was to switch to etanercept with initial clinical and biological improvement and unchanged lesions in MRI after 3 months. The treatment was received for 1 year. The treatment was received for 1 year without any efficiency. A new MRI was then performed showing an inflammatory marrow signal from T1 to T9 complicated by kyphosis at the top of T7 and associated with inflammatory damage at the anterior chest wall, predominantly the right sternoclavicular joint (Figures 5(a)-5(c)). Switch to infliximab was then indicated.

PMC3279507_01

Male

Fifty two year old man of Chinese descent was admitted to hospital with epistaxis and bleeding per rectum. This was a consequence of a high international normalized ratio (INR) due to over-anticoagulation with warfarin. The language barrier impaired our ability to obtain a detailed history. It was incidentally noted that he had a swollen left knee and leg for about three months. It was initially thought to be a deep vein thrombosis and was treated with anti-coagulant, warfarin. A knee aspiration showed haemarthrosis which then required an ultrasound guided joint wash out. The knee aspirate was sent for microscopy, culture and sensitivity and initial results came back negative. The patient was discharged home with conservative treatment. Two week later, he represented to hospital with fever and worsening knee pain. Further detailed history through a trained translator brought to light that he had in fact been having recurrent asymmetrical polyarthritis for almost five years prior to migrating to the United Kingdom. His blood results showed a mild anaemia with a haemoglobin of 10.0 G%, normal white cell count, normal neutrophil count and high inflammatory markers with a C-reactive protein (CRP) of 44. His erythrocyte sedimentation rate (ESR) was 62. He had a normal chest X-ray and normal urinalysis. His rheumatoid factor and anti-cyclic citrullinated protein antibody (anti-CCP) were negative. His HIV test which was performed at an early stage came back negative. Clinical examination revealed swollen and tender joints in the right elbow, right wrist, left knee (Fig. 1) and left ankle which were consistent with active synovitis. He also had dactylitis (Fig. 2) in the left middle proximal interphalangeal joint. He was mildly pyrexial with a temperature of 37.8 degrees Celsius. His inflammatory markers were persistently high during his admission. Knee joint aspiration was repeated and samples were sent again for microscopy, culture and sensitivity for bacteria, viruses and mycobacterium tuberculosis. A differential diagnosis of polyarticular septic arthritis had been considered and intravenous flucloxacillin two grams every six hours was initiated on the advice of the Microbiologist. The fever settled initially and there was a minimal improvement in his inflammatory markers. The intravenous antibiotic was continued for two weeks but there was no further improvement in his inflammatory markers and his fever returned. A concomitant tuberculosis infection was still considered a possibility despite the earlier negative results. A Mantoux test performed was also normal. As the patient continued to have fevers and raised inflammatory markers despite the antibiotics, the possible alternative diagnosis of seronegative inflammatory arthritis was re-considered. Further investigations including a computerised tomographic (CT) scan of his chest and abdomen did not show any obvious pathology apart from small volume hilar lymphadenopathy. Magnetic resonance imaging (MRI) of his pelvis and sacroiliac joints showed no evidence of sacroilitis or a psoas abscess. In view of his mild anaemia, an upper gastrointestinal endoscopy was done which revealed a duodenal ulcer with positive helicobacter pylori. He was treated with eradication antibiotics therapy. As a series of blood cultures and urine cultures were negative, and there was no obvious clinical improvement, the antibiotics were stopped. The Orthopaedic team performed a synovial biopsy from his knee. The result showed granulomatous changes and the synovial tissue was sent for polymerase chain reaction (PCR). Sarcoidosis and tuberculosis were suggested as possible differential diagnosis. After eight weeks in hospital, mycobacterium tuberculosis was grown from the initial synovial fluid sample taken from the knee. An isotope bone scan was performed and it has shown an increased uptake at the wrist, ribs, knees and ankles consistent with inflammatory changes. A diagnosis of multi-focal tuberculous osteomyelitis was made and standard quadruple therapy was initiated. Over the next two weeks, the fever settled and his acute phase markers also gradually improved. He was discharged after two weeks of initiating the anti-tuberculous treatment with an out-patient follow-up appointment. One month after discharge, full sensitivity result from synovial fluid culture was available and it has shown that the patient was found to be resistant to Rifampicin, Isoniazid, and Ethambutol, but sensitive to Pyrazinamide, Amikacin, Moxifloxicin, Protionamide and Cycloserine. Given the complexity of treating multi-drug resistant tuberculosis, he was readmitted to a tertiary hospital where experts with experience in this area are available. In this case series, the time from presentation to hospital to getting a correct diagnosis, was approximately eight weeks.

bone and joint tuberculosis, multi focal tuberculous osteomyelitis, extra-pulmonary tuberculosis, multi-drug resistant tuberculosis, latent tuberculosis

PMC5228665_01

Male

A 14-year-old male was admitted to our clinic for treatment of extremely severe spinal deformity associated with progressive late-onset paraplegia. His medical history included the diagnosis of intramedullary astrocytoma at the age of 3 years in another hospital, where he underwent posterior total laminectomy through the thoracic spine (from T4 to T8), with tumor excision performed without fusion. Intramedullary astrocytoma represents 29% of pediatric spinal cord tumors in the literature. He reported that kyphosis deformity began to appear 1 year after posterior laminectomy. Later, he underwent posterior spinal fusion without any instrumentation at 9 years of age. However, the deformity gradually progressed over the years. Seven months before admission to our hospital, the patient began to feel lack of strength and sensation in lower extremities bilaterally, with no complains regarding bladder or bowel dysfunction. No improvement in spinal cord function was achieved with conservative measures, and the patient gradually lost the ability to walk and required a wheelchair for movement (Fig. 1). The patient and his family denied any recent or remote history of trauma, tuberculosis, or any other infections. The family history was unremarkable; meanwhile, the patient exhibited signs of serious psychosocial problems since he had to use a wheelchair in daily life. The patient's preoperative coronal and sagittal thoracic kyphosis Cobb's angles were 70 and 170 , respectively (Fig. 2). Preoperative whole spine three-dimensional-computed tomography (3-D CT) scans showed extremely severe postlaminectomy thoracic kyphotic deformity; with the apex at T6 vertebra and previous spinal fusion (Fig. 3); magnetic resonance imaging (MRI) of the spinal canal revealed spinal cord compression at the apex of the kyphosis (Fig. 4). There was no neurological abnormality such as split cord malformation or tethered cord. The electrodiagnostic investigation demonstrated neurological deficit. Pulmonary function tests (PFTs) revealed forced vital capacity (FVC) and forced expiratory volume for 1 second (FEV1) of 31.8% and 33.8%, respectively. Cardiac Doppler ultrasonographic investigation demonstrated mitral and tricuspid regurgitation, with no anomalies of other visceral organs. Physical examination showed skin hypoesthesia below the T6 level and lower limb spasticity. The patient had weakness of the intrinsic musculature of lower limbs, with left and right lower extremity Grade 3/5 and Grade 1/5 motor strength in all muscle groups, respectively. His Achilles and knee tendons showed hyperreflexia, and the Babinski sign was positive. The overall spinal cord function was classified as Frankel C. In 2014, the patient underwent preoperative assessment by a team of pediatrics, neurosurgery, anesthesiology, and respiratory specialists, and diagnosis of postlaminectomy rotokyphoscoliosis associated with late-onset paraplegia and severe pulmonary ventilation disorder were confirmed based on the findings. The patient was suggested a revision surgical treatment, and the single stage posterior-only VCR procedure was scheduled. In brief, pedicle screws were inserted using the free-hand technique based on previous studies. The patient underwent a VCR at T6 for spinal cord decompression, deformity correction, and posterior spinal fusion from T2 to L3 (Fig. 5). The autograft and allograft were used for posterior final spine fusion. During the operation, motor evoked potential (MEP), somatosensory evoked potential (SEP), and wake up test were performed to assess intraoperative complications of spinal cord injury. The operation time was 450 minutes, and blood loss was 1500 mL. Intraoperatively, a dural tear was noted and repaired; MEP and SEP signals were lost during the entire operation, and the wake-up test was positive. Postoperatively, the patient was transferred to the intensive care unit (ICU) and required positive pressure ventilation support to improve his respiratory condition. On postoperative day 2, he was extubated and transferred to the orthopedic ward, where he received neurotrophic medicines and rehabilitation exercises. The patient required a chest tube for postoperative pleural effusion. The child experienced unplanned return to the operating room for cerebrospinal fluid leak (CSF) on postoperative day 18. The plastic thoracolumbosacral orthosis braces were preserved for 6 months after revision operation. The spinal cord function improved gradually after the posterior-only VCR procedure. At 3 months, left and right intrinsic musculature of lower limbs both exhibited Grade 3/5 motor strength in all muscle groups. Left and right intrinsic musculature of lower limbs recovered to Grade 4/5 motor strength at 12 months postoperatively. At 18 months postsurgery (follow-up visit), intrinsic musculature of lower limbs displayed Grade 5/5 motor strength, and sensation in lower extremities bilaterally had returned to normal, with the neurological status improving from preoperative Frankel C to Frankel E. At the 24-month follow-up, the good spinal cord function was maintained. Long-standing scoliosis radiographs demonstrated that the major curve at coronal plane was improved to 20 immediately after surgery and 21 (correction rate, 70%) at final follow-up; the thoracic sagittal kyphosis curve was improved to 76 immediately after surgery and 75 (correction rate, 55.9%) at the final follow-up (Fig. 6). PFTs revealed FVC and FEV1 of 40.5% and 43.5%, respectively. Postoperative clinical photographs showed overt improvement (Fig. 7).

PMC10209681_01

Male

A 45-year-old divorced homeless man was admitted to our hospital with abdominal pain. He was a Vietnam veteran. Medical history was significant for MDRTB, chronic hepatitis C, and alcohol use disorder with associated complications including liver cirrhosis with ascites, bleeding from esophageal variceal veins and pancreatits. Five years previously he presented to an outside hospital with incarcerated inguinal hernia and worsening ascites. He underwent surgery with herniorrhaphy and placement of a Denver shunt catheter from the peritoneal cavity to the superior vena cava for management of ascites presumed secondary to cirrhosis and portal hypertension. Histopathology of the hernia sac revealed caseating granulomas. Cultures of tissue and ascitic fluid grew Mycobacterium tuberculosis (MTb). At this time chest x-ray showed no evidence of pulmonary involvement. A four-drug regimen with isoniazid (INH), rifampin (RMP), pyrazinamide (PZA) and ethambutol (EMB) was begun. Susceptibility testing at Utah State Health Laboratory (USHL) revealed isolates were susceptible to all drugs tested. DOT was managed by Salt Lake County Health Department (SLCHD). DOT log showed perfect compliance with his regimen (Supplement Fig. 1). He received four drugs for the first four months and continuation of INH and RMP for a total of ten months. Monthly visits to the SLCHD TB clinic documented clinical response to treatment. The patient gained weight, had no fever and abdominal pain resolved. Near completing treatment, he began to have fever, chills, weight loss and cough. He was admitted to an outside hospital where his chest x-ray suggested pulmonary tuberculosis. Sputum smear showed rare acid-fast bacilli (AFB); culture was positive for Mtb. His isolate was resistant to INH and RMP, and to PZA on one sputum sample but susceptible on another (Supplement Figure 2). INH and RMP were discontinued, PZA was continued, and streptomycin, ofloxacin and cycloserine were begun. DOT records again showed excellent compliance with a good clinical response. After 9 months of treatment, he felt well, and his chest x-ray had improved. At this time, he was lost to follow-up. After a hiatus of almost three years (Supplement Figure 3) he presented to a local emergency room complaining of recurrent abdominal pain. He was referred to our hospital and admitted. He was cachectic with a protuberant abdomen. Vital signs were normal. Denver shunt tubing was visible through a skin defect of the left chest wall with expressible fluid. The abdomen had a doughy consistency. Chest x-ray showed the course of the shunt catheter, which appeared to terminate within the right lung (Fig. 1A). Chest and abdominal CT demonstrated multiple pulmonary cavities including one into which the tip of his shunt catheter protruded (Fig. 1B). There were extensive inflammatory changes of the peritoneal cavity including loculated fluid collections. Sputum, peritoneal fluid and chest wall fluid grew MTb, confirming disseminated infection. All isolates were resistant to INH but susceptible to RMP. A multidrug regimen recommended by the CDC-sponsored TB Hotline was begun. His hospital course was complicated by recurrent emesis due to small bowel obstructions. Attempts at nutritional replacement were unsuccessful, inanition worsened, and aspiration occurred which was fatal. At autopsy the Denver shunt catheter was visible within the lung parenchyma (Fig. 1C) but determining the site of entry into the right lung was obscured by caseous inflammation. It was impossible to "run the intestines" due to their incasement within caseous material. His course is summarized in Supplement Figure 3.

biofilm, denver catheter, foreign body, multi-drug resistance, relapse, tuberculosis

PMC4533481_01

Male

The 31-year-old previously healthy man with no previous medical illness presented to emergency department at a tertiary hospital in Malaysia in May 2012 with complaints of fever and headache for 3 weeks. He had history of loss of appetite and weight loss for 2 months. His condition progressively became worse during the last three weeks as he became more lethargic and was speaking irrelevantly. One day prior to admission, the patient had change in his behaviour. He went to see the general practitioners twice over the course of 3 weeks, but the administration of antibiotics was unknown. The patient was initially sent to a private hospital on 25 May 2012. Glasgow Coma Scale (GCS) was 10/15 (E4V1M5). The power was 3+/5 in both upper and lower limbs. Plantar response was upgoing on the right side. Computed tomography (CT) of the brain (contrasted) done at the private hospital showed widespread meningeal enhancement in the brain with cerebral oedema and hydrocephalus (Fig. 1a-f). The patient was diagnosed with meningoencephalitis and transferred to the University Malaya Medical Centre. On examination, his GCS was E4V2M5 (11/15). He was not responding to questions and was not obeying commands. Neck stiffness was present. Pupils were 4 mm in size bilaterally and were reacting sluggishly. Blood pressure (BP) was 146/88 mm Hg. He was afebrile. The tone was normal in upper and lower limbs bilaterally. The power was at least 3/5 at upper and lower limbs bilaterally. Reflexes were normal in all the limbs. Plantar response was downgoing bilaterally. Lung examination was normal. Lumbar puncture was done. Cerebrospinal fluid (CSF) opening pressure was more than 50 cm H2O. CSF result showed presence of raised white blood cells (WBCs) 210/muL (neutrophils 78%, lymphocytes 12%), glucose 3.1 mmol/L, and raised protein 2.47 g/L, which was consistent with meningitis. He was given intravenous ceftriaxone and acyclovir. He was given anti-tuberculous medication to cover tuberculous meningitis. Chest X-ray was normal. Repeat plain CT brain done after lumbar puncture showed unchanged degree of hydrocephalus and cerebral oedema. Full blood count showed Hb 191 g/L, WBC 9.0 x 109/L (neutrophils 89%, lymphocytes 5%), and platelet count of 251 x 109/L. Renal function and electrolytes were normal. Immunoglobulin titres were not checked. The following day in the morning, he was opening his eyes to call and was able to lift his right upper limb on command. GCS was 9/15 (E3V1M5). At night on the same day, the patient's GCS dropped to 7/15. His pupils were unequal. Right pupil was 4 mm and left pupil was 6 mm. He was intubated and ventilated. Repeat plain CT brain showed increased degree of cerebral oedema and unchanged degree of hydrocephalus (Fig. 2a-e). He was planned for extraventricular drainage (EVD) by neurosurgical team on the following day. But, the patient passed away in the morning the following day. CSF culture grew S. paucimobilis sensitive to ceftriaxone, ceftazidime, ciprofloxacin, and piperacillin/tazobactam (Tazosin). CSF acid-fast bacillus (AFB) smear was negative. CSF AFB C&S was negative. CSF tuberculous (TB) polymerase chain reaction (PCR) was negative. Blood culture showed no growth. A diagnosis of meningitis secondary to S. paucimobilis was made. Permission for autopsy was not obtained. Unfortunately a microphotographic picture has not been kept in stock.

PMC3429378_01

Male

A 27-year-old male farmer presented himself to an integrated health centre in the Bankim health district of the Adamaoua region of Cameroon with two ulcerative lesions with undermined edges on the upper chest and neck as well as enlarged and indurated lymph nodes of the neck (see Figure 1). He had not sought any traditional treatment and indicated that the condition had been ongoing for one month. Given the known high prevalence of Mycobacterium ulcerans (M. ulcerans) disease (Buruli ulcer) in the Bankim health district, ulcer exudates were examined for acid-fast bacilli by Ziehl-Neelsen (ZN) staining at the local health centre and tested positive. Based on the positive ZN stain, a diagnosis of Buruli ulcer (BU) was made and the treatment recommended for BU by the World Health Organization (WHO), daily rifampicin (600 mg p.o.) and streptomycin (1 g i.m.) for 56 days, was administered to the patient. Additional swabs of ulcer exudates were analyzed using the M. ulcerans-specific IS2404 quantitative polymerase chain reaction (qPCR) assay. All four swabs obtained from the patient tested negative. Exudate swabs were also used for the initiation of a culture on Lowensein-Jensen medium after decontamination with 2.5% oxalic acid for 30 minutes at room temperature. After 8.5 weeks of incubation at 30 C, the optimal growth temperature of M. ulcerans, mycobacterial growth was observed. The cultured mycobacteria were ZN positive, but negative in the M. ulcerans-specific IS2404 qPCR. PCR amplification and DNA sequencing of the rifampicin resistance determining region (RRDR) of the rpoB gene identified the strain as belonging to the M. tuberculosis complex; no rifampicin resistance conferring mutation in the RRDR was found. A qPCR identifying a single-nucleotide (A to C) change at position 2'154'724 further characterized the cultivated strain as belonging to Lineage 4 (Euro-American Linage) of M. tuberculosis . Spoligotyping and analysis using the SITVITWEB database revealed that the strain belonged to the "T-family" of M. tuberculosis, a spoligotype of Lineage 4 which encompasses all strains that are difficult to classify into other spoligotype families. While the strain therefore does not belong to the "Cameroon Family" of TB, the obtained spoligo type has previously been reported to occur in Cameroon. Ethical approval (clearance N 041/CNE/DNM/09, 19/06/2009) to analyze patient specimens was obtained from the National Ethics Committee of Cameroon, registered under the N IRB00001954. Written informed consent from the patient was obtained before specimens were used for reconfirmation of clinical diagnosis and detailed laboratory analysis. BU disease presents with a variety of clinical manifestations including nonulcerative forms such as movable subcutaneous nodules, plaques, and oedema, which may eventually progress to ulcerative lesions with characteristic undermined edges. Without treatment, ulcers may enlarge considerably and involve entire limbs or large areas of the trunk. It is believed that mycolactone, the macrolide toxin produced by M. ulcerans, largely contributes to the pathogenesis of BU disease. The diversity in clinical presentation renders clinical diagnosis difficult. Of the four currently available methods for laboratory reconfirmation of BU, only one, ZN microscopy, is suitable as a point-of-care diagnostic test in the African endemic areas, which are usually remote and rural. However, its sensitivity is limited. Cultivation of the slow-growing mycobacteria, histopathology, and PCR-based detection of M. ulcerans DNA can only be performed in central reference laboratories. Given its wide range of clinical presentations, the differential diagnosis of cutaneous tuberculosis, which makes up 1%-2% of all TB cases worldwide, is also difficult. Both infectious and noninfectious diseases of the skin need to be considered when examining a potential case of cutaneous TB. For a definite diagnosis, histological examination, PCR, or optimally isolation of M. tuberculosis is required. All of these diagnostic methods again require sophisticated reference laboratories. Once diagnosed, patients can be treated with the regiment that is also used to treat pulmonary TB. It is remarkable that a clinical manifestation very similar to that of BU disease was observed in the case presented here, although M. tuberculosis does not produce a potent macrolide toxin. For patients from BU-endemic regions, ZN microscopy is usually accepted as reconfirmation of the clinical diagnosis and, to reduce costs, it has been suggested that only ZN negative swabs should be sent to a reference laboratory for analysis by PCR. While the vast majority of ZN positive samples are also PCR positive, sensitivity of PCR is much higher than microscopy and many ZN negative samples still turn out PCR positive. In BU-endemic areas as remote as the Bankim health district, clinical diagnosis by local medical staff is often considered sufficient for treatment decision. It has been shown that if clinical diagnosis is performed by highly trained and experienced staff, more than 90% of suspected cases can be reconfirmed by PCR. However in regions where health care staff does not regularly encounter BU cases, a large proportion of suspected BU cases cannot be confirmed by laboratory tests. Clinical overdiagnosis on one side, and true BU cases missed by relying only on ZN microscopy on the other side, can lead to over- or undertreatment of patients, respectively. It is therefore recommended that all BU cases should be laboratory confirmed. If the decision is made to send only ZN negative swabs for confirmation to a reference laboratory, training of health care staff in BU differential diagnosis becomes even more important. Furthermore, such training should include the clinical presentation of other skin diseases, including other mycobacterial diseases. As demonstrated by the case presented here, lymphadenopathy:not a typical sign of BU:should lead to a more detailed clinical examination. Overall, the case of a misdiagnosed patient with cutaneous TB in a BU-endemic area presented here further underscores the need for a simple, highly sensitive, and specific point-of-care diagnostic test for BU.

PMC9837082_01

Female

A 27-year-old woman presented to the hospital with severe fatigue and generalized muscle weakness that had progressively worsened over several months resulting in multiple falls and decreased oral intake. Her past medical history was pertinent for class III obesity (mass index, 40.0 kg/m2). She presented 5 months earlier to neurology clinic with fatigue and proximal muscle weakness primarily affecting her lower extremities. This had developed over a period of 6 months after she started a low carbohydrate, calorie restricted diet for weight loss. She developed severe vomiting after a week of being on the diet and she stopped it after a month having already lost 20 lbs (9.07 kg). Testing revealed a slightly elevated thyroid stimulating hormone (TSH) at 5.45 muIU/mL (reference range: 0.550-4.780 muIU/mL) with elevated thyroid peroxidase antibodies and creatine kinase (CK) (588.0 units/L, reference range: 34.0-145.0 units/L). She was started on Levothyroxine 25 mcg daily for presumed hypothyroid myopathy but her symptoms continued to worsen and her TSH was still high at 4.17 muIU/mL (reference range: 0.358-3.740 muIU/mL). Antibody testing for myositis (PL-7, PL-12, Jo-1, EJ, OJ, SRP, MI-2, TIF1gamma, MDA-5, NXP-2, PM/SCl, Ku, SS-A, U1-RNP, U2 snRNP, and U3 RNP antibodies; Esoterix Endocrinology), necrotizing myopathy (SRP IFA screen, HMG-CoA reductase antibody; Mayo Clinic Laboratories), myasthenia gravis (ACHR binding antibody, striated muscle antibody, Mayo Clinic Laboratories), and panel-based genetic testing for muscular dystrophies (Comprehensive Muscular Dystrophy Panel, Invitae) was normal. Electromyography suggested an inflammatory, genetic, or metabolic myopathy of her lower extremities. A vastus lateralis biopsy revealed vacuolated muscle fibers with lipid droplets suggestive of a lipid storage myopathy. A plasma acylcarnitine profile (Mayo Clinic Laboratories) revealed elevated small-, medium- and long-chain acylcarnitine species in a pattern suggestive of a defect in fatty acid oxidation. Urine organic acid analysis revealed elevated excretion of orotic acid (91 mmol/mol creatinine [Cr], reference range: <6 mmol/mol Cr) and 2-hydroxy glutaric acid (270 mmol/mol Cr, reference range: <50 mmol/mol Cr). Genetic testing was ordered; however, results were pending at the time of her presentation to the hospital. She presented to the hospital with worsening weakness, multiple falls, and decreased oral intake. Neurological exam in the hospital revealed proximal greater than distal weakness of bilateral upper and lower extremities, neck weakness, and trace to absent lower extremity reflexes. She was also found to have a pulmonary embolism based on intraluminal filling defects in the segmental branches of the bilateral lower lobe pulmonary arteries. She was noted to have developed severe ketoacidosis with venous pH 7.00 (reference range: 7.32-7.43), beta hydroxybutyrate 5.67 nmol/L (reference range: 0.02-0.27 nmol/L), rhabdomyolysis with CK 4656 units/L (reference range: 34.0-145.0 units/L), and lactate peaking at 6.0 mmol/L (reference range: <1.3 mmol/L), prompting admission to the intensive care unit for treatment of acidosis. She was treated with sodium bicarbonate, normal saline, thiamine, dextrose, and heparin infusions, and improved within 24 hours. Her venous pH normalized to 7.45 (reference range: 7.32-7.43), CK improved to 245 units/L (reference range: 34.0-145.0 units/L), and lactate improved to 3.6 mmol/L (reference range: <1.3 mmol/L). She was empirically started on carnitine, riboflavin, cyanocobalamin, and coenzyme Q10 supplementation to treat a presumptive diagnosis of a riboflavin-responsive lipid storage myopathy such as MADD. She did, however, continue to have objective weakness with proximal greater than distal weakness of bilateral upper and lower extremities on physical examination. Her genetic testing results while not immediately available were expedited and ultimately revealed a heterozygous frameshift mutation, c.51dup;p.(A18Cfs*5), in the ETFDH gene likely pathogenic for MADD. After recovery from her acute illness she was discharged to inpatient rehabilitation for physical and occupational therapy. She was maintained on carnitine, riboflavin, cyanocobalamin, coenzyme Q10, and thiamine supplementation along with a high carbohydrate, low-fat diet and discharged home to continue the same treatment. She was able to adhere to a diet with less than 25 g of fat per day and she was also advised to avoid prolonged fasting. Over the next few weeks she continued to have intermittent nausea requiring ondansetron, and neuropathic pain requiring pregabalin but overall her strength and energy started to improve. Her CK normalized, down to 36 units/L (reference range: 34.0-145.0 units/L) within 3 weeks after her presentation to the hospital (Fig. 1) While her initial genetic testing revealed a single pathogenic variant in the ETFDH gene, she underwent additional testing including whole genome trio sequencing with no reportable sequence variants or copy number variants found that would be related to her condition (AR, ATN1, ATXN1, ATXN10, ATXN8OS, CACNA1A, CSTB, DIP2B, DMPK, FMR1, FXN, IL11RA, TBP, TCF4, Whole Genome Sequencing and Deletion/Duplication Trio Analysis, PerkinElmer Genomics), that is, did not find a second variant in the gene or evidence of genetic disorders that can mimic MADD. Karyotype and microarray revealed she was a carrier of a balanced translocation involving chromosomes 5 and 19; 46,XX,t(5;19)(p10;q10). Repeat plasma acylcarnitine profile on treatment showed a relative shift towards short- and medium-chain acylcarnitine species (Fig. 2). Repeat urine organic acid analysis was normal. Over 4 months she gained nearly 30 lbs (13.61 kg) and metformin and eventually liraglutide were initiated in an attempt to help with weight loss. Her TSH was also noted to be as high as 21.58 muIU/mL (reference range: 0.550-4.780 muIU/mL) and her levothyroxine was increased slowly to 100 mcg daily. Nearly a year after her hospitalization she continues to feel well with improved strength and energy.

ck, creatine kinase, etfa, electron transfer flavoprotein a, etfb, electron transfer flavoprotein b, etfdh, electron transfer flavoprotein dehydrogenase, madd, multiple acyl-coenzyme a dehydrogenase deficiency, tsh, thyroid stimulating hormone, electron transfer flavoprotein dehydrogenase, glutaric aciduria type ii, inborn errors of metabolism, lipid storage myopathy, multiple acyl-coenzyme a dehydrogenase deficiency, muscle weakness

PMC3828068_02

Unknown

As the measles vaccination in 9 - 59 months old dropped from 81.63% in 2007 to 52.17% in 2011, the confirmed cases of measles/1,000,000 population increased from 0.68 to 16.81. Furthermore, the number of measles outbreak increased from 0 in 2007 to 5 in 2010 as the proportion of the population immunized dropped (Table 1). On average, between 2007 and 2011, 34% of cases with febrile rash living in urban areas were unimmunized while 41% of those living in rural areas were unimmunized. In 2007, 25% of febrile rash cases living in urban areas and 16% of those living in rural areas were unimmunized while in 2011, 49% of those living in urban areas and 60% of those living in rural areas were not immunized (Table 1). Over the five years under review, for cases with confirmed cases of measles, 61.33% of them were unimmunized while 87% of the confirmed cases of measles occurred during the dry season (Table 2). The peak of measles infection occurred in January and February which accounted for 55% of all cases (Table 3).

immunization, measles, nigeria

PMC4119459_01

Male

A 57-year-old male presented with abdominal pain, fatigue, high fever, and weight loss of 6 kg for two months. His previous medical history was unremarkable. Physical examination revealed pain on the left side of the abdomen and hepatosplenomegaly. Laboratory findings were as follows: erythrocyte sedimentation rate 86 mm/h, leukocyte 12600/microl, neutrophile 7200/microl, thrombocyte 510000/microl, monocyte 2100/microL, hemoglobin 10.2 g/dl, hematocrit 30%, MCV 74.6 fl, and lymphocyte 2200/microl. Computed tomography (CT) of the chest showed multiple mediastinal lymphadenopathies (maximum size 15 mm) and bilateral apical fibrotic bands. A uniform-density mass lesion of 70 mm that filled retrovesical and left pelvic area was detected in abdominal CT. The lesion surrounded superior part of sigmoid colon and there were multiple lymph nodes in the retro-vesical, celiac, para-aortic and para-iliac areas (Figure 1). Histological examination of samples that were obtained during diagnostic laparotomy showed epithelioid granulomas, Langhans? type multinucleated giant cells, and caseous necrosis (Figure 2). Lowenstein-Jensen culture of samples confirmed the presence of TB. Antituberculous therapy comprising rifampicin, isoniazid, ethambutol and pyrazinamide was initiated and continued for two months, and the patient was maintained on rifampicin and isoniazid for 6 months. In the sixth month follow-up of patient, cerebrovascular hemorrhage developed. The patient died due to this.

tuberculosis, abdominal mass, lymphoma

PMC9831003_01

Male

A 50-year-old man with a high fever, non-productive cough, and progressive dyspnea for three days was admitted to our hospital. The body temperature was between 39.4 C and 40 C, accompanied by chills. He was a healthy man before the onset. He denied tuberculosis infection history or other infectious disease exposure history and no history of smoking or alcohol abuse. After moxifloxacin 0.4 g, I.V., qd in an external hospital for two days, his symptoms did not relieve. A chest CT scan was performed 24 hours before admission showing pulmonary infiltrate and consolidation in the lower lobe of the right lung (Figure 1A-C). His vital signs of physical examinations at admission were as follows: temperature 39.5 C, pulse rate 118 beats/ min, blood pressure 128 / 80mmHg, respiratory rate 34 breaths/min. He was tachypnea, and his lips were cyanotic. His saturation of peripheral oxygen was 88% with mask oxygen inspiration (5L/min). Wet rales could be heard in the lower lobe of the right lung. The rest of the physical examination was roughly normal. Laboratory tests on admission showed white cell count 10.7x10^9/L (reference range:4-10x10^9/L), neutrophil ratio 95% (50-70%), hemoglobin 151 g/L (120-160 g/L), and platelet count 221x10^9/L (100-300x10^9/L). C reactive protein was 272mg/L (0-3mg/L). Erythrocyte sedimentation (ESR) was 38mm/1h (0-20 mm/1h). Procalcitonin (PCT) was 0.62ng/mL (<0.5ng/mL). His renal function was normal. He had severe liver function damage. His aspartate aminotransferase (AST) was 195 IU/L (8-40 IU/L), alanine aminotransferase (ALT) 112 IU (5-40 IU/L), albumin 23 g/L (35-55 g/L). The laboratory tests revealed electrolyte disorders- hyponatremia and hypochloremia. Serum sodium concentration was 128mmol/l (130-150mmol/l), chloride concentration 95mmol/l (96-106mmol/l). No etiological evidence was found. Sputum culture results, acid-fast bacilli stain, and GeneXpert MTB/RIF assay was negative. Nasal swabs for detection of Covid-19, influenza virus, adenovirus, and respiratory syncytial virus also found nothing. Intravenous infusion of moxifloxacin 0.4g was continued after admission. A chest CT scan was reexamined the next day after admission. The lung shadow progressed rapidly, showing multiple patchy ground-glass opacity and consolidation in both lungs (Figure 1D-F). The patient's condition deteriorated, with persistent high fever (39-40 C), and worsening dyspnea. With mask oxygen inhalation of 10L/min, arterial blood gas analysis revealed pH 7.52, PO2 40 mmHg (83-108mmHg), PCO2 25 mmHg (35-48mmHg), and HCO3- 24.5 mmol/L (18-23mmol/L). He was treated with non-invasive mechanical ventilation in S/T mode with IPAP 15cmH2O, EPAP 6cmH2O, and FiO2 60%, which could achieve a tidal volume of about 450mL and minute ventilation of 9L/min and peripheral oxygen saturation of 94%. The patient progressed rapidly and was diagnosed with progressive pneumonia. We considered that the disease progressed rapidly, and the risk of death was high. We adjusted the anti-infection therapy regime according to common pathogens of progressive pneumonia. Moxifloxacin was discontinued and upgraded to tigecycline 100mg, I.V., q12h to cover for atypical pathogens, gram-positive cocci, and drug-resistant bacteria. At the same time, extended-spectrum antibiotic meropenem 1.0g, I.V. q8h was combined. In addition, oseltamivir 75mg, P.O., bid was administered to cover the influenza virus. While adjusting the anti-infective regimen, we performed fiberoptic bronchoscopy alveolar lavage in the basal segment of the lower lobe of the right lung and sent the bronchoalveolar lavage fluid (BALF) for mNGS detection. We also conducted tests related to rheumatic connective tissue disease. Connective tissue assays including immunoglobulin levels (IgG, IgM, IgA, and IgE), anti-ARS antibodies (anti-Jo-1, anti-MDA-5, anti-PL-7, anti-PL-12, anti-EJ, anti-KS antibodies), antinuclear antibodies (ANA), rheumatoid factor, cyclic citrullinated peptide antibodies, cytoplasmic antineutrophil cytoplasmic antibodies (cANCA), and perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) antibody titers were all within normal parameters, which provided no clue to rheumatic connective tissue disease. On the seventh day of admission, mNGS of BALF indicated C. psittaci (sequence reads: 205) and Candida albicans (sequence reads: 50). Upon close investigation, the patient had kept a pet bird a week before the onset of the disease. Until the patient was admitted to hospital, the bird did not appear abnormal. On the second day after tigecycline, the fever had gone down, and dyspnea was alleviated. After the mNGS results were reported, we adjusted the treatment regimen: we stopped meropenem and oseltamivir, and doxycycline 0.1g, P.O., q12h was successively administered for 14 days after 7 days of tigecycline administration. After 21 days of anti-psittacosis treatment, the patient's general condition was significantly improved, and there was no complaint of comfort. The patient's body temperature changes and treatment process were shown in Figure 2. A reexamination of chest CT revealed that the infiltrate was obviously absorbed (Figure 1G-I).

chlamydia psittaci, high-dose tigecycline, metagenomic next-generation sequencing, progressive pneumonia

PMC9731873_01

Male

A 30-year-old male with a long-standing history of living with HIV on appropriate antiretroviral therapy presented to the hospital emergency department for evaluation of worsening generalized itchy and painful erythematous rash involving entire face (including around ears), neck, arms, hands, feet and trunk that had developed over a month (Fig. 1). He also complained of soreness in the throat with right ear drainage and purulent eruptions. His past medical history included a skin biopsy for his recalcitrant eczema which showed spongiotic dermatitis. This rash was extensively evaluated in the past with negative PAS stain for fungus, immunofluorescence study, ANA test, anti-mitochondrial antibody, ANCA, celiac antibody test, stool for Entamoeba histolytica/other enteric pathogens (including cryptosporidium and giardiasis), strongyloides antibody serology, urinary Chlamydia and Neisseria gonorrhea testing. The patient had a history of positive CMV antibodies, eosinophilia and elevated IgE levels. The patient was treated with steroids for a prolonged time, eventually stopped due to concern for long-term side effects. The patient had a febrile course. Physical examination was notable for diffuse areas of erythema with monomorphic confluent erosions with yellow crusting, dryness and cracking on the face, neck, palms of the hands, trunk, lower back region and left foot. The patient did not have any lymphadenopathy, conjunctivitis, or neck rigidity. Patient's laboratory workup is presented in the Table 1. WBC-white blood cells, HSV-Herpes Simplex Virus, PCR-polymerase chain reaction. The patient had normal liver and kidney function tests, iron panel, folic acid, and B1/B6 levels. The patient's blood culture did not show any growth. The patient had negative nasal MRSA screen, perirectal VRE, QuantiFERON TB, RPR, Strongyloides antibody IgG, syphilis IgG antibody, hepatitis B surface antigen/antibody, hepatitis B core total antibody, hepatitis C antibody test, hepatitis C quantitative RNA. CT of face and neck on day 5 of the presentation was notable for prominent lymph nodes, most located at left of the midline in the sublingual region, pathological enlarged submental lymph node to left, and borderline enlarged right-sided level 2 cervical lymph node throughout cervical chains. The patient was admitted with a provisional diagnosis of possible atopic dermatitis with cellulitis of face and neck and started on weight-based intravenous vancomycin but left against medical advice. He was readmitted the next day with ongoing symptoms. He declined another skin biopsy as the previous biopsy did not clarify an entity beyond his original eczema. A dermatologist at a different facility assessed his images and suggested collecting Herpes viral PCR samples from any drainage locations. Given the findings, the patient was placed on intravenous acyclovir due to the high likelihood of EH. His drainage from the right external auditory ear canal was positive for both HSV 1 and 2 by PCR DNA. Intravenous antibiotic coverage for superinfection was also continued until the patient course stabilized. The patient's symptoms and rash improved significantly after being started on intravenous acyclovir. The patient was eventually transitioned to oral valacyclovir and clindamycin at discharge time. Patient was maintained on oral valacyclovir for prophylaxis. For the past 2 years, a consultant dermatologist has prescribed dupilumab with success to treat his eczema. Most recently, the patient has been placed back on valacyclovir treatment and then prophylaxis because of relapsing herpes infection. The patient has been followed up for 6 years.

acyclovir, eczema herpeticum, hiv, kaposi’s varicelliform eruption, steroid use

PMC3423662_01

Female

A thirty-eight-year-old married Caucasian female was referred to our reproductive endocrinology clinic by her gynecologist secondary to cyclical urticaria. Patient has a gynecologic history of menarche at the age of 12 and reports 28 day menstrual cycles. Patient states she gets an erythema multiforme, urticaria, and dermatographism one week prior to menses that resolve after menses since one year after menarche. Patient reports no history of joint swelling. Patient as an adolescent was seen by an allergy specialist and dermatologists for evaluation. Allergy testing was done and was reported negative. Patient was placed on antihistamines for treatment, which she reports did not help her symptoms. Patient was told her symptoms were due to stress. The patient's obstetrical history consists of two pregnancies resulting in two full-term cesarean deliveries. She has not had any issues with infertility. The patient reports during pregnancy and while breast feeding that she did not have any episodes of a rash and/or hives. Patient also states that she was on oral contraceptives for one year at age 23 where she noticed her symptoms decreased. She reports multiple drug allergies resulting in a rash. Our patient was diagnosed with autoimmune progesterone dermatitis based on history and physical exam and was treated with oral contraceptives which was successful in controlling her outbreaks.

PMC5818772_01

Male

The patient was a 14-year-old boy (height = 150 cm, weight = 54 kg) with Down syndrome, atrial septal defect (ASD), ventricular septal defect (VSD), and patent ductus arteriosus (PDA). His congenital heart defects were surgically repaired at 5 months of age. Thereafter, he was followed up once a month with echocardiography. No structural or mechanical problems and dysfunction were noted in his cardiovascular system, such as a left-right shunt. The most recent findings of his echocardiogram were as follows: all chambers were balanced; good wall motion; no asynergy; normal interventricular septum; left ventricular ejection fraction, 85 %; left ventricular end-diastolic dimension, 42 mm; no valve regurgitations; and no abnormal flow resulting from the ASD, VSD, and PDA. The attending physician of the pediatric cardiology section categorized the patient's condition as grade 1 heart failure according to the New York Heart Association functional classification system. Therefore, we assessed the patient in accordance with the diagnosis of the attending physician. The patient's intelligence quotient was 35, and his intellectual level was that of a 1.5-year-old child. The patient had many dental caries, as observed during examination at the Fukuoka Dental College Hospital. However, because he was uncooperative owing to his condition and our attempts at physical restraint had failed (he violently refused our intervention), he was scheduled for dental treatment under general anesthesia. At our hospital, we recommend that all patients undergo routine checkup, including blood tests, elective cardiograms, chest radiography, and urine tests. However, because of the patient's violent behavior, we were unable to perform any of the aforementioned tests. Therefore, we referred to the data obtained by the attending physician during the routine checkup of his cardiac condition. According to the preanesthetic examination that was performed at the other institution, the patient had no abnormalities in his blood or urine. A complete right bundle branch block (RBBB) was the only abnormality observed on the electrocardiogram (ECG) (Fig. 1). The patient was not regularly taking prescription medication for his congenital heart disease. His blood pressure (BP), heart rate (HR), peripheral oxygen saturation (SpO2), and body temperature could not be measured because of his violent behavior. The patient's parents were informed about the risks of general anesthesia before they provided consent. We determined that the perioperative risk in this patient was similar to that in other patients who had undergone corrective surgery for ASD, VSD, and PDA because there were no structural or mechanical problems with his cardiovascular system. He did not present with any risk factors for complications resulting from intubation, such as macroglossia, micronesia, and brevicollis. Although we did not check for dislocation of the first cervical vertebra, it did not seem necessary to restrain his head for airway management. He consumed no food for 6 h and no liquid for 2 h before the operation. We decided to intramuscularly inject midazolam before surgery and to gradually and incrementally induce anesthesia by means of inhalation of sevoflurane with oxygen and nitrous oxide through a face mask, after which an intravenous catheter and arterial line were inserted. To prevent infective endocarditis, we also planned to administer intravenous antibiotics during the operation. At 9:30 a.m. on the day of the operation, the patient was administered 10 mg midazolam intramuscularly as a sedative. At 10:00 a.m., he was brought to the operating room on a gurney. However, he was not sedated because the midazolam had not taken effect. Moreover, because of his inability to emotionally cope with the environmental change, he acted violently against physical restraint and was in danger of falling from the operating table; therefore, it became necessary to perform anesthesia induction immediately. We therefore administered sevoflurane (5 %) to induce general anesthesia as rapidly as possible. We intended to decrease the concentration of sevoflurane as soon as the patient's movements were controlled. Because of the patient's violent behavior, we could not measure his BP, HR, SpO2, and body temperature and could not perform the cardiac evaluation with insertion of an intravenous catheter and arterial line before the induction. The anesthetist who performed the anesthesia induction had 15 years of experience at the time. Three anesthetists, who are all co-authors of this paper, performed the anesthesia induction. Approximately 1 min after the induction, the patient's consciousness and combative behavior gradually decreased. His respiration ratio did not change, and his tidal volume progressively subsided. We then began performing assisted ventilation, which was achieved by using a face mask (Fig. 2). The initial vital signs were as follows: BP = 90/42 mm Hg, HR = 75 beats per minute (bpm), and SpO2 = 100 %. The ECG initially showed a normal sinus rhythm (Fig. 3). However, a few seconds later, his ECG indicated severe bradycardia (HR of <30 bpm) and gradually showed prolonged R-R intervals, immediately followed by asystole (Fig. 3). Although we could manage his airway and ventilation, we did not detect a pulse in the carotid artery. We immediately ceased the administration of sevoflurane and nitrous oxide and began cardiopulmonary resuscitation (CPR) with a combination of 15 chest compressions and two ventilations (Fig. 2). We thought that it was unnecessary to perform tracheal intubation during the initial ventilation because controlled ventilation was achievable through a face mask during CPR. Therefore, we performed tracheal intubation during the switch between rescuers in order to minimize interruptions in the chest compressions. A few minutes after CPR, the previous chest compression waveform on the ECG changed, as the patient's heartbeat and breathing returned (Fig. 4). We therefore stopped CPR, inserted an intravenous catheter in the antecubital vein, and continued ventilation and monitoring until the patient regained consciousness. Throughout this incident, his SpO2 did not decrease (Fig. 2). After conferring with the operating dentist, we decided to stop the operation under general anesthesia. After the return of his spontaneous circulation, we decided to perform tracheal intubation while the patient was still unconscious and not spontaneously breathing. The patient regained consciousness relatively early because he only inhaled sevoflurane for a short period. Thereafter, he was transported to the recovery room of the ward (Fig. 4). He was monitored for 1 day at our hospital and was then discharged the next morning without any sequelae. Even after consulting with pediatricians and cardiologists at our hospital, the cause of his cardiac arrest remains unclear. After this incident, the operating dentist scheduled his dental treatment under sedation using midazolam and physical restraint.

cardiac arrest, down syndrome, general anesthesia, pediatric patient, sevoflurane

PMC10461118_01

Female

A-5-year-old girl with 17 kg weight and 104 cm height came to Otolaryngology Outpatient Clinic with the chief complaint of yellow-greenish, foul smelling discharge from right ear. The complaint had lasted for about 3 years. There was also a nonpainful post aural swelling with discharge for the past 6 months. The parents also complained that the patient's weight was decreased about 1 kg in the past 2 months. She had a history of inadequate weight increment. There was no night sweating, cough for more than 2 weeks, or low grade fever for more than 2 weeks. The patient had a history of tuberculosis contact with her father and uncle. The father underwent TB treatment at about 7 year ago but was declared to be healthy at the end of the 6 months treatment 2 years before the patient was born. The patient's uncle died due to TB about 6 months ago and had already had TB treatment for about 2 months. Contact investigation for TB had not been done. The patient had been brought to general practitioners and otolaryngologists since the complaint started. The complaint usually resolved for about 1 month after the patient had eardrops prescribed by the previous clinicians, but it usually happened again every 3-4 months since 3 years ago. On the last examination with the otolaryngologist about 6 months ago, the patient was referred to the district hospital due to the perforated tympanic membrane and from there, the patient was finally referred to our hospital. On the physical examination, we found post aural swelling about 2 x 3 cm, mobile with no pain. There was some greenish discharge came out from the right ear. Other physical examinations were within normal limits. The blood examination and chest X-ray revealed no abnormality. On physical examination, mucopurulent ear discharge and hyperemic posterior auricle at right ear were found. There was no cranial nerve paresis. Audiometry examination revealed moderate conductive hearing loss at right ear (33.75 dB) and no hearing loss at left ear. Head CT scan with contrast was done and the expertise showed right osteomastoiditis with cholesteatoma which destructed right mastoid antrum and right auricle bone. The presence of right posterior auricle abscess was also found. The patient was initially diagnosed with chronic otitis media suppurative right auricle with right mastoiditis and right posterior auricle fistulae. Afterwards, canal wall up mastoidectomy to remove mastoid air cell and mastoid obliteration continued with canaloplasty to widen ear canal, tympanoplasty to repair tympanic membrane, and rotational flap on the right auricle to close the defect were done. Intraoperatively, we found posterior auricle fistulae, dehiscence with cholesteatoma and granulous tissue at mastoid, subtotal tympanic membrane perforation and destruction of ossicles. Histopathology examination was done on the samples obtained from the ear canal. Upon examination, caseous necrosis and datia langhans cells were found. Due to the histopathological findings, the patient was referred to the pediatric pulmonology division. Mantoux test was done, resulting in 25 mm induration suggesting TB infection. GeneXpert test was done on the patient's gastric lavage sample, and no M. tuberculosis was found. Acid fast staining examination for three times also revealed no M. tuberculosis bacteria in the patient's gastric lavage samples. The patient was treated using pediatric fixed dose combination tablets intensive phase (isoniazid, rifampicin, pyrazinamide) added with ethambutol for 2 months based on the standard protocol treatment for extrapulmonary tuberculosis. Afterwards, the therapy was continued with fixed dose combination maintenance phase (isoniazid and rifampicin). The whole treatment was given for 6 months duration. After the therapy was done for 1 month, the patient was evaluated and the body weight was increased 0.5 kg. There was no more discharge coming out from the patient's right ear. The patient had no more complaint after the medication had been completed for 6 months. Upon the completion of the therapy, total weight gain was 3 kg and she was in a healthy condition.

children, diagnosis, mastoiditis tuberculosis

PMC5760466_01

Male

A 68-year-old gentleman presented to the ambulatory clinic with sudden onset of pain in the left lower chest region and upper abdomen. The pain has been persisting for some time, with flare-ups while coughing or rolling over. Significant past medical history included hypertension, diabetes mellitus, hypercholesterolemia, chronic renal insufficiency, renal stones, erectile dysfunction, diverticulosis, colon polyps, obstructive sleep apnea on continuous positive airway pressure (CPAP), peripheral arterial disease, allergic rhinitis and benign prostatic hypertrophy (BPH). Significant surgeries include those for adenoidectomy and tonsillectomy, extracapsular cataract extraction with intraocular lens implantation and lithotripsy for stones. The patient is a chronic smoker and has smoked 2 packs per day for the last 50 years. He consumes 10.5 oz. of alcohol (21 cans of beer) per week. The subject's mother suffered from type 1 diabetes mellitus and his father had undergone colectomy, likely due to cancer. The patient's paternal uncle had cancer of larynx. Current medications included metformin, enalapril, amlodipine, simvastatin and aspirin. The patient worked in a telephone company where he "fixed things". He was exposed to asbestos in childhood. He was also exposed to "thick dust" from a large bird's nest. The patient is a Vietnam veteran. Patient's review of systems did not reveal any fever, sweats, chills or fatigue. Review of all systems were largely within normal limits, except respiratory system elaborated below. There was no frank weight loss. Examination of all systems were normal, and no nodes or masses were palpable anywhere in the body. The lungs were clear to auscultation with normal vesicular breathing but some tenderness over the lower rib margin. An initial electrocardiogram (EKG)performed was normal. Patient was advised for chest X ray and counseled for cessation of smoking. The chest X-ray (CXR) revealed a loculated mass in the right upper lobe (Fig. 1A). His left lower lobe was normal, where he was reporting symptoms. Patient was advised further chest CT scan; given his long smoking history, he was advised to rule out any potential tumor. The scan revealed a 6-cm mass in the right apex with cystic areas centrally, which could represent either necrosis or air bronchogram (Fig. 1B). Patchy ground-glass opacities were seen adjacent to the mass. A 0.2 cm noncalcified nodule was seen in the right upper lobe. No mediastinal lymphadenopathy was observed. Positron emission tomography computerized tomography (PET CT) scan showed some activity, which could result from either infection or malignancy. The chest pain was gone after a month. He though had a productive cough, expectorating whitish mucus. He had mild exertional dyspnea and could climb two flights of stairs before he became short of breath. Otherwise, his energy levels were fine. The patient did not have any unintentional weight loss, neither had any exposure to tuberculosis. Further examination during this follow-up visit revealed severely diminished breath sounds throughout. There was however no pain on inspiration and no tenderness on the chest. The tongue revealed deep brown discoloration. No clubbing, cyanosis or edema were detected in the periphery. The patient was advised needle biopsy of the lung mass. Computerized tomography (CT) guided biopsy was used to obtain tissues from the inferior aspect of the lesion, which contained solid mass. The patient tolerated the procedure well. Pathological examination of the mass revealed necrosis, fibrosis and inflammation. The patient remained on high suspicion for lung cancer, despite the initial histopathology report. The patient was followed up with a thoracic surgery consult after a month. The highest on the differential for the necrotic mass was fungal infection. For the first time, the possibility of tuberculosis was assumed. The possibility of lung cancer was also kept on the list. Tuberculin skin test was ordered, and a bronchoscopy was planned with tuberculosis (TB) precautions. Bronchoscopy brushings revealed anaerobic infection with Gram negative non-Bacillus fragilis group organism. Histopathological examination revealed no malignancy, only necrotic material. Plan for right upper lobe lobectomy was planned with the patient after the results of the lung mass cultures came back. The necrotic process could result in massive hemoptysis or purulent sepsis, thus favoring the decision for surgery. After two weeks, the patient underwent wedge resection of the right upper lobe cavitary mass. Frozen section showed no evidence of malignancy or any specific infection; only necrotic lung tissues were observed. Intraoperatively, a lot of adhesions were observed. The tumor firmly adhered to the chest wall, so an extrapleural dissection was performed to deliver the mass ex vivo. The histopathological examination of the surgical specimen revealed acid fast bacilli, raising strong possibilities for tuberculosis. The patient was isolated with airborne precautions, pending further identification. The patient recovered uneventfully from surgery. The patient was started on an antituberculous regimen with isoniazid (INH), rifampicin, pyrazinamide (PZA) and pyridoxine. The patient was advised for monthly liver function tests and to abstain from alcohol and quit smoking. The histopathological examination of the lung mass revealed caseating necrosis, surrounded by few granulomas with Langhan's giant cells. Acid fast bacilli (AFB) revealed bacilli in clumps. This morphology does not favor Mycobacterium tuberculosis. Multiple sections were forwarded to University of Washington for molecular diagnosis. In paraffin embedded tissues, Mycobacterium xenopi was detected using 16s rRNA (ribosomal ribonucleic acid) gene primer set. No Mycobacterium tuberculosis or Mycobacterium avium complex was detected with hsp65 (heat shock protein 65) amplified probe.

PMC10036178_01

Female

A 44-year-old female patient, without a personal or family history of psychiatric illness, was admitted to a psychiatric ward for a psychotic episode which has started three days before, characterized by perplexity, self-referent and mystical delusions, irritability, disorganized behavior, and aggressiveness, that had emerged shortly after a cluster of nocturnal GTC seizures. Neither Schneider's first-rank symptoms nor negative symptoms of schizophrenia were present. Additionally, some degree of mental confusion with temporal disorientation, as well as sustained, divided attention and memory deficits were noticed during psychiatric hospitalization. Past medical history was relevant for epilepsy since her early thirties, which had developed after a moderate-to-severe traumatic brain injury (TBI). She did not regularly attend follow-up neurology appointments and had poor adherence to antiepileptic treatment. Ancillary tests undergone during a previous hospitalization in a neurology ward (seven years before the hospitalization in psychiatry) had documented a focal slowing activity in the left frontotemporal topography on electroencephalogram (EEG) and a right cortico-subcortical parietooccipital lesion of encephalomalacia (Figure 1) on magnetic resonance imaging (MRI). Additionally, she presented an amnestic mild cognitive impairment, possibly secondary to both the poorly controlled epilepsy and the prior TBI. During the hospitalization in the psychiatric ward for the index psychotic episode, haematological and biochemical screening, thyroid function, folic acid, and cyanocobalamin were normal, serologies for VDRL, HIV, and B and C hepatitis were negative, and valproic acid levels were subtherapeutic. She underwent a computed tomography (CT) scan, which did not reveal additional neuroimaging findings to those evidenced by the previous MRI, and an EEG, which was unremarkable. Psychotic symptoms subsided in the first 36 hours after admission upon treatment with aripiprazole 10 mg/day, valproic acid 1000 mg/day, and diazepam 10 mg taken as required. Aripiprazole was tapered off in the following months. There was no recrudescence of psychotic symptoms with the improvement of seizure control in the outpatient follow-up of neurology appointments.

PMC3326847_01

Female

A 35-year-old female presented with a history of multiple raised lesions over the vulva of 1 year duration. She was asymptomatic initially, later associated with foul smelling discharge and pain. She had similar lesions over the left upper thigh. She was otherwise healthy and there was no history of constitutional symptoms. Thirty three years ago, she was treated for multiple swellings that developed over the right side of her neck and inguinal regions on both sides. Treatment history was suggestive of antituberculosis treatment. She did not undergo any surgery or radiation therapy in the past. Her menstrual cycles were regular. She is married and has four healthy children. On local genital examination, there was a large tender polypoidal growth measuring around 10 x 6 cm involving both sides of the vulva including bilateral labia majora, clitoris, labia minora, and anterior fourchette with clear, foul smelling discharge in a few areas [Figure 1]. The lesion was firm to hard in consistency. There were few grouped papules of similar morphology over the left upper thigh and over pubic area [Figure 2]. Vulval edema was present. Multiple linear scars were present over the upper thighs and groins bilaterally. There was no regional lymphadenopathy. Complete analysis on blood, liver and renal function tests, urinalysis, and stool examinations were within normal limits. Gynecological workup and ultrasonography of the pelvic organs revealed no abnormality. Mantoux test was negative. Screening tests for human immunodeficiency virus and hepatitis B virus were nonreactive. The patient underwent simple vulvectomy and excision of left thigh growth under spinal anesthesia. Histopathological examination of the vulvectomy specimen revealed thin-walled and ectatic lymphatic channels in the superficial dermis. The dermal papillae and the dermis showed proliferating, congested capillary sized blood vessels, melanophages, and diffuse as well as perivascular mixed inflammatory infiltrate [Figure 3]. Section from the papillomatous growth over left medial thigh showed a similar picture. With the above findings, we came to a diagnosis of lymphangiectasia of vulva.

acquired lymphangioma, lymphangiectasia, lymphangioma circumscriptum

PMC9932912_01

Female

A 13-year-old female patient was admitted to our hospital for the first time on June 12, 2010 due to bruises on the right waist for more than 20 days, gross hematuria, and fever for half a month. Figure 1 is a timeline of the patient's clinical course and treatments. The right side of the patient's waist hit a hard object, resulting in lumbago on May 15, 2010. One week later, she began to develop gross hematuria, visible blood clots, no frequent and urgent urination, and no dysuria, with fever and a maximum body temperature of 38 C. She gradually developed nausea, vomiting, and edema of both lower extremities. Physical examination revealed normal blood pressure, normal development, pale complexion, clear consciousness, no jaundice, and no palpable enlargement of superficial lymph nodes. There was no congestion in the pharynx and no swelling of the tonsils. Cardiopulmonary examination showed no abnormalities. The abdomen was flat and soft, no abdominal mass was palpated, the liver was impalpable below the costal margin, there was no percussion pain in the bilateral kidney area, and no tenderness and rebound tenderness in the bilateral ureteral area. Pitting edema occurred in both lower limbs, muscle strength and muscle tone of the limbs were normal, and physiological reflexes were present. Color doppler ultrasound showed hypoechoic masses in the wall of the inferior vena cava (Figure 2A), and of the right renal vein (Figure 2B), considering the possibility of thrombosis. White blood cell count (WBC) was 17.7 x 109/L, hemoglobin was 103 g/L, neutrophil ratio was 76.70%, and platelet count was 159 x 109/L, all normal values of specific detection indexes were showed in Table 1. Albumin 26.7 g/L, blood urea nitrogen (BUN) 10.50 mmol/L, and creatinine 189.5 mumol/L were tested. Coagulation testing showed prothrombin time (PT) 10.6 s, activated partial thromboplastin time (APTT) 31.7 s, and D-dimer quantitative level 33.67 mug/ml. Microscopic examination of erythrocyte 3+/HP was found in urine and 24 hour urinary protein quantity was 5.0 g/L. After hospitalization, albumin supplementation and cefmenoxime anti-infection treatment were given. The day after admission, she suddenly experienced severe chest pain and shortness of breath, which lasted for about 10 s and then improved. The subsequent physical examination showed blood pressure 120-145/75-90 mmHg, transcutaneous oxygen saturation 80%, clear breath sounds in the left lung, decreased breath sounds in the right lower lung, and no dry/wet rales heard. The patient had persistent fever, bad psychosis, and occasional headache. Pulmonary artery CT angiography (CTA) showed embolisms of the distal main pulmonary artery, left pulmonary artery trunk and its intrapulmonary branches, and the right lower pulmonary artery (Figure 2C), as well as exudation and consolidation of bilateral lower lobes, considering the possibility of ischemic infarction. Brain MRI showed normal. Cholesterol was 6.75 mmol/L, 24 hour urinary protein quantity was 1.1 g, albumin was 13.7 g/L, erythrocyte sedimentation rate (ESR) was 97 mm/h and C-reactive protein (CRP) was 5.25 mg/L. Immunoglobulin IgG was 5.67 g/L, there were normal complement C3 and C4 (1.04 g/L and 0.13 g/L respectively), and all negative results for vasculitis, anticardiolipin antibody, anti-ANA, anti-dsDNA, anti-Sm antibodies and extractable Nuclear Antigen (ENA). She was immediately given low molecular heparin and urokinase for thrombolysis. The inferior vena cava filter was implanted under digital substraction angiography (DSA) on June 17, 2010. The patient was diagnosed with NS and thrombogenesis. Due to the use of anticoagulants, the patient was concerned about the risk of bleeding and the kidney biopsy was not completed. Then the patient took cefmenoxime for anti-infection and drugs for anticoagulation and thrombolysis, adding low-dose methylprednisolone for suppressive immunotherapy. However, the patient continued to have hypoalbuminemia and massive proteinuria, BUN and creatinine were at a high level persistently. The inferior vena cava filter was removed under local anesthesia, and cyclophosphamide pulse therapy was added 20 days later. On July 20, she was switched to warfarin for anticoagulation. The edema basically subsided, and the proteinuria gradually decreased. After discharge, the patient underwent regular follow-up checkups, the thrombi disappeared (Figure 2D). Then her urine protein turned negative after half a year, and she continued to take oral prednisone and mycophenolate mofetil (MMF) for immunosuppression, antihypertensive metoprolol, and anticoagulative warfarin for 1 year. As multiple urine analysis tested normal, all drugs were gradually reduced to stop on February 22, 2012. On July 18, 2015, the patient had no obvious cause for non-pitting edema of both eyelids and lower extremities, visible retiform purpura, and a little rash on the back of the feet. Laboratory inspections showed complement C3 < 0.179 g/L, complement C4 < 0.0643 g/L, CRP 0.72 mg/L, negative anticardiolipin IgA and anti-beta2GP1 antibody, while anticardiolipin IgG and IgM, lactic acid (LAC), anti-Anti-nuclear antibody (ANA) (1:160), ds-DNA, anti-neutrophil cytoplasmic antibodies (ANCA), anti-U1-nPNP (3+), anti-Sm (3+), anti-centromere (3+), anti-dsDNA (2+), anti-nucleosome (+), and anti-ribosomal P protein (3+) antibodies were all positive. Moreover, lymphocyte subsets, direct antiglobulin test (DAT), tuberculosis (TB) and hepatitis B tests were all negative. BUN was 7.23 mmol/L, creatinine was 80.0 mumol/L and 24 h urinary protein was 1.0 g/L. Renal pathology suggested lupus nephritis (LN) (type VI according to ISN/RPS Classification Standard) (Figures 3A-I). The patient was given ceftazidime for anti-infection, oral hydroxychloroquine, fosinopril for kidney protection, heparin sodium, urokinase for anticoagulation and thrombolysis, and dipyridamole for antiplatelet aggregation, followed by 5-time cyclophosphamide pulse therapy, then she was treated with oral MMF, and high-dose methylprednisolone for 3 days before oral prednisone. The patient underwent 3-time allogeneic cord blood stem cell infusions and was discharged from the hospital after her condition improved. The patient took medicine regularly post-discharge. The edema of both lower extremities and eyelids progressively worsened, and the knee joints were painful on November 28, 2015. Serum complement C3 was 0.84 g/L and C4 was normal. Jo-1 (+), Scl-70 (+), anti-ANA (homogeneous type) and anti-C1q (+) antibodies and LAC were all positive, anticardiolipin antibody was negative. Vascular B-ultrasound showed bilateral popliteal vein blood flow, and bilateral mural thrombosis was considered (Figures 1E,F). The patient was treated with rituximab for immunosuppressive therapy, cefotiam for anti-infection, heparin sodium, urokinase for anticoagulation and thrombolysis, sequential warfarin and dipyridamole for anticoagulation, and continued oral prednisone, MMF, and hydroxychloroquine. After discharge, the patient was regularly followed up, and the urine protein gradually turned negative, and then all the drugs were gradually stopped. Currently, she has been off medication for 5 years and is generally in good condition.

antiphospholipid antibody, antiphospholipid syndrome, gross hematuria, nephrotic syndrome, systemic lupus erythematosus

PMC9035948_01

Female

The 21-year-old female patient was admitted to the thoracic surgery department of our hospital due to progressive dysphagia accompanied by nausea and vomiting after meal consumption for 2 months. Chest computed tomography (CT) showed a spherical soft tissue mass in the upper thoracic esophagus, with obvious narrowing of the lumen (Fig. 1). The size of the lesion was about 30 x 26 mm, which was mild uniform enhancement. No obvious enlarged lymph nodes were found in the mediastinum. Abdominal CT, neck ultrasound, brain MRI, and bone ECT revealed no obvious abnormalities. Flexible esophagoscopy confirmed a large polypoid mass 18 cm away from the incisor teeth, completely obstructing the esophagus within the intact mucosal surface, presenting with formation of mucosal bridges (Fig. 2a). Endoscopic ultrasonography of esophagus showed that the lesion arose from the esophageal muscularis propria with a smooth and continuous adventitia (Fig. 2b). The primary clinical diagnosis was that of submucosal lesions of the upper thoracic esophagus, possibly a leiomyoma. Thoracoscopic esophageal lesion resection under general intravenous anesthesia after completing all investigation was done. A 2.9 x 2.1 x 3.0 cm mass in the upper thoracic esophagus was seen during the operation. Taking precautions to avoid any damage, the muscle layer was carefully separated, and the mucosa was carefully peeled off. After complete tumor removal, the muscle layer defect was about 3 cm long, and the mucosal layer was damaged in three spots due to dense adhesions. The mucosal layer was repaired thoracoscopically, and the stumping muscle layer was pulled to the middle for an end-to-end anastomotic procedure, which was covered and sutured using the surrounding pleura. The resected esophageal mass was submitted to undergo histology, immunochemistry, and genetic studies. Histologically, the tumor consisted of a markedly cellular tissue with a trabecular growth pattern accompanied by hemorrhage on hematoxylin and eosin staining (Fig. 3a). In addition, the classical Homer-Wright rosettes were also seen (Fig. 3b). Tumor cells had small, uniform, mildly atypical nuclei with granular chromatin and small amounts of cytoplasm (Fig. 3a, b). Immunoperoxidase stains were performed on a Ventana NEXES Automated Immunohistochemistry System (Fuzhou Maixin Biotech Co., Ltd., Fuzhou, China). CD99 (clone O13; Maixin) (Fig. 3c) and P63 (clone MX 013; Maixin) were positive in the tumor cells. Vimentin (clone MX 034; Maixin) was less positive. Furthermore, tumor cells did not stain for synaptophysin (clone SP 11; Maixin), pan-cytokeratin (clone AE1/AE3; Maixin), and CD56 (clone 123C3. D5; Maixin) (Fig. 3d). Ki-67 was reactive in approximately 55% of the tumor cells. Formalin-fixed and paraffin-embedded tissue sections were prepared, and fluorescence in situ hybridization (FISH) was performed with the EWSR1/FLI1 Fusion Translocation t(11;22) Probe (Guangzhou LBP Medicine Science & Technology Co., Ltd., Guangzhou, China), and two hundred interphase cells were examined. The patient's sample was positive for EWS/FLI1 transcripts associated with t(11;22)(q24;q12) (Fig. 3e), which signal modes are as follows: 1 G1R1F 37.0%, 2 G1R1F 10.0%, 2 G2R1F 4.0%, 1 G1F 10.0%, 2 G1F 10.0%, 1R1F 7.5%, 1R2F 5.0%, 1 G2F 7.5%, and 1 G1R2F 9.0%. After 2 months after the operation, the patient received 2 cycles of EP (etoposide/cisplatin) chemotherapy, followed by chest radiotherapy and concurrent EP regimen chemotherapy for 2 cycles and then continued to receive 2 cycles of EP regimen adjuvant chemotherapy. Chest radiation was delivered using intensity-modulated radiation therapy (Fig. 4a-c) as follows: the planning gross tumor volume of the tumor bed (TB) (PGTVtb) and planning target volume (PTV) were administered using 56 and 50.4 Gy in 28 daily fractions of 1.8-2.0 Gy, respectively. The clinical target volume (CTV) depended on the location of the primary tumor and was irradiated using involved-field radiotherapy. The CTV included GTVtb with a radial margin of 0.5-1.0 cm and a longitudinal margin of 3 cm. The CTV and GTVtb with a margin of 0.5 cm in three dimensions formed the PTV and PGTVtb, respectively. Chemotherapy consisted of cisplatin 25 mg/m2 and etoposide 100 mg/m2 per day on days 1 through 3 every 21 days for up to six cycles. The patient has been followed up regularly for one and half years after surgery and for 1 year after adjuvant radiotherapy/chemotherapy including clinical examination, ECT, chest CT, and gastroscopy. No obvious signs of recurrence or metastasis were found, and the patient's general condition was satisfactory.

diagnosis, esophagus, extraosseous ewing sarcoma, primitive neuroectodermal tumor, treatment

PMC5438011_01

Male

A 66-year-old male with comorbidity of diabetes mellitus and polyneuropathy underwent a living donor renal transplantation in 2013. A left-sided kidney was placed in the right iliac fossa. There was primary renal function and baseline creatinine was 83 mmol/L. The patient presented with a one-day history of accidentally tripping and sustaining a fall on his way home from a football match. Though the impact of the fall was on the same side as his renal allograft, his presenting complaint was pain over the right chest wall. On examination, his pulse rate was 90/min and blood pressure was 164/72 mmHg. There was tenderness over the right chest wall but the abdomen was soft and the transplanted kidney was non-tender. A urine dipstick test was negative for red blood cells. There was no decrease in hemoglobin levels (Hb 11.9 gm/dL, WCC 10.3). Serum creatinine increased to 302 mmol/L. An ultrasound scan of the abdomen revealed an increased echogenicity of the kidney with a high resistive index of 0.96 and a perinephric hematoma which was 2.5 cm deep. A CT scan confirmed the presence of hematoma limited to the subcapsular space over the anteromedial surface of the kidney (Figure 1). The patient was managed conservatively for 2 days as there was no decrease in hemoglobin levels. Creatinine levels deteriorated over the next 48 hours to 453 mmol/L and the patient's blood pressure continued to increase to 196/90 mmHg. On the 3rd day of admission, he developed mild tenderness over the transplanted kidney and an ultrasound was repeated. This showed an increase in the size of the subcapsular hematoma to 11 x 4 cm mainly anterior to the kidney and compression of the kidney parenchyma and vasculature (Figure 2). The resistive index increased further with a reversal of diastolic flow but no direct compression of the renal blood vessels (Figure 3). There was no associated hydronephrosis. The transplanted kidney was explored immediately and a large perinephric hematoma was evacuated. There was a small laceration on the anterior surface of the transplanted kidney which was not actively bleeding. A drain was inserted, topical hemostatic agents were applied, and the wound was closed. The patient recovered and creatinine levels returned to baseline (99 mmol/L) within 3 days.

page kidney, renal allograft, trauma

PMC9891144_01

Female

An 80-year-old Caucasian woman was hospitalized with a 2-month course of intermittent fever (max. 38 C), asthenia, weight loss (12%), anorexia and nausea. Her medical history includes breast cancer submitted to radical mastectomy and axillary lymph node dissection, papillary thyroid carcinoma and pulmonary and ocular tuberculosis that had been treated more than 5 years previously. She had heart failure, arterial hypertension, dyslipidaemia and obesity under treatment. Physical examination showed obesity and left upper limb lymphedema. Abdominal and rectal examinations were unremarkable. A laboratory study revealed iron deficiency anaemia with haemoglobin 10 g/dL and ferritin 10 ng/mL (normal = 10-120 ng/mL), elevated lactate dehydrogenase 1,379 U/L (normal <247 U/L), aspartate transaminase 59 U/L (normal <31 U/L), alkaline phosphatase 185 U/L (normal = 30-120 U/L), C-reactive protein 21.9 mg/dL (normal = 0-0.5 mg/dL) and a normal procalcitonin value. A bacterial, mycobacterial, viral or fungal infectious disease was excluded by blood, urine and sputum cultures. A thoracic abdominal and pelvic computerized tomography (CT) scan was negative for malignant disease. During hospital stay she presented with intense nausea and vomiting during most meals. A red blood cell transfusion was necessary due to progressive decrease in haemoglobin. Upper endoscopy was performed showing multiple black nodular lesions in the stomach and duodenum (Fig. 1). Narrow-band imaging revealed the presence of black patches on the top of these nodular lesions (Fig. 2). Histopathological examination showed an epithelioid malignant injury with intense and diffuse HMB45 expression suggestive of pigmented melanoma (Fig. 3). The diagnosis of gastrointestinal metastatic melanoma was made. A positron emission tomography/CT scan revealed the presence of bone, cervical and mediastinal lymph node metastases. BRAF gene mutation was not present. The primary tumour was not found. Due to the patient's limited functional status no treatment was initiated, and death occurred 4 months after diagnosis. We present a metastatic gastric melanoma in an elderly woman without any history of melanoma with a very rare presentation. Melanoma gastrointestinal metastases are rare and represent a late stage of malignant disease. Its incidence in clinical and autopsy series varies between 0.2 and 0.7%, and it has been reported that only 7% of gastric metastases are due to malignant melanoma. Primary tumours commonly occur in the skin but can also develop from other tissues containing melanocytes such as the meninges, gastrointestinal tract and eyes. Primary or metastatic malignant melanoma of the gastrointestinal tract is an uncommon entity, and more than 90% of cases are identified only during autopsy. The most common gastrointestinal metastatic sites are the jejunum and ileum, followed by the colon, rectum and stomach. The diagnosis is difficult due to non-specific symptoms. Symptoms are present in only 1-4% of patients, and they are related to complications such as haemorrhage, obstruction and perforation. Imaging studies have low sensitivity for diagnosing, and CT sensitivity is only 60-70% in detecting metastases. Gastrointestinal endoscopy allows the diagnosis. Depending on the patient's functional status, treatment includes surgical resection, immunotherapy, targeted and radiation therapy. The average life expectancy following diagnosis is 4-6 months. This study did not require review or approval by the appropriate ethics committee. Written informed consent was obtained from the patient's next of kin.

duodenal metastasis, gastric metastasis, melanoma

PMC7608070_01

Female

A 4-year-old malnourished girl (11 kg, < 3 rd percentile) was admitted to the Hospital Infantil Menino Jesus, Sao Paulo State, Brazil, with a history of intermittent fever for 20 days, diarrhea without blood, night sweats, weight loss and dry cough. The patient had no comorbidities, no history of contact with a patient with pulmonary tuberculosis and received BCG vaccination. Laboratory exams revealed anemia (hemoglobin 8.8 g/dL), leukocytosis 21,600/mm 3 (1% band, 79% segmented neutrophils, 15% lymphocytes and 10% monocyte), platelets 269,000/mm 3 , INR 1,25, urea 18 mg/dL (normal range 7-18), creatinine 0.2 mg/dL (normal range 0.66-1.25), alanine transaminase 22 U/L (normal range < 35) and aspartate transaminase 29 U/L (normal range 15-50). Chest radiography presented a miliary pattern ( Figure 1 ). Ceftriaxone and first-line oral anti-tuberculosis agents (RHZ: rifampicin, isoniazid and pyrazinamide) were introduced after the diagnosis of disseminated tuberculosis confirmed by gastric washing that identified a rifampicin-sensitive Mycobacterium tuberculosis (X-pert MTB/RIF assay). The patient evolved with respiratory distress, septic shock, melena and hematochezia with massive bleeding requiring red blood cell transfusion of about 80 mL/kg six days after starting the enteral anti-tuberculous therapy. Upper digestive endoscopy, colonoscopy and angiography failed to identify the bleeding source. The macroscopic findings of endoscopy revealed no abnormalities in the esophagus and stomach. In the duodenum, there was a shallow ulceration in the second portion with no sign of active bleeding. A duodenal biopsy showed chronic duodenitis and a positive acid-fast bacilli test ( Figure 2 ), confirming the diagnosis of disseminated tuberculosis. The abdominal tomography revealed lymphadenopathy, jejunal loops clusters with difficult identification of their contours, distal ileal and sigmoid wall thickening ( Figure 3 ). The patient did not receive any medications that could increase the risk of bleeding, except for hydrocortisone due to the refractory septic shock. The severity of the case and the intestinal involvement cast doubt on the expected response of the enteral absorption of oral drugs. Thereafter, an intravenous second line drug therapy was associated: linezolid (10 mg/kg/day), amikacin (15 mg/kg/day), meropenem (120 mg/kg/day) and ciprofloxacin (20 mg/kg/day). After seven days of combined therapy there was no more bleeding. Linezolid was suspended after 14 days of treatment, amikacin after 7 days, meropenem after 12 days and ciprofloxacin after 14 days. She was discharged after 35 days of hospitalization with RHZ regimen. The patient's parents had neither respiratory symptoms nor abnormalities on their chest radiographs.

PMC2732485_01

Female

A 72-year-old woman with a history of recurrent meningioma of the sphenoidal ridge, dementia, and depression was hospitalized because of fever and general deterioration of 5 days' duration. On admission, the patient was responsive only to painful stimuli and had generalized muscle stiffness and limb tremors. Clinical and laboratory values were consistent with viral encephalitis; thus, the patient was initially treated with intravenous acyclovir for presumptive herpes simplex encephalitis. When polymerase chain reaction (PCR) analysis of cerebrospinal fluid (CSF) showed no evidence of herpes simplex virus infection, and WNV antibodies were detected in serum and CSF, acyclovir was discontinued and ribavirin was initiated at an oral dosage of 2.4 g per day. The patient's clinical status continued to deteriorate with aspiration pneumonia and intermittent generalized seizures. Intravenous immunoglobulin was added (35 g/d for 2 days) without improvement. Approximately one month after onset of illness, the patient died of respiratory failure. Postmortem examination of the brain showed multiple meningiomas, generalized atrophy, and surgical resection of the right parietal lobe. Histology was remarkable for neurofibrillary plaques consistent with Alzheimer's disease, and scattered microglial nodules and perivascular lymphocytic inflammation in the medulla, pons, and midbrain were consistent with viral encephalitis. RNA was extracted from frontal cortex and cerebellum with TRI-Reagent (Molecular Research Center, Cincinnati, OH). Four micrograms of total RNA from each brain region was used as a template for reverse transcription-polymerase chain reaction (RT-PCR) with primer sets representing three regions of sequence conservation in flavivirus genomes: NS3-1 (EDL/Fla-U5004, 5 - GGA ACD TCM GGH TCN CCH AT and EDL/Fla-L5457, 5 - GTG AAR TGD GCY TCR TCC AT), NS5-1.1 (EDL/Fla-U9093, 5 - AGY MGR GCH ATH TGG TWY ATG TGG and EDL/Fla-L9279, 5 - TCC CAV CCD GCK GTR TCA TC), and NS5-2 (EDL/Fla-U9954, 5 - GSS AAA KCH TAY GCN CAV ATG TGG and EDL/Fla-L10098 5 - AGC ATR TCT TCH GTN GTC ATC CA). Amplification products were obtained with RNA derived from the cerebellum in reactions with all three primer sets; no amplification products were obtained with RNA from the cortex. These amplification products were cloned into the pGEM-Teasy vector (Promega, Madison, WI) and subjected to automated dideoxy sequencing (ABI Prism Model 377, Foster City, CA). Sequences were submitted to GenBank (NS3, GenBank accession no. AF394218; NS5, GenBank accession nos. AF394219 and AF394220). Signal of cerebellar amplification products in ethidium bromide-stained gels was reduced in comparison with similar studies performed with brain materials from four patients of the 1999 New York City outbreak (data not shown; New York patients were 75 years to 80 years of age, 3 male, 1 female, who died of severe WNV encephalitis during the 1999 outbreak). The relative virus load was 140 copies/200 ng RNA in the Israeli sample, indicated by 5 -nuclease real-time RT-PCR, compared with 7000 to 20 copies/200 ng RNA in specimens analyzed from the New York City outbreak (Table). However, since the virus load of the sample from Israel was within the range of virus loads observed with the New York samples, this result for a single Israeli sample may not indicate a strain difference. Quantitative analysis was restricted to the NS5 target because no signal was obtained with primer/probe set prNS3 (fwd, 5 - GCa CTG AGA GGA CTG CCc AT; probe, 5 -6FAM-TAc CAG ACA TCc GCA GTG cCC AGA-T-TAMRA; rev, 5 - TGg GTG AGG GTa GCA TGa CA), because of point mutations in WNV-ISR2000 sequence that prevented efficient hybridization with the primer and probe oligonucleotides (fwd - 2 mismatches, probe - 3 mismatches, rev - 3 mismatches; given above in lower case). Sensitivity was not substantially reduced in assays with primer/probe set prNS5, which had one mismatch in the 3'-terminal sequence of the probe oligonucleotide (Table). Sequence analysis of the cloned NS3 and NS5 gene fragments indicated similarity to completely sequenced Romanian and Russian WNV isolates WNV-RO97-50-1996 and WNV-RUS-VLG4-1999, respectively; thus, to facilitate detailed phylogenetic analysis, E gene sequence from the Israel human brain sample was amplified. An E gene sequence of 1509 nucleotides (GenBank Accession Number AF394217) was amplified from total RNA by using GeneChoice UNIPOL polymerase (PGC Scientific, Gaithersburg, MD) and primers EDL/E-U1006 (5 - GGA GTG TCT GGA GCA ACA TGG GT) or EDL/E-U1476 (5 - TCC TGC GGC GCC TTC AT) and EDL/E-L2244 (5 - CCC CTC CAA CTG ATC CAA AGT CC) or EDL/E-L2538 (5 - TCC ATC CAA GCC TCC ACA TCA), respectively. Sequence analysis of this fragment confirmed data from NS3 and NS5 sequence analyses, indicating a closer relationship of WNV-ISR-hISR2000 sequence to Romanian and Russian isolates than to the 1997/98/99 Israeli and the WNV-NY1999 isolates (Figure). The extent to which this WNV genotype contributed to human disease in the 2000 epidemic remains undetermined. WNV-ISR-hISR2000 may have been carried into Israel by migrating birds from reservoirs in southeastern Europe or reservoirs in northeastern Africa, where a highly related virus was isolated in 1998 (WNV-KEN-KN3829-1998). The 2000 Israel isolates in birds (and pigs, strains ISR-00GooMaS and ISR-00PigC) were different from the previous Israeli isolates (1997/98/99; strains ISR-97Goo1, ISR-98Goo1, ISR-IS98St1, ISR-99Goo, and ISR-99Gull [Figure]), but similar to the human isolate. Nonetheless, precedent exists for implicating more than one genotypic variant in a WNV outbreak. During the 1999 outbreak in Volgograd, Russia, two different genotypes were isolated: WNV-RUS-ASTR986-1999 (similar to 1997-98-99 Israeli and the WNV-NY1999 isolates, genotype lineage I subtype 2a) and WNV-VLG22889/WNV-RUS-VLG4-1999 (similar to WNV-ISR-hISR2000, subtype 2b [Figure]). Indeed, even more divergent genotypes were identified during the 1996-97 WNV outbreak in Romania (WNV-RO97-50-1996 similar to WNV-ISR-hISR2000, genotype lineage I subtype 2b; WNV-RO96-1030-1996 and WNV-ROM96(0334)-1996, belonging to a different subtype, subtype 1 [Figure]). The fact that no such divergence of genotypes of WNV isolates was observed during the 1999 New York epidemic (Figure) was interpreted as being compatible with a single, new introduction of this virus to the Western Hemisphere. While this manuscript was under review, another group reported WNV sequences from four patients of the 2000 Israel outbreak: two isolates most closely related to WNV-R097-50-1996 and two identical to the WNV-NY1999isolates. Analysis of additional isolates from the Israel 2000 and other outbreaks, including isolates obtained in 2000, 2001, and subsequent years in the USA, will be required to establish the extent to which avian migration and viral mutation contribute to the epidemiology of WNV-related disease.

PMC3014684_01

Female

Our patient was referred to us at 6 months of age with left axillary lymphadenitis that grew the vaccine strain of Mycobacterium bovis (BCG), a routine vaccine given in day one of life in Saudi Arabia. There was no granuloma formation on the lymph node biopsy. She was otherwise well apart from intermittent fever and night sweats. Her parents were not consanguineous but from the same tribe. She had a 5-years-old brother who had left axillary BCGitis in infancy that resolved promptly after treatment with isoniazid alone for 6 months. She also had a 7-years-old sister who has been completely healthy. She did not respond to isoniazide and rifampicin. Sensitivity results then showed that the organism was resistant to both, so she was started on ethambutol 300 mg OD, cycloserine 250 mg OD, and moxifloxacin 200 mg OD for which the organism was sensitive. Meanwhile, immunological investigations revealed that our patient's lymphocytes have no IFN-gamma production in response to IL-12+BCG as compared to controls (those investigations were performed in Dr. Casanova's lab in Paris. Her parents were travel controls). Her brother had a similar cellular phenotype (i.e., no IFN-gamma production after BCG and BCG+IL-12 stimulation in whole-blood assay) (Table 1). In addition, no cell surface-expressed IL12RB1 could be detected from their PHA-T cell blast (data not shown). Genetic testing confirmed that she and her brother have homozygous 1336delC mutation in the IL12RB1 gene, leading to complete IL12Rbeta1 deficiency. Her sister was functionally and genetically normal. To our knowledge this is the only family with this specific type of mutation to be reported. After parental consent, baseline and followup investigations were obtained including CBC, ESR, liver enzymes, lymphocytes subsets, and tuberculin skin test (TST) every 3 months. Immunoglobulin levels, serum mycobactericidal activity, and lymphocytes proliferation in vitro were performed every 6 months. The patient was seen in the clinic every 6 weeks. IFN-gamma-1b (Imukin, Boehringer Ingelheim) was started at a dose of 50 mug/m2 subcutaneously 3 times/week. If there is no significant response within 3 months the dose will be doubled to 100 mcg/m2, at the same frequency. Blood samples were taken from the patient before starting treatment with IFNgamma (S1), 6 months (S2) and 12 months (S3) after starting treatment. PBMCs were isolated from whole blood by density centrifugation (Lymphoprep, Nycomed, Oslo, Norway) and assayed for in vitro proliferative responses by the thymidine incorporation method against phytohemagglutinin (PHA) (Sigma, St. Louis, Mo.) and IL2 (R&D System, Abington, UK). The proliferation results are expressed as mean count per minute of triplicate cultures for the antigen concentration giving maximum response minus the mean count-per-minute values for 12 wells without antigen (medium only). Two specimens of the patient's serum were collected at 6 months and 12 months of the study period, 2 hours after anti-mycobacterial drug administration, to determine the serum inhibitory and bactericidal titers against the patient's mycobacterial isolate as well as mycobacterium bovis BCG vaccine strain (Statens Serum Institute, Copenhagen S, Denmark) and mycobacterium tuberculosis H37RV reference strain (ATCC, Atlanta, GA, USA), as previously described.

PMC10458975_01

Female

A 5-year-old Chinese girl had persistent cough for a few months following an acute episode of pneumonia, despite multiple courses of oral and intravenous antibiotics. The serial chest X-rays (CXR) showed non-resolving consolidation of the right middle lobe (RML) (Fig. 1a). The inflammatory markers including white cell count, neutrophil count, C-reactive protein, erythrocyte sedimentation rate and procalcitonin were normal. Haemophilus influenzae and Moraxella Catarrhalis were isolated from two respiratory specimens respectively, and antibiotics had been given accordingly. The workup for pulmonary tuberculosis was negative.

activated phosphatidylinositol 3-kinase delta syndrome (apds), bronchial actinomycosis, cobblestone airway, endobronchial nodules

PMC7652781_01

Female

A 32 year-old-woman without past medical history, presented to emergency room for focal motor seizures of the right upper limb, happening thrice, with impaired awareness between the seizures. At admission, physical examination revealed a fever (39 C) and regular heartbeat. Neurologic examination showed a Glasgow Coma Scale score of 15/15 (Eye opening = 4, Verbal response = 5, Motor response = 6). The patient did not complain about headache, vomiting or neck stiffness, she was only drowsy without focal abnormalities. Seizures were controlled with Intra-Venous (I.V) then oral antiepileptic treatment (clonazepam and levetiracetam). The initial anamnesis found no history of seizures, neither signs of high intracranial pressure. Laboratory findings revealed high leukocytes count (15.5 Giga/mm3) and elevated of C-reactive protein (70 mg/L). Brain Magnetic Resonance Imaging (MRI) showed a single round well circumcised lesion in the left frontal lobe, measuring 22*19 mm with low T1 and high T2 signal, heterogeneous with peripheral enhancement, with a distinctive high signal in Diffusion sequences, and ADC restriction in some areas (Fig. 1). These results were in favor of a brain abscess. Extensive investigation found no history of immunologic deficiency, no susceptibility to infections, no diabetes, no intrauterine device, no injectable drugs use. However, the patient revealed that she was self-treating some "tooth pain" with only high doses of non-steroid anti-inflammatory three weeks before. Blood and urine culture were negative. A lumbar puncture (LP) was not performed, because of the raised intracranial pressure and the risk of cerebral herniation. Computed Tomography (CT) scan of chest, abdomen and pelvis showed no associated locations. Transthoracic and transesophageal cardiac sonography were normal. Serology for HIV, hepatitis B and C hepatitis and toxoplasmosis were negatives. Aspergillus antigenemia was also negative. The patient was operated: a puncture of the abscess and a removal of the shell (complete resection) were performed through a small frontal craniotomy, with no postoperative complications. Treatment began with antimicrobial drugs empirically (cefotaxime 18 g IV infusion/d), levofloxacin (500 mg IV 2x/d) and metronidazole (500 mg IV 3x/d). Direct bacteriological and mycological exams were negative. PCR-Based Rapid Detection of Mycobacterium tuberculosis was also negative. After 24 h of culture on Chloramphenicol Sabouraud agar medium with and without Actidione at 37 C, white, creamy, flat, and shiny colonies appeared. C. glabrata was identified by VITEK 2 (Fig. 2). To test the sensitivity to antifungals, we used the automated VITEK 2 using the antibiotic susceptibility testing (AST) card. The antifungal susceptibility testing showed resistance to fluconazole and sensitivity to voriconazole, caspofungin, micafungin, amphotericin B and flucytosine. The Minimum Inhibitory Concentration (MIC) of voriconazole was 1 mg/L. Bacterial culture was negative. Brain abscess due to C. glabrata without candidemia was diagnosed. Antifungal treatment began with voriconazole (400 mg [6 mg/kg] twice first day orally then 200 mg [3 mg/kg] twice daily). The clinical course was rapidly favorable with resolution of neurological symptoms. The patient had undergone subsequent MRI brain (on day 21) showing complete resolution of the rim-enhancing lesion, without evidence of residual or recurrent abscess. Antifungal treatment was stopped on the day 24 and the patient was discharged.

brain abscess, candida glabrata, candida spp, immunocompetent

PMC7399065_01

Male

A 99-day-old boy was admitted to our hospital because of "abdominal B-ultrasound indicating gallbladder sludge for 2 months." The infant was diagnosed with left nephroblastoma at birth. In the second cycle of chemotherapy, abdominal B-ultrasound indicated a low echo area in the gallbladder, and the diagnosis of gallbladder sludge was accordingly considered. The child exhibited jaundice and a progressive elevation in gamma-glutamyl transferase (gamma-GT). He was transferred to our hospital for further treatment. The physical examination on admission revealed the following: temperature: 36.7 C, pulse rate: 154 times/min, respiratory rate: 36 times/min, blood pressure: 90/62 mmHg, percutaneous oxygen saturation: 97%, and weight: 7.5 kg. Mild jaundice was noted. He had no rash or blood spots on his skin. The heart and lung examinations were unremarkable. His abdomen was flat and non-tender and had no rebound tenderness. No mass was palpated. Murphy's sign was negative. The laboratory results revealed the following (Table 1): total bilirubin (TB) 73.4 mumol/L, conjugated bilirubin (CB): 55.9 mu/L, alanine aminotransferase (ALT): 84 U/L, aspartate aminotransferase (AST): 103 U/L, gamma-GT: 2,189 U/L, alkaline phosphatase (ALP): 607 U/L, blood amylase: 3 U/L, white blood cells (WBCs): 10.9 x l09/L, percentage of neutrophils: 8.9%, and percentage of lymphocytes: 81.5%. Blood coagulation function and routine urine and stool values were normal. B-ultrasound was repeated and showed that the diameter of the upper segment of the CBD was 0.8 cm. A hypoechoic mass was noted in the lower CBD. The CBD and intrahepatic bile duct were dilated. After full communication and preoperative examinations were completed, the infant underwent ERCP. He was placed in the prone position and underwent ERCP under general anesthesia with intubation. An Olympus JF240 duodenal endoscope was used. The duodenal papilla appeared and had a granular, fluffy opening. An Olympus triple-lumen needle knife and a 0.025-inch Loach guide wire were used to achieve successful selective biliary cannulation. The bile sample obtained during backsuction was cloudy and dark. Under fluoroscopy, cholangiography was performed from the upper to lower segment of the CBD and showed dilation of the CBD (1.1 cm in diameter). Multiple contrast filling defects were observed in the CBD. At the 12 o'clock site of the bile duct, a small, 0.2 cm longitudinal incision was made in the papilla. No bleeding was observed at the cutting edge. A grasping basket was used to remove multiple black stones. Finally, a stone retrieval balloon was used to remove the stones in the bile duct. A 6 Fr straight-tip nasobiliary drainage catheter was placed at the end of the ERCP (Figures 1A-F). The endotracheal tube was removed upon awakening. The patient had stable vital signs and was returned to the ward. An laboratory results were repeated 72 h after ERCP and showed the following (Table 1): TB: 28.3 mumol/L, CB: 23.7 mumol/L, ALT: 33 U/L, AST: 31 U/L, gamma-GT: 1,033 U/L, AKP: 201 U/L, blood amylase: 3 U/L, WBCs: 9.8 x l09/L, neutrophils: 24.1%, and lymphocytes: 62.3%. The jaundice markedly improved. He was energetic and had acceptable food intake. Four days after ERCP, cholangiography was performed via a nasobiliary catheter and showed smooth draining of the contrast agent and no residual stones in the bile duct. Then, the nasobiliary catheter was removed. A liver function examination was repeated 1 week after ERCP; the profile had returned to normal. The patient was discharged.

ercp (endoscopic retrograde cholangiopancreatography), anesthesiology, child, common bile duct (cbd) obstruction, experience, particularities

PMC5339737_01

Female

This SLS patient was a 19-year old female with generalized ichthyosis, intellectual disability, underlying hypotonia, and spastic paraparesis. She had bilateral radial head dislocation of the elbows and had undergone hamstring release 16 years previously. An ITB trial 6 years earlier made her floppy and unable to walk, so a pump was deferred. At baseline, the patient had daily physical and occupational therapy and was on oral baclofen 10 mg TID. She was capable of walking 2-3 blocks with her posterior walker and ankle-foot braces, but ambulated with great difficulty and employed a manual wheelchair often. Her increasing tone impeded daily care and hygiene. She was considered for ITB therapy to ease care while weighing the potential for interference with her potential for ambulation. After a positive ITB trial, she underwent ITB pump implantation. The initial baclofen dose was 39.9 mcg/day. After surgery and rehabilitation, an observable improvement was noted with muscle tone relaxation in both legs, but without lethargy, excessive hypotonia or loss of axial control. She continued to have daily physical and occupational therapy. Over the ensuing of six months, her ITB dose was increased to 135 mcg/day to progress with gait training, strengthening, and to address residual spasticity. This ITB dose was intermittently too high, resulting in difficulty with gait and hypotonia, causing her knees to buckle, so the ITB dosage was titrated to allow active standing and lower extremity strengthening. A daily flexible dose delivery was eventually programmed. Three years after surgery, her standing dose is 86 mcg/day due to potential drug interaction with an antidepressant (citalopram). At this dose, the patient has a substantial improvement compared to baseline spasticity (see Table 1) and shows no signs or symptoms of ITB over- or underdosage.

modified ashworth scale, sjögren-larsson syndrome, baclofen pump, intrathecal baclofen therapy, spasticity