Association between dipeptidyl peptidase-4 inhibitors and autoimmune disorders: Data mining of the spontaneous reporting system in Japan.

The main objective of this study is to conduct a disproportionality analysis of adverse events in the Japan Adverse Event Report (JADER) database and evaluate the risk of the DPP-4 inhibitor induced autoimmune disorder, the secondary objective is risk assessment of sex difference and age difference. The proportional reporting ratio (PRR) of frequency-based statistics and Bayesian estimates of the information components (IC) were calculated as a measure of signal detection. Sex difference and age difference were evaluated using signal score calculated from the PRR and the Chi-square. In patients taking DPP-4 inhibitors, 94 reports of autoimmune disorders were detected with both signals; PRR: 4.09, chi-square: 158.26 and IC: 1.66, 95 % confidence interval: 1.32-2.00). For other antidiabetic drugs, no signals were detected. The signal of males was PRR: 4.53, chi-square: 110.91 and signal score: 6.22, the signal of female was PRR: 3.53, chi-square: 47.65 and signal score: 5.12. About age difference, the signal scores were 6.71 for patients over 60 years and 0.56 for patients under 60 years old. This study suggests that the DPP-4 inhibitors, unlike other antidiabetic drugs, were associated with autoimmune disorders. Signals of the DPP-4 inhibitors induced autoimmune disorders were detected in both male and female, but no sex difference was observed, but age difference was observed. Especially attention should be paid to patients over 60 years old.

Relationship Between Initial Renal Function and the Inhibitory Effect of Dipeptidyl Peptidase-4 Inhibitor Treatment on Renal Function Decline.

We retrospectively investigated the renal function index of patients with type 2 diabetes mellitus (T2DM) to examine the influence of dipeptidyl peptidase-4 (DPP-4) inhibitors on renal function between patients up to early nephropathy and after overt nephropathy. Patients with T2DM (>18 years old) who had been prescribed hypoglycemic agents for ≥3 months at Gifu Municipal Hospital between March 2010 and April 2014 were included in the study. Renal function was evaluated as the estimated glomerular filtration rate (eGFR) decline from baseline at 12 months. Patients in the DPP-4 inhibitor-treated and untreated groups with an eGFR ≥60 (358 [58.2 %] and 257 [41.8 %], respectively) and eGFR <60 (115 [60.2 %] and 76 [39.8 %], respectively) were subjected to multiple logistic regression analysis. Among patients with an eGFR ≥60, no significant differences were observed in eGFR decline rates over time. However, among patients with an eGFR <60, significant decreases were observed in eGFR decline rates >10 % (6 months; odds ratio, 0.476; P = 0.043, 12 months; odds ratio, 0.413; P = 0.010). Similar results were obtained for an eGFR decline rate >20 % (12 months; odds ratio, 0.369; P = 0.049). DPP-4 inhibitors are renoprotective in patients with T2DM and an eGFR <60.

National surveillance of Salmonella Enteritidis in commercial eggs in Japan.

A total of 105 033 eggs were collected across Japan from June 2010 to January 2011 and tested for Salmonella Enteritidis to provide data for the risk profiling of S. Enteritidis in eggs by the Food Safety Commission of Japan. S. Enteritidis isolates were recovered from three samples (20 eggs/sample) and these samples were different in regard to sampling period, grading and packaging centre and farm. The prevalence of S. Enteritidis in commercial eggs in Japan is estimated at ~0.003% which was a tenfold decrease in prevalence compared to similar surveillance in the mid 1990s. The decrease in the contamination in commercial eggs is considered a contributory factor in the decrease of foodborne diseases associated with S. Enteritidis in this period.

Herd prevalence of Enterobacteriaceae producing CTX-M-type and CMY-2 ß-lactamases among Japanese dairy farms.

AIMS: To determine the herd prevalence of Enterobacteriaceae producing CTX-M-type extended-spectrum ß-lactamases (ESBLs) among 381 dairy farms in Japan. METHODS AND RESULTS: Between 2007 and 2009, we screened 897 faecal samples using BTB lactose agar plates containing cefotaxime (2 µg ml(-1)). Positive isolates were tested using ESBL confirmatory tests, PCR and sequencing for CTX-M, AmpC, TEM and SHV. The incidence of Enterobacteriaceae producing CTX-M-15 (n = 7), CTX-M-2 (n = 12), CTX-M-14 (n = 3), CMY-2 (n = 2) or CTX-M-15/2/14 and CMY-2 (n = 4) in bovine faeces was 28/897 (3·1%) faecal samples. These genes had spread to Escherichia coli (n = 23) and three genera of Enterobacteriaceae (n = 5). Herd prevalence was found to be 20/381 (5·2%) dairy farms. The 23 E. coli isolates showed clonal diversity, as assessed by multilocus sequence typing and pulsed-field gel electrophoresis. The pandemic E. coli strain ST131 producing CTX-M-15 or CTX-M-27 was not detected. CONCLUSIONS: Three clusters of CTX-M (CTX-M-15, CTX-M-2, CTX-M-14) had spread among Japanese dairy farms. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report on the prevalence of multidrug-resistant CTX-M-15-producing E. coli among Japanese dairy farms.

Topical application of PPARα (but not ß/δ or γ) suppresses atopic dermatitis in NC/Nga mice.

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which regulate not only adipogenesis and proliferation/differentiation but also the immune response of cells. Because topical application of the activators of some PPAR isoforms improved clinical symptoms in patients with atopic dermatitis (AD), we investigated the role of PPAR activators using a murine AD model in NC/Nga mice; to the best of our knowledge, this has not been previously reported. METHODS: Activators of three PPAR isoforms (α, ß/δ, γ) were topically applied on inflamed skin in a murine AD model that was developed by repeated topical application of mite antigen in NC/Nga mice. The efficacy of each topical PPAR activator was evaluated immunologically and serologically. RESULTS: Topical application of the PPARα activator, but not of the activators of PPARß/δ or PPARγ, improved clinical dermatitis, reduced inflammatory cell infiltration in the dermis, and alleviated the elevation of serum IgE levels. In addition, PPARα expression was downregulated in the epidermis in our murine AD model, as is seen in patients with AD. CONCLUSIONS: Topical application of PPARα activator could be a potent therapeutic agent for patients with AD and could take the place of topical steroid treatments.

T cell-specific overexpression of interleukin-27 receptor α subunit (WSX-1) prevents spontaneous skin inflammation in MRL/lpr mice.

BACKGROUND: Interleukin (IL)-27 and WSX-1, the receptor α-specific subunit, have been shown to play important roles in initiating Th1 responses and in inducing immune modulation, and the immunosuppressive effect of IL-27 appears to be exerted via suppression of IL-10 and IL-17, which may participate in the pathogenesis of human systemic lupus erythematosus (SLE). OBJECTIVES: To examine the significance of IL-27/WSX-1 signalling in spontaneous skin inflammation of MRL/lpr mice, a model for SLE. METHODS: The severity and development of skin lesions, dermal inflammatory cells and epidermal-dermal depositions in the skin lesions of MRL/lpr mice with CD2-promoted WSX-1 overexpression (WSX-1 Tg mice) and those with globally disrupted WSX-1 (WSX-1 KO mice) were examined and compared with those of MRL/lpr mice. RESULTS: By 4 months of age, both WSX-1 KO mice and control MRL/lpr mice developed predominantly similar skin inflammation, while WSX-1 Tg mice hardly did so, demonstrating that intensifying IL-27/WSX-1 signalling on T cells prevents the spontaneous skin inflammation. WSX-1 KO mice showed Th2-type skin inflammation as evidenced by the Th2-prone dermal infiltrating cells and an absence of cutaneous Th1-type IgG deposition. Interestingly, there were significant IL-17+ dermal infiltrating cells in both WSX-1 KO and control MRL/lpr mice, which might potentially contribute to the formation of skin inflammation in these mice. CONCLUSIONS: These data indicate that IL-27/WSX-1 signalling may play a protective role in the development of SLE-like skin inflammation, and modulating IL-27/WSX-1 signalling might be an interesting therapeutic strategy in the treatment of SLE.

Asymptomatic cor triatriatum incidentally revealed by computed tomography.

We report a case of asymptomatic cor triatriatum in a 75-year-old man in whom the anomaly was incidentally revealed by computed tomography (CT). To our knowledge, this patient is the oldest case reported and the only such case in which the anomaly was demonstrated by CT.

Dengue hemorrhagic fever in Jakarta, Indonesia in 1988: isolation of dengue virus from patient whole blood using cell cultures.

During an outbreak of dengue hemorrhagic fever (DHF) in Jakarta, Indonesia in 1988, we attempted to isolate dengue virus using mosquito cells and a medium containing heparin. Whole blood, immediately after being drawn from patients, was inoculated into Aedes albopictus cell cultures temporarily maintained in the heparin-containing medium. The overall virus isolation rate was 25% (17 of 69) samples collected within three days after admission of the patients to hospital. No virus was obtained thereafter. The successful virus isolation was apparently not related to titers of anti-dengue virus hemagglutination-inhibiting antibodies present in patients' sera. The viruses were recovered from cases of each of the four World Health Organization grades of DHF without significant differences. The technique is simple and easily performed at bedside.

Secondary spontaneous pneumothorax.

To assess the clinical manifestations and therapy of secondary spontaneous pneumothorax (SSP), 123 episodes of SSP in 67 patients were retrospectively reviewed and were compared with 254 episodes of primary spontaneous pneumothorax in 130 patients. The major underlying lung diseases associated with SSP were emphysema (22 patients) and tuberculosis (21 patients). The average age of patients with SSP was 66.8 years, and the most common symptom was dyspnea. The average arterial oxygen tension at onset of SSP was 61.1 +/- 12.1 mm Hg (mean +/- standard deviation), which was lower than that of patients with primary spontaneous pneumothorax (p < 0.01). The recurrence rate of open thoracotomy with pleural abrasion was 12.5% (3 of 24 episodes), which was not lower than that of thoracostomy tube drainage with chemical pleurodesis using tetracycline (recurrence rate, 18.8%) (p > 0.5). We concluded that considering the high age of the patients, the presence of underlying lung diseases, and the increased operative risk, thoracostomy tube drainage rather than open thoracotomy was preferred as the first choice of therapy for SSP.

Glutathione-S-transferase activity toward aflatoxin epoxide in livers of mastomys and other rodents.

In order to study the liver glutathione-S-transferase (GST) activity toward aflatoxin B1 (AFB1) epoxide in mastomys in comparison with other rodents, we performed in vitro studies of the cytosolic GST activity toward AFB1-epoxide using mastomys, rat, mouse and hamster liver. Also AFB1 metabolism by liver microsomes including formation of AFB1-DNA adducts was studied. Cytosolic GST activity toward AFB1-epoxide was highest in mastomys liver, and higher in the hamster and mouse livers than in the rat liver, correlating well with the differences of the sensitivity of these species to the toxicity of AFB1. However, no relationship was noted between the sensitivity of a given species to the toxicity of AFB1 and the microsomal activity of binding of AFB1 to DNA or metabolizing AFB1 to AFM1, AFQ1 and AFP1. These results demonstrate the importance of the GST mediated AFB1-epoxide conjugation with glutathione in determining the differing sensitivities of these species to AFB1 toxicity. The extremely high activity of GST in mastomys indicates that this species would be a good model animal for studying GST toward AFB1-epoxide.

Antioxidative mechanism and apoptosis induction by 3-hydroxyanthranilic acid, an antioxidant in Indonesian food Tempeh, in the human hepatoma-derived cell line, HuH-7.

Recently, a new potent antioxidant was isolated from Tempeh (a traditional fermented soybean food in Indonesia) and was identified as 3-hydroxyanthranilic acid (HAA). This study deals with the antioxidant mechanism of HAA under biological systems and the cytokilling function of HAA to human malignant cells. HAA eliminated free radicals and inhibited the formation of fatty acid hydroperoxide in vitro, suggesting that HAA would serve as an antioxidant in the initial reaction in lipid oxidation systems. Actually, HAA inhibited the formation of the dominant product of membrane lipids, 12-hydroxyeicosatetraenoic acid (12-HETE) at a high concentration, while HAA accelerated 12-HETE formation at a low concentration in mammalian tissue. HAA oxidized glutathione and inhibited superoxide dismutase in vitro. Furthermore, HAA inhibited cell growth and induced apoptosis to HuH-7, a human hepatoma-derived cell line. As long as HAA is taken as a component of Tempeh, and not in large doses as a chemical, it may possibly act as a prooxidant rather than an antioxidant in vivo.

A prospective study on mortality among Japanese coal miners.

We conducted a prospective study to clarify mortality patterns among Japanese coal miners in a former coal mining area. Subjects included 1,796 coal miners and 4,022 non-coal-miners, who were identified by a mail survey between 1987 and 1989, and then followed up from the date of the survey to April 30th, 1994. We applied Cox's proportional hazards model to compare the mortalities between coal miners and non-coal-miners. Among the coal miners, significantly high risk ratios were observed in all causes of death (risk ratio = 1.4, p < 0.05) and all malignant neoplasms (risk ratio = 1.5, p < 0.05). Risk ratios for all causes of death and all malignant neoplasms also rose with the length of experience in coal mining. Analysis of the results for sites of cancer showed that coal miners had high risk ratios for stomach cancer (risk ratio = 1.6), liver cancer (risk ratio = 1.4) and lung cancer (risk ratio = 1.6), though these ratios were not statistically significant. When the risk ratio for lung cancer was analyzed according to the length of experience in coal mining, coal miners with at least 15 years' experience had a significantly high risk ratio (risk ratio = 2.4, p < 0.05), though coal miners with less than 15 years' experience had almost the same risk as non-coal-miners.

Characteristics of laryngeal receptors analyzed by presynaptic recording from the cat medulla oblongata.

In order to clarify the neural mechanisms for the protective laryngeal reflex, we conducted physiological analysis of laryngeal sensory receptors. In the present study, presynaptic unit activities, which might accurately reflect characteristics of the laryngeal receptor, were recorded with a glass microelectrode in the nucleus of the tractus solitarius of the medulla oblongata in ketamine-urethane anesthetized cats, and the responses to the mechanical and/or chemical stimuli were analyzed. From the results, it was demonstrated that highly sensitive mechanoreceptors and polymodal receptors exist in the laryngeal mucosa; they are particularly numerous in the laryngeal surface of the epiglottis and arytenoid region, and uncommon in the vocal fold. Mechanoreceptors on the laryngeal mucosa were classified into a rapidly adapting group and a slowly adapting group, while all polymodal receptors adapted rapidly to mechanical stimulation. These results suggest that these non-specific polymodal and rapidly adapting receptors may correspond to more superficial receptors such as free nerve endings and some taste buds, and also monomodal slowly adapting mechanoreceptors may correspond to deeper terminals in the subepithelium. It is also considered possible that the structures and the characteristics of these receptors are appropriate to elicit the protective laryngeal reflexes by non-specifically detecting various kinds of stimuli.

[An epidemiological study of tuberculosis in the former coal mining area of Chikuho. II. A case-control study on the relationship between socioeconomic factors and tuberculosis].

The authors conducted a case-control study on the relationship between socioeconomic factors and tuberculosis in the former coalmining area of Chikuho where tuberculosis incidence was high. The cases were 292 newly registered tuberculosis patients in Iizuka Health Center District, in the former coalmining area of Chikuho. Controls were randomly selected from resident cards, matched for sex, age, and place of residence. The results of comparing the cases with the controls were as follows: 1) Significantly more of the male cases had had long-term employment in coalmining. Exposure to dust is likely to be associated with the high tuberculosis incidence in males aged 50 or over. 2) The cases showed significantly higher unemployment levels and lower educational levels. Among females, more of the cases were unmarried or divorced, and a significantly higher proportion were receiving welfare benefits. The high incidence of tuberculosis is probably related to a low socioeconomic level resulting from closure of coalmines. 3) No difference was observed in working hours, night shifts, smoking rate, and drinking habits. These factors are unlikely to be singly related to the onset of tuberculosis.

[An epidemiological study of tuberculosis in the former coal-mining area of Chikuho. I. An analysis of newly registered tuberculosis patients in Iizuka Health Center District].

To clarify risk factors and groups at high risk of tuberculosis, a study on tuberculosis was conducted in the former coalmining area of Chikuho, where the death rate from tuberculosis was high. The authors analysed 701 newly registered tuberculosis patients during the 5 years from 1982 through 1986 in Iizuka Health Center District in the Chikuho area, studied the geographical distribution of tuberculosis incidence in Fukuoka Prefecture, and compared the trends of tuberculosis incidence in Iizuka Health Center District, all Japan and Fukuoka Prefecture. The results were as follows: 1) The incidence of tuberculosis in Iizuka Health Center District was higher than those both in all Japan and in Fukuoka Prefecture. The incidence in Iizuka Health Center District has not decreased since 1981. Therefore, the difference in tuberculosis incidence between Iizuka Health Center District, and all Japan and Fukuoka Prefecture has gradually become greater. The incidence of tuberculosis in 1986 was 81.6 (per 100,000) in Iizuka Health Center District, 58.1 in Fukuoka Prefecture, 46.6 in all Japan. 2) A specific pattern was observed in the geographical distribution of tuberculosis incidence in Fukuoka Prefecture. A high incidence was concentrated in the former coalmining area of Chikuho. 3) The positive rate of tubercle bacilli (38.8%) was the same as that in all Japan. However, the positive rate was higher in age groups 10-49 than that in all Japan. 4) A total of 83.5% of tuberculosis cases were detected when visiting doctors, mainly with complaints of cough, fever and sputum. Only 6.9% of the patients were detected by screening examinations.(ABSTRACT TRUNCATED AT 250 WORDS)

[A prospective study on the relationship between body mass index and mortality in middle-aged and elderly people in Japan].

We conducted a prospective study to clarify the relationship between mortality and body mass index (BMI) in a middle-aged and elderly population in Japan. The subjects included 12,649 people (5,686 males and 6,963 females) aged from 40-69 years, who were identified by a mail survey between 1987 and 1989, and thereafter were followed up from the date of the survey until February 28, 1995. Cox's proportional hazards model was used to adjust for age, smoking status, drinking habit and occupation, and hazard ratios were calculated for total mortality and cancer mortality based on levels of BMI, while using a BMI of 22 to approximately 24 as a reference level. Results showed a U shaped relationship between BMI and total mortality in females. Females demonstrated a minimal total mortality in the reference group, but a significantly high hazard ratio in the lowest group of BMI < 20 (hazard ratio = 1.95, p < 0.01) and the highest group of BMI > or= 26 (hazard ratio = 1.71, p < 0.01). On the other hand, males did not demonstrate such a U shaped relationship, but instead showed an L shaped relationship between BMI and total mortality. Males showed a minimal total mortality at a BMI of 24 of approximately 26 (hazard ratio = 0.92), but a significantly high hazard ratio in the lowest BMI group (hazard ratio = 1.57, p < 0.01). In contrast, an elevated hazard ratio was not observed in the highest BMI group (hazard ratio = 1.05). The relationship between BMI and cancer mortality was found to be similar to the relationship between BMI and total mortality in both males and females. Our findings suggest that moderate overweight may be a sign of good health among both middle-aged and elderly men in Japan.

[A malignant thymoma combined with sarcoidosis].

A case of 69-year-old female of malignant thymoma with sarcoidosis was experienced. Although many diseases such as myasthenia gravis are associated with thymoma, sarcoidosis is a rare thymoma-associated disease. Only one case of thymoma with sarcoidosis was reported all over the world, and our case is the first case in Japan. As thymus is essential for the development of T lymphocytes, thymoma may cause T lymphocytes disorder and sarcoidosis. So, we consider thymoma with sarcoidosis as a syndrome rather than as a spectrum of coincidental disease.

[Three cases of bronchial foreign bodies which required thoracotomy].

We experienced three cases of bronchial foreign bodies which required thoracotomy for the removal. In case 1 (51-year-old male), as the foreign body (a nail) was present at extremely peripheral bronchus (left B10b), the removal using bronchoscope was unsuccessfully tried and thoracotomy was performed. In case 2 (12-year-old male), as the foreign body (a lead) was lodged firmly in the bronchus (left B8) surrounded by a granulation tissue, the removal using bronchoscope failed and thoracotomy was performed. In case 3 (6-year-old female), during the removal of the foreign body (a pen-cap) tightly wedged in the left main bronchus using bronchoscope, the general condition was getting worse and emergency thoracotomy was performed. In each case, the foreign body was removed by bronchotomy without sacrifice of significant lung tissue.

[Four cases of spontaneous hemopneumothorax].

We reported four cases of spontaneous hemopneumothorax. Of these, one (a 25-year-old man) had right hemopneumothorax and three (a 28-year-old man, a 21-year-old woman and a 24-year-old man) had left hemopneumothorax. In one case, because massive intrapleural bleeding had continued, an emergency operation was performed. In two cases, thoracotomy was performed because of recurrent pneumothorax. In the other case, about one week after hemopneumothorax had been controlled by pleural drainage, pneumothorax recurred and thoracotomy was performed. In conclusion, early thoracotomy is the best treatment for spontaneous hemopneumothorax.