Objective Recently guidelines for the treatment and prevention of ulcers induced by nonsteroidal anti-inflammatory drugs (NSAIDs) have been established. The aim of the present study was to examine factors influencing orthopedists in Japan in the use of cytoprotective drugs to prevent NSAID-associated gastrointestinal adverse events.
Methods We sent a questionnaire to 402 orthopedists in Hyogo Prefecture. A standardized 10-item questionnaire was used to collect information on NSAID prescriptions (drug name, pharmaceutical form, doses, and duration of use) and associated drugs, especially gastroprotective drugs.
Results Two hundred eight (51.7%) orthopedists returned the questionnaire. The most frequently used NSAIDs, in descending order, were loxoprofen sodium, diclofenac sodium, and etodolac. Most doctors (80%) reported patients with abdominal symptoms associated with NSAIDs. Of these doctors, 59% treated the symptoms by themselves, and prescribed gastroprotective agents (32.2%), histamine H2-receptor antagonists (H2RAs) (26.4%), prostaglandin analogues (PAs) (17.0%), or proton pump inhibitors (PPIs) (16.2%). Sixty-seven percent of doctors reported that those drugs reduced the symptoms. Most orthopedists (96%) prescribed some type of drug to prevent NSAID-associated gastrointestinal events, including gastroprotective drugs (44.6%), H2RAs (19.5%), PAs (17.4%), and PPIs (10.8%). The doctors reported that they prescribed medicines for NSAID-associated gastrointestinal events on the basis of their experience (23%), by considering medical insurance restrictions (17%), and by referring to information provided by pharmaceutical company representatives (16%).
Conclusion Most orthopedists prescribe some type of drug to prevent NSAID-induced ulcers but do not refer to the guidelines. We therefore strongly recommend that the guidelines be made more widely known to gastroenterologists and to physicians in every field of clinical practice, including orthopedics.

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Object Recently, prothrombin fragment F1+2 was shown to be a sensitive direct marker of thrombin formation. We examined the effect of lifestyle (including physical activity) on prothrombin fragment F1+2 levels.
Methods Using the results of a questionnaire, the subjects were classified into groups on the basis of multiple medications, smoking, exercise, and drinking alcohol. The prothrombin fragment F1+2 levels were compared between each pair of groups and differences were analyzed using the unpaired t-test. Correlations between each parameter and the systolic and diastolic blood pressure, as well as with prothrombin fragment F1+2, were examined by multiple regression analysis.
Patients The subjects were 109 patients who had essential hypertension without a past history of thrombotic events
Results Smokers (1.47 ± 0.75 vs 0.98 ± 0.46 nmol/L, p<0.0001), and those without regular exercise (1.22 ± 0.59 vs 0.68 ± 0.30 nmol/L, p<0.0001) had higher levels of prothrombin fragment F1+2. Age, lack of exercise, and smoking were significant predictors of a high concentration of prothrombin fragment F1+2. Of the smokers, the patient with a regular exercise had low F1+2 compared with those without regular exercise (0.75 ± 0.20 vs 2.01 ± 0.49 nmol/L, p<0.0001.
Conclusions In patients with essential hypertension, age, smoking, and lack of regular exercise may increase the risk of thrombosis. Even in smokers, a regular exercise routine may reduce the tendency towards thrombus formation.

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Objective To evaluate the results of treatment with an insulin glargine-based regimen as compared with those of an NPH insulin-based regimen.
Methods We reviewed the charts of 83 Japanese patients with Type 1 diabetes treated with insulin glargine for 12 months.
Patients Median age, 56.9 years (range, 24.6-74.8 years), mean (±S.D.) body mass index, 21.2 (±2.2) kg/m².
Results The average HbA1c level of the cohort was 7.8 ± 1.2% at baseline and 7.7 ± 1.0% at the end of the 12-month treatment (P=0.34). The average insulin requirement per day in the cohort remained unchanged after the 12-month treatment (35.0 ± 11.6 units/day versus 35.2 ± 11.2 units/day (P=0.58). Of the 36 patients who were receiving twice or three times daily injections of NPH insulin, 30 could be switched to a single-daily injection of insulin glargine. The frequency of severe hypoglycemia with unconsciousness became lower after switching to the insulin glargine-based regimen than during treatment with the NPH-based regimen. The average ratio of the daily usage of insulin glargine to that of total insulin after 12 months was smaller than that reported from other countries (0.34 ± 0.09).
Conclusion These results obtained from a larger number of patients as compared to previous Japanese studies confirm earlier reports that insulin glargine provides equivalent glycemic control to human NPH insulin, with a lower incidence of severe hypoglycemia. Thus, treatment with insulin glargine provides some benefits to Japanese patients with Type 1 diabetes.

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Objective Insulin resistance and metabolic syndrome (MeS) are common in end-stage renal disease (ESRD) patients on maintenance hemodialysis (HD). Such metabolic and clinical abnormalities may lead to an increased risk for cardiovascular disease.
Methods The study group included 22 well-nourished and 20 middle- to moderate-malnourished, stable ESRD patients, with median dialysis duration of 48 months (IQR 24.5-82.0). To determine nutritional status, body composition, inflammatory biomarkers and the presence of MeS subjective global assessment (SGA), anthropometrical measurements (BMI and waist circumference), bioelectrical impedance analysis (BIA), and biochemical parameters [the levels of serum albumin, cholesterol, HDL-cholesterol, triglyceride, hematocrit, hemoglobin, iron, TIBC, transferrin saturation (TSAT), ferritin, calcium, phosphorus, intact parathormone (i-PTH), TNF-alpha, IL-6 and high sensitivity C-reactive protein (hs-CRP)] were used. All parameters were evaluated by comparisons between two groups, with MeS (Group 2) and without it (Group 1). Logistical regression analysis was used to evaluate the correlation between measured variables and the presence of MeS in HD patients. Independent variables for MeS were identified by backward multivariate regression analysis. To identify the independent predictors for insulin resistance index (HOMA-IR) multivariate regression analysis was conducted, after linear regression analysis.
Results After adjustment for confounding variables, a model consisting of serum levels of iron, transferrin saturation (TSAT), and BMI which accounted for 62% of the variance in MeS, determined only BMI as an independent marker (according to ATP-III criteria). But, serum glucose level, iron, waist and total fat mass accounted for 68% of the variance in MeS, according to IDF critera. Glucose level was an independent predictor. BMI and iron, as independent variables, contributed to 29% of the variance in IR HOMA, the sensitive marker of MeS.
Conclusion The present study demonstrated that serum iron participated together with independent predictors, glucose and BMI, in the pathogenesis of IR and MeS of ESRD patients on maintenance HD.

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Objective To determine the differences in the clinical features of bacterial pneumonia patients between patients co-infected with influenza virus or not co-infected.
Methods Fifteen adult patients with bacterial pneumonia (7 men and 8 women) who also tested positive for influenza virus antigen were compared with those with bacterial pneumonia alone (n=28).
Results Complications with chronic lung diseases were more frequently found in bacterial pneumonia patients with influenza virus infection, compared with those who had bacteria pneumonia alone. Statistical differences were also found in body temperature, and heart rates between the two groups. CRP levels, chest X-ray infiltrates and the severity of pneumonia, as determined using the criteria of the Japan Respiratory Society (JRS) and/or the Infectious Diseases Society of America (IDSA), were also significantly worse in patients of bacterial pneumonia infected with influenza virus, than in those who had bacterial pneumonia alone.
Conclusions The severity of pneumonia in patients co-infected with influenza virus and bacteria was significantly higher than in those infected with bacteria alone. These data suggested that the influenza virus infection enhanced the bacterial pneumonia. Further study of the pathogenesis of the synergic interaction between influenza virus and bacteria is warranted.

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Objective To evaluate the efficacy and tolerability of Botulinum Toxin Type A (BoNT-A) for migraine prophylaxis.
Methods Nineteen Japanese adult patients (50 ± 10 years old), who met the International Classification of Headache Disorders 2nd Edition (ICHD II) criteria for migraine and had five or more migraine attacks a month, were enrolled in this open-label prospective study. A total of 50 units of BoNT-A were injected in 19-fixed sites of the muscles including procerus, corrugator, frontalis, temporalis and occipitalis. All participants were advised to stop taking preventive medicine from one month before and three months after BoNT-A injection. Migraine disability assessment (MIDAS), migraine questionnaire and headache diary were used for the evaluation of efficacy. Seven patients received repeated injection combined with prophylactic medication.
Result We excluded five patients from the analysis because four patients had medication overuse headache and one continued preventive medicine. Mean MIDAS score decreased significantly two months after the injection. Thirteen of 14 patients stated subjective improvement after the injection on the migraine questionnaire. The amount of analgesics consumption or headache frequency did not change after injection, but the frequency of severe migraine attacks decreased significantly. No serious adverse event was reported. Repeated injections also showed significant reduction in MIDAS score three months after the second and third injections.
Conclusion BoNT-A injection was an effective and safe treatment for migraine prophylaxis among the Japanese population. A randomized placebo control trial is necessary to confirm its efficacy.

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Objects In the present study, we evaluated patients who were admitted to our emergency department with a diagnosis of organophosphate poisoning and discussed clinical, social and demographic features.
Methods A retrospective study was conducted with organophosphate poisoning patients admitted to our emergency department between January 1995 and December 2004. Data regarding the age, sex, occupation, type of agent, route of poisoning, clinical effects of cholinergic overactivity, laboratory findings, and mortality rate were obtained from the patient files.
Results During the study period, 220 patients who had organophosphate poisoning with a known agent were admitted to the ED. The estimated mean admission time to the ED after the exposure was 3.9 ± 3.1 (1-14) hours. There were 131 (59.5%) female and 89 (40.5%) male patients. The most affected age group was 15-24 years (40.5%), in both sexes. Oral ingestion (86.5%) was found to be the most common route of poisoning. The most frequent reason for poisoning was attempted suicide (75.9%). The most common organophosphate compounds exposed were dichlorvos, diazinon and parathion-methyl. The most frequent clinical signs were miosis, respiratory system findings, tachycardia, loss of consciousness, and hypertension. Twenty patients (9.1%) died due to sudden respiratory and cardiac arrest (45%), respiratory failure (25%), CNS depression (5%) and septic shock (25%).
Conclusion We think that the appropriate use of these compounds, instruction of the public about their harmful effects and restriction of their uncontrolled sales by legal regulations can reduce the incidence of organophosphate poisoning.

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A 31-year-old woman who had ingested a toothpick consulted our hospital because of epigastralgia. An abdominal computed tomography (CT) demonstrated a toothpick penetrating the gastric wall. Endoscopic examination demonstrated an ingested toothpick protruding from the prepyloric antrum. The whole toothpick was removed using a basket catheter without complications. CT images were useful to acquire clinical information such as location of the toothpick end. Unintentional ingestion of toothpicks must be considered potentially dangerous. The locations of both ends of the toothpick should be confirmed by CT or ultrasonography;and then, the toothpick should be removed as soon as possible.

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Radiation-induced gastritis is a serious complication of radiation therapy for pancreatic cancer which is difficult to manage. A 79-year-old man had been diagnosed as having inoperable pancreatic cancer (stage IVa). We encountered this patient with hemorrhagic gastritis induced by external radiotherapy for pancreatic cancer that was well-treated using argon plasma coagulation (APC). After endoscopic treatment using APC, anemia associated with hemorrhagic radiation gastritis improved and required no further blood transfusion.

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Pulmonary artery aneurysm (PAA), especially the peripheral type, is a rare disease. We report 2 cases of peripheral PAA with pulmonary artery hypertension. Complication associated with peripheral PAA was hemoptysis. Endovascular coil embolization was performed successfully in one patient. The other with peripheral PAA was died of massive hemoptysis. In patients with peripheral PAA, coil embolization is one therapeutic option. We summarized cases with peripheral PAA in Japan.

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The patient was a 41-year-old man who had suffered from diabetes for 24 years and had been on insulin therapy for 17 years. The patient had commenced hemodialysis in 1999. Some of his toes on both feet had been amputated in 2000 due to diabetic gangrene. The patient was admitted to our hospital in early March 2005 complaining of a painful ulcer on the tip of the penis. At the time of admission, multiple ulcers and necrosis were observed on the prepuce and penis, as well as an ulcer on the left foot and gangrene of the left great toe. Imaging studies demonstrated severe arteriosclerosis with calcification of both large and small arteries. After penile amputation was performed because of severe pain, the wound became ulcerated, and a rectal ulcer as well as skin ulcers also developed in the bilateral inguinal regions. The penile necrosis, skin ulcers, and rectal ulcer were thought to have been caused by calciphylaxis. Calciphylaxis is a disorder in which necrosis occurs at sites of arterial obstruction and calcification, and the prognosis is poor. Seventeen patients with penile necrosis due to calciphyalxis, including our patient, have been reported in Japan. They all had a long history of diabetes, and 15 of the 17 patients were on dialysis.

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A 41-year-old Japanese woman with a 25-year history of systemic lupus erythematosus was admitted because of abrupt onset of nephrotic syndrome and acute renal failure. Renal biopsy specimen showed only mild mesangial proliferative glomerulonephritis associated with mesangial deposition of immunoglobulins/complements. No significant immune deposits were found in the glomerular capillary walls, but mild foot process effacement was observed on electron microscopy. Further, two-month corticosteroid therapy improved her massive proteinuria and renal dysfunction, indicating that this patient showed minimal-change nephropathy superimposed on mesangial proliferative lupus nephritis.

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Protein C is the central component of the major anti-thrombotic regulatory system, and individuals with hereditary protein C deficiency tend to have an increased risk of thromboembolism. During the last several years, mutations causing protein C deficiency have been identified. In the present study, we report familial cases with three nucleotide substitutions: One is a missense mutation Arg169Trp, which was previously reported. The other two are C-154T promoter polymorphism (rs1799808 on dbSNP database), the function of which is unkonwn and Ser99Ser synonymous polymorphism (rs5936). All three mutations were found in a 24-year-old patient with pulmonary thromboembolism and his 54-year-old father who also had pulmonary thromboembolism. C-154T promoter polymorphism (rs1799808 on dbSNP database) and Ser99Ser synonymous polymorphism (rs5936) were found in the patient's mother.

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A 54-year-old man was admitted to our hospital because of intermittent high fever, general malaise, cough and body weight loss after he had been examined and treated at the former hospital for 3 years without a definitive diagnosis and effective therapy. Bacterial examination on admission revealed Streptococcus pyogenes in peripheral blood, bone marrow aspirates and pleural effusion. Furthermore, Mycobacterium avium complex (MAC) was detected in sputum, gastric juice, bone marrow liquid, pleural effusion by acid-fast bacillus culture or polymerase chain reaction (PCR). Biopsy of the neck lymph node showed multiple granulomas and the presence of acid-fast bacilli. Administration of ABPC/SBT and later CLDM resulted in disappearance of Streptococcus pyrogenes after 2 weeks. We suspected of generalized immunodeficiency that might underlie the severe bacteremia/osteomyelitis and disseminated MAC infection. We tested interferon (IFN)-γ production of peripheral blood mononuclear cells (PBMC) of the patient after phytohemagglutinin (PHA)-stimulation and found that these cells produced no or undetectable levels of IFN-γ in the presence of autologous plasma while produced almost normal levels of IFN-γ in the presence of healthy donor's plasma. Since this neutralizing activity was co-purified in the IgG fraction, the immunodeficient state of the patient seemed to be caused by autoantibody to IFN-γ. As far as we know, this is the first report of a Japanese case of disseminated MAC infection presumably due to autoantibody to IFN-γ.

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Isolated extramedullary (EM) relapses of acute myelogenous leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) have been reported to be rare, and are usually followed by bone marrow relapses. We report a 49-year-old man with AML with the unfavorable chromosome abnormality 7q-, who was treated by allo-HSCT. Fifteen months after allo-HSCT, the patient initially developed a relapse only in his inguinal lymph nodes, and then bone marrow relapse became evident one month after the EM relapse. Subsequently, the patient received chemotherapy and a second allo-HSCT from another donor, but he suffered another relapse in different EM sites including the skin and central nervous system with a persistently normal marrow. This case is characterized by repeated relapses in isolated EM sites after allo-HSCT and suggests that the anti-leukemic effects of chemotherapy and/or graft-versus-leukemia effects in the EM sites might not be so uniformly effective as that in the marrow. Accordingly, we should be aware that AML relapses can occur repeatedly only in isolated EM sites post allo-HSCT, resulting in treatment failure and a poor prognosis.

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Previously no alternative therapy approach has been made to ameliorate disturbed circadian arginin vasopressin rhythm (C-AVP-R) in multiple system atrophy (MSA). A 65-year-old man with MSA showed loss of C-AVP-R and nocturnal polyuria. We performed moxibustion at specific acupuncture points on the bladder and inside the feet, once a day, 3 times a week, for 6 months. After the treatment, his C-AVP-R appeared to be normal, and the nocturnal urine output decreased to 75% (p<0.01). Together with the previous studies, it seems possible that somatic warm stimulation by moxibustion in specific points might have facilitated AVP secretion in this patient.

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We report a rare case of paraneoplastic limbic encephalitis with autoantibodies to glutamate receptor (GluR) in the cerebrospinal fluid (CSF). The 35-year-old woman with consciousness disturbance was diagnosed initially as non-herpetic encephalitis. Her signs and symptoms improved with acyclovir and steroid pulse therapy. However, after the treatment, an ovarian tumor was discovered, and we detected autoantibodies to GluR in the CSF. A possible association between the ovarian teratoma and GluR is suggested.

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Charcot-Marie-Tooth neuropathy (CMT) is an inherited degenerative disorder of the peripheral nervous system that results in slowly progressive distal muscle weakness, atrophy and loss of proprioception in the affected areas. X-linked CMT (CMTX) has been localized to the pericentric region of the X chromosome. CMTX neuropathy is usually associated with mutations in exon 2 of the gap junction protein β1 (GJB1) gene. GJB1 is a gap junction protein expressed in various cells including oligodendrocytes, astrocytes and myelinating schwann cells. Here, we report a female case of CMTX with a GJB1 mutation. The patient was severely clinically affected and exhibited both the features of demyelination and axonopathy. This is the first female patient with CMTX who showed permanent atypical scattered lesions in cerebral white matter of the brain on T2-weighted magnetic resonance images (MRI), which is very rare. The existence of a female patient with severe clinical symptoms may show that gain of function mechanism also leads to the disorders seen in these patients.

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A 67-year-old woman was diagnosed with inflammatory polyradiculoneuropathy. The intravenously administered immunoglobulin (IVIG) treatment that she received several times over a 3-year period relieved her clinical symptoms of muscle weakness and sensory disturbances, but these symptoms had worsened thereafter despite further IVIG treatment. MRI detected a solid tumor involving the cauda equina and pathological examinations confirmed this to be malignant lymphoma. The clinical and radiological findings for the malignant lymphoma of the cauda equina in this patient were quite similar to those for the inflammatory polyradiculoneuropathy.

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A 46-year-old woman with systemic lupus erythematosus was hospitalized for purpura, hematochezia and hematuria. One week after admission, she developed grand mal seizures and coma and was diagnosed with thrombotic thrombocytopenic purpura (TTP) when fragmented red cells were found on the peripheral blood smear. Laboratory findings showed severe ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 repeats) deficiency and anti-ADAMTS13 antibodies, which in recent reports have indicated a poor prognosis. She was refractory to methylprednisolone pulse therapy and plasma exchange, but administration of cyclosporine induced remission without adverse effects. We propose that cyclosporine may be an effective treatment for cases of refractory TTP.

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Cryofibrinogenemia (CF) has not been often reported as a complication of various rheumatic diseases. We describe a 44-year-old woman with CF associated with Sjögren's syndrome (SS), who developed digital necrotic ulcerations and purpura of the lower legs. Cryoprecipitate was detected in her plasma, and immunoelectrophoresis showed that the cryoprecipitate was cryofibrinogen. Alprostadil was intravenously administered, but the ulceration was aggravated. Subsequently, administration of high-dose prednisolone (PSL) at 60 mg/day was started, and the ulceration remarkably improved. Cryofibrinogen, detected before the administration of high-dose PSL, was negative after PSL. This is the first case presentation of CF associated with SS successfully treated with high-dose corticosteroid.

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Dengue fever, one of the common endemic viral fevers, often presents with fever, rash, and mild liver dysfunction. However, plasma leakage induced by dengue virus infection can lead to dengue hemorrhagic fever and dengue shock syndrome, and it can cause severe complications including liver failure and encephalopathy. Infection of dengue virus with other pathogens is an unusual but serious complication. We report a case of dengue shock syndrome with liver failure and impaired consciousness. The patient developed a disseminated Candida tropicalis infection, which may have been due to translocation of the fungus from the intestine damaged by the dengue virus.

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A 59-year-old woman without underlying disease was admitted to a local hospital because of lung abscess, cytopenias and renal failure. 3 days before admission, she was diagnosed as influenza infection and was under antiviral therapy. Blood cultures were positive for methicillin-sensitive Staphylococcus aureus (MSSA). She was transferred to our hospital on the 15th day at the local hospital because the clinical manifestations could not improve even though she was treated with multiple intravenous antibiotics directed against MSSA. Sputum cultures yielded methicillin-resistant S. aureus (MRSA) producing toxic shock syndrome toxin-1 (TSST-1) and serologic test indicated hypercytokinemia. She was diagnosed as rapidly progressive glomerulonephritis and hemophagocytic syndrome associated with staphylococcal infection. The pulmonary lesions, cytopenias and renal dysfunction improved as a result of long-term antimicrobial treatment including vancomycin, hemodialysis, short-term administration of corticosteroid and other supportive cares. She was finally weaned from hemodialysis on the 73th hospital days. In recent years, the number of cases of S. aureus producing TSST-1 and enterotoxin has been increasing and in cases of staphylococcal infections, close attention should be given to toxin-mediated as well as non-toxin-mediated clinical manifestations.

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Renal dysfunction and urinary abnormalities, which are usually related to drug toxicity, secondary amyloidosis, or those which overlap with other autoimmune conditions, are frequently observed in patients with rheumatoid arthritis. This is the first case report of membranous nephropathy in a patient with early-stage rheumatoid arthritis treated with the relatively selective cyclooxygenase-2 inhibitor, etodolac. The present case suggests that any kind of non-steroidal anti-inflammatory drug can cause membranous nephropathy; thus, physicians should be aware of this renal toxicity when prescribing these drugs.

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¹Department of Endocrinology and Metabolism, International Medical Center of Japan
²Department of Endocrinology and Metabolism, Toranomon Hospital Wrong:Shigeru Watanabe²
Right:Shigeru Watanabe¹

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