The glycoprotein hormone erythropoietin (EPO) is an essential viability and growth factor for the erythrocytic progenitors. EPO is mainly produced in the kidneys. EPO gene expression is induced by hypoxia-inducible transcription factors (HIF). The principal representative of the HIF-family (HIF-1, -2 and -3) is HIF-1, which is composed of an O₂-labile α-subunit and a constant nuclear β-subunit. In normoxia, the α-subunit of HIF is inactivated following prolyl- and asparaginyl-hydroxylation by means of α-oxoglutarate and Fe²⁺-dependent HIF specific dioxygenases. While HIF-1 and HIF-2 activate the EPO gene, HIF-3, GATA-2 and NFκB are likely inhibitors of EPO gene transcription. EPO signalling involves tyrosine phosphorylation of the homodimeric EPO receptor and subsequent activation of intracellular antiapoptotic proteins, kinases and transcription factors. Lack of EPO leads to anemia. Treatment with recombinant human EPO (rHuEPO) is efficient and safe in improving the management of the anemia associated with chronic renal failure. RHuEPO analogues with prolonged survival in circulation have been developed. Whether the recent demonstration of EPO receptors in various nonhemopoietic tissues, including tumor cells, is welcome or ominous still needs to be clarified. Evidence suggests that rHuEPO may be a useful neuroprotective agent.

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Systemic vasculitides are a heterogeneous group of disorders with inflammation of blood vessels as their common pathogenetic hallmark. They often pose difficulties with regard to diagnosis and monitoring of disease activity, both at the initial presentation and during follow-up. Novel markers of disease activity are therefore eagerly awaited. Circulating endothelial cells have recently emerged as one such marker and we have demonstrated their clinical use in ANCA-associated small-vessel vasculitis. Not only entire cells but also endothelial microparticles can be detected in vasculitis although their use is not established to date. Repair of endothelial damage is believed to occur via endothelial progenitor cells and their precise role in vasculitis is also unclear at present. Circulating endothelial cells may complement, rather than replace, conventional markers of disease activity. The ultimate aim of our studies may thus be a panel of various laboratory markers for systemic vasculitis.

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  Objective  There have been few studies on cyclosporine (CsA) monotherapy in adult minimal change nephrotic syndrome (MCNS). To delineate CsA therapy as new treatment options for MCNS, we conducted a prospective single-center study.
  Methods  We assessed the efficacy of 3 different regimens in 36 patients, consisting of 26 first attacks or 10 relapses, of adult-onset MCNS. In 12 patients, CsA alone was given orally at a dose of 2-3 mg/kg/d, and in 12 patients, CsA after intravenous pulse methylprednisolone therapy (CsA/PMT) was given at the same dose. CsA was given for 12 months, tapered slowly, then stopped. The other 12 patients were treated with oral prednisolone (PSL, 40-60 mg/d) alone for 4 to 6 weeks, followed by daily PSL, with slowly tapering doses.
  Results  Complete remission (CR) was obtained in 75% with CsA alone, 100% with CsA/PMT and 92% with PSL alone (p=0.0379). The days required for CR were shortest in the CsA/PMT group (40.9±35.5 days with CsA alone vs. 11.0±5.6 with CsA/PMT vs. 21.5±15.8 with PSL alone). The cumulative rates of CR were significantly different among the 3 groups (p<0.0001). The real numbers of the relapse were smallest in the CsA/PMT group, however, the cumulative rates of sustained remission among the 3 treatment arms were not statistically different. Renal function was well preserved with each treatment period. CsA-associated adverse effects were minimal but one patient developed new-onset hypertension and gingival hyperplasia. However, the adverse effects of PSL alone were serious in 3 cases: bleeding from gastric ulcer, diabetes mellitus, and aseptic necrosis. Many patients with PSL but few with CsA experienced cosmetic problems.
  Conclusions  CsA/PMT may be the most advantageous when the clinical efficacy of each treatment for MCNS is integrated.

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  Objective  The aim of the present study was to evaluate the influence of inhaled corticosteroids (ICS) on community-acquired pneumonia (CAP) in patients with asthma.
  Patients and Methods  All asthmatic patients who required hospitalization for CAP from the beginning of 1989 through December 2001 were enrolled in this retrospective study. Patients who used oral corticosteroids daily were excluded. Patients were divided into two groups based on whether or not they used ICS, and we analyzed clinical characteristics of the pneumonia. Sixty-two patients (28 males, 34 females; mean age, 54.5 years) were enrolled in this study. Thirty-seven of 62 patients used ICS, with the mean dosage being 777.9 μg/day.
  Results  We found no significant differences between the two groups with regard to mean age, serum albumin level, duration of asthma, pulmonary function and frequency of intravenous infusion of corticosteroids in the outpatient department. There were no significant differences in body temperature, white blood cell count, and CRP value upon admission between the two groups. Differences were not significant in the period of resolution of the pneumonia or in the frequency of pathogens identified between the two groups.
  Conclusion  ICS therapy appears to have no influence on CAP in patients with asthma. We recommend that ICS should be continued to control asthma with adequate antibiotic therapy when asthmatic patients have CAP.

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  Objective  The effect of a small amount of alcohol on the sleep structure in relation to alcohol sensitivity was examined using polysomnography (PSG).
  Methods  Alcohol sensitivity was evaluated using alcohol patch test for all subjects. PSGs were performed on three nights after one night for acclimation, and subjects consumed no alcohol, 0.28 or 0.69 g ethanol/kg body weight, respectively, before going to bed. The percentages of sleep time in each sleep stage of 1, 2, 3+4 and rapid eye movement (REM), REM latency, and REM cycle were calculated.
  Subjects  Thirteen healthy female students (age 21.1±0.7 years) were enrolled in this study.
  Results  In all subjects, there were no significant differences in any of the sleep parameters between baseline night and alcohol nights. Six of the 13 subjects were sensitive to alcohol, in whom %stage REM was significantly decreased by alcohol consumption (baseline night: 18.3±6.2%, alcohol night I: 9.8±5.1% and alcohol night II: 11.0±2.8%), and the REM latency was significantly prolonged. The standard deviation of REM cycle was significantly greater on alcohol nights I and II than baseline night. There were no significant differences in other sleep parameters. In the other seven subjects who were insensitive to alcohol, none of the sleep parameters were significantly affected by alcohol consumption.
  Conclusion  REM sleep was adversely affected by a small amount of alcohol in alcohol-sensitive healthy young women. Alcohol sensitivity might play some important role in impaired REM sleep by an ingestion of a small amount of alcohol.

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  Objective  To quantitatively evaluate motor activity, its fluctuations, and drug effects in patients with Parkinson’s disease (PD), the Lifecorder^®, a new monitoring device, was attached to a group of patients for several weeks. This enabled the continuous recording of motor activity in ten scaled magnitudes at two-minute intervals for 6 weeks.
  Patients and Methods  Thirteen patients with PD who required dopamine receptor agonist therapy were monitored with Lifecorder, and seven healthy subjects served as the control group. The data obtained with this device correlated well with the Unified Parkinson’s Disease Rating Scale (UPDRS) and Hoehn-Yahr grading. The dose of cabergoline, a D2-receptor agonist, was increased every 2 weeks, until optimum improvement was achieved.
  Results  By adding cabergoline, the mean UPDRS improved from 40.5 to 28.4, which was significant. In parallel, the mean daily walking count (WC) also increased from 2, 459 to 3, 315 steps (p<0.01) and movement-related calorie consumption (MCC) increased from 56 to 74 kcal (p<0.05). UPDRS thus correlated well with WC and MCC (p<0.05) obtained with this device. The improvement ratio of WC and MCC of each individual patient was compared with that of UPDRS. WC, and MCC shifted in parallel with UPDRS with one exception. The daily time-dependent fluctuation of motor activity was clearly shown by the Excel-generated graphs to improve with D-agonist therapy. In contrast to enhanced daytime activities, nocturnal restfulness was also clearly documented with this device.
  Conclusion  The unique properties of Lifecorder make this device a useful adjunct to the UPDRS for the objective evaluation of Parkinsonian motor activity. The device has a significant advantage over conventional clinical scales, as daytime as well as nocturnal motor activity can be objectively evaluated over long time periods ranging from one hour to one month, and the magnitude of motor activity is quantifiable in relation to the time-course.

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Our patient was a 71-year-old man who presented with lower abdominal pain, and bloody and white mucosal stools. He purchased by mail-order an electrical muscle stimulation (EMS) device, which he strapped onto his lower abdomen, and for 2 consecutive days he underwent muscle stimulation comprising 600 contractions at 2.40 mA and 1.20 V over a 10 minute period. He experienced the onset of lower abdominal pain immediately following muscle stimulation on the second day, and then passed stools containing blood and white mucus. The cause was thought to be electrical and mechanical stimulation of the lower abdomen by the EMS equipment, either inducing colonic or vascular spasm, or dislodging thrombi associated with atrial fibrillation or atherosclerosis. This is the first known report of ischemic colitis associated with the use of EMS exercise equipment. We report this case in the belief that this condition is likely to become more common with increasing use of such devices.

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A 12-year-old girl with Gianotti-Crosti syndrome caused by hepatitis B virus (HBV) infection was admitted due to eruption on her extremities. Laboratory findings revealed elevation of transaminase, positivity for HB surface antigen (HBsAg), and an IgM type anti-HB core. The eruption and level of transaminase improved, and HBsAg became negative within 2 months of onset. Analysis of the virus revealed it to be genotype D with a genomic length of 3, 182 bases and the HBsAg serotype was ayw3, which is very rare in Japan. The possible relationship between Gianotti-Crosti syndrome and HBV genotype D infection is discussed.

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A 75-year-old man without overt heart failure showed an abnormally high level of brain natriuretic peptide (BNP) in plasma: 600 pg/ml. The left ventricular endomyocardial biopsy revealed prominent vacuolar degeneration in the myocytes, most of which were positive for PAS stain and BNP immunoreaction. Ultrastructurally, degenerative changes of myocytes were marked, such as deposits of glycogen and lipofuscin granules in the cytoplasm, but the most prominent finding was giant vacuoles containing degraded mitochondria, glycogen granules, myofibrils, and myelin-like structures (autophagosomes). This case may belong to one of the unclassified cardiomyopathies characterized by prominent autophagic vacuoles.

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A 51-year-old man was admitted with hyperglycemia and a duodenal tumor. Although his glycemic control was poor, basal C-peptide levels were not suppressed. Further examination revealed a mass measuring 7.8 cm in diameter in the third portion of the duodenum. Duodenectomy revealed a slow-growing sessile tumor located near Treitz’s ligament. The immunohistochemical profile of sections of the specimen revealed the presence of somatostatin. The patient’s serum somatostatin was elevated to 300 pg/ml preoperatively, but was reduced to 10 pg/ml postoperatively. Glycemic control also normalized after the operation.

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A 60-year-old woman who was diagnosed with hereditary angioedema (HAE) developed nephrotic syndrome, with end-stage renal disease (ESRD) occurring about 2.5 years later. During her slide toward ESRD, she experienced three severe episodes of angioedema that each resulted in significant fluid retention. Though the therapeutic administration of C1-inhibitor concentrate was effective in controlling her angioedema, seemed ineffective in preventing her from developing ESRD requiring hemodialysis treatment. We theorized that the patient’s low colloid osmolality and glomerular perfusion were important facilitators of her attacks of angioedema.

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A 57-year-old man who was a heavy smoker was admitted to our hospital for further evaluation of abnormal shadows on a chest X-ray film. Chest radiography and a computed tomography (CT) scan revealed nodular lesions and multiple thin-walled cysts in both lungs. Histopathological examination of one of these cystic lesions showed that the predominant cellular population was Langerhans cells, with the cytoplasm testing positive for S-100 protein and the cell membrane showing a positive reaction for CD1a. The pathological diagnosis was pulmonary Langerhans cell histiocytosis (LCH). A lingual carcinoma that had been detected simultaneously was treated with neoadjuvant therapy and the patient was advised to stop smoking. However, only limited improvement was seen on follow-up chest CT. In view of this, a radical resection of the lingual carcinoma was performed. There was a subsequent dramatic improvement in the pulmonary LCH. Langerhans cells may play a role in the immune response to tumors. In this patient, we suggest the possibility that both the habitual smoking and the lingual carcinoma may have contributed to the development of pulmonary LCH.

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Two Japanese women were diagnosed as having well-differentiated adenocarcinoma of the lung with brain metastases. Since it was considered they could not tolerate conventional chemotherapy, we administered gefitinib without any previous systemic therapy. In both patients gefitinib acted dramatically on all the lesions including the brain metastases, resulting in a marked decrease of the elevated CEA levels, and improvement of their quality of life. Retrospective evaluation of epidermal growth factor receptor expression levels by immunohistochemistry revealed positive results in both cases. Though gefitinib has been recommended for patients previously treated with chemotherapy, it should be considered feasible as a first line therapy.

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NSIP associated with primary lung cancer has been rarely reported. In the present report, three cases of histologically proven non-specific interstitial pneumonia (NSIP) associated with primary lung cancer are described. Importantly, in our 3 cases, interstitial pneumonia which is histologically proven to be NSIP was observed diffusely in both lungs. NSIP in these 3 cases responded to steroid therapy. However, 2 patients died from primary lung cancer and 1 patient died from progression of the interstitial pneumonia. Although the association between lung cancer and NSIP has been rarely documented, this combination was considered to be one of the paraneoplastic phenomena. The possible association between primary lung cancer and NSIP is discussed.

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Metastasis to the tongue seldom occurs, and lingual metastasis as an initial sign of cancer occurs even less frequently. We report a case of lung cancer in which the patient’s initial symptom was related to the tongue metastasis. A 63-year-old man had a submucosal tumor on the left posterolateral aspect of the tongue and a biopsy specimen of the tongue tumor showed poorly differentiated squamous cell carcinoma. A chest X-ray showed a mass in the right lung and cytological examination of the specimen obtained by bronchial brushing showed poorly differentiated squamous cell carcinoma, whose appearance was similar to that of the tongue. Based on these findings, the tongue lesion was diagnosed a metastatic tumor from the lung cancer. The patient received radiation therapy combined with systemic chemotherapy, however, he died 5 months after the diagnosis of lung cancer. An autopsy revealed a lung cancer in the right lower lobe with metastatic tumors in the tongue, right middle lobe, left upper lobe, liver, adrenal gland, pericardium, heart, and subcutaneous tissues. No other possible primary cancer that may have been the cause of the metastases was identified.

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Strongyloidiasis is widely distributed in tropical and subtropical areas. Disseminated strongyloidiasis may develop in patients with immunodeficiencies. In the absence of early diagnosis and treatment, the prognosis of disseminated strongyloidiasis is extremely poor. We report a case of pulmonary strongyloidiasis that was successfully treated. The patient was an 83-year-old woman who had been receiving long-term oral prednisolone therapy for uveitis. The patient visited our emergency department complaining of breathing difficulties and diarrhea. A chest X-ray revealed a diffuse enhancement of interstitial shadows. A bronchoalveolar lavage (BAL) was performed, and both Gram staining and Grocott’s staining revealed the presence of multiple filariform larvae of Strongyloides stercoralis in the bronchoalveolar lavage fluid (BALF). A stool examination performed at the same time also yielded S. stercoralis. The patient was diagnosed as having pulmonary strongyloidiasis and was treated with thiabendazole and ivermectin, in addition to antimicrobial agents; her respiratory symptoms and diarrhea improved, and S. stercoralis was not detected in subsequent follow-up examinations thereafter. In endemic areas of S. stercoralis, pulmonary strongyloidiasis should be considered as part of a differential diagnosis if chest imaging findings like alveolar and interstitial shadow patterns or lobar pneumonia are seen in patients with immunodeficiencies.

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We successfully treated a patient with occupational hypersensitivity pneumonitis (HP) caused by Grifola frondosa (Maitake) mushroom spore with an extra-fine aerosol corticosteroid; beclomethasone dipropionate (BDP) dissolved in hydrofluoroalkane-134a (HFA). A 49-year-old woman developed respiratory symptoms 3 months after beginning work on a mushroom farm. She was diagnosed as HP based on radiological and serological findings. Oral prednisolone therapy improved her HP and she returned to the same farm. Her HP relapsed after 5 months, and daily 400 μg of HFA-BDP was administered with gradual improvement. An extra-fine particle inhaled corticosteroid might reach appropriate alveoli to be effective therapy for mild HP.

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Sinus histiocytosis with massive lymphadenopathy (SHML) is a distinct benign clinicopathological entity, characterized by painless enlargement of lymph nodes due to sinus histiocytosis. Here, we report a case of SHML with diffuse large B-cell lymphoma. A 64-year-old man was admitted to our hospital because of fever. He presented with enlargement of a small cervical lymph node and huge abdominal paraaortic lymphadenopathy. Cervical lymph node biopsy revealed SHML and bone marrow biopsy showed infiltration of large B-cell lymphoma. Several cases of SHML associated with lymphoma have been documented to date, but this type of simultaneous occurrence has not yet been reported.

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We report a patient with recurrent acute meningoencephalitis who had three episodes of headache, fever and unconsciousness; the first episode was at age 6 and the second, at age 7. After a 12-year symptom-free interval, she had a relapse, exhibiting the same symptoms as those in the previous two episodes. Head magnetic resonance imaging also revealed the recurrence of lesions in the basal ganglia and medial portion of the temporal lobe. The occurrences of stereotyped symptoms with meningoencephalitis and the same lesions in the basal ganglia observed in each episode favor the diagnosis of recurrent acute disseminated encephalomyelitis (ADEM) rather than multiple sclerosis or multiphasic disseminated encephalomyelitis. The occurrence of this rare case suggests that ADEM can relapse after a very long symptom-free interval.

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We report a case of methanol intoxication, which was not distinguished from ethylene glycol intoxication during treatment. A 65-year-old man was transferred to our emergency department because of drowsiness and remarkable metabolic acidosis. He was intubated because his consciousness disturbance worsened. The diagnosis was suspected as methanol or ethylene glycol intoxication in addition to ethanol intoxication. Administration of ethanol and hemodialysis were chosen for his essential treatments. When he was extubated, he complained about visual loss. His brain computed tomography scans revealed putaminal lesions, which are rarely reported in methanol intoxication. Diagnosis of methanol intoxication was confirmed by the serum high methanol levels.

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A 29-year-old woman was admitted to our hospital with a 7-day history of elevated temperature to 39.5°C associated with headache and nausea. She had been diagnosed with tuberous sclerosis complex 10 years earlier. Her unconsciousness progressed, and she was diagnosed as having aseptic meningoencephalitis. The next day, she had a generalized seizure with severe hemoptysis, and she suddenly fell into severe respiratory failure (PaO₂/FiO₂=76.9). Transbronchial lung biopsy revealed the findings of lymphangioleiomyomatosis. It was suggested that neurogenic pulmonary edema accompanied with venous flow obstruction by lymphangioleiomyomatosis lesions resulted in diffuse pulmonary hemorrhage with resultant gross hemoptysis accelerating to severe hypoxemia.

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