The bacterial microbiota consists of nine core genera: Prevotella, Sphingomonas, Pseudomonas, Acinetobacter, Fusobacterium, Megasphaera,

Veillonella, Staphylococcus, and Streptococcus [120, 121] but little data exist about the fungal microbiota of the lungs, with the exception of Pneumocystis spp. In a recent study by Charlson et al., the fungal microbiota of the mouth and lungs in select healthy and lung transplant recipients was analyzed by ITS-based pyrosequencing [122]. The fungal distribution in the oral wash of healthy subjects was similar to that found in the study by Ghannoum et al. [82]. In the lung transplant recipients, the fungal microbiota Poziotinib order of the oral cavity was dominated by Candida, likely depending on the antibiotic and immunosuppressant Ceritinib used by these patients [122]. The bronchoalveolar lavage from lung transplant recipients showed detectable Candida spp., Aspergillus spp., or Cryptococcus spp. Because all of the transplant recipients had been treated with antibiotics and immunosuppressants, thus ablating host immune

responses and the prokaryotic milieu of the lung microbiota, this first study supports the notion that host defense, and perhaps some sort of bacterial microbiota-mediated resistance mechanisms, play a major role in keeping fungal colonization extremely low in the lungs. Numerous studies have indicated that Th17 cells and their signature cytokine IL-17A are critical to the airway’s immune response against various infections, including intracellular bacteria [123, 124] and fungi [125]. The

innate IL-17A-producing cells, γδ T cells have been shown to act on nonimmune lung cells in infected tissues Fossariinae to strengthen innate immunity by inducing the expression of antimicrobial proteins and inflammatory chemokines as CCL28, in those cells, causing the migration of IgE-secreting B cells to the infected tissues [126] as well as the proliferation of human airway epithelial cells in vitro. Additionally, IL-17A production by pulmonary γδ T cells in the early phase of tuberculosis infection stimulates neutrophil recruitment to the infected tissues [127, 128]. Neutrophils release their genomic DNA into the extracellular environment in the form of neutrophil extracellular traps (NETs) [129] and ensnare invading pathogens [130, 131]. NETs were found to be induced by opportunistic fungi such as C. albicans [130] in a human in vitro study that demonstrated that NETs interact with yeast in both the single-cell form as well as the multicellular hyphal form, and incapacitate both forms via the action of the granular components of the NETs [130]. In contrast to the protective immune response exemplified by Th1 and Th17 cells [132], Th2 effector cells are considered deleterious in lung fungal infections, in part because they dampen the protective Th1-cell responses.

[14-16] Bongkrekic acid is a highly unsaturated tricarboxylic fatty acid, which inhibits oxidative phosphorylation by blocking the mitochondrial adenine nucleotide translocator.[15] Recently, the biosynthesis of the deadly toxin catalysed by an unusual polyketide synthase (PKS) was elucidated allowing for a better understanding of the pathogenicity of the contaminating bacteria.[17, 18] Besides bongkrekic acid, B. gladioli pv. cocovenenans is also known to produce the azapteridine toxoflavin (2), which might as well contribute to the toxic properties of contaminated tempe bongkrek.[19] Several recent studies indicated that Burkholderia

species are prolific producers of secondary metabolites with potent biological and pharmacological GSK-3 assay properties.[20-28] Interestingly, some species were also found to be associated with mucoralean fungi and are of eminent metabolic importance for the fungi.[4,

29] A prominent example are the bacterial endosymbionts of R. microsporus.[30] The bacteria, Burkholderia rhizoxinica,[31] are producers of highly active antitumoural agents as well as a strong hepatotoxin.[32, 33] The discovery of these natural products is of importance as R. microsporus is not only a plant pathogen but also implicated with human infections.[6] In this regard it should be noted that full genome sequencing of natural product producing this website bacteria indicated that their biosynthetic potential may even be much higher than expected.[34] It is believed that the majority of secondary metabolite encoding GNA12 genes is only expressed under certain conditions and may require a specific trigger.[35] To get an overview of the secondary metabolic capabilities

of the toxinogenic B. gladioli strain and to investigate its metabolic contribution to the bacterial–fungal interaction, we performed a systematic survey on its biosynthetic potential on a genomic and an analytical-chemical level. Here, we report the formation and the biosynthesis of a class of antibiotics previously not known to be produced by these fungus-associated bacteria. We also describe the context-dependent production of the antibiotics and of the toxin bongkrekic acid in the fungal–bacterial coculture. Rhizopus microsporus var. oligosporus HKI 0401 (CBS 337.62; ATCC 46348; NRRL514) and Burkholderia gladioli pv. cocovenenans HKI 10521 (DSM 11318; ATCC 33664) were grown on potato dextrose agar (PDA) at 30 °C. Genomic DNA of B. gladioli was isolated using the MasterPure™ DNA purification kit (Epicentre Biotechnologies, Hessisch Oldendorf, Germany) to perform 454 Shotgun sequencing combined with a 3 kb paired end library. An approximately 25-fold coverage including 10 scaffolds was obtained and subsequent correct assembly of the generated contigs were achieved using the Lasergene SeqMan software (DNA Star, Inc., Madison, WI, USA).

This was in marked contrast to nonstressed mice, which significantly gained body weight during the 24-day experimental period (Fig. 1C and D). To examine how CVS affects HPA axis activity we determined CORT levels in urine samples collected weekly. Overall, for the entire experimental period, cumulative urine CORT levels MK-1775 in vivo were significantly

higher in stressed than in nonstressed mice in both females (358 ± 38 ng/mL and 138 ± 17 ng/mL, respectively; p < 0.001) and males (13.7 ± 1.4 ng/mL and 9.26 ± 0.81 ng/mL, respectively; p < 0.01; Fig. 2A). In addition, CORT levels under both basal and stressful conditions were markedly higher in females compared to males (p < 0.001 for each condition; Fig. 2A). These higher CORT levels were observed mainly during the first 3 weeks of the 24-day experimental period; in the fourth

week of stress, CORT levels in stressed mice were not significantly higher than those in nonstressed mice (Fig. 2B). Of note, whereas CORT was found primarily in its free form in the urine of female and male mice (85 and 78% of total CORT, respectively), in the blood it was mostly bound to CORT-binding globulin (92 and 83% of total CORT in females and males, respectively) and was detected at significantly lower concentrations compared with urine CORT. In addition, although to a lesser extent than in the urine, blood CORT levels were significantly higher in females than in males (Fig. 2D and E). Given the overall stress-induced increase

in CORT levels, Saracatinib purchase and in light of previous studies [8, 32], we expected stress to induce spleen anomalies and, due to its apparent immunosuppressive activity, attenuate the susceptibility to EAE. To evaluate stress-induced spleen anomalies we measured the spleen weight and number of splenocytes in stressed and nonstressed mice following the 24-day experimental period. To determine stress-induced susceptibility to EAE, we immunized stressed and nonstressed mice with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) following Liothyronine Sodium the 24-day experimental period and quantified the severity of EAE-related symptoms. As expected, stressed mice exhibited a significant decrease in splenocyte cell count compared to nonstressed controls (females: 38 × 106 cells compared with 52 × 106 cells; p < 0.01; Supporting Information Fig. 2A. Males: 35 ± 2.37 × 106 cells compared with 62 ± 3.5 × 106 cells; p < 0.001; Supporting Information Fig. 2B), as well as decreased spleen weight (females: 75.0 ± 3.2 mg compared with 97.7 ± 5.7 mg; p < 0.01; Supporting Information Fig. 2C. Males: 71.4 ± 4 mg compared with 95.5 ± 6.2 mg; p < 0.01; Supporting Information Fig. 2D). These differences were not due to overall differences in body weight (e.g. differences resulting from decreased weight gain in stressed mice), as the spleen weight/body weight ratio was also decreased by 15% in stressed mice compared with nonstressed mice (Supporting Information Fig. 2E and F).

We therefore hypothesized that the protective effect in our model could be due to transfer and survival of partially mismatched lymphocytes from pups to the mother during delivery. Despite the potential for such a mechanism in our model, we found no evidence of persistent chimeric CD4+ or CD8+ lymphocytes from paternal origin within the dams’ spleens to support this. As we examined spleens at the end of follow-up it is possible that such cells were transferred, but were not persistent. It is also possible that other cell types such as antigen-presenting cells

or cells in other organs are relevant in the process. An alternative hypothesis is that processing of paternal placental antigens within the maternal circulation leads to increases in the maternal regulatory T cell population [22,23] and that effects on diabetes development are mediated Fluorouracil solubility dmso by such regulatory T cells. In summary, this study C59 wnt manufacturer demonstrates that gestation has no enhancing effects on pre-existent autoimmune destruction of islet beta cells, and that pregnancy via haploidentical male mates can delay the development of autoimmune diabetes in female NOD mice. The mechanism of this effect is unclear. This work forms part of the dissertation of Yannick Fuchs at the University of Technology Dresden and of Katharina Foertsch at the University of Technology Munich. Kerstin Adler received support from the NIH/DFG

Research Career Transition Award Program (KO 3418/1-1). Yannick Fuchs is supported by a grant from the BMBF to the DZD e.V. (FKZ01GI0924) and the DFG Research Center and Cluster of Excellence–Center for Regenerative Therapies Dresden (FZ 111). The authors

have nothing to declare. Fig. S1. Schematic representation of the study design. Litter-matched female non-obese diabetic (NOD) mice were mated to syngeneic NOD, Non-specific serine/threonine protein kinase major histocompatibility complex (MHC) haploidentical CByB6F1/J and fully mismatched C57BL/6J male mice at (a) 10 weeks and (b) 13 weeks of age. The number of females mated and the number of males used for mating are provided in parentheses. Unmated litter-matched female NOD mice were used as control groups. The total number of offspring and the number of NOD dams that had productive litters are also indicated. Fig. S2. Screening for fetal microchimeric cells in splenocytes from non-obese diabetic (NOD) dams after pregnancy from haploidentical CByB6F1/J mates. Fluorescence staining of major histocompatibility complex (MHC) H-2Kb (ordinate) molecules on CD4+ and CD8+ T cells was analysed by flow cytometry. The left column shows all viable cells additionally stained for H-2Db molecules. The column in the middle shows cells gated for CD4+, and the right column shows cells gated for CD8+. The numbers represent the percentage of H-2Kb-positive cells within the gated area of each graph. (a) To control the staining experiments, splenocytes of one C57BL/6J and one unmated NOD mouse were stained and analysed individually as well as in mixtures of 1:100 and 1:1000.

Control antibodies included Rat IgG2a isotype control mAb (eBioscience), mouse anti-Border disease virus p125/p80 mAb VPM21 and purified rabbit immunoglobulin (Sigma-Aldrich, St. Louis, MO, USA), for rat, mouse and rabbit primary antibodies, respectively. All antibodies were diluted in PBS/T80 containing 10% NGS. Slides Torin 1 manufacturer were washed twice in PBS, and the appropriate secondary antibody (peroxidase-labelled anti-mouse or anti-rabbit EnVision™+ reagent, Dako) was applied to sections for 30 min at RT. After a final PBS wash, sections were incubated with 3,3′-diaminobenzidine (DAB) for 7·5 min at RT, washed in distilled water, counterstained

with haematoxylin, dehydrated and mounted in Shandon synthetic mountant (Thermo Scientific). Each nodule was scanned under the light microscope. The initial scanning was performed with a wide-angle lens at low power (×20), and the following data were recorded: the predominant inflammatory cell type, the distribution of the cell infiltrate (diffuse or focal/multifocal) and the location of the infiltrate within the nodule (peripheral, central

or both). CD3+ and Pax5+ cells tended to occur in a focal/multifocal distribution pattern in the sections, and the foci of CD3+ and Pax5+ cells were counted in the most active ×20 field (the field with the highest number of foci). CD3+ and Pax5+ infiltrates were subjectively scored 0–3 (Table 1). MAC387+ infiltrates

were also scored 0–3; however, MAC387+ cells occurred more diffusely in sections, either evenly distributed or in patches, and therefore, the scoring system was slightly different selleck compound (Table 2). Numbers of FoxP3+ cells were counted in 10 nonoverlapping ×400 fields (five peripheral and five central fields per oesophageal nodule using a 0·0625 mm2 graticule). In the normal oesophagus control group and lymph nodes, five nonoverlapping ×400 fields were counted. Counting was confined to CD3+ areas. Statistical analyses were performed with GraphPad Prism (GraphPad Software, Inc. CA, USA). The difference in prevalence and distribution Fossariinae of the different proportions of cell types was tested using the chi-square test. The differences between the scores of the different types of infiltrate were tested for significance between all groups using a Kruskal–Wallis test, followed by Dunn’s post hoc test. P values of <0·05 were considered significant. Myeloid cells predominated in 70% of cases, while T cells predominated in 23% of cases. In the remaining 7% of cases, the number of T cells and myeloid cells was approximately equal. There was no difference in the proportion of myeloid and T cells between the neoplastic and non-neoplastic groups (P = 0·27). When cells were present in normal oesophageal sections, they were diffusely scattered and myeloid and T cells tended to occur in equal proportions (Table 3).

Colonization of C. rodentium on the

intestinal epithelial surface resulted in a Th1-type immune response, and Th1 cytokines play a role in host-protective immunity (Simmons et al., 2002); Chen et al., 2005; Gonçalves et al., 2001). To test the hypothesis that early inoculation of probiotic La and/or prebiotic inulin may alter developmental patterns of the GAI, Th1, Th2, and T reg cytokine production and expression in the intestine- and gut-associated lymphoid tissue in young mice following pathogen challenge were determined. Analysis of bacterial (Cr) antigen (Cr-Ag)-specific cytokine production of the MLN revealed that the lymphocytes from mice pretreated with probiotic La, prebiotic inulin, or the synbiotic combination of probiotic La and prebiotic inulin had significantly enhanced Cr-Ag-specific IL-10 secretion (Fig. 4a) compared with that detected in mice with C. rodentium infection selleck chemicals llc alone. Pretreatment

Inhibitor Library chemical structure of mice with the synbiotic combination of probiotic La and prebiotic inulin resulted in a more pronounced IL-10 production by the MLN cells compared with other groups (Fig. 4a). In contrast, the MLN of mice pretreated with the synbiotic combination of probiotic La and prebiotic inulin had significantly reduced Cr-Ag-specific IFN-γ response (Fig. 4b) at 2 weeks post-Cr infection. To further determine the impact of La, inulin, and combined treatments on pro-inflammatory and regulatory cytokine responses in the colonic tissue, we measured gene expression of IL-10 and TGF-β, the regulatory cytokines, using real-time PCR. The results showed that

mice of the synbiotic combination treated group had significantly greater colonic expression of TGF-β, in comparison with C. rodentium-infected control, prebiotic- and probiotic-treated groups (Fig. 5a), and pretreatment of mice with La only resulted in an increase in colonic TGF-β expression. These observations, therefore, suggest that probiotic La and synbiotics enhance the expression and production of TGF-β, a key regulator of immunity and vital for the suppression of enteric pathogen-induced inflammatory responses. Similarly, probiotic La and synbiotic combination treatments resulted in a significant increase in colonic IL-10 expression (Fig. 5b) in comparison with Cr Silibinin infected alone. TGF-β can act as a potent negative regulator of mucosal inflammation. However, Smad 7, by physically interfering with activation of Smad2/Smad 3 and preventing their interaction with TGF-β, causes disruption of TGF-β signaling. This may contribute to the enhanced pro-inflammatory responses in the intestine (Hayashi et al., 1997; Maggio-Price et al., 2006). Studies have suggested that NF-κB (Jobin & Sartor, 2000) and Smad 7 (Monteleone et al., 2001, 2004b) are up-regulated in IBD patients and may be responsible for colonic inflammation. NF-κB plays a key role in regulating the immune response to infection and inflammation.

Control (WT) and KO thymocytes were labeled with different concentrations of CFSE, mixed at a 1:1 ratio and subsequently injected directly into the thymus of a PD0325901 price C57BL/6 recipient mouse, at a dose of 4 × 106 cells/mouse, and analyzed 3 days later for developmental progression. CD4+ or CD8+ T cells were

sorted by negative selection using CD4+ T and CD8+ T cell kits and magnetized columns (Miltenyi Biotech) according to the manufacturer’s specifications. Briefly, cells were labeled with biotin-conjugated antibodies (against CD8a (or CD4), CD11b, CD11c, CD19, B220, DX5, CD105, Ter119, and anti-MHC class II) followed by binding to antibiotin beads. The labeled cells were passed through magnetized columns to deplete all non-CD4+ or non-CD8-α+ T cell fractions, thus resulting in purified CD4+ or CD8+ T-cell populations. Subsequently, the purified cells were washed with sorting buffer (PBS supplemented with 2 mM EDTA and 2% FCS), followed by counting and resuspension in DMEM-10 media or PBS. A proliferation assay using thymidine incorporation was carried out as described [45] with minor modifications. Sorted cells were used at a concentration of 1 × 105 cells per well together with 2 × 105 cells per well of irradiated (2000 rads) splenocytes and appropriate stimuli at indicated doses for 3 days. A total of 1 μCi 3H-thymidine was applied to each well

for the last 18–20 h of the 3-day culture period. After cell culture, cells were harvested with the FilterMate Universal Harvester (PerkinElmer, Sheleton, CT, USA) on glass fiber filters (Wallac) and counted with MicroBeta Trilux 1450 LSC (PerkinElmer) STA-9090 in vitro using dedicated software. In CFSE assays, sorted cells were stained with 2 μM CFSE and incubated Interleukin-3 receptor for 72 h with appropriate stimuli at indicated doses. After incubation, CFSE-labeled cells were stained with appropriate antibodies and CFSE dilution within Vα2 positive cells was analyzed using a FACS Calibur cytometer. For adoptive transfer of transgenic T cells the experiments

were performed as previously described [46] with minor modifications. C57BL/6 mice were first immunized in the footpad with OVA protein or with OVA-coated beads in the presence of CFA followed by adoptive transfer of 5 or 10 × 106 cells (labeled with CFSE) from OT1 and OT2 transgenic mice, respectively. Three days after transfer, the proliferation of CFSE-labeled cells in the draining lymph node, within Vα2 positive cells, was analyzed by FACS. For evaluation of homeostatic cell expansion, purified OT1 or OT2 cells stained with CFSE were injected i.v. into RAG recipients (on the C57BL/6 background). The RAG recipients were left untreated for 2 weeks and splenocytes were harvested and analyzed. The proliferation of CFSE-labeled Vα2+ cells was analyzed by FACS and the absolute cell number of Vα2+ and CFSE+ DP cells was calculated.

In lymphoid tissues ATP and STA-9090 molecular weight ADP are primarily hydrolyzed to AMP by NTPDase1/CD39, and further to adenosine by CD73. To trigger signaling cascades in the responding cells ATP and ADP bind to a series of ligand-gated (P2X) and G-protein-coupled (P2Y) receptors, whereas adenosine binds to one of the four adenosine receptors. Intriguingly, ATP and ADP generally evoke proinflammatory signals, whereas adenosine shows opposite effects by acting as an anti-inflammatory mediator.

Along with the “classical” nucleotide-inactivating chain, the counteracting adenylate kinase (AK) and nucleoside diphosphate (NDP) kinase enzymes co-exist on the cell surface. The balance between these opposing nucleotide-scavenging and ATP-regenerating pathways may represent a key element in controlling the duration and magnitude of purinergic signaling 1–3. CD73 is a glycosylphosphatidylinositol-linked surface protein expressed

on subsets of leukocytes, vascular endothelial cells and on certain epithelial cells 4–7. The preferential expression of CD73, together with NTPDase, on CD4+CD25+FoxP3+ immunosuppressive Tregs has recently drawn much attention 8–11. The enzymatic activity of CD73 modulates leukocyte–endothelial Selleckchem PLX3397 cell contacts and it improves barrier functions of the vascular lining 12–14. Altered inflammatory reactions have been reported in CD73-deficient mice in multiple find more different models, including ischemia-reperfusion injuries and autoimmune diseases 13, 15–19.

CD73 can be expressed on several cancer types such as leukemia, glioblastoma, melanoma, and ovarian, bladder, thyroid, eosophageal, gastric, colon, prostate and breast cancer 3. The ecto-nucleotidase activity on the malignant breast cancer cells is known to enhance the migration, invasion and neovascularization of these cells and to support the growth of tumors 20, 21. CD73 expression has even been suggested to serve as a prognostic marker in certain cancer types, such as breast cancer 21. Although the functions of CD73 in cancer cells have been studied to some extent, the contribution of host CD73 activity to cancer progression has not been addressed. Here, we report that CD73-deficient T cells show up-regulated NTPDase activity, and that tumor progression and intratumoral accumulation of Tregs and mannose receptor (MR)+ macrophages, which are typically considered to be type 2 macrophages 22–24, are attenuated in CD73-deficient mice. Moreover, the composition of intratumoral leukocyte populations and tumor growth can be therapeutically manipulated by targeting CD73 and NTPDase. These data indicate that suppression of the host’s CD73 activity might be a new tool to keep cancer cells under the control of anti-tumor immune responses.

One of the striking observations in the IL-17/IL-22 axis in

our experimental model of DENV-2 infection is the fact that infected IL-22−/− mice presented increased production of IL-17A in the spleen and liver, and neutralization of IL-17A in these mice reverted the worsened phenotype observed in mice lacking IL-22. Other studies have addressed the cross-talk between IL-17A and IL-22 production. Besnard et al.[132] showed that IL-22 may regulate the expression and pro-inflammatory properties of IL-17A in allergic lung inflammation. Sonnenberg et al.[112] described that IL-17A could suppress IL-22 expression in Th17 cells after bleomycin-induced lung inflammation and fibrosis. Although a Akt inhibitor in vivo reciprocal regulation Selleckchem XL184 of IL-17A and IL-22 is observed in vivo, the underlying cellular and molecular mechanisms that may affect the functional properties of these cytokines in distinct peripheral tissues are yet to be described. Therefore, IL-22 seems to counterbalance the

production of IL-17A in experimental severe dengue infection. Pro-inflammatory mediators produced by epithelial cells in response to IL-17A are neutrophil- and granulocyte-attracting chemokines (i.e. CXCL1, CXCL2), IL-6 and several growth factors.[13-15] Neutrophil accumulation and activation are increased in DENV infection, so this could be an important function for IL-17A in this disease. In addition, IL-17A expression is markedly reduced in the spleens of iNKT-cell-deficient mice (Jα18−/−) during infection (R. Guabiraba, J. Renneson, and F. Trottein, unpublished data). The close association of iNKT 17-DMAG (Alvespimycin) HCl cells and the production of IL-17 or IL-22 in experimental DENV infection might require further investigation. Although thrombocytopenia is observed

in mild and severe forms of DENV infection, the role of platelet activation in dengue pathogenesis has not been fully elucidated. Hottz et al.[133] hypothesize that platelets have major roles in inflammatory amplification and increased vascular permeability during severe forms of dengue. They reported an increased expression of IL-1β in platelets and platelet-derived microparticles from patients with dengue or after platelet exposure to dengue virus in vitro. Further, DENV infection led to microparticle release through mechanisms dependent on NLRP3 inflammasome activation and caspase-1-dependent IL-1β secretion by platelets. Inflammasome activation and platelet shedding of IL-1β-rich microparticles correlated with signs of increased vascular permeability. Moreover, microparticles from DENV-stimulated platelets induced enhanced permeability in vitro in an IL-1-dependent manner.

Interestingly, GWAS have highlighted several genes associated with susceptibility to schizophrenia, many of which have a VDR-binding site within or close to them. The genes that are potentially regulated by vitamin D subserve a diverse range of biological functions including membrane transport, maintenance of nucleosome structure, and signal transduction to name a few (see Table 1). Some of these vitamin D mediated genes have an intimate relationship with brain

morphology and function as evidenced by their demonstrated role www.selleckchem.com/products/Nolvadex.html in neuronal migration and gyration, dendritic spine morphology, and neuronal connectivity (see Table 1) [105-108]. The full scope of the functional impact of vitamin D on the expression of these schizophrenia-associated genes in the brain warrants further study. Autism is part of a spectrum of developmental disorders characterized by deficits in social cognition, language,

communication, and stereotypical patterns of behaviour [109]. Neuropathological features lack clear definition; however, the disorder shows changes consistent with pre- and post-natal developmental HDAC inhibitors cancer abnormalities that involve multiple brain regions, including the cerebral cortex, subcortical white matter, amygdala, brainstem, and cerebellum [110]. It has been proposed that autism demonstrates developmentally specific neural changes, with early brain overgrowth at the beginning of life (thought to be secondary to excessive neurone number), slowing or arrest of growth during early childhood, and neurodegeneration in adult life, at least in a subset of patients [111]. As vitamin D has been shown to inhibit excessive cellular proliferation in early rat brain development [27, 62], it has been argued that gestational hypovitaminosis ADP ribosylation factor D contributes to excessive neuronal proliferation

in the developing brain and, therefore, could serve as a useful model for autism [112]. Epidemiological evidence for a contribution of vitamin D to the pathogenesis of autism exists but is less striking than for schizophrenia. This, in part, relates to issues of ascertainment, sensitivity/specificity of diagnosis, and differences in study methodology. Seasonality of birth has been reported to be associated with autism in the early spring in Scandinavia, Japan, United Kingdom, and the USA [113-115]. Some studies report an increased peak of births during summer months [116], and others show this effect restricted to men [114] or not existent at all [117]. A latitude effect has been illustrated on both the magnitude of the month of birth effect and in overall disease prevalence [118]; however, the effect has only been discernible in a cohort prior to the surge in autism prevalence in the 1990s. Migration appears to affect prevalence rates of autism.