Common Molecular Etiologies Are Rare in Nonsyndromic Tibetan Chinese Patients with Hearing Impairment

Background: Thirty thousand infants are born every year with congenital hearing impairment in mainland China. Racial and regional factors are important in clinical diagnosis of genetic deafness. However, molecular etiology of hearing impairment in the Tibetan Chinese population living in the Tibetan Plateau has not been investigated. To provide appropriate genetic testing and counseling to Tibetan families, we investigated molecular etiology of nonsyndromic deafness in this population. Methods: A total of 114 unrelated deaf Tibetan children from the Tibet Autonomous Region were enrolled. Five prominent deafness-related genes, GJB2, SLC26A4, GJB6, POU3F4, and mtDNA 12S rRNA, were analyzed. Inner ear development was evaluated by temporal CT. A total of 106 Tibetan hearing normal individuals were included as genetic controls. For radiological comparison, 120 patients, mainly of Han ethnicity, with sensorineural hearing loss were analyzed by temporal CT. Results: None of the Tibetan patients carried diallelic GJB2 or SLC26A4 mutations. Two patients with a history of aminoglycoside usage carried homogeneous mtDNA 12S rRNA A1555G mutation. Two controls were homozygous for 12S rRNA A1555G. There were no mutations in GJB6 or POU3F4. A diagnosis of inner ear malformation was made in 20.18 % of the Tibetan patients and 21.67 % of the Han deaf group. Enlarged vestibular aqueduct, the most common inner ear deformity, was not found in theTibetan patients, but was seen in 18.33 % of the Han patients. Common molecular etiologies

A Noncoding Point Mutation of Zeb1 Causes Multiple Developmental Malformations and Obesity in Twirler Mice

Heterozygous Twirler (Tw) mice develop obesity and circling behavior associated with malformations of the inner ear, whereas homozygous Tw mice have cleft palate and die shortly after birth. Zeb1 is a zinc finger protein that contributes to mesenchymal cell fate by repression of genes whose expression defines epithelial cell identity. This developmental pathway is disrupted in inner ears of Tw/Tw mice. The purpose of our study was to comprehensively characterize the Twirler phenotype and to identify the causative mutation. The Tw/+ inner ear phenotype includes irregularities of the semicircular canals, abnormal utricular otoconia, a shortened cochlear duct, and hearing loss, whereas Tw/Tw ears are severely malformed with barely recognizable anatomy. Tw/+ mice have obesity associated with insulin-resistance and have lymphoid organ hypoplasia. We identified a noncoding nucleotide substitution, c.58+181G>A, in the first intron of the Tw allele of Zeb1 (Zeb1Tw). A knockin mouse model of c.58+181G>A recapitulated the Tw phenotype, whereas a wild-type knockin control did not, confirming the mutation as pathogenic. c.58+181G>A does not affect splicing but disrupts a predicted site for Myb protein binding, which we confirmed in vitro. In comparison, homozygosity for a targeted deletion of exon 1 of mouse Zeb1, Zeb1ΔEx1, is associated with a subtle abnormality of the lateral semicircular canal that is different than those in Tw mice. Expression analyses of E13.5 Twirler and Zeb1ΔEx1 ears confirm that Zeb1ΔEx1 is a null allele, whereas Zeb1Tw RNA is expressed at increased levels in comparison to wild-type Zeb1. We conclude that a noncoding point mutation of Zeb1 acts via a gain-of-function to disrupt regulation of Zeb1Tw expression, epithelial-mesenchymal cell fate or interactions, and structural development of the inner ear in Twirler mice. This is a novel mechanism underlying disorders of hearing or balance

Overactivation of Notch1 Signaling Induces Ectopic Hair Cells in the Mouse Inner Ear in an Age-Dependent Manner

Background: During mouse inner ear development, Notch1 signaling first specifies sensory progenitors, and subsequently controls progenitors to further differentiate into either hair cells (HCs) or supporting cells (SCs). Overactivation of NICD (Notch1 intracellular domain) at early embryonic stages leads to ectopic HC formation. However, it remains unclear whether such an effect can be elicited at later embryonic or postnatal stages, which has important implications in mouse HC regeneration by reactivation of Notch1 signaling. Methodology/Principal Findings: We performed comprehensive in vivo inducible overactivation of NICD at various developmental stages. In CAG CreER+; Rosa26-NICD loxp/+ mice, tamoxifen treatment at embryonic day 10.5 (E10.5) generated ectopic HCs in the non-sensory regions in both utricle and cochlea, whereas ectopic HCs only appeared in the utricle when tamoxifen was given at E13. When tamoxifen was injected at postnatal day 0 (P0) and P1, no ectopic HCs were observed in either utricle or cochlea. Interestingly, Notch1 signaling induced new HCs in a non-cell-autonomous manner, because the new HCs did not express NICD. Adjacent to the new HCs were cells expressing the SC marker Sox10 (either NICD+ or NICDnegative). Conclusions/Significance: Our data demonstrate that the developmental stage determines responsiveness of embryonic otic precursors and neonatal non-sensory epithelial cells to NICD overactivation, and that Notch 1 signaling in the wild type, postnatal inner ear is not sufficient for generating new HCs. Thus, our genetic mouse model is suitable to test additiona

Dynamique de l’érosion sous différentes utilisations du sol au niveau d’un versant en zone méditerranéenne subhumide : influence des cultures, des aménagements de GCES et des couvertures forestières en Algérie

Sur les versants des zones méditerranéennes subhumides du Nord ouest algérien, les diverses formes d’érosion sont très actives : le décapage des terres entraîne une diminution de la productivité tout en entraînant un déséquilibre entre eau-sol- végétation.L’objectif de cette recherche est d’étudier la dynamique de l’érosion, dans cette zone agrosylvo-pastorale, sous différentes utilisations de sol et d’examiner les relations entre les facteurs de cette dynamique et l’impact des aménagements, en particulier les actions de GCES par les paysans. Pour atteindre ces objectifs, on a étudié un transect au niveau d’un versant de 4 km de long. Le long de ce transect, on rencontre plusieurs utilisations et aménagements sur un même type de sol. L’approche est basée sur la comparaison de certains critères morphologiques et des indicateurs analytiques tels que pierrosité, infiltrabilité (mesurée au simulation de pluies), matière organique, épaisseur du sol (évacuation et accumulation des matériaux).Les résultats montrent qu’à l'échelle du versant, la dynamique est sous l’influence de la pente et surtout de l’utilisation du sol. A la variation d’occupation des sols (formations arbustives, buissonnantes et des zones cultivées, arboriculture et céréales associées aux aménagements de GCES) correspond une variation de la dynamique érosive, que l’on peut suivre grâce aux indicateurs. En forte pente et sous couvert végétal faible, les sols sont érodés par la pluie et ceci est bien démontré par la charge caillouteuse et le décapage de l’horizon A. Par contre, Les sols très couverts sont mieux conservés malgré la présence de fortes pentes. Cette stabilité trouve son explication dans la densité du couvert végétal (reboisement dense et formation buissonnante) la litière et la richesse en matières organiques du sol, qui rendent la structure du sol plus stable et qui facilite l’infiltration des pluies. Les aménagements (murets de 1 à 2 m) réalisés sur les zones cultivées par les riverains apparaissent comme une solution ingénieuse. Ils permettent de cultiver des surfaces très pentues tout en limitant au minimum les risques d'érosion. Ces techniques, parallèle aux courbes de niveau, ont bien montré leur efficacité dans la réduction de l’érosion et le piégeage des sédiments. L’application de la gestion durable de l’eau et des sols (GCES) dans certaines exploitations en amont du versant (Intensification, cultures en étages avec arboriculture (cerisier) très valorisante et très économique, fumier, emploi de techniques antiérosives) a bien montré son efficacité dans la conservation du sol et dans l’amélioration des revenus.The study of erosion manifestations along a landscape transect with the same red soils showed the importance of slope, land use and stone walls on the contour line. The topsoil fertility & depth are in relation with the vegetation cover and the erosion intensity. The application of intensive agricultural techniques (land husbandry, manure, crops under fruit trees plantations) had a great effect on erosion reduction and the net income improvement

Direct diagnosis of Pasteurella multocida meningitis using next-generation sequencing

International audienc

Electrochemotherapy : an easy, highly effective and safe treatment of cutaneous and subcutaneous metastases: Results of ESOPE (European Standard Operating Procedures for Electrochemotherapy) study.

International audiencePurpose: To evaluate and confirm efficacy and safety of electrochemotherapy with bleomycin or cisplatin on cutaneous and subcutaneous tumour nodules of patients with malignant melanoma and other malignancies in a multicenter study. Patients and Methods: This was a two year long prospective non-randomized study on 41 patients evaluable for response to treatment and 61 evaluable for toxicity. Four cancer centers enrolled patients with progressive cutaneous and subcutaneous metastases of any histologically proven cancer. The skin lesions were treated by electrochemotherapy, using application of electric pulses to the tumours for increased bleomycin or cisplatin delivery into tumour cells. The treatment was performed using intravenous or intratumoural drug injection, followed by application of electric pulses generated by a Cliniporator using plate or needle electrodes. Tumour response to electrochemotherapy as well as possible side effects with respect to the treatment approach, tumour histology and location of the tumour nodules and electrode type were evaluated. Results: An objective response rate of 85% (73.7% complete response rate) was achieved on the electrochemotherapy treated tumour nodules, regardless of tumour histology, and drug used or route of its administration. At 150 days after the treatment (median follow up was 133 days and range 60-380 days) local tumour control rate for electrochemotherapy was 88% with bleomycin given intravenously, 73% with bleomycin given intratumourally and 75% with cisplatin given intratumourally, demonstrating that all three approaches were similarly effective in local tumour treatment. Furthermore, electrochemotherapy was equally effective regardless of the tumour type and size of the nodules treated. Side effects of electrochemotherapy were minor and acceptable, as reported by the patients. Conclusion: We demonstrated that electrochemotherapy is an easy, highly effective, safe and cost-effective approach for the treatment of cutaneous and subcutaneous tumour nodules of different malignancies. Electrochemotherapy can provide immediate clinical benefit in patients with advanced cutaneous and subcutaneous metastases