The Ras Antagonist, Farnesylthiosalicylic Acid (FTS), Decreases Fibrosis and Improves Muscle Strength in dy2J/dy2J Mouse Model of Muscular Dystrophy

The Ras superfamily of guanosine-triphosphate (GTP)-binding proteins regulates a diverse spectrum of intracellular processes involved in inflammation and fibrosis. Farnesythiosalicylic acid (FTS) is a unique and potent Ras inhibitor which decreased inflammation and fibrosis in experimentally induced liver cirrhosis and ameliorated inflammatory processes in systemic lupus erythematosus, neuritis and nephritis animal models. FTS effect on Ras expression and activity, muscle strength and fibrosis was evaluated in the dy2J/dy2J mouse model of merosin deficient congenital muscular dystrophy. The dy2J/dy2J mice had significantly increased RAS expression and activity compared with the wild type mice. FTS treatment significantly decreased RAS expression and activity. In addition, phosphorylation of ERK, a Ras downstream protein, was significantly decreased following FTS treatment in the dy2J/dy2J mice. Clinically, FTS treated mice showed significant improvement in hind limb muscle strength measured by electronic grip strength meter. Significant reduction of fibrosis was demonstrated in the treated group by quantitative Sirius Red staining and lower muscle collagen content. FTS effect was associated with significantly inhibition of both MMP-2 and MMP-9 activities. We conclude that active RAS inhibition by FTS was associated with attenuated fibrosis and improved muscle strength in the dy2J/dy2J mouse model of congenital muscular dystrophy

Functional Phenotypic Rescue of Caenorhabditis elegans Neuroligin-Deficient Mutants by the Human and Rat NLGN1 Genes

Neuroligins are cell adhesion proteins that interact with neurexins at the synapse. This interaction may contribute to differentiation, plasticity and specificity of synapses. In humans, single mutations in neuroligin encoding genes lead to autism spectrum disorder and/or mental retardation. Caenorhabditis elegans mutants deficient in nlg-1, an orthologue of human neuroligin genes, have defects in different behaviors. Here we show that the expression of human NLGN1 or rat Nlgn1 cDNAs in C. elegans nlg-1 mutants rescues the fructose osmotic strength avoidance and gentle touch response phenotypes. Two specific point mutations in NLGN3 and NLGN4 genes, involved in autistic spectrum disorder, were further characterized in this experimental system. The R451C allele described in NLGN3, was analyzed with both human NLGN1 (R453C) and worm NLG-1 (R437C) proteins, and both were not functional in rescuing the osmotic avoidance behavior and the gentle touch response phenotype. The D396X allele described in NLGN4, which produces a truncated protein, was studied with human NLGN1 (D432X) and they did not rescue any of the behavioral phenotypes analyzed. In addition, RNAi feeding experiments measuring gentle touch response in wild type strain and worms expressing SID-1 in neurons (which increases the response to dsRNA), both fed with bacteria expressing dsRNA for nlg-1, provided evidence for a postsynaptic in vivo function of neuroligins both in muscle cells and neurons, equivalent to that proposed in mammals. This finding was further confirmed generating transgenic nlg-1 deficient mutants expressing NLG-1 under pan-neuronal (nrx-1) or pan-muscular (myo-3) specific promoters. All these results suggest that the nematode could be used as an in vivo model for studying particular synaptic mechanisms with proteins orthologues of humans involved in pervasive developmental disorders

Neurexins and Neuroligins: Recent Insights from Invertebrates

During brain development, each neuron must find and synapse with the correct pre- and postsynaptic partners. The complexity of these connections and the relatively large distances some neurons must send their axons to find the correct partners makes studying brain development one of the most challenging, and yet fascinating disciplines in biology. Furthermore, once the initial connections have been made, the neurons constantly remodel their dendritic and axonal arbours in response to changing demands. Neurexin and neuroligin are two cell adhesion molecules identified as important regulators of this process. The importance of these genes in the development and modulation of synaptic connectivity is emphasised by the observation that mutations in these genes in humans have been associated with cognitive disorders such as Autism spectrum disorders, Tourette syndrome and Schizophrenia. The present review will discuss recent advances in our understanding of the role of these genes in synaptic development and modulation, and in particular, we will focus on recent work in invertebrate models, and how these results relate to studies in mammals

Supplementary Material for: Fatal Overdoses of Opioids in Israel 2005–2014

<b><i>Aims:</i></b> To explore previously unreported rates and trends in opioid-related mortality in Israel, 2005–2014. <b><i>Methods:</i></b> Data was obtained from the national database on causes of death. Drug poisoning deaths were divided into opioid-related deaths and deaths related to other drugs according to International Classification of Diseases (ICD)-10 code of underlying cause, and included drug poisoning of accidental, intentional or undetermined intent. Age-adjusted rates were calculated per 100,000 population. Rate ratios were calculated and a logistic model constructed to compare the risk of opioid-related deaths in both halves of the decade (2006–2009 and 2009–2013) and between various demographic groups. <b><i>Results:</i></b> While age-adjusted rates of deaths related to other drugs remained relatively stable, rates of opioid-related deaths significantly decreased during this period across all groups. During the study period, the number of opioid-related deaths in Israel declined from 1.3 to 0.3 per 100,000. Opioid-related deaths were more common among men, young adults and immigrants from the Former Soviet Union.<b><i> Conclusions:</i></b> Rates of opioid-related deaths in Israel were low compared to those reported in the United States and United Kingdom. In addition, the decline in opioid-related deaths in Israel is contrary to trends observed in the United States and United Kingdom. Factors that may contribute to these differences are discussed

"The next-generation": Long-term reproductive outcome of adults born at a very low birth weight

Background Preterm birth at very low birth weight (VLBW, &lt;1500g) has a multitude of consequences that extend to various aspects of adult life. Little is known about the long-term reproductive outcome of VLBW that survive to adulthood. Aims To evaluate the reproductive outcome of VLBW infants who survive to adulthood (next-generation). Study design Retrospective cohort Subjects Infants born at a single tertiary center between the years 1982–1997 who survived to 18 years of age (first-generation). Outcome measures The number and the birth weight of offspring from adults born with VLBW were compared to those of other birth weight groups born in the same epoch: 1500–2499g, 2500–3799g (reference group) and ≥3800g. We calculated the ratio of actual compared to expected number of children in the next-generation for extreme birth weight parents, using the reference group as a control group and adjusting for birth year. Thereafter, we measured whether first-generation VLBW had an increased risk for a VLBW in the next-generation. Results After exclusions, we identified first-generation 67,183 births, including 618 (9.2%) VLBW. There were 193 males and 184 female VLBW infants who survived to adulthood. Both female and male first-generation patients from the VLBW group had half the reproductive rate relative for the normal birth weight group. After adjusting for parental age, male and female VLBW survivors had no significant risk for a VLBW neonate in the next-generation, however, the overall number of are small and may limit any conclusion. Conclusions VLBW children who reach adulthood may be at a significantly lower reproductive capacity.</p

Influenza Season Hospitalization Trends in Israel: a Multi-year Comparative Analysis 2005/2006 Through 2012/2013

BACKGROUND: Influenza-related morbidity impacts healthcare systems, including hospitals. OBJECTIVE: To obtain a quantitative assessment of hospitalization burden in pediatric and internal medicine departments during influenza seasons compared with the summer months in Israel. METHODS: Data on pediatric and internal medicine hospitalized patients in general hospitals in Israel during the influenza seasons between 2005 and 2013 were analyzed for rate of hospitalizations, rate of hospitalization days, hospital length of stay (LOS), and bed occupancy and compared with the summer months. Data were analyzed for hospitalizations for all diagnoses, diagnoses of respiratory or cardiovascular disease (ICD9 390-519), and influenza or pneumonia (ICD9480-487), with data stratified by age. The 2009-2010 pandemic influenza season was excluded. RESULTS: Rates of monthly hospitalizations and hospitalization days for all diagnoses were 4.8% and 8% higher, respectively, during influenza seasons as compared with the summers. The mean LOS per hospitalization for all diagnoses demonstrated a small increase during influenza seasons as compared with summer seasons. The excess hospitalizations and hospitalization days were especially noticed for the age groups under 1 year, 1-4 years, and 85 years and older. The differences were severalfold higher for patients with a diagnosis of respiratory or cardiovascular disease and influenza or pneumonia. Bed occupancy was higher during influenza seasons compared with the summer, particularly in pediatric departments. CONCLUSIONS: Hospital burden in pediatric and internal medicine departments during influenza seasons in Israel was associated with age and diagnosis. These results are important for optimal preparedness for influenza seasons