Aims Several studies have shown that twice-daily injection of premixed insulin analog (MIX) therapy achieves glycemic control equivalent to that with basal-bolus (BB) therapy. However, glycemic fluctuations that lead to oxidative stress may be associated with the risk of diabetic complications. Therefore, in this study, we compared oxidative stress markers between MIX therapy and BB therapy.
Methods In this cross-sectional study, we recruited a total of 37 patients (17 patients in the BB group and 20 patients in the MIX group) and compared urinary 8-isoprostane and urinary 8-hydroxydeoxyguanosine (8-OHdG) levels.
Results There were no significant differences in urinary 8-isoprostane (BB vs MIX: 199±92 pg/mg Cr vs 266±107 pg/mg Cr) or urinary 8-OHdG (4.7±1.6 ng/mg Cr vs 5.4±1.9 ng/mg Cr, respectively).
Conclusion These results suggest that MIX is equivalent to BB in terms of glycemic fluctuations and oxidative stress.

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Objective The aim of this study was to investigate the clinicopathological characteristics of interstitial lung disease (ILD) patients with anti-aminoacyl-tRNA synthetase (anti-ARS) autoantibodies.
Patients and Methods We examined 14 ILD patients with anti-ARS autoantibodies between 2004 and 2007 and retrospectively investigated their clinical, radiographic, and pathological findings.
Results Anti-Jo-1 antibodies were the most common (10 of 14), followed by anti-OJ, anti-KS, and anti-EJ (1 each for 3 patients); 1 patient with polymyositis had both anti-Jo-1 and anti-PL-12 antibodies. Ten patients had a chronic clinical course, whereas 4 presented with subacute deterioration. Of 8 patients with myositis, 1 (12.5%) had myositis-preceding ILD, 3 (37.5%) had ILD-preceding myositis, and 4 (50%) had simultaneous onset. Chest high-resolution computed tomography frequently showed lung-base predominant ground glass opacities (GGO) with volume loss. The results of surgical lung biopsies indicated that 4 patients had nonspecific interstitial pneumonia (NSIP) and/or organizing pneumonia (OP) patterns. All but 1 received corticosteroid therapy, and 6 patients were also given cyclosporin. The mean duration of follow-up was 22 months (range, 5-47 months). ILD improved in 9 patients and stabilized in 3; however, in 1 patient, it initially improved during 6 months, then progressively worsened despite treatment, and finally resulted in death.
Conclusion These results indicate that ILD patients with anti-ARS antibodies usually have a chronic clinical course, lung-base predominant GGO with volume loss, NSIP and/or OP patterns, and a good response to corticosteroid treatment; however, some have a rapidly worsening course and recurrence, despite therapy.

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Objective The aim of this study was to investigate the responses of serum osteocalcin (OC), undercarboxylated osteocalcin (ucOC) and N-terminal telopeptide of type I collagen (NTx) to corticosteroids, and to examine the effects of risedronate therapy with or without vitamin K₂ supplementation on bone metabolic markers in corticosteroid-treated patients.
Methods Sixteen patients on corticosteroid therapy for neuromuscular disorders were assigned randomly to 2 groups (A: risedronate monotherapy, n=8; B: combined risedronate and vitamin K₂ therapy, n=8) and treated for 1 year. Another 6 patients who received intravenous steroid pulse therapy were assigned to group C for investigation of the effects of corticosteroids on OC and ucOC 1 month after pulse therapy.
Results Serial measurements revealed that significant decreases of OC, ucOC and NTx persisted with a similar time course profile during 1 year of treatment in groups A and B, and between-group analysis failed to demonstrate any additional effects of vitamin K₂ on risedronate therapy. Intravenous steroid pulse therapy induced a transient depression of OC and ucOC within 1 week in group C.
Conclusion These results indicate that serum concentrations of OC and ucOC become consistently low during corticosteroid administration despite risedronate therapy with or without vitamin K₂ supplementation, and the serum ucOC level may not be a reliable indicator of vitamin K status under corticosteroid administration.

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A 79-year-old Japanese woman diagnosed with pure red cell aplasia (PRCA) associated with thymoma and hypogammaglobulinemia (Good's syndrome) was successfully treated with cyclosporine-A after a thymectomy. We further studied the etiology of this case. A burst-forming unit erythroid (BFU-E) assay with SCF restored erythropoiesis in vitro. SCF production was reduced in bone marrow stromal cells; however, it was restored in vitro and in vivo after cyclosporine-A treatment.

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We herein present a case of membranous nephropathy associated with chronic hepatitis B following acute hepatitis B virus (HBV) infection. A 22-year-old man was admitted to our hospital for evaluation of proteinuria, pitting edema on both legs, and increased body weight in December 2002. At the age of 18, he had suffered from acute hepatitis A and syphilis, and was found to be negative for hepatitis B surface antigen (HBsAg). Furthermore, he suffered from acute hepatitis B (AH-B) at the age of 21; he was found to be positive for HBsAg and anti-IgM antibody to core antigen (IgM HBcAb). However, he discontinued outpatient treatment before confirmation of HBsAg clearance or the appearance of antibody to HBsAg (HBsAb). At the present admission, HBsAg, antibody to hepatitis B e antigen (HBeAg), and HBcAb were positive, while IgM HBcAb was negative. His genotype of HBV was type A (HBV/A). Histopathological findings of the renal biopsy specimen confirmed glomerulonephritis and glomerular deposition of HBsAg. Thus, he was diagnosed as having nephrotic syndrome caused by membranous nephropathy (MN) associated with chronic hepatitis B (CH-B) following AH-B. Although interferon-alpha (IFN-α) administration was started for the treatment and temporary improvement of proteinuria was observed, remission of MN was not achieved.

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A delayed pericardial effusion developed in a recipient of a cardioverter defibrillator (ICD). After an uneventful implant procedure and postoperative recovery, the patient suffered loss of appetite and fatigue, and was re-admitted to the hospital 48 days later. Her vital signs were stable and cardiac silhouette on chest roentgenogram was normal. However, blood cell counts and chemistry revealed the presence of anemia and liver dysfunction, an echocardiogram showed a diffuse pericardial effusion, and computed tomography suggested that the ICD lead, screwed in the right ventricular outflow tract, had perforated the wall. In order to make a prompt diagnosis and initiate timely corrective treatment, the physician in charge of long-term follow-up should remember that a pericardial effusion can be delayed and accumulate in the absence of typical signs of cardiac tamponade after ICD lead implantation.

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The patient was a 69-year-old woman with a family history of type 2 diabetes. Her body mass index was 31.5. She was diagnosed as type 2 diabetes 32 years previously, and treated with insulin for 8 years. She had no episode of weight loss. She was hospitalized with diabetic ketoacidosis for the first time. Her GAD antibodies were not detected. However, ICA antibodies and insulin antibodies were positively detected. She was diagnosed with type 1 diabetes. Interestingly, her diabetes state was controlled to the same level after recovery from ketoacidosis.

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A 60-year-old woman diabetic patient presented with a subcutaneous mass in right lower abdominal quadrant where recombinant human insulin or insulin analogue had been injected for 16 years. Her diabetes has been insulin resistant with insufficient blood glucose control. The mass was extirpated under the suspicion of neoplasm but it was found to consist of diffuse deposition of eosinophilic amorphous materials mixed with inflammatory change. Congo-red staining demonstrated positive red color and yielded green birefringence by polarized microscopy. Pre-digestion with potassium permanganate was incomplete to quench positive Congo-red stains. Immunostains with insulin antibody were positive for this deposition but not so with amylin or AA or AL amyloid. Thus, the mass was considered to be localized amyloidosis composed of iatrogenic A-Ins type amyloid. Thus, the case suggested that her insulin resistance, i.e. refractoriness of insulin treatment, may be ascribed to poor penetration of injected insulin and human insulin itself or its analogue is amyloidogenic to form a local mass.

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We report two cases of type 1 diabetes mellitus (T1DM) which developed after interferon (IFN) therapy for chronic hepatitis C. The patients had experienced abrupt hyperglycemia with positive anti-glutamic acid decarboxylase antibodies, resulting in initiation of insulin therapy. In one case, insulin therapy could be discontinued because endogenous insulin secretion was preserved at the onset and pancreatic β cell function was recovered thereafter. In the other case with Hashimoto's thyroiditis and Sjögren's syndrome, continuation of insulin therapy was necessary because blood glucose levels were unstably controlled. Lasting autoimmunity superior to immunosuppressive mechanism may be associated with distinct clinical courses in these cases.

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Drug rash with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS), is a severe adverse drug reaction affecting multiple organs caused by drug treatment. The current report describes a man who was prescribed zonisamide for epilepsy and subsequently developed widespread skin rash, acute kidney injury, high-grade fever, eosinophilia, liver dysfunction, lymphadenopathy and an increase in antihuman herpesvirus-6 immunoglobulin G titer. Hypersensitivity to zonisamide was confirmed by the skin patch test. Based on these findings, the patient was diagnosed with DRESS/DIHS caused by zonisamide. This is the first report of acute kidney injury due to zonisamide-induced DRESS/DIHS.

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In this 71-year-old man diagnosed as obstructive sleep apnea syndrome initially, the apnea-hypopnea index in polysomnography was 31.3/hour. He started auto-adjusted continuous positive airway pressure (auto-CPAP) treatment in July 2005 but developed congestive heart failure in December 2007. Pulmonary arterial pressure (PAP), estimated by echocardiography, was 71 mmHg. In January 2008, during simplified sleep examination with a breath-movement sensor under auto-CPAP, many central-type apneas were recognized. After replacing auto-CPAP with adaptive servo-ventilation (ASV), the apnea-hypopnea index was 5.3/hour and PAP became 36 mmHg after 3 months. It was thought that the increase of PAP was due to long-term inadequate use of auto-CPAP.

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A 74-year old man was admitted to our hospital with right diffuse pleural thickening and effusion and with subcarinal lymph node swelling. The effusion obtained by thoracentesis showed no malignant cells, although positron emission tomography showed abnormal uptake in the right pleural thickening and subcarinal lymph node. Histopathological examination of the lymph node specimens obtained by endobronchial ultrasound-guided transbronchial needle aspiration showed a sheet of epithelioid-like large atypical cells. The tumor cells were immunohistochemically positive for calretinin and cytokeratin 5/6, and negative for CEA and TTF-1. Therefore, malignant pleural mesothelioma of epithelioid type was diagnosed.

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A 40-year-old woman with no major medical illness except for morbid obesity (BMI 40.7) was admitted to our hospital because of bilateral pneumonia due to a novel swine-origin influenza A (H1N1) virus (S-OIV). Non-invasive ventilation was introduced because of the hypoxemia. The description of bronchoalveolar lavage fluid findings showed an alveolar hemorrhage and neutrophilic inflammation. No evidence of bacterial infection was found. She was treated with oseltamivir and sivelestat sodium, neutrophil elastase inhibitor and thereafter was successfully discharged from the hospital. This case is the first report of a patient with acute lung injury with an alveolar hemorrhage caused by the S-OIV.

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Percutaneous cryotherapy (PCT) under computed tomographic guidance is minimally invasive, with satisfactory local control of primary lung cancer and pulmonary metastatic lesions. We report a case of acute respiratory distress syndrome (ARDS) in a patient who underwent PCT for lung metastasis of recurrent esophageal cancer. The patient responded to pulse steroid therapy and recovered from severe respiratory failure. Excessive inflammatory response to necrotic debris might contribute to the development of ARDS. To the best of our knowledge, this is the first report describing the details of ARDS following PCT.

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A 51-year-old man was admitted to our hospital with cough, hemosputum, dyspnea and chest pain. Chest high-resolution computed tomography (HRCT) revealed diffuse ground-glass opacities in both lungs with peripheral predominance. Bronchoalveolar lavage fluid was fresh-bloody and analysis indicated an increase in the eosinophil proportion. Benzbromarone-induced lymphocyte stimulation test was positive. Therefore, the patient was diagnosed as having drug-induced eosinophilic pneumonia with pulmonary alveolar hemorrhage caused by benzbromarone. After discontinuation of benzbromarone and administration of corticosteroids, chest HRCT images and respiratory manifestation improved. Here, we report this rare case of benzbromarone-induced eosinophilic pneumonia with pulmonary alveolar hemorrhage.

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A 30-year-old Japanese woman with lymphangioleiomyomatosis (LAM) developed a left chylothorax and chylous ascites. A pleuro-peritoneal communication was confirmed by a scintigram with ⁹⁹mTc-labeled macroaggregated-albumin injected into the peritoneal cavity. Video-assisted thoracic surgery revealed a protruding papillary lesion on the left diaphragm. Chyle was oozing into the pleural cavity through this lesion. Histopathological analyses demonstrated that the protrusion was a diaphragmatic LAM lesion and that LAM-associated lymphangiogenesis enabled communication between the pleural and peritoneal cavities through lymphatic vessels. This case demonstrated a new mechanism for chylous pleural effusion in LAM and illustrates the significance of LAM-associated lymphangiogenesis.

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This report describes a patient with extramedullary relapse of acute myeloid leukemia (AML) without involving bone marrow. A 57-year-old man was diagnosed as having acute monoblastic leukemia with t(9;11)(p22;q23) and trisomy 8. Ten months after achieving complete response (CR) with chemotherapy, masses developed in his left forearm and in the back of his thigh, preceded by enigmatic peripheral neurological symptoms. Aspiration from the forearm showed leukemic relapse, and fluorescence in situ hybridization (FISH) revealed that the majority of the cells had 11q23 anomaly and tetrasomy 8. Bone marrow or meningeal relapse was not observed. To our knowledge, this is the first case report of clonal evolution associated with the development of myeloid sarcoma as a relapse in AML.

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A 21-year-old man who was diagnosed with Diamond-Blackfan anemia at 2 years of age came to our hospital with the hope of undergoing bone marrow transplantation (BMT). He had been red cell transfusion-dependent for about 8 years; at presentation he had transfusion-induced hemochromatosis, a subsequent low left ventricular ejection fraction (LVEF) of 43%, and diabetes mellitus requiring insulin therapy. He received unrelated BMT with reduced intensity conditioning and sufficient GVHD prophylaxis. Regardless of the cardiac dysfunction, he had an uneventful course during pre- and post-grafting periods, and is currently doing well with an improved LVEF (55%), although he is still insulin dependent.

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A 77-year-old man who developed pancytopenia was administered granulocyte colony-stimulating factor (G-CSF) by another doctor, and referred to us for the evaluation of pancytopenia. He had hepatocellular carcinoma and was treated with transcatheter arterial chemoembolization (TACE) containg epirubicin (total dose: 300 mg over the last two years). Bone marrow aspiration smear demonstrated hypercellular marrow with promyelocytes. Cytogenetic analysis demonstrated del(7), t(15;17)(q22;q12), and a fluorescence in-situ hybridization (FISH) study demonstrated chimeric fusion genes of PML-RAR-α. He was diagnosed with therapy-related acute promyelocytic leukemia (APL), and treated with all trans-retinoic acid (ATRA). He showed the progressive accumulation of ascites with liver damage, without pulmonary symptoms of ATRA differentiation syndrome. After 60 days of ATRA treatment, complete hematological and cytogenetic responses were achieved. However, the patient died of septic circulatory failure.

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A 55-year-old woman was diagnosed with POEMS syndrome; however, we could not perform high-dose chemotherapy with autologous peripheral blood stem cell transplantation (auto-PBSCT) because of rapidly progressive congestive heart failure. Thus, we treated the patient with thalidomide plus dexamethasone, which brought about a marked improvement of systolic dysfunction, POEMS syndrome-related symptoms and the serum concentrations of vascular endothelial growth factor. Subsequently, we safely performed high-dose chemotherapy with auto-PBCST. This report strongly suggests that thalidomide is effective for POEMS syndrome, even if complicated by congestive heart failure which is considered to be related to POEMS syndrome.

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Cerebral venous thrombosis presenting as subarachnoid hemorrhage (SAH) is very rare. We present a woman with thrombosis of the superior sagittal, straight, transverse and sigmoid sinuses who presented with SAH in the right temporal sulcus and bilateral cerebellar sulci. Brain perfusion CT demonstrated a delay of the mean transit time and high cerebral blood volume around the right posterior temporal lobe and cerebellum. These findings were compatible with venous congestion and they suggest the possibility that extension of the dural sinus thrombosis into the superficial veins caused localized venous hypertension with dilatation of the thin, fragile-walled cortical veins which eventually ruptured into the subarachnoid space.

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Peripheral neuropathy is a rare manifestation of sarcoidosis, and previous studies have shown axonal degeneration as the main pathology. We herein report three patients with sarcoidosis who presented with multiple mononeuropathy as the initial manifestation. Nerve conduction studies showed prominent multifocal conduction blocks in the intermediate nerve trunk. In all three patients, corticosteroid treatment resulted in a dramatic clinical improvement associated with rapid resolution of conduction blocks. The sequential electrodiagnostic findings suggest that demyelinative or ischemic-functional conduction block is responsible for their neuropathy. To date, only three cases of acute conduction block neuropathy associated with sarcoidosis have been reported, but it may occur more frequently than expected.

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A 52-year-old man presented with hyperhydrosis, painful pseudomyotonia and gait disturbance. The condition was diagnosed as Isaacs' syndrome on the basis of characteristic findings noted on an electromyogram. Carbamazepine treatment was only partially and transiently effective. Intravenous immunoglobulin therapy was effective. The basal metabolic rate (BMR) was serially monitored using an automatic integrated system for breath analysis. Serial monitoring of the BMR facilitates therapeutic evaluation in an Isaacs' syndrome patient with chronic fluctuating symptoms.

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Myoclonic epilepsy with ragged red fibers (MERRF), also called Fukuhara's disease, is sometimes accompanied by the rare symptom of multiple symmetric lipomatosis (MSL). MSL associated with MERRF has been reported mainly in Caucasians; such cases have not been reported in Japanese patients. We report the case of a 59-year-old Japanese woman with MERRF syndrome associated with A→G substitution at nucleotide 8,344 of mtDNA. This case suggests that differences in lifestyle and gene polymorphism among races may be related to the prevalence of MSL due to mitochondrial abnormality, and that mitochondrial abnormalities should be considered as a cause of MSL even in Japanese patients.

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We report a patient with neuro Behçet's disease (BD) initially presenting with meningitis and severe hearing loss. A 51-year-old man with no noteworthy past history was hospitalized for evaluation of non-pulsating headache and high fever. Lumbar puncture on admission only showed slight pleocytosis (6 /μL, monomorphonuclear cells predominantly) but no evidence of meningitis. However, after admission, he continued to have a fever of over 38 degrees, and he developed painful oral aphthous ulcer and pseudofolliculitis on the upper limbs and trunk. Prior to admission he had often experienced oral ulceration and had bought commercially available mouthwash for prophylaxis. Subsequently, genital ulceration appeared. A small ulcer was observed at the blood collection site, leading to the diagnosis of BD. On the seventh hospital day, the patient developed sudden hearing loss, which was diagnosed as severe sensorineural hearing loss. Lumbar puncture was performed again. Cerebrospinal fluid (CSF) analysis showed mild pleocytosis (60 /μL, predominantly monomorphonuclear cells), with high CSF IL-6 levels. Neither edematous change nor atrophy of the brainstem was noted and there were no other abnormal findings on the brain MRI/MRA. Auditory brainstem response was normal, suggesting that the patient had developed hearing loss due to peripheral neuropathy. We speculate that the hearing loss was likely due to vasculitis associated with BD. This case is considered to be a rare case of Behçet's disease caused by severe hearing loss and meningitis.

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Type B insulin resistance is characterized by the appearance of autoantibodies to the insulin receptor. We present a 59-year-old Japanese man with type B insulin resistance complicated with systemic lupus erythematosus (SLE). A high titer of anti-insulin receptor autoantibodies was revealed when SLE was defined as active disease. Intravenous boluses of cyclophosphamide (IVCY) with oral prednisolone and cyclosporin A induced remission of SLE, and a subsequent disappearance of anti-insulin receptor autoantibodies, followed by a recovery of glucose intolerance. This is a rare and important case report showing a clear correlation between anti-insulin receptor autoantibodies of type B insulin resistance and SLE disease activity.

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Histoplasmosis, caused by Histoplasma capsulatum, is an endemic mycosis in many countries of the world except for Japan. Outbreaks of histoplasmosis among Japanese people are very rare and are mainly imported by travelers. We report an outbreak of histoplasmosis among healthy Japanese people who traveled to a resort area in Southeast Asia. Three young Japanese women traveled to Langkawi island, Malaysia and stayed on the island for five days without visiting caves, a known reservoir of H. capsulatum. All three individuals developed flu-like symptoms with multiple nodule shadows on chest X rays or chest CT scans at around ten days after their return to Japan. Serum samples obtained from the three subjects were positive for anti-Histoplasma antibody and specific PCR for H. capsulatum on lung biopsy specimens and the serum from one patient was positive. The clinical course of all three patients improved without the use of anti-fungal agents and no recurrence has been confirmed. Clinical attendants should consider histoplasmosis when they see patients with flu-like symptoms with abnormal chest X-rays after visiting H. capsulatum endemic areas, especially Southeast Asia.

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Diffuse alveolar hemorrhage (DAH) syndrome is potentially fatal. We encountered a nearly fatal case of DAH possibly due to intravenous itraconazole (ITCZ). A 53-year-old man with chronic pulmonary aspergillosis underwent pneumonectomy of the left lung 15 days prior to the onset of DAH, which was confirmed by bronchoalveloar lavage. The battery of diagnostic evaluations performed revealed no other positive etiological factor, leading to the diagnosis of DAH possibly induced by intravenous ITCZ with a positive drug lymphocyte stimulation test. The patient did not respond to pulse methylprednisolone therapy, but responded dramatically to direct hemoperfusion using a polymyxin B-immobilized fiber column (PMX) therapy.

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An adult Malaysian woman returned to Japan from Kuala Lumpur and had onset of dengue fever-like symptoms including high fever, malaise and arthritis in early January 2009. Serum obtained on the following day was tested at the National Institute of Infectious Diseases in Tokyo, where it was determined to be positive for chikungunya virus (CHIKV) RNA. IgM antibody against CHIKV was negative on January 6 and sero-converted to be positive on January 14, confirming a recent CHIKV infection. Except for arthralgia, all her symptoms resolved uneventfully within 10 days.

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