Sensorineural hearing loss and ischemic injury: Development of animal models to assess vascular and oxidative effects.

Hearing loss may be genetic, associated with aging or exposure to noise or ototoxic substances. Its aetiology can be attributed to vascular injury, trauma, tumours, infections or autoimmune response. All these factors could be related to alterations in cochlear microcirculation resulting in hypoxia, which in turn may damage cochlear hair cells and neurons, leading to deafness. Hypoxia could underlie the aetiology of deafness, but very few data about it are presently available. The aim of this work is to develop animal models of hypoxia and ischemia suitable for study of cochlear vascular damage, characterizing them by electrophysiology and gene/protein expression analyses. The effects of hypoxia in infarction were mimicked in rat by partial permanent occlusion of the left coronary artery, and those of ischemia in thrombosis by complete temporary carotid occlusion. In our models both hypoxia and ischemia caused a small but significant hearing loss, localized at the cochlear apex. A slight induction of the coagulation cascade and of oxidative stress pathways was detected as cell survival mechanism, and cell damages were found on the cuticular plate of outer hair cells only after carotid ischemia. Based on these data, the two developed models appear suitable for in vivo studies of cochlear vascular damage.

Karyotype-phenotype correlation in partial trisomies of the short arm of chromosome 6: a family case report and review of the literature.

The first child (proband) of nonconsanguineous Caucasian parents underwent genetic investigation because she was affected with congenital choanal atresia, heart defects and kidney hyposplasia with mild transient renal insufficiency. The direct DNA sequencing after PCR of the CHD7 gene, which is thought to be responsible for approximately 60-70% of the cases of CHARGE syndrome/association, found no mutations. The cytogenetic analysis (standard GTG banding karyotype) revealed the presence of extrachromosomal material on 10q. The chromosome analysis was completed with array CGH (30 kb resolution), MLPA and FISH, which allowed the identification of three 6p regions (6p.25.3p23 × 3): 2 of these regions are normally located on chromosome 6, and the third region is translocated to the long arm of chromosome 10. The same chromosomal rearrangement was subsequently found in the father, who was affected with congenital ptosis and progressive hearing loss, and in the proband's sister, the second child, who presented at birth with choanal atresia and congenital heart defects. The mutated karyotypes, which were directly inherited, are thought to be responsible for a variable phenotype, including craniofacial dysmorphisms, choanal atresia, congenital ptosis, sensorineural hearing loss, heart defects, developmental delay, and renal dysfunction. Nevertheless, to achieve a complete audiological assessment of the father, he underwent further investigation that revealed an increased level of the coagulation factor XIII (300% increased activity), fluctuating levels of fibrin D-dimer degradation products (from 296 to 1,587 ng/ml) and a homoplasmic mitochondrial DNA mutation: T961G in the MTRNR1 (12S rRNA) gene. He was made a candidate for cochlear implantation. Preoperative high-resolution computed tomography and magnetic resonance imaging of the temporal bone revealed the presence of an Arnold-Chiari malformation type I. To the best of our knowledge, this study is the second report on partial 6p trisomy that involves the 10q terminal region. Furthermore, we report the first case of documented Arnold-Chiari malformation type I and increased factor XIII activity associated with 6p trisomy. We present a comprehensive report of the familial cases and an exhaustive literature review.

Hair phenotype in non-syndromic deafness.

The GJB2 gene is located on chromosome 13q12 and it encodes the connexin 26, a transmembrane protein involved in cell-cell attachment of almost all tissues. GJB2 mutations cause autosomal recessive (DFNB1) and sometimes dominant (DFNA3) non-syndromic sensorineural hearing loss. Moreover, it has been demonstrated that connexins are involved in regulation of growth and differentiation of epidermal tissues. Hence, mutations in GJB2 gene, which is responsible for non-syndromic deafness, may be associated with an abnormal skin and hair phenotype. We analyzed hair samples from 96 subjects: a study group of 42 patients with hearing impairments of genetic origin (38 with a non-syndromic form, 4 with a syndromic form), and a control group including 54 people, i.e. 43 patients with other, non-genetic hearing impairments and 11 healthy volunteers aged up to 10 years old. The surface structure of 49 hair samples was normal, whereas in 45 cases it was altered, with a damaged appearance. Two hair samples were considered unclassifiable: one from the patient heterozygotic for the pendrin mutation (Fig. 2C), the other from a patient from Ghana with a R134W mutation (Fig. 2D). Among the 43 altered hair samples, 31 belonged to patients with connexin mutations and the other 12 came from patients without connexin mutations.