Influence of growth modulation on the effective permeability of the vertebral end plate. A porcine experimental scoliosis model

Background: Abnormal mechanical loading occurs in scoliosis as compared to normal spines. Intervertebral disc degeneration has been correlated with alteration of bone density in adjacent vertebral bodies. How vertebral end plate remodels in scoliosis and the consequences on disc homeostasis are not well understood. Permeability is a relevant physical measure to quantify mass transport in porous media. We hypothesized that effective permeability of the vertebral end plate was modified by growth modulation in a scoliosis animal model. Methods: Flexible asymmetric posterior instrumentation was undertaken on six healthy four-week-old pigs. Two sets of left pedicle screws were inserted and connected with a stainless steel cable. After two months, the apical intervertebral unit and three units located cranially and caudally, were harvested. One central and two lateral specimens were investigated using a previously validated method for measuring permeability. Findings: A three-dimensional deformity was obtained in all six animals with an average of 42 degrees right thoracic curve. 44 degrees lordosis and 21 degrees rotation. Permeability was significantly greater in the center of the end plates than in the periphery and it was decreased by -45% towards the apex of the deformity. Fluid flow direction did not play a significant role. No significant difference was found between the convex side and the concave side. Interpretation: The end plate is a crucial zone for diffusive and convective transport and we showed in a scoliosis animal model that a growth modulation may decrease its effective permeability. The proposed methodology and associated results could help to understand degenerative changes in human spine

In vitro activity of an aqueous allicin extract and a novel allicin topical gel formulation against Lancefield group B streptococci

Background: Studies have shown the efficacy of intra-partum antibiotics in preventing early-onset group B streptococcal sepsis. This approach results in a high intra-partum antibiotic use. Worryingly, the same antibiotics used in prophylaxis are also first-line treatment for neonatal sepsis, and antibiotic exposure in the peri-natal period has been shown to be a risk factor for late-onset serious bacterial infections and allergic disease. Antibiotic exposure in the peri-natal period is becoming a major public health issue; alternative strategies are needed. Garlic has been traditionally used to treat vaginal infections. Allicin is the main antibacterial agent isolated from garlic. Objectives: The aim of the study was to investigate the in vitro activity of a novel allicin extract in aqueous and gel formulation against 76 clinical isolates of Lancefield group B streptococci (GBS). Methods: MICs and MBCs of allicin were determined for 76 GBS isolates by agar dilution and microtitre plate methods. Killing kinetics were determined for a selected 16 of the 76 strains. Agar diffusion tests were compared for allicin liquid and gel (500 mg/L). Results and conclusions: MICs and MBCs of allicin liquid were 35 to 95 mg/L and 75 to 315 mg/L, respectively. Time/dose kill curves produced a 2–3 log reduction in cfu/mL within 3 h and no detectable growth at 8 and 24 h. A novel 500 mg/L allicin gel produced an average zone size of 23+-6 mm compared with 21+-6 mm for allicin in water. Aqueous allicin is bactericidal against GBS isolates and maintains activity in a novel gel formulation

Submicroscopic Deletions at 13q32.1 Cause Congenital Microcoria.

International audienceCongenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR

High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in France and characterization of biochemical and clinical features.

International audiencePURPOSE:To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report six novel mutations, to characterize the biochemical features of a recurrent novel mutation and to study the clinical features of adRP patients.DESIGN:Retrospective clinical and molecular genetic study.METHODS:Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot.RESULTS:We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1 to 0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families.CONCLUSIONS:The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases which could be underdiagnosed

Genetic landscape of a large cohort of Primary Ovarian Insufficiency : New genes and pathways and implications for personalized medicine

Background Primary Ovarian Insufficiency (POI), a public health problem, affects 1-3.7% of women under 40 yield-ing infertility and a shorter lifespan. Most causes are unknown. Recently, genetic causes were identified, mostly in single families. We studied an unprecedented large cohort of POI to unravel its molecular pathophysiology.Methods 375 patients with 70 families were studied using targeted (88 genes) or whole exome sequencing with pathogenic/likely-pathogenic variant selection. Mitomycin-induced chromosome breakages were studied in patients' lymphocytes if necessary. Findings A high-yield of 29.3% supports a clinical genetic diagnosis of POI. In addition, we found strong evidence of pathogenicity for nine genes not previously related to a Mendelian phenotype or POI: ELAVL2, NLRP11, CENPE, SPATA33, CCDC150, CCDC185, including DNA repair genes: C17orf53(HROB), HELQ, SWI5 yielding high chromo-somal fragility. We confirmed the causal role of BRCA2, FANCM, BNC1, ERCC6, MSH4, BMPR1A, BMPR1B, BMPR2, ESR2, CAV1, SPIDR, RCBTB1 and ATG7 previously reported in isolated patients/families. In 8.5% of cases, POI is the only symptom of a multi-organ genetic disease. New pathways were identified: NF-kB, post-translational regulation, and mitophagy (mitochondrial autophagy), providing future therapeutic targets. Three new genes have been shown to affect the age of natural menopause supporting a genetic link.Interpretation We have developed high-performance genetic diagnostic of POI, dissecting the molecular pathogene-sis of POI and enabling personalized medicine to i) prevent/cure comorbidities for tumour/cancer susceptibility genes that could affect life-expectancy (37.4% of cases), or for genetically-revealed syndromic POI (8.5% of cases), ii) predict residual ovarian reserve (60.5% of cases). Genetic diagnosis could help to identify patients who may benefit from the promising in vitro activation-IVA technique in the near future, greatly improving its success in treating infertility.Funding Universite? Paris Saclay, Agence Nationale de Biome?decine.Copyright (c) 2022 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)Peer reviewe

Primal health research in the age of epigenetic clocks

International audienceIn the field of developmental origins of health and diseases among humans, classical epidemiology has limited power. We hypothesize that widely available "biological clocks" would introduce a new era in the history of health research. By contrasting chronological age and physiological age, "biological clocks" might become instrumental, without any delay, in exploring the possible long-term effects of a highly modified lifestyle during the "primal period". The aging process, life expectancy and health in general would be the main criteria. Today "DNA methylation GrimAge", based on estimations of plasma protein levels, may be considered to be the best predictor of lifespan and healthspan

La evolución de la salud: De la vulneravilidad del feto a la capacidad de adaptación del adulto

The six months following conception represen! the phase of human life with the highest risks of death. This is one aspect of fetal vul nerabil ity another aspect of this vulnerability: anything happening during the phase of intra-uterine formation can have irreversible and l ile long effects. In contrast with fetal vulnerability, the capacity adults have to recover from adverse circumstances is amazingLa fase de la vida con mayor riesgo de perder la vida son los seis meses que siguen a la concepción . Este es uno de los aspectos de la vulnerabilidad del feto. Otro aspecto de esta vulnerabilidad: todo lo que ocurre durante la fase de formación intrauterina puede tener a largo plazo efectos irreversibles sobre la salud . En contraste con la vulnerabilidad del feto, la capacidad que tiene el adulto a recuperarse de las adversidades es extraordinaria

El método acordeón Método de descontaminación prenatal: Una nueva visión de la preparación preconcepcional

In the begginings of XXI century, a wide variety of chemical pollutants are produced by mankind. These chemicals are accumulated in fat tissues of human bodies and are transmitted by generations in pregnancy. Scientific studies have demonstrated a nocive effect in medium and long term times, and is logical to propose decontamination methods

¿Se ha convertido el líquido amniótico en un mar de estrógenos?

Human embryos and phoetus are actually exposed to high levels of estrogens, that origines serious disorders in the male reproductive tract, and is connected too with the high proportion of male sterility. The increasing levels of estro gens in prenatal environment answer to severa! causes: diet, oral anovulatories and chemical wastes in the environment. The author thinks over the probability that the exposition to high levels of estro gens in the prenatal phase presidsposes to breast cancer in the adult age