Coeliac Disease and Mast Cells

Over the last decades, there has been an impressive progress in our understanding of coeliac disease pathogenesis and it has become clear that the disorder is the final result of complex interactions of environmental, genetic, and immunological factors. Coeliac disease is now considered a prototype of T-cell-mediated disease characterized by loss of tolerance to dietary gluten and the targeted killing of enterocytes by T-cell receptor \u3b1\u3b2 intraepithelial lymphocytes. Accumulating evidence, however, indicates that the induction of a gluten-specific T helper-1 response must be preceded by the activation of the innate immune system. Mast cells are key players of the innate immune response and contribute to the pathogenesis of a multitude of diseases. Here, we review the results of studies aimed at investigating the role of mast cells in the pathogenesis of coeliac disease, showing that these cells increase in number during the progression of the disease and contribute to define a pro-inflammatory microenvironment

A Local Signature of LTP-Like Plasticity Induced by Repetitive Paired Associative Stimulation

Repetitive paired associative stimulation (rPAS) repeatedly pairs electrical nerve stimulation (ENS) with transcranial magnetic stimulation (TMS) of the contralateral motor hand area (M1) at 5 Hz frequency. So far, there are only few studies concerning the effects of PAS on the modulation of EEG power. Hence, aim of the present study was to investigate rPAS long term after-effects on cortical excitability looking at EEG power spectra. In four experimental sessions, separated by 2 weeks interval, 12 awake subjects received rPAS of the right median nerve and left M1 at a fixed interval (ISI) of 25 ms (real condition), 5 Hz-TMS on left M1, 5 Hz-ENS, of the right median nerve, and rPAS with changing ISI (sham condition). We measured peak-to-peak MEP amplitude, evoked from the target muscle (right abductor pollicis brevis muscle) at rest and the absolute power (POW) in four frequency bands: \u3b1 (8-12 Hz), \u3b2 (13-30), \u3b8 (4-7) and \u3b4 (1-3), under rest conditions. All these parameters were evaluated in three detection blocks: baseline, immediately after and after 30' from the end of the conditioning protocol. Real rPAS induced a long-lasting homotopic cortical excitability modulation, as indexed by MEP amplitude increase, that was paralleled by a long-lasting reduction of \u3b1/\u3b2-POW and by a widespread \u3b8-\u3b4-POW modulation. rPAS applied over the sensory-motor cortex induced an LTP-like plasticity, as indexed by a robust reduction in the \u3b1/\u3b2 POW positively correlated with the MEP amplitude increase. rPAS25ms may be a useful tool for motor neurorehabilitation promoting a sensory-motor coupling within \u3b2 oscillations

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

A molecular pathway analysis informs the genetic background at risk for schizophrenia

Background: Schizophrenia is a complex mental disorder marked by severely impaired thinking, delusional thoughts, hallucinations and poor emotional responsiveness. The biological mechanisms that lead to schizophrenia may be related to the genetic background of patients. Thus, a genetic perspective may help to unravel the molecular pathways disrupted in schizophrenia. Methods: In the present work, we used a molecular pathway analysis to identify the molecular pathways associated with schizophrenia. We collected data of genetic loci previously associated with schizophrenia, identified the genes located in those positions and created the metabolic pathways that are related to those genes' products. These pathways were tested for enrichment (a number of SNPs associated with the phenotype significantly higher than expected by chance) in a sample of schizophrenic patients and controls (4486 and 4477, respectively). Results: The molecular pathway that resulted from the identification of all the genes located in the loci previously found to be associated with schizophrenia was found to be enriched, as expected (permutated p(106)=9.9999e-06).We found 60 SNPs amongst 30 different genes with a strong association with schizophrenia. The genes are related to the pathways related to neurodevelopment, apoptosis, vesicle traffic, immune response and MAPK cascade. Conclusions: The pathway related to the toll-like receptor family seemed to play a central role in the modulation/connection of various pathways whose disruption leads to schizophrenia. This pathway is related to the innate immune system, further stressing the role of immunological-related events in increasing the risk to schizophrenia

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Background: Bipolar disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study, we tested the association of several single-nucleotide polymorphisms (SNPs) within 3 strong candidate genes (CACNA1C, CHRNA7, and MAPK1) with BPD. These genes are involved in monoamine-related pathways, as well as in dendrite development, neuronal survival, synaptic plasticity, and memory/learning. Methods: One hundred and thirty-two subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17, and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. Results: Significant differences in the distribution of alleles between the cases and controls were detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7, and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. Limitations: Limited sample size and risk of false-positive findings. Discussion: Our data suggest a possible role of these 3 genes in BPD. Alterations of 1 or more common brain pathways (e.g., neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results

Neuroplasticity and second messenger pathways in antidepressant efficacy: pharmacogenetic results from a prospective trial investigating treatment resistance

Genes belonging to neuroplasticity, monoamine, circadian rhythm, and transcription factor pathways were investigated as modulators of antidepressant efficacy. The present study aimed (1) to replicate previous findings in an independent sample with treatment-resistant depression (TRD), and (2) to perform a pathway analysis to investigate the possible molecular mechanisms involved. 220 patients with major depressive disorder who were non-responders to a previous antidepressant were treated with venlafaxine for 4\ue2\u80\u936\uc2\ua0weeks and in case of non-response with escitalopram for 4\ue2\u80\u936\uc2\ua0weeks. Symptoms were assessed using the Montgomery Asberg Depression Rating Scale. The phenotypes were response and remission to venlafaxine, non-response (TRDA) and non-remission (TRDB) to neither venlafaxine nor escitalopram. 50 tag SNPs in 14 genes belonging to the pathways of interest were tested for association with phenotypes. Molecular pathways (KEGG database) that included one or more of the genes associated with the phenotypes were investigated also in the STAR*D sample. The associations between ZNF804A rs7603001 and response, CREB1 rs2254137 and remission were replicated, as well as CHL1 rs2133402 and lower risk of TRD. Other CHL1 SNPs were potential predictors of TRD (rs1516340, rs2272522, rs1516338, rs2133402). The MAPK1 rs6928 SNP was consistently associated with all the phenotypes. The protein processing in endoplasmic reticulum pathway (hsa04141) was the best pathway that may explain the mechanisms of MAPK1 involvement in antidepressant response. Signals in genes previously associated with antidepressant efficacy were confirmed for CREB1, ZNF804A and CHL1. These genes play pivotal roles in synaptic plasticity, neural activity and connectivity

Incidence of Respiratory Disease During the First Two\ua0Years of Life in Children with Hemodynamically Significant Congenital Heart Disease in Italy: A Retrospective Study

Children affected by hemodynamically significant congenital heart disease (HSCHD) experience severe respiratory complications that can increase the frequency of hospitalizations. The aim of the SINERGY study was to describe the incidence of respiratory diseases and to collect information on active and passive immunoprophylaxis in the first 2\ua0years of life. In this retrospective, multicenter, and epidemiologic study, children with HSCHD were enrolled across 11 Italian sites. Children born between December 31, 2007, and December 31, 2012, were observed during their first 2\ua0years of life. Data were collected through hospital database searches and parent interviews. Four hundred twenty children were enrolled: 51.7\ua0% were female, 79.5\ua0% were born full-term ( 6537\ua0weeks), and 77.6\ua0% weighed >2500\ua0g at birth. The most frequent heart defects were ventricular septal defect (23.1\ua0%) and coarctation of the aorta (14.3\ua0%). The incidence of respiratory diseases was 63.1\ua0%. Frequent respiratory diseases not requiring hospitalization were upper respiratory tract infections (76.4\ua0%), acute bronchitis (43.3\ua0%), and influenza (22.1\ua0%), while those requiring hospitalization were bronchitis and bronchiolitis (8.3\ua0% each one). While active immunoprophylaxis was applied with wide compliance (diphtheria/pertussis/tetanus, 99.5\ua0%; Haemophilus influenzae type b, 72.5\ua0%; pneumococcus, 79.9\ua0%; meningococcus, 77.4\ua0%), only 54\ua0% of children received respiratory syncytial virus (RSV) passive prophylaxis (palivizumab). Of the 35 hospitalizations due to bronchiolitis, 27 (77.1\ua0%) did not receive prophylaxis against RSV, compared with 8 (22.9\ua0%) who received prophylaxis (P\ua0<\ua00.0001). Children with HSCHD are at major risk of respiratory diseases. Passive immunoprophylaxis can help to prevent hospitalizations for bronchiolitis

Neuroplasticity, Neurotransmission and Brain-Related Genes in Major Depression and Bipolar Disorder: Focus on Treatment Outcomes in an Asiatic Sample

Introduction: Mood disorders are common and disabling disorders. Despite the availability of over 100 psychotropic compounds, only one-third of patients benefit from first-line treatments. Over the past 20&nbsp;years, many studies have focused on the biological factors modulating disease risk and response to treatments, but with still inconclusive data. In order to improve our current knowledge, in this study, we investigated the role of a set of genes involved in different pathways (neurotransmission, neuroplasticity, circadian rhythms, transcription factors, signal transduction and cellular metabolism) in the treatment outcome of major depressive disorder (MDD) and bipolar disorder (BD) after naturalistic pharmacological treatment. Methods: Totals of 242 MDD, 132 BD patients and 326 healthy controls of Asian ethnicity (Koreans) were genotyped for polymorphisms within 19 genes. Response and remission after 6\u20138&nbsp;weeks of treatment with antidepressants and mood stabilizers were evaluated. In secondary analyses, genetic associations with disease risk and some disease-associated features (age of onset, suicide attempt and psychotic BD) were also tested. Results: None of the variants within the investigated genes was significantly associated with treatment outcomes. Some marginal association (uncorrected p &lt; 0.01) was observed for HTR2A, BDNF, CHL1, RORA and HOMER1 SNPs. In secondary analyses, HTR2A (rs643627, p = 0.002) and CHL1 (rs4003413, p = 0.002) were found associated with risk for BD, HOMER1 (rs6872497, p = 0.002) with lifetime history of suicide attempt in patients, and RORA with early onset and presence of psychotic features in BD. Marginal results were also observed for ST8SIA2 and COMT. Discussion: Despite limitations linked to multiple testing on small samples, methodological shortcomings and small significance of the findings, this study may support the involvement of some candidate genes in the outcomes of treatments for mood disorders, as well as in BD risk and other disease features

Role of neurodevelopment involved genes in psychiatric comorbidities and modulation of inflammatory processes in Alzheimer's disease

Introduction With the increase of the population's average age, Alzheimer's disease (AD) is becoming one of the most disabling diseases worldwide. Recently, neurodevelopment processes have been involved in the AD etiopathogenesis. Genetic studies in this field could contribute to our knowledge and suggest new molecular targets for possible treatments. Methods Our primary aim was to investigate the associations among single nucleotide polymorphisms (SNPs) within neurodevelopment related genes (BDNF, ST8SIA2, C15orf32, NCAPG2, ESYT2, WDR60, LOC154822, VIPR2, GSK3B, NR1I2, ZNF804A, SP4) and AD. A number of exploratory analyses was also performed to evaluate the associations with the presence of behavioral and psychiatric symptoms of dementia (BPSD), as well as with variations in hematological parameters. Two independent samples were investigated, one of 228 Greek subjects and one sample of 229 Italian subjects, including 156\uc2\ua0Alzheimer's Disease patients CE patients and 301 healthy controls. All patients were affected by late onset AD (LOAD). Results None of the analyzed SNPs was associated with AD in our samples. In the exploratory analyses, several genetic variants were associated with inflammation parameters in the Greek sample and in the merged one, suggesting a relationship among these genes and the modulation of inflammation and the immune response. Other exploratory analyses showed associations among several SNPs and psychiatric symptomatology in the Greek sample, suggesting a possible modulation of these variants on psychiatric comorbidities in AD. Conclusions Although we failed to find a direct relationship between AD and the genetic variants investigated, possible connections with inflammation and psychiatric symptoms were suggested