A CTNNA3 compound heterozygous deletion implicates a role for \u3b1T-catenin in susceptibility to autism spectrum disorder.

Autism spectrum disorder (ASD) is a highly heritable, neurodevelopmental condition showing extreme genetic heterogeneity. While it is well established that rare genetic variation, both de novo and inherited, plays an important role in ASD risk, recent studies also support a rare recessive contribution. METHODS: We identified a compound heterozygous deletion intersecting the CTNNA3 gene, encoding \u3b1T-catenin, in a proband with ASD and moderate intellectual disability. The deletion breakpoints were mapped at base-pair resolution, and segregation analysis was performed. We compared the frequency of CTNNA3 exonic deletions in 2,147 ASD cases from the Autism Genome Project (AGP) study versus the frequency in 6,639 controls. Western blot analysis was performed to get a quantitative characterisation of Ctnna3 expression during early brain development in mouse. RESULTS: The CTNNA3 compound heterozygous deletion includes a coding exon, leading to a putative frameshift and premature stop codon. Segregation analysis in the family showed that the unaffected sister is heterozygote for the deletion, having only inherited the paternal deletion. While the frequency of CTNNA3 exonic deletions is not significantly different between ASD cases and controls, no homozygous or compound heterozygous exonic deletions were found in a sample of over 6,000 controls. Expression analysis of Ctnna3 in the mouse cortex and hippocampus (P0-P90) provided support for its role in the early stage of brain development. CONCLUSION: The finding of a rare compound heterozygous CTNNA3 exonic deletion segregating with ASD, the absence of CTNNA3 homozygous exonic deletions in controls and the high expression of Ctnna3 in both brain areas analysed implicate CTNNA3 in ASD susceptibility

Alteration Ocular Motility in Retinitis Pigmentosa: Case–Control Study

Anna Maria Comberiati,1 Chiara Lomartire,1 Mariaelena Malvasi,1 Raffaele Migliorini,1 Fernanda Pacella,2 Vito Maurizio Malvasi,3 Paolo Turchetti,4 Elena Pacella1 1Department of Sense Organs, Sapienza University of Rome, Rome, Italy; 2Department of Ophthalmology, Carlo Poma Hospital, Mantua, Italy; 3Department of Odontostomatological and Maxillo-Facial Sciences, Sapienza University of Rome, Rome, Italy; 4National Institute for Health, Migration and Poverty (INMP/NIHMP), Rome, ItalyCorrespondence: Mariaelena Malvasi, Department of Sense Organs, University of Rome, “Sapienza” via Del Policlinico 155, Rome, 00161, Italy, Tel +393402114859, Email [email protected]: To evaluate ocular motility (OM) disorders and strabismus in a sample of patients with retinitis pigmentosa (RP) and a control sample.Methods: In this cross-sectional retrospective analysis, we studied a sample of RP patients with a mean age of 48.74 years and an average visual acuity of 7/10 based on Snellen optotype and a sample of control patients with similar mean age (49 years [men], 47 years [women]) and sex and an average visual acuity of 9.9/10, with the aim of assessing correlations between alteration of OM and strabismus in RP patients based on age, high refractive defect, or severely impaired binocular vision. The examination followed a protocol of testing for anamnesis and best-corrected visual acuity, as well as a complete eye examination, corneal reflex, cover test, OM, Hess screen, and Lang test.Results: At the first orthoptic evaluation, 45.16% of patients showed strabismus, 41.93% exotropia (25% of cases intermittent), 3.22% esotropia, and 6.45% vertical deviation. Later evaluation showed strabismus in 25.80% of patients, exotropia in 19.35% (9.67% intermittent), esotropia in 3.22%, and vertical deviation in 3.22%. Assessment of eye motility study showed 51.6% overaction of the inferior oblique and hypofunction of the superior rectus, and 18% overaction of the lateral rectus and hypofunction of the medial rectus. According to our results, alterations in OM and strabismus in RP patients are not correlated with age or high refractive defect. Therefore, motility disorders and strabismus are attributed to a genetic factor to which men are more susceptible.Conclusion: The incidence of OM disorder was 77.42%, and strabismus was present in 45.16% of patients.Keywords: retinitis pigmentosa, orthoptic evaluation, strabismus, genetic factor, ocular motilit

A double-blind, placebo-controlled clinical trial to assess the effects of a combined nutraceutical on endothelial function in patients with mild-to-moderate hypercholesterolaemia

Introduction: There is growing interest in lipid-lowering nutraceuticals; however, there are a relative scarcity of data on combined compounds. This study was aimed to assess the efficacy and tolerability of a combined nutraceutical (CARDIOL\uae Forte - CF) containing polyunsaturated fatty acids, hydroxytyrosol, Coenzyme Q10, folic acid, B12 and E vitamins, piperine, and red yeast rice in patients with mild-to-moderate hypercholesterolaemia. Material and methods: In this single-centre, double-blinded, placebo-controlled study enrolled subjects who were randomised to receive the tested combined nutraceutical for 16 weeks (CF group) or placebo (control group), in association with a low-fat diet. After 8 weeks of treatment, all patients underwent a 15-day washout period; then, a further 8 weeks of treatment was planned. Results: Of 80 enrolled subjects, 37 completed the study in the CF group and 38 in the control group. After 8 weeks of treatment, low-density lipoprotein cholesterol levels were reduced by 17% in the CF group and by 6.4% in the control group, compared to baseline (p = 0.0001); these changes were improved at the end of study. Total cholesterol and triglyceride levels significantly decreased during treatment; high-density lipoprotein cholesterol did not change. In the CF group, flow-mediated dilation increased by 18.8% after 8 weeks and by 39.3% at the end of treatment. No adverse events or musculoskeletal disorders were reported in either group. Conclusions: The tested combined nutraceutical, in association with a controlled diet, can reduce cholesterol levels and improve endothelial function, thus reducing the cardiovascular risk in patients with mild-to-moderate hypercholesterolaemia

Predictors of Sickness Absence in a Clinical Population With Chronic Pain

Chronic pain-related sickness absence is an enormous socioeconomic burden globally. Optimized interventions are reliant on a lucid understanding of the distribution of social insurance benefits and their predictors. This register-based observational study analyzed data for a 7-year period from a population-representative sample of 44,241 chronic pain patients eligible for interdisciplinary treatment (IDT) at specialist clinics. Sequence analysis was used to describe the sickness absence over the complete period and to separate the patients into subgroups based on their social insurance benefits over the final 2 years. The predictive performance of features from various domains was then explored with machine learning-based modeling in a nested cross-validation procedure. Our results showed that patients on sickness absence increased from 17% 5 years before to 48% at the time of the IDT assessment, and then decreased to 38% at the end of follow-up. Patients were divided into 3 classes characterized by low sickness absence, sick leave, and disability pension, with eight predictors of class membership being identified. Sickness absence history was the strongest predictor of future sickness absence, while other predictors included a 2008 policy, age, confidence in recovery, and geographical location. Information on these features could guide personalized intervention in the specialized healthcare. Perspective: This study describes sickness absence in patients who visited a Swedish pain specialist interdisciplinary treatment clinic during the period 2005 to 2016. Predictors of future sickness absence are also identified that should be considered when adapting IDT programs to the patient's needs

The value of interdisciplinary treatment for sickness absence in chronic pain: A nationwide register-based cohort study

Background: Interdisciplinary treatment (IDT) is an internationally recommended intervention for chronic pain, despite inconclusive evidence of its effects on sickness absence. Methods: With data from 25,613 patients in Swedish specialist healthcare, we compared sickness absence, in the form of both sick leave and disability pensions, over a 5-year period between patients either allocated to an IDT programme or to other/no interventions (controls). To obtain population-average estimates, a Markov multistate model with theory-based inverse probability weights was used to compute both the proportion of patients on sickness absence and the total sickness absence duration. Results: IDT patients were more likely than controls to receive sickness absence benefits at any given time (baseline: 49% vs. 46%; 5-year follow-up: 36% vs. 35%), and thereby also had a higher total duration, with a mean (95% CI) of 67 (87, 48) more days than controls over the 5-year period. Intriguingly, sick leave was higher in IDT patients (563 [552, 573] vs. 478 [466, 490] days), whereas disability pension was higher in controls (152 [144, 160] vs. 169 [161, 178] days). Conclusion: Although sickness absence decreased over the study period in both IDT patients and controls, we found no support for IDT decreasing sickness absence more than other/no interventions in chronic pain patients. Significance: In this large study of chronic pain patients in specialist healthcare, sickness absence is compared over a 5-year period between patients in an interdisciplinary treatment programme and other/no interventions. Sickness absence decreased over the study period in bothgroups; however, there was no support forthat it decreased more with interdisciplinary treatment than alternative interventions

Immune system, cell senescence, aging and longevity - Inflamm-aging reappraised.

Inflamm-aging, that is the age-associated inflammatory status, is considered one of the most striking consequences of immunosenescence, as it is believed to be linked to the majority of age-associated diseases sharing an inflammatory basis. Nevertheless, evidence is emerging that inflamm-aging is at least in part independent from immunological stimuli. Moreover, centenarians who avoided or delayed major inflammatory diseases display markers of inflammation. In this paper we proposed a reappraisal of the concept of inflamm-aging, suggesting that its pathological effects can be independent from the total amount of pro-inflammatory mediators, but they would be rather associated with the anatomical district and type of cells where they are produced and where they primarily act