Oxidative stress contributes differentially to the pathophysiology of Charcot-Marie-Tooth disease type 2K.

Charcot-Marie-Tooth (CMT) disease is a common inherited peripheral neuropathy. The CMT2K axonal form is associated with GDAP1 dominant mutations, which according to the affected domain cause a gradient of severity. Indeed, the p.

Severe early-onset manifestations of pseudoxanthoma elasticum resulting from the cumulative effects of several deleterious mutations in ENPP1, ABCC6 and HBB: transient improvement in ectopic calcification with sodium thiosulfate.

Pseudoxanthoma elasticum (PXE) is a rare disorder characterized by fragmentation and progressive calcification of elastic fibres in connective tissues. Overlap has been reported between the inherited PXE phenotype associated with ENPP1, ABCC6 or NT5E mutations and acquired PXE clinical manifestations associated with haemoglobinopathies induced by HBB mutations. No treatment is currently available for PXE.

Metabolomics shows no impairment of the microenvironment of the cumulus-oocyte complex in women with isolated endometriosis.

Research Question: Is there any metabolomic evidence of impairment of the cumulus-oocyte complex (COC) microenvironment in the follicular fluid of women with endometriosis?

Design: A prospective observational study from January to July 2018 at the Angers University Hospital, France. Seventy-nine women undergoing IVF with or without intracytoplasmic sperm injection (ICSI) were included: 39 for endometriosis-related infertility and 40 controls with other causes of infertility. A targeted quantitative metabolomic and lipidomic analysis was performed.

Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy.

Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases.

Effects of Resistance Exercise and Nutritional Supplementation on Dynamic Cerebral Autoregulation in Head-Down Bed Rest.

Head-down bed rest (HDBR) is commonly considered as ground-based analog to spaceflight and simulates the headward fluid shift and cardiovascular deconditioning associated with spaceflight. We investigated in healthy volunteers whether HDBR, with or without countermeasures, affect cerebral autoregulation (CA). Twelve men (at selection: 34 ± 7 years; 176 ± 7 cm; 70 ± 7 kg) underwent three interventions of a 21-day HDBR: a control condition without countermeasure (CON), a condition with resistance vibration exercise (RVE) comprising of squats, single leg heel, and bilateral heel raises and a condition using also RVE associated with nutritional supplementation (NeX).

The walking estimated limitation stated by history (WELSH): a visual tool to self-reported walking impairment in a predominantly illiterate population.

Background: The prevalence of cardiovascular diseases is increasing in low-income countries. Various questionnaires to estimate walking capacity in patients are available in multiple languages but they are not suitable for illiterate patients.

Objective: The walking estimated limitation stated by history (WELSH) tool aims at rating individual walking disability using only drawings and four items.

Vitamin D and Calcium Supplementation Accelerates Randall's Plaque Formation in a Murine Model.

Most kidney stones are made of calcium oxalate crystals. Randall's plaque, an apatite deposit at the tip of the renal papilla, is considered to at the origin of these stones. Hypercalciuria may promote Randall's plaque formation and growth.

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

AMPA receptors (AMPARs) are tetrameric ligand-gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca-impermeable, with a linear relationship between current and trans-membrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE).

Venous thromboembolism risk stratification for patients with lower limb trauma and cast or brace immobilization.

Background: Thromboprophylaxis for patients with non-surgical isolated lower-limb trauma requiring immobilization is a matter of debate. Our aim was to develop and validate a clinical risk- stratification model based on Trauma, Immobilization and Patients' characteristics (the TIP score).

Methods: The TIP score criteria and the cut-off were selected by a consensus of international experts (n = 27) using the Delphi method.

Effects of sildenafil on maximum walking time in patients with arterial claudication: The ARTERIOFIL study.

Background: Patients with lower extremity peripheral artery disease (PAD) frequently experience claudication, a clinical symptom indicative of reduced walking capacity. Recommended care consists of exercise rehabilitation combined with optimal medical treatment and surgery. The effects of a single oral dose of sildenafil, a phosphodiesterase type-5 inhibitor, on patients with claudication are discussed.

Warburg-like effect is a hallmark of complex I assembly defects.

Due to its pivotal role in NADH oxidation and ATP synthesis, mitochondrial complex I (CI) emerged as a crucial regulator of cellular metabolism. A functional CI relies on the sequential assembly of nuclear- and mtDNA-encoded subunits; however, whether CI assembly status is involved in the metabolic adaptations in CI deficiency still remains largely unknown. Here, we investigated the relationship between CI functions, its structure and the cellular metabolism in 29 patient fibroblasts representative of most CI mitochondrial diseases.

Treadmill Measured vs. Questionnaire Estimated Changes in Walking Ability in Patients With Peripheral Artery Disease.

Objective: Determining the maximum walking time (MWT) using the treadmill test is the gold standard method for evaluating walking capacity and treatment effect in patients with peripheral arterial disease (PAD). However, self reported functional disability is important when assessing quality of life. Changes in the Walking Estimated Limitation Calculated by History (WELCH) questionnaire scores were compared with the MWT.

A snapshot of some pLI score pitfalls.

The pLI score reflects the tolerance of a given gene to the loss of function on the basis of the number of protein truncating variants, that is, the frameshift, splice donor, splice acceptor, and stop-gain variants referenced for this gene in control databases weighted by the size of the gene and the sequencing coverage. It is frequently used to prioritize candidate genes when analyzing whole exome or whole genome data. We list here the main pitfalls to consider before using this score.

Microvascular Response to the Roos Test Has Excellent Feasibility and Good Reliability in Patients With Suspected Thoracic Outlet Syndrome.

Exercise oximetry allows operator-independent recordings of microvascular blood flow impairments during exercise and can be used during upper arm provocative maneuvers. To study the test-retest reliability of upper-limb oximetry during the Roos test in patients with suspected thoracic outlet syndrome (TOS). Forty-two patients (28 men, 14 women; mean age: 40.

Virus-mediated delivery of antibody targeting TAR DNA-binding protein-43 mitigates associated neuropathology.

The cytoplasmic aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of degenerating neurons in amyotrophic lateral sclerosis (ALS) and subsets of frontotemporal dementia (FTD). In order to reduce TDP-43 pathology, we generated single-chain (scFv) antibodies against the RNA recognition motif 1 (RRM1) of TDP-43, which is involved in abnormal protein self-aggregation and interaction with p65 NF-κB. Virus-mediated delivery into the nervous system of a scFv antibody, named VH7Vk9, reduced microgliosis in a mouse model of acute neuroinflammation and mitigated cognitive impairment, motor defects, TDP-43 proteinopathy, and neuroinflammation in transgenic mice expressing ALS-linked TDP-43 mutations.

Bioinformatics Tools and Databases to Assess the Pathogenicity of Mitochondrial DNA Variants in the Field of Next Generation Sequencing.

The development of next generation sequencing (NGS) has greatly enhanced the diagnosis of mitochondrial disorders, with a systematic analysis of the whole mitochondrial DNA (mtDNA) sequence and better detection sensitivity. However, the exponential growth of sequencing data renders complex the interpretation of the identified variants, thereby posing new challenges for the molecular diagnosis of mitochondrial diseases. Indeed, mtDNA sequencing by NGS requires specific bioinformatics tools and the adaptation of those developed for nuclear DNA, for the detection and quantification of mtDNA variants from sequence alignment to the calling steps, in order to manage the specific features of the mitochondrial genome including heteroplasmy, i.

Painless local pressure application to test microvascular reactivity to ischemia.

Background: Forearm cutaneous blood flux (CBF) measurement with post-occlusive reactive hyperemia (PORH) is uncomfortable and may not be devoid of risks. We aimed to investigate post-compression reactive hyperemia (PCRH) with a custom-made indenter that was designed to be easily used routinely by inexperienced observers.

Methods: Medical students evaluated PCRH with 1- to 4-min pressure applications of 16 to 34 kPa and PORH with 3-min forearm cuff occlusion using laser speckle contrast imaging in 15 healthy volunteers.

Hydroxychloroquine partially prevents endothelial dysfunction induced by anti-beta-2-GPI antibodies in an in vivo mouse model of antiphospholipid syndrome.

Background: Antiphospholipid syndrome is associated with endothelial dysfunction, which leads to thrombosis and early atheroma. Given that hydroxychloroquine has anti-thrombotic properties in lupus, we hypothesized that it could reduce endothelial dysfunction in an animal model of antiphospholipid syndrome. We evaluated the effect of hydroxychloroquine in preventing endothelial dysfunction in a mouse model of antiphospholipid syndrome.

eKLIPse: a sensitive tool for the detection and quantification of mitochondrial DNA deletions from next-generation sequencing data.

Purpose: Accurate detection of mitochondrial DNA (mtDNA) alterations is essential for the diagnosis of mitochondrial diseases. The development of high-throughput sequencing technologies has enhanced the detection sensitivity of mtDNA pathogenic variants, but the detection of mtDNA rearrangements, especially multiple deletions, is still poorly processed. Here, we present eKLIPse, a sensitive and specific tool allowing the detection and quantification of large mtDNA rearrangements from single and paired-end sequencing data.