FDXR Mutations Cause Sensorial Neuropathies and Expand the Spectrum of Mitochondrial Fe-S-Synthesis Diseases.

Hearing loss and visual impairment in childhood have mostly genetic origins, some of them being related to sensorial neuronal defects. Here, we report on eight subjects from four independent families affected by auditory neuropathy and optic atrophy. Whole-exome sequencing revealed biallelic mutations in FDXR in affected subjects of each family. FDXR encodes the mitochondrial ferredoxin reductase, the sole human ferredoxin reductase implicated in the biosynthesis of iron-sulfur clusters (ISCs) and in heme formation. ISC proteins are involved in enzymatic catalysis, gene expression, and DNA replication and repair. We observed deregulated iron homeostasis in FDXR mutant fibroblasts and indirect evidence of mitochondrial iron overload. Functional complementation in a yeast strain in which ARH1, the human FDXR ortholog, was deleted established the pathogenicity of these mutations. These data highlight the wide clinical heterogeneity of mitochondrial disorders related to ISC synthesis.

High prevalence of congenital deafness on Reunion Island is due to a founder variant of LHFPL5.

Reunion Island is a French oversea department in the Indian Ocean with 1.6/1000, an estimated prevalence of deafness that is almost double as compared to the mainland France. Twelve children having isolated bilateral prelingual profound deafness along with motor delay attributed to vestibular areflexia were enrolled. Their mean walking age was 19 months. Electroretinography and temporal bone CT-scans were normal in all cases. A novel homozygous frameshift lipoma HMGIC fusion partner-like 5 (LHFPL5) variant c.185delT p.(Phe62Serfs*23) was identified using whole-exome sequencing. It was found in seven families. Four patients from two different families from both Reunion Island and mainland France, were compound heterozygous: c.185delT p.(Phe62Serfs*23) and c.472C > T p.(Arg158Trp). The phenotype observed in our patients completely mimics the hurry-scurry (hscy) murine Tmhs knock-out model. The recurrent occurrence of same LHFPL5 variant in Reunion Island is attributed to common ancestor couple born in 1693.

Contributions of adhesive proteins to the cellular and bacterial response to surfaces treated with bioactive polymers: case of poly(sodium styrene sulfonate) grafted titanium surfaces.

The research developed on functionalized model or prosthetic surfaces with bioactive polymers has raised the possibility to modulate and/or control the biological in vitro and in vivo responses to synthetic biomaterials. The mechanisms underlying the bioactivity exhibited by sulfonated groups on surfaces involves both selective adsorption and conformational changes of adsorbed proteins. Indeed, surfaces functionalized by grafting poly(sodium styrene sulfonate) [poly(NaSS)] modulate the cellular and bacterial response by inducing specific interactions with fibronectin (Fn). Once implanted, a biomaterial surface is exposed to a milieu of many proteins that compete for the surface which dictates the subsequent biological response. Once understood, this can be controlled by dictating exposure of active binding sites. In this in vitro study, we report the influence of binary mixtures of proteins [albumin (BSA), Fn and collagen type I (Col I)] adsorbed on poly(NaSS) grafted Ti6Al4V on the adhesion and differentiation of MC3T3-E1 osteoblast-like cells and the adhesion and proliferation of Staphylococcus aureus (S. aureus). Outcomes showed that poly(NaSS) stimulated cell spreading, attachment strength, differentiation and mineralization, whatever the nature of protein provided at the interface compared with ungrafted Ti6Al4V (control). While in competition, Fn and Col I were capable of prevailing over BSA. Fn played an important role in the early interactions of the cells with the surface, while Col I was responsible for increased alkaline phosphatase, calcium and phosphate productions associated with differentiation. Poly(NaSS) grafted surfaces decreased the adhesion of S. aureus and the presence of Fn on these chemically altered surfaces increased bacterial resistance ≈70% compared to the ungrafted Ti6Al4V. Overall, our study showed that poly(NaSS) grafted Ti6Al4V selectively adsorbed proteins (particularly Fn) promoting the adhesion and differentiation of osteoblast-like cells while reducing bacterial adhesion to create a bioactive surface with potential for orthopaedic applications.

Psychosocial determinants associated with quality of life in people with usher syndrome. A scoping review.

Background: In Usher syndrome, deafness is congenital and blindness is acquired. Therefore, the progressive loss of one of the two senses forces individuals with this syndrome to reorganize their everyday tasks and relationships, creating new strategies to communicate, access information, and move within a given space. This reorganization can interfere with the subjects' capacity to build a good quality of life.Methods: We conducted a scoping review of both peer-reviewed and gray literature, to identify existing evidence of the role of psychosocial determinants on the quality of life of people with Usher syndrome.Results: Twenty-one references met the inclusion criteria. Findings suggest that people with Usher syndrome seem to adjust their life habits to their condition, maintaining hope for the future, and believe in their capacities to accomplish their goals in spite of the various difficulties they encounter. However, this scoping review highlights a lack of research on adaptive strategies, as well as a lack of knowledge concerning the integration of the syndrome in one's identity, the relations to caregivers, and the specificities of the psychotherapeutic support. More information on these topics would enable better-adjusted social, psychotherapeutic, and medical responses.Implications for rehabilitationUsher syndrome, a rare genetic disease, leads to deafblindness, a cluster of related multiple sensory disabilities. People with Usher encounter several obstacles in their daily life. It is also difficult to adapt to the progressive loss of hearing and sight.This paper proposes a scoping review: we identify the main adaptation strategies used by people with Usher Syndrome in order to become autonomous in spite of these obstacles. In becoming more autonomous, they come to a better quality of life.We summarize the most frequent adaptation strategies (at school, work, leisure, interpersonal relationships, etc.) to help programs aimed at rehabilitation for people with Usher syndrome, and to find unexplored research perspectives (e.g., psychotherapies).

[Congenital aortic valve stenosis with left ventricular dysfunction: effect of percutaneous valvuloplasty]. / Retrecissement valvulaire aortique congenital avec dysfonction ventriculaire gauche: effet de la dilatation percutanée.

Two girls aged 6 and 15 years with severe congenital valvular aortic stenosis and left ventricular (LV) dysfunction underwent successful balloon aortic valvotomy (BAV). Both patients had severe symptoms at the time of initial evaluation. The electrocardiograms showed LV hypertrophy and cardiac enlargement (cardiothoracic ratio 0.7 and 0.65) was evident in the chest roentgenograms. Immediately after BAV, the aortic valve peak-to-peak gradients decreased from 60 to 8 mmHg and 120 to 30 mmHg respectively, the LV end-diastolic pressures decreased from 47 to 13 mmHg and 40 to 15 mmHg, the LV ejection fractions improved from 40 to 65% in the second girl. On follow-up (30 and 36 ms respectively), both patients were asymptomatic with normalization of LV function and without a change in the residual gradient a cross the aortic valve.

Characterization of extended spectrum ß-lactamase-producing Escherichia coli in community-acquired urinary tract infections in Tunisia.

This study was conducted to investigate the molecular epidemiology of extended spectrum ß-lactamase (ESBL)-producing Escherichia coli in community-acquired (urinary tract) infections (CA-UTI) in Tunisia. Between January 2007 and December 2009, 15 E. coli isolates were collected at the laboratory of microbiology of Charles Nicolle Hospital of Tunis. Microbial identification was done with conventional methods. Antibiotic susceptibility was determined by disk diffusion method and ESBL detection was done with double-disk synergy test. ESBL typing was performed by polymerase chain reaction (PCR) and sequencing. Phylogenetic groups, virulence factors, and sequence type (ST)131 were determined by PCR. Genetic relatedness between strains was examined by pulsed-field gel electrophoresis (PFGE) after restriction with XbaI. The prevalence of ESBL-producing E. coli in CA-UTI was 0.046%. The majority of isolates were multidrug resistant. ESBL types were CTX-M-15 (n=13) and SHV-12 (n=2). The most common phylogenetic group was B2 (n=11) and virulence score was greater than or equal to 9 in nine strains. PFGE revealed 12 clusters. The majority of isolates (n=14) belonged to ST131 clone and 11 of them were CTX-M producers. In conclusion, this is the first detailed documentation of CA-ESBLs producing E. coli in Tunisia. Of particular concern is the emergence in our community of the highly diffusing CTX-M-15-B2-ST131 E. coli clone, which requires strengthening surveillance measures to countervail this emergent public health problem.