CHM/REP1 Transcript Expression and Loss of Visual Function in Patients Affected by Choroideremia

PURPOSE. To evaluate the disease progression in patients with clinical and genetic diagnoses of choroideremia during a long-term follow-up and to investigate the relationship between pathogenic variants in the CHM/REP1 gene and disease phenotypes. METHODS. We performed a retrospective longitudinal study on 51 affected men by reviewing medical charts at baseline and follow-up visits to extract the following ocular findings: best-corrected visual acuity, Goldmann visual field, optical coherence tomography, microperimetry. Data obtained from the analysis of DNA and mRNA were reevaluated for genetic classification of patients. RESULTS. The longitudinal analysis showed a significant (P < 0.001) worsening of best-corrected visual acuity with a mean rate of 0.011 logMar per year before 50 years and 0.025 logMar per year after 50 years. Similarly, V4e Goldmann visual field area significantly (P ≤ 0.01) decreased at a mean rate of 2.7% per year before 40 years and 5.7% after 40 years. Moreover, we observed a significant (P < 0.05) decrease of macular sensitivity with a mean rate of 5.0% per year and a decrease of mean macular thickness with a mean rate of 0.8% per year. We classified our patients into two groups according to the expression of the CHM/ REP1 gene transcript and observed that mutations leading to mRNA absence are associated with an earlier best-corrected visual acuity and Goldmann visual field loss. CONCLUSIONS. Our analysis of morphological and functional parameters in choroideremia patients showed a slow disease progression, particularly in the first decades of life. Overall, reevaluation of clinical and molecular data suggests exploring the genotype–phenotype relationship based on CHM/REP1 transcript expression. PURPOSE. To evaluate the disease progression in patients with clinical and genetic diagnoses of choroideremia during a long-term follow-up and to investigate the relationship between pathogenic variants in the CHM/REP1 gene and disease phenotypes. METHODS. We performed a retrospective longitudinal study on 51 affected men by reviewing medical charts at baseline and follow-up visits to extract the following ocular findings: best-corrected visual acuity, Goldmann visual field, optical coherence tomography, microperimetry. Data obtained from the analysis of DNA and mRNA were reevaluated for genetic classification of patients. RESULTS. The longitudinal analysis showed a significant (P < 0.001) worsening of best-corrected visual acuity with a mean rate of 0.011 logMar per year before 50 years and 0.025 logMar per year after 50 years. Similarly, V4e Goldmann visual field area significantly (P ≤ 0.01) decreased at a mean rate of 2.7% per year before 40 years and 5.7% after 40 years. Moreover, we observed a significant (P < 0.05) decrease of macular sensitivity with a mean rate of 5.0% per year and a decrease of mean macular thickness with a mean rate of 0.8% per year. We classified our patients into two groups according to the expression of the CHM/ REP1 gene transcript and observed that mutations leading to mRNA absence are associated with an earlier best-corrected visual acuity and Goldmann visual field loss. CONCLUSIONS. Our analysis of morphological and functional parameters in choroideremia patients showed a slow disease progression, particularly in the first decades of life. Overall, reevaluation of clinical and molecular data suggests exploring the genotype–phenotype relationship based on CHM/REP1 transcript expression

LIFE Monza: comparison between ante and post-operam noise and air quality monitoring activities in a Noise Low Emission Zone

AbstractLIFE MONZA project (Methodologies fOr Noise low emission Zones introduction And management) aims at defining an easy-replicable method for the identification and management of theNoise Low Emission Zones(Noise LEZ), urban areas subject to traffic restrictions, usually introduced in order to ensure compliance with the air pollutants limit values, prescribed by the European Directive on ambient air quality 2008/50/EC, whose impacts and potential benefits regarding noise issues have been taken into account, tested and analysed in a pilot area of the city of Monza, located in North Italy. Noise LEZ has been established in Libertà district, introducing infrastructural interventions carried out by the municipality (top-down actions) and encouraging an active involvement of the citizens, in the definition of a more sustainable lifestyle (bottom-up actions). The analysis of potential effects on noise reduction due to the Noise LEZ can contribute to the implementation of the EU Directive 2002/49/EC, related to the assessment and management of environmental noise (Environmental Noise Directive – END), which introduces noise action plans, designed to manage noise issues and their effects, suggesting the adoption of urban and mobility planning. Noise and air quality monitoring activities have been carried out in pilot area inanteandpost-operamconditions. The monitoring methods, the measurement techniques, the analysis procedures, able to describe the effects due to Noise LEZ establishment, for both the main environmental issues are reported in this paper, as proposals to be applied in other different contexts. Results of monitoring activities highlight a reduction of noise, in term of sound pressure levels, betweenanteandpost-operam, during the day and particularly during the night period, and it is essentially due to the interventions realised. The effect of the Noise LEZ on air pollution seems to be negligible for combustion related pollutant and carbon fractions of PM, due both to the moderate spatial effects of the measures undertaken and confounding factors due to concomitant emission sources and meteorology

Exploring the genetics of irritable bowel syndrome: A GWA study in the general population and replication in multinational case-control cohorts

OBJECTIVE: IBS shows genetic predisposition, but adequately powered gene-hunting efforts have been scarce so far. We sought to identify true IBS genetic risk factors by means of genome-wide association (GWA) and independent replication studies. DESIGN: We conducted a GWA study (GWAS) of IBS in a general population sample of 11\u2005326 Swedish twins. IBS cases (N=534) and asymptomatic controls (N=4932) were identified based on questionnaire data. Suggestive association signals were followed-up in 3511 individuals from six case-control cohorts. We sought genotype-gene expression correlations through single nucleotide polymorphism (SNP)-expression quantitative trait loci interactions testing, and performed in silico prediction of gene function. We compared candidate gene expression by real-time qPCR in rectal mucosal biopsies of patients with IBS and controls. RESULTS: One locus at 7p22.1, which includes the genes KDELR2 (KDEL endoplasmic reticulum protein retention receptor 2) and GRID2IP (glutamate receptor, ionotropic, delta 2 (Grid2) interacting protein), showed consistent IBS risk effects in the index GWAS and all replication cohorts and reached p=9.31 710(-6) in a meta-analysis of all datasets. Several SNPs in this region are associated with cis effects on KDELR2 expression, and a trend for increased mucosal KDLER2 mRNA expression was observed in IBS cases compared with controls. CONCLUSIONS: Our results demonstrate that general population-based studies combined with analyses of patient cohorts provide good opportunities for gene discovery in IBS. The 7p22.1 and other risk signals detected in this study constitute a good starting platform for hypothesis testing in future functional investigations. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions

Prevalence of macular abnormalities assessed by optical coherence tomography in patients with Usher syndrome

Background: To investigate the prevalence of macular abnormalities in patients affected by Usher syndrome (USH), by comparing the clinical findings between two types (i.e., USH1 and USH2). Material and methods: A retrospective study was performed by reviewing optical coherence tomography (OCT) in 134 USH patients to determine the presence of macular abnormalities, including cystoid macular edema (CME), epiretinal membrane (ERM), vitreo-macular traction syndrome (VMT), and macular hole (MH). Results: Macular abnormalities were observed in 126/268 (47.0%) examined eyes. The most frequent abnormality was ERM observed in 51 eyes (19%), followed by CME observed in 42 eyes (15.7%). Moreover, CME was significantly (p &lt; 0.05) associated with younger age (CME: 30.1 \uc2\ub1 11.1 years; without CME: 36.9 \uc2\ub1 14.9 years), whereas VMT and full thickness MH were associated with older age (p &lt; 0.05). Moreover, a significantly (p &lt; 0.05) decreased best-corrected visual acuity was associated with MH compared to eyes without MH. Finally, CME was more frequent in USH1 compared to USH2. Conclusion: Our study, for the first time in the literature, showed the distribution of all macular abnormalities assessed by SD-OCT in a large USH cohort, comparing USH1 and USH2 patients. We observed that ocular abnormalities are highly prevalent in USH patients compared to general population, with ERM and CME being the most common alterations. Based on these findings, OCT screening in USH patients is recommended for early detection of macular changes and early treatment

OCT Analysis in Patients with Relapsing-Remitting Multiple Sclerosis during Fingolimod Therapy: 2-Year Longitudinal Retrospective Study

Many studies have demonstrated the usefulness of some optical coherence tomography (OCT) parameters, like total macular volume (TMV) and retinal nerve fiber layer thickness (RNFL-T), for monitoring patients with multiple sclerosis (MS). However, there are no real-world, long-term studies on patients with relapsing-remitting MS (RR-MS) treated with fingolimod. Therefore, the purpose of this study was to describe retinal changes associated with fingolimod therapy during a two-year follow-up while considering previous episodes of optic neuritis (ON). Patients diagnosed with RR-MS and treated with fingolimod (46 in total) underwent a two-year follow-up. Based on previous ON history, we identified 16 ON+ and 30 ON&minus; patients. The ophthalmological evaluations, including visual field (VF) examination and OCT, were performed at a baseline at 3&ndash;6, 12 and 24 months to evaluate the progression rate for each parameter. When analyzing the whole sample, OCT showed no cases of macular edema. Instead, we observed a significant reduction rate in the central retinal thickness (CRT) (p &lt; 0.001), TMV (p &lt; 0.001) and RNFL (p &lt; 0.05). Moreover, we observed a significant difference in the progression rate between ON+ and ON&minus; patients, relative to the VF and RNFL (p &lt; 0.05) examinations. OCT highlighted a significant progression rate of retinal damage in MS patients despite fingolimod therapy, especially in MS ON+ patients

Clinical presentation and disease course in Choroideremia patients

Purpose : To report the disease progression in patients with clinical and genetic diagnosis of Choroideremia (CHM) over a long-term follow-up. Methods : A retrospective longitudinal study was performed in 30 subjects. Medical charts of the baseline and follow-up visits were reviewed to extract the following ocular findings: Best-Corrected Visual Acuity (BCVA), fundus examination, Goldmann Visual Field (GVF), Optical Coherence Tomography (OCT), Microperimetry (MP1) and standard full-field Electroretinogram (ERG). Baseline data are presented as mean ± standard error of the mean. For the statistical regression analysis, BCVA was converted in LogMAR. Repeated measure regression models based on GEE were adopted to analyze the change of the clinical variables over follow-up. A p-value less than 5% was considered statistically significant. The study adhered to the tenets of the Declaration of Helsinki and received approval by the Local Ethics Committee. Moreover, each patient gave written informed consent. Results : The mean age at baseline was 34.7 ± 3.1 years (range: 7-65 years). The mean visual acuity (at first visit) in the cohort was 0.6 ± 0.2 LogMar in both eyes. Moreover, all the patients showed a constricted GVF (mean: 4758 ± 1603°2 in right eyes; 5105 ± 1615°2 in left eyes). Dark-adapted ERG responses were below the noise level in all the patients, while light-adapted ERG responses were detectable in 8 patients, even if with a marked reduction of amplitude. The patients were followed up for a mean time period of 6.7 years. The analysis showed a significant reduction of BCVA with a mean rate of 0.038 LogMar (about 2 ETDRS letters) per year (p&lt;0.001), associated with a decrease of GVF area with a mean exponential rate of 6.4% per year (p&lt;0.001), and of MS with a mean exponential rate of 4.3% per year (p&lt;0.001). Finally, the Mean Macular Thickness significantly decreased with a mean exponential rate of 0.9% per year (p=0.009). Conclusions : Our longitudinal analysis showed a progressive decline of visual functionality, although slow. Moreover, the function loss was associated with progression of retinal degeneration, detectable by OCT. Our longitudinal data about the natural disease course could be helpful to identify patients most amenable for gene therapy and to show efficacy in open label clinical trials. This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016

Dietary Supplementation with the Probiotic SF68 Reinforces Intestinal Epithelial Barrier in Obese Mice by Improving Butyrate Bioavailability

Scope Modifications in intestinal microbiota and its metabolites, the short-chain fatty acids (SCFA) are main factors altering intestinal epithelial barrier integrity and eliciting the onset of a meta-inflammation observed in obesity. The present study is aimed at evaluating the efficacy of Enterococcus faecium (SF68) administration in counteracting the impairment of gut barrier and enteric inflammation in a model of diet-induced obesity, characterizing the molecular mechanisms underlying such beneficial effects. Methods and ResultsMale C57BL/6J mice, fed with standard diet (SD) or high-fat diet (HFD), are treated with SF68 (10(8) CFU day(-1)). After 8 weeks, plasma interleukin (IL)-1 beta and lipopolysaccharide binding protein (LBP) are measured, analysis of fecal microbiota composition and butyrate content as well as intestinal malondialdehyde, myeloperoxidase, mucins, tight junction protein, and butyrate transporter expression are investigated. After 8 weeks, SF68 administration counteracts the body weight gain in HFD mice, reducing plasma IL-1 beta and LBP. In parallel, SF68 treatment acts against the intestinal inflammation in HFD-fed animals and improves the intestinal barrier integrity and functionality in obese mice via the increase in tight junction protein and intestinal butyrate transporter (sodium-coupled monocarboxylate transporter 1 ) expression. ConclusionsSupplementation with SF68 reduces intestinal inflammation and reinforces the enteric epithelial barrier in obese mice, improving the transport and utilization of butyrate