Aims/hypothesisImpaired intestinal barrier function is observed in type 1 diabetes patients and animal models of the disease. Exposure to diabetogenic antigens from the intestinal milieu due to a compromised intestinal barrier is considered essential for induction of the autoimmune process leading to type 1 diabetes. Since a hydrolysed casein (HC) diet prevents autoimmune diabetes onset in diabetes-prone (DP)-BioBreeding (BB) rats, we studied the role of the HC diet on intestinal barrier function and, therefore, prevention of autoimmune diabetes onset in this animal model.MethodsDP-BB rats were fed the HC diet from weaning onwards and monitored for autoimmune diabetes development. Intestinal permeability was assessed in vivo by lactulose–mannitol test and ex vivo by measuring transepithelial electrical resistance (TEER). Levels of serum zonulin, a physiological tight junction modulator, were measured by ELISA. Ileal mRNA expression of Myo9b, Cldn1, Cldn2 and Ocln (which encode the tight junction-related proteins myosin IXb, claudin-1, claudin-2 and occludin) and Il-10, Tgf-ß (also known as Il10 and Tgfb, respectively, which encode regulatory cytokines) was analysed by quantitative PCR.ResultsThe HC diet reduced autoimmune diabetes by 50% in DP-BB rats. In DP-BB rats, prediabetic gut permeability negatively correlated with the moment of autoimmune diabetes onset. The improved intestinal barrier function that was induced by HC diet in DP-BB rats was visualised by decreasing lactulose:mannitol ratio, decreasing serum zonulin levels and increasing ileal TEER. The HC diet modified ileal mRNA expression of Myo9b, and Cldn1 and Cldn2, but left Ocln expression unaltered.Conclusions/interpretationImproved intestinal barrier function might be an important intermediate in the prevention of autoimmune diabetes by the HC diet in DP-BB rats. Effects on tight junctions, ileal cytokines and zonulin production might be important mechanisms for this effect.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-010-1903-9) contains supplementary material, which is available to authorised users.

The objective of this study was to conduct a systematic and critical appraisal of the quality of previous publications and describe diagnostic methods, diagnostic criteria and definitions, repeatability, and agreement among methods for diagnosis of vaginitis, cervicitis, endometritis, salpingitis, and oophoritis in dairy cows. Publications (n=1,600) that included the words "dairy," "cows," and at least one disease of interest were located with online search engines. In total, 51 papers were selected for comprehensive review by pairs of the authors. Only 61% (n=31) of the 51 reviewed papers provided a definition or citation for the disease or diagnostic methods studied, and only 49% (n=25) of the papers provided the data or a citation to support the test cut point used for diagnosing disease. Furthermore, a large proportion of the papers did not provide sufficient detail to allow critical assessment of the quality of design or reporting. Of 11 described diagnostic methods, only one complete methodology, i.e., vaginoscopy, was assessed for both within- and between-operator repeatability (κ=0.55-0.60 and 0.44, respectively). In the absence of a gold standard, comparisons between different tests have been undertaken. Agreement between the various diagnostic methods is at a low level. These discrepancies may indicate that these diagnostic methods assess different aspects of reproductive health and underline the importance of tying diagnostic criteria to objective measures of reproductive performance. Those studies that used a reproductive outcome to select cut points and tests have the greatest clinical utility. This approach has demonstrated, for example, that presence of (muco)purulent discharge in the vagina and an increased proportion of leukocytes in cytological preparations following uterine lavage or cytobrush sampling are associated with poorer reproductive outcomes. The lack of validated, consistent definitions and outcome variables makes comparisons of the different tests difficult. The quality of design and reporting in future publications could be improved by using checklists as a guideline. Further high-quality research based on published standards to improve study design and reporting should improve cow-side diagnostic tests. Specifically, more data on intra- and interobserver agreement are needed to evaluate test variability. Also, more studies are necessary to determine optimal cut points and time postpartum of examination.

Early-life stress is a critical risk factor for developing psychopathological alterations later in life. This early adverse environment has been modeled in rats by exposure to stress during the peripubertal period—that is, corresponding to childhood and puberty—and has been shown to lead to increased emotionality, decreased sociability and pathological aggression. The amygdala, particularly its central nucleus (CeA), is hyperactivated in this model, consistent with evidence implicating this nucleus in the regulation of social and aggressive behaviors. Here, we investigated potential changes in the gene expression of molecular markers of excitatory and inhibitory neurotransmission in the CeA. We found that peripubertal stress led to an increase in the expression of mRNA encoding NR1 (the obligatory subunit of the N-methyl D-aspartate (NMDA) receptor) but to a reduction in the level of mRNA encoding glutamic acid decarboxylase 67 (GAD67), an enzyme that is critically involved in the activity-dependent synthesis of GABA, and to an increase in the vesicular glutamate transporter 1 (VGLUT1)/vesicular GABA transporter (VGAT) ratio in the CeA. These molecular alterations were present in addition to increased novelty reactivity, sociability deficits and increased aggression. Our results also showed that the full extent of the peripubertal protocol was required for the observed behavioral and neurobiological effects because exposure during only the childhood/prepubertal period (Juvenile Stress) or the male pubertal period (Puberty Stress) was insufficient to elicit the same effects. These findings highlight peripuberty as a period in which stress can lead to long-term programming of the genes involved in excitatory and inhibitory neurotransmission in the CeA.

Individual hosts normally respond to parasite attack by launching an acute immune response (a phenotypic plastic response), while host populations can respond in the longer term by evolving higher level of defence against parasites. Little is known about the genetics of the evolved response: the identity and number of genes involved and whether it involves a pre-activation of the regulatory systems governing the plastic response. We explored these questions by surveying transcriptional changes in a Drosophila melanogaster strain artificially selected for resistance against the hymenopteran endoparasitoid Asobara tabida. Using micro-arrays, we profiled gene expression at seven time points during development (from the egg to the second instar larva) and found a large number of genes (almost 900) with altered expression levels. Bioinformatic analysis showed that some were involved in immunity or defence-associated functions but many were not. Previously, we had defined a set of genes whose level of expression changed after parasitoid attack and a comparison with the present set showed a significant though comparatively small overlap. This suggests that the evolutionary response to parasitism is not a simple pre-activation of the plastic, acute response. We also found overlap in the genes involved in the evolutionary response to parasitism and to other biotic and abiotic stressors, perhaps suggesting a 'module' of genes involved in a generalized stress response as has been found in other organisms.

Chronic transplant dysfunction (CTD) is the leading cause of long-term renal allograft loss and is characterized by specific histological lesions including transplant vasculopathy, interstitial fibrosis, and focal glomerulosclerosis. Increasing evidence indicates that aldosterone is a direct mediator of renal damage via the mineralocorticoid receptor (MR). The MR antagonist spironolactone is renoprotective in native chronic kidney disease, but its effects on CTD are unknown. We studied the effects of spironolactone treatment on CTD development in the Dark Agouti-to-Wistar-Furth renal allograft transplant model, by treatment with 20 mg/kg spironolactone or vehicle daily by oral gavage from 2 days before transplantation (donors and recipients) throughout the experiment (12 wk, recipients). Dark Agouti-to-Dark Agouti isografts served as negative controls. Spironolactone significantly ameliorated the development of transplant vasculopathy in allografts by reducing the number of affected intrarenal arteries. In addition, spironolactone treatment showed a trend toward reduced proteinuria and focal glomerulosclerosis, and significantly reduced glomerular macrophage influx. However, spironolactone treatment did not affect interstitial fibrosis, interstitial macrophage influx, creatinine clearance, and systolic blood pressure. We conclude that spironolactone selectively ameliorates transplant vasculopathy and glomerular lesions in renal CTD in rats. These results suggest that spironolactone may have renoprotective potential as an adjunct treatment in renal transplantation to ameliorate CTD.

Chronic transplant dysfunction (CTD) is

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PPARgamma agonists may offer a new therapeutic strategy in clinical transplantation to attenuate the development of transplant arteriosclerosis and thereby chronic transplant dysfunction.