Mécanismes et conséquences des mutations

L’identification des mutations à l’origine de maladies génétiques chez l’homme a pris ces dernières années un essor considérable. Il est devenu possible d’établir le spectre des mutations délétères pour une maladie génétique donnée, et des bases de données internationales sont aujourd’hui accessibles via le réseau Internet. Le diagnostic génotypique des maladies héréditaires occupe actuellement une place prépondérante en matière de conseil génétique et de diagnostic prénatal. La connaissance du type de mutation délétère et des mécanismes en cause est essentielle pour déterminer la stratégie de diagnostic moléculaire adaptée à chaque situation. Cet article a pour objectif de présenter les différents types de mutations responsables de maladies génétiques (substitutions nucléotidiques, délétions ou insertions de petite taille, mutations dynamiques, grands remaniements…) et de récapituler les connaissances actuelles concernant les mécanismes moléculaires à l’origine de ces mutations. Leurs conséquences sur l’expression du gène (transcription et maturation du transcrit) et sur la fonction de la protéine sont également abordées dans cet article.The identification of mutations leading to human genetic diseases has grown into an intensive research field during the last few years. Through novel DNA analysis progress, it is now possible to determine the mutational spectrum for a given genetic disease and international databases are now available online. Genetic diagnosis of hereditary diseases has become an essential tool in genetic counselling and prenatal diagnosis. The knowledge of the deleterious mutation type and the molecular associated mechanism is fundamental in order to devise the optimal molecular diagnosis strategy. This review aims to present the various mutation categories involved in genetic diseases (single base-pair substitutions, small deletions or insertions, dynamic mutations, gross DNA lesions…) and to summarize our current knowledge about the main molecular mechanisms responsible for these mutations. Their deleterious consequences on gene expression, including transcription and transcript maturation, and protein loss or gain of function are also discussed in this review

From cave to spring: Understanding transport of suspended sediment particles in a fully phreatic karst conduit using particle analysis and geochemical methods

Karst aquifers are vulnerable to contamination, especially in the context of heavy rainfall events. Contamination is often associated with turbidity that can originate from the soil zone, infiltrating surface waters or resuspension of previously deposited sediments within the aquifer. While turbidity events can be well monitored at karst springs, related information about the sediment origin and the spatiotemporal input function usually remain unknown. Thus, the mobility and attenuation of the particulate matter and associated pollutants can hardly be determined quantitatively. A tracer test with suspended cave sediments and solute tracers for comparison has hence been performed in a karst aquifer at the Blue Spring (Blautopf) in Southern Germany. The tracers were injected in the cave system, at the beginning of a fully phreatic karst conduit, and monitored at the spring after a travel distance of 1250 m. The particle-size distribution was monitored using a particle counter and sediment samples were filtered with 0.45-μm cellulose acetate filters. Particles on the filter were analysed for major and trace elements as well as rare earth elements (REE) by ICP-MS after acid digestion. Results show that (1) sediment particles were transported faster than solutes, which was interpreted as a transport in the main flow path of the conduit, whereas conservative tracers tend to diffuse into smaller fissures as well. (2) All measured particles sizes were transported at similar flow velocities. (3) A transport associated to sediment particles could be shown for all measured elements. This study presents a methodological improvement of comparative sediment tracer tests as well as deeper insights into particle and element transport processes in karst aquifers, originating from previously deposited cave sediment. Results provide deeper knowledge into transport processes of sediment-associated contaminants, such as heavy metals which may strongly be affected by the particle size. This knowledge contributes to a better management of karst water resources in the context of turbidity events

Deliberately light interpersonal contact affects the control of head stability during walking in children and adolescents with cerebral palsy

Objective: To evaluate the potential of deliberately light interpersonal touch (IPT) for reducing excessive head and trunk sway during self-paced walking in children and adolescents with cerebral palsy (CP). Design: Quasi-experimental, proof-of-concept study with between-groups comparison. Setting: Ambulant care facility, community center. Participants: 26 individuals with CP (spastic and ataxic; GMFCS I-III; mean=9.8y; f=11, m=15) and in 39 typically developed (TD) children and adolescents (mean=10.0y; f=23, m=16). Interventions: IPT applied by a therapist to locations at the back and the head. Main Outcome Measures: As primary outcomes head and trunk sway during self-paced walking were assessed by inertial measurement units. Secondary outcomes were average step length and gait speed. Results: CP group: apex and occiput IPT reduced head velocity sway compared to thoracic IPT (both p=0.04) irrespective of individuals’ specific clinical symptoms. TD group: all testing conditions reduced head velocity sway compared to walking alone (all p≤0.03) as well as in apex and occiput IPT compared to paired walking (both p≤0.02). Conclusions: Deliberately light IPT at the apex of the head alters control of head sway in children and adolescents with CP. The effect of IPT varies as a function of contact location and acts differently in TD individuals

Rotigotine in Hemodialysis-Associated Restless Legs Syndrome : A Randomized Controlled Trial

Background: Restless legs syndrome (RLS) has been associated with insomnia, decreased quality of life, and increased morbidity and mortality in end-stage renal disease. This randomized controlled trial investigated effects of rotigotine in patients with RLS and end-stage renal disease. Study Design: Double-blind placebo-controlled study. Setting & Participants: Adults with moderate to severe RLS (International RLS Study Group Rating Scale [IRLS] >= 15) and Periodic Limb Movement Index (PLMI) >= 15 who were receiving thrice-weekly hemodialysis enrolled from sites in the United States and Europe. Intervention: Following randomization and titration ( Outcomes & Measurements: Primary efficacy outcome: reduction in PLMI, assessed by ratio of PLMI at end of maintenance to baseline. Secondary/other outcomes (P values exploratory) included mean changes from baseline in PLMI, IRLS, and Clinical Global Impression item 1 (CGI-1 [severity of illness]) score. Results: 30 patients were randomly assigned (rotigotine, 20; placebo, 10); 25 (15; 10) completed the study with evaluable data. Mean (SD) PLMI ratio (end of maintenance to baseline) was 0.7 +/- 0.4 for rotigotine and 1.3 +/- 0.7 for placebo (analysis of covariance treatment ratio, 0.44; 95% CI, 0.22 to 0.88; P = 0.02). Numerical improvements were observed with rotigotine versus placebo in IRLS and CGI-1 (least squares mean treatment differences of -6.08 [95% CI, -12.18 to 0.02; P = 0.05] and -0.81 [95% CI, -1.94 to 0.33; P = 0.2]). 10 of 15 rotigotine and 2 of 10 placebo patients were CGI-1 responders (>= 50% improvement). Hemodialysis did not affect unconjugated rotigotine concentrations. The most common adverse events (>= 2 patients) were nausea (rotigotine, 4 [20%]; placebo, 0); vomiting (3 [15%]; 0); diarrhea (1 [5%]; 2 [20%]); headache (2 [10%]; 0); dyspnea (2 [10%]; 0); and hypertension (2 [10%]; 0). Limitations: Small sample size and short duration. Conclusions: Rotigotine improved periodic limb movements and RLS symptoms in the short term among ESRD patients requiring hemodialysis in a small-scale study. No dose adjustments are necessary for hemodialysis patients. (C) 2016 by the National Kidney Foundation, Inc.Peer reviewe

Identification and validation of potential new biomarkers for prostate cancer diagnosis and prognosis using 2D-DIGE and MS

This study was designed to identify and validate potential new biomarkers for prostate cancer and to distinguish patients with and without biochemical relapse. Prostate tissue samples analyzed by 2D-DIGE (two-dimensional difference in gel electrophoresis) and mass spectrometry (MS) revealed downregulation of secernin-1 (P < 0.044) in prostate cancer, while vinculin showed significant upregulation (P < 0.001). Secernin-1 overexpression in prostate tissue was validated using Western blot and immunohistochemistry while vinculin expression was validated using immunohistochemistry. These findings indicate that secernin-1 and vinculin are potential new tissue biomarkers for prostate cancer diagnosis and prognosis, respectively. For validation, protein levels in urine were also examined by Western blot analysis. Urinary vinculin levels in prostate cancer patients were significantly higher than in urine from nontumor patients (P = 0.006). Using multiple reaction monitoring-MS (MRM-MS) analysis, prostatic acid phosphatase (PAP) showed significant higher levels in the urine of prostate cancer patients compared to controls (P = 0.012), while galectin-3 showed significant lower levels in the urine of prostate cancer patients with biochemical relapse, compared to those without relapse (P = 0.017). Three proteins were successfully differentiated between patients with and without prostate cancer and patients with and without relapse by using MRM. Thus, this technique shows promise for implementation as a noninvasive clinical diagnostic technique

Investigation of cardiorespiratory effects of the selective 5-HT4 agonist BIMU-8 in etorphine-immobilised goats (Capra aegagrus hircus) in a randomized, blinded and controlled trial

BACKGROUND : Opioid-induced respiratory compromise remains a significant challenge in etorphine-immobilised wildlife. Serotonergic agonists offer a potential avenue for preventing or treating opioid-induced respiratory compromise. We therefore aimed to determine whether the selective 5- hydroxytryptamine receptor 4 (5-HT4) agonist, BIMU-8, reverses opioidinduced respiratory compromise in etorphine-immobilised goats. METHODS : Seven healthy adult goats were immobilised with etorphine, then treated with BIMU-8 or sterile water 5 minutes later in a randomised, prospective cross-over study. Cardiorespiratory variables were measured at 1-minute intervals from 4 minutes before etorphine to 15 minutes after its administration. Arterial blood gas analyses were also performed before and after etorphine administration and the respective treatments. RESULTS : Intravenous injection of BIMU-8 attenuated etorphine-induced respiratory compromise, as indicated by improvements, compared to baseline and between treatments, in respiratory rate (ƒR), peripheral arterial blood oxygen saturation (SpO2), partial pressure of arterial oxygen (PaO2) and the alveolar-arterial oxygen partial pressure gradient (P(A-a)O2). BIMU-8 caused an increase in heart rate and a temporary decrease in arterial blood pressure. Mild movements and slight muscle spasm occurred but BIMU-8 did not reverse immobilisation. CONCLUSION : Our results indicate that BIMU-8 may be a potential drug candidate for the treatment, or prevention, of etorphine-induced respiratory compromise in immobilised ungulateshttps://bvajournals.onlinelibrary.wiley.com/journal/20427670dm2022Centre for Veterinary Wildlife StudiesParaclinical Science

Toward Effective Collaborations between Regional Climate Modeling and Impacts-Relevant Modeling Studies in Polar Regions

What: The aim of this workshop was to discuss the needs and challenges in using high-resolution climate model outputs for impacts-relevant modeling. Development of impacts-relevant climate projections in the polar regions requires effective collaboration between regional climate modelers and impacts-relevant modelers in the design stage of high-resolution climate projections for the polar regions. When: 8 November 2021 Where: Online

O MANEJO DO PACIENTE ODONTOLÓGICO COM PRÉ-DISPOSIÇÃO A DESENVOLVER ENDOCARDITE BACTERIANA

Introduction: Bacterial endocarditis (BE) is a disease that favors the invasion of endocardial surfaces by infectious agents, producing inflammation and lesions in these structures, which may, in some susceptible patients, lead to uncontrollable and even tragic consequences. The Dental Surgeon in the midst of this reality must be prepared to carry out proper management with the patient susceptible to developing Bacterial Endocarditis and who needs to undergo invasive dental procedures. Objective: the objective of this work is to carry out a literature review on dental patients at risk or susceptible to developing bacterial endocarditis, to study the correct management of this patient susceptible to developing bacterial endocarditis, as well as to understand that dentistry is related to other areas of health, such as Cardiology. Materials and Methods: This is a literature review that was carried out by collecting data and information from articles from 1986 to March 2022. Discussion and Conclusion: Bacterial Endocarditis is a disease that shows us that Dentistry it is fully correlated with other areas of health. Despite being a disease that causes the destruction of the endocardium, its bacteria have oral origin. It is essential that the dental surgeon knows how to recognize predisposed patients, as well as to avoid complications inherent to this disease.Introdução: A endocardite bacteriana (EB) é uma doença que favorece que seus agentes infecciosos invadam as superfícies endocárdicas, produzindo inflamações e lesões nessas estruturas, podendo, em alguns pacientes susceptíveis, levar a consequências não controláveis e até mesmo trágicas. O Cirurgião Dentista em meio a essa realidade deve estar preparado para a realização do devido manejo com o paciente susceptível a desenvolver a Endocardite Bacteriana e que precise se submeter a procedimentos odontológicos invasivos. Objetivo: o objetivo deste trabalho é realizar uma revisão de literatura sobre os pacientes odontológicos de risco ou susceptíveis a desenvolver endocardite bacteriana, estudar o correto manejo deste paciente susceptível a desenvolver Endocardite Bacteriana, assim como compreender que Odontologia está relacionada com outras áreas da saúde, como por exemplo, a Cardiologia. Materiais e Métodos: Trata-se de uma revisão de literatura que foi realizado por meio da coleta de dados e informações de artigos desde o ano 1986 até março de 2022. Discussão e Conclusão: A Endocardite bacteriana é uma doença que nos mostra que a Odontologia está totalmente correlacionada com as outras áreas da saúde. Apesar de ser uma doença que provoca a destruição do endocárdio, sua bactéria tem origem bucal. É imprescindível que o cirurgião-dentista saiba reconhecer os pacientes predispostos assim como evitar complicações inerentes a esta doença