The utility of patent ductus arteriosus closure with hemostatic clip in dogs.

This study investigated the utility of patent ductus arteriosus (PDA) closure with hemostatic clip by comparing with traditional PDA closure. Medical records of 51 dogs with surgical closure of PDA were reviewed and retrospective study was conducted. 29 dogs were treated by procedure with hemostatic clip (Group HC), and 22 dogs were treated by surgical ligation (Group SL). Data pertaining to breed, sex, age and body weight at the time of surgery, echocardiographic minimal ductal diameter, duration of surgery, hemostatic clip size, echocardiographic findings, hemor-rhage, residual ductal flow and recanalization were collected from records. The results showed that procedure with hemostatic clip had been selected in lighter dogs than traditional PDA closure. Duration of surgery performed only hemostatic clip technique was significantly shorter than that in group SL. Preoperative LVIDd, E-wave and FS were significantly lower than postoperative ones. As regard all parameters, the differences between pre- and postoperative periods were not significantly different between group HC and group SL. Hemorrhage, residual ductal flow, and recanalization were not significantly different in both groups. The present study showed that procedure with hemostatic clip is beneficial in that it is available in smaller dogs and can make shorter operation duration than traditional PDA closure. Moreover, the procedure is effective for the resolution of volume overload of the left atrium and ventricle in short-term outcome. Complications including hemorrhage, residual ductal flow and recanaliza-tion were not significantly different with both techniques.

Wire-loop lesion is associated with serological immune abnormality, but not renal prognosis, in lupus nephritis.

BACKGROUND: Wire-loop lesion (WL) is one of the active lesions of lupus nephritis (LN). However, few reports have focused on the clinicopathological relationships of WL to serological immune abnormality and renal prognosis. METHODS: We enrolled 126 Japanese LN patients subjected to renal biopsy in 11 hospitals from 2000 to 2018. In patients with class III or IV of the International Society of Nephrology/Renal Pathology Society classification, we retrospectively compared clinicopathological findings between those with WL (WL+ group) and without WL (WL- group) to detect factors associated with WL. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate of <60 mL/min/1.73m2 for more than three months. We also compared these findings between those with CKD (CKD+ group) and without CKD (CKD- group) at the last visit to investigate factors associated with renal prognosis. RESULTS: Of 126 patients, 100 (79.4%) were classified as class III or IV. WL was found in 36 (36.0%) of them. Although the renal function did not differ, the WL+ group had a higher titre of serum anti-dsDNA antibodies and lower serum complement 3 levels than the WL- group. Linear regression analysis revealed a significant association only between anti-dsDNA antibodies and WL (ß = 0.27, 95% confidence interval (CI) 0.001-0.100, p = 0.01). Of these patients, 69 were tracked for 59.6 ± 55.1 months. Kaplan-Meier analysis showed no difference in renal prognosis between these groups. Next, the CKD+ group included 15 (22.1%) patients. They were older and had higher frequencies of hypertension and hyperuricaemia, serum creatinine (Cr) level, glomerulosclerosis, interstitial inflammation, interstitial fibrosis and tubular atrophy than the CKD- group at the time of renal biopsy. The frequency of WL was not significantly different. Cox regression analysis revealed significant associations of CKD with hypertension, hyperuricaemia, serum Cr level at the time of renal biopsy clinically and with tubular atrophy histologically. CONCLUSIONS: WL was associated with serum anti-dsDNA antibodies but not with renal prognosis, suggesting that WL reflects immune abnormality but is not an independent factor predictive of renal prognosis in LN.

Bayesian Estimation of CBF Measured by DSC-MRI in Patients with Moyamoya Disease: Comparison with 15O-Gas PET and Singular Value Decomposition.

BACKGROUND AND PURPOSE: CBF analysis of DSC perfusion using the singular value decomposition algorithm is not accurate in patients with Moyamoya disease. This study compared the Bayesian estimation of CBF against the criterion standard PET and singular value decomposition methods in patients with Moyamoya disease. MATERIALS AND METHODS: Nineteen patients with Moyamoya disease (10 women; 22-52 years of age) were evaluated with both DSC and 15O-gas PET within 60 days. DSC-CBF maps were created using Bayesian analysis and 3 singular value decomposition analyses (standard singular value decomposition, a block-circulant deconvolution method with a fixed noise cutoff, and a block-circulant deconvolution method that adopts an occillating noise cutoff for each voxel according to the strength of noise). Qualitative and quantitative analyses of the Bayesian-CBF and singular value decomposition-CBF methods were performed against 15O-gas PET and compared with each other. RESULTS: In qualitative assessments of DSC-CBF maps, Bayesian-CBF maps showed better visualization of decreased CBF on PET (sensitivity = 62.5%, specificity = 100%, positive predictive value = 100%, negative predictive value = 78.6%) than a block-circulant deconvolution method with a fixed noise cutoff and a block-circulant deconvolution method that adopts an oscillating noise cutoff for each voxel according to the strength of noise (P < .03 for all except for specificity). Quantitative analysis of CBF showed that the correlation between Bayesian-CBF and PET-CBF values (ρ = 0.46, P < .001) was similar among the 3 singular value decomposition methods, and Bayesian analysis overestimated true CBF (mean difference, 47.28 mL/min/100 g). However, the correlation between CBF values normalized to the cerebellum was better in Bayesian analysis (ρ = 0.56, P < .001) than in the 3 singular value decomposition methods (P < .02). CONCLUSIONS: Compared with previously reported singular value decomposition algorithms, Bayesian analysis of DSC perfusion enabled better qualitative and quantitative assessments of CBF in patients with Moyamoya disease.

Experimental study of fast-neutron production and moderation for accelerator-based BNCT system.

This work aims to study the fast-neutron production and moderation for the development of a compact accelerator-based multi-port Boron Neutron Capture Therapy (AB-mBNCT) system. An initial energy distribution and the efficiency of a test moderator assembly (TMA) for fast neutrons from a tungsten (W) target bombarded with a 53 MeV proton beam were measured using organic scintillators. The experimental results were reproduced with reasonable accuracy by simulations using the PHITS code. This paper will discuss about the experimental outcome and the related benchmark calculations by PHITS code.

Noninvasive Evaluation of CBF and Perfusion Delay of Moyamoya Disease Using Arterial Spin-Labeling MRI with Multiple Postlabeling Delays: Comparison with 15O-Gas PET and DSC-MRI.

BACKGROUND AND PURPOSE: Arterial spin-labeling MR imaging with multiple postlabeling delays has a potential to evaluate various hemodynamic parameters. To clarify whether arterial spin-labeling MR imaging can identify CBF and perfusion delay in patients with Moyamoya disease, we compared arterial spin-labeling, DSC, and 15O-gas PET in terms of their ability to identify these parameters. MATERIALS AND METHODS: Eighteen patients with Moyamoya disease (5 men, 13 women; ages, 21-55 years) were retrospectively analyzed. CBF values of pulsed continuous arterial spin-labeling using 2 postlabeling delays (short arterial spin-labeling, 1525 ms; delayed arterial spin-labeling, 2525 ms) were compared with CBF values measured by 15O-gas PET. All plots were divided into 2 groups by the cutoff of time-based parameters (the time of the maximum observed concentration, TTP, MTT, delay of MTT to cerebellum, and disease severity [symptomatic or not]). The ratio of 2 arterial spin-labeling CBFs (delayed arterial spin-labeling CBF to short arterial spin-labeling CBF) was compared with time-based parameters: time of the maximum observed concentration, TTP, and MTT. RESULTS: The short arterial spin-labeling-CBF values were significantly correlated with the PET-CBF values (r = 0.63; P = .01). However, the short arterial spin-labeling-CBF value dropped in the regions with severe perfusion delay. The delayed arterial spin-labeling CBF overestimated PET-CBF regardless of the degree of perfusion delay. Delayed arterial spin-labeling CBF/short arterial spin-labeling CBF was well correlated with the time of the maximum observed concentration, TTP, and MTT (ρ = 0.71, 0.64, and 0.47, respectively). CONCLUSIONS: Arterial spin-labeling using 2 postlabeling delays may detect PET-measured true CBF and perfusion delay in patients with Moyamoya disease. Provided its theoretic basis and limitations are considered, noninvasive arterial spin-labeling could be a useful alternative for evaluating the hemodynamics of Moyamoya disease.

The effect of aprepitant and dexamethasone combination on paclitaxel-induced hypersensitivity reaction.

PURPOSE OF INVESTIGATION: Dexamethasone (DEX) is often administered to prevent paclitaxel (PTX)-induced hypersensitivity reactions (HSR). The DEX dose is reduced when administered in combination with aprepitant (APR). However, the influence of that dose reduction on PTX-induced HSR has not been thoroughly studied. The present authors aimed to investigate the effects of the combined administration of APR and DEX on PTX-induced HSR. MATERIALS AND METHODS: Fifty-one patients who received a three-week PTX regimen in combination with APR and DEX were retrospectively analysed. The authors compared the dose of DEX with the incidence of HSR and other toxicities. RESULTS: Patients were stratified into two groups depending on the DEX dose, > 20 mg (group D, 33 patients), and < 12 mg (group reD, 26 patients). The incidence of HSR in Groups D and reD were 51.5% (17/33) and 53.8% (14/26), respectively. The frequencies of other toxicities between the groups were comparable. CONCLUSION: The findings suggest that although a reduction in DEX dose is possible when APR is co-administered, this does not affect the PTX-induced HSR. However, adverse effect should be closely monitored.

Impact of tubulointerstitial lesions on anaemia in patients with biopsy-proven diabetic nephropathy.

AIMS: To investigate the relationship between the progression of anaemia and renal pathological findings in patients with diabetic nephropathy. METHODS: A total of 223 patients with diabetes underwent renal biopsy from 1985 to 2010 and were confirmed to have pure diabetic nephropathy according to the recent classification, of whom 113 (baseline haemoglobin ≥ 11 g/dl) were enrolled in the study. Linear regression analysis was used to estimate the changes in haemoglobin levels during the follow-up period. RESULTS: In a multivariate model adjusted for clinical and histopathological variables, higher interstitial fibrosis and tubular atrophy scores were more strongly associated with a decrease in haemoglobin levels than were lower scores. Compared with an interstitial fibrosis and tubular atrophy score of 0, the standardized coefficients for interstitial fibrosis and tubular atrophy scores of 1, 2 and 3 were 0.20 (95% CI -0.31 to 0.93), 0.34 (95% CI -0.22 to 1.34) and 0.47 (95% CI 0.07 to 1.96), respectively, whereas a higher glomerular class, a higher vascular lesion score and the presence of exudative lesions were not strongly correlated with the decrease in haemoglobin. CONCLUSIONS: Tubulointerstitial lesions that are more advanced are significantly associated with the progression of anaemia in patients with diabetic nephropathy after adjustment for numerous covariates. This finding suggests that tubulointerstitial lesions may be a useful prognostic indicator for anaemia in patients with diabetic nephropathy, and that decreased erythropoietin production attributable to the progression of tubulointerstitial lesions is a major cause of anaemia in these patients.

Different mechanisms of hydroxyl radical production susceptible to purine P2 receptor antagonists between carbon monoxide poisoning and exogenous ATP in rat striatum.

Previous studies have suggested that carbon monoxide (CO) poisoning stimulates cAMP production via purine P2Y11-like receptors in the rat striatum, activating cAMP signaling pathways, resulting in hydroxyl radical ((•)OH) production. Extracellular ATP was thought likely to trigger the cascade, but the present study has failed to demonstrate a clear increase in the extracellular ATP due to CO poisoning. The CO-induced (•)OH production was attenuated by the P2Y11 receptor antagonist NF157, in parallel with its abilities to suppress the CO-induced cAMP production. The (•)OH production was more strongly suppressed by a non-selective P2 receptor antagonist, PPADS, which had no effect on cAMP production. More selective antagonists toward the respective P2 receptors susceptible to PPADS, including NF279, had little or no effect on the CO-induced (•)OH production. The intrastriatal administration of exogenous ATP dose-dependently stimulated (•)OH production, which was dose-dependently antagonized by PPADS and NF279 but not by NF157. Exogenous GTP and CTP dose-dependently stimulated (•)OH production, though less potently. The GTP-induced (•)OH production was susceptible to both of NF279 and PPADS, but the CTP-induced (•)OH production was resistant to PPADS. The mechanism of (•)OH production may differ between CO poisoning and exogenous ATP, while multiple P2 receptors could participate in (•)OH production. The CO-induced (•)OH production was susceptible to the inhibition of NADPH oxidase, but not xanthine oxidase. Also, the NADPH oxidase inhibition suppressed (•)OH production induced by forskolin, a stimulator of intracellular cAMP formation. It is likely that (•)OH is produced by NADPH oxidase activation via cAMP signaling pathways during CO poisoning.

Leiomyosarcoma of the broad ligament: a case report with CT and MRI images.

Primary leiomyosarcoma of the broad ligament is a very rare and highly malignant gynecological tumor. The authors report a 61-year-old postmenopausal woman with signs and symptoms of malignant ovarian tumor. Preoperative magnetic resonance imaging (MRI) was interpreted as being suspicious for malignant tumors, such as an ovarian cancer or a leiomyosarcoma of the broad ligament, so laparotomy was performed. Macroscopically, the tumor was revealed with a 18 x 13.7 x 9.5 cm degenerated, multiple cystic part and solid whitish part arising from broad ligament which on histopathology proved to be leiomyosarcoma. To the best of the authors' knowledge, primary leiomyosarcoma of the broad ligament has been documented in 21 reports or so, and no imaging findings are available. Here the authors present the MRI findings of primary leiomyosarcoma of the broad ligament.

Expression of protein gene product 9.5 and Sal-like protein 4 in canine seminomas.

The aim of the present study was to characterize canine classical seminoma (SE) and spermatocytic seminoma (SS) by immunohistochemical expression of gonocytic and spermatogonial cellular markers (c-Kit, placental alkaline phosphatase [PLAP], protein gene product 9.5 [PGP9.5] and Sal-like protein 4 [Sall4]) and histochemically by the periodic acid-Schiff (PAS) reaction. Twenty-five cases of SE and 23 cases of SS were investigated. Two cases of dysgerminoma were also examined. c-Kit was expressed on the cell membrane of 13 of 25 cases of SE (52%) and four of 23 cases of SS (16%). This marker was not expressed in dysgerminoma. PLAP immunoreactivity was observed in the cytoplasm of neoplastic cells of six of 25 cases of SE (24%). PLAP was not expressed in cases of SS and dysgerminoma. All samples of SE, SS and dysgerminoma showed cytoplasmic expression of PGP9.5 and nuclear immunoreactivity for Sall4. There was fine granular cytoplasmic PAS staining in neoplastic cells in five of 25 cases of SE (20%), while all samples of SS and dysgerminoma cases were PAS negative. These findings suggest that it is not possible to differentiate canine SE and SS using these markers. This may be because canine SS may be derived from spermatogonia that can differentiate to spermatocytes and also because cases of canine SE might consist of neoplastic cells that have lost their gonocytic nature. This study was the first to show positive immunoreactivity for Sall4 in canine seminomas and dysgerminomas and expression of PGP9.5 in canine dysgerminomas.

Comparison of different aspects of BMI history to identify undiagnosed diabetes in Japanese men and women: Toranomon Hospital Health Management Center Study 12 (TOPICS 12).

AIMS: To examine current BMI and various aspects of BMI history as pre-screening tools for undiagnosed diabetes in Japanese individuals. METHODS: This cross-sectional study included 16 226 men and 7026 women aged 30-75 years without a self-reported history of clinician-diagnosed diabetes. We estimated the probability of having undiagnosed diabetes (fasting glucose ≥ 7.0 mmol/l and/or HbA1c ≥ 48 mmol/mol (≥ 6.5%) for the following variables: current BMI, BMI in the early 20s (BMI(20y)), lifetime maximum BMI (BMI(max)), change between BMI in the early 20s and current BMI (ΔBMI(20y-cur)), change between BMI in the early 20s and maximum BMI (ΔBMI(20y-max)), and change between lifetime maximum and current BMI (ΔBMI(max-cur)). RESULTS: The prevalence of undiagnosed diabetes was 3.3% (771/23252) among participants. BMI(max) , ΔBMI(20y-max) and current BMI (1-sd increments) were more strongly associated with diabetes than the other factors (multivariate odds ratio 1.58 [95% CI 1.47-1.70] in men and 1.65 [95% CI 1.43-1.90] in women for BMI(max) ; multivariate odds ratio 1.47 [95% CI 1.37-1.58] in men and 1.61 [95% CI 1.41-1.84] in women for ΔBMI(20y-max) ; multivariate odds ratio 1.47 [95% CI 1.36-1.58] in men and 1.63 [95% CI 1.40-1.89] in women for current BMI). The probability of having diabetes was markedly higher in those with both the highest tertile of BMI(max) and greatest ΔBMI(20y-max) ; however, a substantially lower likelihood of diabetes was observed among individuals with the lowest and middle tertiles of current BMI (< 24.62 kg/m² in men and < 22.54 kg/m² in women). CONCLUSIONS: Lifetime maximum BMI and BMI changes from early adulthood were strongly associated with undiagnosed diabetes. Adding BMI history to people's current BMI would improve the identification of individuals with a markedly higher probability of having undiagnosed diabetes.

Latent mesangial immunoglobulin A deposition in long-term functioning kidney does not correlate with disease progression and may exhibit fluctuating patterns.

BACKGROUND: Latent mesangial immunoglobulin (Ig)A deposition in long-term functioning kidney does not correlate with disease progression and may exhibit fluctuating patterns Mesangial IgA deposition without urinary abnormalities (latent mesangial IgA deposition) is occasionally observed in non-episode biopsies of kidney allografts. However, the histologic features of latent IgA deposition have not been fully characterized. METHODS: To better identify the clinicopathologic background of subclinical mesangial IgA deposition, we compared the clinical and histologic characteristics of long-term functioning kidney allografts with and without latent IgA deposition. RESULTS: Among 29 patients with a posttransplant duration of >10 years, 37.9% exhibited latent mesangial IgA deposition. Biopsies indicated that renal function at the time of and 5 years before subclinical mesangial IgA deposition was generally similar. HLA-DR4 and HLA-Bw51 showed a nonsignificant trend to be more frequent in the IgA-positive group. Histologic investigation demonstrated no changes in disease scores based on the Banff 2009 classification between groups. Immunofluorescence revealed co-deposition of C3 at >1+ intensity in 72% IgA-positive patients. Immunohistochemical analysis revealed that IgA deposition per se did not cause notable increases in intraglomerular α-smooth muscle actin (SMA)-positive cells. One patient with subclinical IgA deposition demonstrated a waxing and waning pattern in the amount of IgA deposition. CONCLUSION: This study suggests that subclinical IgA deposition in long-term functioning kidney allografts is not associated with progressive course in clinical and pathologic findings. Furthermore, the amount of subclinical IgA deposition may exhibit fluctuating patterns in some cases.

A non-joint tissue biphasic synovial sarcoma in a dog.

A subcutaneous tumour was identified in the malar region of a 14-year-old neutered female mixed breed dog. The dog was humanely destroyed and necropsy examination was performed. The tumour did not invade neighbouring tissues and no metastasis was found. Microscopically, the tumour showed a range of features including the presence of multinucleated giant cells, chondrocyte differentiation and cystic or slit-like structures. All of these features are consistent with previously reported descriptions of synovial sarcomas in dogs. Mesenchymal cells accounted for the majority of the tumour, but cytokeratin-positive epithelioid components were also confirmed by immunohistochemistry. The tumour was diagnosed as a biphasic type of synovial sarcoma. Synovial sarcoma in man may develop in tissues unrelated to joints and this is the first report of a non-joint synovial sarcoma in a dog.

Transcriptional activation of Mina by Sp1/3 factors.

Mina is an epigenetic gene regulatory protein known to function in multiple physiological and pathological contexts, including pulmonary inflammation, cell proliferation, cancer and immunity. We showed previously that the level of Mina gene expression is subject to natural genetic variation linked to 21 SNPs occurring in the Mina 5' region. In order to explore the mechanisms regulating Mina gene expression, we set out to molecularly characterize the Mina promoter in the region encompassing these SNPs. We used three kinds of assays--reporter, gel shift and chromatin immunoprecipitation--to analyze a 2 kb genomic fragment spanning the upstream and intron 1 regions flanking exon 1. Here we discovered a pair of Mina promoters (P1 and P2) and a P1-specific enhancer element (E1). Pharmacologic inhibition and siRNA knockdown experiments suggested that Sp1/3 transcription factors trigger Mina expression through additive activity targeted to a cluster of four Sp1/3 binding sites forming the P1 promoter. These results set the stage for comprehensive analysis of Mina gene regulation from the context of tissue specificity, the impact of inherited genetic variation and the nature of upstream signaling pathways.

Association of living alone with the presence of undiagnosed diabetes in Japanese men: the role of modifiable risk factors for diabetes: Toranomon Hospital Health Management Center Study 13 (TOPICS 13).

AIMS: To investigate whether living alone was associated with the presence of undiagnosed diabetes and whether this association could be attenuated by modifiable lifestyle habits. METHODS: This cross-sectional study included 6400 Japanese men without a history of diagnosed diabetes. Individuals with currently undiagnosed diabetes were identified through fasting glucose concentration ≥7.0 mmol/l or HbA1c concentration ≥ 48 mmol/mol (≥ 6.5%). Effect modification was examined using body mass index, hypertension, history of dyslipidaemia, drinking habits, smoking habits, physical activity, vegetable intake, emotional stress and depressed mood. RESULTS: Men who lived alone (n = 1098) had a significantly elevated odds ratio for having undiagnosed diabetes in an age-adjusted model (odds ratio 1.45, 95% CI 1.07, 1.96; P = 0.018). After adjustment for lifestyle factors, the association was slightly attenuated (odds ratio 1.40, 95% CI 1.02, 1.91; P = 0.036). After further adjustment for all factors mentioned above, living alone was still marginally significantly associated with the presence of undiagnosed diabetes (odds ratio 1.38, 95% CI 1.003, 1.90; P = 0.048). A significant association of living alone with the presence of undetected diabetes was particularly observed among men who were overweight, currently smoked and were physically inactive, or had any one of those three factors. CONCLUSIONS: The association between undiagnosed diabetes and living alone can be partially influenced by modifiable lifestyle factors. Men who lived alone, especially those who did not engage in favourable lifestyle habits, were more likely to have undiagnosed diabetes. Such individuals have a higher probability of having undetected diabetic hyperglycaemia and would need to undergo glucose tests to identify the disease.

Feasibility of a novel approach for rapid detection of simulated bloodstream infections via enzymatic template generation and amplification (ETGA)-mediated measurement of microbial DNA Polymerase activity.

Bloodstream infections (BSIs) caused by bacteria and fungi are associated with significant morbidity and mortality. Currently, blood culture is the gold standard for confirming a suspected BSI, but has the drawback of lengthy time-to-detection (TTD) required for indicating the presence of microbes. Detection of conserved microbial nucleic acid sequences within blood culture samples via PCR has been demonstrated to offer potential for reducing the TTD of BSI; however, these approaches have various other limitations. We report a novel approach toward rapid detection of microbes from simulated BSI via differential hematopoietic cell lysis followed by enzymatic template generation and amplification (ETGA)-mediated measurement of microbial DNA polymerase extension activity. The differential cell lysis procedure effectively reduced the level of detectable DNA polymerase extension activity associated with human-derived hematopoietic cells present in blood culture samples taken from healthy donors. After treatment with the differential cell lysis procedure, the ETGA assay detected a panel of clinically prevalent bacteria and Candida albicans from spiked blood culture samples. The ETGA blood culture method also reduced by threefold the TTD required for simulated BSI, compared with a continuous-monitoring blood culture instrument. In summary, these findings demonstrate the feasibility of an innovative approach toward a rapid, sensitive, and universal screen for microbes within blood culture samples. Potential for clinical application and automation are also addressed.

Etiology of recurrent acute pancreatitis, with special emphasis on pancreaticobiliary malformation.

PURPOSE: This study was aimed to investigate etiology and clinical profiles of recurrent acute pancreatitis (RAP), particularly from the morphology of the pancreaticobiliary duct system. MATERIAL AND METHODS: Pancreaticobiliary morphology was examined in 230 of 381 patients with acute pancreatitis (AP) using endoscopic retrograde cholangiopancreatography. We analyzed factors associated with RAP including the pancreaticobiliary duct system. RESULTS: RAP was diagnosed in 74 patients (19%). Major etiologies of RAP were alcoholic (38%), idiopathic (26%) and pancreaticobiliary malformation (22%). Patients with alcoholic RAP were significantly younger (47.2±11.6 years) than those with gallstone RAP (67.3±16.8; p<0.05). RAP with pancreaticobiliary malformation (male-to-female ratio: 1:4.3; p<0.01) and gallstone RAP (1:1.7; p<0.05) occurred predominantly in females in comparison with alcoholic RAP (1:0.2). Recurrence rate was 80% for AP with pancreaticobiliary malformation, significantly higher than for the others (p<0.01). Pancreas divisum was suspected as the etiology of mild RAP in 7 patients. Four RAP patients with pancreas divisum underwent endoscopic minor papilla sphincterotomy and improved. Pancreaticobiliary maljunction with biliary dilatation (choledochal cyst) was suspected as the etiology of mild RAP in 3 patients. The 3 RAP patients with choledochal cyst underwent prophylactic flow diversion surgery with complete resection of the dilated common bile duct, and achieved improvement. High confluence of pancreaticobiliary ducts was suspected as the etiology of mild RAP in 6 patients. CONCLUSION: Pancreaticobiliary malformation is one of the major causes of RAP. As some of them benefit from endoscopic or surgical treatment, morphology of the pancreaticobiliary duct system should be examined where possible in RAP patients.

Development of a new scoring system for predicting the 5 year incidence of type 2 diabetes in Japan: the Toranomon Hospital Health Management Center Study 6 (TOPICS 6).

AIMS/HYPOTHESIS: The aims of this study were to assess the clinical significance of introducing HbA(1c) into a risk score for diabetes and to develop a scoring system to predict the 5 year incidence of diabetes in Japanese individuals. METHODS: The study included 7,654 non-diabetic individuals aged 40-75 years. Incident diabetes was defined as fasting plasma glucose (FPG) ≥7.0 mmol/l, HbA(1c) ≥6.5% (48 mmol/mol) or self-reported clinician-diagnosed diabetes. We constructed a risk score using non-laboratory assessments (NLA) and evaluated improvements in risk prediction by adding elevated FPG, elevated HbA(1c) or both to NLA. RESULTS: The discriminative ability of the NLA score (age, sex, family history of diabetes, current smoking and BMI) was 0.708. The difference in discrimination between the NLA + FPG and NLA + HbA(1c) scores was non-significant (0.836 vs 0.837; p = 0.898). A risk score including family history of diabetes, smoking, obesity and both FPG and HbA(1c) had the highest discrimination (0.887, 95% CI 0.871, 0.903). At an optimal cut-off point, sensitivity and specificity were high at 83.7% and 79.0%, respectively. After initial screening using NLA scores, subsequent information on either FPG or HbA(1c) resulted in a net reclassification improvement of 42.7% or 52.3%, respectively (p < 0.0001). When both were available, net reclassification improvement and integrated discrimination improvement were further improved at 56.7% (95% CI 47.3%, 66.1%) and 10.9% (9.7%, 12.1%), respectively. CONCLUSIONS/INTERPRETATION: Information on HbA(1c) or FPG levels after initial screening by NLA can precisely refine diabetes risk reclassification.

Cyclin-dependent kinase inhibitor Cdkn2c deficiency promotes B1a cell expansion and autoimmunity in a mouse model of lupus.

The lupus-prone NZM2410 mice present an expanded B1a cell population that we have mapped to the Sle2c1 lupus susceptibility locus. The expression of Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18(Ink4c) and located within Sle2c1, is significantly lower in B6.Sle2c1 B cells than in B6 B cells. To test the hypothesis that the B1a cell expansion in B6.Sle2c1 mice was due to a defective p18 expression, we analyzed the B1a cell phenotypes of p18-deficient C57BL/6 mice. We found a dose-dependent negative correlation between the number of B1a cells and p18 expression in B cells, with p18-deficient mice showing an early expansion of the peritoneal B1a cell pool. p18 deficiency enhanced the homeostatic expansion of B1a cells but not of splenic conventional B cells, and the elevated number of B6.Sle2c1 B1a cells was normalized by cyclin D2 deficiency. These data demonstrated that p18 is a key regulator of the size of the B1a cell pool. B6.p18(-/-) mice produced significant amounts of anti-DNA IgM and IgG, indicating that p18 deficiency contributes to humoral autoimmunity. Finally, we have shown that Sle2c1 increases lpr-associated lymphadenopathy and T cell-mediated pathology. B6.p18(-/-).lpr mice showed a greater lymphadenopathy than B6.Sle2c1.lpr mice, but their renal pathology was intermediate between that of B6.lpr and B6.Sle2c1.lpr mice. This indicated that p18-deficiency synergizes, at least partially, with lpr-mediated pathology. These results show that Cdkn2c contributes to lupus susceptibility by regulating the size of the B1a cell compartment and hence their contribution to autoimmunity.