The Medical Somatic Dissociation Questionnaire Assessment For Childhood Sexual Abuse: A Brief Report.

Child sexual abuse is a prevalent phenomenon worldwide. However, a gap exists between its incidence and its disclosure rate. Furthermore, assessment tools and techniques capable to identify the source of symptoms are lacking. This study investigates the extent to which the validated Medical Somatic Dissociation Questionnaire (MSDQ) can differentiate between sexually and non-sexually abused children. A total of 794 children and youth between the ages of 8 and 18 (mean age: 12.2 (SD = 2.3); 42% female, 58% male) were recruited from the general population; other participants were residents of boarding schools and children who were referred to medical treatment. The anonymous online questionnaire included queries about demographics, a condensed version of the Traumatic Life Events Questionnaire, and the MSDQ. Findings indicate strong internal consistency, reliability, incremental validity, and predictive validity of the instrument, indicating the superiority of the MSDQ's ability to predict sexual abuse compared to physical abuse or the loss of a family member. It is concluded that the MSDQ can be integrated into the evaluation process performed by healthcare professionals in the diagnosis of minors with unexplained symptomatology.

Dlk1-Dio3 cluster miRNAs regulate mitochondrial functions in the dystrophic muscle in Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a severe muscle disease caused by impaired expression of dystrophin. Whereas mitochondrial dysfunction is thought to play an important role in DMD, the mechanism of this dysfunction remains to be clarified. Here we demonstrate that in DMD and other muscular dystrophies, a large number of Dlk1-Dio3 clustered miRNAs (DD-miRNAs) are coordinately up-regulated in regenerating myofibers and in the serum. To characterize the biological effect of this dysregulation, 14 DD-miRNAs were simultaneously overexpressed in vivo in mouse muscle. Transcriptomic analysis revealed highly similar changes between the muscle ectopically overexpressing 14 DD-miRNAs and the mdx diaphragm, with naturally up-regulated DD-miRNAs. Among the commonly dysregulated pathway we found repressed mitochondrial metabolism, and oxidative phosphorylation (OxPhos) in particular. Knocking down the DD-miRNAs in iPS-derived skeletal myotubes resulted in increased OxPhos activities. The data suggest that (1) DD-miRNAs are important mediators of dystrophic changes in DMD muscle, (2) mitochondrial metabolism and OxPhos in particular are targeted in DMD by coordinately up-regulated DD-miRNAs. These findings provide insight into the mechanism of mitochondrial dysfunction in muscular dystrophy.

Deciphering the Molecular Mechanism of Incurable Muscle Disease by a Novel Method for the Interpretation of miRNA Dysregulation.

It is now well-established that microRNA dysregulation is a hallmark of human diseases, and that aberrant expression of miRNA is not randomly associated with human pathologies but plays a causal role in the pathological process. Investigations of the molecular mechanism that links miRNA dysregulation to pathophysiology can therefore further the understanding of human diseases. The biological effect of miRNA is thought to be mediated principally by miRNA target genes. Consequently, the target genes of dysregulated miRNA serve as a proxy for the biological interpretation of miRNA dysregulation, which is performed by target gene pathway enrichment analysis. However, this method unfortunately often fails to provide testable hypotheses concerning disease mechanisms. In this paper, we describe a method for the interpretation of miRNA dysregulation, which is based on miRNA host genes rather than target genes. Using this approach, we have recently identified the perturbations of lipid metabolism, and cholesterol in particular, in Duchenne muscular dystrophy (DMD). The host gene-based interpretation of miRNA dysregulation therefore represents an attractive alternative method for the biological interpretation of miRNA dysregulation.

Co-Administration of Simvastatin Does Not Potentiate the Benefit of Gene Therapy in the mdx Mouse Model for Duchenne Muscular Dystrophy.

Duchenne muscular dystrophy (DMD) is the most common and cureless muscle pediatric genetic disease, which is caused by the lack or the drastically reduced expression of dystrophin. Experimental therapeutic approaches for DMD have been mainly focused in recent years on attempts to restore the expression of dystrophin. While significant progress was achieved, the therapeutic benefit of treated patients is still unsatisfactory. Efficiency in gene therapy for DMD is hampered not only by incompletely resolved technical issues, but likely also due to the progressive nature of DMD. It is indeed suspected that some of the secondary pathologies, which are evolving over time in DMD patients, are not fully corrected by the restoration of dystrophin expression. We recently identified perturbations of the mevalonate pathway and of cholesterol metabolism in DMD patients. Taking advantage of the mdx model for DMD, we then demonstrated that some of these perturbations are improved by treatment with the cholesterol-lowering drug, simvastatin. In the present investigation, we tested whether the combination of the restoration of dystrophin expression with simvastatin treatment could have an additive beneficial effect in the mdx model. We confirmed the positive effects of microdystrophin, and of simvastatin, when administrated separately, but detected no additive effect by their combination. Thus, the present study does not support an additive beneficial effect by combining dystrophin restoration with a metabolic normalization by simvastatin.

A revised model for mitochondrial dysfunction in Duchenne muscular dystrophy.

We recently identified a signaling pathway that links the upregulation of miR-379 with a mitochondrial response in dystrophic muscle. In the present commentary, we explain the significance that this pathway may have in mitochondrial dysfunction in Duchenne muscular dystrophy (DMD). We identified the upregulation of miR-379 in the serum and muscles of DMD animal models and patients. We found that miR-379 is one of very few miRNAs whose expression was normalized in DMD patients treated with glucocorticoid. We identified EIF4G2 as a miR-379 target, which may promote mitochondrial oxidative phosphorylation (OxPhos) in the skeletal muscle. We found enriched EIF4G2 expression in oxidative fibers, and identified the mitochondrial ATP synthase subunit DAPIT as a translational target of EIF4G2. The identified signaling cascade, which comprises miR-379, EIF4G2 and DAPIT, may link the glucocorticoid treatment in DMD to a recovered mitochondrial ATP synthesis rate. We propose an updated model of mitochondrial dysfunction in DMD.

Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca2+ homeostasis, activation of proteases, mitochondrial damage, and tissue degeneration. A recently emphasized secondary aspect of the dystrophic process is a progressive metabolic change of the dystrophic tissue; however, the mechanism and nature of the metabolic dysregulation are yet poorly understood. In this study, we characterized a molecular mechanism of metabolic perturbation in DMD. METHODS: We sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4-8, 8-12, and 12-20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis. RESULTS: We identified 96 dysregulated miRNAs (adjusted P-value <0.1), of which 74 were up-regulated and 22 were down-regulated in DMD. We confirmed the dysregulation in DMD of Dystro-miRs, Cardio-miRs, and a large number of the DLK1-DIO3 miRNAs. We also identified numerous dysregulated miRNAs yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP-1 and SREBP-2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol-reducing agent, normalized these perturbations and partially restored the dystrophic parameters. CONCLUSIONS: This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD.

Farewell to Professor David Yaffe - A pillar of the myogenesis field.

It is with great sadness that we have learned about the passing of Professor David Yaffe (1929-2020, Israel). Yehi Zichro Baruch - May his memory be a blessing. David was a man of family, science and nature. A native of Israel, David grew up in the historic years that preceded the birth of the State of Israel. He was a member of the group that established Kibbutz Revivim in the Negev desert, and in 1948 participated in Israel's War of Independence. David and Ruth eventually joined Kibbutz Givat Brenner by Rehovot, permitting David to be both a kibbutz member and a life-long researcher at the Weizmann Institute of Science, where David received his PhD in 1959. David returned to the Institute after his postdoc at Stanford. Here, after several years of researching a number of tissues as models for studying the process of differentiation, David entered the myogenesis field and stayed with it to his last day. With his dedication to the field of myogenesis and his commitment to furthering the understanding of the People and the Land of Israel throughout the international scientific community, David organized the first ever myogenesis meeting that took place in Shoresh, Israel in 1975. This was followed by the 1980 myogenesis meeting at the same place and many more outstanding meetings, all of which brought together myogenesis, nature and scenery. Herein, through the preparation and publication of this current manuscript, we are meeting once again at a "David Yaffe myogenesis meeting". Some of us have been members of the Yaffe lab, some of us have known David as his national and international colleagues in the myology field. One of our contributors has also known (and communicates here) about David Yaffe's earlier years as a kibbutznick in the Negev. Our collective reflections are a tribute to Professor David Yaffe. We are fortunate that the European Journal of Translational Myology has provided us with tremendous input and a platform for holding this 2020 distance meeting "Farwell to Professor David Yaffe - A Pillar of the Myogenesis Field".

Minor gifts from pharmaceutical companies to doctors: A comparison between psychiatry and general medicine.

Pharmaceutical companies in countries that have community-oriented models of healthcare, unlike other countries with highly privatised healthcare systems, such as the United States, cannot legally advertise medications directly to patients. Thus, the physician is entirely responsible for choosing the right medication, and needs to take important professional and ethical concerns into consideration during this decision-making process. Pharmaceutical companies invest considerably in in marketing products to physicians. Often, this is in the form of "minor gifts" to the physician. This study examines variations in the number and type of such minor gifts present in the offices of psychiatrists and internists in various medical contexts in Israel. Our results showed that psychiatrists received more minor gifts than physicians in general hospitals. No significant differences were found between inpatient and outpatient psychiatric departments. It is important to increase awareness and highlight the impact of exposure to minor gifts as advertising products on doctors in order to avoid bias and maintain objectivity in clinical judgement regarding pharmacological management of patients. Keywords: Pharmaceutical, gifts, ethics, physicians.

Spontaneous Descemet Membrane Detachment After Penetrating Keratoplasty-Clinical Presentation and Outcome of Air/Gas Descemetopexy.

PURPOSE: To describe the clinical characteristics and treatment of spontaneous Descemet membrane (DM) detachment occurring decades after penetrating keratoplasty (PK). METHODS: A multicenter interventional case series design was used. We reviewed the medical records of 4 patients with a history of PK presenting with spontaneous DM detachment at 3 university hospitals in Israel and an ocular surgery institute in The Netherlands in 2016 to 2019. Patient demographic and clinical data, postoperative best corrected visual acuity, findings on preoperative and postoperative anterior segment optical coherence tomography (AS-OCT), and graft survival were recorded. RESULTS: Patients were aged 46 to 50 years. All had undergone PK for keratoconus 20 to 26 years previously. Patients presented within 18 to 180 days of onset of visual disturbance. Symptoms included sudden painless visual loss (2 patients), gradual visual loss and foreign body sensation (1 patients), and visual loss not otherwise specified (1 patient). Slit-lamp examination showed corneal edema, and AS-OCT showed DM detachment of variable extent. In 2 patients, the initial diagnosis was graft rejection and failure. Treatment consisted of anterior chamber injection of air (n = 3) or 20% SF6 (n = 1). In 3 patients, the DM reattached and the cornea regained its clarity. The fourth patient had persistent DM detachment that required repeated PK. CONCLUSIONS: Spontaneous DM detachment can mimic late graft failure in patients after PK. If diagnosed early, DM reattachment may be performed by air/gas injection, avoiding repeated keratoplasty. Eyes with presumed late penetrating graft rejection or failure should be examined by AS-OCT to exclude DM detachment.

An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress.

Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress.

A Novel Screening Tool for Assessing Child Abuse: The Medical Somatic Dissociation Questionnaire-MSDQ.

Somatic dissociation is known to be associated with childhood abuse, particularly with childhood sexual abuse (CSA). Currently, the diagnosis of CSA is hampered by the lack of a validated questionnaire. While some questionnaires are excellent research tools, there is no suitable applied measure for the assessment of distress due to CSA. The current study's objective was to validate a novel questionnaire, designated the Medical Somatic Dissociation Questionnaire-MSDQ, for evaluating somatic dissociation in the healthcare system setting. A total of 541 adults, 160 (30%) male and 381 (70%) female, of average age 35 years were recruited from the general population via the Internet. The Life Events Checklist for DSM-5 (LEC-5) was used for screening subjects for reporting a history of CSA. Our examination of the MSDQ indicated powerful internal consistency, reliability, and convergent validity of the instrument, with high correlations between the MSDQ and the SDQ-20 and also between the MSDQ and psychological symptomatology. In addition, there was known-groups validity when differences between adults who experienced CSA and those who did not were compared. Importantly, the MSDQ can be easily integrated into the evaluation process performed by medical professionals in the diagnosis of adult patients with apparently unexplained symptomatology.

Environment dominates over host genetics in shaping human gut microbiota.

Human gut microbiome composition is shaped by multiple factors but the relative contribution of host genetics remains elusive. Here we examine genotype and microbiome data from 1,046 healthy individuals with several distinct ancestral origins who share a relatively common environment, and demonstrate that the gut microbiome is not significantly associated with genetic ancestry, and that host genetics have a minor role in determining microbiome composition. We show that, by contrast, there are significant similarities in the compositions of the microbiomes of genetically unrelated individuals who share a household, and that over 20% of the inter-person microbiome variability is associated with factors related to diet, drugs and anthropometric measurements. We further demonstrate that microbiome data significantly improve the prediction accuracy for many human traits, such as glucose and obesity measures, compared to models that use only host genetic and environmental data. These results suggest that microbiome alterations aimed at improving clinical outcomes may be carried out across diverse genetic backgrounds.

IpiRId: Integrative approach for piRNA prediction using genomic and epigenomic data.

Many computational tools have been proposed during the two last decades for predicting piRNAs, which are molecules with important role in post-transcriptional gene regulation. However, these tools are mostly based on only one feature that is generally related to the sequence. Discoveries in the domain of piRNAs are still in their beginning stages, and recent publications have shown many new properties. Here, we propose an integrative approach for piRNA prediction in which several types of genomic and epigenomic properties that can be used to characterize these molecules are examined. We reviewed and extracted a large number of piRNA features from the literature that have been observed experimentally in several species. These features are represented by different kernels, in a Multiple Kernel Learning based approach, implemented within an object-oriented framework. The obtained tool, called IpiRId, shows prediction results that attain more than 90% of accuracy on different tested species (human, mouse and fly), outperforming all existing tools. Besides, our method makes it possible to study the validity of each given feature in a given species. Finally, the developed tool is modular and easily extensible, and can be adapted for predicting other types of ncRNAs. The IpiRId software and the user-friendly web-based server of our tool are now freely available to academic users at: https://evryrna.ibisc.univ-evry.fr/evryrna/.

Circulating miRNAs are generic and versatile therapeutic monitoring biomarkers in muscular dystrophies.

The development of medical approaches requires preclinical and clinical trials for assessment of therapeutic efficacy. Such evaluation entails the use of biomarkers, which provide information on the response to the therapeutic intervention. One newly-proposed class of biomarkers is the microRNA (miRNA) molecules. In muscular dystrophies (MD), the dysregulation of miRNAs was initially observed in muscle biopsy and later extended to plasma samples, suggesting that they may be of interest as biomarkers. First, we demonstrated that dystromiRs dysregulation occurs in MD with either preserved or disrupted expression of the dystrophin-associated glycoprotein complex, supporting the utilization of dystromiRs as generic biomarkers in MD. Then, we aimed at evaluation of the capacity of miRNAs as monitoring biomarkers for experimental therapeutic approach in MD. To this end, we took advantage of our previously characterized gene therapy approach in a mouse model for α-sarcoglycanopathy. We identified a dose-response correlation between the expression of miRNAs on both muscle tissue and blood serum and the therapeutic benefit as evaluated by a set of new and classically-used evaluation methods. This study supports the utility of profiling circulating miRNAs for the evaluation of therapeutic outcome in medical approaches for MD.

Behavioral and Neural Mechanisms of Overgeneralization in Anxiety.

Overgeneralization of dangerous stimuli is a possible etiological account for anxiety disorders, yet the underlying behavioral and neural origins remain vague. Specifically, it is unclear whether this is a choice behavior in an unsafe environment ("better safe than sorry") or also a fundamental change in how the stimulus is perceived. We show that anxiety patients have wider generalization for loss-conditioned tone when compared to controls and do so even in a safe context that requires a different behavioral policy. Moreover, patients overgeneralized for gain-conditioned tone as well. Imaging (fMRI) revealed that in anxiety only, activations during conditioning in the dACC and the putamen were correlated with later overgeneralization of loss and gain, respectively, whereas valence distinction in the amygdala and hippocampus during conditioning mediated the difference between loss and gain generalization. During generalization itself, neural discrimination based on multivoxel patterns in auditory cortex and amygdala revealed specific stimulus-related plasticity. Our results suggest that overgeneralization in anxiety has perceptual origins and involves affective modulation of stimulus representations in primary cortices and amygdala.

Personalized Nutrition by Prediction of Glycemic Responses.

Elevated postprandial blood glucose levels constitute a global epidemic and a major risk factor for prediabetes and type II diabetes, but existing dietary methods for controlling them have limited efficacy. Here, we continuously monitored week-long glucose levels in an 800-person cohort, measured responses to 46,898 meals, and found high variability in the response to identical meals, suggesting that universal dietary recommendations may have limited utility. We devised a machine-learning algorithm that integrates blood parameters, dietary habits, anthropometrics, physical activity, and gut microbiota measured in this cohort and showed that it accurately predicts personalized postprandial glycemic response to real-life meals. We validated these predictions in an independent 100-person cohort. Finally, a blinded randomized controlled dietary intervention based on this algorithm resulted in significantly lower postprandial responses and consistent alterations to gut microbiota configuration. Together, our results suggest that personalized diets may successfully modify elevated postprandial blood glucose and its metabolic consequences. VIDEO ABSTRACT.