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PMC4664794_01

Female

A 57-year-old woman presented to the rheumatology clinic with recurrent fever and painful ulcers on her legs since two months. Eight months prior to current presentation, she developed vertigo and decreased hearing in her left ear which she felt was "full of air" all the time. She was found to have sensorineural deafness in her left ear. Two weeks later, she developed fever with chills. A chest radiograph revealed infiltrates in her right lung and an elevated ESR. She was treated with oral antibiotics which relieved her symptoms. Then she developed gingival hypertrophy and a CT scan of the paranasal sinuses revealed subcutaneous soft tissue thickening of the right buccal area suggestive of an inflammatory process. She was treated with ibuprofen and felt better. Her past medical history was notable for hypothyroidism for 20 years and she as well was maintained on 50 mcg of thyroxin daily. She had undergone hysterectomy for uterine fibroids 15 years ago. She reported no recent travel history. Of note, she revealed contact with sick animals. She nursed her paralyzed pet dog and also had cats. She was treated with antibiotics yet continued to spike fever and came to our center for comprehensive evaluation. On examination, she appeared weak and ill. The temperature was 37.5 C, the blood pressure 139/69 mm Hg, the pulse 78 beats per minute, and the respiratory rate 16 breaths per minute, with 99% oxygen saturation at room air. Erythematous tender nodules were noticed on bilateral lower extremities (Figure 1). The remainder of the examination was unremarkable. Her complete blood count revealed normocytic, normochromic anemia with normal white cell and platelet count. Her biochemistry showed normal kidney and liver function. No active sediment was present on urinalysis. Her three sets of blood cultures and one urine culture reported no growth. The test for latent tuberculosis by interferon gamma release assay (IGRA) was also negative. Serology for Brucella abortus and melitensis also came negative. Tests for chronic viral hepatitis B and C were also normal. Serological tests for connective tissue disease were negative as was the serum angiotensin converting enzyme level. Other relevant investigations are outlined in Table 1. An upper abdominal ultrasound showed hypoechoic, cystic lesions scattered across both lobes of the liver (Figure 2). A subsequent CT scan of the abdomen with contrast showed multiple oval hypoattenuating lesions in both lobes of the liver (Figure 3). On liver biopsy there was evidence of cholestasis and multiple large irregular areas of necrosis, palisaded by epitheloid cells with associated granulomatous inflammation with a number of plasma cells (Figure 4). Acid-fast bacilli culture of liver biopsy specimen after six weeks came out negative. Meanwhile, the patient continued to spike fever with maximum temperature of 101 F. Leg lesions were becoming worse with central necrosis and purulent discharge (Figures 5 and 6). Pus cultures were negative for bacterial, fungal, and mycobacterial growth. A biopsy of the skin was performed. Pathological examination of frozen sections revealed surface ulceration with fibrinoid necrosis and vasculitis involving superficial and deep dermal vessels along with granuloma formation, neutrophilic infiltration, and debris (Figure 7). Immunohistochemical testing was performed on biopsy specimen using immune-alkaline phosphatase technique which came negative for mycobacterial species. Real-time PCR for mycobacterial species also turned out to be negative. It was concluded from the skin biopsy that the patient had cutaneous granulomatous vasculitis. Treatment was commenced with prednisone 1 mg/kg/day and the patient was offered induction with cyclophosphamide which she refused due to associated toxicities. Meanwhile, azathioprine 2 mg/kg/day was added to prednisone. After seven weeks on prednisone and six weeks of azathioprine her lesions had healed almost completely (Figure 8). She was maintained on prednisone 5 mg bid and azathioprine 50 mg bid with healing lesions. A repeat CT scan of the abdomen revealed normal architecture of hepatic parenchyma. Therefore, considering a chronic inflammatory process characterized by hearing loss, gingival hypertrophy, granulomatous hepatic lesions, and cutaneous ulcers with necrotizing granulomatous inflammation on skin biopsy, a unifying diagnosis of granulomatosis with polyangiitis (GPA) was made.

PMC3949549_01

Male

A 47-year-old male with no medical history was referred to the St. Catharins Hospital (Eindhoven, the Netherlands) in May 2010 following a two-week history of fever and dyspnoea. There were no complaints of cough and no history of smoking. His mother died in an other hospital three months before this episode due to an unknown pulmonary infection. On physical examination, the patient was dyspnoeic with 24 breaths per minute and an oxygen saturation of 88% on ambient air. His blood pressure was 115/70 mmHg with a heart rate of 105 beats/min. Body temperature was 38.8 degrees Celsius. Apart from bilateral inspiratory fine crackles no other physical abnormalities were observed. Laboratory investigations showed a mild normocytic anaemia (haemoglobin 7.9 mmol/L), white blood count 3.7/nL and C-reactive protein 200 mg/L. Alanine-aminotransferase, aspartate-aminotransferase, alkalic phosphatase and gamma-glutamyl-transferase were all raised tenfold the upper limit. Serum electrolyte levels and renal function indices were normal. Arterial gas analysis indicated pH 7.42, pO2 32 mmHg, pCO2 74 mmHg and bicarbonate 20.4 mmol/L. Chest X-ray on admission disclosed bilateral consolidations (Fig. 1). Under suspicion of an atypical pulmonary infection broncho-alveolar lavage (BAL) was performed in the middle lobe. Direct smear microscopy examination of the sample and sputum for the presence of acid-resistant bacilli by using Ziehl-Neelsen method was negative. However the Polymerase Chain Reaction (PCR) for M. tuberculosis complex (MTBC) DNA was positive. Patient was tested HIV negative and no signs of immunosuppressive disorders were found. During the first day of hospitalisation the patient became respiratory insufficient and tracheal intubation was necessary for five days. Treatment was started with broad spectrum antibiotics and on suspicion of a human tuberculosis infection standard anti-tuberculosis drug regimen was started. (isoniazid (H) 300 mg daily, rifampin (R) 600 mg daily, pyrazinamide (Z) 2000 mg daily, ethambutol (E) 1600 mg daily and pyridoxin 600 mg daily). Three weeks after admission the culture of the BAL fluid was positive for M. tuberculosis. Antibiogram showed a normal sensitivity pattern so the ethambutol was discontinued. In total the patient was treated with HRZ for two months followed by four months of HR. 14 days after initiating therapy sputum conversion was reached as presence of acid-resistant bacilli by using Ziehl-Neelsen method was negative in sputum sample, during 3 consecutive days. 10 Days after discharge from the intensive care unit patient was discharged from the ward. Clinical parameters all improved rapidly during his treatment. Furthermore the liver enzymes normalised during his hospital stay and remained normal during the total treatment period. One month after initiating treatment for tuberculosis patient complained of lumbar back pain. Further radiologic evaluation using MRI showed abnormal signal intensity of L4, which was interpreted as spondylitis for which patient was referred to the orthopaedic surgeon. No further actions were taken and complaints resolved. At radiologic follow-up 3 months after MRI sclerosis was seen, but no signs of spondylitis anymore. After treatment of the M. tuberculosis infection no abnormalities were seen on radiologic evaluation using X-ray of the chest, especially no parenchymal abnormalities or lymphadenopathy. In November 2011 the patient was referred to the ophthalmologist by the general practitioner with complaints of red eye which did not resolve with chloramphenicol. The ophthalmologist diagnosed uveitis and initiated treatment with ocular prednisolon and atropine. Under this treatment uveitis resolved completely except for remaining synechia. Under suspicion of reactivation of tuberculosis the patient was referred to our outpatient clinic. At that time he had no pulmonary complaints, in particular no cough, weight loss or dyspnoea. He did not appear to be ill with a blood pressure of 115/70 mmHg, heart rate 105 beats/min and oxygen saturation 98% on ambient air. No physical abnormalities were observed. His body temperature was 37.1 degrees Celsius. Laboratory investigations showed normal electrolytes including calcium and renal function. Erythrocyte sedimentation rate was 5 mm/h and C-reactive protein was <6.0 mmol/L. Angiotensin converting enzyme was 86 U/L (normal range 12-82 U/L). Chest radiogram disclosed suspicion of mediastinal and hilar lymphadenopathy and interstitial densities in the right lobe which was confirmed on computed tomography of the thorax (Fig. 2). Bronchoscopy was performed with lavage in the right upper lobe in combination with trans-bronchial needle aspiration (TBNA) of a pretracheal lymph node. No acid-resistant bacilli were found in the fluid lavage or in the cytologic material of TBNA. PCR for M. tuberculosis DNA was negative. Nevertheless since there was high suspicion on reactivation of pulmonary tuberculosis anti-tuberculosis drug therapy was initiated. Two months following initiating treatment for M. tuberculosis another computed tomogram of the thorax was performed which was completely unchanged in comparison to the earlier scan, except now there were multiple nodules located at the right major fissure. An endoscopic ultrasound with fine needle aspiration of a subcarinal lymph node was performed. Microscopic analysis revealed a population of lymphoid cells with spread granulomas. Necrosis was not observed. PCR for MTBC DNA was negative and acid-resistant bacilli were not present. Apart from the fine needle aspiration, a biopsy of an erythematosquamous lesion on the left upper arm was taken which revealed granulomatous structures, consisting of epitheloid histiocytes and few polynucleid giant cells, surrounded by small atypic lymphocytes. No central necrosis or caseiting was seen. The patient was diagnosed with sarcoidosis and anti-tuberculosis therapy was discontinued. Cardiac magnetic resonance imaging revealed no cardiac granulomas. Diffusion capacity for carbon monoxide was normal and during exercise testing no oxygen uptake problem could be observed. As there was no indication for initiating immunosuppressive therapy patient was seen at our outpatient clinic every three months for follow-up.

aetiology, sarcoidosis, tuberculosis

PMC5866856_01

Female

A 76-year-old woman was admitted to our department because of 10-day history of right upper quadrant abdominal pain that extended to the back and progressive deep jaundice. The patient had sought medical help 7 days before admission because of the same pain which was considered as of musculoskeletal origin and, therefore, nonsteroid anti-inflammatory drugs (NSAIDs) were prescribed by her doctor. The patient received diclofenac 50 mg PO twice per day, which was stopped at admission. Blood biochemistry at that time point was normal. However, there was no relief of the symptoms, while she mentioned the onset of nausea and vomiting accompanied by jaundice after 3 days of diclofenac administration but she continued taking the drug. The patient had a past medical history of primary myelofibrosis diagnosed two years ago and arterial hypertension under treatment with quinapril for fifteen years, while she was heterozygous for beta thalassemia trait. She denied ever consuming herbal agents and/or dietary supplements, intravenous or nasal illicit drugs, or alcohol use. Her past medical history for liver disease was also negative. Apart from jaundice, physical examination revealed hepatosplenomegaly with no signs of hepatic encephalopathy. The laboratory work-up (abnormal values) was as follows: haemoglobin 10.8 g/dL, platelets 73 x 103/muL, international normalized ratio (INR) 2.32, albumin 3.3 g/dL, total bilirubin 21.6 mg/dL, direct bilirubin 15.4 mg/dL, AST 717 IU/L, ALT 679 IU/L, gamma-GT 56 IU/L, and immunoglobulin G (IgG) 1760 mg/dL (upper limit of normal 1500 mg/dL). Chest X-ray showed pleural effusion on the left and the electrocardiogram right bundle branch block (RBBB). Arterial blood gases showed respiratory alkalosis (pH 7.52, pO2 68 mmHg, pCO2 28 mmHg, and HCO3 22.9 mEq/L). The remaining haematological, microbiological, virological, and biochemical parameters including blood cultures and investigation for hepatitis viruses A, B, C, and E as well as Epstein-Barr virus (EBV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), herpes simplex virus (HSV), tuberculosis, leishmaniasis, brucellosis, and leptospirosis were negative. Liver autoimmune serology according to our standard protocols for the diagnosis of AIH was positive for antinuclear (ANA; titre: 1/80) and smooth muscle antibodies (SMA; titre: 1/320) by indirect immunofluorescence; SMA specificity proved to be against F-actin antigen as confirmed by ELISA. Abdominal ultrasonography revealed massive splenomegaly, which was attributed to primary myelofibrosis and hepatomegaly with dilation of splenic and portal veins. No signs of thrombosis were observed in hepatic, portal, and splenic veins. Due to the presence of pleural effusion, in combination with RBBB and respiratory alkalosis in a patient with underlying procoagulant condition (primary myelofibrosis), a computerized tomography of pulmonary vessels was performed, which excluded the presence of pulmonary embolism/thrombosis. Liver biopsy at this moment although valuable was not performed because of absolute contraindications. The differential diagnosis included all potential causes of acute severe hepatitis and, first of all, acute viral hepatitis, which was excluded by the careful negative serological and virological tests. Due to patient's medical history of primary myelofibrosis, acute Budd-Chiari syndrome and ischemic hepatitis as a consequence of massive pulmonary embolism or thrombosis were also considered. However, both diagnoses were excluded by imaging studies. In addition, alcoholic hepatitis was excluded as there was no history of alcohol consumption. The case of an idiosyncratic drug induced liver injury (DILI) was seriously taken into account in the differential diagnosis, because the patient had a history of NSAID use and especially diclofenac administration for the last 7 days before admission. Last but not least, AS-AIH was considered to be the most likely diagnosis, either genuine or induced by diclofenac administration (idiosyncratic DILI-induced AS-AIH), due to the exclusion of other causes and especially viral hepatitis, the presence of hypergammaglobulinemia, which is infrequent in DILI cases, and the positive liver autoimmune serology. Indeed, the simplified score for the diagnosis of AIH without the histological data was 6 corresponding to the diagnosis of probable AIH. It should be stated, however, that this score has not been developed for the diagnosis of acute severe cases of AIH as the typical or compatible histological lesions of chronic cases of AIH are typically completely different from those reported in AS-AIH. As the most probable diagnosis of the patient was AS-AIH (either pure AS-AIH or idiosyncratic DILI-induced AS-AIH), intravenous corticosteroids were initiated (1 g of methylprednisolone per day for 3 days followed by 1 mg/kg of prednisolone per day) as rescue therapy according to our experience and the guidelines of AIH management recently published by the European Association for the Study of the Liver (EASL). Of note, multiple sets of urine and blood cultures before and after corticosteroid administration were sterile for bacteria and fungi infections, making the diagnosis of sepsis in a haemodynamically stable patient very unlikely. Despite the intravenous corticosteroid treatment, the patient deteriorated clinically, while her laboratory findings kept worsening (INR 4.74, albumin 2.66 mg/dL, total bilirubin 48.9 mg/dL, direct bilirubin 27 mg/dL, AST 1402 IU/L, and ALT 855 IU/L). On the 3rd day of hospitalization, she developed advanced hepatic encephalopathy and upper gastrointestinal hemorrhage, while her MELD score was 39. However, due to her medical history of primary myelofibrosis and her relatively advanced age, she was not considered as a good candidate for liver transplantation (LT). Finally, on the 4th day of hospitalization, she passed away. Her son did not consent to perform autopsy, but he consented to perform a postmortem liver biopsy, which revealed centrilobular confluent necrosis, focal interface hepatitis, portal inflammatory infiltration predominately with lymphocytes and portal fibrosis, cholestasis, and lobular inflammation with many giant hepatocytes (Figures 1 and 2). The whole histological picture was compatible with severe PIGCH probably as a result of AS-AIH.

PMC7582096_01

Female

A 48-year-old woman with no significant past medical history apart from elective bilateral breast implantation 10 years prior, presented with new onset of fever, rigors, night sweats and shortness of breath. Initial workup revealed microcytic anemia (Hb 8.9 g/dL, MCV 78 fL leukopenia and elevated CRP 143 mg/dL and ESR >130 mm/h). Chest CT scan revealed 3 cm pericardial effusion with large conglomerate mediastinal lymph nodes (LN) and scant tree-in-bud opacities on lung images. She underwent pericardiocentesis and transthoracic paratracheal LN biopsy which were negative for infection or malignancy. Due to progressive cough, fatigue, night sweats and weight loss further diagnostic testing including bronchoscopy and endobronchial ultrasound (EBUS) were performed. Fine needle aspirates (FNA) demonstrated caseating granulomatous inflammation with growth of MAC on broth culture but no evidence of malignancy. Interferon gamma release assay was negative and sputum with PCR for mycobacterium tuberculosis, were all negative. Subsequently, one of three sputum cultures grew MAC (broth) but all other microbiologic cultures remained negative. Additional testing for alternative infectious etiologies including HIV, syphilis, cytomegalovirus, toxoplasma, aspergillus, cryptococcus and histoplasma were negative. She underwent further LN assessment via mediastinoscopy which again revealed caseating granulomatous inflammation and growth of MAC (broth). Flow cytometry, performed on EBUS and mediastinoscopy samples were negative for malignancy. Based on the finding of MAC on two separate LN cultures and biopsy finding of non-caseating granuloma, with no alternative diagnosis, she was started on daily triple antibiotic therapy with Ethambutol 1200 mg, Azithromycin 500 mg and Rifampin 600 mg. However, she failed to demonstrate any improvement in her clinical condition after 6 months of therapy. Further diagnostic testing inclusive of a bone marrow biopsy returned negative for malignancy. Repeat whole body CT imaging demonstrated widespread lymphadenopathy along with a new right ovarian mass. An extensive workup focused on evaluation for underlying malignancies or secondary immunodeficiencies was carried out. CA-125, CA19-9, CEA biomarkers were normal, LDH levels remained <200 U/L. Gynecology was consulted for the ovarian mass which was determined to be benign. Further immunologic evaluation demonstrated low CD3, CD4 and CD56 levels. A rheumatology profile including ANA, extended autoimmune panel, rheumatoid factor, vasculitis panel, anti-CCP were all within normal limits. Ultimately, a core biopsy of an iliac LN demonstrated abnormal CD30-positive lymphoid infiltrate, suspicious for Hodgkin's lymphoma (HL). An excisional left supraclavicular lymph node biopsy was performed, confirming the diagnosis of Hodgkin's lymphoma along with histologic evidence of granulomatous inflammation and AFB smear positivity. The subject was started on steroids followed by initiation of chemotherapy whilst being maintained on MAC treatment with Ethambutol and Azithromycin three times a week. Rifampin had to be discontinued due to persistent leukopenia. The patient tolerated chemotherapy well with symptomatic improvement, however an interim Positron Emission Tomography (PET)/CT scan revealed residual disease with widespread hypermetabolic lymphadenopathy involving the neck, mediastinum, and abdomen. The chemotherapeutic regimen was subsequently escalated and follow-up PET/CT scan demonstrating overall decrease in the tumor volumetric activity with minimal disease relating to either residual MAC/granulomatous inflammation or Hodgkin's disease. A repeat excisional biopsy of cervical LNs was negative for lymphoma but revealed necrotizing granuloma with negative AFB cultures Patient is currently doing well on continued suppressive MAC treatment with Ethambutol and Azithromycin while undergoing close surveillance for any recurrence of her lymphoma.

disseminated, lymph node biopsy, lymphoma, mycobacterium avium complex

PMC3914247_01

Female

A 45-year-old female resident in Ireland, originally from the Philippines, was transferred to our institution for further management of acute renal failure. She initially presented to the referring hospital with generalized malaise and fatigue over the preceding month associated with a small, painless swelling on the left side of the neck. She denied any fevers, chills, rigors, night sweats, photosensitive rash, joint pains, weight loss, or urinary tract symptoms. She did not suffer from any upper respiratory tract symptoms, sinusitis, or rash. She was not taking any medications or herbal remedies. Her past medical history was unremarkable except for lumpectomy for a benign breast cyst several years ago. Her menstrual cycles were normal and there was no history of miscarriages in the past. Her serum creatinine on admission was 205 mumol/L with an active urine sediment. On examination, she appeared unwell, was afebrile, with a blood pressure 130/80 mmHg, and weighed 57 kgs. A bedside urine dipstick was positive for blood (+) and protein (+++). There was no evidence of oral ulceration, rashes, or joint swelling. Her neck was supple to palpation except for a solitary 1 cm nontender, mobile lymph node in the left anterior triangle of neck. The thyroid gland was not enlarged. The remainder of her cardiovascular, respiratory, and abdominal examination was unremarkable. Biochemical investigations revealed a serum creatinine which had risen to 568 mumol/L and urea of 23.4 mmol/L. Haematological parameters showed a normal haemoglobin level of 13 g/dL with a serum C-reactive protein of 74 mg/L (normal < 10). No prior biochemical parameters were available for comparison. A full vasculitic screen was performed; antinuclear factor (ANF) was positive with a homogenous pattern, antidouble-stranded DNA antibodies were raised (anti-dsDNA titre 59, >30 positive) and antineutrophil cytoplasmic (ANCA) and antiglomerular basement membrane antibodies were negative. Antistreptolysin O titres were also within normal limits. Serum complement levels showed depletion of C4 and normal C3 levels. Serology was negative for human immunodeficiency virus (HIV), toxoplasmosis, and brucellosis. A 24-hour urine collection quantified the proteinuria at 1.2 g/24 hrs. Her admission chest radiograph was normal. Renal ultrasonography revealed normal sized kidneys with good corticomedullary differentiation and no evidence of hydronephrosis. Fine needle aspiration biopsy of the neck lump showed mature lymphocytes admixed with neutrophils, with 90% of the cells showing positivity for CD45:strongly suggestive of nonspecific inflammatory changes. In view of the presentation of acute renal failure, haematuria, and proteinuria with serological evidence suggestive of lupus, a renal biopsy was performed to clarify the diagnosis. Histopathology results, however, showed widespread caseating granulomata with Langerhan's cells (Figure 1) consistent with renal tuberculosis. No acid fast bacilli (AFB) were seen on light microscopy. On further review, our patient had been vaccinated with BCG in her childhood. She could not recall any contact with tuberculosis carriers nor was there any history of recent travel abroad. A mantoux test was subsequently performed and was positive at 12 mm. Sputum microscopy was negative for AFB. Serial early morning urine samples were also examined and cultured for the presence of AFB but were negative. In view of the renal biopsy findings, a CT of the thorax, abdomen, and pelvis was performed which revealed enlarged retrogastric lymph nodes measuring up to 2.8 x 1.2 cm and further subcentimetre mediastinal and retroperitoneal lymph nodes. She was commenced on standard combination antituberculous chemotherapy consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide. She subsequently developed deranged liver enzymes which normalized following withdrawal of rifampicin. Our patient completed 18 months of treatment for renal tuberculosis, but failed to recover renal function and is now dialysis dependent, awaiting renal transplantation. A repeat renal biopsy was performed following completion of anti-tuberculous therapy. This confirmed significant tubulointerstitial fibrosis in the absence of any caseating granulomas (Figure 2). A follow-up CT scan showed resolution of the previously detected lymphadenopathy.

PMC10407729_01

Female

Two months prior to presentation, the patient, a 41-year-old woman, was accidentally bitten by a "wild dog" on the skin at the back of the middle and lower parts of the right leg while walking. After the incident, the patient experienced a localized pain and discomfort associated with minimal bleeding. Later, she went to the District People's Hospital for wound treatment. She was administered with the tetanus antitoxin and rabies vaccine. Subsequently, the patient self-managed the wound without much success with the healing process. Twenty days before admission, no obvious cause of skin redness and swelling were observed on the inner skin of the proximal right thigh of the patient. Initially, the patient did not pay much attention to it. The area of redness and swelling increased to 14 cm x 5 cm, with slight pain and discomfort. Concurrently, the wound site began to ooze a secretion. Therefore, she revisited the District People's Hospital and was administered with topical drugs for disinfection and antibacterial treatment (the specific drug name is unknown). After symptomatic treatment, the volume of the secretion from the wound surface decreased slightly. However, the signs of redness and swelling in the right thigh increased. Subsequently, the patient was treated at our outpatient department. After treatment, the secretion from the wound site ceased. The swelling of her right thigh was slightly reduced, but the skin around the wound site was broken and exudative. For further management, the patient was admitted for treatment of a skin abscess. Since the onset of the disease, no symptoms and signs of appetite loss, sleep disturbance, stool and urine-associated changes, and weight loss were reported. Further laboratory investigations after admission showed that the infection indicators, such as white blood cell count, neutrophils C-reactive protein, and procalcitonin, were normal. Liver function, renal function, electrolyte balance, routine blood parameters, chest radiograph, and electrocardiogram were normal. As shown in Fig. 1A, a physical examination revealed the presence of an irregular skin redness and swelling of size of about 3.0 cm x 2.5 cm at the posterior aspect of the midsection of the right leg. The surface could be covered by an irregular scab shell of about 1.00 cm x 0.8 cm. The adhesion was not tight. After the scab shell was opened, a small amount of necrotic tissue was observed under the scab. A minimal amount of purulent secretion could be observed around the extrusion. A red and swollen skin of size, 14 cm x 6.0 cm, was observed on the inner side of the right thigh. The texture of the local skin was relatively tough. Two oval skin ulcer wounds of about 2.0 cm x 1.0 cm were present (Fig. 1B). The necrotic skin was attached to the wound surface with relative tightness. A light microwave motion could be observed whenever the inner ulcer was squeezed. After the necrotic skin was removed from the wound surface, necrotic tissues with associated minimal purulent secretions in the tissue gaps were observed. From experience, we used Laxef sodium for its anti-infection effect. We further incised and drained the abscess on the right thigh. Culture of the purulent secretion obtained from the wound site revealed the presence of the Staphylococcus squirrel subspecies. The wound healed well after symptomatic treatment by anti-infection and dressing change. The patient was discharged 7 days after the procedure. Three days after discharge, the patient found a mass of about 4 cm x 4 cm in size on the medial side of the right thigh (Fig. 2). The mass was associated with tenderness, no wave motion and skin temperature rise. Therefore, she revisited the hospital. Upon admission, various laboratory investigations showed no abnormalities in liver function, renal function, electrolyte balance, and routine blood parameters. An ultrasound examination showed a fluid accumulation under the right thigh root incision. The ranges of two dark areas under the right thigh root incision were 3.0 cm x 1.9 cm x 1.0 cm and 4.0 cm x 3.5 cm x 1.6 cm (Fig. 3). We performed a local puncture and extracted 25 ml of clear yellowish liquid (Fig. 4). No positive findings were obtained from acid-fast staining, fungal culture, and bacterial culture. Thereafter, the mass on the proximal end of the right thigh was resected again. During the operation, the skin, fat, and superficial fascia layers were cut to locate the two liquid dark areas shown by ultrasonography. The liquids in both areas were yellow and clear, and they communicated with each other through the sinus. Two swollen lymph nodes were found above the liquid dark area. After blunt separation, two dark and necrotic lymph nodes with sizes of 3.0 cm x 2.0 cm and 0.5 cm x 0.5 cm were found (Fig. 5). We completely excised the lymph nodes, ligated lymph vessels, and reduced tension sutured after hemostasis. Postoperative pathological examination showed that the right inguinal lymph node had undergone a caseous necrotizing granulomatous inflammation. A test for nucleic acids of Mycobacterium tuberculosis was negative (Fig. 6). After the operation, the patient were treated by anti-infection, pressure bandaging, and dressing change. She was discharged afterwards.

dog bite, metastatic abscess, necrosis of lymph node

PMC7256686_01

Female

A fit, physically active 32-year-old female with no underlying risk factors underwent a left knee anterior cruciate ligament (ACL) reconstruction and partial lateral meniscectomy. She was not taking oral contraceptives. She presented 19 days postoperatively with acute dyspnea, chest pain, tachycardia, and complaints of feeling light-headed of 5 days duration. In the emergency department, she had sinus tachycardia on electrocardiography, a heart rate of 126 bpm, blood pressure of 107/68 mmHg, respiratory rate of 18/min, and an oxygen saturation of 95% on room air. Her examination was noted to be otherwise unremarkable. There was no evidence of surgical site infection and no limb swelling noted. A complete blood count and electrolyte and metabolic panel were normal. Her troponin was 80 ng/L (normal 0-14 ng/L). A chest radiograph and D-dimer were not performed. Her pretest probability of pulmonary embolism was moderate based on Wells' criteria. Computed tomography pulmonary angiogram (CTPA) reported the patient as having PTE. Findings included saddle PE, extensive clot extending into lobar and segmental branches of all lobes (Figure 1) as well as evidence of right heart strain with marked right atrial (RA) and RV dilation as well as flattening and deviation of the interventricular septum. The RV/LV ratio was 1.3. Unfractionated low-molecular-weight heparin was immediately initiated. Her simplified PE Severity Index (sPESI) was 1 (high risk, 8.9% mortality). The patient was admitted to the Internal Medicine service. On day 1, her clinical status was unchanged; laboratory indices were similar with a troponin level of 35 ng/L and NTpro-BNP of 3859 ng/L (normal 0-300). ICU was consulted on day 1 of admission, and a transthoracic echocardiogram (TTE) was immediately requested. This demonstrated a 3.3 cm maximum diameter multilobulated, mobile right atrial thrombus, which extended from the RV inlet through the pulmonic valve to the pulmonary artery (i.e., an RHTT). Intraventricular septal flattening and severe RV dilation with moderate systolic dysfunction and tricuspid regurgitation were also observed. McConnell's sign was present with apical hypercontractility and basal and mid-ventricular segmental hypokinesis. The right ventricular systolic pressure (RVSP) was 48.1 mmHg (Figure 2). She was transferred to the intensive care unit (ICU) with a diagnosis of clinical submassive pulmonary embolism with clot in transit. Arterial blood gas was pH 7.52, pCO2 29 mmHg, PaO2 74 mmHg, O2 saturation 96%, and lactate 0.8 mmol/L. The case, as well as treatment options, was reviewed with a member of the pulmonary embolism response team (PERT). A decision was made to proceed with low-dose thrombolysis, despite the recent surgery, employing the regimen described in the MOPETT trial. The potential benefits and risks were discussed with the patient who consented. She received a 10 mg recombinant tPA bolus followed by an additional 40 mg over two hours intravenously (IV). IV heparin was continuously infused at 10 U/kg/hr during the thrombolysis as well and for three hours afterwards at which time the heparin nomogram infusion of 18 U/kg/hr with serial adjustments based on PTT was re-introduced. Serial echocardiograms at 2 hours after thrombolysis and the next day (Figure 3) demonstrated improvement in her RV function. The RVSP was 27 mmHg at 2 hours and 26 mmHg the following day. The in-transit clot was no longer visible on the posttreatment echocardiograms. She was eventually discharged home on day 5 on tinzaparin for two weeks and then transitioned to rivaroxaban. She was continued on anticoagulation for 6 months. Seven months after discharge, she was doing very well. Her breathing had returned back to baseline, and she was rehabilitating well from her reconstruction. She had no bleeding complications from the rivaroxaban therapy. Her DASH score was 1 (3.9% annual risk of DVT recurrence), and her HERDOO2 score was 0 (3% risk of major recurrent venous thromboembolism per 100 patient years). The anticoagulation was discontinued. She had returned to the gym, though had not yet returned to more vigorous-intensity physical activities, such as basketball. A repeat echocardiogram at this time demonstrated normal left and right ventricular systolic function with no hemodynamically significant valvular disease. Serial D-dimers, every three months, for the following year were scheduled. Testing for inherited thrombophilia was negative.

PMC8184137_01

Female

A 26-year-old female was referred to our hospital in June 2014 with a complaint of dull pain in the right knee for six months. Physical examination showed tenderness in the proximal right tibia. Radiography and computed tomography (CT) revealed eccentric, well-defined osteolytic destruction in the proximal metaphysis of the right tibia, suggesting the imaging diagnosis of GCTB (Campanacci grade II) (Figure 1A-D). Chest CT scan (Figure 2A) and single-photon emission CT (Figure 1E) did not reveal any metastatic lesions.An open biopsy from a lateral incision was performed thereafter, and pathological results showed multinucleated osteoclast giant cells with a large number of nuclei scattered among mononuclear tumor cells, which confirmed the diagnosis of a benign GCTB (Figure 3A). Subsequently, the patient underwent intralesional curettage following the biopsy tract. Utilizing high-speed drilling and ethyl alcohol, 1 cm of spongy bone and 1 mm of cortical bone were removed. The remaining cavity was then packed with cement (Figure 4A and B). After the procedures, immobilization was recommended to prevent pathological fracture. However, nine months later, a palpable mass was detected in the right popliteal fossa. Radiography, CT, and magnetic resonance imaging revealed local cortical bone destruction with soft tissue extension (Figure 4C-F) which indicated Campanacci grade III. Chest CT showed no evidence of metastases. Because of the extensive recurrence and stage III rating, the patient underwent wide resection of the lesion with prosthetic reconstruction. Postoperative pathologic features and presence of multinucleated giant cells were detected by immunohistochemical (IHC) staining with a monoclonal antibody against CD68 (PG-M1) and were similar to that of the pre-surgical specimens, revealing the recurrence of GCTB without malignant transformation (Figure 3B and C). The IHC staining also identified tumor cells positive for VEGFR-2 (Figure 3D). The patient was regularly followed-up every three months in our orthopedic clinic. Two years after the latest surgery, the patient presented to our clinic with a complaint of hemoptysis. The lung CT scans were evaluated by experienced musculoskeletal surgeons and radiologists who verified more than 100 pulmonary nodules in both lungs (Figure 2B). Although biopsy of the lung mass was not performed owing to the refusal of the patient, the imaging diagnosis of metastatic GCTB was considered based on the presence of multiple lesions. Meanwhile, lung cancer was excluded because the level of serum cytokeratin fragment antigen 21-1, a sensitive tumor marker of lung cancer, was negative. Since both biopsy and resection are traumatic operations with risks and complications, and the multiple metastases could not be completely removed by surgery or benefit from it. On the other hand, our patient could not tolerate chemotherapy because of an Eastern Cooperative Oncology Group performance status score of 3. Therefore, the patient chose subcutaneous denosumab administration, which was initiated at a dose of 120 mg every 28 days, with additional doses on days 8 and 15 of the first month. The patient was also supplemented with calcium and vitamin D. However, after four months of denosumab therapy, the symptoms of hemoptysis became more severe. The lung CT scan showed the metastatic nodules had increased in size and number, indicating progression of disease (Figure 2C). After multiple interdisciplinary team discussions, and in view of the high-level VEGFR-2 expression and rapidly progression, the patient was tentatively administered the TKI apatinib in combination with denosumab treatment. Denosumab was injected every month with a dose of 120 mg and apatinib was administered with an oral dosage of 500 mg daily. After three months of denosumab and apatinib treatment, the patient showed noticeable improvement of hemoptysis and visibly reduced tumor size (Figure 2D). At a follow-up of 42 months, chest CT images showed a significant size reduction in the lung nodules. The largest one had greatly decreased in size from 12.2x8.5 cm to 3.5x1.5 cm (Figure 2E and F), and the tumor volume shrinkage rate was 95%. Moreover, the number of metastatic nodules decreased to less than 30. After initiation of apatinib therapy, a few drug-related toxicity reactions were noted, including hand-foot skin syndrome, gastrointestinal discomfort, and hypopigmentation of the hair. All adverse reactions were mild (grade 1 or 2) according to the Common Terminology Criteria for Adverse Events and were easily controlled by symptomatic treatments. The efficacy was evaluated as a significant partial response (PR) to denosumab and apatinib treatment by the Response Evaluation Criteria for Solid Tumors 1.1. The patient is under stable condition at the time of this writing.

vegfr-2, apatinib, denosumab, giant cell tumor of bone, pulmonary metastasis

CT of the chest. (A) Local recurrence but without pulmonary metastasis.

PMC8184137_01

Female

A 26-year-old female was referred to our hospital in June 2014 with a complaint of dull pain in the right knee for six months. Physical examination showed tenderness in the proximal right tibia. Radiography and computed tomography (CT) revealed eccentric, well-defined osteolytic destruction in the proximal metaphysis of the right tibia, suggesting the imaging diagnosis of GCTB (Campanacci grade II) (Figure 1A-D). Chest CT scan (Figure 2A) and single-photon emission CT (Figure 1E) did not reveal any metastatic lesions.An open biopsy from a lateral incision was performed thereafter, and pathological results showed multinucleated osteoclast giant cells with a large number of nuclei scattered among mononuclear tumor cells, which confirmed the diagnosis of a benign GCTB (Figure 3A). Subsequently, the patient underwent intralesional curettage following the biopsy tract. Utilizing high-speed drilling and ethyl alcohol, 1 cm of spongy bone and 1 mm of cortical bone were removed. The remaining cavity was then packed with cement (Figure 4A and B). After the procedures, immobilization was recommended to prevent pathological fracture. However, nine months later, a palpable mass was detected in the right popliteal fossa. Radiography, CT, and magnetic resonance imaging revealed local cortical bone destruction with soft tissue extension (Figure 4C-F) which indicated Campanacci grade III. Chest CT showed no evidence of metastases. Because of the extensive recurrence and stage III rating, the patient underwent wide resection of the lesion with prosthetic reconstruction. Postoperative pathologic features and presence of multinucleated giant cells were detected by immunohistochemical (IHC) staining with a monoclonal antibody against CD68 (PG-M1) and were similar to that of the pre-surgical specimens, revealing the recurrence of GCTB without malignant transformation (Figure 3B and C). The IHC staining also identified tumor cells positive for VEGFR-2 (Figure 3D). The patient was regularly followed-up every three months in our orthopedic clinic. Two years after the latest surgery, the patient presented to our clinic with a complaint of hemoptysis. The lung CT scans were evaluated by experienced musculoskeletal surgeons and radiologists who verified more than 100 pulmonary nodules in both lungs (Figure 2B). Although biopsy of the lung mass was not performed owing to the refusal of the patient, the imaging diagnosis of metastatic GCTB was considered based on the presence of multiple lesions. Meanwhile, lung cancer was excluded because the level of serum cytokeratin fragment antigen 21-1, a sensitive tumor marker of lung cancer, was negative. Since both biopsy and resection are traumatic operations with risks and complications, and the multiple metastases could not be completely removed by surgery or benefit from it. On the other hand, our patient could not tolerate chemotherapy because of an Eastern Cooperative Oncology Group performance status score of 3. Therefore, the patient chose subcutaneous denosumab administration, which was initiated at a dose of 120 mg every 28 days, with additional doses on days 8 and 15 of the first month. The patient was also supplemented with calcium and vitamin D. However, after four months of denosumab therapy, the symptoms of hemoptysis became more severe. The lung CT scan showed the metastatic nodules had increased in size and number, indicating progression of disease (Figure 2C). After multiple interdisciplinary team discussions, and in view of the high-level VEGFR-2 expression and rapidly progression, the patient was tentatively administered the TKI apatinib in combination with denosumab treatment. Denosumab was injected every month with a dose of 120 mg and apatinib was administered with an oral dosage of 500 mg daily. After three months of denosumab and apatinib treatment, the patient showed noticeable improvement of hemoptysis and visibly reduced tumor size (Figure 2D). At a follow-up of 42 months, chest CT images showed a significant size reduction in the lung nodules. The largest one had greatly decreased in size from 12.2x8.5 cm to 3.5x1.5 cm (Figure 2E and F), and the tumor volume shrinkage rate was 95%. Moreover, the number of metastatic nodules decreased to less than 30. After initiation of apatinib therapy, a few drug-related toxicity reactions were noted, including hand-foot skin syndrome, gastrointestinal discomfort, and hypopigmentation of the hair. All adverse reactions were mild (grade 1 or 2) according to the Common Terminology Criteria for Adverse Events and were easily controlled by symptomatic treatments. The efficacy was evaluated as a significant partial response (PR) to denosumab and apatinib treatment by the Response Evaluation Criteria for Solid Tumors 1.1. The patient is under stable condition at the time of this writing.

vegfr-2, apatinib, denosumab, giant cell tumor of bone, pulmonary metastasis

CT of the chest. (B) Multiple pulmonary metastases were found and denosumab initiated.

PMC7170120_01

Male

A 47-year-old male patient suffered from intermittent cough and fever for over 2 months, these symptoms aggravated for at last 20 days without sputum, shortness of breath, thoracalgia or hemoptysis. Initially, computed tomography (CT) scan of his chest showed a mass lesion in right upper lobe of his lung and partial of right pleural thickening, with diffuse consolidation and ground-glass opacity in bilateral pulmones (Figure 1). The doctors considered about interstitial pneumonia owing to infection. While after several days of antibiotic therapy (including sulbenicillin disodium and etimicin), his symptoms had not improved. So bronchoscopy was carried out. Atypical epithelial cells inclined to denocarcinoma were found in transbronchial smear of cytology, while bronchial brushing and biopsy was negative. Unexpectedly the patient felt swollen of his neck just after bronchoscopy, so he underwent another CT at the same day. The CT scan showed bilateral pneumothorax and emphysema of mediastinum superius. Then he transfered to another hospital for symptomatic treatment 5 days later, positron emission tomography/computed tomography (PET/CT) revealed a nodule of about 2.7 cm of its long diameter with characteristics of lobulation and spiculation in the right lung apex section and diffuse consolidation shadow spreading over rest of lung field. The nodular lesion was deemed to be peripheral lung cancer, which average uptake value of (18)F-FDG was 4.3 and maximal uptake value was 5.7. Remaining consolidation was considered as diffuse lung cancer with mildly elevated uptake value of (18)F-FDG (Figure 2). Furthermore, lymph node metastasis of left hilar was likely to have arised. The patient came to our hospital for further diagnosis and therapy. After admission, the patient never had a fever again and auscultation of lung was normal. His results of test for complete blood count, erythrocyte sedimentation rate (ESR), C reactive protein(CRP), procalcitonin (PCT) and biochemical parameters (including lactate dehydrogenase, LDH) were normal. The patient's T cell subpopulations were normal and human immunodeficiency virus (HIV) antibody was negative. Serum tumor markers assay showed normal results as carcinoembryonic antigen (CEA): 3.4 ng/ml, section 19 of cytokeratin (CYRFA21-1): 10.9 ng/ml, squamous cell carcinoma antigen (SCC): 0.8 ng/ml, and neuron specific enolase (NSE): 15.9 ng/ml. Blood gas analysis showed hyoxemia with partial pressure of oxygen (PaO2) being 68 mmHg and peripheral blood saturation (SpO2) being 93% on room air,while potential of hydrogen (PH) and partial pressure of carbon dioxide (PaCO2) was normal. Spirometric abnormality is mildly restrictive defect manifested by decreased vital capacity (76.27% of predicted value) and mildly reduced diffusing capacity for carbon monoxide (73.28% of predicted value). Fiberoptic bronchoscopy was applied again for diagnosis. BALF showed a large amount of amorphous red-dyed materials and a few alveolar macrophages scattered in endoalveolar space with PAS positive (Figure 3). Transbronchial lung biopsy (TBLB) found great numbers of unstructured, red-dyed granules with PAS+ and adenocarcinoma with differentiated grade II with immunohistochemical analysis for ALK-D5F3(-), CEA(-), EGFR-E746(-), EGFR-L858(-), Ki-67(5%+), NapsinA(+), TTF-1(+), SPA(+), CD68(+) and CK(+) (Figure 4). Follow-up EGFR detection (ARMS used) showed mutations in exon 19 of the EGFR gene, while mutations were not detected in exon 18, 20 and 21. We judged clinical stage IIB (cT1cN1M0) according to PET/CT, BALF and lung biopsy. Thoracic surgeons carried out wedge resection in VATS (video-assisted thoracoscopic surgery) with mediastinal lymphnode sampling (group 2,4). Pathological findings (in upper right lung) confirmed adenocarcinoma differentiated grade II~III, mainly presenting as acinar and solid type, rarely papillary type. Amorphous eosinophilic substance can be seen in the alveolar of pulmonary tissue around, which was consistent with PAP (Figure 5). In addition, bilateral lymph nodes of group 2 and 4 proved metastasis and carcinoma did not involve the visceral pleura. Then we revised as stage IIIB(pT1cN3M0) and administered adjuvant chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1, every 28 days for 4 cycles). Chest CT after 2 cycles of postoperative chemotherapy (Figure 6) showed no tumor recurrence and no patchy, ground-glass opacities. Chest CT of follow-up visits once every three months in local approved SD (stable disease).However ninth months after therapy, the patient felt pain on the left chest. CT showed multiple, subsolid nodules in both lungs and suspected metastasis in the left sixth rib bone and T8 vertebral bone (Figure 7).SPECT/CT for whole body bone planar imaging showed multiple bone metastasis, considered the recurrence and metastasis of the adenocarcinoma. Then we reassessed as stage IVB (rT4N3M1c) and administered 2cycles of primary chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1,every 28 days for 4 cycles) up to now.

lung cancer, peripheral adenocarcinom, pulmonary alveolar proteinosis

Chest computerized tomography (CT) before any therapy. (A, B) CT slices showed a mass lesion in the upper lobe of right lung and partial of right pleural thickening.

PMC7170120_01

Male

A 47-year-old male patient suffered from intermittent cough and fever for over 2 months, these symptoms aggravated for at last 20 days without sputum, shortness of breath, thoracalgia or hemoptysis. Initially, computed tomography (CT) scan of his chest showed a mass lesion in right upper lobe of his lung and partial of right pleural thickening, with diffuse consolidation and ground-glass opacity in bilateral pulmones (Figure 1). The doctors considered about interstitial pneumonia owing to infection. While after several days of antibiotic therapy (including sulbenicillin disodium and etimicin), his symptoms had not improved. So bronchoscopy was carried out. Atypical epithelial cells inclined to denocarcinoma were found in transbronchial smear of cytology, while bronchial brushing and biopsy was negative. Unexpectedly the patient felt swollen of his neck just after bronchoscopy, so he underwent another CT at the same day. The CT scan showed bilateral pneumothorax and emphysema of mediastinum superius. Then he transfered to another hospital for symptomatic treatment 5 days later, positron emission tomography/computed tomography (PET/CT) revealed a nodule of about 2.7 cm of its long diameter with characteristics of lobulation and spiculation in the right lung apex section and diffuse consolidation shadow spreading over rest of lung field. The nodular lesion was deemed to be peripheral lung cancer, which average uptake value of (18)F-FDG was 4.3 and maximal uptake value was 5.7. Remaining consolidation was considered as diffuse lung cancer with mildly elevated uptake value of (18)F-FDG (Figure 2). Furthermore, lymph node metastasis of left hilar was likely to have arised. The patient came to our hospital for further diagnosis and therapy. After admission, the patient never had a fever again and auscultation of lung was normal. His results of test for complete blood count, erythrocyte sedimentation rate (ESR), C reactive protein(CRP), procalcitonin (PCT) and biochemical parameters (including lactate dehydrogenase, LDH) were normal. The patient's T cell subpopulations were normal and human immunodeficiency virus (HIV) antibody was negative. Serum tumor markers assay showed normal results as carcinoembryonic antigen (CEA): 3.4 ng/ml, section 19 of cytokeratin (CYRFA21-1): 10.9 ng/ml, squamous cell carcinoma antigen (SCC): 0.8 ng/ml, and neuron specific enolase (NSE): 15.9 ng/ml. Blood gas analysis showed hyoxemia with partial pressure of oxygen (PaO2) being 68 mmHg and peripheral blood saturation (SpO2) being 93% on room air,while potential of hydrogen (PH) and partial pressure of carbon dioxide (PaCO2) was normal. Spirometric abnormality is mildly restrictive defect manifested by decreased vital capacity (76.27% of predicted value) and mildly reduced diffusing capacity for carbon monoxide (73.28% of predicted value). Fiberoptic bronchoscopy was applied again for diagnosis. BALF showed a large amount of amorphous red-dyed materials and a few alveolar macrophages scattered in endoalveolar space with PAS positive (Figure 3). Transbronchial lung biopsy (TBLB) found great numbers of unstructured, red-dyed granules with PAS+ and adenocarcinoma with differentiated grade II with immunohistochemical analysis for ALK-D5F3(-), CEA(-), EGFR-E746(-), EGFR-L858(-), Ki-67(5%+), NapsinA(+), TTF-1(+), SPA(+), CD68(+) and CK(+) (Figure 4). Follow-up EGFR detection (ARMS used) showed mutations in exon 19 of the EGFR gene, while mutations were not detected in exon 18, 20 and 21. We judged clinical stage IIB (cT1cN1M0) according to PET/CT, BALF and lung biopsy. Thoracic surgeons carried out wedge resection in VATS (video-assisted thoracoscopic surgery) with mediastinal lymphnode sampling (group 2,4). Pathological findings (in upper right lung) confirmed adenocarcinoma differentiated grade II~III, mainly presenting as acinar and solid type, rarely papillary type. Amorphous eosinophilic substance can be seen in the alveolar of pulmonary tissue around, which was consistent with PAP (Figure 5). In addition, bilateral lymph nodes of group 2 and 4 proved metastasis and carcinoma did not involve the visceral pleura. Then we revised as stage IIIB(pT1cN3M0) and administered adjuvant chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1, every 28 days for 4 cycles). Chest CT after 2 cycles of postoperative chemotherapy (Figure 6) showed no tumor recurrence and no patchy, ground-glass opacities. Chest CT of follow-up visits once every three months in local approved SD (stable disease).However ninth months after therapy, the patient felt pain on the left chest. CT showed multiple, subsolid nodules in both lungs and suspected metastasis in the left sixth rib bone and T8 vertebral bone (Figure 7).SPECT/CT for whole body bone planar imaging showed multiple bone metastasis, considered the recurrence and metastasis of the adenocarcinoma. Then we reassessed as stage IVB (rT4N3M1c) and administered 2cycles of primary chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1,every 28 days for 4 cycles) up to now.

lung cancer, peripheral adenocarcinom, pulmonary alveolar proteinosis

Chest computerized tomography (CT) before any therapy. (A, B) CT slices showed a mass lesion in the upper lobe of right lung and partial of right pleural thickening.

PMC7170120_01

Male

A 47-year-old male patient suffered from intermittent cough and fever for over 2 months, these symptoms aggravated for at last 20 days without sputum, shortness of breath, thoracalgia or hemoptysis. Initially, computed tomography (CT) scan of his chest showed a mass lesion in right upper lobe of his lung and partial of right pleural thickening, with diffuse consolidation and ground-glass opacity in bilateral pulmones (Figure 1). The doctors considered about interstitial pneumonia owing to infection. While after several days of antibiotic therapy (including sulbenicillin disodium and etimicin), his symptoms had not improved. So bronchoscopy was carried out. Atypical epithelial cells inclined to denocarcinoma were found in transbronchial smear of cytology, while bronchial brushing and biopsy was negative. Unexpectedly the patient felt swollen of his neck just after bronchoscopy, so he underwent another CT at the same day. The CT scan showed bilateral pneumothorax and emphysema of mediastinum superius. Then he transfered to another hospital for symptomatic treatment 5 days later, positron emission tomography/computed tomography (PET/CT) revealed a nodule of about 2.7 cm of its long diameter with characteristics of lobulation and spiculation in the right lung apex section and diffuse consolidation shadow spreading over rest of lung field. The nodular lesion was deemed to be peripheral lung cancer, which average uptake value of (18)F-FDG was 4.3 and maximal uptake value was 5.7. Remaining consolidation was considered as diffuse lung cancer with mildly elevated uptake value of (18)F-FDG (Figure 2). Furthermore, lymph node metastasis of left hilar was likely to have arised. The patient came to our hospital for further diagnosis and therapy. After admission, the patient never had a fever again and auscultation of lung was normal. His results of test for complete blood count, erythrocyte sedimentation rate (ESR), C reactive protein(CRP), procalcitonin (PCT) and biochemical parameters (including lactate dehydrogenase, LDH) were normal. The patient's T cell subpopulations were normal and human immunodeficiency virus (HIV) antibody was negative. Serum tumor markers assay showed normal results as carcinoembryonic antigen (CEA): 3.4 ng/ml, section 19 of cytokeratin (CYRFA21-1): 10.9 ng/ml, squamous cell carcinoma antigen (SCC): 0.8 ng/ml, and neuron specific enolase (NSE): 15.9 ng/ml. Blood gas analysis showed hyoxemia with partial pressure of oxygen (PaO2) being 68 mmHg and peripheral blood saturation (SpO2) being 93% on room air,while potential of hydrogen (PH) and partial pressure of carbon dioxide (PaCO2) was normal. Spirometric abnormality is mildly restrictive defect manifested by decreased vital capacity (76.27% of predicted value) and mildly reduced diffusing capacity for carbon monoxide (73.28% of predicted value). Fiberoptic bronchoscopy was applied again for diagnosis. BALF showed a large amount of amorphous red-dyed materials and a few alveolar macrophages scattered in endoalveolar space with PAS positive (Figure 3). Transbronchial lung biopsy (TBLB) found great numbers of unstructured, red-dyed granules with PAS+ and adenocarcinoma with differentiated grade II with immunohistochemical analysis for ALK-D5F3(-), CEA(-), EGFR-E746(-), EGFR-L858(-), Ki-67(5%+), NapsinA(+), TTF-1(+), SPA(+), CD68(+) and CK(+) (Figure 4). Follow-up EGFR detection (ARMS used) showed mutations in exon 19 of the EGFR gene, while mutations were not detected in exon 18, 20 and 21. We judged clinical stage IIB (cT1cN1M0) according to PET/CT, BALF and lung biopsy. Thoracic surgeons carried out wedge resection in VATS (video-assisted thoracoscopic surgery) with mediastinal lymphnode sampling (group 2,4). Pathological findings (in upper right lung) confirmed adenocarcinoma differentiated grade II~III, mainly presenting as acinar and solid type, rarely papillary type. Amorphous eosinophilic substance can be seen in the alveolar of pulmonary tissue around, which was consistent with PAP (Figure 5). In addition, bilateral lymph nodes of group 2 and 4 proved metastasis and carcinoma did not involve the visceral pleura. Then we revised as stage IIIB(pT1cN3M0) and administered adjuvant chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1, every 28 days for 4 cycles). Chest CT after 2 cycles of postoperative chemotherapy (Figure 6) showed no tumor recurrence and no patchy, ground-glass opacities. Chest CT of follow-up visits once every three months in local approved SD (stable disease).However ninth months after therapy, the patient felt pain on the left chest. CT showed multiple, subsolid nodules in both lungs and suspected metastasis in the left sixth rib bone and T8 vertebral bone (Figure 7).SPECT/CT for whole body bone planar imaging showed multiple bone metastasis, considered the recurrence and metastasis of the adenocarcinoma. Then we reassessed as stage IVB (rT4N3M1c) and administered 2cycles of primary chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1,every 28 days for 4 cycles) up to now.

lung cancer, peripheral adenocarcinom, pulmonary alveolar proteinosis

Chest CT after 2 cycles of postoperative chemotherapy. (A) No tumor recurrence in right upper lobe of lung.

PMC7170120_01

Male

A 47-year-old male patient suffered from intermittent cough and fever for over 2 months, these symptoms aggravated for at last 20 days without sputum, shortness of breath, thoracalgia or hemoptysis. Initially, computed tomography (CT) scan of his chest showed a mass lesion in right upper lobe of his lung and partial of right pleural thickening, with diffuse consolidation and ground-glass opacity in bilateral pulmones (Figure 1). The doctors considered about interstitial pneumonia owing to infection. While after several days of antibiotic therapy (including sulbenicillin disodium and etimicin), his symptoms had not improved. So bronchoscopy was carried out. Atypical epithelial cells inclined to denocarcinoma were found in transbronchial smear of cytology, while bronchial brushing and biopsy was negative. Unexpectedly the patient felt swollen of his neck just after bronchoscopy, so he underwent another CT at the same day. The CT scan showed bilateral pneumothorax and emphysema of mediastinum superius. Then he transfered to another hospital for symptomatic treatment 5 days later, positron emission tomography/computed tomography (PET/CT) revealed a nodule of about 2.7 cm of its long diameter with characteristics of lobulation and spiculation in the right lung apex section and diffuse consolidation shadow spreading over rest of lung field. The nodular lesion was deemed to be peripheral lung cancer, which average uptake value of (18)F-FDG was 4.3 and maximal uptake value was 5.7. Remaining consolidation was considered as diffuse lung cancer with mildly elevated uptake value of (18)F-FDG (Figure 2). Furthermore, lymph node metastasis of left hilar was likely to have arised. The patient came to our hospital for further diagnosis and therapy. After admission, the patient never had a fever again and auscultation of lung was normal. His results of test for complete blood count, erythrocyte sedimentation rate (ESR), C reactive protein(CRP), procalcitonin (PCT) and biochemical parameters (including lactate dehydrogenase, LDH) were normal. The patient's T cell subpopulations were normal and human immunodeficiency virus (HIV) antibody was negative. Serum tumor markers assay showed normal results as carcinoembryonic antigen (CEA): 3.4 ng/ml, section 19 of cytokeratin (CYRFA21-1): 10.9 ng/ml, squamous cell carcinoma antigen (SCC): 0.8 ng/ml, and neuron specific enolase (NSE): 15.9 ng/ml. Blood gas analysis showed hyoxemia with partial pressure of oxygen (PaO2) being 68 mmHg and peripheral blood saturation (SpO2) being 93% on room air,while potential of hydrogen (PH) and partial pressure of carbon dioxide (PaCO2) was normal. Spirometric abnormality is mildly restrictive defect manifested by decreased vital capacity (76.27% of predicted value) and mildly reduced diffusing capacity for carbon monoxide (73.28% of predicted value). Fiberoptic bronchoscopy was applied again for diagnosis. BALF showed a large amount of amorphous red-dyed materials and a few alveolar macrophages scattered in endoalveolar space with PAS positive (Figure 3). Transbronchial lung biopsy (TBLB) found great numbers of unstructured, red-dyed granules with PAS+ and adenocarcinoma with differentiated grade II with immunohistochemical analysis for ALK-D5F3(-), CEA(-), EGFR-E746(-), EGFR-L858(-), Ki-67(5%+), NapsinA(+), TTF-1(+), SPA(+), CD68(+) and CK(+) (Figure 4). Follow-up EGFR detection (ARMS used) showed mutations in exon 19 of the EGFR gene, while mutations were not detected in exon 18, 20 and 21. We judged clinical stage IIB (cT1cN1M0) according to PET/CT, BALF and lung biopsy. Thoracic surgeons carried out wedge resection in VATS (video-assisted thoracoscopic surgery) with mediastinal lymphnode sampling (group 2,4). Pathological findings (in upper right lung) confirmed adenocarcinoma differentiated grade II~III, mainly presenting as acinar and solid type, rarely papillary type. Amorphous eosinophilic substance can be seen in the alveolar of pulmonary tissue around, which was consistent with PAP (Figure 5). In addition, bilateral lymph nodes of group 2 and 4 proved metastasis and carcinoma did not involve the visceral pleura. Then we revised as stage IIIB(pT1cN3M0) and administered adjuvant chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1, every 28 days for 4 cycles). Chest CT after 2 cycles of postoperative chemotherapy (Figure 6) showed no tumor recurrence and no patchy, ground-glass opacities. Chest CT of follow-up visits once every three months in local approved SD (stable disease).However ninth months after therapy, the patient felt pain on the left chest. CT showed multiple, subsolid nodules in both lungs and suspected metastasis in the left sixth rib bone and T8 vertebral bone (Figure 7).SPECT/CT for whole body bone planar imaging showed multiple bone metastasis, considered the recurrence and metastasis of the adenocarcinoma. Then we reassessed as stage IVB (rT4N3M1c) and administered 2cycles of primary chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1,every 28 days for 4 cycles) up to now.

lung cancer, peripheral adenocarcinom, pulmonary alveolar proteinosis

Chest CT of ninth months after therapy. (B) A part-solid nodule found in the upper lobe of left lung.

PMC7170120_01

Male

A 47-year-old male patient suffered from intermittent cough and fever for over 2 months, these symptoms aggravated for at last 20 days without sputum, shortness of breath, thoracalgia or hemoptysis. Initially, computed tomography (CT) scan of his chest showed a mass lesion in right upper lobe of his lung and partial of right pleural thickening, with diffuse consolidation and ground-glass opacity in bilateral pulmones (Figure 1). The doctors considered about interstitial pneumonia owing to infection. While after several days of antibiotic therapy (including sulbenicillin disodium and etimicin), his symptoms had not improved. So bronchoscopy was carried out. Atypical epithelial cells inclined to denocarcinoma were found in transbronchial smear of cytology, while bronchial brushing and biopsy was negative. Unexpectedly the patient felt swollen of his neck just after bronchoscopy, so he underwent another CT at the same day. The CT scan showed bilateral pneumothorax and emphysema of mediastinum superius. Then he transfered to another hospital for symptomatic treatment 5 days later, positron emission tomography/computed tomography (PET/CT) revealed a nodule of about 2.7 cm of its long diameter with characteristics of lobulation and spiculation in the right lung apex section and diffuse consolidation shadow spreading over rest of lung field. The nodular lesion was deemed to be peripheral lung cancer, which average uptake value of (18)F-FDG was 4.3 and maximal uptake value was 5.7. Remaining consolidation was considered as diffuse lung cancer with mildly elevated uptake value of (18)F-FDG (Figure 2). Furthermore, lymph node metastasis of left hilar was likely to have arised. The patient came to our hospital for further diagnosis and therapy. After admission, the patient never had a fever again and auscultation of lung was normal. His results of test for complete blood count, erythrocyte sedimentation rate (ESR), C reactive protein(CRP), procalcitonin (PCT) and biochemical parameters (including lactate dehydrogenase, LDH) were normal. The patient's T cell subpopulations were normal and human immunodeficiency virus (HIV) antibody was negative. Serum tumor markers assay showed normal results as carcinoembryonic antigen (CEA): 3.4 ng/ml, section 19 of cytokeratin (CYRFA21-1): 10.9 ng/ml, squamous cell carcinoma antigen (SCC): 0.8 ng/ml, and neuron specific enolase (NSE): 15.9 ng/ml. Blood gas analysis showed hyoxemia with partial pressure of oxygen (PaO2) being 68 mmHg and peripheral blood saturation (SpO2) being 93% on room air,while potential of hydrogen (PH) and partial pressure of carbon dioxide (PaCO2) was normal. Spirometric abnormality is mildly restrictive defect manifested by decreased vital capacity (76.27% of predicted value) and mildly reduced diffusing capacity for carbon monoxide (73.28% of predicted value). Fiberoptic bronchoscopy was applied again for diagnosis. BALF showed a large amount of amorphous red-dyed materials and a few alveolar macrophages scattered in endoalveolar space with PAS positive (Figure 3). Transbronchial lung biopsy (TBLB) found great numbers of unstructured, red-dyed granules with PAS+ and adenocarcinoma with differentiated grade II with immunohistochemical analysis for ALK-D5F3(-), CEA(-), EGFR-E746(-), EGFR-L858(-), Ki-67(5%+), NapsinA(+), TTF-1(+), SPA(+), CD68(+) and CK(+) (Figure 4). Follow-up EGFR detection (ARMS used) showed mutations in exon 19 of the EGFR gene, while mutations were not detected in exon 18, 20 and 21. We judged clinical stage IIB (cT1cN1M0) according to PET/CT, BALF and lung biopsy. Thoracic surgeons carried out wedge resection in VATS (video-assisted thoracoscopic surgery) with mediastinal lymphnode sampling (group 2,4). Pathological findings (in upper right lung) confirmed adenocarcinoma differentiated grade II~III, mainly presenting as acinar and solid type, rarely papillary type. Amorphous eosinophilic substance can be seen in the alveolar of pulmonary tissue around, which was consistent with PAP (Figure 5). In addition, bilateral lymph nodes of group 2 and 4 proved metastasis and carcinoma did not involve the visceral pleura. Then we revised as stage IIIB(pT1cN3M0) and administered adjuvant chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1, every 28 days for 4 cycles). Chest CT after 2 cycles of postoperative chemotherapy (Figure 6) showed no tumor recurrence and no patchy, ground-glass opacities. Chest CT of follow-up visits once every three months in local approved SD (stable disease).However ninth months after therapy, the patient felt pain on the left chest. CT showed multiple, subsolid nodules in both lungs and suspected metastasis in the left sixth rib bone and T8 vertebral bone (Figure 7).SPECT/CT for whole body bone planar imaging showed multiple bone metastasis, considered the recurrence and metastasis of the adenocarcinoma. Then we reassessed as stage IVB (rT4N3M1c) and administered 2cycles of primary chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1,every 28 days for 4 cycles) up to now.

lung cancer, peripheral adenocarcinom, pulmonary alveolar proteinosis

Chest CT of ninth months after therapy. (C, D) Multiple subsolid nodules in lower lobe of both lungs.

PMC7170120_01

Male

A 47-year-old male patient suffered from intermittent cough and fever for over 2 months, these symptoms aggravated for at last 20 days without sputum, shortness of breath, thoracalgia or hemoptysis. Initially, computed tomography (CT) scan of his chest showed a mass lesion in right upper lobe of his lung and partial of right pleural thickening, with diffuse consolidation and ground-glass opacity in bilateral pulmones (Figure 1). The doctors considered about interstitial pneumonia owing to infection. While after several days of antibiotic therapy (including sulbenicillin disodium and etimicin), his symptoms had not improved. So bronchoscopy was carried out. Atypical epithelial cells inclined to denocarcinoma were found in transbronchial smear of cytology, while bronchial brushing and biopsy was negative. Unexpectedly the patient felt swollen of his neck just after bronchoscopy, so he underwent another CT at the same day. The CT scan showed bilateral pneumothorax and emphysema of mediastinum superius. Then he transfered to another hospital for symptomatic treatment 5 days later, positron emission tomography/computed tomography (PET/CT) revealed a nodule of about 2.7 cm of its long diameter with characteristics of lobulation and spiculation in the right lung apex section and diffuse consolidation shadow spreading over rest of lung field. The nodular lesion was deemed to be peripheral lung cancer, which average uptake value of (18)F-FDG was 4.3 and maximal uptake value was 5.7. Remaining consolidation was considered as diffuse lung cancer with mildly elevated uptake value of (18)F-FDG (Figure 2). Furthermore, lymph node metastasis of left hilar was likely to have arised. The patient came to our hospital for further diagnosis and therapy. After admission, the patient never had a fever again and auscultation of lung was normal. His results of test for complete blood count, erythrocyte sedimentation rate (ESR), C reactive protein(CRP), procalcitonin (PCT) and biochemical parameters (including lactate dehydrogenase, LDH) were normal. The patient's T cell subpopulations were normal and human immunodeficiency virus (HIV) antibody was negative. Serum tumor markers assay showed normal results as carcinoembryonic antigen (CEA): 3.4 ng/ml, section 19 of cytokeratin (CYRFA21-1): 10.9 ng/ml, squamous cell carcinoma antigen (SCC): 0.8 ng/ml, and neuron specific enolase (NSE): 15.9 ng/ml. Blood gas analysis showed hyoxemia with partial pressure of oxygen (PaO2) being 68 mmHg and peripheral blood saturation (SpO2) being 93% on room air,while potential of hydrogen (PH) and partial pressure of carbon dioxide (PaCO2) was normal. Spirometric abnormality is mildly restrictive defect manifested by decreased vital capacity (76.27% of predicted value) and mildly reduced diffusing capacity for carbon monoxide (73.28% of predicted value). Fiberoptic bronchoscopy was applied again for diagnosis. BALF showed a large amount of amorphous red-dyed materials and a few alveolar macrophages scattered in endoalveolar space with PAS positive (Figure 3). Transbronchial lung biopsy (TBLB) found great numbers of unstructured, red-dyed granules with PAS+ and adenocarcinoma with differentiated grade II with immunohistochemical analysis for ALK-D5F3(-), CEA(-), EGFR-E746(-), EGFR-L858(-), Ki-67(5%+), NapsinA(+), TTF-1(+), SPA(+), CD68(+) and CK(+) (Figure 4). Follow-up EGFR detection (ARMS used) showed mutations in exon 19 of the EGFR gene, while mutations were not detected in exon 18, 20 and 21. We judged clinical stage IIB (cT1cN1M0) according to PET/CT, BALF and lung biopsy. Thoracic surgeons carried out wedge resection in VATS (video-assisted thoracoscopic surgery) with mediastinal lymphnode sampling (group 2,4). Pathological findings (in upper right lung) confirmed adenocarcinoma differentiated grade II~III, mainly presenting as acinar and solid type, rarely papillary type. Amorphous eosinophilic substance can be seen in the alveolar of pulmonary tissue around, which was consistent with PAP (Figure 5). In addition, bilateral lymph nodes of group 2 and 4 proved metastasis and carcinoma did not involve the visceral pleura. Then we revised as stage IIIB(pT1cN3M0) and administered adjuvant chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1, every 28 days for 4 cycles). Chest CT after 2 cycles of postoperative chemotherapy (Figure 6) showed no tumor recurrence and no patchy, ground-glass opacities. Chest CT of follow-up visits once every three months in local approved SD (stable disease).However ninth months after therapy, the patient felt pain on the left chest. CT showed multiple, subsolid nodules in both lungs and suspected metastasis in the left sixth rib bone and T8 vertebral bone (Figure 7).SPECT/CT for whole body bone planar imaging showed multiple bone metastasis, considered the recurrence and metastasis of the adenocarcinoma. Then we reassessed as stage IVB (rT4N3M1c) and administered 2cycles of primary chemotherapy (Cisplatin 75 mg/m2 day 1, pemetrexed 500 mg/m2 day 1,every 28 days for 4 cycles) up to now.

lung cancer, peripheral adenocarcinom, pulmonary alveolar proteinosis

Chest CT of ninth months after therapy. (C, D) Multiple subsolid nodules in lower lobe of both lungs.

PMC5608601_01

Male

A 65-year-old man presented with a one-month history of cough, sputum and chest pain. He was a current smoker (20 cigarettes a day for 40 years) and reported no occupational exposure. His medical history was unremarkable. Symptoms persisted without medication. At admission, temperature was 36.5 C, respiratory rate was 18/minute, and moist rales were heard in left lung. Arterial blood gases at 21% FiO2 (fraction of inspiration O2) showed PaO2 (partial pressure of oxygen) 69 mmHg, PaCO2 (partial pressure of carbon dioxide in artery) 36 mmHg, pH 7.43. Laboratory parameters were as follows: White blood cell count of 7.99 x 109 cells/l [normal range (NR), 4-10 x 109 cells/l], differential neutrophil count of 69% (NR, 40-70%) and a C-reactive protein (CRP) level of 36.38 mg/l (NR, <10 mg/l). Serum electrolytes, renal and liver function tests were normal, as well as serological tests for tumor markers, Legionella pneumonia, Mycoplasma, Chlamydia, Coxiella psittaci, hepatitis C and B viruses, and HIV. Antinuclear antibody, perinuclear antineutrophil cytoplasmic antibody (P-ANCA), cytoplasmic-ANCA, and cyclic citrullinated protein antibody tests were negative. High-resolution computed tomography (CT) demonstrated extensive shadows of high density in left lung, with bronchial ventilation sign, pleural thickening, and enlargement of lymph nodes in hilum and mediastinum. No abnormal enhancement was showed (Fig. 1). Lung cancer was considered by imaging diagnosis, without the exception of lymphatic metastasis. Bronchofibroscope showed mucosa thickening and tracheobronchial stenosis in left lung (Fig. 2). Transbronchial biopsy indicated interstitial fibrous tissue hyperplasia and chronic inflammatory cell infiltration (Fig. 3A). After 10 days antibiotic therapy with amoxicillin/clavulanic acid and roxithromycin, the symptom improved, but there was no significant change of CT sign. Percutaneous lung biopsy was arranged. Percutaneous biopsy from the left lower lobe also indicated interstitial fibrous tissue and chronic inflammatory cells without specificity (Fig. 3B). One month later, the patient completed PET-CT (positron emission tomography-computed tomography) scan outside the hospital. The results showed high density shadow in left lung with increased metabolism, without obvious change in the range than before (Fig. 4). PET-CT indicated inflammation, without the exception of adenocarcinoma. Percutaneous biopsy was suggested again. The second percutaneous biopsy results was the same as above, showed interstitial fibrous tissue and chronic inflammatory cells. Next, the patient visited Shanghai Chest Hospital, did EBUS-TBNA (endobroncheal ultrasonography-transbronchial needle aspirations) check. Pathology still suggested inflammatory. There were no characteristic pathological changes and definite diagnosis. After four times pulmonary biopsies, there was no definitive pathological evidence. Also, there was no characteristic imaging finding. Other infectious diseases were less likely to be diagnosed based on the patient's clinical characteristics, tumor was the main differential diagnosis, but no tumor cells were found after multiple biopsies. The patient and his family defused to do further open lung biopsy, and the treatment could not be delayed. According to the clinical features, we diagnose OP in this case after excluding other diseases and gave corticosteroid therapy. Oral corticosteroid therapy was started at 0.75mg/kg/day. Improvement of CT sign was observed after 1 month treatment, the shadow had dramatically decreased. Steroids were tapered over 6 months and lung CT scans significantly improved (Fig. 5). But new small shadow appeared, as the sign of recurrence (Fig. 5). Once again, we persuaded the patient to do another biopsy. The patient underwent percutaneous biopsy again, and finally, the pathological manifestation indicated OP by finding granulation tissue plugs in the lumen of alveoli (Fig. 6). So far, the patient has been followed up for one year. Informed consent was signed by the patient.

bronchofibroscope, cop, cryptogenic organizing pneumonia, crp, c-reactive protein, ct, computed tomography, fio2, fraction of inspiration o2, op, organizing pneumonia, organizing pneumonia, pet-ct, positron emission tomography-computed tomography, paco2, partial pressure of carbon dioxide in artery, pao2, partial pressure of oxygen, percutaneous lung biopsy

PMC4106255_01

Male

A 60-year-old man with a medical history of schizoaffective disorder and polysubstance abuse presented in Birmingham, Alabama, with bilateral "black feet." He reported "a few hours out in the cold" 3 weeks ago. Physical examination revealed forth degree frostbite of the bilateral lower extremities (Figs 1 and 2). What is the incidence of frostbite and what populations are at risk of developing the condition? What is the pathophysiology of frostbite? What are the classification systems for frostbite and how is the severity of frostbite determined? What are the current recommendations for the surgical management frostbite?

cold, frostbite, injury, salvage, tissue

PMC8342167_01

Female

A 26-year-old African American female with a medical history of SLE, ESRD due to LN, remote history of Steven-Johnson Syndrome due to sulfa allergy, and resistant hypertension presented to the emergency department with painful, peeling, blistering, rash and fever. She reported that the rash developed over a period of 3 months with an intermittent response to prednisone therapy. Three weeks prior to presentation, the rash became progressively worse. She developed fevers came on one week prior to presentation. The rash started on her arms and progressively spread. She admitted associated shortness of breath accompanied by a productive cough with green, bloody sputum, as well as nausea and vomiting. Patient reported compliance with her home dose of prednisone but may have not taken her mycophenolate mofetil regularly. She missed two sequential hemodialysis sessions due to pain with walking from the blistering rash on her soles of the feet. Her physical exam was significant for fever of 100.6 F and tachycardia with heart rate of 130 beats per minute. Skin exam was evident for brown plaques on the forehead and bilateral cheeks with sparing of the nasolabial folds, with erosions and hemorrhagic crust involving the philtrum, ears, forehead, nose, chin, and lips. There were dark brown plaques with few erosions and atrophic scars on bilateral forearms and lower legs with deep red to violaceous painful targetoid lesions on the palms and plantar surfaces (Figures 1 and 2). The skin over the trunk had pink eroded macules, and there were pink patches on the back within a background of dusky necrotic plaques. There were multiple full-thickness epidermal necroses with large areas of bleeding with the denuded skin on the arms and chest in the sun exposed distribution (Figure 3). Oral mucosae were negative for any oral lesions. Patient was found to be pancytopenic with white blood cell count (WBC) 2.03 (Ref: 3.4-10.8 x 103/UL), absolute neutrophil count (ANC) of 1.25 (Ref: 1.4-7.0 x 103/UL), hemoglobin (Hb) 8.8 g/dL (Ref: 11.1-15.9 g/dL), hematocrit (Hct) 28.9% (Ref: 34-46%), platelet 69 (150-450 x 103/UL), sodium 138 mmol/L, potassium 3.9 mmol/L, chloride 98 mmol/L, CO2 21 mmol/L, BUN 41 mg/dL (Ref: 6-20 mg/dL), Cr 5.49 mg/dL (Ref: 0.57-1.0 mg/dL), calcium 7.2 mg/dL (8.7-10.2 mg/dL), albumin 3.2 g/dL, phosphorous 5.0 mg/dL (Ref: 1.2-2.2 mg/dL), AST 286 IU/L (Ref 0-40 IU/L), ALT 31 IU/L (0-32 IU/L), total bilirubin 0.5 mg/dL, alkaline phosphatase 136 IU/L, CK 91 U/L, serum lactate was 0.80 mmol/L, and ferritin was 5885 ng/mL (Ref: 15-50 ng/mL). Electrocardiogram was consistent with sinus tachycardia. Chest X-ray did not show any lung infiltrates or effusions. Ultrasound of the abdomen did not show an acute abdominal process, and the liver demonstrated normal echogenicity, echotexture, and size; the spleen was not enlarged. Sputum gram stain and cultures were unremarkable. Blood cultures were negative for bacteria and yeast. Patient was anuric due to chronic dialysis. Evaluation of lupus activity showed double-stranded DNA (dsDNA) antibody 42 IU/mL (Ref: 0-9 IU/L). Complement 3 (C3) was 43 mg/dL (Ref: 90-180 mg/dL) and complement 4 (C4) was 9 mg/dL (Ref: 10-40 mg/dL). Rheumatoid factor was negative. Sjogren's anti-SSA was >8.0 AI (Ref: 0-0.9 AI) and Sjogren's anti-SSB was <0.2 AI (Ref: 0-0.9 AI). HIV screen was negative, and viral hepatitis panels for hepatitis A, B, and C were negative. Skin biopsies showed focal interface changes, and periodic acid Schiff (PAS) stain was negative for fungal microorganisms. Gram stain highlighted surface cocci bacteria. VZV and herpes I/II immunostains were negative. The direct immunofluorescence revealed that finely granular deposition of C3, IgM, and fibrinogen is consistent with lupus. Given her presentation of a fever, shortness of breath, and productive cough, there was a concern for postinfectious erythema multiforme. The nucleic acid amplification tests for multiple respiratory pathogens such as Mycoplasma, influenza A, influenza H1, influenza H3, influenza A virus H1 2009, influenza B, respiratory syncytial virus, parainfluenza virus type 1, 2, 3, 4, human metapneumovirus, rhinovirus/enterovirus, adenovirus, Chlamydia pneumoniae, and Mycoplasma pneumoniae were negative. Blood cultures did not grow any bacteria or fungal organisms. Skin wound cultures were also negative for any organisms except for skin flora. Historically, there were no preceding infections reported. Our presumptive primary diagnosis was acute on chronic cutaneous lupus with epidermal necrolysis due to noncompliance with medications; differentials included Rowell syndrome, bullous lupus, Steven-Johnsons syndrome, and toxic epidermal necrolysis (TEN). Hemophagocytic lymphohistiocytosis/mast cell activation syndrome (HLH/MAS) was also a concern given pancytopenia, fevers, elevated transaminases, and elevated ferritin. However, after further evaluation by hematology, HLH/MAS was less likely given halving of ferritin after first dose of intravenous steroids, lack of hepatosplenomegaly, lack of elevation in bilirubin and triglycerides, patient did not have persistent fevers, and soluble IL-2 receptor was 2021 pg/mL (Ref: 175.3-858.2 pg/mL), needed to be greater than 2400 pg/mL (greater than 2 standard deviations of reference range) to meet criteria, and clinical picture was also not as critical as usually seen. The clinical picture of atypical EM-like lesions, presence of chilblains, speckled ANA pattern, elevated anti-Ro/SSA, and absence of infectious or pharmacologic triggers in a patient with SLE confirmed our suspicion for Rowell syndrome. Due to the extensive skin surface area involvement, the patient was treated with vancomycin intravenously for primary and secondary skin infection. Gram-negative coverage was held due to severe allergy to penicillin and cephalosporin antibiotics. The pancytopenia was suspected due to an acute flare of systemic lupus erythematosus, and the patient was initially started on methylprednisolone 1.5 mg/kg intravenously daily. Given more than 60% of body surface area (BSA) involvement, the patient was transferred to the burn unit for extensive debridement and multifaceted wound care. Mycophenolate mofetil was held given the elevated transaminases. Pulse doses of intravenous methylprednisolone were escalated to 1000 mg intravenous daily for three days given the concern for acute cutaneous lupus erythematosus with epidermal necrosis and concomitant MAS. After normalization of transaminases, negative testing for latent tuberculosis and hepatitis B and C, and negative blood cultures, the patient was given rituximab 375 mg/m2 intravenously at day 0 and day 15 with excellent maintenance of remission of skin disease and cytopenias. This dose was chosen by the treating provider, given patient being dialysis dependent, thus more immunosuppressed state at baseline and recent elevation in transaminases. It was reassuring that early suspicion for MAS appeared steroid-responsive to pulse intravenous methylprednisolone. The soluble IL-2 receptor alpha measurement was not elevated, and serum ferritin halved after the first dose of pulse steroids. Despite the improvements in serum and systemic symptoms, the skin manifestations were slow to respond. During 2-week and 12-week follow-up of the patient, there has been maintenance of clear skin without any active cutaneous lupus manifestations. Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) was 0 at 12-week follow-up.

PMC3253153_01

Unknown

Three young men (Case A 19 year-old, Case B 21 year-old, Case C 25 year-old) came to our observation for recurrent attacks of migraine-like headache of a pulsating quality and severe intensity, with nausea, photo- and phonophobia, that resolved spontaneously within 12 h if untreated. The attacks were preceded by reversible visual symptoms presenting as fortification spectrum and ipsilateral cheiro-oral paresthesia (Cases B and C only), that lasted for 15-40 min. Onset of the symptoms occurred a few years earlier: 4 years for Cases A and C, 2 years for Case B. In all cases the symptoms occurred when they were in the locker room: in Cases B and C shortly after a football match, but never after training; whilst in Case A the symptoms occurred occasionally after swimming pool and gym training or after participating in physical education activities at school. No other subtypes of headache, or head trauma were reported by the patients. The father of Case A and the mothers of Cases B and C suffered from episodic attacks of migraine without aura. The patients' medical history, physical and neurological examination did not suggest any other secondary disorder (Cases A and B are smokers). Case A also suffers from episodic migraine without aura according to the current International Classification of Headache Disorders (ICHD-II) Criteria. The patients, however, underwent extensive diagnostic investigation: brain magnetic resonance with angiographic sequences, electroencephalography, vertebral and carotid echo-doppler, complete ocular examination, electrocardiography, transthoracic echocardiography and complete blood cell count, general chemistry profile, coagulation studies, protein C, protein S, antithrombin III, anticardiolipin antibody, erythrocyte sedimentation rate, C-reactive protein, antinuclear antibody and thyroid function test. The results of the laboratory tests and determinations were normal.

PMC6256140_02

Female

Personal pathological antecedents: chicken pox at four years old. Heredo-collateral antecedents: healthy parents, 3 healthy brothers, an aunt, related to her mother, with psoriasis. Anamnesis. The onset was 2 weeks before, with an erythematous rash at the abdominal level. She went to the dermatologist who recommended a local treatment with Fluocinolone ointment and magistral prescription with salicylic acid, urea and jelly. The rash generalized: squamous patches appeared and subsequently she was admitted to our clinic. When admitted: no fever, weight= 20 kg, fair general state, erythematous rash in patches, erythematous plaques covered with silvery, thick, easily exfoliating, not painful, non-pruriginous squamae, with the presence of Auspitz signs and white spots, at the level of scalp, earlobes, retro-auricular, anterior and posterior torso, abdomen, lower and upper limbs; pustules surrounded by red skin at the axillary, genital and inguinal level. Pulmonary - normal, normal heartbeat, CF=98/min, supple abdomen, liver 1 cm below costal margin, based-flared thorax, tooth caries (Fig.1). Investigations. Hemogram: Hb= 12.2g%, Tr= 236000/mm3, L= 16000/mm3, NS=62%, Ly=32%, M=6%, VSH= 7/14 mm after 1/2 hours, fibrinogen= 397 mg/dl, CRP= 0.4 mg/l, creatinine= 0.4 mg/dl, uric acid = 3.53 mg/dl, glycemia= 82 mg/dl, calcemia= 8 mg/dl, total serical proteins= 6.5 g/dl, sideremy= 103 mg/dl, GOT= 19 U/l, GPT= 14 U/l, negative coproparasitary examination, normal urine summary examination, ASLO= 116.86UI. Immunogram: IgA= 76.67 mg/dl, (N=70-400), IgG= 865.5 mg/dl (N=700-1600), IgM= 167.2 mg/dl (N=100-230), pharyngeal exudate: absent streptococcus, staphylococcus, nasal exudate: present staphylococcus aureus, sensitive to: Biseptol, Linezolid, Gentamicin, Vancomycin, resistant to: Penicillin, Clarithromycin, Oxacillin. Normal abdominal ultrasound. Dermatologic examination: psoriasis vulgaris in patches and plaques. Cutaneous biopsy / histopathological examination - microscopic examination: epidermis with orthokeratosis, large areas of hypo- and agranulocytosis, acanthosis, mild perivascular chronic inflammatory infiltrate in the dermis. The HP aspect most probably suggests psoriasis vulgaris (Fig.2, Fig.3). The patient received a local treatment recommended by the dermatologist, with magistral prescription with salicylic acid, ihtiol, vitamin A, vitamin E, Advantan cream - applied once per day and Diprosalic scalp application. Starting with the 3rd day of the treatment, the patient presented progressive desquamation of the squamae. She was discharged after 7 days, without squamae (Fig.4). Discharge diagnosis: Psoriasis vulgaris in patches and plaques. Nasal staphylococcus aureus. Hypocalcemia. Hypoproteinemia. Tooth cavities. Weight hypotrophy.

child, diagnosis, psoriasis

PMC7533271_01

Female

A 55-year-old Caucasian woman was admitted to our Hospital after a two-day history of fever (38.5 C) and acute dyspnea with severe respiratory distress and room-air oxygen saturation of 70% occurring few hours after the administration of chemoimmunotherapy. The patient was diagnosed with a triple negative, BRCA1-related, PD-L1 positive right breast cancer four years earlier and was treated with quadrantectomy, radiotherapy and adriamycin-cyclophosphamide and docetaxel-based adjuvant chemotherapy. The tumor had spread with multiple bone metastasis -skull, vertebral, sternum, scapula, ribs, and femurs- and caused bone marrow infiltration-related severe pancytopenia. She was treated with atezolizumab and nab-paclitaxel as first line chemotherapy. She suspended, two weeks before, the self-administration of Ganoderma lucidum medicinal mushrooms as an anticancer supplement. Patient recently received flu vaccination and her remaining medical history comprised chemical diabetes. The physical examination revealed Glascow Coma Scale 14, body temperature 37.7 C, blood pressure 105/60 mmHg, heart rate 117 beats/minute, respiratory rate 25 breaths/minute, oxygen saturation 90% while receiving a 100% fraction of inspired oxygen (FiO2) on reservoir mask -pH 7.55; pCO2 30 mmHg; pO2 87 mmHg, arterial bicarbonate level of 27.5 mmol/L, arterial lactated level of 21, partial pressure of oxygen (pO2)/FiO2 87 mmHg (stage III Acute Respiratory Distress Syndrome)- BMI 30 kg/m2. Chest examination showed scattered wheezes, rales, and bilateral dry crackles in the middle and lower lung fields; regular cardiac rhythm with paraphonic cardiac sounds. Neurological examination revealed lower limb paresis. Laboratory tests results included hemoglobin of 6.7 g/dL, hematocrit of 20.2%, platelet count of 18,000/microL, white blood cells of 2210/microL -neutrophil and lymphocytic count of 1720 (77%) and 440/microL (19.9%), respectively- erythrocyte sedimentation rate of 76 mm/h, C-reactive protein of 43.06 mg/dL, procalcitonin of 0.55 ng/dL, and albumin of 2.6 g/dL. The microbiological sample results for Chlamydia pneumoniae, Mycoplasma pneumoniae, Respiratory Syncytial, Adenoviruses, Coxsackieviruses, Influenza A and B viruses turned out negative, as well as the nasopharyngeal swab for SARS-CoV2. Further tests included negative Streptococcus pneumoniae and Legionella pneumophila urinary antigens, serum galactomannan assay, beta D-glucan assay, immunofluorescence assay for the detection of Pneumocystis jirovecii and blood culture. Quantiferon TB Gold test resulted indeterminate, and Staphylococcus aureus was isolated from endotracheal aspirate. The chest computed tomography (CT) scan showed the presence of large areas of parenchymal consolidation with aerial bronchogram, bilateral "ground glass" areas reaching the highest extension on the upper and middle zones, and a moderate bilateral pleural effusion. Nonspecific sub-centimetric ilo-mediastinal lymph nodes and several metastatic lytic bone lesions were also revealed (Figure 1A-C). The artificial intelligence software (CT deep learning algorithm) estimated a positive predictive value of 64% for COVID-1-related pneumonia. The chest physical examination was suggestive for interstitial pneumonia that was confirmed by the CT scan. Furthermore, based on current epidemiology, the oncologic patient's frailty suggested the need for an endotracheal aspirate detecting spike protein (S) and envelope (E) genes for SARS-CoV2 molecular test that resulted positive (Figure 2A). The bilateral lung consolidation along with the interstitial radiologic pattern and the recent history of G. lucidum administration questioned the real nature of the pneumonia. However, to date, no data are available on fungal pneumonia due to G. lucidum administration. The patient started an empiric antimicrobial treatment with vancomycin 2 g/day, meropenem 3 g/day, and levofloxacin 500 mg/day along with amphotericin B therapy (loading dose of 6 mg/kg bid, followed by 300 mg bid) and high flow oxygen supplementation (FiO2100%). Otherwise, the endotracheal aspirates showed positive results for SARS-CoV2 and for methicillin-sensible S. aureus. Antimicrobial therapy was, therefore, de-escalated and lopinavir-ritonavir plus hydroxychloroquine therapy was started. Unfortunately, the patient died five days after hospital admission.

covid-19, sars-cov2, staphylococcus aureus, cancer patient, computed tomography, pneumonia

PMC4897600_01

Female

A 16-year-old previously healthy female presented to this hospital with a two-year history of treatment-refractory tinea capitus of the scalp, left ear, and neck. At that time, she denied fever, malaise, arthralgia, fatigue, weight loss, or any other constitutional symptoms. She further denied cough, shortness of breath, or dyspnea. Her tinea capitus ultimately was treated successfully by terbinafine after failing several other antifungal regimens. One year later, the patient presented again to this hospital with an eight-month history of chronic cough with decreased energy, a 15-pound weight loss, and cervical lymphadenopathy. During the three months before admission, she developed a right-sided neck mass that had been nontender and not inflamed. She was afebrile. She had been seen by her primary care physician and subsequently referred for a biopsy of the neck mass about two weeks before admission. A chest radiograph showed diffuse, widespread pulmonary disease with associated lymphadenopathy. Pathologic analysis of the cervical lymph node biopsy demonstrated findings consistent with Coccidioides infection. Serology also revealed a coccidioidal antigen antibody titer of 1:128 (no antibodies are detected in normal individuals). The patient had a negative Purified Protein Derivative (PPD) tuberculosis test. CT of the abdomen and pelvis without contrast revealed bilateral pleural effusions and multiple small pulmonary nodules seen throughout all pulmonary lobes. Cavitation was seen in a right lower lobe consolidation, with the formation of a bronchopleural fistula. Moderate compression of the superior vena cava and right pulmonary artery were noted, but no intraluminal filling defects were observed. An enlarged and presumably infected right inferior sternocleidomastoid muscle was also noted. Additionally, the patient had significant hepatosplenomegaly with diffuse calcifications dispersed throughout the liver and spleen. A periportal mass was also observed. The kidneys bilaterally had multiple calcified lesions, and a necrotic node was noted in the peritoneum. Additionally, there were multiple retroperitoneal and mesenteric node calcifications. Free fluid was seen in the right pericolic gutter, within the pelvis and bilateral lower quadrants. Multiple lytic lesions were visualized within the right clavicle and right aspect of the T6 vertebral body, the right T5 vertebral body, the sternum, and the right transverse process of the T10 vertebra. Spina bifida was observed at S1. The bowel appeared normal in caliber and free of involvement. The pancreas, adrenal glands, gallbladder, and bladder also appeared unremarkable. CT of the head further revealed incidental bilateral basal ganglia calcifications, but was otherwise unremarkable. There was no definite acute intracranial hemorrhage or territorial infarct. There was no mass effect or hydrocephalus. The orbits and paranasal sinuses were within normal limits. No suspicious focal osseous lesions were present. CT of the sinuses and orbits revealed mucous retention cysts involving the left maxillary and right sphenoid sinuses, without air-fluid levels to suggest acute infection. In the context of this patient's presentation with chronic cough, immune deficiency, negative PPD, and residence in southern Arizona, the imaging findings presented here are most consistent with disseminated coccidioidomycosis infection. Since this admission, the patient's condition has improved considerably. The patient initially required a gastric tube for feeds, but has since had the tube removed and is now feeding orally and maintaining a normal body weight. The patient is currently maintained on prophylactic Posaconazole (a triazole with more efficacy than fluconazole or itraconazole in the prevention of fungal infections) and trimethoprim-sulfamethoxazole for her immunodeficiency. Followup imaging has not been conducted. The exact cause of the patient's immunodeficiency remains undetermined. Several laboratory results for specific known causes of immunodeficiency returned negative or unequivocal during her hospital stay. At the time of publication, the Infectious Disease group was following the case closely and preparing to send the patent to Bethesda, Maryland to the National Institutes of Health for further genetic testing.

ct, computed tomography, mri, magnetic resonance imaging

PMC6430072_01

Male

A 64 year old Caucasian male with recent history of constrictive pericarditis and 4.7 cm ascending aortic aneurysm was admitted to the hospital for an elective surgery. He underwent repair of his ascending aortic aneurysm and pericardiectomy on day 1 of admission. During his hospital stay, he had a cardiac arrest with ventricular fibrillation and underwent pacemaker placement (day 7). He also developed acute kidney injury and underwent tunneled central venous catheter (CVC) placement for hemodialysis (day 10). He was transferred to the intensive care unit (ICU) with hypotension and fever, and blood cultures were drawn (day 20). Microbiology laboratory reported blood cultures positive for RGM, possibly mycobacterium smegmatis based on in-house MALDI-TOF (matrix-assisted laser desorption ionization time-of-flight mass spectrometry) (day 24). Mycobacterium tuberculosis PCR was negative. Infectious diseases team was consulted and CVC was removed per their advice (day 26). Repeat blood cultures drawn on day 24 and day 26 were reported positive for RGM. The patient was started on empiric intravenous (IV) amikacin 15 mg/kg every 24 h, IV meropenem 1 g every 8 h, oral (PO) ethambutol 1200 mg daily and PO doxycycline 100 mg daily (day 26). The CVC tip was positive for Mycobacterium smegmatis (day 28). Post catheter removal, he improved clinically and his repeat blood cultures obtained on day 28 were negative. Mycobacterium smegmatis isolate was send to National Jewish Medical Center for susceptibility testing (day 35). The isolate was resistant to ceftriaxone, cefotaxime and cefepime; intermediate to clarithromycin, cefoxitin and amoxicillin/clavulanate; and susceptible to aminoglycosides, trimethroprim/sulfamethaxole, tetracyclines, imipenem, fluoroquinolones, linezolid, and clofazamine based on RPOB (beta subunit of bacterial RNA polymerase) gene sequencing (day 48). The patient received 28 days of empiric IV amikacin 15 mg/kg every 24 h, IV meropenem 1 g every 8 h, PO ethambutol 1200 mg daily and PO doxycycline 100 mg daily and once susceptibilities were available, he was deescalated to PO doxycycline 100 mg daily and PO ciprofloxacin 500 mg twice a day for 8 weeks. Patient was followed at the infectious diseases outpatient clinic at the end of treatment and was still clinically stable by week 12.

atypical mycobacteria, cvc infection, line infection, m smegmatis, mycobacterium

PMC4354055_01

Female

A 50-year-old female from low socioeconomic background presented at Lok Nayak Hospital, New Delhi, India in 2011 with complaints of a dull aching suprapubic pain for the past six weeks. The pain was persistent throughout the day and increased further on standing and walking. Patient also had a history of low grade evening rise in temperature and weight loss of 8 kg since three months. There was no history suggestive of any trauma, athletic exertion, infection or surgical procedure in the patient. There was no history of tuberculosis in self or in contact with patient with tuberculosis. On examination, deep tenderness was localized to pubic symphysis. There was no localized swelling and palpation did not reveal any inguinal lymphadenopathy. Rectal examination was also normal. Radiograph of the pubic bones showed bony erosion of the public symphysis [Figure 1]. An initial diagnosis of osteitis pubis was made and the patient was prescribed rest, hot water fomentation and non-steroidal anti-inflammatory drugs (NSAIDS) for three weeks. Patient continued to have pain even after six weeks of treatment. Laboratory tests done on follow-up revealed moderately increased white cell counts (14,300/mm3, Normal range: 4000-11000) and raised Erythrocyte Sedimentation Rate (54 mm/hr, Normal: <20 mm/hr). Mantoux test was non-conclusive. Chest radiographs were normal. MRI (Magnetic resonance imaging)/CT (computed tomography) scan of pelvis could not be done due to financial reasons, and so a decision was taken to do fine needle aspiration cytology (FNAC) from the affected region. Fine needle aspiration (FNA) from the pubic symphysis showed epithelioid cell clusters admixed with histiocytes in a background of caseous necrosis. In our case, patient had no active cough and no symptoms/sign of active TB and so no smear was taken. Based on these findings a diagnosis of tuberculosis of symphysis pubis was made and patient was started on multi drug anti-tubercular chemotherapy comprising of Rifampicin, Isoniazid, Ethambutol and Pyrazinamide. One month following the treatment, patient improved symptomatically and started to gain weight. Patient was kept on anti- tuberculous therapy for 12 months. A repeat radiograph did not show signs of progression. Finally, follow up after 12 months of chemotherapy, the patient was symptom-free with a normal activity level without any signs of recurrence.

musculoskeletal, osteitis pubis, tuberculosis

PMC5856679_01

Female

Following SCARE Guidelines and with the patient consent we present the case of a Hispanic unemployed, female patient 59 years old, with a history of high blood pressure and overweight. Surgical history of OTB at the age of 29. She came with symptoms abdominal pain, emesis of intestinal characteristics and obstipation, with an evolution of 5 days. At the examination, no peristalsis was found in abdominal auscultation, and in thoracic auscultation intensive peristaltic was noticed. She also referred dyspnea; she went to another institution where made a CAT scan finding a GPEH (Fig. 1). Our laboratory findings leukocytosis, raised LDH and lactate. We came with the diagnosis of upper intestinal occlusion due GPHE with a chance incarcerated complication. The patient prior to surgery was stable and in good conditions for intervention, we administered IV crystalloids and antibiotics. The surgery was performed by attending surgeon Dr. Gracia-Puig with advanced training in endoscopy and minimal invasive procedures. With these results, we decided to realize the procedure laparoscopically. Under anesthesia we proceed to perform a diagnostic laparoscopy. We found HH with a hiatus of 4 x 4 cm and the hernia containing 100% stomach, omentum 100%, and transverse colon. We follow the principal objectives, reducing the hernia, dissecting al de hernia sac excision, Hiatal reparation with no mesh, and Nissen type fundoplication without Collis Gastroplasty (Fig. 2). The dissection took around 5 h, unfortunately we had to perform omentectomy, with the loss of some blood vessels. The fundoplication was performed with Prolene 0-0 USP, with no adverse events. After the mediastinal dissection, sac excision and fundoplication we had a 4 cm long intraabdominal esophagus with purple coloration. For this reason, we monitored LDH levels daily and in rising LDH scenarios reintervention would be performed. The patient stayed for seven days for surveillance and when the leukocyte and LDH went to a regular rate patient was discharged. With no complications with normal intestinal function and nearly no pain. Follow up was no possible, the patient didn't came back to additional checkups (Fig. 3).

case report, giant paraesohagic hernia, intestinal occlusion, laparoscopic surgery

PMC6330799_01

Female

A 34-year-old female presented to the emergency department of our institute with massive hemoptysis. Initially, the patient had streaky hemoptysis for 1 week, followed by a bout of massive hemoptysis (~300 ml in 24 h). The patient had a past history of sputum positive pulmonary TB for the past 2 years, for which she had received antitubercular therapy. On examination, the patient had tachycardia (pulse 110/min), hypotension (blood pressure: 90/58 mmHg), and respiratory rate was 18/min with oxygen saturation of 92% on room air. Local examination revealed crepitation in the left upper zone. Laboratory investigations revealed leukocytosis (18 x 103/dl), elevated erythrocyte sedimentation rate was 60 mm/h, and anemia (hemoglobin was 9 g/dl). Liver and renal function tests and coagulation profile were within normal limits. Chest radiograph showed fibrocavitary changes in bilateral upper zones (not shown here). Computed tomography bronchial angiography (CTBA) was performed with bolus tracking technique with the preset trigger of 100 HU at descending thoracic aorta at the level of T4, on a 64 slice CT (Lightspeed VCT, GE Healthcare, USA) with detector collimation of 64 mm x 0.625 mm. 80 ml of iodinated nonionic contrast medium (omnipaque, GE Healthcare, USA) was administered during the study at a rate of 3.8 ml/s. CTBA revealed fibrocavitary changes with surrounding consolidation in bilateral upper lobes with centrilobular nodules in left upper lobe consistent with reactivation of disease. A small contrast-filled outpouching was seen within the cavity in left upper lobe [Figure 1a and b]. However, a vessel of origin could not be traced and was presumed to be arising from one of the pulmonary artery branches. (Rasmussen's aneurysm); no evidence of bronchial artery hypertrophy was seen, however intercostal arteries on the left side were prominent. The patient was subsequently considered for endovascular management. Diagnostic angiogram of bronchial arteries using 5F SIM 1 catheter (Cook, Bloomington, USA) using the right transfemoral approach showed normal bronchial arteries on both sides with no abnormal parenchymal blush. A pseudoaneurysm was seen arising from the left 3rd posterior intercostal artery with abnormal parenchymal blush and systemic pulmonary shunting [Figure 2a]. Selective cannulation of the intercostal artery was done with progreat microcatheter (Terumo, NJ, Japan) [Figure 2b] and embolized using polyvinyl alcohol particles (PVA) 500 mm-700 um and gelfoam slurry. Postembolization check angiograms did not show opacification of pseudoaneurysm [Figure 2c]. The procedure was uneventful with improved hemodynamic status postprocedure. There was no further episode of hemoptysis on follow-up for 3 months.

embolization, endovascular, hemoptysis, intercostal artery pseudoaneurysm, tuberculosis

PMC8075734_01

Unknown

The disease profile which is dominated by infectious and neglected tropical diseases is not uniform across the country. Higher prevalences are found in the north and central regions. Taken together HIV/AIDS and malaria account for over half of the deaths in the general population, with 27% and 29% of the rate mortality, respectively. More specifically, in 2018 Mozambique shows a general seroprevalence of 12.6% for HIV/AIDS in the age group of 15 to 49 years old, 55.2% for malaria, 52% for diarrheal infection and respiratory infections, and 43% for chronic malnutrition. Further, Mozambique is amongst the countries with a high burden of active tuberculosis infections with 559/100,000 inhabitants active cases. Though neglected tropical diseases such as intestinal parasites (53%), lymphatic filariasis (13%), schistosomiasis (47%) are not direct causes of mortality, they lead to physical and mental disabilities in children and are correlated with anemia and malnutrition in general. Mozambique has very limited information on distribution and prevalence of these diseases though a number of restricted area information can be found. This study was conducted at Lurio University (UniLurio), located in the north of Mozambique in Nampula province. It was created to serve the most populated province of Mozambique, with approximately 6.1 million inhabitants, an illiteracy rate of 62.3% with most of the population (71.4%) living in rural areas. According to the most recent demographic health survey, in 2011 the prevalence of malaria in children aged 6-55 months is of 55.2%, while in Maputo province is of 4.8%. Nampula is also amongst the provinces in the country with higher rates of intestinal parasites (95%), lymphatic filariasis (12%), cysticercosis (15-57%), schistosomiasis (c.a. 78%), and leprosy (0.006%). Nampula is one of the provinces with the highest number of active cases of tuberculosis (13,938 cases in 2019) inhabitants with the majority of cases due to co-infection with HIV/AIDS. Furthermore, the northern and central provinces are less served by health professionals. In 2016, the country national average, was 100.2/100.000 inhabitants, in Nampula with 75.6/100,000 while in Maputo province and Maputo city, the number of healthcare workers was 92.8 and 242.7/100.000 inhabitants, respectively. Despite Mozambican governmental investments in higher education, since independence from Portugal in 1975, by 2010 there were only three public medical schools in Mozambique. These were located at Eduardo Mondlane University (UEM) from a previous well-established University created during the colonial era, in 1963, and located in the capital Lourenco Marques, now called Maputo. Later on, two new public Universities were established, UniLurio in 2006 and Zambeze University (UniZambeze) in 2009. Both Universities included instructions in several health-related subjects including medicine. Postgraduate training programs in health sciences only began in 1999, at UEM-FoM with introduction of three Master programs in Public Health and, later on, in Mental Health and in Field Epidemiology. The first Doctoral program was established in 2006 at UEM Faculty of Humanitarian Sciences. It was recognized a limited capacity to train both undergraduate and postgraduate students in Mozambique, due to a limited number of faculty members with didactic, research, and mentorship skills, with proven training requirements. Research teaching infrastructure and financial resources were also necessary. For the period of 2004-2010, only 67% of Mozambican University faculty members had a University level degree, 22% a Master degree and only 11% had a PhD degree. Most of this were obtained abroad. A number of private institutions, mostly located in Maputo city, have also offered graduate and postgraduate training programs, though quality control of these programs and certification by the Ministry of Higher Education is ongoing. In 2003, a Higher Institute for Health Sciences (Instituto Superior de Ciencias de Saude (ISCISA) was created, supporting previous training of other mid-level health-related training professionals (nurses, non-physician technicians, dentists, and anesthetists) undertaken by other institutions of Health Sciences in the provinces of Mozambique. In general, it was noted that most investments in higher education were concentrated in and around Maputo, the capital located at the extreme southern end of Mozambique (see Figure 1). Under, the Medical Education Partnership Initiative (MEPI), a collaboration was established with UEM, and the University of California San Diego (UCSD) and supported by the US Department of State through the President's Emergency Plan for AIDS Relief (PEPFAR) and the National Institutes of Health (NIH). A number of postgraduate programs were created at UniLurio, aiming at scaling up training of physicians, improving research capacity and bioinformatics, and developing inter collaborative communities of practice in 12 sub-Saharan African countries. The aim of this manuscript is to describe the strategies and processes adopted to design and implement three new postgraduate programs at UniLurio, located in a geographically resource-limited setting of Mozambique.

mepi, faculty development, health professionals education, health system strengthening, implementation science, research capacity building

PMC5683279_03

Female

To date, there is no report of the use of ustekinumab for pediatric JIA, uveitis, or BD. Of note, there is one case report of the successful use of ustekinumab for the treatment of BD in a 39-year-old woman with concurrent psoriasis and hidradenitis suppurativa. After a flare-up of psoriasis, she was prescribed 45 mg of subcutaneous ustekinumab at weeks 0, 4, and 12, and achieved PASI-50 in 4 weeks and PASI-75 by 3 months. During this time, her symptoms of hidradeni-tis suppurativa and BD both resolved and she remained in remission for at least 3 years. As stated earlier, with the possible association of IL-17 and IL-23 with pediatric-onset BD, it is possible that ustekinumab, and other biologic agents, may in the future play a role in the treatment of this poorly characterized disease. Through week 12 of the PHOENIX 1 trial in adults with psoriasis, the most common AEs from ustekinumab were nasopharyngitis (8.2%-10.2%), upper respiratory tract infection (6.3%-7.1%), and headache (5.1%-5.5%). Serious AEs (SAEs) occurred in two patients on the 45 mg dose, four patients on the 90 mg dose, and two patients in the placebo group. There were three serious infections, one cardiovascular event, and no cutaneous or noncutaneous cancers. By week 76, 5.1% of patients had developed antibodies to ustekinumab. Through week 12 of PHOENIX 2, the most common AEs from ustekinumab in adults with psoriasis were nasopharyngitis (6.8%-7.3%), headache (4.6%), and upper respiratory tract infection (2.9%-4.4%). SAEs occurred in eight patients in the 45 mg dose group, five patients in the 90 mg dose group, and eight patients in the placebo group. There were three serious infections, two cutaneous cancers, one noncutaneous cancer, and one cardiovascular event. By week 52, 5.4% of patients had antibodies to ustekinumab. Although the clinical trials highlighted the efficacy of ustekinumab, one of the major concerns was the long-term safety, especially with regards to malignancies. Here, we will briefly review the 1- to 5-year follow-up data in adults with psoriasis treated with ustekinumab. Pooled safety data from Phase II and III clinical trials showed that during the placebo-controlled periods (12-20 weeks), there were comparable rates of AEs between patients on the 45 mg dose (57.6%), 90 mg dose (51.6%), and placebo (50.4%). The rates of overall infections and malignancies were also similar between patients on the 45 mg dose, 90 mg dose, and placebo. There were no reports of TB or demyelinating conditions. Apart from nonmelanoma skin cancers, the rates of malignancies were similar to those observed in the general US population. Importantly, by the third year, the rates of overall infections, AE, SAE, and malignancies remained stable over time. Five-year follow-up studies in adult patients with psoriasis enrolled in the PHOENIX 1 and 2 trials individually demo nstrated favorable safety profiles. In the PHOENIX 1 study, the data revealed comparable rates of AEs, SAEs, infections, malignancies, and major adverse cardiovascular events among those in the 45 and 90 mg dose groups. There was one case of disseminated cutaneous herpes zoster but no reports of active TB, atypical mycobacterial, systemic fungal or salmonella infections, anaphylaxis, or serum-sickness-like reactions. Only 5.2% of patients developed antibodies and none reported injection-site reactions. Safety monitoring of PHOENIX 2 until week 264 showed that cumulative rates of AEs and SAEs were similar among patients in the 45 mg dose group, 90 mg dose group, and the general population. Importantly, there was no increase in the rates of SAEs, serious infections, nonmelanoma skin cancers, other malignancies, or major adverse cardiovascular events. The most common serious infections were diverticulitis (seven cases), cellulitis (five cases), and cholecystitis (three cases), with no reports of active TB, atypical mycobacterial, systemic fungal or salmonella infections, anaphylaxis, or serum-sickness-like reactions. Pooled safety data from PHOENIX 1 and 2, as well as their 5-year follow-up studies, demonstrated that the rates of overall mortality and malignancies (excluding nonmelanoma skin cancers) were found to be comparable to those in the general US population. The event rates for overall AEs, SAEs, serious infections, nonmelanoma skin cancers, other malignancies, and major adverse cardiovascular events were comparable between patients on the 45 and 90 mg doses. The rates of AEs were found to be comparable to other biologics used to treat psoriasis, and the study did not show evidence of cumulative toxicity up to 5 years. Safety data from the TRANSIT trial was analyzed through week 52. The rates of AEs were comparable between patients on the 45 and 90 mg doses and only led to cessation of ustekinumab in 0.4% of these patients. There were four serious infections, two of which required cessation of ustekinumab (pneumonia and acute hepatitis B), and four malignancies (keratoacanthoma, cervical carcinoma in situ, breast cancer in situ, and metastatic prostate cancer). There were three major adverse cardiovascular events: one cerebrovascular accident, one myocardial infarction, and one death from cardiorespiratory arrest. The overall rates of serious infections, malignancies, and major adverse cardiovascular events were 0.85, 0.85, and 0.64, respectively, per 100 patient-years of treatment. During the first 12 weeks of the ACCEPT trial comparing ustekinumab with etanercept for adult psoriasis patients, 66.0% of patients on ustekinumab and 70.0% of patients on etanercept reported at least one AE. In this time period, the most common adverse events were nasopharyngitis (8.6% of those on etanercept, 10.0% of those on 45 mg ustekinumab, and 9.8% of those on 90 mg ustekinumab), upper respiratory tract infection (5.8%, 6.2%, and 6.3%, respectively), headache (11.0%, 14.8%, and 12.1%, respectively), back pain (2.0%, 6.7%, and 4.3%, respectively), and injection-site reaction (24.8%, 4.3%, and 3.7%, respectively). The rate of infections as well as proportions of patients who stopped treatment due to adverse events were similar between the three treatment arms. Two patients receiving 45 mg ustekinumab and one patient receiving 90 mg ustekinumab were found to have nonmelanoma skin cancers. Safety data was also reported through week 64 of the ACCEPT trial. Patients on 45 and 90 mg doses of ustekinumab had similar rates and types of common adverse events, with the exception of injection-site reactions. One patient in each treatment arm died (motor vehicle accident, gunshot wound, and multisystem organ failure and sepsis, the latter in a patient who received 90 mg ustekinumab). Serious infections occurred in four patients who received etanercept, two patients who received 45 mg ustekinumab, and ten patients who received 90 mg ustekinumab (P=0.23 when comparing the low- and high-dose ustekinumab groups). There were nine reports of nonmelanoma skin cancers, and five patients who received ustekinumab had other malignant conditions. Three patients experienced major adverse cardiovascular events (one patient in the 45 mg ustekinumab group, one patient in the 90 mg ustekinumab group, and one patient who had crossed over to ustekinumab after etanercept). Although 3.8% of patients developed antibodies to ustekinumab, it was not associated with injection-site reactions. With regard to the use of ustekinumab in children, we have the pooled data of the five case reports and the CADMUS trial. Among the five previously described case reports, there was one report of elevated liver function tests and one report of intolerance necessitating treatment cessation. The addition of the CADMUS trial greatly expanded available safety data in adolescents; patients were monitored for adverse events though week 60. By week 12, the percentage of patients who had reported more than one AE was 44.4% in the SD, 51.4% in the HSD, and 56.8% in the placebo groups - no dose effect was noted. The most common AEs were nasopharyngitis (2.8% in SD, 13.5% in HSD, and 27% in placebo) and headache (8.3% SD, 10.8% HSD, and 5.4% placebo). One SAE (worsening of psoriasis) was reported in the HSD group. By week 40, after the placebo group had crossed over and received ustekinumab, the most common side effects were nasopharyngitis (34.5%), upper respiratory tract infections (12.7%), and pharyngitis (8.2%). By week 60, an additional five SAEs were also reported - one transient incident of leukopenia, pyelonephritis, ear infection, allergic contact dermatitis from hair dye, and one death from a motor vehicle accident, as well as one injection-site reaction. Although nine patients had developed antibodies to the drug - six in the HSD group and three in the SD group - six reached PGA 0/1 and only one reported an injection-site reaction, which was mild. Importantly, through week 60, there were no reports of malignancies, opportunistic infections, active TB, anaphylaxis, or serum-sickness-like reaction. The long-term safety of ustekinumab is also supported by data from PSOLAR - the Psoriasis Longitudinal Assessment and Registry that prospectively follows patients with plaque psoriasis being treated with biologic agents including ustekinumab. In 2014, Papp et al analyzed data accumulated from 12,093 patients: the unadjusted rates of serious infection were lower for ustekinumab (0.93 per 100 patient-years) as compared with infliximab (2.91 per 100 patient-years) and other biologic agents (1.91 per 100 patient-years). Importantly, no increased risk of malignancies, mortality, serious infections, or major adverse cardiovascular events were observed with the use of ustekinumab. Additional safety data accumulated from PSOLAR indicates a lower rate of serious infections with ustekinumab (0.83 per 100 patient-years) compared to etanercept (1.47 per 100 patient-years), adalimumab (1.97 per 100 patient-years), and infliximab (2.49 per 100 patient-years).

il-12, il-23, tnf agent, pediatric psoriasis, ustekinumab

PMC7256324_01

Male

A 50-year-old man presented to the hospital with cervical nodules evolving 3 weeks before admission. He was an active smoker with 68 pack-year tobacco intoxication. He had an history of pulmonary tuberculosis treated 20 years ago. He was admitted first in Otorhinolaryngology (ENT) Department. Initial physical examination revealed a palpable thyroid nodule in the left lobe with bilateral cervical lymph nodes. The pulmonary examination was without particularities. Serum levels of thyroid stimulating hormone (TSH) and free thyroxine were within normal limits. Neck ultrasonography showed bilateral cervical lymph nodes and a 2.8 x 2.2 cm solid hypoechoic nodule of his left thyroid lobe. The nodule presented irregular borders with extra-thyroid extension. He underwent ultrasonography-guided fine-needle aspiration cytology (FNAC) of the thyroid nodule and a cervical lymphadenopathy. The two FNAC findings matched and showed clusters of tumor cells with basophilic cytoplasm and atypical nucleated nuclei in favor of a poorly differentiated adenocarcinoma (Fig. 1). Cervical lymphadenopathy biopsy under local anesthesia was performed. Pathological examination of the lymphadenopathy showed a massively infiltrated lymph node tissue by carcinomatous proliferation. The tumor cells were polygonal with eosinophilic cytoplasm and moderately atypical nuclei. Mitosis were numerous. Immunohistochemistry (IHC) showed positive tumor cells with cytokeratin (CK) 7 but negative with TTF1 (Fig. 1). Hence, further explorations were conducted. Chest X-ray showed a lung right sided suspicious opacity with a mediastinal widening. Contrast-enhanced Computed Tomography (CT) scan of the thorax showed a 11.4 x 10 x 9.7 cm right hilar mass presenting a mediastinal extension involving carina, pericardium, and esophagus with multiple hilar and mediastinal lymph nodes (Fig. 2. C + D). Cervical CT sections confirmed the ultrasound findings (Fig. 2. A + B). The abdominal CT scan showed multiple renal, adrenal, and splenic metastasis (Fig. 2. E). Bronchial fibroscopy was not performed due to a rapid deterioration of the lung function. After discussion of this case at the multidisciplinary discussion group meeting, the diagnosis of lung adenocarcinoma stage IVB was retained. The patient was planned for chemotherapy. Unfortunately, he presented a massive hemoptysis and succumbed to his disease despite a bronchial arterial embolization.

adenocarcinoma of lung, neoplasm metastasis, thyroid neoplasms

PMC5018067_01

Female

We describe the case of a 55 year old Italian female with an AIDS diagnosed in June 2015. At diagnosis, CD4 cell count was 20/mm3 and plasma HIV-1-RNA was 796,000 copies/mL. Antiretroviral treatment with elvitegravir/cobicistat/emtricitabine and tenofovir disoproxil ( Stribild) was initiated. The patient was subsequently hospitalized in our Department in September 2015 for fever, weight loss, and fatigue. Her blood tests at admission revealed pancytopenia, increased inflammatory markers: ESR 63 mm/h (normal <20), CRP 15.55 mg/dL (<0.75), procalcitonin 38.28 ng/mL (<0.05). Hepatitis C was also diagnosed (genotype 1a, HCV-RNA 500 IU/mL) with normal AST and ALT and slightly elevated alkaline phosphatase and gamma-glutamyl-transpeptidase. An abdomen ultrasound revealed two small liver lesions and one spleen lesion with an apparent hypoechoic/hypodense cystic appearance. She denied any history of tuberculosis but a high-resolution chest CT revealed a nodular, centrally calcified lesion (10 mm in size) of the posterior-apical segment of the left upper lobe, attributable to the outcome of a tuberculosis Ghon complex, and absence of mediastinic lymphadenopathy. Brain CT was negative. Abdominal CT revealed splenomegaly (15 cm in size) with the presence of multiple nodular formations. The largest formation was multilocular, hypovascular, 34 mm large, presented contrast enhancement and a spoke wheel pattern (Fig. 1a and b ); it was initially considered a cystic formation of parasitic nature. The CT also indicated the presence of two hypodense nodular lesions of 8 mm and 3 mm in the liver as well a cystic lesion. No abdominal lymph nodes were noted. Serology for Echinococcus and Leishmania proved negative. Quantiferon TB Gold interferon gamma release assay gave an undetermined result. Since the lesions presented similar characteristics, a needle aspiration biopsy was attempted on the largest hepatic formation. The extracted material proved insufficient for a diagnosis. The patient then underwent another needle aspiration biopsy, this time of the splenic lesion; the aspirated material was purulent in nature and routine bacterial and fungal cultures were negative. Ziehl-Neelsen stain of smears prepared from the aspirated material revealed the presence of a huge number of clustered acid-fast bacilli (Fig. 2). Mycobacterium tuberculosis complex was detected by the BD ProbeTec ET Mycobacterium tuberculosis Complex strand displacement amplification assay (DTB test, Becton Dickinson, USA), performed directly on the sample. Continuous-monitoring cultures of abscess fluid in liquid Middlebrook 7H9 medium (BD MGIT 960 Becton Dickinson) flagged positive within 48 h, and molecular identification was performed by reverse hybridization multiple DNA probe assay (INNO-LiPA MYCOBACTERIA v2 Innogenetics, Ghent, Belgium). The isolate was sensitive to all first-line drugs for M. tuberculosis. Prior to the institution of anti-tuberculous therapy, the patient underwent a splenectomy for a suspected splenic rupture. Her postoperative progress was complicated by bilateral pleural effusions, more on the left, that required drainage. The pleural fluid cultures were negative including PCR and culture for M. tuberculosis. Anti-tuberculosis treatment with four drugs (isoniazid, ethambutol, rifampin and pyrazinamide at full dosage) was started, with rapid reduction of the hepatic lesions and improvement of her general state. At the time of splenic TB diagnosis her CD4 cell count was 43/mm3 and plasma HIV-1-RNA was not detectable. Two months later, the HIV viral load remained undetectable and the CD4 cell count had risen to 108/mmc without any symptoms attributed to IRIS. Her general clinical conditions has greatly improved both subjectively and objectively with some weight gain and improvement in her mood and she has returned to work.

hiv infections, molecular assays, splenic tuberculosis

PMC6404043_02

Female

His 39-year-old partner presented a normal weight (body mass index: 24.6 kg/m2). She had no significant medical history concerning assisted reproduction. She has a normal menstrual history. Since 2003, she has had two spontaneous pregnancies that resulted in one birth and one late-term abortion. The cause was determined to be that the heart stopped beating. She has undergone one in vitro fertilization attempt, which resulted in one embryo transferred but with no biochemical pregnancy. For this cycle, her hormonal profile was normal: FSH (6.2 IU/L, normal range: 4.7-21.5 IU/L), LH (4.3 IU/L, normal range: 1.0-18.0 IU/L), progesterone (0.9 nmol/L on day 21 of the menstrual cycle, normal range: (<=3.2 nmol nmol/L), prolactin (1.2 nmol/L, normal range: 0.17-1.30 nmol/L), TSH (1.6 mIU/L, normal range: 0.5-5.0 mIU/L), FT4 (6.2 pmol/L, normal range: 10.30-23.17 pmol/L), and FT3 (3.5 pmol/L, normal range: 3.53-6.45 pmol/L) and her karyotype analysis indicates 46, XX. The patient reported been previously treated (in other facilities and the previous years) with antioxidants, L-carnitine, clomiphene citrate, and recombinant human chorionic gonadotropin (hCG), yielding no improvement in semen parameters. Since then, the patient has discontinued any previous treatments for in vitro fertilization or antioxidants for 24 months. Here, a semen sample was collected by masturbation after 3-day abstinence. Seminogram analysis indicated that the patient suffered from OAT. Characteristics are presented in Table 1. The patient was administered once a day 1.5 IU of human growth hormone (hGH)/IGF-1 (Saizen 5.83 mg/mL, 1.33 mg equivalent to 4IU) by intradermal injection for 2 months, typically at 10:00 pm. The dose and method of delivery were chosen because multiple reports have shown that at this concentration, IGF-1 can elicit a response. During the in vitro fertilization procedure, the patient did not indicate any adverse side-effects during treatment, post-treatment, and at his partner's final appointment. After 60 days of daily treatment, a subsequent semen sample was collected and the specimen was evaluated within 1 h after collection. To note, the patient was still under treatment at the time of the second seminogram. Marked improvement in semen parameters was noted as determined for concentration, progressive mobility, and total progressive motility (TPM; Table 1). Due to the improvement in the quality of the semen sample, and because the partner's controlled-ovarian stimulation concluded successfully, the sperm was used for in vitro fertilization, and the patient was instructed to stop taking the IGF-1. The female partner underwent a standard ovarian stimulation protocol with a daily dose of gonadotropin-releasing hormone (GnRH) antagonists with total dosage of FSH 2700 UI and hCG 10,000 UI. A total of 12 M-II ovules were captured and were fertilized by intracytoplasmic sperm injection (fertilization rate = 75%). Of the nine embryos, three had <10% fragmentation at day 3, 6-8 cells at day 3, and were symmetrical. At day 5, three blastocysts were of Grade 2. Three embryos were transferred, and pregnancy was confirmed 14 days after transfer measuring hCG (288 mIU/L) and the presence of two gestational sacs and fetal heartbeats at week 20. She has given birth to twins, one male and one female.

growth hormone, insulin-like growth factor, oligoasthenoteratozoospermia, sperm quality

PMC10159276_01

Male

A 5-year-old boy from South Sudan presented with complaints of sudden onset, progressive bilateral lower limb weakness for the past month, and inability to walk or stand without assistance. Before the onset of symptoms, he could walk and run without support. He has had urinary incontinence since the onset of weakness. He had experienced a few episodes of fever and cough for the past month. His prior medical history did not reveal any other clinical comorbidity. The family was from a peri-urban area of South Sudan known for its endemic intestinal and urogenital schistosomiasis, particularly with Schistosoma mansoni species. On examination, he was noted to have grade 2 weakness of the lower limbs, right more than left. He could not stand and sit without support but could roll over in bed and had areflexia, which involved absent knee, ankle and plantar reflexes. He was also observed to have no cremasteric reflex, lax anal tone, and neurogenic bladder. MRI of the brain with the whole spine showed an intramedullary lesion extending from D11 to L1 with irregular margins in conus medullaris and perilesional edema [Figure 1]. Differential diagnoses of astrocytoma, ependymoma, and granulomatous conditions were suspected, and he was investigated to rule out the differentials. Urine and stool routine examinations were done to observe viable Schistosoma eggs, which were reported negative. Serum angiotensin converting enzyme (ACE) level was done to rule out Sarcoidosis, which was noted to be within normal limits. Serum neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) levels were done to rule out immune-mediated disorders, Brucella antibodies IgG/IgM to rule out brucellosis and immunoblot antinuclear antibody (ANA) profile to rule out antinuclear antibody-positive disease were reported negative. Systemic involvement of schistosomiasis was ruled out as well. Since there was no definitive diagnosis, a surgical biopsy was contemplated, and therefore, he underwent a laminoplasty proceed biopsy under intraoperative neuromonitoring, C-arm, and fluorescein guidance. Intraoperatively, the edematous and inflamed nerve roots were noted, along with an intramedullary conus lesion [Figure 2]. The culture of tissues showed no growth of organisms after 48 h of incubation. Gene X-pert and acid-fast bacilli were done to rule out tuberculosis, which was reported to be negative. Histopathological examination of the spinal cord lesion showed necrotising granulomatous chronic inflammation with Schistosoma eggs and no evidence of malignancy [Figure 3]. As per the clinical, laboratory, and imaging evidence of neuroschistosomiasis, he was treated with steroids and Praziquantel 300 mg. He was initially treated with a high dose of parenteral steroid, tapered down, and converted to the oral route along with the oral anti-parasitic agent Praziquantel as recommended by the World Health Organization protocol. Postoperatively, he was given regular intensive in-house rehabilitation and physiotherapy. Before his discharge, he became well ambulant and had gross improvement in the power of his lower extremities, the tone of the anal sphincter improved, and he was voiding well by himself. The postoperative MRI scan showed decreased conus swelling and decreased enhancement in the residual conus medullaris lesion with edema cranial to the conus medullaris completely resolved [Figure 4].

conus intramedullary schistosomiasis, schistosoma mansoni, schistosomal myeloradiculopathy, schistosomiasis, spinal neuroschistosomiasis

PMC10344630_01

Male

M.D., a 40-year-old male patient, presented to the Emergency Department (ED) of Dubti General Hospital, the Afar regional state in Ethiopia, with a complaint of shortness of breath, palpitation, extreme fatigue, and chest pain of a day's duration. He had a dry, intermittent cough, a low-grade intermittent fever, and fatigue for a week before his current symptoms. He had no past medical or surgical history except that he was treated for pulmonary tuberculosis (PTB) six years ago. He denied alcohol intake, smoking, or any drug intake. On arrival, his blood pressure (BP) was 80/50 mmHg, his radial pulse rate was weak and fast, and his apical heart rate (HR) was also fast, making them difficult to count. His respiratory rate (RR) was 28/min, the temperature was 37.2 C, and his oxygen saturation was 98% with room air. He had cold extremities. Otherwise, he was fully conscious, and no other pertinent physical findings were noted. Immediately after arrival, he was transferred to the intensive care unit (ICU), and on a monitor, his HR was 208. A bedside ECG was done, which showed paroxysmal supraventricular tachycardia (PSVT) (Figure 1). Considering his clinical presentations and ECG findings, unstable PSVT and pneumonia were entertained, and at this time, carotid sinus massage and modified Valsalva maneuvers were attempted, which proved ineffective. The patient and his family members were informed about the case scenario so that they could give written informed consent for synchronized electrical cardioversion. But the family members and the patient himself refused to sign informed consent due to fear and a bad perception of the outcome from the patient himself and due to religious influence from the family members. Even though he was not a candidate for pharmacotherapy because of instability, unfortunately, the commonly used drugs to manage PSVT (adenosine, beta-blockers, and calcium channel blockers) were not available in the hospital. This was because of the ongoing civil war in Ethiopia, which resulted in a shortage of foreign currencies to import essential drugs from developed countries and transportation problems from pharmaceutical supply agencies to hospitals. The only available drug was digoxin. Even though it is not a common practice to use digoxin to manage PSVT, taking into consideration its negative chronotropic effect and its action to suppress the AV nodal conduction velocity, digoxin 0.25 mg IV was given after informed consent was obtained from the patient and family members. After 10 minutes of digoxin administration, the HR dropped to 105 beats per minute, which were regular and full in volume. His BP came up to 95/65 mmHg, and his chest discomfort was relieved. At this time, a repeat ECG was done, which showed normal sinus rhythm (Figure 2). He was investigated with a complete blood count (CBC), renal function test, liver function test, serum electrolyte test, and thyroid function test, but they were all normal. A chest X-ray and echocardiography were also done, and they turned out to be normal. He stayed in the ICU for 24 hours and was in stable condition. On the next day, metoprolol (12.5 mg PO BID) and amoxicillin/clavulanate (625 mg PO TID) were started, and he was transferred to the medical ward for observation. He stayed for 72 hours in the ward, and on his 4th day of admission, he was referred to a better setup to have regular follow-ups with a cardiologist.

PMC5749263_01

Female

A fifteen-year-old female was transferred to the intensive paediatric care unit due to pulmonary haemorrhage, requiring mechanical ventilation, and renal insufficiency. She has no relevant family history and has neonatal antecedents of extreme prematurity and bronchopulmonary dysplasia. At eleven years of age, she started having episodes of respiratory distress, wheezing, coughing, and stridor that lead to multiple hospitalizations despite therapy with beta2 long-acting agonists, antileukotrienes, and inhaled corticosteroids. In the exacerbations, she presented weak response to salbutamol and improvement with adrenaline and methylprednisolone. In this context, an etiological investigation was carried out at the hospital in her residential area: negative allergy screening; normal immunoglobulin and complement levels; normal alpha-1 antitrypsin level; negative sweat test; negative Ziehl-Neelsen staining and Mycobacterium tuberculosis culture in gastric juice; and normal upper gastrointestinal endoscopy, esophageal-gastroduodenal transit, and thoracic computed tomography.

PMC9837258_01

Male

A 28-year-old married male sought medical advice at a urology clinic in his rural hometown after complaining of painful scrotal swelling for 1 week. On a spot diagnosis, the urologist identified the patient as having bilateral EO. The only requested investigation, at that time, was a urine analysis, which indicated 12-15 pus cells/HPF. The patient received a prescription containing ciprofloxacin 500 mg tablet/12 hours, and some analgesics. Five days later, the patient noticed stepping pain in his scrotum, along with worsening scrotal swelling. Also, he started to have a fever (40 C), chills, a sense of unease, anorexia, and nausea. The patient, therefore, consulted another urologist in his hometown for these emerging symptoms. This second urologist clinically confirmed the previous diagnosis of bilateral EO. Sulbacef (sulbactam & cefoperazone) 1.5 g vial/day and Voltaren injection every 12 hours were prescribed by the urologist. This treatment was planned to last for 7 days. Until the fourth day, the patient did not show any improvement, although he strictly followed the recently scheduled treatment regimen. Instead, the patient got extremely sick. The fever rose (41.5 C), and he started vomiting. He could not sleep for 24 hours a day, and he was exceptionally exhausted. A laboratory biochemical check-up, at that time, showed an elevated leucocytic count (24. 3 x 103/mL; the normal is 4-11 x 103/mL), neutrophilic predominance (88%; the normal is 35%-80%), and high C-reactive protein (96 mg/dL; the normal is <6 mg/dL). Blood urea and serum creatinine were normal. A digital rectal examination revealed tender cystic structures over the prostate, indicating enlarged seminal vesicles. Because transrectal ultrasound (TRUS) was not available, transabdominal ultrasound was done first in the urologist's office. The scanning showed markedly dilated seminal vesicles. The urologist requested TRUS to further clarify the pathological nature of the dilated vesicles. The TRUS confirmed the existence of markedly distended seminal vesicles (up to 4 cm in diameter) with hyperechogenic contents suggesting abscesses formation (Figure 1), and a midline prostatic cyst (5 mm in diameter) (Figure 2). A cystourethroscopy was done, and an enlarged cystic prostatic utricle was seen, which was immediately resected. During the resection, a gush of frank pus appeared coming from the right side of the utricle. A urethral catheter was fixed for 24 hours and the patient was kept again on Sulbacef in the emergency department. The patient showed considerable improvement starting the next day. The fever disappeared, and the body temperature was around 37 C. He could sleep after several days of continuous insomnia. His appetite improved, and oral feeding was resumed. However, 4 days later, the previously annoying symptoms recurred. Herein, the patient's family sought counsel at the Urology Outpatient Clinic, Alexandria Main University Hospital. The patient denied a history of any genital trauma, diabetes, tuberculosis, urethral discharge, sexually transmitted diseases, extramarital relations, or previous similar conditions. He had a history of primary infertility for 7 years. The repeated semen analyses showed azoospermia with a low semen volume (0.7-0.9 mL), and the FSH assay was high-normal (11.5; the normal level is 1.5-12.4 mIU/mL). Physical examination disclosed tachycardia (112 beats/minute), low blood pressure (100/65), and fever (40.5 C). The upper abdomen was lax, but the supra-pubic area and both inguinal regions were tender and rigid. The scrotum was erythematous and swollen, with excoriated skin on its left side. On palpation, the scrotum was tender and indurated, and the epididymes were not palpable from the testes. The spermatic cords were also tender and indurated. A digital rectal examination revealed remarkably enlarged and tender seminal vesicles. The patient received a magnetic resonance imaging (MRI)-pelvis examination. The image showed notably dilated seminal vesicles (Figure 3) with diverse signal intensities from normal. The left testis also suspiciously showed a fluid collection in its lower pole, suggesting an impending abscess formation (Figure 3). An immediate transrectal aspiration of seminal vesicles was done under MRI guidance. The aspiration yielded frank yellowish pus, around 75 mL in volume. The aspirate was referred for bacteriologic examination, and the culture later grew Escherichia coli (E. coli) with susceptibility to Merional (Meropenem). The patient was scheduled to receive Merional (1 gm/12 hours) for 5 days on an outpatient basis immediately after the aspiration and before getting the bacteriologic report. Three days later, the patient came for a follow-up. He showed distinct clinical improvement. His laboratory results returned close to the normal ranges (total leucocytic count fell to 12 x 103/mL, neutrophils subpopulation fell to 77%, and C-reactive protein fell to 48 mg/dL). The right testis started recovering but on the contrary, the left testis was still tender and enlarged. The next day, while at home, pus started to come from the lower pole of the left testis. The patient was immediately re-admitted to the hospital and received surgical exploration of the scrotum. An abscess (2 cm x 3 cm) in the lower pole of the markedly left swollen testis was detected (Figure 4) with areas of necrosis. A fibrous capsule surrounded the abscess except at the site of the discharge. The drainage of the abscess produced a frank yellow discharge. Testicular sparing surgery with debridement of the necrosed parts was expedited. The testicular tissue around the abscess seemed viable. The patient left the hospital after a few hours and continued on Merional for 2 days. The patient then began a 2-week course of oral Augmentin 1 g/12 hours until his first follow-up visit. Two weeks later, the patient attended the outpatient clinic. His general condition was fine. The scrotal incision healed, and the previous tenderness and swelling of the left testis almost disappeared. A repeat transabdominal ultrasound showed normal-sized seminal vesicles. The total leucocytic count was 9 x 103/mL and CRP was 5 mg/dL. The patient continued to be symptomless for 5 months after ending the Augmentin course. A scrotal duplex, at that time, showed unremarkable findings. Two repeated semen analyses revealed normal semen volumes (4.5 cc and 3.8 cc) but with azoospermia.

epididymo-orchitis, abscess, seminal vesicle, testis

PMC8054818_01

Male

A male patient, 60 years old, was admitted due to an intermittent cough that had been present for 2 weeks. According to the patient, he had suffered from tuberculous pleurisy about in 20 years ago, and at that time an assessment, made after 3 months' regular anti-TB treatment, showed no explicit evidence indicated the tuberculosis remained. The physical examination revealed the following: the right lung activity was reduced, the mobility of the inferior boundary of the lung by percussion was 4-5 cm, and the breathing sounds of the right lung were slightly weakened. Chest CT made after admission revealed a clear arcuate thickened calcification shadow in the right visceral pleura (Figure 1A) and obvious calcification lesions in the thickened pleura from the mediastinal window, with arcuate distribution and with a localized beaded shape (Figure 1B). Laboratory testing revealed a white blood cell count of 5.7x109/L, an erythrocyte sedimentation rate (ESR) of 40 mm/h, and a C-reactive protein level of 8.08 mg/L.

calcification, pleura, thickening, tuberculosis

PMC5009572_01

Male

A 54-year-old man with a history of diverticulitis complicated by intra-abdominal abscess status postbowel resection presented with nuchal rigidity, proximal weakness from upper extremities to lower extremities, and associated numbness shortly after surgery. Admission LP revealed a leuko-pleocytosis (146 cells/mul) with 93% lymphocytes and elevated protein (162 mg/dL). Antibiotics were initiated with a repeated tap performed 4 days after initial LP. Concern for autoimmune disorder grew when antibiotic coverage failed to resolve the patient's bilateral inflammatory cervical polyradiculopathies. A course of intravenous immunoglobulin was administered with marginal improvement of his weakness. Repeat tap performed under fluoroscopic guidance 11 days postinitial LP demonstrated resolution of the leukocytosis; however, the tap was notably traumatic with red blood cells (RBCs) above 31,000/mul. On postadmission day 19 and 8 days status post-LP under fluoroscopy, the patient reported severe lower back pain, worsening lower extremity weakness, saddle anesthesia, and urinary retention. Magnetic resonance imaging (MRI) of the lumbar spine with and without gadolinium contrast demonstrated an intrathecal subarachnoid and subdural hematoma extending from L3 through the sacral levels [Figure 1]. Urgent neurosurgery consultation resulted in decompressive surgery within 24-h of symptom onset. Laminectomies were performed between inferior L2 and L5, at which time a small ventrolateral epidural hematoma was identified compressing the spinal cord at the L4 level. Initially, the thecal sac appeared tightly stretched and bluish discolored from intradural hemorrhage; however, removal of the epidural hematoma and maneuvers to mobilize the dura and spinal cord dislodged the intradural collection as evidenced by adequate ventilation-synchronous respiratory pulsations of the CSF with each breath, as well as a slack and tension-free thecal sac. As a result, the dura was not opened for clot evacuation since decompression (the goal of surgery) had been achieved without perioperative complication. Postoperatively, the patients' urinary retention resolved and the patient began ambulating with wide-based stable gait. Follow-up appointments at 6 and 12 months revealed significant improvements in strength with near resolution of all proximal weakness and only residual dyspnea secondary to underlying pulmonary disease. No bowel/bladder dysfunction, lower extremity weakness, or anesthesia was present.

cauda equina, epidural hematoma, lumbar puncture, mass effect, spinal hematoma, spinal hemorrhage, subdural hematoma

PMC3843700_01

Unknown

Of the 614 children, 41.2% (95% CI: 37.3 - 45.2) had features of asthma syndrome, 27.2% (95% CI: 23.7 - 30.9) had bacterial pneumonia, 26.5% (95% CI: 23.1 - 30.2) had viral pneumonia, while 5.1% (95% CI: 3.5 - 7.1) had other diagnoses including pulmonary tuberculosis and pneumocystis jirovecii pneumonia (Figure 1). Of the 253 children with asthma syndrome, 50 (19.8%) had combined asthma and bacterial pneumonia. Only 9.5% of the children with asthma syndrome had been previously diagnosed with asthma. The majority (80.2%) of the children with asthma syndrome were aged 24 months old and below. Of these, 61.6% had bronchiolitis and 38.4% had asthma. Overall, 380 of 614 (61.9%) children had pneumonia; 167 (44.0%) had bacterial pneumonia, 163 (43.0) had viral pneumonia and 50 (13%) had combined asthma and bacterial pneumonia. During the panel discussions, discordance among all the three experts occurred in 33 (5.4%) of the 614 cases. Of the 253 children with asthma syndrome, an audible wheeze was appreciated in only 35% (95% CI: 29.7 - 41.8). There was no statistically significant difference in proportion of children with hypoxia between asthma syndrome and bacterial pneumonia (OR 1.1, 95% CI: 0.7 - 1.6, p=0.669) or the children with viral pneumonia (OR 1.2, 95% CI: 1.0 - 1.6, p=0.110). Likewise, there was no statistically significant difference in proportion of children with low peripheral oxygen saturation between asthma syndrome and combined asthma and bacterial pneumonia (OR 1.0, 95% CI: 0.8 - 1.3, p=0.863). Even though some laboratory characteristics were part of particular diagnoses, positive results were noted among the different diagnostic categories. For example, 50 (24.6%) of the 203 children with asthma syndrome alone had raised serum C-reactive protein and 18 (8.9%) had raised total white cell counts. The proportion of children with positive RSV test was similar in all diagnostic categories (table 2). Overall, 26.4% (95% CI: 22.9 - 30.1) of the children had a positive blood smear for malaria parasites, most of whom (31.5%) had viral pneumonia. HIV testing was performed on 589 (95.9%) of the children and of these, 41(7%) were found to be HIV positive (95% CI: 5.0 - 9.3). The primary radiologists agreed on the chest x-ray findings in 79.4% of the cases (Cohen's kappa = 0.72, SD = 0.03, p = 0.000). A total of 599 (97.6%) of the study participants had prescriptions for antibiotics. Of the 253 children with asthma syndrome, 95.3% (95% CI: 91.9 - 97.5) had a prescription for antibiotics, 87.7% (95% CI: 83.1 - 91.5) for short-acting beta2 agonists (SABA) and 43.1% (95% CI: 36.9 - 49.4) for systemic steroids. However, of these, 50 (19.8%) had bacterial pneumonia and their antibiotic prescriptions were justified.

PMC7714592_01

Male

A 27-year-old Caucasian male with a noncontributory medical history and no previous trauma was referred from the maxillofacial department of the hospital for the endodontic evaluation of the mandibular right first and second molars, which were connected to an extensive asymptomatic osteolytic lesion incidentally discovered on a routine panoramic radiograph and scheduled to be treated surgically under general anesthesia. The patient reported that he had experienced pain and swelling in the right mandible months before, while the first molar had a history of caries, extensive amalgam restoration, and incongruous endodontic treatment performed ten years earlier. The clinical examination showed no sign of buccal or lingual bone expansion, no lymph node involvement, and intact overlaying mucosa. The first mandibular molar was asymptomatic. The right second mandibular molar was asymptomatic with an intact crown, and it responded normally to the sensitivity tests at the time of our examination. The panoramic radiograph showed a well-defined unilocular osteolytic lesion with sclerotic margins located between the two molar teeth and superimposed on the alveolar inferior nerve with a slight displacement of the second molar. The first molar showed inadequate root canal treatment with signs of resorption in the apical third of the distal root involved in the osteolytic lesion. A preoperative periapical radiograph taken using the paralleling technique confirmed these findings (Figure 1). Cone beam computed tomography (CBCT) revealed a well-defined unilocular lesion, with considerable expansion toward the lingual wall and consequent thinning of the lingual plate. From the axial and sagittal sections, it was possible to diagnose a perforation both in the distal and lingual aspects of the apical third of the distal root of the right first molar (Figure 2). To assess the content and vascularity of the lesion, a real-time ultrasound examination with the application of color-power-Doppler (CPD) was performed using a Toshiba Aplio XG (Toshiba Medical Systems, Crawley, UK) apparatus with a regular size, linear, high definition, and multifrequency ultrasound probe at 8-12 MHz. The exam displayed a transonic, fluid-filled lesion with a well-defined hyperechoic bone contour, perilesional vascularity, and no internal vascular supply, suggestive of a cystic lesion (Figure 1). The diagnosis, based on all the exams performed, was a nonendodontic cystic lesion of the right mandible in the area of the first and second mandibular molars and AP in a previously treated first mandibular molar with a perforation in the distal root. The treatment plan was discussed with the patient and comprised the following steps: (1) surgical excision and biopsy of the lesion for the histopathologic evaluation; (2) endodontic retreatment of the right mandibular first molar, with the repair of the perforating defect on the distal root; (3) a possible postsurgical root canal treatment of the second molar. Surgery was performed in the maxillofacial clinic under general anesthesia after an inferior alveolar nerve block together with infiltration with anesthetic of the surrounding tissues. A mucoperiosteal flap was raised exposing the buccal bone, which did not present any sign of resorption or expansion. A bone window was created using a surgical bur with continuous water cooling to reach the lesion (Figure 3); the disclosed bone cavity had the size and shape shown by CBCT and was filled with serum/blood fluid, as seen in the ultrasound exam; thus, a temporary intraoperative diagnosis of TBC was made. The fluid was evacuated, and the walls of the lesion were carefully explored and curetted; however, only a few specimens of tissue were collectable for histopathologic examination. After the formation of the blood clot, the flap was repositioned and sutured. Histologic examination of the tissue fragments reported fibrosclerotic tissue with calcifications and cholesterol clefts, extensively interested in a chronic inflammatory infiltrate with numerous foamy histiocytes and foreign body-like multinucleated giant cells (Figure 3). Four weeks later, the patient was asymptomatic; however, at the postsurgical endodontic assessment, the second molar did not respond to the sensitivity tests, which was due to a possible resection of the alveolar neurovascular bundle, and a diagnosis of pulp necrosis was made. After informed consent was obtained, local anesthesia was administered using mepivacaine 2% 1 : 100 000 epinephrine followed by isolation of the teeth using a rubber dam. Root canal treatment of the second molar was performed in 1 appointment without complications. Two weeks later, the patient was still asymptomatic, and secondary treatment was performed on the first molar. After informed consent, local anesthesia administration, rubber dam isolation, and root canal retreatment of the mesial canals were achieved without obstacles, while the working length determined with the apex locator in the distal root canal was considerably shorter than the length of the root because of perforation, which was established by measuring the CBCT scans. The canals were instrumented manually and irrigated with 5.25% NaOCl and a final rinse of 17% EDTA solution. The apical half of the distal canal was dried with paper points and obturated using Ortho-MTA (BioMTA, Seoul, Republic of Korea) applied with a carrier to seal the perforating defect, while the remaining coronal half was filled with flowable gutta-percha and the tooth restored with composite (Figure 4). Four months later, the patient was asymptomatic, and radiographic control showed an increase in radiopacity and trabeculae formation in the bone (Figure 4). The patient attended the periodical recall visits, and at the five-year follow-up was asymptomatic. The radiographic examination showed complete healing of the lesion, with remineralization of the area around and within the perforated root. An additional CBCT examination depicted the complete formation of the vestibular and lingual cortical plates (Figures 4 and 5).

PMC5227131_01

Male

A previously well 21-year-old Bangladesh-born man presented with a six-month history of night sweats, fever, and axillary lymphadenopathy and a four-week history of evolving neurological symptoms including vertigo, diplopia, ataxia, left sided weakness, and right facial droop. On examination there were multiple cranial nerve palsies, reduced power in the left upper and lower limbs, and enlarged left axillary lymph nodes. Multiple enhancing lesions in the pontomedullary junction, right cerebellum, and left frontal lobe were detected on magnetic resonance imaging (MRI) (see Figure 1(a)). A left axillary mass biopsy demonstrated granulomatous lymphadenitis, with negative Truant's stain and negative mycobacterial PCR. HIV testing was negative, and a CT of the chest, abdomen, and pelvis showed isolated left axillary lymphadenopathy. Rifampicin, isoniazid, pyrazinamide, ethambutol (HREZ), and dexamethasone were commenced. He had partial neurological improvement in left sided weakness but approximately one month later developed nausea, vomiting, dysphagia, and headache, with further reduction in power and coordination on the left. Repeat MRI showed increased oedema and size of the pontomedullary and right cerebellar lesions with hydrocephalus (see Figure 1(b)). The dexamethasone dose was increased, HREZ continued, and he improved symptomatically. Mycobacterium tuberculosis was isolated from the lymph node biopsy and after seven weeks of therapy provisional rifampicin and probable isoniazid resistance was identified. Therapy was changed to rifabutin, isoniazid, pyrazinamide, ethambutol, amikacin, moxifloxacin, cycloserine, and prothionamide. Final susceptibility results demonstrated resistance to isoniazid, rifampicin, rifabutin, clofazimine, and streptomycin with sensitivity to ethambutol, pyrazinamide, amikacin, capreomycin, ciprofloxacin, cycloserine, and ethionamide. The regimen was continued without rifabutin. After two weeks of inpatient treatment, he was discharged on a weaning dose of dexamethasone, with mild left facial droop and paresthesia in the left arm. Repeat MRI approximately two months after commencement of the MDR TB regimen showed a marked reduction in the size of the right-sided pontine and cerebellar lesions (see Figure 1(c)). Dexamethasone was ceased, precipitating an adrenal crisis and immune reaction in the right middle lobe of the lung. He was recommenced on steroids, improved, and was discharged on a weaning dose of cortisone. Amikacin was ceased after twelve months while other treatment was continued for a total of two years after repeat MRI showed almost complete resolution of the lesions. He was monitored for the next five years with repeat MRI scanning showing complete resolution of the right cerebellar lesion and continued improvement in the pontomedullary lesion (see Figure 1(d)). Complications during treatment included avascular necrosis of the hip, which was managed conservatively. After seven years of follow-up, his residual symptoms included minor difficulty with left upper limb fine motor tasks and hip pain.

PMC9533801_01

Female

A 31-year-old woman presented to the Emergency Department (ED) with generalized fatigue and lethargy. Medical history was significant for type II diabetes mellitus, sickle cell trait and SLE complicated by lupus nephritis class III. SLE was diagnosed one-year prior following presentation with discoid cutaneous lesions and high ANA titers with initiation of hydroxychloroquine. Her lupus course was marked by flare manifesting as pericardial and pleural effusion treated with pulsed IV Methylprednisolone 100 mg daily for 3 days and transitioned to prednisone 20 mg. Before prednisone could be tapered, lupus nephritis developed with plans to start cyclophosphamide during which latent TB was diagnosed and she was started on isoniazid (INH) and rifampin (RFP). Labs on presentation showed leukopenia, thrombocytopenia, mild transaminitis and elevated inflammatory markers with mild atelectasis in bilateral lower lobes on a chest x-ray. Her symptoms were thought to be due to COVID-19 infection and she was sent home to self-quarantine while awaiting SARS-CoV-2 PCR test result. She returned two days later with abdominal pain, nausea, vomiting, diarrhea, and fevers. Vital signs revealed a temperature of 101 F, BP 110/82, HR 122, RR 24 and SpO2 100% on room air. Labs on the day of admission showed persistent leukopenia, thrombocytopenia, rising inflammatory markers and worsening transaminitis. Details of lab results from her initial ED visit and on the day of admission are shown in Table 1. In addition, CT chest, abdomen and pelvis was notable for bulky adenopathy in bilateral axilla, iliac, and inguinal regions. The initial plan of treatment included broad spectrum antibiotics due to concern for an infection, discontinuation of rifampin and INH due to elevated transaminases and continuation of her home dose of prednisone and HCQ. Given the presence of lymphadenopathy, abnormal laboratory results and her clinical presentation, extensive workup was performed for a broad differential diagnoses including infections, TB lymphadenitis, SLE flare and hemophagocytic lymphohistiocytosis (HLH). Blood cultures were negative for bacterial, fungal, and TB infections. ANA titers were elevated at 1:1280 with decreased C3 37 mg/dL (76-100 mg/dL), pointing to an autoimmune case. Tests for HLH revealed mildly elevated sIL-2R at 2137 pg/mL (532-1891 pg/mL) and low NK cell activity at 48 cells/uL (70-760 cells/uL). A lymph node biopsy was done which revealed necrotizing lymphadenitis without evidence of lymphoproliferative disorders or infections (Fig. 1). These findings were concerning for Kikuchi-Fujimoto disease (KFD) or lupus lymphadenitis. A bone marrow biopsy showed normocellular marrow without evidence of hemophagocytosis, favoring reactive changes from infection or autoimmune disease. With these findings, HLH and infection were thought less likely but rather lymphadenitis from a lupus flare or KFD. The patient's symptoms improved on her home dose of prednisone and HCQ after discontinuation of RFP and INH, suggesting that the most likely cause of her presentation was an SLE flare due to drug-drug interactions. She was discharged in stable condition on her home medications except for INH and RFP. On rheumatology follow-up, she was started on immunosuppressive medicines. This allowed subsequent resumption of a course of isoniazid and rifampin and successful completion of treatment of latent TB.

hemophagocytic lymphohistiocytosis, kikuchi-fujimoto disease, latent tuberculosis, lymphadenopathy, systemic lupus erythematosus

PMC4729429_01

Female

A 34-year-old Nigerian woman presented to the ED with a chief complaint of dyspnea, cough, and fever for two days. The patient also complained of epigastric pain and intermittent emesis. She denied any significant prior medical or surgical history. Physical exam revealed a toxic-appearing female in respiratory distress. Vital signs were temperature 100.5 F; blood pressure 103/76mmHg; heart rate 126bpm; respiratory rate 32bpm; and 99% oxygen saturation on room air. She had decreased breath sounds on the right side, and exhibited right upper quadrant tenderness on palpation. The cardiovascular exam was remarkable only for the tachycardia. A portable chest radiograph (CXR) revealed complete atelectasis of the right lung with adjacent large right pleural effusion, causing mediastinal shift to the left, consistent with tension hydrothorax (Figure 1). A computed tomography (CT) angiogram of the chest confirmed the above findings; there was no evidence of pulmonary embolism or aortic dissection (Figure 2). An ultrasound-guided thoracentesis removed 1.5L of serosanguinous fluid. The patient reported relief of chest pain and dyspnea after the thoracentesis. The patient was admitted to the hospital and treated for presumed pneumonia and sepsis with broad spectrum antibiotics. A purified protein derivative for tuberculosis was negative. She had a chest tube placed on hospital day 2 for recurrent right pleural effusion, with return of two liters of serosanguinous fluid. Pleural fluid cultures, acid fast bacteria (AFB) and cytology were all negative. Because of worsening abdominal pain and distention, on hospital day 4 a CT of the abdomen/pelvis was ordered and revealed a pelvic mass of unclear uterine or adnexal etiology, with abdominal implants and ascites, suspicious for malignancy. A follow-up pelvic ultrasound was less suggestive of malignancy, and revealed two solid uterine lesions and an enlarged right ovary with cyst. Magnetic resonance imaging of the abdomen and pelvis revealed bilateral complex cystic adnexal structures with hemorrhage; a tubo-ovarian abscess was suspected. On hospital day 14, the patient underwent laparoscopy with biopsy. Laparoscopy revealed blue-tinged lesions on the central omentum, a nodular omental lesion, and pelvic wall nodule. The peritoneum was described as having a fibrinous exudate with mucinous appearance along the surface. Biopsies of the omental and pelvic nodules confirmed the lesions to be consistent with endometriosis and a pelvic wall abscess. The final diagnosis was disseminated endometriosis resulting in tension hydrothorax and pelvic inflammatory disease. The patient was discharged on hospital day 22 to complete an outpatient course of antibiotics.

PMC115203_01

Male

A 61-yr-old man, born and raised in Crete, was admitted to our hospital with a 6-month history of diarrhea, weight loss of 7 kg, weakness, anorexia, low grade fever, and episodes of pain in the right lower abdominal quadrant. He did not reported arthralgias, rash, cough, or the presence of blood in his stools. There was no family history of inflammatory bowel disease or colon cancer. His past medical history included a diagnosis of hypothyoidism under treatment with thyroxine 100 mcg/d, and an episode of haemoptysis five years ago attributed to bronchiectasis. The patient had no past history of TB and was not aware of any TB exposure. He had been drinking alcohol (50-60 g/d) for 25 years, but stopped drinking five years ago. He did not smoke and worked as auxiliary staff in a community mental clinic. Physical examination revealed mild abdominal tenderness, mostly confined to the right lower quadrant. The remainder of the examination was unremarkable. The laboratory workup showed a mild anaemia (Hb 11.5 g/dl, Hct 35.8%, MCV 68.1 fl), a serum ferritin of 7.71 (normal, 12-237 ng/ml) and a serum folate of 4.2 ng/ml (normal, 5.3-14.4 ng/ml). Liver biochemistries, total cholesterol, serum proteins, prothrombin time and thyroid hormones were within normal range. Serologic testing for HIV, Yersinia and E. histolytica were negative. Stool samples were negative for infectious organisms. A chest x-ray examination presented no significant findings. Colonoscopy revealed a tumorous lesion in the ascending colon near the caecum. The colonoscope could not be introduced beyond the lesion. Initial endoscopic diagnosis was that of a malignant lesion, and multiple biopsies were obtained. Histology showed chronic inflammatory changes and noncaseating epithelioid granulomas, a pattern consistent with Crohn's disease. Esophagogastroduodenoscopy showed an axial hiatal hernia and a diffusely erythematous gastric mucosa. A small bowel series was normal. A tentative diagnosis of Crohn's disease was made and a treatment with Budesonide 9 mg/d and Mesalamine 3 g/d was initiated. However, no improvement was noticed and the diarrhea and fever rather deteriorated in the next days. A CT-scan examination was performed to rule out an abdominal or pelvic abscess. The CT scan revealed a concentric wall thickening confined to the caecal-ascending colon border, luminal stenosis, extensive thickening of the mesenteric folds, the peritoneum and great omentum, small mesenteric lymph nodes, and a small amount of high density peritoneal fluid (Figures 1 and 2). CT findings were not consistent with Crohn's disease and raised the possibility of TB involvement. Tuberculin test was negative. A thoracic CT revealed nodular and fibrotic changes in the apical segments of the upper lobes, a pattern consistent with past TB exposure. Bronchoscopy was normal and acid-fast bacilli were not detected in the sputum, bronchoalveolar lavage or gastric aspirate. In view of our failure to confirm the diagnosis of colonic TB, a second colonoscopy was planned to obtain new biopsy specimens for culture and PCR analysis. When however the biopsies from the tumorous lesion were reevaluated and appropriately stained to look for acid-fast rods, several tubercle bacilli were identified upon Zielh-Neelsen staining. The patient was treated with Rifampicin (10 mg/kg/d), Isoniazid (5 mg/kg/d), Pyrazinamide (30 mg/kg/d) and Ethambutol (15 mg/kg/d). Over the next 10 days, the patient became afebrile, the stools were formed, at a frequency of 2-3 times per day, and he was subsequently discharged from the hospital in good condition. The patient was seen 2 months after discharge at which time he had gained weight and he was asymptomatic. Colonoscopy revealed a normal appearing caecal mucosa. Currently, six months after diagnosis, the patient is free of symptoms and is continuing the anti-tuberculous treatment.

PMC3226427_01

Male

An 18-year-old man with past medical history significant only for asymptomatic creatine phosphokinase (CPK) elevation (familial) was transferred to our medical intensive care unit after developing malignant hyperthermia (MH) intraoperatively at an outside hospital. History of his presenting illness revealed that the patient was in his usual state of health till a day prior to admission when he got injured at a local high school football game. He was noted to have a right tibia-fibula fracture and underwent IM nailing (rodding) of the right tibia by orthopedics. Review of his operative records revealed that early in the course of his surgery, it was noted that patient's end tidal carbon dioxide concentration (ETCO2) was noted to have increased from 42 to 100 mm Hg during the course of the surgery and his temperature went up to >104 (apparently was not measureable) following which concern was raised for malignant hyperthermia (MH). Labs were consistent for acidosis (pH 7.29) and hyperkalemia (K+-7 mMol/L). Patient was given dantrolene IV (recommended initial dose being 2.5 mg/kg) immediately along with calcium gluconate, kayexalate, insulin/dextrose 50% and albuterol as well for the hyperkalemia and transferred to our facility for further management and care. Cooling blankets, fluids, and acetaminophen were also concomitantly administered to bring his temperature down. Dantrolene (1 mg/kg) IV was continued till hyperthermia resolved and was then transitioned to dantrolene PO 6 mg/kg in 4 divided doses for the next 3 days. CPK levels peaked up to 3922 IU/L initially when the patient had presented and subsequently decreased during the course of his stay. In terms of medications charted at the outside hospital, patient got sevoflurane, propofol, lidocaine, labetalol, rocuronium, fentanyl, and versed. It was presumed that this would have been likely secondary to sevoflurane (one of the volatile gaseous inhalation anesthetics which is a known trigger to MH in susceptible individuals). Once we were able to talk to the family, it revealed a very interesting family history. Apparently patient's father was noted to have CPK elevations after being started on a statin, but these levels remained elevated despite the discontinuation of the medication. It was at that point in time that the patient's primary care physician was concerned for a possible familial elevation and screened his family too, which also revealed high CPK levels. The highest CPK level of the patient's father has been up to 1600 IU/L. Patient's CPK level has been in the range of 500-600 (IU/L) and sisters' levels have been up to 1100 IU/L. No family history of malignant hyperthermia in the family or any history of any adverse reactions to medications was reported. Patient's family was extensively worked up for known genetic mutations to explain the high CPK levels along with screening for dystrophies and myopathies, but the results were inconclusive. The significance of this in the context of susceptibility to MH is discussed as follows. High creatine phosphokinase (CPK) levels usually signify underlying myopathies or muscle injury. However, in some cases the cause is not identified and these patients continue to have asymptomatic elevations of the enzyme. This is referred to as idiopathic hyperCKemia (IHCK) and classically is defined by "at least 3 serum CK levels more than twice normal that remain increased over at least 3 months in patients with no evidence of neuromuscular disease". The condition is noted more often in males and appears to be familial (see Table 1). A high percentage of autosomal dominant cases have also been reported. Reviewing the literature, it is interesting to note that these patients have been shown to be susceptible to developing malignant hyperthermia. Usually this is determined by in vitro contracture testing, which is considered the gold standard for assessing malignant hyperthermia susceptibility (MHS). Table 1 outlines the outcomes of 2 studies specifically assessing the susceptibility to malignant hyperthermia (MHS) in IHCK. As evident, the incidence is noted to vary widely and may also depend on the selection of cases selected for testing. However, it is important to note that the test is not 100% sensitive in ruling out susceptibility to developing MH; thus, the true incidence of developing MH in patients with idiopathic hyperCKemia is not known. At the same time it is argued by some reports that it is questionable if patients with asymptomatic elevations of CPK should undergo MH susceptibility testing especially if they do not have a family history of anesthesia-related complications, given the incidence is variable and sometimes can also lead to false positives. However, in our opinion with the fact that the condition can be life threatening, and as seen in our case as well, patient not having a family history of any anesthesia-related complications, we would recommend susceptibility testing if available. We sent our patient's blood work for testing at UPMC laboratories and the sequence analysis identified a heterozygous nucleotide substitution of C to T at nucleotide 487 [c.487C > T] in exon 6 of the RYR1 gene (type 1 ryanodine receptor gene, a gene for calcium channel of skeletal muscle which is located on chromosome 19q13.1). The change involves the 1st nucleotide of codon 163 and results in a missense amino acid variant: [p.Arg163Cys] that is known to cause the disease. Per laboratory data here, it is estimated that more than 50% of the malignant hyperthermia cases are located in regions where many of the reported mutations are clustered. Furthermore, in this day and age with numerous other alternatives available from anesthesia standpoint, it would not be reasonable to take the risk of exposing patients to triggering agents even if the risk is small. Table 2 summarizes some of the known triggering agents for MH along with classes of drugs that have been questionably linked to MH. As advocated by some authors, we would also recommend that family members receive nontriggering agents when undergoing anesthesia and wear Medic Alert tags. The establishment of registries to keep track of such rare disorders and conduct research would be helpful in not only providing diagnostic testing but also in further elucidating the pathogenetic mechanisms responsible for the life-threatening complications seen.

PMC8560286_01

Female

A 55-year-old woman with no notable medical and family history was referred to our department by her general practitioner following the appearance of multiple lesions of the oral mucosa. The intraoral clinical examination revealed poor oral hygiene, hypersialorrhea, and extensive mucosal damage affecting the entire oral cavity and causing discomfort, pain, and dysphagia. The lesions were located in the internal surfaces of the lips and cheeks, the dorsal and ventral surface of the tongue, and the soft palate mucosa (Figure 1). There were epithelial erosions and postbullous ulcerations with a positive Nikolsky sign indicating acantholysis with dislocation of the epithelial layers (Figure 2). Bulloerosive umbilical involvement was associated with the oral impairment without noting any other cutaneous lesions for four months (Figure 3). In front of these signs, we conducted an oral biopsy and prescribed topical prednisolone (20 mg; 3 times per day) and chlorhexidine-based (0.12%; 3 times per day) mouthwashes in order to reduce the oral pain awaiting the biopsy result. In a while, her condition worsened (Figure 4). We referred her to the department of dermatology where she was hospitalized and an umbilical biopsy was performed. On histopathological examinations, the oral biopsy concerned a squamous mucosa lined with a partially visualized coating, with disappearance of the superficial layers and the presence of cells of the basal layer which remain attached to the underlying chorion, drawing a "tapestry nail" appearance, surmounted by a few acantholytic cells. In the chorion, we noted the presence of a polymorphic inflammatory infiltrate rich in eosinophilic polynuclear cells. Direct immunofluorescent examination was negative (Figure 5). As for the umbilical biopsy, the sample received was carried to the deep dermis. It was bordered by the basal layer of the epidermis, drawing the same "tapestry nail" appearance with extensive suprabasal acantholysis and separation of the overlying epidermal layers. The dermis was the site of an inflammatory infiltrate rich in neutrophils and eosinophils of perivascular arrangement with extravasation of red blood cells and without alteration of their wall. Intercellular immunoglobulin G and C3 deposits were observed on direct immunofluorescent examination with a characteristic mesh-like appearance (Figure 6). Based on clinical, histopathological, and immunofluorescence findings, a diagnosis of pemphigus vulgaris (PV) was established. On laboratory investigations, we found an inflammatory syndrome with increased erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Hepatitis (VHB and VHC) and VIH serologies were negative. Mycological direct examination and cultures were negative. On bacteriological culture performed from the umbilicus, Staphylococcus aureus growth was observed. As for the therapeutic management, due to oral pain, a nasoenteral probe was used to feed her. Daily intravenous administration of prednisolone (120 mg/day) and amoxicillin-clavulanic acid (1000 mg thrice a day) was started. The nursing team was instructed to clean the oral cavity and the umbilicus using chlorhexidine (0.12%) mouthwash and ointment. Her condition improved gradually during hospitalization. There was a complete remission of the lesions in the mouth and umbilicus. The patient was advised to continue oral prednisone intake at a dose of 20 mg/day. She underwent monthly follow-ups in dentistry and dermatology departments after discharge from the hospital. Four months later, the disease recurred. We noticed the appearance of severe cutaneous lesions added to the oral and umbilical ones located in the elbows, forearms, and the periungual area. She was newly hospitalized.

PMC4868928_01

Female

A 57-year-old woman was diagnosed with SS-DE and pemphigus vulgaris at another hospital and had been experiencing severe subjective symptoms such as dryness, ocular pain, and foreign body sensation in both eyes. Although she was treated with sodium hyaluronate (SH) ophthalmic solution 0.3% (Hyalein mini, Santen Pharmaceutical Co., Ltd., Osaka, Japan) and artificial tears, her symptoms did not improve at all. She performed frequent instillation of the SH ophthalmic solution 10-15 times daily because of severe symptoms. In April 2014, she visited the Department of Ophthalmology, Nihon University Itabashi Hospital. The Dry Eye-related Quality of life Score (DEQS) was used to assess the subjective score of the patient. The DEQS at the baseline observational point and 5 weeks after initial treatment was 93.3 and 88.3, respectively. Slit-lamp examination of objective findings of ocular surface showed conjunctival swelling with follicular formation in the upper palpebral conjunctiva (fig. 1a) and SPK with fluorescein staining in the lower mid-peripheral cornea (fig. 1b). Blepharitis with skin erosion caused by pemphigus vulgaris was also observed (fig. 1c), and blinking imperfection might thereby occur. Abnormalities of tear dynamics were shown by Schirmer's test values of 3 mm in right eye and 5 mm in left eye, and tear brake-up time (TBUT) of 7 s in right eye and 8 s in left eye. The fluorescein staining was scored as follows. The ocular surface was divided into three areas (nasal conjunctiva, cornea, and temporal conjunctiva) that were assessed for fluorescein staining. Each area was judged a staining score from 0 (no damage) to 3 (severe damage) points, and the total score of fluorescein staining was calculated ranging from 0 to 9 points. Fluorescein scores of the right and left eyes were 1 and 1 point, respectively. The patient was treated with a combination of rebamipide ophthalmic suspension four times daily and fluorometholone ophthalmic suspension (Flumetholon ophthalmic suspension 0.1%, Santen Pharmaceutical Co., Ltd.) once daily for dry eye. As for the SH instillation, frequent instillation was changed to twice-daily instillation after the initial presentation. Blepharitis was treated with dexamethasone ophthalmic ointment (Santezon ophthalmic ointment 0.05%, Santen Pharmaceutical Co., Ltd.). After having been treated with dexamethasone ophthalmic ointment for 1 week, the blepharitis treatment was continued using white petroleum gel (PROPETO ; Maruishi Pharmaceutical; Tokyo, Japan). The Schirmer's test value, TBUT, and fluorescein score did not improve after 3 months with combined treatment for dry eye (fig. 1d). However, her subjective symptoms including ocular pain improved dramatically; DEQS score (93.3 to 88.3) and expression levels of ocular surface mucin also improved (shown in fig. 1e, f). MUC5AC at baseline point showed an extremely low level and was restored by the combined treatment to the levels comparable to those in healthy subjects. MUC16 also gradually increased by these treatments.

dry eye, fluorometholone, muc16, muc5ac, mucin, rebamipide

PMC4868928_02

Male

A 62-year-old man with a clinical diagnosis of cGVHD-DE had undergone related-donor bone marrow transplantation for acute myelogenous leukemia in 2011 and experienced irritation and foreign body sensation in both eyes. He was treated with ophthalmic administration including rebamipide ophthalmic suspension four times daily, methylprednisolone containing fradiomycin sulfate (Neo-Medrol EE Ointment, Pfizer Co., Ltd., Tokyo, Japan) once daily, and betamethasone sodium phosphate containing fradiomycin sulfate (Rinderon -A, Shionogi Pharmaceutical Co., Ltd., Osaka, Japan) 3 times daily. However, his symptoms gradually worsened despite treatment, and he was referred to us. Slit-lamp examination showed SPK with mucous thread and filamentary keratitis (fig. 2). Abnormalities of tear dynamics were shown by Schirmer's test values of 4 mm in the right eye and 10 mm in the left eye, and TBUT of 1 s in the right eye and 1 s in the left eye. The patient's treatment was changed to combined treatment of rebamipide ophthalmic suspension four times daily and fluorometholone ophthalmic suspension once daily. The SH ophthalmic solution was used at any time, if necessary. Subjective symptoms related with cGVHD-DE and corneal epithelial damage improved after change of prescription. DEQS score was restored to 26.7 from 51.2. SPK with mucous thread and filamentary keratitis of his left eye disappeared at 1 month after the combined treatment. SPK with mucous thread and filamentary keratitis of his right eye also disappeared at 3 months after the combined treatment. The condition of both eyes had subsided after 5 months. MUC5AC and MUC16 at baseline point showed high-level MUC5AC and low-level MUC16, and they were restored by combined treatment to levels comparable to those in healthy subjects. Considering the relationship between MUC expression on ocular surface including MUC5AC and MUC16 and ocular findings with fluorescein staining, MUC expression showed high levels when SPK with mucous thread and filamentary keratitis persisted, whereas MUC expression levels were restored to the same levels as those in healthy subjects when their clinical findings disappeared.

dry eye, fluorometholone, muc16, muc5ac, mucin, rebamipide

PMC9801097_01

Male

A 66-year-old man visited our hospital complaining of fever with chill which has started three days prior. The patient had a history of appendectomy for appendicitis, hypertension, hyperuricemia, and gastroesophageal reflux disease, which were managed with allopurinol 100 mg once a daily, amlodipine 5 mg once a daily, and vonoprazan 20 mg once a daily. The patient had no history of dental treatment in the past decade. The patient drank about 2 glasses of Awamori, a type of rice wine with 30-40 % alcohol content unique to Okinawa, daily and has smoked 60 cigarettes a day for past 44 years. He denied having sexual intercourse in the past year and denied having homosexual intercourse. Vital signs on arrival showed a temperature of 39.7 , heart rate of 128 beat per minute, blood pressure of 106/62 mmHg, SpO2 of 95 % in room air. Physical examination showed that his conscious was clear, and his abdomen was soft and had no significant tenderness. Laboratory tests revealed high hepatic enzymes and C-reactive protein (CRP), and increased white blood cells with neutrocyte dominant (Table 1). Computed tomography (CT) scan revealed that the small hypodense area in S4 and a huge hypodense area with the well-defined boundary of more than 100 mm in diameter in S5-6 (Fig. 1). Initially, we suspected metastatic liver tumor, but we could not rule out liver abscess, thus the patient was admitted to our hospital to start intravenous administration of meropenem 1.0 g per 8 h after collected two sets of blood culture. On the hospital day 8, blood culture on admission day reported Streptococcus intermedius was positive in both two sets. In view of the findings of bacteremia and low-density area in the liver on CT scan, we finally diagnosed pyogenic liver abscess. We could not point out any other abscesses through head and body imaging. Based on bacterial susceptibility, antibiotics was changed from meropenem to ceftriaxone 2 g per a day plus metronidazole 500 mg per 8 h. We had recommended percutaneous drainage to the patient, but he refused because of needle phobia, thus we continue antibiotics alone. His fever resolved on the day 5 and CRP was on downtrend with the treatment (Fig. 2). Two sets of blood cultures taken on days 8 and 15 were both negative. On the day 27, the patient again had a fever of 38.3 degrees, and tested for SARS-CoV-2 antigen was positive. Because of the outbreak in the hospital, he was diagnosed with nosocomial COVID-19, however his symptom was recovered within 2 days. On day 29, blood test showed white blood cell count of 2900/microL, whose percentages of neutrophil was 40.7 %. Because of the gradual decrease in white blood cell count, drug-induced neutropenia was suspected, and vonoprazan was discontinued and filgrastim 75 microg was administered. On the day 40, neutrophil counts were recovered to 4400/microL with 52 % of neutrocyte. A total of 6 weeks of antimicrobial therapy was completed on day 40, and we confirmed that liver abscess had been almost completely diminished on enhanced CT scan (Fig. 1). Esophagogastroduodenoscopy (EGD) and colonoscopy (CS) were performed to search the bacterial entry. There was no suspicious findings of on esophagus and stomach, but there were the brownish stains under the patient's teeth, suggesting that periodontal disease (Fig. 3). CS revealed diverticulum and 0-Isp polyp on sigmoid colon; pathological diagnosis was low grade tubular adenoma. After discharge from our hospital on day 42, the patient was followed up in an outpatient clinic for 3 months. There was no recurrence of liver abscess and no elevation of CRP.

bacteremia, liver abscess, pyogenic, streptococcus intermedius

PMC8291962_01

Male

A 75-year-old male patient was admitted to Zhejiang Provincial People's Hospital on 23 November 2018 after two-week-history of post-exercise dyspnea and chest pain. Physical examination revealed decreased breath sound, increased tactile fremitus on the affected side, and dullness to percussion of the left lung. Chest computed tomography (CT) showed diffuse thickening and calcification of the pleura on both sides, pleural effusion and atelectasis on the left side (Figure 1A and B). After hospitalization, the patient received a thoracentesis on November 26, 2018. The pleural fluid was bloody exudate, and no tumor cells were found in the exfoliated cells of the pleural fluid sample. According to the imaging findings, we tracked the patient's occupational history and learned that the patient had a history of close contact with asbestos for 30 years. The diagnosis of pleural mesothelioma needs to be ruled out clinically, and it is planned to be transferred to surgery for open pleural biopsy. At the same time, laboratory examination revealed elevated plasma D-dimer (26190Ug/L), combined with the patient's chest pain, dyspnea symptoms, and a large amount of pleural effusion, the possibility of pulmonary embolism should be considered. Then, the computed tomography pulmonary angiography (CTPA) was performed for the patient, and the results showed that there was embolism in the right pulmonary artery branch (Figure 2). After the diagnosis of pulmonary embolism, we immediately used anticoagulant drugs for the patient. Because anticoagulants are easy to cause massive hemorrhage, no open pleural biopsy was performed. After anticoagulation therapy, the patient's symptoms of pleural effusion and dyspnea were improved and the patient discharged on December 18, 2018. However, after being discharged from the hospital, the patient was still admitted to the hospital several times due to chest pain and dyspnea, and the reexamined chest CT still showed a large amount of pleural effusion on the left side (Figure 3A and B). When he was hospitalized again on July 8, 2019, there was no obvious abnormality in plasma D-dimer and CTPA, which ruled out the possibility of recurrent pulmonary embolism. We also considered the possibility of pneumonia and tuberculous pleurisy, but repeated pleural effusion and sputum culture did not show any positive results and there was no evidence for tuberculosis. Because of the long-term bloody pleural effusion, the possibility of lung cancer is also considered. The patient's pleural fluid was sent for pathological examination for many times, but no tumor cells were found. PET-CT examination showed diffuse thickening of the bilateral pleura with calcification, mainly on the left side. FDG metabolism was increased, and malignant tumors were considered (Figure 4). We consider that this patient may have malignant mesothelioma. Later, the patient underwent an ultrasound-guided pleural biopsy, and the pathological examination revealed fibroblast-like spindle cells arranged in bundles or chaotic shapes (Figure 5A and B). The results of immunohistochemistry were: CK(Pan)(+), WT1(+), GATA3(+), P63(-), TTF-1(-), EMA(-), CD117(-), DOG1(-), Calretinin(-), CK5/6(-), CD34(-), ERG(-), SMA(-), Desmin(-), S100(-), MiTF(-), HMB45(Melanoma)(-), MyoD1(-), Caldesmon(-), D2-40(-), CEA(-), Vimentin(-) (Figure 6). Combined with the above examination results, the final diagnosis was sarcomatoid pleural mesothelioma. However, two days later, the patient suddenly developed a coma, facial cyanosis, and sudden cardiac arrest. And the blood pressure, oxygen saturation cannot be measured at that time. We consider that the cause of cardiac arrest may be an acute myocardial infarction or acute pulmonary embolism. After tracheal intubation, electric defibrillation and chest compression, the patient discharged voluntarily. The patient died after being discharged from the hospital 2 days later.

asbestos, malignant pleural mesothelioma, pleural effusion

Mediastinal windows of computed tomography (A and B) confirm the previously noted bilateral pleural thickening, calcification. There is associated left lobe Pleural effusion and atelectasis.

PMC8291962_01

Male

A 75-year-old male patient was admitted to Zhejiang Provincial People's Hospital on 23 November 2018 after two-week-history of post-exercise dyspnea and chest pain. Physical examination revealed decreased breath sound, increased tactile fremitus on the affected side, and dullness to percussion of the left lung. Chest computed tomography (CT) showed diffuse thickening and calcification of the pleura on both sides, pleural effusion and atelectasis on the left side (Figure 1A and B). After hospitalization, the patient received a thoracentesis on November 26, 2018. The pleural fluid was bloody exudate, and no tumor cells were found in the exfoliated cells of the pleural fluid sample. According to the imaging findings, we tracked the patient's occupational history and learned that the patient had a history of close contact with asbestos for 30 years. The diagnosis of pleural mesothelioma needs to be ruled out clinically, and it is planned to be transferred to surgery for open pleural biopsy. At the same time, laboratory examination revealed elevated plasma D-dimer (26190Ug/L), combined with the patient's chest pain, dyspnea symptoms, and a large amount of pleural effusion, the possibility of pulmonary embolism should be considered. Then, the computed tomography pulmonary angiography (CTPA) was performed for the patient, and the results showed that there was embolism in the right pulmonary artery branch (Figure 2). After the diagnosis of pulmonary embolism, we immediately used anticoagulant drugs for the patient. Because anticoagulants are easy to cause massive hemorrhage, no open pleural biopsy was performed. After anticoagulation therapy, the patient's symptoms of pleural effusion and dyspnea were improved and the patient discharged on December 18, 2018. However, after being discharged from the hospital, the patient was still admitted to the hospital several times due to chest pain and dyspnea, and the reexamined chest CT still showed a large amount of pleural effusion on the left side (Figure 3A and B). When he was hospitalized again on July 8, 2019, there was no obvious abnormality in plasma D-dimer and CTPA, which ruled out the possibility of recurrent pulmonary embolism. We also considered the possibility of pneumonia and tuberculous pleurisy, but repeated pleural effusion and sputum culture did not show any positive results and there was no evidence for tuberculosis. Because of the long-term bloody pleural effusion, the possibility of lung cancer is also considered. The patient's pleural fluid was sent for pathological examination for many times, but no tumor cells were found. PET-CT examination showed diffuse thickening of the bilateral pleura with calcification, mainly on the left side. FDG metabolism was increased, and malignant tumors were considered (Figure 4). We consider that this patient may have malignant mesothelioma. Later, the patient underwent an ultrasound-guided pleural biopsy, and the pathological examination revealed fibroblast-like spindle cells arranged in bundles or chaotic shapes (Figure 5A and B). The results of immunohistochemistry were: CK(Pan)(+), WT1(+), GATA3(+), P63(-), TTF-1(-), EMA(-), CD117(-), DOG1(-), Calretinin(-), CK5/6(-), CD34(-), ERG(-), SMA(-), Desmin(-), S100(-), MiTF(-), HMB45(Melanoma)(-), MyoD1(-), Caldesmon(-), D2-40(-), CEA(-), Vimentin(-) (Figure 6). Combined with the above examination results, the final diagnosis was sarcomatoid pleural mesothelioma. However, two days later, the patient suddenly developed a coma, facial cyanosis, and sudden cardiac arrest. And the blood pressure, oxygen saturation cannot be measured at that time. We consider that the cause of cardiac arrest may be an acute myocardial infarction or acute pulmonary embolism. After tracheal intubation, electric defibrillation and chest compression, the patient discharged voluntarily. The patient died after being discharged from the hospital 2 days later.

asbestos, malignant pleural mesothelioma, pleural effusion

Mediastinal windows of computed tomography (A and B) confirm the previously noted bilateral pleural thickening, calcification. There is associated left lobe Pleural effusion and atelectasis.

PMC8291962_01

Male

A 75-year-old male patient was admitted to Zhejiang Provincial People's Hospital on 23 November 2018 after two-week-history of post-exercise dyspnea and chest pain. Physical examination revealed decreased breath sound, increased tactile fremitus on the affected side, and dullness to percussion of the left lung. Chest computed tomography (CT) showed diffuse thickening and calcification of the pleura on both sides, pleural effusion and atelectasis on the left side (Figure 1A and B). After hospitalization, the patient received a thoracentesis on November 26, 2018. The pleural fluid was bloody exudate, and no tumor cells were found in the exfoliated cells of the pleural fluid sample. According to the imaging findings, we tracked the patient's occupational history and learned that the patient had a history of close contact with asbestos for 30 years. The diagnosis of pleural mesothelioma needs to be ruled out clinically, and it is planned to be transferred to surgery for open pleural biopsy. At the same time, laboratory examination revealed elevated plasma D-dimer (26190Ug/L), combined with the patient's chest pain, dyspnea symptoms, and a large amount of pleural effusion, the possibility of pulmonary embolism should be considered. Then, the computed tomography pulmonary angiography (CTPA) was performed for the patient, and the results showed that there was embolism in the right pulmonary artery branch (Figure 2). After the diagnosis of pulmonary embolism, we immediately used anticoagulant drugs for the patient. Because anticoagulants are easy to cause massive hemorrhage, no open pleural biopsy was performed. After anticoagulation therapy, the patient's symptoms of pleural effusion and dyspnea were improved and the patient discharged on December 18, 2018. However, after being discharged from the hospital, the patient was still admitted to the hospital several times due to chest pain and dyspnea, and the reexamined chest CT still showed a large amount of pleural effusion on the left side (Figure 3A and B). When he was hospitalized again on July 8, 2019, there was no obvious abnormality in plasma D-dimer and CTPA, which ruled out the possibility of recurrent pulmonary embolism. We also considered the possibility of pneumonia and tuberculous pleurisy, but repeated pleural effusion and sputum culture did not show any positive results and there was no evidence for tuberculosis. Because of the long-term bloody pleural effusion, the possibility of lung cancer is also considered. The patient's pleural fluid was sent for pathological examination for many times, but no tumor cells were found. PET-CT examination showed diffuse thickening of the bilateral pleura with calcification, mainly on the left side. FDG metabolism was increased, and malignant tumors were considered (Figure 4). We consider that this patient may have malignant mesothelioma. Later, the patient underwent an ultrasound-guided pleural biopsy, and the pathological examination revealed fibroblast-like spindle cells arranged in bundles or chaotic shapes (Figure 5A and B). The results of immunohistochemistry were: CK(Pan)(+), WT1(+), GATA3(+), P63(-), TTF-1(-), EMA(-), CD117(-), DOG1(-), Calretinin(-), CK5/6(-), CD34(-), ERG(-), SMA(-), Desmin(-), S100(-), MiTF(-), HMB45(Melanoma)(-), MyoD1(-), Caldesmon(-), D2-40(-), CEA(-), Vimentin(-) (Figure 6). Combined with the above examination results, the final diagnosis was sarcomatoid pleural mesothelioma. However, two days later, the patient suddenly developed a coma, facial cyanosis, and sudden cardiac arrest. And the blood pressure, oxygen saturation cannot be measured at that time. We consider that the cause of cardiac arrest may be an acute myocardial infarction or acute pulmonary embolism. After tracheal intubation, electric defibrillation and chest compression, the patient discharged voluntarily. The patient died after being discharged from the hospital 2 days later.

asbestos, malignant pleural mesothelioma, pleural effusion

PET-CT suggests thickening and calcification of the pleura on both sides, increased FDG metabolism, more pronounced on the left.

PMC3550313_01

Female

A 70-year-old female presented with a history of painless swelling of the left lower eyelid for one year (Fig. 1A). She had no systemic complaints. On examination, her visual acuity was 20 / 20 (left eye), and a slitlamp examination of the left eye revealed no abnormalities except for corneal granular dystrophy. The lower eyelid of the left eye was diffusely swollen without any palpable mass. The left upper eyelid showed a 3-mm ptosis with 10-mm levator function, without swelling, and the ptosis resolved after administration of 2.5% phenylephrine in the left eye. No exophthalmos was present, and the extraocular movements were normal. A fundus examination revealed no abnormalities. A computerized tomography (CT) scan of the orbit was unremarkable (Fig. 1B and 1C). The patient's white blood cell count, chemistry panel, and thyroid function tests were normal. The erythrocyte sedimentation rate was 31 mm in the first hour, and serum angiotensin converting enzyme (ACE) levels were 58 units (normal, 8 to 52 units). A chest radiograph revealed an old tuberculous lesion without hilar lymphadenopathy (Fig. 2), and a Mycobacterium tuberculosis antigen-specific interferon gamma assay was negative. As these results were inconclusive, surgical debulking of the swollen lower eyelid via an inferior conjunctival fornical approach for diagnosis and treatment was performed, as well as a conjunctivo-mullerectomy for ptosis correction. The operative findings showed stiff and coarse orbital fat particles, and the histopathologic examination demonstrated non-caseating granulomas consisting of epitheloid histiocytes in the orbital fat, most likely caused by sarcoidosis (Fig. 3). Special stains for acid-fast bacilli and fungi were negative. The patient was further reviewed by a pulmonologist who noted hilar lymphadenopathy on the chest CT. The patient was diagnosed with orbital sarcoidosis, and started on prednisolone (10 mg/day) in consideration of the significant improvement in eyelid swelling after surgical debulking (Fig. 4). The symptoms completely resolved within one month, and she has been followed for 12 months without a recurrence.

chronic swelling, lower lid, orbital sarcoidosis

PMC9561240_01

Male

A 53-year-old man from Hubei Province, China, was admitted to our hospital with a 1-month history of intermittent fever (highest temperature, >39 C), abdominal pain, diarrhea, fatigue, and weight loss associated with anorexia and cough. However, the patient had lived in Guangdong Province for a long period of time. Half a month before the patient's admission, an upper gastrointestinal (GI) endoscopy revealed chronic non-atrophic gastritis with erosion, fungal esophagitis, and xanthoma of the gastric corpus, without specific intervention. During the patient's hospital visit, a physical examination revealed the following: temperature, 37.8 C; pulse rate, 107/min; respiratory rate, 20/min; and blood pressure, 117/85 mmHg. The rest of the patient's physical examination results were unremarkable. Laboratory examinations showed low levels of hemoglobin (98 g/L), leukocytes (3.17 x 109/L), albumin (26.8 g/L), and prealbumin (0.062 g/L), increased levels of high-sensitivity C-reactive protein (78.44 mg/L), erythrocyte sedimentation rate (73 mm/h), neutrophils (76.1%), D-dimer (1.55 mg/L), and antinuclear antibody (1:100) and a positive result for the cytomegalovirus (CMV)-DNA (<4.00E+02 copies/ml). The patient's absolute neutrophil count was in the normal range (2.41 x 109/L). Electrolyte parameters were abnormal, with hyponatremia (129.0 mmol/L) and hypochloremia (88.8 mmol/L). Anti-HIV antibody was positive, and the patient's CD4 T count was 10 cells/mul, accounting for 2.16% of total T lymphocytes. The rest of the blood tests, including immunoglobulin, complement 3 (C3) and 4 (C4), hepatic transaminase, creatinine, extractable nuclear antigen, antineutrophil cytoplasmic antibody, and tuberculosis T-SPOT, were within the normal range. Alpha-fetoprotein, carcinoembryonic antigen, severe acute respiratory syndrome coronavirus 2 nucleic acid, and blood culture results were negative. Chest computed tomography (CT) revealed a thickened and blurred lung texture and multiple enlarged lymph nodes (abdominal, retroperitoneal, bilateral axillary, and supraclavicular). Abdominal ultrasound was non-contributory, except for gallbladder polypoid. A colonoscopy revealed multiple scattered and swollen ulcers in the ileocecal region and ascending, transverse, descending, and sigmoid colon, and multiple site biopsies were performed ( Figures 1A, B ). Ulcers were characterized by clear boundaries, with moss attached to the bottom of the erosions, and the largest ulcer (approximately 1.0 x 1.5 cm) was located in the transverse colon. The demarcation between the normal and flared areas was clear. Therefore, the patient was treated with cefixime, mesalazine, and ilaprazole for 1 week before the completion of colonic histopathology, but without clinical improvement. After 7 days, histopathological evaluation of the biopsies using hematoxylin and eosin staining revealed a chronic ulcer of the colonic mucosa with fungal granuloma and focal small abscess ( Figures 1C, D ). Next, biopsy tissues were specifically stained with periodic acid-Schiff (PAS) and Gomorrah's methylamine silver (GMS) stains. Briefly, the former involves staining with periodate followed by binding with Schiff's solution to reveal glycogen and polysaccharides in the tissue, whereas the latter involves the oxidation of periodic acid followed by the reaction of the aldehyde group with hexamine silver to expose metallic silver. PAS staining ( Figures 1E, F ) and GMS ( Figures 1G, H ) staining of the intestinal biopsy specimens were positive. Fungal spores with a transverse septum were observed in the tissue cells, which were presented in the form of short fusiform or sausage-shaped spores aggregated into mulberry shapes. Combined with the results of immunohistochemistry, cluster of differentiation (CD) 68(+), pan-cytokeratin(-), CD34(-), S100(-), and CMV(-) confirmed T. marneffei infection. Subsequently, the patient received antifungal therapy with intravenous fluconazole (400 mg once daily) and intravenous ganciclovir (250 mg twice daily) for 5 days, followed by oral fluconazole (200 mg once daily) for 9 days and ganciclovir (1,000 mg once daily) for 23 days. During hospitalization, the patient was continuously administered symptomatic treatment, such as mesalazine, amino acid, and alanyl-glutamine. A change in the antifungal treatment with fluconazole led to defervescence, and the patient's symptoms improved quickly. The patient was discharged from our hospital and maintained oral antifungal agents.

hiv, talaromyces marneffei, endoscopy, intestine, talaromycosis

PMC4844496_01

Male

A 16 year old boy presented to the outpatient department in November 2009 with the history of painful swelling around the anterior aspect of both proximal tibia. On examination both the tibial tubercles were tender and prominent. Knee joints examination did not have any positive findings. He was diagnosed clinically to have bilateral OSD and treated conservatively with NSAIDS and compression bandage. Patient was symptomatically improved with the treatment. He was brought to the outpatient department after 2 months in February 2010 with the history of jumping from the school compound wall (two feet height) while playing, followed by severe pain around anterior aspect of both knees and difficulty in walking. After few minutes the knees were swollen and he was unable to bear weight on both the legs and to flex and extend the knees. There was a palpable defect distal to the tibial tubercles with high riding patellae. Radiographs of both knee joints AP and lateral views were taken which showed bilateral tibial tubercle avulsion fractures. (Fig. 1) According to Ogden classification right side was type IIa and leftside was IIb tibial tubercle avulsion fracture. Both sides were treated with open reduction and internal fixation with Tension Band Wiring (TBW) (Fig. 2 and 3). Patient was positioned supine under tourniquet control. 7 cm medial parapatellar incision was taken to expose the fracture site. Fracture was reduced and confirmed clinically and radiologically under image intensifier and fixed with two 2 mm K wires and tension band wiring. The figure-of-eight wire was passed deep to the patellar ligament and through a transosseous tunnel 4cm distal to the fracture. Kirschner wires provided rotational stability, and were inserted through the proximal part of the tubercle and engaged the posterior cortex of the tibia under direct guidance of image intensification. Patient was put on cylindrical slab for 2 weeks and gradual mobilization of knee was started. Patient was allowed to bear weight with the help of walking frame. Patient was followed up clinically and radiologically at 6 weeks, 12 weeks, and 6 months and 12 months and 22 months (Fig. 4). Implants were removed at the end of 12 months. At final follow up the knee range was 0 to 120 and completely pain free with patient doing all his activities without any functional limitations

osgood-schlatter disease (osd), avulsion of tibial tubercle, tibial tubercle fracture, traction apophysitis

PMC8555708_01

Male

A previously healthy 16-month-old male child was transferred to our hospital for continuous high-grade fever associated with erythematous and target-like rash (Figure 1) 5 days after the beginning of fever. At the local hospital, on clinical examination neurological symptoms such as irritability and lethargy were noted; blood examinations showed leukocytosis with neutrophilia (white blood cell count: 21,000/muL) and elevated procalcitonin (PCT: 15.6 ng/mL; n.v: normal values < 0.5) and C-reactive protein (CRP: 8.9 mg/L; n.v: normal values < 5) levels. Intravenous (IV) fluids and ceftriaxone had been immediately administered for suspected meningococcemia. On admission to our unit, a body temperature of 39.6 C was recorded. The boy appeared extremely irritable, and physical examination demonstrated an erythematous eruption with round lesions characterized by polycyclic contours covering the limbs and the abdomen with many targeted lesions involving the abdomen, the arms, and the face. Bilateral erythema and edema of palms and soles were also described (Figure 1). His mother reported the beginning of the rash 2 days after the onset of fever. Initially, erythematous-purpuric lesions on the limbs were noted, spreading confluently later to the inferior abdomen, where some peripheral targeted lesions were also present. Similar well-delineated, target-like lesions appeared in the upper abdomen quadrants and subsequently on his face and arms. Cervical lymph nodes were not swollen on clinical evaluation. The physical examination showed a strawberry tongue and intense pharyngeal hyperemia, although the conjunctiva and the lips appeared normal. The peripheral blood test exhibited leukocytosis (white blood cell count, 11,660 cells/muL, with 82.6% neutrophils), thrombocytosis (platelets 777,000 cells/muL), and increased fibrinogen (772 mg/dL, n.v: normal values < 500) and d-dimer (13,030 ng/mL, n.v: normal values 200-400) with partial thromboplastin time and activated partial thromboplastin time values in the normal range. Marked elevated levels of CRP (98 mg/L; n.v: normal values < 0.5) and PCT (54 ng/mL; n.v: normal values < 0.5) were seen. Lumbar puncture was performed and cerebrospinal fluid (CSF) analysis was normal. The antibiotic therapy (ceftriaxone) was continued, and acyclovir was prescribed until results of microbiological analyses in the CSF were available. Reverse transcriptase-polymerase chain reaction (RT-PCR) analyses for detection of cytomegalovirus (CMV), Epstein-Barr virus (EBV), polyomavirus JC, enterovirus, herpes simplex virus, human herpesvirus type 6 (HHV-6), and varicella zoster virus genome in CSF came back negative. RT-PCR analyses for detection of the enterovirus genome in stool and pharyngeal swabs gave negative results. Suspecting a viral infection, serological tests for adenovirus, EBV, CMV, coxsackievirus, influenza A and B, human parainfluenza virus, and parvovirus B19 were performed and came back negative too. The urinary examination revealed sterile pyuria and mild proteinuria. CSF, blood, and pharyngeal swab cultures were also negative. On the second day of hospitalization, we documented sudden-onset drowsiness with progressive lethargy. Brain computed tomography (CT) was performed, giving a negative result. The infant developed tachycardia, systolic hypotension (60/50 mm Hg), oliguria, and mild dyspnea, with cold extremities a few hours later. An initial echocardiographic examination revealed first-degree mitral valve regurgitation and left ventricular hypokinesia with pericardial effusion (3 mm in thickness). Hyperechogenic coronary arteries with a normal size were also documented. Ejection fraction (EF) was estimated to be 35-40%. A chest X-ray revealed a small retrocardiac consolidation. The development of hypotension, despite massive IV fluids resuscitation, associated with the neurological deterioration of the child required inotropic support (dobutamine infusion) given until the second dose of IV immunoglobulin (IVIG) was administered and continuous monitoring in the intensive care unit. On the second day, suspecting KD shock syndrome (KDSS), a first dose of IVIG was administered (2 g/kg) but not effective on the fever spikes. On the same day, oral aspirin was given in an anti-inflammatory dose (100 mg/kg per day for 3 days then at a dose of 30 mg/kg per day). Abdominal ultrasound demonstrated a hydropic gallbladder and mild ascitic effusion surrounding the liver and in the pelvis. On the fourth day, a second dose of IVIG was prescribed with clinical improvement and effect on the fever spikes. Hypotension regressed after 1 day of dobutamine infusion. EF increased after the first dose of immunoglobulins and further after the second dose. Interestingly, the rash was initially mitigated by the first dose of IVIG, but the second was more effective with simultaneous blanching in the areas concerned. Echocardiographic examination on the 6th day revealed exclusively residual and persistent hyperechogenicity of the coronary arteries. Blood tests showed a decreased hemoglobin level (from 11 to 7.6 g/dL) requiring blood transfusion. Serum immunoglobulin levels were normal. Albumin (ALB) was decreased (total protein: 61 g/L, reference range: 57-80 g/L; ALB: 27 g/L, reference range: 37-51 g/L); total bilirubin (TBIL) (TBIL: 0.2 mg/dL; reference range: 0.3-1.2 mg/dL), alanine aminotransferase, and aspartate aminotransferase were normal. Other blood biochemical tests, including glucose, triglycerides, and calcium were all within reference limits. Renal function and electrolytes were normal; the myocardial enzyme spectrum was also normal, but an increased level of N-terminal prohormone brain natriuretic peptide was evidenced (26,696 pg/mL, n.v: normal values < 150), confirming an ongoing cardiac dysfunction. The throat culture, anti-streptolysin O, and anti-DNase B came back negative; therefore, the hypothesis of streptococcal infection was discarded. Brain magnetic resonance imaging (MRI) was performed 1 week later after the admission to rule out a neurological disease, showing hyperintensities in diffusion and T2-weighted imaging at the level of the anterior perforated substance and hypothalamus, with proton density reduction only in the anterior commissure (Figures 2, 3). Radiologists had suggested an underlying inflammatory/postinfectious process (related to HHV-6 virus), a hypothesis not supported by diagnostic tests (Figures 2, 3). A retropharyngeal abscess (diameter: 10 x 15 mm) with phlogistic involvement of the next longus colli muscle was also described on brain MRI scans, likewise previously reported in KD in literature. To rule out a vasculitic rash complement levels, antineutrophil cytoplasmic antibody, antinuclear antibody, and anticardiolipin antibody tests were studied and came back normal, such as C3 and C4 levels. Brain MRI without lesions in the white matter and multifocal involvement, CSF negative results without pleocytosis, and absent history of past infection/vaccination and/or demyelinating disorders led us to exclude acute disseminated encephalomyelitis. The patient has been followed for 12 months without any neurological and/or cardiac complications as confirmed by subsequent brain and cardiac MRI. Pituitary disorders were excluded.

cns inflammation in kawasaki disease shock syndrome, cns involvement in kawasaki disease, kawasaki disease, kawasaki disease shock syndrome, misc

PMC3738493_02

Female

A 19-year-old female presented to our clinic with fever, headache, retro-orbital pain, and muscle ache for two days. In addition hematemesis and epistaxis started on the day of admission. Her medical history revealed sickle cell anemia (SCA) (homozygosity for abnormal HbS; HbSS). On examination she was alert, with a temperature of 37 C, BP 120/80 mmHg, HR 100/min, and RR 15-20/min. She had right upper-quadrant abdominal tenderness. No other abnormalities on physical examination were found. Initial lab results revealed moderate increase of CRP, anemia, thrombocytopenia, and increased liver enzymes. NS1-antigen tested positive and dengue serology was negative for IgM (0.41) and positive for IgG (5.71), and RT-PCR showed DENV-2. Shortly after admittance she became hypotensive, with distension of her abdomen. Intravenous fluid resuscitation was started and further intervention was implemented on the basis of the monitoring of hematocrit, urine output, and blood glucose. Profuse abdominal bleeding was suspected, with marked decrease of Hb, low platelets, severe disrupted coagulation parameters, and intra- and retro-abdominal free fluid with fibrin strands on ultrasound. Moreover extensive capillary leakage and anuria developed. She was intubated due to seizures and following sedation. Although in the course of time shock and bleeding stabilized, she continued to develop MODS and both pupils became progressively less reactive to light until nonreactive. CT brain imaging could not be performed. On day four, she died due to cardiac arrest. No autopsies were performed on either of the patients. Written informed consent for publication of the disease histories was obtained from the direct relatives of both patients. During the past decades dengue has been reported to occur in Curacao. Until now fatal cases were never documented. However the 2010-2011 outbreak with 1,822 serologically confirmed cases was associated with four deaths (personal communication). Two of these patients had been previously diagnosed with SCD type HbSC and SCA. SCD is not uncommon in Curacao, with a prevalence of approximately 0.25%. Although chronic diseases such as SCD are considered to be a risk factor for development of severe dengue, few cases of children or adolescents have been reported. The clinical findings of the two cases described here are difficult to interpret because of the apparent complementary vascular endothelial damage in SCD, SCA, and severe dengue. As proposed in the model of dengue pathogenesis by Martina et al., DENV might replicate in selective endotheliocytes. In SCD, endothelial dysfunction is known to occur. There is no direct evidence from fatal dengue cases that dengue virus replicates in endothelial cells. Nonetheless, damage to endothelial cells as reflected by increased vascular permeability is central to the dengue vascular permeability syndrome (DHF/DSS). Vascular endothelial cells (VEC) play an important roll in inflammation and coagulation. By damaging the VEC either through infection of DENV or by sickling of erythrocytes, the permeability of the vascular endothelial layer can increase, which may induce plasma leakage, release of cytokines, and cause profound shock. Based on these findings, we hypothesize an essential role for endothelial cells to contribute to disease severity. The similarities between the cases are striking: shock, plasma leakage, hemorrhage, and MODS. However plasma leakage predominated in case 1, whereas hemorrhage did in case 2. The onset of vaso-occlusion with SCD and SCA is often triggered by inflammation, as is the case in a DENV infection. Severe bleeding seldom happens in children, but only in cases of profound shock, and no thrombotic complications are seen. In treating dengue patients with underlying SCD or SCA, the treating physician is facing a dilemma. In SCD and SCA, it is preferred to maintain a low Ht to reduce the risk of vaso-occlusion. Treating physicians may be reluctant to perform blood transfusions in SCD patients because of concerns of excessive accumulation of iron, transfusion reactions, and alloimmunization. However severe anemia as a result of SCD or dengue may necessitate blood transfusion. The WHO reports an increase of Ht as a sign of plasma leakage with subsequently a decrease that may be due to hemorrhage. Both cases showed a continuing decrease of Ht, associated with hemorrhage with plasma leakage also predominating, suggesting Ht should not be used as a marker in patients with SCD or SCA. Iatrogenic interstitial fluid overload in patients with SCD, SCA, and severe dengue, due to preexisting vascular endothelial damage, is not just a theoretical hazard. Whether the clinical manifestations would just have been the result of secondary DENV infection only, despite SCD or SCA, remains a matter for debate. To further address this issue, we suggest that a case-control study should be performed to further elucidate the proposed association between severe dengue and SCD or SCA. This report is based on two fatal cases of severe dengue with underlying SCD/SCA in Curacao during the 2010-2011 epidemic. Currently no guidelines exist on how to treat such patients. In populations with a high prevalence of SCD, SCA, and dengue activity, clinicians should be aware of the challenges in clinical management.

PMC9039355_01

Female

A 13-year-old girl with T1DM was admitted to our hospital for poor glucose control under multiple daily insulin injections. A review of her medical history and physical examination at presentation suggested that the girl had been suffering from chronic spontaneous urticaria unresponsive to antihistamine therapy. T1DM was diagnosed at the age of 11, appropriate treatment was initiated (multiple daily insulin injection therapy), and other type 1 diabetes-associated autoimmune diseases (celiac disease, autoimmune thyroiditis, and autoimmune atrophic gastritis) were excluded at diagnosis and yearly follow-up. Two years after the diagnosis of T1DM, she developed severe symptoms of chronic urticaria. Treatment with cetirizine (10 mg/day) was initiated, although no significant response was observed. There was no apparent correlation with exposure to common allergens nor physical stimuli. No history of allergy was reported; in particular, she did not report symptoms of oculorhinitis, asthma, or atopic dermatitis. She only referred one episode of urticaria in early childhood after taking amoxicillin-clavulanic acid. The timing of onset and the frequency and duration of the hives were not consistent with insulin allergy. Skin tests with insulin were not performed due to the persistence of hives and ongoing antihistamine treatment and the absence of concrete evidence supporting insulin skin test reliability. Laboratory work-up revealed normal complete blood count and leukocyte formula (mild eosinophilia was detected: 600/mmc, n.v. 0-450) and normal serum total IgE. Specific IgE against common food and inhalant allergens showed weak positivity for only dust mites and ragweed. Liver, kidney, and thyroid function were normal; thyroid autoimmunity (anti-thyroid peroxidase, 11 IU/ml; anti-thyroglobulin, 31 IU/ml; and anti-TSH receptor, <0.8 IU/L) was negative. Celiac disease was also excluded, and inflammatory markers (CRP, ESR) were negative. Screening for other autoantibodies most frequently associated with CSU (ANA and ENA) showed negative results, with the exception of antinuclear antibodies (titer, 1:160). Complement fractions (C3, 1.13 g/L; C4, 0.22 g/L) and immunoglobulin classes were normal. Microbiological tests (including fecal Helicobacter pylori antigen) and stool parasite tests yielded negative results. Streptococcal infection was excluded. Urinalysis was also normal. Due to treatment failure on standard cetirizine prescription, the dose was increased twofold, with only minimal improvement. We monitored the disease course on a weekly basis with a mean Urticaria Activity Score (UAS) of 36. Given the persistence of clinical symptoms and the patient's poor quality of life, omalizumab was started at a standard recommended dose of 300 mg intramuscular injection every 4 weeks. After the third dose and concomitant oral antihistamine treatment, symptoms significantly improved (UAS, 14), and only small urticarial elements remained on the extremities. After the sixth dose, CSU symptoms completely subsided, and antihistamine treatment was suspended ( Figure 1 , picture before and after treatment). Treatment was completed after 11 administrations of omalizumab with no relapsing CSU to date. Glucometric data derived by flash glucose monitoring during treatment is shown in Table 1 . Time spent in specific glucose ranges at baseline and after treatment were compared by chi-squared test. From baseline, time below range (TBR) has shown a slight but statistically significant reduction. However, this improvement has been apparently at the expense of an increased time above range (TAR) of 180-250 mg/dl. Time in range (TIR) did not vary. Baseline and post-treatment HbA1c were 6.8% and 6.9%, respectively, showing a substantial stable average glucose control during the treatment period. Daily insulin doses also did not vary significantly and were 1.1 U/kg at baseline and 0.9 U/kg post-treatment.

chronic spontaneous urticaria, glycemic, omalizumab, pediatrics, type 1 diabetes

PMC3087462_01

Female

A 64-year-old female patient with a 30-pack-year smoking history was admitted to the outpatient clinic for analyses of a hilar and mediastinal lymphadenopathy. Her past medical history revealed a follicular NHL stage IVa diagnosed in 2003. This disease presented with iliac lymphadenopathy and bone marrow localisation. She was initially treated with palliative radiotherapy for lymphoma in the left iliac area. In 2007, there was clinical evidence of disease progression based on palpable lymph nodes in the right iliac and the left-sided supraclavicular areas. A computed tomography (CT) of the abdomen also showed para-aortal lymphadenopathy. She underwent palliative radiotherapy on the right iliac lymphoma to treat its symptomatic mass effect. In September 2008, she was admitted for dyspnoea and a loss of appetite and a subsequent CT scan of the thorax, neck, and abdomen was performed. The CT scan revealed massive left hilar lymphadenopathy with compression of the surrounding bronchial and venous structures and mediastinal (subcarinal) and parasternal lymphadenopathy with a small left sided pleural effusion. A subsequent positron emission tomography (PET) scan showed multifocal disease activity in the pathological areas corresponding to the previous CT scan and low disease activity in the para-aortal region. Nonetheless, despite these extensive radiological investigations it was not possible to differentiate between progression of NHL or another disease pathology such as an underlying primary lung carcinoma. Accordingly, a bronchoscopy was performed that showed a slightly oedematous bronchial mucosa in the left lower lobe. Brushing, bronchial lavage and endobronchial biopsies of the oedematous mucosa with a transbronchial needle aspiration (TBNA) of the subcarinal node and a pleuracentesis were performed. Further sampling of the left sternal mass with transthoracic FNA was also conducted but all these tests failed to deliver a diagnosis. Therefore, it was deemed necessary to perform an EUS-FNA with material being obtained from the subcarinal lymphoma location 7 and from the possible primary process. Both aspirations delivered macroscopic "worm-like" material. From this material, there were small tissue fragments on which the pathologist was able to perform histological analysis and immunohistochemical tests clearly showing localisation of the follicular lymphoma. EUS was performed according to published guidelines with an Olympus EUS EXERA ultrasonic video gastroscope GF-UC160P-OL5. After identification of the suspected lymph node, the FNA needle was introduced (model Olympus NA-200H-8022 needle width 22 Gauge). Following infiltration of the node, the mandarin was pulled back and in excess of 15 passes into the lymph node were performed before the needle was finally retracted. The mandarin was reintroduced to push any collected tissue fragments, that possessed a "worm-like" appearance, into a cytorich red (CRR) medium. Finally, after the mandarin was removed again, the remaining droplets were collected on glasses by clearing the needle with air, using a 20cc syringe. This procedure resulted in the collection of: "Worm-like" coherent material in the CRR, Air dried smeared droplets on glasses, and Cytospin fluid after the "worm-like" material was extracted. These materials were then processed and investigated as follows Cytological examination was performed on II and III, using May Grunwald-Giemsa colouring and Shandon EZ Megafunnel (Thermo Fisher) method with Papanicolaou colouring, respectively. The "worm-like" fragments in CRR (I) were added to liquid agar, compressed on the bottom of a mold and left for solidification. The solidified agar was then taken out from the mold and encased in a cassette. The cassette was further processed according to routine histological investigative techniques. The following day, two slices were made at two different levels allowing standard and supplemental histological and immunohistochemical staining to be performed. Our approach represents a subtle but significant adaptation to the routine handling of this material as a smear is not made from the "worm-like" fragment. By using our modified technique, we can generate two important advantages; firstly, it allows optimal use of the collected material including histological investigation. Secondly, it leads to a reduction in processing time owing to a reduction in the number of smears that are made. We opted to collect the material in CRR and not directly in formalin solution for the following reasons: firstly, due to the characteristics of CRR (fixation, haemolysis, denaturation of proteins, and compatibility with immunohistochemical staining), a specimen of superior quality could be obtained. Secondly, cytological examination could be performed on the diagnostic material in the CRR, after the "worms" were removed, using the Shandon EZ Megafunnel. This process is particularly advantageous as it is both quick and the equipment is relatively simple to use. Conversely, using an alternative formalin solution would have made the process markedly more complicated. However, it should be noted that in our aforementioned example, the cytological material referred to in II and III did not contribute to the diagnosis of lymphoma. Nonetheless, histological tissue fragments that were intact and possessed structural integrity, as illustrated in Figures 1, 2, and 3, were obtained from step I coherent material in CRR. Therefore, a subsequent diagnosis of follicular non-Hodgkin lymphoma could be made after immunohistochemical staining.

PMC5828649_01

Female

The patient, a 44-year-old woman, was admitted to our center in December 2011 suffering from cough, asthma, and asthenia. Peripheral blood studies showed severe iron-deficiency anemia, elevations of C-reactive protein, and polyclonal hypergammaglobulinemia. Computed tomogram demonstrated diffuse (lung, axillary, and mediastinal) lymphadenopathy, interstitial pneumonitis, and splenomegaly (Figures 1 and 1). Histology of left pulmonary nodule accessed by thoracic surgery revealed atretic follicles with plasmacytosis, prominent paracortical vascularity, and sinus histiocytosis with an overall appearance consistent with MCD (Figures 1 and 1). Immunohistochemistry for IgG and CD138 was positive, and IgG4 was negative (Figures 1 and 1). Based on clinical and pathological suspicion of Castleman disease, further testing revealed high interleukin-6 (IL-6) of 23.0 pg/mL and normal IgG4 of 1.28 g/L. The patient's serum tested negative for HIV, and no cytomegalovirus, Epstein-Barr virus, or human herpes virus-8 (HHV-8) replication was detected. She was diagnosed with HIV-negative and HHV-8-negative multicentric Castleman disease of plasma cell variant. She was started on monotherapy chemotherapy with low-dose cyclophosphamide, accompanied by oral steroids from March 2012. Unfortunately, she was later readmitted to our hospital for severe abdominal pain and skin and mucous membrane bleeding in August 2015 with a history of type-II diabetes for two years. Just one month ago, she followed the doctors' advice of cessation of the cyclophosphamide for severe anemia (Hb, 4.4 g/dL). Continued monitoring of routine blood count showed normocytic normochromic anemia (Hb, 6.0-8.0 g/dL), severe thrombocytopenia (PLT, 10,000-20,000/muL), and mild leukocytosis (10,000-12,000/muL), while monocytes were at normal levels. Bone marrow (BM) study showed an increased number of megakaryocytes, and myeloid series hypercellularity and dysplastic change were evident. Abdominal CT showed severe splenomegaly and multifocal and wide-area infarction. Subsequently, she underwent laparoscopic splenectomy, and the pathological section demonstrated the structural breakdown and significant hypercellularity (Figures 2 and 2). In next nine months, there was a stable increase of WBC (20,000-100,000/muL), especially peripheral blood monocytes (1,500-10,000/muL), which was still accompanied by decreased platelet counts (15,000-60,000/muL) and anemia (Hb, 6.0-8.0 g/dL). At this period, BM examination was again performed and revealed a significant increase in monocytes (12%) and prominent dysplastic changes in myeloid lineages. High expression levels of CD13, CD33, CD14, CD64, and CD56 were detected in her bone marrow cells. The karyotype was normal, and BCR/ABL fusion gene was not detected by the fluorescent in situ hybridization. At the same time, molecular studies were negative for TET2, SRSF2, ASXL1, and SETBP1 mutations, which are reported in about 90% of patients with CMML. According to World Health Organization (WHO) classification, a diagnosis of CMML and MCD, which were simultaneously present, was made. Then, she received front-line treatment with decitabine (DAC, 20 mg/m2 for 5 d in a 4-week cycle) for CMML. Surprisingly, after just one cycle, the WBC count had declined to 15,000/muL and the Hb increased to 9.0 g/dL and PLT to 220,000/muL (Figure 3). She also was recommended allogeneic hematopoietic stem cell transplant (HSCT) as the only potentially curative option.

PMC6757007_01

Male

A 56-year-old male with a past medical history of seronegative rheumatoid arthritis (treated with abatacept 1000 mg every 4 weeks and sulfasalazine), neuropathy, obstructive sleep apnea and prior right hip arthroplasty completed 9 years previously in the setting of avascular necrosis, presented to clinic with a 3-month history of malaise and low-grade temperature of 99 F. He had returned from a mission trip to Honduras 3 months previously. He initially developed a low-grade temperature 1 month after returning, which was followed by unintentional weight loss and night sweats. He had mild congestion and took a course of amoxicillin without improvement in temperature or night sweats. Subsequently, he developed progressive right hip pain. A bone scan was unremarkable. A fever of 103 F prompted hospital admission for evaluation. The patient reported no additional symptoms at the time of admission and his abatacept was held. He reported drinking only bottled water in Honduras with no adventurous eating. He was born in California but had lived in the Midwest United States much of his life. He is married, monogamous, and had no history of tobacco or recreational drug use. He had traveled to Mexico previously but denied other recent travel. He reported no tuberculosis or animal exposures. On examination, extremities were atraumatic without synovitis. He had mild discomfort with internal rotation of the right hip. The examination was otherwise unremarkable. Laboratory evaluation revealed a white blood cell count (WBC) of 6.3 K/UL (normal 4.5 - 11.0 K/UL) and hemoglobin of 12.4 grams (normal 13.5 - 16.5 gm/dL). Erythrocyte sedimentation rate (ESR) was 25 mm/h (normal < 20 mm/hr). Liver transaminases were normal. The following infection diagnostics were negative: malaria smear and Ag, HIV ag/Ab, Syphilis Ab, Histoplasma serum Ag and Ab, Coccidiodes serology, Cryptococcal serum Ag, Bartonella and Brucella IgG/IgM, T spot TB, Chikungunya IgG and 2 sets of blood cultures. A chest radiograph and echocardiogram were unremarkable. A 2-view hip radiograph demonstrated right hip arthroplasty without periprosthetic lucency or fracture. The patient underwent a tagged white blood cell scan, which did not demonstrate any increased uptake (Figure 1). An MRI scan of the right hip joint without contrast demonstrated fluid collections medial to the lesser trochanter, consistent with hematoma or pseudotumor (Figure 2). Joint aspirate was grossly purulent. The patient was taken to the operating room for prosthetic explant with antibiotic spacer placement. Antibiotic spacer was ceramic total hip system, which was cemented in with antibiotic-impregnated cement with 5g of Vancomycin and 1.2g of Gentamicin. Testing from the operated room revealed that the joint aspirate cell count was unreadable as the cells were degenerated. Gram stain of the aspirate was negative for microorganisms. Aspirate routine culture was negative, with no growth at 5 days on aerobic and anaerobic culture. Aspirate grew acid-fast bacteria at 10 days, identified later as MAC. Fungal cultures remained negative. Tissue cultures including femoral head component had negative routine culture and fungal culture. AFB culture of the tissue grew MAC. Blood cultures were negative for mycobacteria at 6 weeks. Macrolide sensitivities were performed and the isolate was found to be clarithromycin susceptible. Initial broad-spectrum antibiotics were adjusted and he was discharged on intravenous amikacin three times weekly with oral rifampin, ethambutol, and azithromycin. Amikacin was discontinued after 4 weeks of treatment. The remainder of antimicrobial therapy was continued for 12 months. The patient's rheumatoid arthritis treatment included sulfasalazine and hydroxychloroquine, resumed after 3 months of antimicrobial treatment. He started methotrexate treatment 6 months after starting antimicrobial therapy for better joint pain control. Eleven months after treatment initiation, repeat joint aspiration culture was negative. He underwent repeat right THA and tissue cultures were negative. One year following the revision THA he remains free of infection. To date, he remains off biologic immunosuppression.

mac, immunosuppression, joint infection, prosthetic joint

PMC7283146_01

Female

A 64-year-old woman with a history of heart transplantation and renal failure requiring dialysis was admitted to our hospital in September 2019 with a suspected diagnosis of lung cancer. The patient had been complaining about progressive dyspnea, a productive cough, chest pain, and weight loss for about six weeks. In August 2019, an initial outpatient chest X-ray was performed that revealed an infiltrate in the superior left lung. Blood tests showed an elevated white blood cell count of 16,5 Gpt/l and an elevated C-reactive protein of 245 mg/l. Consequently, bacterial pneumonia was suspected and an oral course of amoxicillin was started. Due to a lack of improvement both clinically and radiologically antibiotic treatment was changed to ciprofloxacin. Ten days later the patient was admitted to a hospital due to increased shortness of breath. On the day of admission, she presented with a leukocyte count of 18,2 Gpt/l and a C-reactive protein of 278 mg/l suggesting a lack of response to antibiotic treatment for the second time. Computed tomography of the lungs finally revealed an eight by eight-centimeter mass in the left upper lobe (Fig. 1). Bronchoscopy with transbronchial biopsy and bronchoalveolar lavage was performed. The former showed no evidence of malignancy. However, lung cancer remained the most likely diagnosis. Therefore, the patient was transferred to our hospital for further evaluation. At this point, the microbiologic results of the bronchoalveolar lavage were still incomplete. We performed an ultrasound-guided transthoracic needle biopsy of the tumor in the left upper lobe. Similar to the histological assessment of the transbronchial biopsy, the sample showed an inflammatory process with no evidence of malignancy. Meanwhile, we received the results of the bronchoalveolar lavage obtained in the previous hospital identifying Nocardia nova by culture. Antibiotic susceptibility testing showed sensitivity towards amoxicillin, cefotaxime, amikacin, tobramycin, imipenem and linezolid. We started the patient on a combination of amikacin and imipenem. Because the patient suffered from renal failure requiring dialysis, there was a need for dose adjustment. On days of dialysis our patient received 500 mg of amikacin administered after dialysis if the trough level was below 1 mg/l in combination with 1000 mg of imipenem. On dialysis-free days she received 500 mg of imipenem twice daily. Immunosuppressive medication given to avoid rejection after heart transplantation was adapted meaning the tacrolimus trough level was reduced from 8 to 10 mug/l to 4-6 mug/l. The dose of Cellcept was initially reduced by fifty percent to 500 mg twice daily and eventually paused. Prednisolon 10 mg was continued. A follow up computed tomography after two weeks of antibiotic treatment showed an improvement of the alterations in the left upper lobe. However, a new infiltrate in the right upper lobe was found. To exclude an additional malignant disease with maximum certainty a CT-guided needle biopsy of the infiltrate in the right upper lobe was performed. Histopathology showed an inflammatory process as well as a mycotic superinfection through a positive periodic acid schiff reaction, but still no malignancy. In a second bronchoalveolar lavage pseudomonas aeruginosa was detected. Neither fungi nor Nocardia species were found. Consequently, no further specification of the mycotic superinfection was possible. Therefore, the established antibiotic treatment against Nocardia nova based on imipenem and amikacin was supplemented with piperacillin/tazobactam and voriconazole for a period of three weeks. After eight weeks of antibiotic treatment respiratory symptoms such as productive cough, dyspnea and chest pain improved significantly. At this point the chest X-ray showed a reduction of the inflammatory tumor of the left upper lobe to half of the original extent. Furthermore, inflammatory values normalized to a white blood cell count of 4,9 Gpt/l and a C-reactive protein of 2,13 mg/l. Consequently, the patient was discharged from our hospital. She continued antibiotic treatment with amikacin given after outpatient dialysis when the trough level was below 1 mg/l. Computed tomography of the chest one month after the patient was discharged showed further reduction of all infiltrates indicating a successful treatment (Fig. 2). Due to difficulties in monitoring the amikacin trough level in an outpatient setting and signs of hearing loss antibiotic therapy was stopped after twelve weeks. A reevaluation after another twelve weeks and possibly a restart and completion of the antibiotic therapy is planned. Nocardiosis is a rare opportunistic bacterial infection. More than 50 Nocardia species associated with human disease have been identified. Nocardia is a genus within the order of Actinomycetales that are gram-positive and partially acid-fast. As ubiquitous bacteria they can be found in soil, both fresh and salt water, and decomposing vegetation. Most patients suffering from Nocardiosis are immunocompromised. Incidences of Nocardiosis up to 3,5% have been described following heart or lung transplantation. Almost 70% of the study population in a series of 55 cases of Nocardiosis had received a long-term corticosteroid therapy making chronic steroid exposure an important risk factor. Other relevant risk factors include pulmonary comorbidities such as chronic obstructive pulmonary disease or tuberculosis. Airborne droplet infection is the most common route of transmission. Consequently, pulmonary disease is the predominant clinical presentation of Nocardiosis. Symptoms can include non-productive or productive cough, shortness of breath, chest pain and weight loss. Radiographic findings may suggest a wide range of differential diagnoses. A recently published study of 55 cases described a variety of consolidation, nodules, cavitation, bronchiectasis and infiltrates as possible imaging manifestations. In the case demonstrated an unusually large solid lesion in the patient's left upper lobe suggested lung cancer as the most likely diagnosis. Secondary extrapulmonary disease occurs in about fifty percent of all cases and usually manifests as abscess formation. To confirm the diagnosis of Nocardiosis a positive culture is necessary. Usually sputum or a bronchoalveolar lavage is obtained. Cultures of Nocardia may take a long time to grow and can easily be missed in mixed cultures. Molecular methods can be helpful with the identification of Nocardia species. Prognosis of Nocardiosis is poor. A retrospective study described a mortality rate of 34,5% with cardiopulmonary arrest due to septicemia or respiratory failure being the most common causes of death. Organ transplant recipients with Nocardiosis have a significantly lower one year survival rate than other patients. Therefore, early diagnosis and effective treatment are crucial. Due to a lack of prospective controlled trials there are no standard treatment guidelines. Initial antibiotic therapy should be selected depending on the severity and location of the infection as well as the patient's comorbidities and the species of Nocardia. Susceptibility testing should always be performed. trimethoprim-sulfamethoxazole (TMP-SMX) has successfully been used in stable patients with pulmonary disease. However, drug resistance is not uncommon. In a retrospective study of over 700 Nocardia isolates 42% were resistant to TMP-SMX. Patients with severe pulmonary or disseminated disease and immunocompromised individuals should receive a combination of two antibiotics. Imipenem in combination with amikacin or TMP-SMX proofed to be successful in many cases. In life-threatening situations, all three substances can be administered simultaneously. In addition to antibiotic treatment surgery can become necessary in the presence of abscess formation. Duration of treatment should be at least six months. In case of severe disease or an immunocompromised host treatment should be continued for at least twelve months. Therefore, we strive to restart antibiotic therapy in our patient after the current interruption despite the difficulties due to dialysis.

PMC7176938_01

Female

A 43-year-old woman with well-controlled HIV was prescribed a 6-month course of isoniazid preventative therapy (IPT) (300 mg daily) and pyridoxine (50 mg daily) for latent tuberculosis as part of a nationwide effort in Uganda to decrease the burden of tuberculosis among persons with HIV. Approximately 4 months later, she developed symmetric, photo-distributed, well-demarcated, severely pruritic plaques with scale resembling peeling paint on her bilateral forearms, posterior neck, and upper back (Fig. 1). She denied gastrointestinal or neurologic symptoms. Before visiting the dermatology clinic, the working diagnosis of her primary provider was allergic contact dermatitis, but she remained untreated. Based on the morphology, distribution, and developmental time course of her rash, a clinical diagnosis of isoniazid-related pellagra was made. Given the high cost of niacin locally, a twice-daily B complex multivitamin containing 7.5 mg niacinamide was prescribed. Topical betamethasone ointment twice daily was given for pruritus. Her IPT was also stopped, as she had received five of six months of the planned course. One month later, her rash had completely resolved, leaving behind post-inflammatory hyperpigmentation and mild, steadily improving residual pruritus. Pellagra is a clinical syndrome caused by vitamin B3 (niacin) deficiency. Although classically associated with altered vitamin B6 (pyridoxine) metabolism, isoniazid also interferes indirectly with the conversion of tryptophan to nicotinamide. Isoniazid may therefore cause pellagra despite pyridoxine supplementation. This is especially relevant in settings where maize is the staple dietary carbohydrate for the population. If available, clinicians practicing in such areas should consider obtaining baseline tryptophan and nicotinamide serum levels and initiating B complex vitamin and/or nicotinamide supplementation at the onset of IPT. In settings planning broad IPT implementation, patients should be educated about possible adverse effects of isoniazid, and physicians should be comfortable recognizing and treating these, including pellagra. Isoniazid-related pellagra usually resolves after the offending medication is stopped. For patients that must continue IPT, nicotinamide or a B complex multivitamin, in addition to dietary counseling regarding niacin-rich food sources (including beef liver, chicken breast, marinara sauce, tuna fish, brown rice, and peanuts), are appropriate initial steps. Medium- to high-potency topical corticosteroid ointment can help relieve symptoms while the underlying cause is being addressed. For those with severe symptoms refractory to these measures, physicians should consider premature termination of IPT followed by careful monitoring for signs of active TB. Alternative regimens such as rifampin, which is associated with greater completion rates and less hepatotoxicity compared to isoniazid, should also be considered. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request

adverse drug reaction, hiv, ipt, latent tuberculosis

PMC3322896_01

Female

A 36-year-old, previously healthy, Asian woman (gravida 2, para 1) at 19 weeks' gestation with a low-lying placenta traveled in late February from the United States to Hong Kong with her husband and child. Before departing from the United States, the patient had been complaining of a mild, intermittent cough without fever for approximately 10 days. The cough, similar to one she had during her previous pregnancy, did not impair her ability to function. While in Hong Kong, between February 19 and March 2, 2003, she stayed at the same hotel and on the same floor as a physician from southern China, who is believed to have been the source of infection for patients who were the index case-patients in subsequent outbreaks of SARS in Hong Kong, Singapore, Hanoi, and Toronto, Canada. On February 24, fever, headache, weakness, anorexia, increasing cough, and shortness of breath developed in the patient. The next morning, she sought medical attention and was prescribed chlorpheniramine and acetaminophen. Her symptoms worsened, prompting her to see another physician 2 days later. A fetal ultrasound performed at this time was reportedly normal. Cephalexin was added to her regimen, but her condition did not improve; that night, she noted blood-tinged sputum. On March 2, the patient returned to the United States where, acutely short of breath, she was hospitalized with pneumonia. Her highest temperature on admission was 102.5 F (39.2 C). Although chest auscultation was normal, chest radiography showed diffuse bilateral lower lobe infiltrates (Figure, part a). Admission arterial blood gas analysis showed pH 7.47, PaCO2 31 mm Hg, and PaO2 75 mm Hg on room air. Other pertinent laboratory findings included a leukocyte count of 3,300/mm3 (normal range 4,500-11,500/mm3) with a differential of 83% polymorphonuclear cells, 12% lymphocytes, and 5% monocytes; platelets of 103,000/mm3 (normal range 150,000-450,000/mm3); and alanine aminotransferase of 42 U/L (normal range 10-40 U/L). She was given supplemental oxygen for hypoxia and intravenous azithromycin and ampicillin to treat typical and atypical respiratory pathogens associated with community-acquired pneumonia. A fetal ultrasound performed on March 3 demonstrated a live intrauterine fetus of approximately 21 weeks gestational age and complete placenta previa. Despite antibiotic therapy, over the next 3 days, the patient became increasingly dyspneic; rales and decreased breath sounds developed, and she had radiographic evidence of progressive pulmonary infiltrates (Figure, part b). During this time, ticarcillin-clavulanate was added to her antimicrobial regimen, and rifampin was initiated as adjuvant therapy for possible legionellosis. Because the patient's diagnosis remained elusive, tuberculosis was considered, and she was placed in airborne isolation. Arterial blood gas analysis on March 5 showed: pH 7.48, PaCO2 31 mm Hg, and PaO2 57 mm Hg on a 100% nonrebreather mask. The patient was subsequently placed on a mechanical ventilator. When avian (H5N1) influenza was considered in the differential diagnosis, oseltamivir was added to her therapy. During the next several days, she began to improve. Chest auscultation demonstrated few bibasilar rales, and a chest radiograph showed interval improvement (Figure, part c). She was afebrile by March 9 and extubated on March 12. On March 13, she had a fetal ultrasound that showed fetal growth consistent with dates and complete placenta previa. On March 17, she was discharged to home. Sputum, blood, and urine cultures; smears for acid-fast bacilli; and tests for Legionella urinary antigen, influenza nasopharyngeal antigen, and cold agglutinins were negative. Serum specimens collected 12 and 29 days after illness onset were tested at the Centers for Disease Control and Prevention (CDC) and found to be positive for SARS-CoV antibody. A follow-up ultrasound examination on April 29 during routine prenatal care showed fetal growth consistent with dates and persistent complete previa. On May 2 (approximately 30 weeks' gestation), the patient was diagnosed with gestational diabetes after an abnormal oral glucose tolerance test. Her diabetes was well-controlled by diet during the remainder of her pregnancy. Because serial ultrasounds performed on May 28 and June 24 demonstrated complete placenta previa, she underwent a cesarean section at 38 weeks' gestation. A 6-lb, 15-oz (3,145-g) healthy female infant was delivered without complications. Apgar scores at 1 and 5 minutes were 9 and 9. Gross and microscopic inspection of the placenta did not show major abnormalities. After informed consent was obtained, the following specimens (collected approximately 130 days after illness onset) were submitted to CDC for coronavirus testing: serum, whole blood, nasopharyngeal and rectal swab specimens from the mother, postdelivery placenta, cord blood, amniotic fluid, and breast milk. No viral RNA was detected in specimens tested by reverse transcriptase-polymerase chain reaction. Antibodies to SARS-CoV were detected in maternal serum, cord blood, and breast milk by enzyme immunoassay and indirect immunofluorescence assay (Table).

PMC1187886_01

Female

A 17-year-old girl was admitted to the local gynaecology unit with recurrent abdominal cramps, nausea and vomiting. She had a history of repeated episodes of abdominal pain in the past. The symptoms had begun some years earlier, causing several hospitalizations and two laparoscopic interventions. Medical history revealed allergic coryza and neurodermatitis, but no food allergy. No other diseases were reported. Laboratory rendered a high white blood cell count (WBC) 13.300 x 109/liter with an eosinophil count of 58% and CRP 5.2 mg/l. Laparoscopy showed a large amount of ascites and swollen intraabdominal lymph nodes. Thus, screening for tuberculosis was initiated. A chest x-ray showed no signs of pulmonary disease, Mantoux test and all cultures remained negative. However, one pcr from ascites was positive and the diagnosis of intestinal tuberculosis was established. The patient was started on rifampicin, isoniazid, ethambutol and pyrazinamide. Despite treatment symptoms persisted for the following six month. On admission the patient was still under therapy with rifampicin and isoniazid. Physical examination demonstrated diffuse abdominal tenderness without peritoneal signs. The WBC was 13100 x 109/liter with an eosinophilic count of 53 %, total IgE 1870 kU/l and CRP 32 mg/l. Clinical and laboratory indices for autoimmune disease were absent. Abdominal ultrasound and computed tomography showed ubiquitous ascites and thickening of the wall of the lower oesophagus, stomach and bowel (Fig. 1). The patient developed severe abdominal pain, only controlled by opoid analgesia. An iliac crest biopsy showed an eosinophilic count over 40 percent but no signs of leukaemia. Again the ascitic fluid rendered a high eosinophilic count. Blood tests as well as stool cultures and microscopy for ova and parasites were negative. Endoscopy of the upper intestinum and the colon showed no abnormalities of the intestinal mucosa. Remarkably biopsies from oesophagus, stomach, ileum and colon yielded distinct eosinophilic infiltrations reaching the lamina propria which finally lead to the diagnosis of a primary eosinophilic gastrointestinal disorder (Fig. 2). Thus, this patient fulfilled all diagnostic criteria for eosinophilic gastroenteritis. Since active tuberculosis was ruled out we stopped anti-mycobacterial treatment. The patient was switched to 40 mg prednisone per day. Symptoms were alleviated quickly in the beginning. The patient was set on a taper. Reaching a dose of 10 mg a day symptoms started again. Therefore the dose was doubled and Montelukast 10 mg/d was started. The symptoms resolved within days and the prednisone could be tapered within six weeks. Currently, the patient remains completely off steroids. She has been symptom free for the last 24 months under Montelukast. Regular physical examinations and blood tests have shown normal results.

PMC4027829_04

Male

Father, 46 years old, body weight 68 kg, height 176 cm and BMI 22 kg/m2. In the early years of his life he suffered from recurrent respiratory infections, diarrhoea, abdominal pain and aphthae on oral cavity mucosa, then at the age of 16 he was treated due to tuberculosis (similar pathological symptoms and tuberculosis in the medical history of his father). Due to abdominal pain, loose stools and weakness, at the age of 40 years he decided to exclude gluten from his diet (both his sons already followed a gluten-free diet). After about 2 weeks of the diet he noticed improvement in his general feeling and regression of abdominal pain and previously observed bad breath. The genotype examination for HLA-DQ2/DQ8 was negative, which rather allows exclusion of genetic susceptibility to celiac disease. The patient on his own, without any arrangements, had serological tests performed: IgE specific for wheat, rye and gluten in class 0, total IgA and IgE concentration within normal limits and tTGA IgA < 0.6 U/ml. Serological testing performed in the course of a diet has no diagnostic significance and thus does not allow confirmation or exclusion of food allergy to gluten. The patient was informed about the need of provocation with small doses of gluten in the diet.

antibodies, celiac disease, children, genotype, gluten

PMC5820662_01

Female

The students in the EG had to solve five virtual patient cases chosen by the lecturer in order to be in line with the learning objectives of the subject. Each student had to solve the same five virtual patient cases. The students in the CG had to solve five paper-based clinical cases, which were the same as the virtual ones but presented in written form. The cases were a 65-year-old woman with insomnia, a 24-year-old woman with headache, a 42-year-old man with pain in the right upper abdomen, a 55-year-old man with fatigue, and a 30-year-old woman with palpitations. The virtual patient case comprised 15-30 pages in which students assume the role of a virtual student working with a preceptor. The students move through the stages of a patient's presentation, engaged in continuous practice of their clinical reasoning skills, from eliciting the main complaint to taking a history, performing a physical exam, composing an assessment, formulating a differential diagnosis, and on to diagnostic testing and management. The methods applied consist of reading additional material (articles, textbook chapters), photographic images of patients during a physical exam, video clips of topics associated with the case, and so on. The paper-based clinical case consisted of patient history, results from a clinical examination, and investigations. No additional material was provided. Data was collected by paper forms consisting of demographic data (gender and age of the students), a learning strategies scale, a learning habits scale, and a knowledge of family medicine scale. We collected data in two phases: (1) before the beginning of the experiment (in October 2014) we obtained data on the students' initial knowledge of family medicine, learning strategies, and learning habits and (2) at the end of the experiment, after four months of teaching (in February 2015), we checked the students' final knowledge of family medicine. Both tests included 50 multiple choice questions (MCQs) on factual knowledge of family medicine, and the same MCQs were used for the initial and the final knowledge tests. The maximum number of points in each test was 50. The MCQ questions were based on the learning outcomes of the family medicine subject in the 4th study year and were taken from the textbook of family medicine used in the curriculum as the obligatory learning source. This scale is composed of 20 statements covering four sets of learning strategies: strategies of conditions management (e.g., real-time learning, time distribution); strategies of processing learning material (e.g., repetition of old material, independent renewal, and linking courses); metacognitive strategies (e.g., self-questioning); and strategies of controlling emotional motivation states (e.g., concentration in learning). The statements can be rated on a 3-point scale: 1:disagree, 2:partly agree, and 3:agree. The scale's total score is 60 points; a higher total result indicates a better mastery of the internal and external factors of learning and a better processing of learning material and hence a higher quality (durability, usability) of knowledge. This scale is composed of 20 statements which assess internal learning motivation positively and negatively (e.g., self-initiative learning; learning beyond others' demands; striving for knowledge rather than marks). The statements can be rated on a 3-point scale: 1:disagree, 2:partly agree, and 3:agree. The scale's total score is 60 points; a higher total outcome in the scale denotes a higher level of internal learning motivation. Both scales are established tools for the measurement of learning motivation and strategies and have been proven to be valid and reliable. Both scales have been adapted for the Slovenian language and have proved to be reliable. Data was processed at the level of descriptive and inferential statistics. The following methods were applied: descriptive statistics for sample description; independent samples t-test and paired samples t-test for analyses of differences between groups; analysis of covariance (ANCOVA) for homogeneity; and effect size measures (eta2, R2) for determining the size of the study effect. The reliability of the scales was assessed by Cronbach's alpha. A P value of <0.05 was considered as statistically significant.

PMC6423671_01

Male

A 14-year-old boy was in his usual state of good health until October 2015, when he developed psychiatric symptoms including feeling overwhelmed, confused, depressed, and agitated. He said that he was an "evil, damned son of the devil" and wanted to kill himself because he was afraid of his new-onset homicidal thoughts toward those he cared about. In October 2015, he was admitted for emergency psychiatric hospitalization at a local hospital and was placed on aripiprazole for major depressive disorder (MDD) with psychotic features. He was discharged after 1 week, still somewhat psychotic but no longer suicidal or homicidal. His early history was unremarkable except for an episode of depression in the 3rd grade (9 years of age) that the parents attributed to his feeling unchallenged in school and being bullied by peers, as he was very bright, but socially awkward. Placement on sertraline 25 mg for 1 year plus transfer to a small school for gifted children resulted in complete remission. The evaluating psychiatrist noted the possibility of Asperger's syndrome as a secondary diagnosis. In April 2014, he was treated with antibiotics for Mycoplasma pneumoniae with a recurrence and retreatment in December 2014. In June 2015, he was treated with topical steroids for poison ivy and an oral cephalosporin for multiple bug bites, obtained while visiting a farm in Missouri. The family history was positive for depression and alcohol abuse on both sides of the family tree, possible bipolar disorder, compulsive gambling, and possible attention deficit hyperactivity disorder (ADHD): maternal side:ulcerative colitis, fibromyalgia in 2 relatives, and rheumatoid arthritis; paternal side:multiple sclerosis and adult-onset diabetes mellitus. Historically, prior to psychiatric symptom onset, the boy was socially, athletically, and academically active, as evidenced by participation in national geography and history competitions, and a lead actor in a school play, winning an award in fencing and achieving excellent course grades. In the context of animal and arthropod exposures, the family resided in a Midwestern state, in suburban housing, and had multiple pets: cats, a dog, a spotted gecko, and a giant African millipede. Two cats were adopted as strays in 2010, 1 of which had an open wound over his back requiring treatment. A visiting dog infested with fleas entered the household in 2011. The boy had sustained cat bites and scratches prior to illness onset. Outdoor activities consisted of gardening and hiking. In addition to fleas and ticks, his parents reported exposure to mosquitoes and spiders. He had traveled in northeastern, southeastern, and western states. International travel was limited to 2 trips to Mexico in June 2013 (family vacation) and July 2015 (mission trip to impoverished areas). Weeks after initial hospitalization in October, he became more dysfunctional; school was not possible; he developed progressively severe psychiatric symptoms including obsessional intrusive thoughts, phobias, irrational fears, emotional lability, unpredictable rage outbursts, and increased psychotic thinking. He believed that he had special powers and that a family cat wanted to kill him. By December 2015, his illness had progressed in severity, causing his mother to quit her job to provide full-time supervision. In addition to persecutory delusions related to his pets, he developed auditory, visual, and tactile hallucinations and began refusing to leave the house. A second psychiatric hospitalization occurred in December 2015. In January 2016, following discharge after a week-long hospitalization, he developed non-specific somatic symptoms, including excessive fatigue, daily headaches, chest pains, shortness of breath (possible panic anxiety), and urinary frequency. Figure 1 depicts a timeline including major medical interventions, physician consultations, and hospitalizations, during which he was treated with multiple different psychotropic medications including antipsychotics, mood stabilizers, antidepressants, and benzodiazepines, often in combination with other pharmacologic agents (Figure 2). Two local psychiatrists diagnosed schizophrenia. In the summer of 2016, he was hospitalized for 11 weeks at a large out-of-state psychiatric teaching hospital where extensive testing, including inflammation markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), a Mayo Clinic Encephalopathy Autoimmune Evaluation Panel, voltage-gated potassium channel antibody testing, an electroencephalogram (EEG), and a brain magnetic resonance imaging (MRI) were performed, all of which were considered unremarkable. Provisional discharge diagnoses were schizophrenia and obsessive-compulsive disorder. After returning home in August 2016, the parents noted cutaneous "stretch marks." Although he remained quite ill, his parents refused psychiatric re-hospitalization in favor of in-home treatment. In October 2016, a consulting neurologist proposed the diagnosis of autoimmune encephalitis based on a positive antinuclear antibody (ANA) titer (1:320), increasing CRP levels = 1.03 (Nl < 0.30 mg/dL) on August 31 and 1.96 on October 11, as well as increased CSF gamma interferon level = 6.0 (Nl < 4 pg/mL). His CSF neopterin value was 2.0 nmol/L (NI < 16.5 nmol/L). An outpatient lumbar puncture was otherwise unrevealing. He was treated with rituximab infusion for autoimmune encephalitis, which decreased the duration and frequency of psychotic episodes; however, daily behavioral disruptions continued. In January 2017, PANS was diagnosed based on historical symptoms (Table 1). Testing for Group A streptococcal infection, including antistreptolysin O titer, anti-DNase B titer, and other infections including M pneumoniae Immunoglobulin class G (IgG) and Immunoglobulin class M (IgM) antibodies, a Lyme enzyme-linked immunosorbent assay (ELISA) and Western blot IgG and IgM and viral titers were negative or equivocal. ANAs were not detected. When the evaluating physician observed the cutaneous "stretch mark-like" lesions on the boy's thighs and armpit (Figure 3), neurobartonellosis was proposed as a differential diagnostic consideration. Subsequent consultation with a dermatologist confirmed that cutaneous lesions were not oriented along the skin tension lines and the location and color were not consistent with striae and fluctuations in body weight. Histological examination of a 3-mm punch biopsy revealed sparse lymphohistiocytic dermal infiltration. Doxycycline monohydrate (100 mg BID) was administered. Preantibiotic Bartonella spp. diagnostic testing was not pursued. In February, the parents requested that their son be entered into a research study approved by North Carolina State University's Institutional Review Board (Protocol No. 1960, Detection of Bartonella Species in the Blood of Healthy and Sick People).

bacteria, bartonella, psychosis, schizophrenia, stretch marks, transmission

PMC3369392_01

Male

A 47-year-old Sri Lankan male presented in October 2006 with a 3-month history of bilateral red watery eyes with a foreign body sensation. He had RA, which was quiescent at presentation for which he was taking oral diclofenac, prednisolone (PDN), and methotrexate (MTX) with calcium and folic acid supplements. On examination, his best corrected visual acuity (BCVA) was 6/19 right eye (OD) and 6/9 left eye (OS). There was an inferonasal peripheral crescent-shaped area of corneal thinning (80%) forming a gutter from 3 to 6 o'clock, 1.4 mm wide in the right eye, while in the left eye there was a smaller inferonasal gutter with 20% thinning. His PDN and MTX were increased and hourly topical carmellose sodium 0.5% added. Initial reduction of ocular discomfort prompted reduction of his systemic medication, but on review within 9 days BCVA OD was reduced to 6/38 and the right anterior chamber was shallow with a small corneal perforation noted in the corneal gutter. This was plugged with iris and not actively leaking. The perforation was repaired with corneal cyanoacrylate glue and a bandage contact lens (BCL) was placed for comfort and exchanged at 6 weekly intervals thereafter. Slow tapering of his systemic medication was attempted again. On review 4 months later in February 2007, a small leak from the previous perforation was noted. After further cyanoacetate glue repair, he underwent multilayered amniotic membrane graft (AMG) to the right eye in March 2007. Initially his postoperative course was satisfactory but attendance at follow-up appointments was poor. In June 2009, he attended with marked discomfort and redness of both eyes and BCVA of 6/15 OD and 6/7 OS. He was systemically well with no signs of active RA. He was found to have marked bilateral inferior corneal stromal thinning with perforations in the inferotemporal mid-periphery and a small iris prolapse plugging the hole in both eyes (Figure 1). Bilateral emergency tectonic penetrating keratoplasties (PKP) were performed, decentered infero-nasally in order to replace the thinned cornea (Figure 2). Lamellar grafts were initially attempted but was converted to a PKP as a satisfactory lamellar plane was impossible to create due to a soft eye from the perforations. His systemic medications were again increased. One week postoperatively, BCVA was 6/38 OD and 6/19 OS but one month later he presented with recurrent, bilateral paracentral corneal melts. Glue repair was again performed and topical cyclosporine 0.5% twice daily was added to both eyes. He subsequently underwent a further triple-layered AMG and second PKP to both eyes in September 2009. Infliximab (5 mg/kg intravenously) was commenced on the first postoperative day and he continued to receive cycles at the same dose at weeks 2 and 6 and then every 8 weeks, while PDN and MTX were gradually reduced. Since he was from an area of high prevalence of tuberculosis, prophylactic isoniazid was commenced. He underwent uncomplicated phacoemulsification with posterior chamber intraocular implantation in both eyes in June 2010. Eighteen months following infliximab therapy both eyes remained quiet with no signs of further corneal melting. The BCVA was 6/48 in both eyes, limited by subepithelial haze and thinning of his corneal grafts (Figure 3).

PMC8120316_01

Female

We provide an interactional analysis of a therapy session with a young child. Ina (pseudonym) is a 4-year-old girl. After giving birth to her, her mother left her in the care of a hospital. Ina was placed with a foster care family for half a year and then was adopted. She is brought to treatment because of frequent outbreaks of rage against other children and her adoptive parents. The clinical hypotheses for her are that she has a deep desire for her mother's love and in the same moment a strong hatred toward her for having left her alone. This is a strong emotional burden and a cognitive conundrum she cannot solve. A further clinical hypothesis is: parents in adoptive families often wish to be accepted as "genuine parents," addressed as "mom" and "dad." After some time, adoptive children often realize what a powerful position in family life they can achieve by not fulfilling their parent's wishes (Feder,; Nickman,; Haimes,):a generalized example of "doing contrariness." Ina's situation, as a child having suffered from traumatic losses in early years requires a different therapeutic approach than the one documented in Hutchby. The session has been recorded on video and audio. The parents have given their permission to use the material for publications. How are the conventions of conversation adapted to the purpose of therapeutic talk between therapist and child? Do they use playing scenarios to negotiate and solve conflicts arising from the traumatic history of the child, and if so, how? How is their conversation affected by whether they have aligning and non-aligning interactional goals? We focus on one interactional practice (doing contrariness) and strategies to address it (remedying/avoiding doing contrariness) which we identify in various multimodal guises and show which role they play in answering these questions as well as for the therapeutic process of treating a child with traumatic experiences. We hope to contribute to a better understanding of therapeutic interactions, which has potential benefits also for therapy: applied analyses such as the one we are presenting can have a kind of supervisory function for therapeutic talk and for institutional conditions (Karim,). CA research has also contributed to a better understanding of the details of children's talk about traumatic experience (Bateman et al.,). Although we are oriented toward CA in our analytical approach, we also make use of the toolbox of broader linguistic analysis as well as insights from psychotherapeutic research and clinical experience. There are two main issues that are particularly important for our analysis of the interactional processes in child therapy and of how they influence therapy outcome, in our view. They concern the length of conversational stretches that are usually considered in analysis and the question of how to deal with less conventionalized language (here, of and toward young children). Regarding the first issue, in CA, analyses are often conducted on sequences of only a few turns in length; this has produced the very influential concept of the adjacency pair (Schegloff and Sacks,). Certain adjacency pairs in specialized contexts have not only produced highly conventionalized linguistic forms, such as greeting-greetings, but also various kinds of offers, requests, invitations, and their respective responses. There is a preference bias for the production of positive responses over negative ones, and in perception, negative responses are also dispreferred in that they cause a higher cognitive load (Bogels et al.,; Kendrick and Torreira,), leading to conventionalization also in the type of response, not only its form. Sometimes, analytical attention in CA can seem to focus on short sequences and strict sequentiality. However, this is not so on principle: Sidnell discusses several types of evidence in CA that are not restricted in this way, and Schegloff substantially extends the notion of adjacency pair beyond immediate sequentiality via expansion. Recent pragmatic models also show the relevance of meaning dependencies across longer stretches of discourse in everyday conversation (Farkas and Bruce,; Ginzburg,; Roberts,; Goodwin,). Together, these approaches allow to take effects into consideration that arise from the interaction of the content and illocutionary force of the current turn with (the retrospective interpretation on behalf of the participants of) conversational acts having taken place many more turns before. This is particularly important for understanding conversation in a psychotherapeutic setting, where long-distance effects and their negotiation between therapist and patient are part and parcel of the interaction (Buchholz and Kachele,). One of the aims of CA has been to contribute to an understanding of how meaning is "achieved" in interaction (Garfinkel,; Heritage,). The understanding of meaning underlying this idea is that it ...lies not with the speaker nor the addressee nor the utterance alone as many philosophical arguments have considered, but rather with the interactional past, current, and projected next moment. The meaning of an entire utterance is a complex, not well-understood, algorithm of these emergent, non-linear, sense-making interactions (Schegloff et al.,, p. 40). Since we here are also interested in this interactional aspect of meaning as something that arises out of the pragmatic negotiation between therapist and patient, we also adopt a methodological stance that considers more than the immediate context of a turn in order to make this meaning visible. Focusing on a single session and proceeding chronologically over a relatively long part of it (roughly 20 min), our analysis shows how certain topics occurring at the beginning resurface at a later stage and are then negotiated again in the light of the progressing discourse. Themes from the previous day's session are also continued. The second issue concerns unconventional language. In close adherence to ethnomethodology (Garfinkel,), the action a turn performs can be interpreted in CA partially via the immediately ensuing response of the interlocutor, relatively independent of the formal linguistic content of the turn. That does not mean that the formal content is of no interest to CA analyses. As an example, if an interlocutor begins a conversation by saying, "I hate having to see your face again every morning," and this is met by a response along the lines of "Yeah, good to see you too, Bob," then by the principles of CA, the facts that these are the initial turns of a conversation and that the first turn is treated by the interlocutors as if it were a greeting, will make sure that such a sequence is correctly analyzed as a greeting-greeting pair, even though the first turn is a highly unconventional member of such a pair. Here, we are also interested in this unconventionality, and what effects it might have. While such an exchange might actually conform to the specialized greeting conventions established between a specific pair of coworkers, treating it as just any greeting-greeting would miss crucial aspects of the social actions performed by it, especially if it occurred in a therapeutic context. Heritage has pointed out the risks of concentrating on conventional language in the context of medical interactions1. This is at least as appropriate in the case of psychotherapy. Although psychotherapeutic theory has developed just as much specialized jargon as any profession, in the conversation between patient and therapist, there is no predefined set of conventionalized terms one has to learn in order to participate successfully. Pawelczyk talks of "personalized meanings." For each therapy, patient and therapist invent and locally conventionalize a set of terms and routines together. For the successful analysis of psychotherapeutic interaction, it is necessary to allow for the treatment of (in a global sense) unconventional linguistic and interactional behavior, including not only neologisms, creative imagery, and metaphors but also the omission or delay of expected responses and other forms of non-cooperative communication, as meaningful in its unconventionality. All of these forms of communicative behavior are means to expressing thought processes, intentions, and emotions which the interlocutors are not used to putting into words and for whose expression perhaps no conventionalized means exist, and which the goal of the therapy it is to negotiate and resolve in the personal interaction between therapist and patient. In child therapy, these challenges and difficulties are exacerbated many times. An individualized way of interaction has to be established between the interlocutors, only by means of which conversational meaning can be created. In the conversation we analyze, therapist and patient often ostensibly talk about some object in their surroundings, while at the same time they negotiate a personal issue of the patient in a therapeutically relevant way. In order to show that this is the case, we make use not only of CA methods but also of a broader range of pragmatic analysis as well as insights from clinical experience. However, our analysis is empirically anchored to the observables of the interaction. Psychotherapy talk-in-interaction is accessible to empirical methods beyond introspection. We provide an interaction analysis of segments from the transcript of the first 20 min of a video-taped child therapy single session conducted in the private practice of the third author2. We present English translations of the German GAT-2 transcripts (Selting et al.,) including descriptions of the bodily behavior of both participants, additionally illustrated by pictures. The entire interaction was divided into segments that constitute therapeutically relevant episodes. We proceed chronologically through the segments, however omitting some of them for reasons of space. Those that are included were selected for showing how some therapeutically relevant development is related to instances of doing or resolving contrariness. For speech acoustic analyses of the same session, see Dreyer. Other analyses with the same material (a qualitative multimethod project) have been published (Brandstetter,; Dreyer,; Hamburger and Bleimling,; Heller,) as part of a collaborative effort from our Berlin-based research network to throw a light on the complexity and variety of information contained in such material by illuminating it from the angles of various disciplines and approaches. In the first segment, directly from the beginning of the session, we witness how Ina uses conversational non-participation to do contrariness, with the effect of excluding her adopted father from the conversation. The session starts when Ina, just brought in by her adoptive father, puts her head around the door frame to look into the play therapy room: The therapist offers several greetings to Ina (1-5), who does not respond with a greeting of her own. This constitutes an act of refusing to submit to what Goffman termed "mutual monitoring": "Persons must sense that they are close enough to be perceived in whatever they are doing, including their experiencing of others, and close enough to be perceived in this sensing of being perceived." (Goffman,, p. 17) That is just what the therapist attempts to initiate with Ina, after she has been brought in by her adoptive father. People take note of each other in greeting and give a conventionalized signal that they acknowledge the interaction as such. In adult life, greeting response is considered conditionally relevant (Sacks and Schegloff,). A refused greeting can be experienced as a violation of expectations by the greeter and this can potentially be exploited by the non-greeter. A non-greeter does more than just refuse greeting: s/he denies "mutual monitoring" by purposefully violating expectations. Such an omission has been termed a "noticeable absence" by Sacks and Jefferson. Omitting the greeting can here also be considered an instance of "doing contrariness." Silently Ina takes off her coat (during a long pause, line 6). The therapist initiates the expectable process of saying good-bye to the father as a next step by articulating an expectation: "and NOW?" (line 10). After a pause the father responds with a second position utterance, his slightly extended "Yes" (12). This sequence seems to have no content. However, the situational context indicates that it is time to say good-bye to the father, so that Ina's session can begin. Both adults seem to expect Ina to initiate or at least to contribute to this procedure, none of which she does. Her continued conversational inactivity has strong effects on the "participation framework" (Goodwin,) of the two adults: the therapist now assumes Ina's role and starts the farewell sequence (line 13), indicated by adding "papa" after her "BYE." The therapist seems to "jump in" (Corrin,): she must have deemed a contribution by Ina to be so necessary that not only did she take it upon herself to provide it, but she also performed it as if she were Ina herself. Ina's "doing contrariness" by non-participation in the practice of saying goodbye amounts to refusing to acknowledge the father's presence at all. The father tries four times, with pauses in between, to get Ina to say goodbye (14-20):but no response from Ina can be elicited although he uses a variety of prosodic contours and lexical expressions to say goodbye. His expectation to be responded to is not fulfilled, and yet he simply tries again and again, instead of explicitly addressing Ina's failure to conform to interactional expectations:we could call this "doing vulnerability," as counterpart to Ina's "doing contrariness." Both adults interpret Ina's "doing contrariness" as repairable via a silent but powerful communicative agreement to further ignore Ina's behavior. The therapist attempts to mitigate the affiliative damage caused by Ina's behavior by acting as a version of Ina that does comply with the adults' expectation. Their agreement is sealed by the father accepting to be vicariously addressed as "Papa" by the therapist:a rather unusual communication among adults. Father and therapist seem to agree to treat the therapists' response in Ina's stead as if it were sufficient "absence of evidence of misunderstanding" (Albert and Ruiter,, p. 281) to be able to treat the entire episode as constituting successful communication. A new participation framework between Ina and the therapist is eventually established by Ina's first remark, "how good," after the father leaves. That she speaks for the first time only once he leaves, and gives a positive evaluation directly upon his departure indicates that her "doing contrariness" was directed against the father. She is willing to participate but only once he is gone. We have seen in this first segment how "doing contrariness" (DC) is characterized by behavior that violates conversational expectations and uses this violation to affect the affiliation and emotional ties between participants. Fundamentally, DC makes a contrastive distinction, valuing one side as positive, the other as negative. In this first segment, it is the adoptive father as participant in the interaction who is valued negatively by Ina's refusal to participate until he is gone. Both the act(s) by which DC can be performed and its effects are highly contingent upon the existing affiliative network between the participants and the roles they take on in the conversation: if it had been the therapist who had performed a silent non-participation, this would certainly not have affected the father in the same way. Attempts at repairing DC (which we call "remedying contrariness") must be equally sensitive to the participants' network. The therapist's "jumping in" for Ina, and the father's going along with it, can be seen in this light. This is an action which only repairs the conversational dimension of the disruption Ina has produced in the sense that it at least allows the conversation to proceed in the direction projected by the father and the therapist. The therapist-as-Ina and the father use this role performance to eventually move on beyond Ina's non-participation, but by allowing his multiple attempts at saying goodbye to remain unreciprocated, the father shows that the affiliative damage is left unrepaired. However, under the circumstances, it might have been the least damaging course of action overall. Directly addressing Ina's non-participation and asking her to "correct" it would probably have caused further affiliative damage. Executing a correction implies that the preceding move is faulty or problematic in some aspect, and thus that the sequence is marked/unexpected from the perspective of a smooth discourse progression (Ginzburg et al.,; Lupkowski and Ginzburg,). Between adult speakers, and executed without face-saving actions, a correction would additionally violate conventional social expectations and thus threaten the affiliation between participants. It would be a claim to authority by the correcting speaker and reduce the other speaker's agency. It would thus also be what we call doing contrariness. The therapist (or the father) could have presented Ina's non-participation as such a disruption by attempting to "correct" it with a direct request toward her to participate. This might have "repaired" the conversation by forcing her to contribute, but given Ina's demonstrated contrariness, it would have likely been taken as a rebuke and, instead of repairing the affiliational disruption with Ina, would have instead exacerbated it. Foregoing the opportunity to assert their own deontic authority and power and to incurring some face loss themselves, the therapist and her father spare Ina the face-impairing and emotionally hurtful act of correction. ADC can therefore be distinguished from other repairs by targeting not only the communicative disruption but also the social-affiliative disruption caused by DC; it cannot be performed via an act of DC itself. The type of creative solution the therapist and father use to try to avoid the incurrence of further affiliation cost is often what is needed in psychotherapy in various modes and situations, and one of the reasons it can be so difficult. "Doing repair," especially self-repair, can help to maintain or improve social relationships (Schegloff,). After one party has violated the other's expectation, repair acknowledges a failure in performing a relevant contribution and accepts the obligation to an undisturbed common sociality. The crucial aspect here consists of acknowledging the other's expectations. In Schegloff's words: "This is the sense in which these repair positions provide a defense of intersubjectivity. They are the last structurally provided positions because after these positions there is no systematic provision for catching divergent understandings." (Schegloff,, p. 1325) Young children in medical consultations have often been observed to not respond to greetings (Cahill,). In our case, several attempts at repair do not succeed and leave the affiliation partly damaged. Our analysis of this DC performed through silence shows that the new framework between therapist and Ina has a "history" burdened with this failed repair. In the following segment, we will further explore the crucial dependence of DC on the role that a participant takes on in a conversation, in that we will see it creating a negative evaluation of part of one's self. The therapist's question (24), prefaced with a playful interjection of surprise and amazement, is accompanied by a deictic gesture; via her gaze, she points at Ina's jumper. Slightly disparagingly, Ina calls it a baby dress (German "Babykleid") (26). This is contrasted by her subsequent assertion of the "bigness" of the jumper (29). The therapist initiates the next sequence of questions, "how big?" (30 f.). She suggests a size via gesture (32) and Ina rejects the suggestion via a shaking of her head and a negative interjection (34). The following rhythmical copy of that interjection by the therapist uttered with question intonation (35) resonates at the affiliative level, while also conveying amazement and surprise. The epistemic question of how big the sweater is, repeated in abbreviated form, is replied to by Ina's embodied demonstration (36), responded to by the therapist's surprised response (37) again with a gestural demonstration of size. After a pause (38), suggesting the topic has closed, the therapist takes the topic up again: "And you fit in?" (40), explicitly establishing the link between the jumper's size and Ina's. Ina's strong embodied response (40) demonstrates her body control and strength, signaling that she is already big. Only then follows her spoken confirmation (41). Ina clearly shows a very different attitude to the attribute of "bigness" than to that of baby-like qualities from the beginning of the segment. Moving to a more therapeutic aspect of the analysis, Ina's disparaging voice when talking about the "baby dress" indicates a distance to the "baby-self" in favor of a more grown-up "child-self," which is as "big" as the jumper. Talking about the size of the jumper implicitly has a bearing on Ina's status as either baby or older child. The jumper is used for a comparative contrast between two available selves, a "big" one and a baby one. Ina clearly positions herself as being "big," and expresses a negative evaluation toward being "a baby." There are observable indications (disparaging prosody when discussing the "baby dress," augmentative repetition and emphatic prosody when discussing the "bigness," the explicit link made by the therapist between the sweater and Ina, agreed to by her) that the conversation is not only about the sweater, but also between two versions of Ina in play here. Ina distances herself from a version of herself that is "small." While children occasionally express wishes to be more grown up, in this specific case, we take this to be a clinically relevant observation, namely as an indication of a strong negative affect toward her own (past) self, probably related to her traumatic adoption experience. In this section, DC is mostly visible in the negative attitude Ina expresses toward her "baby-self." The contrariness that is being done, the hostile attitude Ina expresses toward herself and the repair efforts undertaken against it is best analyzed from a perspective which understands that Ina can act as either of these roles, the "baby-self" and a "child-self," that are in conflict with each other. We argue that this is an example for how therapeutic observations can work together with CA in an understanding of what happens in therapeutic conversation. An analysis of therapeutic conversation must be able to capture such aspects in order to establish a connection between interactional observation and clinical interpretation and outcome. We suggest that there exists a need in the analysis of child therapeutic conversation both for special attention to unconventional means of creating pragmatic meaning (talking about the sweater as a stand-in for talking about Ina) and for observing long-distance relationships within the discourse progression. Conversational events and actions diverging from expectations have high epistemic ("novelty") value because they have the potential to increase knowledge by adding unexpected (i.e., new) information. However, they bear the risk of causing affiliative disruptions, especially when concerning issues that the participants are emotionally invested in. For therapeutic practice, this means a delicate balancing task: therapists aim at exploring expectation discrepancies not as disappointments (= violating their own affiliative expectations in order to achieve a high epistemic value) but instead work to combine their high informativity with an effort at restoring the affiliative dimension at the same time. We have seen an attempt at such an other-oriented affiliative repair already when the therapist stood in for Ina saying goodbye to her father. In the following segment, we will see how such an repair attempt can also be self-oriented to prevent a previous action from becoming a disruption and damaging affiliation, literally seeking to avoid doing contrariness. Such a task includes transforming the therapist's own affiliative disappointments (and other affects) into something that is epistemically relevant. We will see how such an attempt can fail. Both move to play at the table. Ina indicates continuation of a play project from the past session (43). The therapist reformulates Ina's project (45), yet in a slightly different way. Ina declares that she wants to do "it" again with play dough (German "wir machen das wieder mit Knete"), but the therapist asks for confirmation about playing with the dough. It seems that for Ina, playdough is not the actual object of play, but a tool for another play activity. Her non-response to the therapist's clarification question is again a "noticeable absence," indicating a contrast between the two projects, or perhaps an objection to the therapist's question. Ina tries to assign play roles (48), but her deontic authority is limited; now, it is the therapist who does not respond. Another obstacle materializes: Ina cannot find the playing equipment where she expected it to be (49-52). Noisily, she searches for the play dough baby, without success. The therapist, after silently observing Ina's activities, starts an account (53), prefaced by "you know what, Ina?," responded to by an intense exchange of gazes. Then follows another preface after a self-repair:the turn construction is interrupted (54) by a reference to what Ina did (55) and a confirmation that the therapist understood what Ina was looking for, with a projected ending with a tag (56), to which Ina agrees by nodding. However, she crosses her arms, a gesture expressing a mood between expectation and defiance. By using several prefacing moves, the therapist attempts to avoid doing DC herself, because she probably suspects that her intention to inform Ina that the baby is "taken to safety" (58) is likely to become troublesome, since Ina is already signaling some discontent. However, she cannot fully avoid DC here. By opening the can, presenting the playdough baby with "there it is" (63) and "you see" (65), the contrariness is exacerbated: Ina is informed that she was searching in vain while the therapist knew where the baby is, that the therapist did not cooperate in her project. The affiliation framework is at risk, Ina's disappointment might transform into defiance. The therapist attempts to restore a "common ground" by presenting the play dough baby, efforts designed at balancing their epistemic positions by sharing knowledge with her that had been privileged before. The therapist clearly indicates that she appreciates the complexity of this interaction. She cannot entirely avoid doing contrariness directed at Ina, in the sense of taking an opposing position, because her actions of hiding the figure and only disclosing its location at her own discretion reveal that while Ina might make claims to authority, it is the therapist whose deontic (protecting the doll) and epistemic (determining and knowing its location) authority is actually superior. She tries to mitigate the force of this contrariness via special conversational means, by formulating cautiously, using tags like "right?," and by integrating Ina's perspective with phrases like "you mean...," "look" and "see." In this, she treats Ina as if Ina's and her own claims to authority (epistemic and deontic) were actually balanced, i.e., she affords Ina some authority as if she were an equal, e.g., another adult (Hagemann,; Jefferson,). Her hedges all gently ask for Ina's agreement to the goal that the baby figure should be protected, that in fact the therapist's project, while seemingly contrasted with Ina's, actually aligns with her interests too. In this way, she attempts to convey the epistemic content (the act of revealing the figure's location and her motives for hiding it) without incurring affiliative costs, and to point out ways of conversational negotiation that do not have to involve all the negative effects of "doing contrariness." Ina makes no indication of giving this agreement. We suggest that the therapist's effort at not doing contrariness has parallels in other aspects of human interaction. Hutchby describes how the child in his case uses "I don't know" sometimes as a game or a strategy. He adds: "However, at certain points in the child's talk we find evidence that, for him, answering with 'Don't know' is itself a way of producing serious talk. In other words, the child occasionally uses 'Don't know' in such a way as to display that he is not playing a game." (Hutchby,, p. 115)

adoptive children, children in treatment, conversation analysis, doing contrariness, psychotherapy, trauma

PMC6487351_01

Male

A 32 year-old male presented with a 6 day history of an intermittent fever with chills and non-productive cough. He was previously well and did not report any haemoptysis, night sweats, weight loss or chest pain. His past medical and surgical histories were unremarkable. There was no history of exposure to ill contacts, institutionalization or cigarette smoking. Of note, the patient was a Chinese immigrant who spoke minimal English. The patient's vital signs were stable on admission. Auscultation of his chest revealed decreased breath sounds in the right mid-to-lower zones, as well as diminished vocal fremitus in these regions. These regions were stony-dull to percussion, suggestive of an effusion. The remainder of his physical examination was unremarkable. Laboratory investigations revealed an elevated C-reactive protein (CRP) levels (220.2 mg/L) without a leukocytosis. Chest radiography demonstrated a large right pleural effusion. A chest tube was inserted (Fig. 1) under local anesthesia and drained 900mls of pleural fluid in the first 24 hours. Pleural fluid biochemical analysis revealed pleural fluid protein/serum protein ratio was 0.69 with a pleural fluid LDH of 3925 U/L, indicating an exudate. Sputum and pleural fluid cultures demonstrated no bacterial growth, but few pus cells and no malignant cells were identified. His tuberculin skin test was negative (0 mm, read at 72 hours). Sputum and pleural fluid smears were negative for acid-fast bacilli. He was also HIV-negative with no evidence of immunocompromise. The patient was treated empirically with broad spectrum antibiotics (Ceftazidime) for 5 days without improvement. A computed tomography (CT) scan of the chest (Fig. 2) revealed a right pleural effusion with pockets of air and associated right lower lobe compressive atelectasis, suggestive of an early empyema. In an effort to attain a definitive diagnosis and treat his empyema, a video-assisted thoracoscopy (VATs) procedure with pleural biopsy and drainage was performed. Multiple adhesions and fibrinous exudates were noted intra-operatively. Five pleural biopsies were taken at varying sites. Post-operatively, due to a high degree of clinical suspicion he was commenced on anti-tuberculosis therapy (ATT). An immediate clinical response was noted as his fevers subsided, and his CRP decreased to normal levels. He recovered uneventfully and was discharged after 48 hours, pending outpatient clinic follow-up. The pleural biopsy samples demonstrated active chronic granulomatous pleuritis with many Langerhans type giant cells highly suggestive of tuberculosis. The Ziehl-Neelsen stain for acid fast bacilli was negative. At our last outpatient visit, the patient had completed 6 months of ATT with complete disease resolution. He is clinically well and will continue follow-up in the Thoracic Medicine outpatient clinic.

Computed Tomography (CT) scan of the chest showing a right pleural effusion with air pockets and compressive right lower lobe atelectasis, suggestive of an early empyema.

PMC7254079_01

Female

Our patient was a 26-year-old female with history of end-stage renal disease secondary to systemic lupus erythematosus. She received her first kidney transplant from a living donor in 1994 and the second transplant from a deceased donor in 2003 due to primary loss of the first graft. She had no history of acute rejection episodes of her graft. Other significant past medical history included hypertension, migraines, and GERD. She presented at the transplant outpatient clinic for an urgent visit after she noticed continuous bilateral milky white discharge from her breast nipples for a couple of days prior to her presentation consistent with galactorrhea. The patient's kidney graft function had been stable until eighteen months prior to this visit with a glomerular filtration rate (GFR) of 40-50 mL/min/1.7m2 (by CKD-EPI equation) when it gradually started to drop to less than 15 mL/min/1.73m2. At the time of presentation, her renal function had further worsened to GFR 11 mL/min/1.73 m2 (chronic kidney disease stage 4-5). She reported that about a week earlier, she had visited the emergency department due to migraine headaches and at that time, she was given metoclopramide by mouth as needed for nausea and naratriptan in place of sumatriptan. She had also reported that about three months ago, due to worsening gastroesophageal reflux disease symptoms, omeprazole dose had been increased from 20 mg twice a day to 40 mg twice a day. Other oral medications included tacrolimus (levels ranging from of 4 to 6 ng/mL) and prednisone 5 mg for immunosuppression, amlodipine 10 mg once daily and labetalol 100 mg every 8 hours for hypertension, lovastatin 20 mg daily for hypercholesterolemia, nortriptyline 10 mg at bedtime for anxiety, and pyridoxine 50 mg once a day. Other than the recent omeprazole dose change, no other changes were reported for any of the medications above. At that time, we attributed galactorrhea to metoclopramide as the most probable causative agent and stopped it since to our knowledge and based on the literature, none of the other long-term medications have been linked to an effect on prolactin secretion. However, four weeks later, the symptoms persisted. Further investigation was initiated to look for other possible causes. She had been on nortriptyline for years without any issues so that was ruled out as the cause. A urine pregnancy test was negative. Thyroid function tests were normal, with a thyroid-stimulating hormone of 1.69 muIU/mL (0.55-4.78 muIU/mL). She had no history of liver disease or alcohol misuse. Laboratory investigation showed that she had normal liver function tests with alanine aminotransferase 20 U/L (normal range: <53 U/L), aspartate aminotransferase 18 U/L (normal range: 15-46 U/L), total bilirubin 0.6 mg/dL (normal range: <1.4 mg/dL), total alkaline phosphatase 94 U/L (normal range: 38-126 U/L), serum albumin 3.9 g/dL (normal range: 3.4-4.9 g/dL, total protein 6.8 g/dL (normal range: 6.5-8.3 g/dL), platelet count of 395000, and prothrombin time of 12.4 (INR 1.1). Furthermore, abdominal ultrasound few months earlier did not show abnormal liver. Magnetic resonance imaging (MRI) of the brain ruled out any pituitary lesions or other pathology. However, fasting serum prolactin level was elevated for a nonpregnant woman at 140 ng/mL (normal range: 2.8-29.2 ng/mL). At that point, based on few previous case reports suggesting a possible link between PPIs and hyperprolactinemia, we stopped omeprazole 40 mg twice daily and the patient was given calcium carbonate as needed for heartburn as an alternative treatment. Two weeks after stopping omeprazole, fasting serum prolactin level returned to normal (18.8 ng/mL) accompanied by resolution of galactorrhea. She remained heartburn-free for about 2 months. Unfortunately, her kidney graft function deteriorated further and she started in-center hemodialysis. Due to worsening heartburn, it was decided to restart omeprazole but this time, at a lower dose 20 mg once a day. Two months later, her fasting serum prolactin level had remained normal at 9.5 ng/mL and without galactorrhea.

PMC2964912_01

Female

A 20-year-old woman presented with a five-week history of otalgia, ear discharge, and deafness. There were no additional systemic symptoms or signs. Audiometry showed bilateral conductive hearing loss. She initially received antibiotics; however due to severe otalgia, she had bilateral myringotomies with grommet insertion without improvement. CT and MRI revealed fluid in the middle ear clefts and mastoid cells bilaterally. Blood tests showed a C-reactive protein (CRP) of 50 mg/l, normal full blood count, renal and liver function tests, and a negative ANCA. Urinalysis was negative. Oral prednisolone 60 mg daily resulted in some symptomatic improvement. Seven weeks later, she developed a left lower motor facial nerve palsy and reduced sensation in the middle third of her face. Repeat MRI showed bilateral middle ear inflammation but no additional intracranial abnormalities. Further oral steroids again improved her symptoms. Nasal and middle ear biopsies revealed evidence of a necrotising inflammatory process, but no features of infection. Further oral prednisolone improved the clinical symptoms with some subjective improvement in the facial weakness and general well-being, and reduction in CRP. Reducing steroids to 20 mg resulted in deterioration of symptoms, with increasing facial and ear pain plus a rise in CRP. With this further deterioration despite corticosteroids, a decision was taken to escalate therapy and she received cyclophosphamide with methylprednisolone plus cotrimoxazole, with slow improvement noted in her left ear hearing, clinical symptoms, and CRP. After three pulses, a CT scan of her lungs was requested to investigate a persistent cough. Despite normal repeat chest radiographs, cavitating lung lesions consistent with a diagnosis of WG were demonstrated. Other possible differential diagnoses including infections such as tuberculosis or Staphylococcus aureus abscesses were considered less likely due to the clinical and biochemical improvement with immunosupppression. She also developed a saddle nose deformity at this time. Relapsing polychondritis was thought to be unlikely given the pulmonary manifestations and the absence of external ear cartilage involvement. Histology had not shown atypical lymphocytes or histiocytes and so was not suggestive of midline granulomatosis. Following six pulses of cyclophosphamide, she developed stridor, and a flow volume loop was in keeping with a subglottic tracheal stenosis. She required multiple tracheal dilatations plus local steroid injections which brought temporary relief for approximately six to eight weeks at a time. After a further three pulses of cyclophosphamide, she remained well with no symptoms of active disease and a normal CRP. However, seven weeks after finishing cyclophosphamide, she developed pain over the right mastoid and maxillary sinus, shortness of breath, recurrent tracheal stenosis, increasing saddle nose deformity, and a rise in CRP to 26 mg/l. Despite her ANCA negativity, we felt that rituximab was a reasonable therapeutic option. She received two 1 g doses of rituximab a fortnight apart, leading to a marked improvement in mastoid, ear and nose pain, and a fall in CRP within two months to normal levels. She was subsequently commenced on mycophenolate although was not initially able to take this regularly due to side effects. A reduction in oral steroid dose was possible. She has been retreated empirically with rituximab on two occasions with an average of seven months between infusions. She has since felt well enough to return to her university studies. Disease remission has been maintained as demonstrated by a suppression of CRP, which has largely remained below 5 mg/l on subsequent testing.

PMC5849790_01

Male

A 68 year old Caucasian male initially presented to outpatient infectious disease clinic with a chief complaint of intermittent fever for 3-4 weeks. The fever was associated with chills, night sweats, nausea, headaches, and a fifteen pound unintentional weight loss. His past medical history was significant for recurrent small bowel obstruction with multiple previous abdominal surgeries, chronic watery diarrhea, factor V Leiden deficiency, recurrent urinary tract infections, MRSA infection, and type II diabetes. Patient had a trans-psoas Hickman catheter initially placed about 3 years ago for total parenteral nutrition (TPN) and hydration purposes. The catheter was replaced about 2 months ago prior to presentation due to malfunctioning and retraction issues. Vital signs included blood pressure: 98/50 mm-hg, pulse 70 beats per minute, respiratory rate of 18 per minute and temperature of 98 F. There was no focus of infection on physical examination, including the port site. He denied recent travel outside Illinois, had a pet cat at home, and used tap water for drinking. His white cell count was within normal limits, and ESR was elevated 55 (normal limit: 0-15 mm/h). Work up including blood cultures, Quantiferon gold test, sputum for acid fast bacilli (AFB), and a trans-esophageal echocardiography (TEE) was ordered. Two sets of blood cultures 2 weeks apart were positive for Mycobacterium neoaurum. Work up for histoplasmosis, and human immunodeficiency virus (HIV) was unremarkable. Tagged white blood cell (WBC) scan showed increased uptake in bilateral lungs consistent with pneumonitis. Computed tomography (CT) chest was ordered due to new onset cough which showed numerous bilateral small non calcified centrilobular nodules within upper and lower lobes, consistent with pneumonitis (Fig. 1). Interferon-Gamma Release Assay (IGRA) for TB (QuantiFERON -TB Gold In-Tube test, Qiagen, NV, Venlo, Netherlands) was also positive. Transesophageal echocardiogram (TEE) showed no vegetation or abnormalities. The Hickman catheter was removed, and catheter tip was sent for AFB cultures. A temporary right femoral central venous catheter was placed. The patient was started on intravenous (IV) cefoxitin 2 g 4 times daily, IV ciprofloxacin 500 mg twice daily, and oral doxycycline 100 mg twice daily. Blood cultures drawn after the initiation of anti-microbial drugs yielded no growth. Catheter tip culture showed growth of acid fast bacilli after 8 days. Culture susceptibilities showed the mycobacterium being susceptible to cefoxitin (MIC: 8 mcg/mL), imipenem (MIC < = 2 mcg/mL), ciprofloxacin (MIC: 0.25 mcg/mL), moxifloxacin (MIC < = 0.25 mcg/mL), amikacin (MIC< = 1 mcg/mL), doxycycline (MIC: 1 mcg/mL), trimethoprim-sulfamethoxazole (MIC: 0.5-9.5 mcg/mL), linezolid (MIC: 4 mcg/mL) and resistant to clarithromycin (MIC > 16 mcg/mL) and tobramycin (MIC: 16 mcg/mL). The Hickman catheter was replaced a week after negative blood cultures. This 3-drug combination therapy was continued for 6 weeks and patient was transitioned to oral ciprofloxacin and doxycycline with plans for another 6 weeks of treatment. Treatment was stopped three weeks after transition (9 weeks total) as patient developed a diffuse macular erythematous rash on face and arms. CT chest obtained at the time of completion of treatment showed resolution of pulmonary nodules (Fig. 2). The patient was afebrile without further respiratory symptoms, fevers or chills at 6 months' follow up.

CT scan showing pulmonary nodules before treatment.

PMC6260530_01

Female

A 48-year-old woman presented with a rapid enlargement of a preexisting goiter without compressive symptoms. Her past medical history included type 2 diabetes mellitus, hypertension, goiter, and primary hypothyroidism for fifteen years. There was no past or present history of smoking and her family history was unremarkable. She was complaining of productive cough for two weeks. However, she did not have any history of fever, night sweats, or anorexia. Clinical examination showed a normal body temperature, a body mass index of 35.88 kg/m2, a blood pressure of 120/80 mmHg, a regular pulse of 89 beats/min, and a normal respiration rate of 20 breaths/min. The lung breath sounds were normal without any rales being heard. Cervical examination revealed a plunging multinodular goiter without any lymphadenopathy. Other systemic and regional examinations did not show any abnormalities. The blood routine tests showed a fasting blood glucose of 7.19 mmol/l, a plasma creatinine level of 49 mumol/l, a C-reactive protein level of 5 mg/l (reference range < 5 mg/l), an erythrocyte sedimentation rate of 57 mm/first hour, a red blood cells count of 4.38 * 106/mm3, a total hemoglobin concentration of 12.8 g/dl, a white blood cells count of 6800/mm3, a neutrophil count of 3640/mm3, and a lymphocyte count of 2220/mm3. Liver function tests were normal. The thyroid function tests disclosed normal serum thyroid stimulating hormone (TSH) level at 0.5 muIU/ml (reference range: 0.35-4.94) and normal free thyroxin (FT4) level at 9.14 pmol/L (reference range: 8.5-25) on daily 100 mug of levothyroxine. Thyroid ultrasound showed a heterogeneous multinodular goiter. Her chest X-ray showed a mediastinal enlargement and a suspicious lesion located at the upper lobe of the right lung. Cervical and chest computed tomography scan revealed an enlarged plunging multinodular thyroid gland (right lobe: 113 x 39 x 41 mm, left lobe: 90 x 53 x 44 mm) with an extension of the right lobe into Barety's space (Figure 1) and multiple bilateral lung nodules. Sputum smear microscopy was negative. Thyroid cancer was suspected. Fine needle aspiration (FNA) cytology was not available for technical reasons. Surgical treatment was indicated and the patient underwent a total thyroidectomy. Multiple lung biopsies were also performed using a left anterior minithoracotomy through the fifth intercostal space. Histopathological examination showed a benign multinodular hyperplasia with epithelioid cell granulomas and giant cells (Figure 2). These morphological signs were compatible with multiple tuberculous foci of the thyroid gland. The histopathological examination of the lung biopsies showed foci of granulomatous inflammation along with caseous necrosis (Figure 3). The diagnosis of tuberculosis involving both the lung and the thyroid gland was established and the patient was treated with antituberculosis drugs for 6 months.

PMC3916803_01

Female

A 78-year-old Japanese-Mongoloid woman (body weight: 48kg) with a 3-year history of hypertension and hyperlipidemia visited our hospital because of a persisting fever and generalized joint pains which had developed 2 weeks before initial presentation. She had been treated as having a common cold at a local clinic for 2 weeks previously, but her symptoms had not improved. After visiting our hospital, a drip infusion therapy of cefpirome with oral administration of loxoprofen was initiated on an out-patient basis. However, this treatment was not effective for the fever but caused toxic eruptions on the back of both her hands. Thus, this treatment was suspended 3 days later. She was admitted 4 days after initial presentation. Neither respiratory nor ocular symptoms were present. She had past history of panhysterectomy due to uterine cancer at the age of 38 and a fracture of her left wrist joint at the age of 68. She had no environmental or occupational history of beryllium or other metal exposure. A physical examination on admission showed bilateral inguinal and axillary lymph node swelling and erythematous eruptions on the back of both her hands. A chest X-ray showed minimal bilateral hilar lymphadenopathy (BHL); however, a chest computed tomography (CT) scan clearly revealed mild BHL without pulmonary infiltrates (Figure 1). Since respiratory function tests were normal, bronchoscopy was not performed. Electrocardiogram and ophthalmologic evaluations were normal. A complete blood cell count showed slight anemia (red blood cell count, 3.70x1012/L; hemoglobin, 10.8g/dL), slight leukocytosis (white blood cell count, 11.9x109/L with 74% neutrophils, 13% lymphocytes, 11% monocytes, 1% eosinophils, and 1% basophils) and normal platelet count (360x109/L). Elevated levels of erythrocyte sedimentation rate (110mm/hour), C-reactive protein (CRP; 13.73mg/dL; normal range 0 to 0.26mg/dL), soluble-interleukin (IL)-2 receptors (s-IL2R; 1300IU/mL; normal range 124 to 466IU/mL), antinuclear antibodies (x640; normal range <x40) and ferritin (722ng/mL; normal range 39.4 to 340ng/mL), and reduced levels of serum iron (34mug/dL; normal range 54 to 181mug/dL) and albumin (2.5g/dL; normal range 3.9 to 4.9g/dL) were observed. Serum electrolytes and renal function indices were normal. Rheumatoid arthritis particle agglutination, anti-double-stranded deoxyribonucleic acid (DNA), anti-Sm, anti-thyroglobulin, anti-microsome, anti-Ro and anti-La antibody titers were within normal limits. No increments of serum angiotensin-converting enzyme and lysozyme were seen. The results of an anti-acid fast bacterium antibody and a tuberculin skin test were negative (0x0mm). Serologic tests for syphilis, hepatitis B virus, hepatitis C virus and human immunodeficiency virus were negative. Serum Epstein-Barr virus (EBV) and Chlamydia pneumoniae titers showed prior infection patterns. The results of serologic studies for Cytomegalovirus, Brucella, Legionella, Coxiella burnetii, Mycoplasma and Toxoplasma were negative. Her urine showed nothing remarkable. A positron emission tomography-CT (PET-CT) scan, which was carried out 4 days after admission, showed 18F-fluorodeoxyglucose (FDG) uptakes in her peripharyngeal, axillary, mediastinal, hilar, iliac and inguinal lymph nodes with splenic involvement. In addition, remarkable FDG uptake at her submandibular dental roots wearing ceramic crowns was observed, suggesting chronic periodontitis (Figure 2). A right inguinal lymph node biopsy specimen, which was obtained 9 days after the initiation of CAM treatment, showed non-caseating epithelioid cell granulomas with abundant multinucleated giant cells (Langhans giant cells) in the background of epithelioid cells, macrophages, lymphocytes and plasma cells (Figure 3A). In the present case, the sarcoid granulomas were somewhat diminished in size and number, and ill defined from surrounding tissue (Figure 3B). In addition, some of the giant cells showed condensed heterochromatin (pyknosis; Figure 3A), multiple fragmented nuclei (apoptotic bodies; Figure 4A) and multiple nuclear remnants with indistinct nuclear configurations in the eosinophilic condensed cytoplasm (Figure 4B). These findings indicate that the giant cells were, although atypical, in the apoptotic process according to the features described by Wyllie et al.. These degenerated giant cells appeared to have transformed into eosinophilic homogenous substances with fibrotic configuration (that is, hyaline-like degeneration; Figure 4C). The degenerating/degenerated giant cells showed slightly increased stainability with periodic acid-Schiff (Figure 4D). Neither acid-fast bacterium nor fungus was demonstrated by Ziehl-Neelsen and Grocott stains (not shown). Immunohistochemical staining for Mycobacterium tuberculosis showed a negative result (not shown). EBV-encoded small ribonucleic acid (RNA) was not detected in the sarcoid granulomas (not shown). To demonstrate the presence of P. acnes in the granulomas, the lymph node specimens were tested by immunohistochemistry using a specific monoclonal antibody against P. acnes lipoteichoic acid (PAB antibody). PAB-positive reaction products were observed preferentially in the degenerated homogenous substances. Small positive dots were scattered sparsely in the sarcoid granulomas (Figure 5). Since a considerable number of plasma cells were admixed with lymphocytes in the lymph node, immunohistochemical staining was carried out for immunoglobulin (Ig) G, IgA, IgM, IgD and IgG4 to dispel the possibility of IgG4-related disease (Figure 6). Infiltrated plasma cells were positive for IgG, IgA, IgM, IgD and IgG4 at different degrees. Positive reactions for IgG4 were only occasionally seen in the plasma cells, thus negating the possibility of IgG4-related disease. Some of the giant cells and degenerated homogenous substances were positively stained with anti-IgG antibody, and the reaction was more intense in degenerating/degenerated giant cells than in intact ones (Figure 6A). The giant cells were faintly stained with anti-IgD antibody (Figure 6B) but not with anti-IgA (not shown), anti-IgM (not shown) and anti-IgG4 (Figure 6C) antibodies. In this case, an oral administration of CAM (200mg at 12-hour intervals) coupled with acetaminophen (400mg at 12-hour intervals) was empirically initiated on the day of admission. After the initiation of this treatment, her fever rapidly subsided coupled with the disappearance of joint pains and toxic eruptions within 1 week. The elevated levels of CRP returned to normal within 2 weeks and elevated s-IL2R levels were remarkably decreased within 3 weeks (Figure 7). She was discharged 25 days after admission and followed as an out-patient. Administration of acetaminophen was suspended at the time of discharge. The levels of s-IL2R returned to normal within 2 months. The follow-up PET-CT scan 2 months after admission showed minimal FDG uptake in her bilateral hilar lymph nodes and distinct uptake at submandibular dental roots and in peripharyngeal lymph nodes. The FDG uptake in her spleen also disappeared (Figure 8). CAM treatment was discontinued 3.5 months after its initiation. No unfavorable adverse effects were observed with CAM. During the course of illness, the patient was found to have urinary bladder cancer, which was successfully removed by endoscopy in the urologic department of another hospital. Her levels of s-IL2R remained slightly elevated (less than 750IU/mL) after cessation of CAM treatment without any symptoms. She stopped visiting our hospital 1.5 years after initial presentation because of traffic inconvenience to visit the hospital. Recently, she visited our hospital to undergo medical check-ups and was told that she was in good condition.

Chest X-ray and computed tomography scan images on admission. (A) Chest X-ray showing minimal bilateral hilar lymphadenopathy with clear lung fields.

PMC3916803_01

Female

A 78-year-old Japanese-Mongoloid woman (body weight: 48kg) with a 3-year history of hypertension and hyperlipidemia visited our hospital because of a persisting fever and generalized joint pains which had developed 2 weeks before initial presentation. She had been treated as having a common cold at a local clinic for 2 weeks previously, but her symptoms had not improved. After visiting our hospital, a drip infusion therapy of cefpirome with oral administration of loxoprofen was initiated on an out-patient basis. However, this treatment was not effective for the fever but caused toxic eruptions on the back of both her hands. Thus, this treatment was suspended 3 days later. She was admitted 4 days after initial presentation. Neither respiratory nor ocular symptoms were present. She had past history of panhysterectomy due to uterine cancer at the age of 38 and a fracture of her left wrist joint at the age of 68. She had no environmental or occupational history of beryllium or other metal exposure. A physical examination on admission showed bilateral inguinal and axillary lymph node swelling and erythematous eruptions on the back of both her hands. A chest X-ray showed minimal bilateral hilar lymphadenopathy (BHL); however, a chest computed tomography (CT) scan clearly revealed mild BHL without pulmonary infiltrates (Figure 1). Since respiratory function tests were normal, bronchoscopy was not performed. Electrocardiogram and ophthalmologic evaluations were normal. A complete blood cell count showed slight anemia (red blood cell count, 3.70x1012/L; hemoglobin, 10.8g/dL), slight leukocytosis (white blood cell count, 11.9x109/L with 74% neutrophils, 13% lymphocytes, 11% monocytes, 1% eosinophils, and 1% basophils) and normal platelet count (360x109/L). Elevated levels of erythrocyte sedimentation rate (110mm/hour), C-reactive protein (CRP; 13.73mg/dL; normal range 0 to 0.26mg/dL), soluble-interleukin (IL)-2 receptors (s-IL2R; 1300IU/mL; normal range 124 to 466IU/mL), antinuclear antibodies (x640; normal range <x40) and ferritin (722ng/mL; normal range 39.4 to 340ng/mL), and reduced levels of serum iron (34mug/dL; normal range 54 to 181mug/dL) and albumin (2.5g/dL; normal range 3.9 to 4.9g/dL) were observed. Serum electrolytes and renal function indices were normal. Rheumatoid arthritis particle agglutination, anti-double-stranded deoxyribonucleic acid (DNA), anti-Sm, anti-thyroglobulin, anti-microsome, anti-Ro and anti-La antibody titers were within normal limits. No increments of serum angiotensin-converting enzyme and lysozyme were seen. The results of an anti-acid fast bacterium antibody and a tuberculin skin test were negative (0x0mm). Serologic tests for syphilis, hepatitis B virus, hepatitis C virus and human immunodeficiency virus were negative. Serum Epstein-Barr virus (EBV) and Chlamydia pneumoniae titers showed prior infection patterns. The results of serologic studies for Cytomegalovirus, Brucella, Legionella, Coxiella burnetii, Mycoplasma and Toxoplasma were negative. Her urine showed nothing remarkable. A positron emission tomography-CT (PET-CT) scan, which was carried out 4 days after admission, showed 18F-fluorodeoxyglucose (FDG) uptakes in her peripharyngeal, axillary, mediastinal, hilar, iliac and inguinal lymph nodes with splenic involvement. In addition, remarkable FDG uptake at her submandibular dental roots wearing ceramic crowns was observed, suggesting chronic periodontitis (Figure 2). A right inguinal lymph node biopsy specimen, which was obtained 9 days after the initiation of CAM treatment, showed non-caseating epithelioid cell granulomas with abundant multinucleated giant cells (Langhans giant cells) in the background of epithelioid cells, macrophages, lymphocytes and plasma cells (Figure 3A). In the present case, the sarcoid granulomas were somewhat diminished in size and number, and ill defined from surrounding tissue (Figure 3B). In addition, some of the giant cells showed condensed heterochromatin (pyknosis; Figure 3A), multiple fragmented nuclei (apoptotic bodies; Figure 4A) and multiple nuclear remnants with indistinct nuclear configurations in the eosinophilic condensed cytoplasm (Figure 4B). These findings indicate that the giant cells were, although atypical, in the apoptotic process according to the features described by Wyllie et al.. These degenerated giant cells appeared to have transformed into eosinophilic homogenous substances with fibrotic configuration (that is, hyaline-like degeneration; Figure 4C). The degenerating/degenerated giant cells showed slightly increased stainability with periodic acid-Schiff (Figure 4D). Neither acid-fast bacterium nor fungus was demonstrated by Ziehl-Neelsen and Grocott stains (not shown). Immunohistochemical staining for Mycobacterium tuberculosis showed a negative result (not shown). EBV-encoded small ribonucleic acid (RNA) was not detected in the sarcoid granulomas (not shown). To demonstrate the presence of P. acnes in the granulomas, the lymph node specimens were tested by immunohistochemistry using a specific monoclonal antibody against P. acnes lipoteichoic acid (PAB antibody). PAB-positive reaction products were observed preferentially in the degenerated homogenous substances. Small positive dots were scattered sparsely in the sarcoid granulomas (Figure 5). Since a considerable number of plasma cells were admixed with lymphocytes in the lymph node, immunohistochemical staining was carried out for immunoglobulin (Ig) G, IgA, IgM, IgD and IgG4 to dispel the possibility of IgG4-related disease (Figure 6). Infiltrated plasma cells were positive for IgG, IgA, IgM, IgD and IgG4 at different degrees. Positive reactions for IgG4 were only occasionally seen in the plasma cells, thus negating the possibility of IgG4-related disease. Some of the giant cells and degenerated homogenous substances were positively stained with anti-IgG antibody, and the reaction was more intense in degenerating/degenerated giant cells than in intact ones (Figure 6A). The giant cells were faintly stained with anti-IgD antibody (Figure 6B) but not with anti-IgA (not shown), anti-IgM (not shown) and anti-IgG4 (Figure 6C) antibodies. In this case, an oral administration of CAM (200mg at 12-hour intervals) coupled with acetaminophen (400mg at 12-hour intervals) was empirically initiated on the day of admission. After the initiation of this treatment, her fever rapidly subsided coupled with the disappearance of joint pains and toxic eruptions within 1 week. The elevated levels of CRP returned to normal within 2 weeks and elevated s-IL2R levels were remarkably decreased within 3 weeks (Figure 7). She was discharged 25 days after admission and followed as an out-patient. Administration of acetaminophen was suspended at the time of discharge. The levels of s-IL2R returned to normal within 2 months. The follow-up PET-CT scan 2 months after admission showed minimal FDG uptake in her bilateral hilar lymph nodes and distinct uptake at submandibular dental roots and in peripharyngeal lymph nodes. The FDG uptake in her spleen also disappeared (Figure 8). CAM treatment was discontinued 3.5 months after its initiation. No unfavorable adverse effects were observed with CAM. During the course of illness, the patient was found to have urinary bladder cancer, which was successfully removed by endoscopy in the urologic department of another hospital. Her levels of s-IL2R remained slightly elevated (less than 750IU/mL) after cessation of CAM treatment without any symptoms. She stopped visiting our hospital 1.5 years after initial presentation because of traffic inconvenience to visit the hospital. Recently, she visited our hospital to undergo medical check-ups and was told that she was in good condition.

Chest X-ray and computed tomography scan images on admission. (B) Chest computed tomography scan clearly showing mild bilateral hilar lymphadenopathy (arrows) without pulmonary infiltrates.

PMC4927215_01

Male

A 62-year-old man referred to our facility for the management of abnormal computed tomography of the chest identified during investigation for atypical chest pain. His past medical history was significant for chronic hepatitis C complicated by liver cirrhosis and hepatocellular carcinoma (HCC). He underwent chemoembolization and radiofrequency ablation of the liver as bridging therapies prior to uneventful orthotopic liver transplantation (OLT), a curative treatment for HCC. The explanted liver was cirrhotic and contained two 4.5 cm extensively necrotic lesions consistent with poorly differentiated HCC on pathological examination. There was an extensive intravascular invasion, and tumor was presented within an intracaval thrombus, which was removed during surgery. After the OLT, he was maintained on immunosuppressive therapy with tacrolimus and prednisone. Unfortunately, he was diagnosed with prostate cancer a few months later and underwent prostatectomy as curative treatment. At this time, his immunosuppressant was changed from tacrolimus to sirolimus, which had shown to delay HCC recurrence when compared to regimens that use tacrolimus in retrospective study. Physical examination of his chest revealed normal breath sounds. Cardiovascular examination was unremarkable for abnormal heart sounds or murmurs. The rest of his physical examination was normal. Cardiac workup was negative for myocardial injury. Computed tomography of his chest images is shown in Figure 1. The patient subsequently underwent endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) of right paratracheal lymph node station 4R (Figure 2). Pathological examination revealed highly cellular and clusters of large, loosely cohesive sheets of tumor with thin-walled traversing blood vessels. The tumor cells had a moderate amount of granular cytoplasm containing occasional hyaline globules. Nuclei were round to oval in shape and moderately pleomorphic, with prominent nucleoli and scattered intranuclear pseudoinclusions. Bile pigment was not identified. Numerous nuclei stripped of cytoplasm were present in the background of the smears (Figure 3). The specimen did not contain appreciable lymphoid tissue, but small aggregates of macrophages with anthracotic pigment were present; these macrophages indicate that the tumor was located within a mediastinal lymph node (Figure 4). Immunohistochemical stains were positive for hepatocyte paraffin 1 (HepPar1) (Figure 5) and alpha-fetoprotein (AFP), and stains for cytokeratin (CK)-7, CK-20, thyroid transcription factor-1 (TTF-1), and monoclonal carcinoembryonic antigen (CEA) were all negative. Recurrent metastatic HCC in mediastinum.

endobronchial ultrasound, liver transplantation, recurrent hepatocellular carcinoma

PMC3500405_01

Male

A 58 year old right handed man with 14 years of education presented to the UCLA Behavioural Neurology Clinic with a chief complaint of memory loss. He had worked as a salesman and then owned a lamp manufacturing company for 38 years before retiring. The patient had been having trouble remembering names for the last 3 years. He had also developed difficulty with language comprehension, curtailed his reading, could not concentrate, and was noted to be much more facetious by his family. On mental status testing at presentation 3 years into his illness, the patient's behaviour was appropriate to the context of the visit. His verbal output was fluent, but with a distinct emptiness. He circumlocuted, attempting to give descriptions for nouns that he was unable to produce. His comprehension was intact for simple commands, as demonstrated by pointing accurately at objects about the room or answering yes/no questions appropriately. His repetition was very well intact. On the Boston Naming Test (BNT), he was able to name only a few of the most commonly-used words (tree, bed). Although by history he was not reading as much for pleasure, he was able to read sentences aloud without difficulty. In formal neuropsychological evaluation, there was a striking discrepancy between verbal (VIQ= 77) and performance (PIQ= 110), with impairment isolated to language function. Semantically significant words had lost their symbolic meaning. In contrast, the patient was able to handle syntactical language in a basically normal manner. He showed no impairment on tests of attention or mental control in year 3 but was unable to determine similarities and differences, or to interpret idioms or proverbs, almost completely because of his aphasia. When asked "How are an apple and a pear alike?" he responded, "Pear, Pear, I don't know what a Pear is," which may be described as word alienation. One year later, word alienation had progressed, but the patient was still able to repeat simple sentences. On the Frontal Assessment Battery at 3 years into illness, the patient performed well on reciprocal programs and go-no go. He was able to perform the Luria hand sequences without errors. He showed no evidence of ideomotor apraxia. Memory was tested with an 8-item supraspan word list: his learning curve over 4 trials was 2, 3, 4, 5; after 15 minutes he recalled 4 of the 8 words spontaneously, not benefitting from category clues and retrieved only one additional word from multiple choice. He had similar impairment in non-verbal recall. He showed good memory for current events and presented his own history with little correction or prompting from family members; thus he appeared to have good insight at presentation. At 3 years, visuoconstructive function for figure copy was intact. When asked to generate a drawing on command, however, he was able to make a circle but was unable to place the rest of the features of a clock. He had no difficulty with right/left discrimination or finger gnosis. The impression at this time was that of a primary progressive aphasia, specifically semantic dementia. At 5 years, the patient could only score 3/15 on the abbreviated BNT. In year 9, the patient was still able to mimic one step commands. Folstein Mini-Mental State exam scores declined from 27/30 to 24 at 5 years, 21 and then 14 at 7 years. The fact that the patient's figure copy was still intact on the MMSE at year 9 supported a diagnosis of FTD more than Alzheimer's disease. He was, unfortunately, unable to complete the rest of the MMSE due to his advancing aphasia. By year 10, the patient was variably able to copy a complex figure. At year 13, he was unable to recognize pictures of familiar people. Full testing was not possible, but he had significant difficulty with language, both reduction of output to verbal stereotypies and palilalia, as well as in comprehension. Four years into illness, his Neuropsychiatric Inventory (NPI) score was 4/144, with mild scores for apathy and disinhibition simultaneously. The following year, behavioral changes became more prominent than the aphasia. The patient was more talkative and disinhibited with strangers. Behavioral changes noted for year 7 included an increase in inappropriate laughter, decreased libido, a rigid time-table for meals, and routinized or stereotypic eating behaviours, such as counting all the pepperoni pieces on the pizza before he could eat. He would count everything. The patient apparently suffered a traumatic incident while washing or being washed and subsequently developed hydrophobia, fearful of the shower and rain, which persisted throughout the remainder of his illness. In year 9, the patient was having verbally agitated episodes in the bathroom. He would berate himself, but these were short-lived episodes. The following year found the patient occupying himself at home with computer games and puzzles during the day. At year 11, he had angry outbursts, was inappropriately loud in public, and was increasingly familiar with strangers, wandering out into the street several times per day after disarming the home alarm system and pacing when indoors. A new compulsion was nose-blowing, up to 75 times daily, and he had a new verbal stereotypy, "I'm Alzheimer's." A new routine was waiting for the delivery of the morning paper. He began to use the floor of the bathroom as opposed to the toilet. On examination he was awake and alert, was much less outgoing and euphoric than on previous visits, and made poor eye contact. He had blunted affect and could not understand any commands. When not blunted in affect, he would be sad and tearful with self-deprecating statements. By year 12, the verbal stereotypy was reduced to responding "no" to every question or comment and addressing familiar women in his household as "honey". There was some evidence of palilalia. He had become fully dependent for basic activities of daily living but on a rigid routine. The patient maintained his interest in playing board games, happy to be among people most of the time. For example, after being separated from his wife for the examination he returned to her room to make sure she was still there and stated "you are here, and that is good". At other times, the patient showed excitement over seeing his daughters after long intervals. Contradictory to these signs of affection, there was emotional blunting, in that if his wife was ill, he showed no clear understanding or concern. Another example of his retained social graces was a sense of modesty in the bathroom with his female caregiver. He would not allow her to help him with hygiene, although he would also have incontinence in public without concern, often smearing his feces over surfaces if left unchecked. At year 13, the patient began to eat to excess, with an emphasis on bread, cereals and pasta. This led to a 40-pound weight gain. Neurological Examination revealed stable anisocoria, bilateral resting tremor after the first 10 years of illness, inconsistent hyperflexia and no frontal release signs. Medication trials: donepezil 10 mg daily at 6 years equivocally caused a complaint of diffuse joint pain in left elbow, migrating up to both shoulders and down to the wrist, additionally in the left knee. The myalgia may not have been related to the cholinesterase inhibitor use, because the patient continued to have symptoms even after he stopped taking the medication. At 7 years, the patient was tried on clomipramine 25 mg orally per day for obsessive-compulsive behaviors, but this resulted in hyperhidrosis when dosage was increased from 25mg daily to 100 mg. Paroxetine caused stomach aches and hyperhydriosis at doses of 5 and 10 mg per day. Sertraline 50 mg, the 3rd drug for compulsions, was also not well-tolerated, for reasons unavailable from the chart or family members. Valproic acid was not noted to cause adverse effects. Quetiapine 25 mg daily resulted in more calmness and better sleep habits in year 9. Citalopram up to 10mg po qAM to 10 mg po BID, then escitalopram 10 mg daily, haloperidol 1 mg daily, then olanzapine 15 mg po daily were tried. His behavior did respond to the olanzapine, but the patient developed parkinsonism: a resting tremor was noted on the left more so than right upper extremity. Cogwheeling was present at both wrists. He also had mild bradykinesia. The patient had also been exhibiting some day/night confusion. Trazodone 100 mg was started, in hope of consolidating sleep and avoiding the extrapyramidal side effects of olanzapine. At around the time that he switched to trazodone, the patient wandered 6 miles from home and was frightened enough by his experience with the police that he did not leave home by himself afterwards. An MRI of the brain at 10 years showed severe atrophy of both temporal lobes and mild to moderate atrophy in frontal and insular regions (see Figure 1). A SPECT scan of the brain ordered by the treating neurologist for diagnostic purposes was performed one year into illness showed no significant abnormalities. A PET scan of the brain at 3 years showed severe left temporal lobe hypometabolism and moderate right temporal hypometabolism, mild widening of the longitudinal intercerebral fissure, and increased separation between the caudate heads. Repeat SPECT scan at 5 years showed the prior deficits plus significant left greater than right orbito-frontal and parietal hypoperfusion. Another SPECT scan at 8 years showed further decrease in perfusion. Because dorsal posterior parietal and anterior portions of the intrahemispheric fissure were now involved, clinicians agreed that an atypical temporal variant of Alzheimer's disease could not be ruled out. The patient died at home of unstated causes 14 years after onset of illness. His body by that time was markedly cachectic. His family submitted him for autopsy restricted to examination of the brain, which was carried out after a post-mortem interval of approximately 2 hours. Fresh brain weight was 1030 grams. Negligible atherosclerosis was noted in the basal vessels. The brain showed pronounced gyral atrophy, affecting frontal and temporal lobes symmetrically, with questionable relative sparing of the left superior temporal gyrus, i.e. a pattern suggestive of Pick's disease. Severe gyral atrophy was also noted in the cingulate gyri, corpus callosum and hippocampi. The basal ganglia were remarkable for atrophy of the caudate nuclei. Coronal sections of the brainstem and midand parasagittal sections of cerebellum were normal. There was relative sparing of parietal and occipital lobes. There was at most slight atrophy of the pons. Pick bodies were not present, despite the gross appearance suggestive of Pick's Disease. Marked neuronal loss with astrocytic gliosis and focal spongy change in neocortex was seen on H & E stain, especially involving superficial cortex of the frontal and temporal lobes and insular neocortex (Figure 2). Neuron loss and pronounced gliosis in the inferior basal ganglia were also seen. There was minimal Alzheimer type pathology of the brain, with sparse diffuse A-beta 1-42 immunoreactive cortical deposits on immunohistochemistry and negligible neuritic plaques. There were rare tau-immunoreactive neurons in the hippocampal pyramidal cell layer but not the granule cell layer. Significant neocortical tau immunoreactivity and significant amyloid angiopathy were not found. The substantia nigra was well-pigmented without Lewy Bodies per alpha-synuclein immunohistochemistry. Scattered rod-like or axonal/dendritic ubiquitin immunoreactivity ("ubiquitin neurites") were widespread throughout neocortex, including the insular cortex. There were rare cells (including scattered neurons) with cytoplasmic TDP-43 immunoreactivity and a 'neuritic' pattern of ubiquitin immunoreactivity was noted in many cortical regions, including the insular cortex (Figure 3).

PMC3996915_01

Female

The participant in this case study was a 58-year-old Caucasian female who was recruited to participate in a larger research study (data not published) observing the effects of an 8-week exercise intervention on CR fitness and a physical function test (six-minute walk test). Prior to the onset of stroke, the participant reported incorporating regular exercise 45 minutes per day, 4-5 days per week. Her risk factors for stroke included: hyperlipidemia, hypertension and pre-diabetes. The participant was admitted to the hospital with right sided weakness and word finding difficulties. Diagnosis by the neurologist who read the MRI scan revealed an ischemic stroke in the left basal ganglia affecting the globus pallidus and posterior limb of the internal capsule. Primary deficits post-stroke included aphasia, difficulty writing with the right hand, and difficulty performing activities of daily living (ADL's). The participant's hospital stay was 4 days in length and included physical, occupational, and speech therapies. In order to be enrolled into the study, the participant had to meet the following criteria: (1) Between 45-70 years of age; (2) Admission to hospital with diagnosis of a first-time, unilateral stroke; (3) Ability to walk with stand-by-assist; (4) Ability to travel or have transportation to participate in all testing and exercise sessions. The subject did not demonstrate the following exclusion criteria: (1) Acute renal failure; (2) Acute ischemic cardiovascular event or coronary artery bypass surgery less than 3 months ago; (3) Severe peripheral artery disease (Ankle-Brachial Index (ABI) < 0.40); (4) Diagnosis of congestive heart failure; (5) Current smoker; (6) Either unable to physically perform the exercise test using the recumbent stepper or demonstrate absolute indications for terminating exercise testing that follows the American College of Sports Medicine's (ACSM) guidelines; (7) Uncontrolled blood pressure with medication in the hospital (BP > 190/110mmHg). The participant in this case study was enrolled in a larger exercise trial. The parent study was approved by the Institutional Review Board at the University of Kansas Medical Center. After initial screening, institutionally approved written informed consent was obtained. The participant's Ankle-Brachial Index (ABI) was 1.12, indicating normal or negligible obstruction in the periphery, and had a total Fugl Meyer score of 124 out of 124 possible points. Physician clearance was obtained for participation in the study. At 15 days post-stroke the participant completed baseline testing. Baseline measures for all tests were repeated at the end of the 8-week exercise intervention and again at a 4-week follow-up visit. Day 1 included anthropometric measures, and a 6 Minute Walk Test (6-MWT).On Day 2 she returned for a graded exercise test (GXT) using an exercise protocol specifically developed for post-stroke patients. Prior to exercise testing we gathered anthropometric data. The participant was 154.9 cm tall with a body weight was 64.0 kg and a body mass index (BMI) of 24.75 kg*m2-1. At baseline her resting heart rate (HR) was 79 bpm and blood pressure (BP) was 121/86 mmHg. The 6 Minute Walk Test (6-MWT) is an outcome measure used in the stroke population to quantify an individual's functional capacity and endurance. The 6-MWT was used in this study to assess walking endurance. The 6-MWT was performed in a tiled hallway measuring 22.2 meters in length between each marker cone. The subject was told to walk as quickly as possible between the two cones for six minutes and was given standard encouragement. The participant's baseline was 476.7m, which is below the normal mean value of 538 m for a female between 60-69 years of age. A total body recumbent stepper (TBRS) (NuStep T5XR, Ann Arbor, MI) was used as the exercise modality for the graded exercise test (mTBRS-XT). The mTBRS-XT begins at 25 Watts and increases 15 Watts every 2 minutes until fatigue or test termination criteria are met. A metabolic cart (ParvoMedics, Sandy, UT) was used to assess gas exchange during the exercise test and determine VO2 peak. Due to the fact that a stroke diagnosis is considered a high cardiac risk, a physician supervised the exercise test. Borg's Rate of Perceived Exertion (RPE) Scale of 6-20 was used to assess exertion and HR was continuously monitored using a 12-lead EKG. BP and VO2 were recorded every 2 minutes along with RPE and HR. Standard guidelines of the American College of Sports Medicine (ACSM) were used to determine exercise test endpoints. Absolute indications for terminating an exercise test include; drop in systolic BP of > 10 mmHg from baseline BP, moderately severe angina, increasing nervous system symptoms (ataxia, dizziness, etc), signs of poor perfusion, technical difficulties monitoring the ECG or systolic BP, subject's desire to stop, sustained ventricular tachycardia, ST elevation (+1.0 mm) in leads without diagnostic Q-waves. The participant's exercise test lasted 14 minutes, her VO2 peak was 20 mL*kg-1*min-1, her peak HR was 158 bpm, and her peak BP was 158/88 mmHg. The subject reported a RPE of 20 indicating her maximal effort. The participant stopped the exercise due to volitional fatigue. A progressive aerobic exercise intervention using the TBRS was designed based on the values obtained from the exercise test. The peak HR achieved during the exercise test was used to determine a target HR training zone using the Karvonen formula. The intensity was set to maintain HR between 50-59% of HR reserve for weeks 1-4 and during weeks 5-8 the intensity was increased to 60-69% of HR reserve. Exercise duration began at 20 minutes with the goal of reaching 30 minutes of continuous exercise at a specified workload. The TBRS was programmed to maintain a constant workload based on target HR with a rate of 100-105 steps per minute. HR was monitored using a Polar T31 coded chest strap (Polar USA, Kempele, Finland). HR and BP were measured at rest, at peak exercise, and at post-exercise during rest. The RPE scale was used to rate the level of intensity of the exercise session. The intervention was three times per week for eight weeks. Since cardiac medications can affect HR and BP response during exercise, the participant was asked at each visit whether any changes in medications occurred. She was taking medications for high BP, specifically an angiotensin-converting enzyme, calcium channel blocker and a diuretic. There were no medication changes during the intervention period or at the follow-up. The results illustrate an improvement in outcome measures after 8 weeks of a moderate to high intensity aerobic exercise intervention. See table 1 for a summary of outcome measures. This individual started the exercise intervention just 15 days post-stroke and did not have any adverse events during the peak exercise tests or exercise intervention. This individual had notable improvements in the 6-MWT, improving from a distance of 476.74 meters at baseline to 500.71 meters post-intervention and then 551.4 meters at the 4-week follow-up. Normal ranges for the 6-MWT that have been reported in the literature include a walking distance calculated between 538 +- 95m and 576 +- 87m for women between 20 and80 years of age . Compared to normative data, the participant walked 61.26 m less at baseline, which demonstrates decreased functional endurance. After the exercise intervention she increased walking distance but was still considered below normative values. At the 4-week follow-up the participant was within the normal range. This is an important measure for endurance and ability to perform ADL's and functional activities such as walking in the community. The subject's initial VO2 peak of 20 mL*kg-1*min-1 is between the 1stand 5th percentiles when compared to healthy, age and gender-matched peers, indicating her CR fitness to be very poor. After the exercise intervention, she improved her peak capacity by 21% to 24.2 mL kg-1 min-1 and then continued to improve to 27.4 mL kg-1 min-1 at the 4-week follow-up. Improvements in other exercise testing measures are reported in Table 1.

PMC5237735_01

Female

Seventeen-year-old girl, Guinea native, living in Portugal, was screened for tuberculosis after pulmonary tuberculosis was diagnosed in a girl living in the same school residence. She had a positive tuberculin skin-test and interferon-gamma release assay, and a nodular image on the chest X-ray. Mycobacterium tuberculosis was isolated on the sputum, susceptible to all first-line antituberculosis drugs. Treatment with isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) was started, with daily-observed administration, achieving negative sputum cultures in the first month of treatment. Three weeks after starting treatment, elevation of Alanine Aminotransferase (ALT) and aspartate aminotransferase (AST), 136 and 89 UI/L, respectively, and palmoplantar desquamation was first detected, with further increase (ALT 281 IU/L and AST 186 IU/L) by the 5th week of treatment, leading to the interruption of the classic scheme and initiation of a second-line one with amikacin, levofloxacin, and ethambutol. By the third month of treatment, maintaining changes on serum transaminases, despite the changes on treatment, without jaundice, cholestasis, or liver dysfunction, she was referred and admitted by the first time to our hospital. At this point, she had 31 doses of HRZE, 9 days without treatment followed by 34 doses of amikacin, levofloxacin, and ethambutol. With a suspected DILI, withdraw of the antituberculosis drugs was determined and other causes of liver injury were excluded, such as viral hepatitis, concomitant HIV infection, alcohol consumption, and the use of other hepatotoxic offenders. During investigation, an alpha-thalassemia trait (-alpha/-alpha homozygotic), Hope Hemoglobin in beta chains, and hepatitis B immunity due to past infection (HBs and HBe antigen negative; anti-HBs and anti-HBe antibody positive) were diagnosed. Without treatment, liver enzymes rapidly normalized. Progressive introduction of antituberculosis HRZE was then made: gradual increase in the dose each day until therapeutic dose was reached; at the third day of each drug, serum ALT and AST were measured and then another drug was added. By 12th day of treatment, because of nausea complaints, worsening of the palmoplantar desquamation, and a sevenfold increase of ALT (283 IU/L), pyrazinamide was stopped. However, there was still clinical and analytical deterioration, with a peak serum ALT of 600 IU/L and AST of 300 IU/L, and all antituberculosis drugs were suspended five days later. Further investigation to rule out autoimmune and metabolic causes was completed, all negative with exception of a positive anti-smooth-muscle antibody (ASMA 1/80). Intradermal skin tests with HRZE tested positive for rifampicin, raising the possibility of DILI by mechanisms of hypersensitivity. Considering the patient previous treatment schemes, and based on expert's opinion, after normalization of liver enzymes, a slower reintroduction of second-line drugs was made: starting with levofloxacin 750 mg/day and amikacin 750 mg/day, twenty days later adding ethionamide 500 mg/day and 27 days later adding cycloserine 500 mg/day. There was no elevation on serum transaminases, the palmoplantar desquamation got progressively better, and she remained asymptomatic. She was discharged having 37 doses of levofloxacin plus amikacin, 17 doses of ethionamide, and 9 doses of cycloserine. Two months later, during follow-up visits, she complained again of nausea, anorexia, weight lost, pruritus, and palmoplantar desquamation. Serum transaminases increased again (ALT 466 IU/L and AST 656 IU/L; normal alkaline phosphatase) and a mild hypergammaglobulinaemia (1580 mg/dL) with normal IgA levels (135 mg/dL), positive anti-nuclear (ANA 1/80), anti-neutrophil cytoplasmic (ANCA 1/80), smooth-muscle (ASMA 1/40), and F-actin (23.3 U) antibody were detected, raising the suspicion of drug-induced autoimmune hepatitis. Other organ autoimmune injuries (namely, thyroiditis and celiac disease) were negative. Liver biopsy showed mild lymphocytic infiltrate on histology, with no signs of interface hepatitis or portal plasma cell infiltration. Focal lymphocytic infiltrate and reticular collapse, reflecting focal hepatocytic necrosis, was evident at a lobular level. Facing a possible immune-mediated DILI, treatment with the same antituberculosis drugs was reestablished simultaneously with prednisolone 1 mg/kg/day (40 mg/day) and maintained for a month, followed by a gradual decrease until a dose of 5 mg/day of prednisolone was reached, showing clinical improvement, no signs of liver cytolysis, normalization of hypergammaglobulinaemia, and negative autoantibodies. While still under treatment, 5 mg in alternate days was tried but liver enzymes slightly increased (ALT 42 U/L and AST 52 U/L), so she maintained 5 mg/day until 18th months of TB treatment was completed, with no side effects of steroids. After that gradually reduction of prednisolone dose to complete suspension was accomplished, maintaining normal liver enzymes and with no relapses.

PMC9540073_01

Male

This report involves a 74-year-old male, suffering from metabolic syndrome with insulin-dependent diabetes mellitus type 2, arterial hypertension, obesity (BMI 39 kg/m2), and hypercholesterolemia. Furthermore, the patient has a medical history of pontine stroke, leading to dysarthria and an atactic paresis in the right hand. Relevant spinal history includes a herniated disk on the right at the level of L4-L5 which was successfully treated conservatively with transforaminal epidural infiltrations. On initial presentation, the primary complaint of the patient was a pain in the right gluteal area with radiation to the right upper leg and impaired walking tolerance. MR imaging showed degenerative discopathies at the L3-L4 and L4-L5 levels:with disc extrusion. On level L4-L5, there is additionally ligamentum flavum hypertrophy resulting in compression of the origin of the L4 root on the right. These findings result in a spinal canal stenosis at both L3-L4 and L4-L5 levels. Electromyographic findings showed a right radiculopathy on level L4. After unsuccessful conservative treatment with epidural infiltrations and exercise therapy, a L4 spinous process resection with laminectomy in combination with a right discectomy L3-L4 was performed (Fig. 1). A facetectomy was not carried out. After surgery, initial pain control was obtained with alleviation of the sciatica and improved gait performance. However, after a few weeks, the patient presented with a relapse of lumbalgia. This lumbalgia got worse over the following months, with the development of bilateral mechanical sciatica. On clinical examination, there were no signs of motor deficit in the legs, with intact and symmetric knee and Achilles tendon reflexes. At this point, a walking aid was necessary as his walking distance was limited to 100 m. MRI findings showed a hypointense interruption with surrounding bone-marrow edema in the right pedicle of the L4 vertebra (Fig. 2). On electromyography, a L5 radiculopathy was described by new unstable motor units without d enervation activity; this was considered a new finding in comparison with older EMG results. On the left side, a stable multi-level radiculopathy was shown. Epidural infiltrations failed to achieve pain reduction. Additional Tc99m-HDP-SPECT-CT imaging showed a metabolically active, linear lucency with sclerotic margins in the right pedicle of the L4 vertebra, suggesting a stress fracture (Fig. 3). Interdisciplinary deliberation with representatives of the different departments incl. neurosurgery, algology, and physical and rehabilitation medicine was scheduled. In retrospect, this pedicular lesion was already apparent on an MRI of the lumbar spine four months after the laminectomy procedure, with bone marrow edema centered around a sclerotic pedicle. A percutaneous posterolateral fusion of L4-L5 was performed. Due to the COVID-19 pandemic outbreak, postoperative rehabilitation physiotherapy was postponed and started only 3 months after lumbar fusion surgery. Until then, the patient's lumbalgia had significantly improved, but did not resolve completely.

case report, laminectomy, stress fracture

PMC6791237_01

Male

A four-year-old Maasai boy who was accompanied by his elder brother presented to the hospital with a one-year progressive history of dry cough and difficulty in breathing to the extent of compromising the child's physical activity accompanied by intermittent fever. There was no history of tuberculosis contact or trauma but a positive history of living with cattle and dogs. The patient received multiple courses of antibiotics and herbal medication with no relief. During admission, the child had a baseline plain chest X-ray done which revealed 80% homogenous opacification of the right hemithorax (Figure 1). For further clarification, chest computed tomography (CT) scan was done which demonstrated a large thick walled cystic lesion in the right hemithorax measuring approximately 11.7 cm x 8.6 cm x 11.0 cm. Fluid in the cyst appeared clear with no solid components, septations, or floating membranes. The right middle and lower lobes were completely collapsed. There was a mediastinal shift towards the left, but the left lung appeared normal. It was concluded that the features were suggestive of a hydatid cyst of the right hemithorax (Figure 2). With this radiologic diagnosis, albendazole was initiated and the patient was prepared for surgery. With the consent from the guardian, thoracotomy with right lower lobectomy was done. Intraoperatively, a cyst of about 20 cm in diameter in the lower lobe of the right lung with some fibrin attachment to the right hemidiaphragm was found (Figure 3). The whole cyst was removed with no spillage and a draining tube thoracostomy with underwater seal was placed (Figure 4). The postoperative course was uneventful. The tube thoracostomy drain was removed on day 11 and the patient was discharged on the 12th day.

PMC4075924_01

Female

A 62-year-old female patient with a 20-year history of RA had been on methotrexate, leflunomide, and prednisone. Because the articular inflammatory process persisted, we decided to start the patient on adalimumab, continuing her on methotrexate. A chest X-ray showed no changes suggestive of previous tuberculosis or signs of incipient ILD; and the intradermal (PPD) test for tuberculosis was negative (0 mm). One week after receiving the second dose of adalimumab (40 mg weekly), the patient started experiencing dry cough, dyspnea on moderate exertion, and daily fever (38 C). At that point, the results of chest X-ray, physical examination, and laboratory tests, including blood workup, were normal-hemoglobin, 13.1 g/dL; hematocrit, 39.2%; 8,380 leukocytes (75% neutrophils, 0.4% eosinophil, 9.8% lymphocytes); and 355,000 platelets, except for an increase in inflammatory markers (C-reactive protein, 326 mg/dL; reference value < 3 mg/dL) and in ESR (67 mm, reference value < 20.2 mm). Sputum smears for AFB and blood cultures were negative. The patient was started on empiric treatment with levofloxacin; however, she continued to have fever and dyspnea. A HRCT scan of the chest, performed two weeks after symptom onset, revealed ground-glass opacities, predominantly in the upper and middle lung fields, associated with areas of smooth interlobular septal thickening (Figure 1). Therefore, a presumptive diagnosis of ILD secondary to the use of adalimumab was made. We decided to discontinue the patient from the anti-TNF agent and methotrexate and to continue her on low-dose prednisone (5 mg/day). The patient showed progressive reduction in dyspnea, remission of fever, and normalization of inflammatory markers, without reactivation of the articular inflammatory process. Three weeks after the onset of the condition, the results of physical examination and spirometry were normal, with an SpO2 of 98% on room air. A second HRCT, performed three weeks after symptom onset, showed near-complete resolution of the ground-glass areas (Figure 2).

PMC8064790_01

Male

Our patient was a 61-year-old Hispanic man who had not seen a health care provider in many years and presented with one month history of vague abdominal pain, 20 pound weight loss in 1 month, and generalized weakness with malaise as well as occasional cough that worsened and became productive of clear sputum over the last week before presentation. He also reported occasional episodes of nausea and nonbloody diarrhea. He denied any fevers, chills, or rash but reported some arthralgias. The patient was born in Chihuahua, Mexico, but had lived in Texas, USA, since age seven. He was divorced, estranged from his children, and lived alone. There was no significant tobacco or alcohol use but he confirmed exposure to high intensity dust when he used to work in a ceramic and tile factory without wearing a mask for the last five years. He was evaluated by a private community physician a few days before presentation to our hospital who prescribed for him a combination of oral ciprofloxacin and metronidazole without specific diagnostic testing. The patient did not have any improvement so he presented to the emergency room. In the emergency department, his temperature was 98.3 F, blood pressure 84/61 mmHg, pulse rate 128/minute, and respiratory rate 27/minute with pulse oximetry 92% on ambient air. He was acutely ill-looking but alert. While lung examination was limited on admission due to COVID-19 restrictions and the use of disposable stethoscopes, there were decreased air sounds but no rales. His abdominal examination was benign but positive findings were significant for large lymph nodes in the cervical, supraclavicular, inguinal, and axillary areas, some measuring more than 3 cm in diameter. Laboratory findings on admission showed white blood cell count was 8,900/mm3 with 80% neutrophils, 0.5% band forms, and 11% eosinophils, hemoglobin was 8.9 gm/dL, hematocrit was 27.6%, and platelet count was 447,000/mm3. Electrolytes showed bicarbonate of 17, blood urea 54, creatinine 1.5, albumin 2.2, lipase 14, lactic acid 2.5, ALT 57, and AST 139. Procalcitonin was 6.1. His chest film on admission showed a diffuse micronodular pattern which triggered testing for COVID-19 which turned out to be negative. CT scan of the chest without contrast revealed extensive diffuse bilateral micronodules in a miliary pattern, mediastinal and axillary lymphadenopathy with pericardial thickening, while the CT scan of abdomen and pelvis revealed enlarged lymph nodes in the para-aortic, gastrohepatic, inguinal, external, and internal iliac chains (Figures 1(h) and 1(i)). While the patient was seen by many physicians to rule out lymphoma and tuberculosis, as well as to manage his respiratory failure, acute renal failure, and septic shock, the infectious disease physician suspected coccidioidomycosis and began a work up for the patient with serologic testing. Since he was in shock, blood and urine cultures were sent and he was treated with IV isotonic fluid resuscitation with empiric intravenous vancomycin and cefepime along with intravenous methylprednisolone 60 mg every 8 hours and admitted to the intensive unit. Further testing showed that he was positive for HIV-1 with viral load 309,000 and CD4 count 38. We did not begin antifungal medications at the outset because we did not have a diagnosis of HIV at the time. Upon a diagnosis of HIV in the hospital, we expanded our differentials to miliary tuberculosis, histoplasmosis, and coccidioidomycosis. Histoplasmosis antigen, acid fast bacilli (AFB), and Cryptococcus antibody tests did not yield a positive result; however, sputum culture was positive for Candida albicans. Despite aggressive treatment with vasopressors, mechanical ventilation, and continuous renal replacement therapy, the patient died on hospital day 3. The family agreed to an autopsy which showed diffuse coccidioidomycosis with negative AFB stain and no evidence of malignancy. The cause of death was acute respiratory distress syndrome (ARDS) secondary to disseminated coccidioidomycosis secondary to HIV/AIDS infection. At autopsy, there were bilateral pleural lung effusions (left: 300ml, right: 400ml), congestion of the lungs with areas of consolidation, and extensive intra-alveolar edema. There were innumerable diffuse tan nodules showing miliary spread in the upper and lower lung lobes with predominance in the upper lobes in the lungs bilaterally (see Figures 1(e) and 1(f). These nodules microscopically consisted of granulomatous inflammation. The lung alveolar spaces were filled with proteinaceous material and Coccidioides fungal microorganisms. Coccidioides fungal microorganisms have spherules that may be empty or filled with endospores. Coccidioides fungal microorganisms are accentuated with Grocott-Gomori's methenamine silver stain (GMS) (see Figures 1(c) and 1(d)).The decedent grossly had extensive cervical, supraclavicular, inguinal, and axillary lymphadenopathy. The lymph nodes grossly showed a cut tan surface (see Figure 1(g)). Microscopically, normal lymph node architecture was replaced with caseating granulomas with Coccidioides fungal microorganisms that are accentuated with Grocott-Gomori's methenamine silver stain (GMS) (See Figures 1(a) and 1(b)). It should be noted that acid fast bacilli (AFB) stain was performed and was negative for acid fast microorganisms on both lung and lymph node sections. Autopsy Findings and Figures are presented in Figure 1.

PMC10350683_01

Female

In February 2020, a 68 years-old woman with an ECOG performance status of zero presented with dry cough and hemoptysis. She never smoked and had a medical history of arterial hypertension, an adrenal non-progressing hyperplasia, a gastric bypass and a cholecystectomy. In the familial oncological history, we note an adrenal carcinoma in two brothers and a metastatic neoplasia of unknown origin in her father. A genetic testing for germinal mutations was not performed. Chest computed tomography (CT) revealed pulmonary infiltration of the left lower lobe, with small mediastinal lymph nodes. Bronchial left lower lobe biopsy revealed a lung adenocarcinoma, TTF1 (+), P40(-). The NGS (QiaSeq targeted DNA Panel CDHS-15662Z-617) testing for oncogenic driver mutations showed a p.773-774HVdelinsLM variant located in exon 20 of the EGFR gene and a TP53 co-mutation ( Table 1 ). ALK and ROS immunochemistry staining were negative, whereas PD-L1 expression was estimated to be 90% with the 22C3 antibody (Dako PharmDx assay). The work-up was completed by a PET-CT and a brain MRI. Three asymptomatic brain metastases were observed on MRI, leading to the diagnosis of a cT3N2M1 lung adenocarcinoma. Afterwards, the disease was evaluated every three months by chest and abdominal CT, brain MRI and PET-CT on progression of single lesions. In the multidisciplinary tumour board first-line immuno-chemotherapy was initially considered as an appropriate treatment option, because specific exon-20 targeted therapies were not yet available at the time of diagnosis and single agent immunotherapy is considered as less effective in EGFR-mutated lung carcinomas even with high PDL1 expression. The treatment options were discussed at our multidisciplinary molecular tumor board (MTB). As a case report reported a favorable response in a patient presenting this specific mutation, our patient was put on osimertinib treatment at a daily dose of 80mg. She noted significant regression of coughing after one month of treatment. At the first tumor assessment after 3 months of treatment, there was a partial response according to the RECIST 1.1 criteria with a moderate decrease in the pulmonary tumor infiltration, a significant regression of the brain metastases and disappearance of the cerebral perilesional oedema, the main lesion decreasing from 12,5 x 13 mm to 7.5 x 8 mm. Stereotaxic radiotherapy of an occipital 8 mm brain lesion was performed after 8 months, as some asymptomatic perilesional edema had reappeared without change in size of the lesion. After 20 months of treatment, stereotaxic radiotherapy was performed on a second frontal brain lesion that increased discretely from 3 to 5 mm. Osimertinib treatment was continued as there was no progression of the other tumor locations ( Figure 1 - April 2022). In August 2022, 30 months after the initiation of osimertinib, the patient presented a focal asymptomatic progression in the main left thoracic lesion, without signs of other extracerebral or cerebral progression, as confirmed by PET-scan ( Figure 2 ) and brain MRI. The thoracic progression was treated by stereotaxic radiotherapy, and osimertinib was continued. At the last tumor evaluation on April the 26th 2023, 38 months after diagnosis, the patient is still on Osimertinib and free of symptoms, without signs of progression on brain MRI and thoraco-abdominal CT. Timeline of the combined targeted treatment and stereotaxic radiotherapy on focal progressing lesions

egfr, exon 20, multimodal, non-small cell lung cancer, osimertinib, stereotaxic radiotherapy, tyrosine kinase inhibitor

PMC6606769_01

Female

A 62 year-old woman was admitted after 4 months history of intermittent frontal headache, nausea, and gait and balance disturbances. She had a 3 year history of IgM-RF and anti-CCP positive RA, with a previously episode of pleuritis. Within the last year, she had been treated with Leflunomide, Infliximab, and was currently treated with Methotrexate and Salazopyrine entabs. Neurological examination was normal, except for a mild gait ataxia and her RA was well-controlled with no symptoms of active synovitis at time of admission. Due to chronic headache a brain MRI was performed. This showed patchy interhemispheric pachy- and leptomenigeal enhancement adjacent to the parietal- and occipital lobes (Figure 1A). Blood tests revealed signs of inflammation with high levels of IgM RF (56 IU/mL), anti-CCP (>1,600 U/mL), Interleukin-2 receptor (ILR-2-1,065 kU/L) (Table 1), c-reactive protein (43 mg/L), and erythrocyte sedimentation rate (106 mm). Remaining systemic antibody examinations were negative (anti-DNA antibody, anti-nuclear antibody (ANA) IgG, anti-neutropil cytoplasmatic antibody (ANCA) IgG, Anti-Ro (SSA)/La (SSB), anti-cardiolipin antibody, phospholipid antibody, and lupus anticoagulant). Immunoglobulin A, G, and M levels were normal. Cerebrospinal Fluid (CSF) analysis revealed a mononuclear pleocytosis (170 E6/L) and elevated protein level (1.16 g/L). Due to the pleocytosis, intravenous ceftriaxone, and aciclovir were administered, to cover for bacterial meningitis and Herpes Simplex Virus (HSV) encephalitis. Subsequent CSF cultures revealed no growth of bacteria, no Borrelia antibodies, and viral/bacterial PCR (E. coli, hemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, hemolytic streptococcus, streptococcus pneumoniae, cytomegalovirus, enterovirus, herpes simplex virus, varicella zoster, Cryptococcus, and micromiome 16S/18S), and flowcytometry, and cytological analysis for malignancy were negative. Therefore, antiviral- and antibiotic- treatment was terminated. The following days the patient displayed sporadic confusion, delusions, and fever (38.5 C). Subsequent tests, including HIV, syphilis, and tuberculosis were negative. Re-examination of CSF showed continuous mononuclear pleocytosis (130 E6/L), high IgG index (1.45) and presence of oligoclonal bands, suggestive of inflammation. Repeated cultures for bacteria were negative and cytological analysis showed an inflammatory pattern with an elevated number of B-lymphocytes (7.8 %) and plasma cells (1.8%, Table 1). To investigate possible systemic inflammation or malignancy whole-body FDG-PET CT was performed. This showed hypermetabolism of the cerebral cortex, adjacent to the meningeal enhancement found on MRI, and a right medial lobe infiltrate of the lung. CT of thorax and abdomen confirmed an infiltrate, slight pleural effusion, and pleural thickening. Endobronchial ultrasound with biopsy was performed revealing no malignancy or infection. On suspicion of RM, we performed analysis on undiluted CSF showing moderately positive IgM RF (92.7 IU/mL) and strongly positive anti-CCP (19,600 IU/mL) and CXCL-13 (>500 ng/L, Table 1). Subsequent, biopsy of meninges (Figure 1C) confirmed chronic inflammation dominated by CD138 positive plasma cells and a limited number of CD3 positive T-lymphocytes with limited infiltration into the underlying gray matter (Figures 1E,F). Additionally, granulomatous inflammation with dense infiltration of CD68+ histiocytes and the presence of rheumatoid nodules were found (Figures 1D,G). Microbial stains, PCR, and cultures of biopsy tissue for fungi, parasites, acid-fast bacilli, HSV 1, HSV 2, CMV, SV40, M. tuberculosis, and toxoplasmosis were negative. Based on the (i) MRI findings with patchy meningeal enhancement, (ii) high titer of IgM-RF and anti-CCP in CSF and (iii) histopathological chronic inflammation of meninges with plasma cells and rheumatic nodules, the diagnosis RM was established. Concurrently, the patient displayed extra articular manifestations of RA in her lungs. Intravenous high dose methylprednisolone (750 + 1,000 + 1,000 mg on three consecutive days) followed by oral tapering was administered in addition to current treatment with methotrexate. Within days symptoms improved, but did not completely resolve. The following weeks, the patient received Rituximab (1,000 mg intravenous, repeated after 14 days). CSF levels of IgM RF, anti-CCP, and CXCL-13 decreased accordingly to the patient reporting significant treatment response (Table 1). A 6 month follow-up MRI showed regression of meningeal enhancement (Figure 1B) and follow-up FDG-PET CT showed almost complete regression of pulmonary findings. Neurological examination at 6 month follow up confirmed resolution of clinical symptoms.

cxcl13, anti-ccp, biomarker, inflammation, rheumatoid meningitis

PMC4861884_01

Female

At our institution, IRB approval is not required for case report studies. Our patient was a 56-year-old Caucasian female who presented to her gastroenterologist with nonspecific epigastric pain. She was subsequently found to have a 2cm intrahepatic cholangiocarcinoma infiltrating the liver hilum and resulting in right-sided biliary obstruction. The patient was initially treated at an outside institution, where a failed attempt at endoscopic biliary decompression resulted in a right-sided PTBD. The patient was then referred to us for definitive management. Once at our institution, the patient was evaluated by the transplant surgery and interventional radiology services. She underwent a successful right-portal-vein embolization; an anticipated right-liver trisegmentectomy awaited adequate future liver remnant hypertrophy, proposed to occur approximately 1 month after embolization. Unfortunately, the patient developed cholangitis in the interim. CT demonstrated the development of left biliary system dilation, in addition to multiple new punctate peritoneal implants concerning for carcinomatosis. The colon, however, was situated in such a way that a safe window for percutaneous access was not felt to exist (Fig. 1). Consequently, the decision was made to perform a diagnostic laparoscopic procedure before opening for the trisegmentectomy to rule out carcinomatosis. The laparoscopic exploration revealed multiple peritoneal implants along the right hemidiaphragm from tumor seeding after the prior right-sided PTC placement. The implants were then biopsied, and the planned liver resection was averted. The left biliary system remained obstructed and, in the setting of elevated bilirubin and the need for systemic therapy and possible radiation, the decision was made to decompress the left side. Fluoroscopic examination revealed unchanged colonic positioning. After discussion with the transplant surgeons, a combined approach, using laparoscopic techniques to displace the colon and provide percutaneous access for biliary drainage, was deemed the best option-especially given the clinical situation, as the patient was suffering from repetitive bouts of obstructive cholangitis. Informed consent was obtained for the individual in this study before any procedure was performed. The patient was placed under general anesthesia and prepped and draped in the typical sterile fashion. This was followed by a timeout and the administration of 2 grams of IV cefotetan as a preoperative antibiotic. A stab incision in the left upper quadrant was then made without complication, and the abdomen was insufflated. An additional 5mm trocar was then placed in the umbilical area, and the left upper quadrant trocar was upgraded to a 12mm. Exploration revealed multiple small nodules within the peritoneum, including nodules on the liver dome and within the omentum (Fig. 2). Several biopsies were taken from multiple locations. The laparoscope was used to displace the colon inferiorly. Laparoscopic ultrasound was performed, and the patient was noted to have a dilated left hepatic biliary system. The initial frozen sections from the biopsies revealed adenocarcinoma, consistent with malignant carcinomatosis. At this point, the interventional radiology (IR) team joined the surgical team in the OR. The IR team performed a 21-gauge-needle and antegrade percutaneous puncture with dilute contrast into the liver parenchyma. On the second pass, a left hepatic duct was opacified. A second 21-gauge needle was used to access a more peripheral left bile duct (Fig. 2). A limited cholangiogram was performed that demonstrated left peripheral biliary ductal dilation with central occlusion; however, a patent common bile duct was identified. A 0.018-inch wire was then advanced through the left peripheral biliary duct and through the common bile duct down into the duodenum. The needle was then exchanged to a 4/6 French coaxial dilator system. The 4 French inner dilator and inner stylet were removed, and a Bentson wire was advanced through the 6 French outer dilator into the small bowel. The 6 French dilator was then removed, and a micro wire was secured as a safety wire. The Bentson wire was then exchanged for an Amplatz super-stiff wire with the use of a 4 French short hockey-stick catheter. Then an 8 French internal/external, Cope-loop-type, biliary catheter was placed with its peripheral side holes distal to the stricture and its tip coiled in the duodenum. The Amplatz and safety wire were removed, and a repeat injection confirmed appropriate placement of the side holes; the catheter was then sutured into place (Fig. 3). Hemostasis was checked, and a right-upper-quadrant Jackson-Pratt drain was left. The trocars were removed, followed by suture closure of the trocar sites and suturing of the JP drain into place. The patient was then brought out of general anesthesia and recovered well.

PMC5113911_01

Female

A 27-year-old woman was seen in the eye emergency department with a 10-day history of decreased vision and pain in her right eye. The visual acuity measured by the Snellen chart was limited to 20/100 in her right eye. The visual acuity in her left eye was 20/20. Fundus examination showed an elevated nonpigmented mass in the right eye that measured ~2.5x2.5 disc diameters just superior and temporal to the optic disc (green arrows, Figure 1). There was a flat retinal detachment in the macula area, and optical coherence tomography (OCT) showed a choroidal elevated mass (892 microm diameter) associated with a serous retinal detachment (Figure 1). Differential diagnosis included choroidal neoplasia (primary tumor or metastasis), as well as infectious and inflammatory diseases. Malignancy was less likely considering the age of the patient and the presence of ocular pain, however could not be ruled out in the absence of another confirmed etiology. Blood workup showed a negative angiotensin-converting enzyme titer and negative toxoplasma and HIV serologies. The patient was considered to be at a high risk of contracting tuberculosis (TB) and had an unclear history of bacilli Calmette-Guerin vaccination (BCG) vaccination; therefore, she underwent both a QuantiFERON-TB test and a purified protein derivative skin testing. The former was positive and the latter revealed an induration of 13 mm. However, chest X-ray (CXR) was normal. The patient was then addressed to the internal medicine department for further investigations, systemic assessment, and treatment. No pulmonary or systemic involvement was detected. The diagnosis of isolated choroidal tuberculoma was retained and antituberculosis therapy (ATT) was started with daily doses of isoniazid 5 mg/kg, rifampin 10 mg/kg, and pyrazinamide 30 mg/kg, in addition to levofloxacin 750 mg/day as a second-line molecule replacing ethambutol that we wanted to avoid due to its potential of ocular toxicity. This intensive phase lasted 2 months and was followed by a continuation phase of isoniazid and rifampin for at least 4 other months, depending on the response. Visual acuity in the right eye was 20/30 after 3 months of treatment, with a shrinked choroidal tuberculoma (499 microm in diameter) as shown by OCT (Figure 2).

mycobacterium tuberculosis, oct, quantiferon-tb, choroid, choroidal mass, optical coherence tomography, tuberculoma

PMC3271300_01

Female

A 9-month-old Korean girl was referred to our clinic because of a progressive inability to move her right elbow on January 9, 2007. Approximately 3 weeks ago, the child was seen by a local orthopedic physician. The parents had noted that she was reluctant to move her right arm through complete ranges. Also, the patient would cry when the arm was abducted. At that time, the doctor of the local clinic had an initial diagnosis of a pulled elbow, in which the arm was reducted and put into an arm cast. Three days later, painful swelling in her right elbow developed with the limitation in active movement and inability to rotate. The patient was born by normal vaginal delivery with normal Apgar score. She was vaccinated with Tokyo-172 BCG on the left upper arm at one month of age. BCG vaccine was administered percutaneously by multipuncture method. She had received routine immunizations up to date including hepatitis B, diphtheria-tetanus-pertussis (DTaP), polio (IPV) in accordance with the national vaccination program guidelines. She lived in Ansan and had no history of farm or zoo visit. The patient had no previous history of illness and no known familial tuberculosis history. Physical examination revealed obvious swelling, erythema, tenderness in the area of the right elbow. Furthermore, the range of elbow movement was restricted. Other physical examinations were normal. The laboratory results at admission revealed the erythrocyte sedimentation rate 107 mm/hr and C-reactive protein (CRP) 1+. Radiological studies suggested the lesion in the elbow. Also, MRI revealed contrast enhancement in and around the right elbow, compatible with septic elbow. Signal change and contrast enhancement in the epiphysis and metaphysis of right distal humerus were noted. These features suggested septic elbow combined with osteomyelitis. No other significant abnormal finding was shown in other skeletal areas. Initially, septic elbow was diagnosed and surgery was performed to treat osteomyelitis of right elbow and revealed concentrated dirty granulation tissue in the elbow joint space that was removed. After operation, the child had been treated with ampicillin/sulbactam before the proper diagnosis had been established. Since the osteomyelitis lesion was refractory with antibiotic therapy, we considered mycobacterium as the pathogen. A lesion biopsy specimen was sent to the pathology department. Histopathological examination of the biopsy specimen revealed a chronic caseating granulomatous inflammatory reaction. Microscopic examination of the pus with Ziehl-Neelsen staining showed no Acid-fast bacilli but a culture of the biopsy was identified with Mycobacterium tuberculosis. As the postoperative diagnosis was osteomyelitis of M. tuberculosis, we started treatment with regimen of rifampin, isoniazid and pyrazinamide. Following the culture report, the sensitivity test showed that the strain was resistant to pyrazinamide. This sensitivity study was a distinguishing characteristic of M. bovis. Therefore, we requested multiplex polymerase chain reaction (PCR) for the Mycobacterium complex colony to differentiate the pathogen. A mycobacterium culture of the biopsy sample later revealed to have an identical amplification with the BCG Tokyo-172 strain on the multiplex PCR for the Mycobacterium complex colony (Fig. 1). Based on these findings, the diagnosis of osteomyelitis due to Tokyo-172 BCG vaccination was confirmed. Immunological investigation for the evaluation of cellular and humoral immunity was performed, including complement CH50, C3, and C4, immunoglobulins and intracellular oxidation (dihydrorhodamine) and revealed normal findings. Therefore, immunodeficiency disorders were ruled out. In addition, an evaluation for extrapulmonary TB was negative. The patient had been treated with a regimen consisting of rifampin (10 mg/kg body weight per day), isoniazid (10 mg/kg body weight per day) and pyrazinamide (25 mg/kg body weight per day) as an outpatient. However, after two months of treatment, MRI showed no interval change (Fig. 2). We added streptomycin (30 mg/kg body weight per day intramuscularly for 10 days) and ethambutol (15 mg/kg body weight per day) instead of pyrazinamide due to the sensitivity result. Pyrazinamide was eliminated because of it is generally considered ineffective for the treatment of BCG osteomyelitis. Following the change of regimen, debridement and curettage was again performed four months after the first surgery. The planned chemotherapy regimen was continued during 12 months. She has been followed up for 2 yr and has remained without signs of growth disturbances or impairment of function in adjacent joints. The function of the right arm was normal in terms of range of motion and activity. The most recent radiological examination showed the decrease of geographic osteolytic lesion on the distal humerus and periosteal reaction, disappearance of neighboring soft tissue swelling, which suggested improving state of osteomyelitis and arthritis. The patient recovered without complications.

bacilli calmette-guérin vaccination, complication, osteomyelitis

PMC7531285_01

Male

A 69-year-old male presented with thoracic pain, cough and fever. Past medical history consisted of diabetes mellitus, hypertension, kidney transplant (immunosuppressive regimen consisting of betalacept and sirolimus), myocardial infarction requiring the placement of a coronary stent, dual chamber pacemaker, anticoagulation for deep venous thrombosis and a laparoscopic cholecystectomy performed five months earlier in the setting of gallbladder empyema (Fig. 1). Clinical examination revealed a blood pressure of 100/80 mmHg and a heart rate of 91 bpm. Auscultation showed decreased air entry at the right pulmonary base. Abdominal and neurological exam were normal. Chest X-ray showed moderate sized right pleural effusion (Fig. 2). Computed tomography (CT) of the chest and the abdomen revealed right loculated pleural effusion associated with passive collapse of the lung and mediastinal pleural thickening. Nodular structures with peripheral calcifications of 23 mm and 31 mm were observed in relation with the right hepatic lobe and below the posterior costo-diaphragmatic recess respectively (Fig. 3). Fortunately, the operative report informed iatrogenic perforation of the gallbladder and stone spillage. Furthermore, we retrieved the surgical video, so we had a high index of suspicion of complications due to spilled gallstones (Fig. 1). Transthoracic ultrasound guided aspiration of the pleural effusion was performed. Gram negative bacteria grew in cultures. Due to patient s frailty we opted for a minimally invasive approach placing a thoracic drain guided by CT (Fig. 4). Because of the persistence of the loculated pleural effusion and the lack of clinical improvement we decided to perform a lung decortication by video assisted thoracoscopy (VATS). The patient was operated under general anesthesia, using a double-lumen tube. The surgical team was formed by a thoracic surgery resident (operating surgeon) and a staff surgeon as an assistant. We used two 12 mm incisions and performed an extension over the place where the previous thoracostomy tube was inserted for the use of an Alexis retractor device. After decorticating the lung, we exposed the fissure and drained a collection in the posterior costo-diaphragmatic recess, seen in the CT. During the procedure a 1 cm defect was observed in the diaphragm (Fig. 5). Remnants of gallstones were retrieved from the subphrenic space and sent for bacteriological study. We performed the closure of the diaphragm defect with a non-resorbable suture and placed two chest tubes. The procedure was well tolerated by the patient and recovered in the intensive care unit (ICU) until post-operative day 3 when he was transferred to the general ward. Bacterial culture was positive for Extended Spectrum Beta-Lactamase (ESBL)-positive Escherichia coli, susceptible to erythromycin, imipenem, meropenem and tigecycline. Chest tubes were withdrawn on days 5 and 7 respectively. Post-operative was uneventful until day 13, when the patient breakthrough with fever. A chest CT scan and a Covid 19 test (reverse-transcription polymerase chain reaction) were performed. The chest CT revealed persistence of the right pleural effusion with spontaneous hyperdense content, suggestive of hemothorax (Fig. 6). The Covid test result was positive. After analyzing the case in a multidisciplinary team, we decided to perform a second VATS lung decortication to evacuate clotted blood and prevent further consequences. No active bleeding was found. Chest tubes were withdrawn on day 4 and 5 respectively. Chest x ray showed no pleural effusion or pneumothorax (Fig. 7). On post-operative day 7 the patient developed type 1 respiratory failure, with elevated breathing rate and requirement of a venturi mask at 40 % O2 to maintain blood saturation over 93 %. A new chest CT revealed multifocal ground glass patterns with thickened interlobular and intra lobular lines (Fig. 8). The patient was presented to the palliative care specialists and the ethics committee. Due to Covid-19 outbreak and the risk of aerosolization, non-invasive positive pressure ventilation (NIPPV) was not an option. Also, the patient was tagged as "low priority" for admission to ICU, since the scarce of beds and the few chances to benefit from the ICU. After considering the patient s preferences with his surrogates, the comfort-focused care was opted. The patient died on post-operative day 11.

case report, laparoscopic cholecystectomy, spilled gallstones, thoracic complications

CT guided thoracostomy tube placement. B) Thoracentesis needle advancing into the pleural space.

PMC10333569_01

Female

The mother was a first-time mother, and the baby was conceived naturally. The mother enjoyed eating cheese both before and during the pregnancy. She noted decreased fetal movements at 31 weeks and 1 day, and increased abdominal tension and bloating at 31 weeks and 2 days. Ultrasonography revealed intestinal dilatation and peri-intestinal strong echo patterns in the fetus, and the mother was sent to our hospital on suspicion of fetal meconium peritonitis due to intestinal tract perforation. Ultrasonography performed on arrival at the hospital revealed fetal heartbeats and fetal movements, together with dilated gastric bubbles and honeycomb-shaped intestinal dilatations (Figures 1A,B). The amniotic fluid index (sum of four quadrant measurements of the deepest pocket in the vertical dimension with a normal range of 5-25 cm) was high (27 cm). The echo intensity of the gastric bubbles and amniotic fluid was biphasic, with areas of high intensity. The maximum systolic blood flow velocity of the middle cerebral artery was 71 cm/s, which suggested severe anemia. The cardiotocogram revealed the disappearance of baseline fetal heart rate changes. Based on the above findings, we suspected hydramnios and hematogenous amniotic fluid and determined that the nonreassuring fetal status was due to intestinal obstruction and impaired placental function. Therefore, an emergency Cesarean section was performed due to the nonreassuring fetal status. The amniotic fluid was brown and had a mixture of turbidity due to fecal material and old blood. The baby cried immediately after delivery and had no bradycardia. Immediately after birth, old bloody fluid was withdrawn from the oral cavity and stomach, and one minute after birth, watery old bloody stools were seen at the anus. The Apgar scores at 1 min and 5 min were 8 points and 9 points, respectively. The birth weight was 2,127 g, height was 45 cm, and the newborn's vitals were stable. There was no external malformations. Ultrasonography revealed dilatation of the small intestine, and chest radiography revealed little intestinal gas (Figures 2A,B). Peripheral blood examination revealed a low Hb level of 12.7 g/dl. The white blood cell count was 47,100/mul (Seg: 50.0%, Band: 12.0%, Eosino: 6.0%). Leukocytosis and eosinophilia were initially observed; however, the eosinophil count started to decrease thereafter. The patient's clotting profile was normal, PIVKA-II was 69 mAU/ml, and vitamin K deficiency was ruled out. Blood culture was negative; sputum and stool culture did not detect any significant bacteria either. The stool mucus test revealed eosinophil accumulation. The IgE level was 2 IU/ml (not elevated). The specific IgE antibody titers by CAP-Radioallergosorbent test method test was negative for milk antigens (alpha-lactoglobulin, beta-lactoglobulin, milk, and casein, at <0.10 UA/ml each). Allergy testing by the allergen-specific lymphocyte stimulation test (ALST) was negative for kappa-casein (SI 0.79), positive for lactoferrin (SI 3.21), and negative for alpha-lactalbumin (SI 1.48). Bloody stools and intragastric residues decreased and improved with time after admission. Oral food challenge test of the extensively hydrolyzed protein formula (new MA-1, Morinaga Milk Industry Company, Ltd., Tokyo, Japan) was started at 3 days of age. After that, she underwent an oral food challenge test using breast milk without maternal intake of dairy product and was allowed to feed independently on breast milk without dairy products after 48 days of age. Her condition stabilized and she was discharged from the hospital at 67 days of age. She is currently corrected 11 months old, and no neurodevelopmental disorders are observed. This study was approved by the Institutional Review Board of the Ethics Committee of the University of Tokyo Hospital (approval ID: 2701).

fetal gastrointestinal bleeding, food allergy, honeycomb sign, neonatal transient eosinophilic colitis, non-ige-mediated gastrointestinal food allergy, premature infants

PMC5322244_01

Female

A 77-year-old female residing at home with probable AD of moderate severity and history of depression for two to three years prior to the onset of AD, was evaluated for increasing agitation and psychosis. Caregivers reported that the patient was sleepless, had intense anger outbursts, persecutory auditory hallucinations, and paranoia. She continually paced, opening drawers, unpacking and repacking their contents. At the time of evaluation, she was being treated with quetiapine 25 mg and paroxetine 10 mg daily. Based on the physician's discussion with the patient and family the patient did not receive cholinesterase inhibitors. Lithium 150 mg was added and increased from 150 mg to 300 mg daily after two weeks. By week two she had a normal sleep cycle with a marked decrease in paranoia, auditory hallucinations, agitation, and aggression. Her serum lithium level was 0.32 mmol/L after 10 weeks of treatment and she experienced no adverse events.

PMC5322244_02

Male

A 67-year-old male with probable AD and a history of depression was evaluated for worsening auditory and visual hallucinations, paranoia, anxiety, anger and frustration. He presented with persistent agitation, anger outbursts and shuffling gait. The patient repeatedly called his son every day. At the time of evaluation, he was taking quetiapine 100 mg, memantine 20 mg and sertraline 100 mg daily; trazodone 50 mg was added for insomnia a few weeks later. Lithium 150 mg was added and titrated up to 600 mg daily in intervals of 150 mg every two weeks. After six weeks on lithium, olanzapine 15 mg daily was added, and quetiapine was stopped. At the final clinic visit he remained on olanzapine 15 mg, sertraline 100 mg, trazodone 50 mg and lithium 600 mg daily. He exhibited marked reduction in symptoms with a decrease in anger outbursts, physical aggression, paranoid delusions and accusations, and improved gait after 12 weeks on lithium and 6 weeks on olanzapine. His serum lithium level was 0.30 mmol/L at 12 weeks and he experienced no adverse events. The patient's agitation was effectively managed during 24 months of follow-up, although he was institutionalized when his disease progressed.

PMC5322244_03

Male

A 79-year-old male with mild probable AD and a history of late-onset anxiety and depression was evaluated for uncontrollable anger outbursts and agitation. He had become extremely argumentative with both his wife and his co-workers at a part-time job. When unable to complete a task he would become uncontrollably angry and grabbed his wife's wrists once. At the time of evaluation, the patient was taking donepezil 10 mg, bupropion 300 mg, lorazepam 0.5 mg, and trazodone 50 mg daily. He was started on lithium 150 mg, which was increased to 300 mg daily after two weeks. After 12 weeks of lithium treatment, he exhibited a significant decrease in angry thoughts, frustration, and irritability. His last recorded serum lithium level, after 8 weeks of treatment, was 0.32 mmol/L. He remained on lithium and continued to work part-time without any adverse events. He continued to decline cognitively with persistent but less severe agitation.

PMC5322244_05

Male

A 55-year-old male with semantic variant-primary progressive aphasia was evaluated for outbursts of severe agitation, skin picking, frequent elopement attempts, and multiple instances of shoplifting. At the time of evaluation, he was being treated by another psychiatrist with donepezil 23 mg, clonazepam 1 mg, duloxetine 60 mg, fluvoxamine 100 mg, venlafaxine 37.5 mg, lisdexamfetamine 30 mg, and lithium 600 mg daily. When behavioral symptoms did not fully resolve, lithium was increased to 1200 mg daily, which was reduced to 600 mg after one week when he became sedated and developed a tremor. The initial improvement in behavioral symptoms was maintained and all other psychiatric medications were tapered and discontinued over time. The patient remained on lithium until his death two years after starting treatment. Serum lithium levels were not recorded.

PMC3685357_01

Female

A 72-year-old woman, in good general performance status, with 4-year symptoms of a slowly growing tumor located at the base of the nose, is presented. The first symptom of disease was a small tubercle located at the base of the nose, near to the internal angle of the right eye, which occurred in January 2003. The patient was initially diagnosed by an ophthalmologist in Rzeszow, Poland, and computed tomography (CT) was ordered. It was performed in May 20, 2003 and it revealed: "Within the sclerotic ethmoid sinus, osteolytic defect with diameter 2 cm and Hounsfield density 37 is present, filled by soft-tissue mass. Penetration to frontal sinus and right orbit with destruction of its medial wall is observed but without infiltration of intraorbital structures". A representative sample for histopathology examination was taken and showed: "Abundant inflammatory infiltration composed of plasmatic and lymphocytic cells, epithelial granulomas with caseation necrosis, tuberculous like, focally pyonecrosis and squamous cell metaplasia within surface" (Department of Pathology, Rzeszow). Based on this, the decision to leave the patient in regular follow-up was taken. One month later control CT showed stable disease, with suggestion of sarcoidosis and tuberculosis as well as the possibility of Wegener's granulomatosis. Chest X-ray and abdominal cavity ultrasonography excluded the presence of other pathologies. All blood tests (morphology, liver and renal parameters) and urinalysis were in the normal ranges, so follow-up examinations were suggested. The next CT, performed on September 13, 2003 revealed: "At the right base of nose, soft tissue mass with size 3.1 x 2.9 cm, non-enhancing significantly after contrast injection, is observed. This pathologic structure brings skin in frontal region into relief, penetrates into right orbit with pressure on its structure, resulting in exophthalmos. Tumor is located in non-formed right frontal sinus. It causes massive destruction of right frontal bone, nasal bones, especially right, laminae of the ethmoid bone. Tumor does not penetrate into anterior cranial fossa. Destruction of nasal conchae (upper and middle), nasal septum and medial walls of both maxillary sinuses causing communication with nasal cavity is present. Progression of disease". As a consequence of disease progression, verification of histopathology specimens was performed in the Department of Pathology, Cancer Center and Institute of Oncology in Warsaw (October 2003). A diagnosis of Wegener's granulomatosis was ascertained. Immunosuppression therapy was started: between October 2003 and March 2004 therapy with cyclophosphamide and prednisone was applied, and then therapy based on methotrexate and prednisone was continued to January 2005. Partial regression with long lasting (more than two years) stagnation of tumor size was observed. In June 2007 the patient reported the regrowth of the tumor. For this, radiotherapy was offered and the patient was directed to the Cancer Center and Institute of Oncology, Gliwice Branch. The first visit and the examination in the First Department of Radiation Oncology of the Institute took place on September 21, 2007. Frontal headache and excessive right eye tear secretion were the main complaints of the patient. During physical examination a smooth, well-contoured tumor located at the right base of the nose and near the internal angle of the right eye with size 5 x 4 cm (measured with skin, skin not infiltrated) was described. The tumor caused a slight right exophthalmos, but without eyeball movement limitation, diplopia or vision defects. CT performed in our institute was consistent with the previous one, but progression to 3.4 cm in the greatest dimension was observed (Figs. 1A, 1B). Radiotherapy was performed in November, 12-29, 2007 in the First Department of Radiation Oncology. The treatment was planned with the intensity modulated radiotherapy (IMRT) technique. The arrangement of the irradiation fields is presented in Fig. 2. Because of close proximity to the right eyeball and lens, a total radiation dose of 30 Gy conventionally fractionated (2 Gy) was prescribed. Therefore the maximal radiation dose within the right lens did not exceed 5 Gy. No acute effects were observed; tolerance of treatment was very good. The left lens received a radiation dose insignificant for late complications. Routine follow-up has been performed since the end of treatment in our center. No regression was observed during the first visit, two months after radiotherapy. However, slow, but gradual shrinkage progressed, at first as flattening of the tumor and next as decrease of its dimensions. The regression process lasted 12 months, to March 2009, when complete clinical response was achieved. To ascertain radiological remission, in June 29, 2009, computerized tomography was done - "At present CT no previously described tumor is observed. In its bed only scarring and loss of tissue without contrast enhancement is present. Also partial loss in nasal and frontal bones is seen. Part of nasal septum, nasal conchae and middle walls of maxillary sinuses are not visualized" (Figs. 3A, 3B). The eye examination, performed 3 years after the end of radiotherapy, showed no radiation complications within the organ of vision. Also acuity of vision was still in the normal range. The last examination was performed in March 2011 and no symptoms of relapse were observed.

wegener's granulomatosis, head and neck, radiotherapy, treatment

PMC3578668_01

Female

A 19-year-old girl presented to the Emergency Department at 1 am after having a football kicked from a distance of 5-10 m into her abdomen 7 h previously whilst watching a game. She complained of worsening diffuse abdominal pain and vomiting. Her observations were stable; however, on examination, her abdomen was diffusely tender and there was evidence of generalized peritonism. She had a white cell count of 18.8 x 109/l, but the rest of her blood tests, including amylase, was normal. Her chest radiograph did not show any evidence of free air under the diaphragm. A computed tomographic (CT) scan of her abdomen and pelvis was arranged, which showed abnormal areas of low attenuation and multiple pockets of air in the right flank, surrounding the right kidney and in the right sub-hepatic space, consistent with a perforation of either the ascending colon or the duodenum (Fig. 1). A laparotomy was performed and a 0.5 cm perforation was seen in the antero-lateral border of the duodenum at the junction of the first and second parts of the duodenum following kocherization. The perforation was oversewn and repaired with an omental patch. She recovered well from the operation and was discharged 4 days later.

PMC5686224_01

Female

A liver tumor was incidentally detected in a 64-year-old female during a medical examination. The patient had no significant past medical history, drug history, family history, including any relevant genetic information, or psychosocial history. The results of a general physical examination were normal. No abnormal laboratory findings were observed. Serum carcinoembryonic antigen and carbohydrate antigen 19-9 were 4.0 ng/mL and 20.3 U/mL, respectively. These values were within the standard ranges. Abdominal ultrasonography revealed a 20-mm liver tumor of segment 8. CT showed a 20-mm liver tumor of segment 8 with no enhancement in the early phase and very slight enhancement in the late phase (Fig. 1a and b). MRI with contrast revealed a 20-mm liver tumor of segment 8 with low signal intensity on T1-weighted images and slightly high signal intensity on T2-weighted images (Fig. 1c and d). The preoperative radiological findings were assumed to resemble the enhancement pattern of cholangiocellular carcinoma. Thus, this lesion was assigned a preoperative classification of pT1N0M0 stage I according to the 7th Union for International Cancer Control guidelines. Therefore, the patient underwent a partial liver resection of segment 8. This patient had good cardiopulmonary function and performance status in preoperative assessment. The operation was performed by R.M., who was a senior hepatobiliary pancreatic surgeon. The patient's postoperative recovery was uneventful, and she was discharged from the hospital after 10 days. At the time of publication, the patient exhibited no systemic sarcoidosis reaction, including in the liver. Therefore, the patient was observed without pharmacological therapy. Histologically, the liver tumor was 20 x 15 x 14 mm3 in volume (Fig. 2a). The tumor exhibited sarcoidosis lesions with a conglomerate of epithelioid granulomas with giant cells surrounded by a thin layer of lymphocytes (Fig. 2b and c). No histopathological findings indicated other granulomatous liver diseases, including Mycobacterium tuberculosis or mycosis.

cholangiocarcinoma, cholangiocellular carcinoma, hepatic sarcoidosis, liver, sarcoidosis, surgery

PMC2874368_01

Female

We report pneumonia associated with pandemic (H1N1) 2009, which resulted in respiratory and renal failure and death, in a 39-year-old HIV-positive woman. She had type 1 diabetes and a diagnosis of AIDS 7 years ago and had received highly active antiretroviral therapy. She also had an ill child at home with an influenza-like illness. Her medical history included pleuropericardial Nocardia spp. infection, recurrent pleural effusions requiring thoracentesis, and hepatomegaly of unknown cause. Her most recent CD4 cell count was 166 cells/muL with undetectable viral load 1 month before admission. Medications prescribed included combivir, efavirenz, and trimethoprim/sulfamethoxazole but she was noncompliant. She had received the 2008-09 seasonal influenza vaccine and pneumococcal vaccine. The patient was admitted to Winthrop-University Hospital (Mineola, NY, USA) on June 5, 2009, for community-acquired pneumonia. She received empiric moxifloxacin and atovaquone. Because of concern for persistent Nocardia spp. infection, she was also treated with doxycycline. The result of a rapid influenza test (QuickVue; Quidel, San Diego, CA, USA) was negative for a nasal swab specimen on day 1 of hospitalization. Over the next 48 hours, her clinical status deteriorated, and she experienced worsening hypotension and respiratory distress. On admission, she had fever (101 F) for 3 days, pulse rate of 109 beats/min, blood pressure of 86/52 mm Hg, respiratory rate of 22 breaths/min (oxygen saturation of 88% on room air), generalized weakness, nonproductive cough, and increasing shortness of breath. She was alert and oriented. Physical examination showed decreased breath sounds at bases, hepatomegaly, and bilateral edema in the lower extremities. Laboratory tests showed 3,000 leukocytes/mm3 (93% neutrophils, 2% bands, and 3% lymphocytes), hemoglobin level of 12.7 g/dL, and 118,000 platelets/mm3. Other laboratory values were blood urea nitrogen 66 mg/dL, creatinine 2.9 mg/dL, creatinine phosphokinase 2,276 IU/L, and lactic acid 3.6 mmol/L (anion gap 13). A chest radiograph showed moderate pleural effusion in the right lung and retrocardiac air space disease. Test results for influenza virus, respiratory fluorescent antibodies (D3 Ultra DFA Respiratory Virus Screening and Infectious Disease Kit; Diagnostic Hybrids, Inc., Athens, OH, USA), and virus culture were negative. The patient was transferred to the intensive care unit and required intubation, pressor support, and continuous venovenous hemofiltration for fluid removal. Empiric oseltamivir (150 mg 2x/d) was started on hospital day 3; moxifloxicin was discontinued, and meropenem was given for pneumonia. Thoracentesis showed transudative fluid negative for acid-fast bacilli, bacteria, and fungi. Results of blood cultures and urine analysis for Legionella spp. antigen were negative. Repeat chest radiography showed a right-sided pneumothorax and worsening bilateral airspace disease. A chest tube was inserted in the right lung, and bronchoscopy was performed on hospital day 5. Results of bronchoalveolar lavage were negative for Pneumocystis jiroveci, virus inclusions, fungi, acid-fast bacilli, bacteria, and mycobacteria. However, clusters of filamentous organisms were seen. On hospital day 5, results of a second rapid influenza test, respiratory fluorescent antibody test, and nasopharyngeal virus culture were negative. Diagnosis was based on a positive result for pandemic (H1N1) 2009 by real-time reverse transcription-PCR (RT-PCR) for a nasopharyngeal swab specimen (New York State Department of Health). Despite empiric treatment with oseltamivir, the patient died on June 15, 2009 (day 11 of hospitalization). Symptoms of pandemic (H1N1) 2009 in HIV-infected persons are not known. However, these persons have a higher risk for complications. In previous seasonal influenza outbreaks, HIV-infected persons had more severe infections and increased hospitalization and mortality rates. Although a diagnosis of pandemic (H1N1) 2009 was first considered for our patient because of her ill child, she was not initially treated with oseltamivir because of the negative influenza test result and concern for opportunistic infections. Only the result of an RT-PCR for pandemic (H1N1) 2009 was positive. No other pathogens were detected in her blood, urine, sputum, bronchoalveolar lavage, or thoracenthesis fluid. Empiric treatment in patients with pandemic (H1N1) 2009 should be considered in those seeking treatment for influenza-like symptoms, especially in the setting of sick contacts with respiratory illnesses. Rapid influenza tests, respiratory fluorescent antibody tests, and viral cultures may not provide a diagnosis. An RT-PCR for pandemic (H1N1) 2009 may be needed to provide a diagnosis.

PMC5461570_01

Female

A 49-year-old woman presented with the chief complaint of "I can hear my eyes move." Her symptoms included chronic dizziness, sensitivity to loud sounds, and autophony. Approximately 10 years prior to presentation, she began noticing that she would feel vertigo when near sirens, during applause in stadiums, or when the radio volume was high while driving in the car. She would experience momentary dizziness with coughing or straining, and could hear her heartbeat constantly in her left ear. In addition to hearing her eyes move, she heard her back cracking in her left ear and each swallow transmitted loudly to that ear. On physical examination, her ears appeared normal by otoscopy. She had normal vestibulo-ocular reflex function to rapid head impulses in the planes of each semicircular canal. Dix-Hallpike positioning maneuvers did not elicit any positional nystagmus or vertigo. Using infrared goggles, however, vertical nystagmus was seen in the plane of the left superior semicircular canal when 500 Hz and 750 Hz tones were applied to the left ear at 110 dB hearing level (HL). Simultaneous head movements in the plane of the left superior semicircular canal were also observed with application of these tones. An audiogram showed normal hearing bilaterally, with a 20 dB gap between air conduction and bone conduction thresholds at 250 Hz in the left ear and a bone-conduction threshold of -10 dB HL indicating bone-conduction hyperacusis [Figure 1a]. Ocular VEMPs were performed and showed abnormally large amplitudes in response to 500 Hz tone bursts applied to the left ear (70.9 muV, Figure 1b), suggesting a diagnosis of SCDS. Cervical VEMPs in response to click stimuli revealed a reduced threshold of 70 dB nHL in the left ear and a normal threshold in the right ear (90 dB nHL). CT scan of the temporal bone was performed and demonstrated a dehiscence of the left superior semicircular canal [Figure 2]. She elected to proceed with surgical plugging and resurfacing of the affected canal by the middle cranial fossa approach. During surgery, ECochG and ABR were simultaneously recorded, and are shown in Figures 3 and 4. A large elevation of SP resulted in an SP/AP ratio >1 [Figure 3a], which persisted throughout the case as shown by the stacked traces and the post-plugging result [Figures 3b, c and e]. This is in contrast to the conventional SP/AP ratio on the contralateral side [Figure 3d]. Note the typical wave I of the ABR for the contralateral side [Figure 4a] but the appearance of a separate wave preceding wave I on the affected side, which appears to represent the large SP. The elevated baseline SP and wave I of the ABR increased further in amplitude during the case, and remained elevated at the conclusion of surgery. She recovered well from surgery, with complete resolution of her symptoms of autophony and sound or pressure-induced vertigo. As expected, she transiently had oscillopsia with head movements in the plane of the superior semicircular canal that symptomatically improved after vestibular physical therapy. Follow-up audiogram 3 months after surgery demonstrated resolution of the air-bone gap and bone conduction hyperacusis, with no sensorineural hearing loss [Figure 1c]. Similarly, the elevated ocular VEMP amplitude was normal after surgery [Figure 1d].

electrocochleography, auditory brainstem response, superior canal dehiscence syndrome