Mutations of the gene encoding otogelin are a cause of autosomal-recessive nonsyndromic moderate hearing impairment.

Already 40 genes have been identified for autosomal-recessive nonsyndromic hearing impairment (arNSHI); however, many more genes are still to be identified. In a Dutch family segregating arNSHI, homozygosity mapping revealed a 2.4 Mb homozygous region on chromosome 11 in p15.1-15.2, which partially overlapped with the previously described DFNB18 locus. However, no putative pathogenic variants were found in USH1C, the gene mutated in DFNB18 hearing impairment. The homozygous region contained 12 additional annotated genes including OTOG, the gene encoding otogelin, a component of the tectorial membrane. It is thought that otogelin contributes to the stability and strength of this membrane through interaction or stabilization of its constituent fibers. The murine orthologous gene was already known to cause hearing loss when defective. Analysis of OTOG in the Dutch family revealed a homozygous 1 bp deletion, c.5508delC, which leads to a shift in the reading frame and a premature stop codon, p.Ala1838ProfsX31. Further screening of 60 unrelated probands from Spanish arNSHI families detected compound heterozygous OTOG mutations in one family, c.6347C>T (p.Pro2116Leu) and c. 6559C>T (p.Arg2187X). The missense mutation p.Pro2116Leu affects a highly conserved residue in the fourth von Willebrand factor type D domain of otogelin. The subjects with OTOG mutations have a moderate hearing impairment, which can be associated with vestibular dysfunction. The flat to shallow "U" or slightly downsloping shaped audiograms closely resembled audiograms of individuals with recessive mutations in the gene encoding α-tectorin, another component of the tectorial membrane. This distinctive phenotype may represent a clue to orientate the molecular diagnosis.

Novel Pathogenic Variants in the Gene Encoding Stereocilin (STRC) Causing Non-Syndromic Moderate Hearing Loss in Spanish and Argentinean Subjects.

Non-syndromic hearing impairment (NSHI) is a very heterogeneous genetic condition, involving over 130 genes. Mutations in GJB2, encoding connexin-26, are a major cause of NSHI (the DFNB1 type), but few other genes have significant epidemiological contributions. Mutations in the STRC gene result in the DFNB16 type of autosomal recessive NSHI, a common cause of moderate hearing loss. STRC is located in a tandem duplicated region that includes the STRCP1 pseudogene, and so it is prone to rearrangements causing structural variations. Firstly, we screened a cohort of 122 Spanish familial cases of non-DFNB1 NSHI with at least two affected siblings and unaffected parents, and with different degrees of hearing loss (mild to profound). Secondly, we screened a cohort of 64 Spanish sporadic non-DFNB1 cases, and a cohort of 35 Argentinean non-DFNB1 cases, all of them with moderate hearing loss. Amplification of marker D15S784, massively parallel DNA sequencing, multiplex ligation-dependent probe amplification and long-range gene-specific PCR followed by Sanger sequencing were used to search and confirm single-nucleotide variants (SNVs) and deletions involving STRC. Causative variants were found in 13 Spanish familial cases (10.7%), 5 Spanish simplex cases (7.8%) and 2 Argentinean cases (5.7%). In all, 34 deleted alleles and 6 SNVs, 5 of which are novel. All affected subjects had moderate hearing impairment. Our results further support this strong genotype-phenotype correlation and highlight the significant contribution of STRC mutations to moderate NSHI in the Spanish population.

ADAMTS-1 and ADAMTS-4 levels are elevated in thoracic aortic aneurysms and dissections.

BACKGROUND: ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently identified family of extracellular metalloproteinases that has been shown to participate in tissue destruction. We hypothesized that ADAMTS-1 and ADAMTS-4 expression is increased in aortic tissues from patients with thoracic aortic aneurysms and dissections. METHODS: We examined ADAMTS-1 and ADAMTS-4 expression in human descending thoracic aortic aneurysms (n = 14), chronic descending thoracic aortic dissections (n = 16), and descending thoracic aortas from age-matched control organ donors (n = 12). In these tissues, we also evaluated the degradation of versican, a proteoglycan substrate of ADAMTS-1 and ADAMTS-4. In cultured macrophages, we examined whether ADAMTS-4 functions in macrophage infiltration by using a transwell assay. RESULTS: ADAMTS-1 and ADAMTS-4 protein and mRNA expression was significantly higher in thoracic aortic aneurysm and dissection tissues than in control aortic tissues. Double immunofluorescence staining showed the expression of ADAMTS-1 and ADAMTS-4 in smooth muscle cells and macrophages. Consistent with the upregulation of ADAMTS-1 and ADAMTS-4 in thoracic aortic aneurysm and dissection tissues, versican was degraded significantly more in these tissues than in control aortic tissues. In cultured macrophages, transforming growth factor-ß increased ADAMTS-4 protein levels and induced macrophage invasion, and the knockdown of ADAMTS-4 reduced cell invasion. CONCLUSIONS: Increased expression of ADAMTS proteins may promote thoracic aortic aneurysm progression by degrading versican and facilitating macrophage invasion.

Impact of cardiovascular comorbidity on ovarian cancer mortality.

BACKGROUND: A retrospective cohort study utilizing prospectively collected data was conducted from August 2003 until March 2008 at M.D. Anderson Cancer Center. It is unknown whether cardiovascular comorbidity and chronic stress impact ovarian cancer outcome, which remains poor despite advances in therapy. The purpose of this study was to determine whether cardiovascular disease and markers that may be associated with stress are also associated with survival in patients with ovarian cancer. METHODS: Participants with newly diagnosed epithelial ovarian cancer were followed until time of death or truncation of study period (median follow-up = 4.2 years; n = 271). Tumor characteristics (stage, tumor grade, histology, debulking status), demographic variables, and cardiovascular comorbidity were documented and compared to overall survival. RESULTS: Of the nine cardiovascular events tracked during follow-up, venous thromboembolism [VTE; HR, 3.2; 95% confidence interval (CI), 1.8-5.5] and pulmonary hypertension (HR, 8.5; 95% CI, 3.9-18.7) were associated with shorter survival in multivariate analysis. In addition, high tumor grade, suboptimal cytoreduction, and baseline heart rate (HR, 1.02; 95% CI, 1.01-1.04) were related to decreased survival. CONCLUSION: Careful management of certain cardiovascular comorbidities may extend survival in patients with ovarian cancer. Our findings suggest that increased baseline heart rate and the development of VTE and pulmonary hypertension after cancer diagnosis may be significant predictors of survival in women with ovarian cancer. IMPACT: Our study emphasizes the importance of identifying and optimally treating tachycardia, VTE, and pulmonary hypertension in conjunction with cancer therapy.

Axillary artery cannulation in surgery for acute or subacute ascending aortic dissections.

BACKGROUND: Perfusion through the right axillary artery is an alternative to aortic or femoral artery cannulation during surgery for ascending aortic dissections. The results of this strategy, particularly beyond the immediate postoperative period, are not well described. METHODS: Eighty-three patients (median age, 58 years) with acute or subacute ascending aortic dissection underwent surgical repair with right axillary artery perfusion through an interposition Dacron graft. Sixty-five patients (78%) had DeBakey type I dissections. Procedures performed concomitantly with ascending aortic replacement included root replacement (n = 16; 19%), aortic valve repair or replacement (n = 51; 61%), and coronary artery bypass grafting (n = 13; 16%). Hypothermic circulatory arrest with antegrade cerebral perfusion was used in the majority of patients (n = 60; 72%). We retrospectively studied short-term and midterm outcomes, including survival and complications relating to the axillary cannulation. RESULTS: No patient incurred intraoperative axillary artery injuries or had arm ischemia. Fourteen patients (17%) died in the hospital or within 30 days of surgery, and 9 patients (11%) had strokes. Actuarial survival was 73% +/- 5% at 1 year and 64% +/- 6% at 3 years. Forty-six of the 57 surviving patients could be contacted by telephone; they reported few late complications related to the axillary artery cannulation site. These complications included 1 case each of right-arm weakness and right-arm numbness. CONCLUSIONS: Surgical repair of acute aortic dissection with right axillary artery perfusion can be performed safely, with a relatively low risk of stroke and a high probability of midterm survival.

Valve-sparing and valve-replacing techniques for aortic root replacement in patients with Marfan syndrome: analysis of early outcome.

OBJECTIVE: A prospective, international registry study was initiated to provide contemporary comparative data on short-term clinical outcomes after aortic valve-sparing and aortic valve-replacing root operations in patients with Marfan syndrome. The purpose of this initial report is to describe the study design and to compare early outcomes in the first 151 enrolled patients. METHODS: We assessed 30-day outcomes in 151 patients who met strict Ghent diagnostic criteria for Marfan syndrome and underwent aortic root replacement with either valve-replacing (n = 46) or valve-sparing techniques (n = 105) at one of 18 participating centers. In the valve replacement group, a mechanical composite valve graft was used in 39 (85%) patients and a bioprosthetic valve in 7 (15%). In the valve-sparing group, David V procedures were performed in 57 (54%) patients, David I in 38 (36%), David IV in 8 (8%), Florida sleeve in 1 (1%), and Yacoub remodeling in 1 (1%). RESULTS: No in-hospital or 30-day deaths occurred. Despite longer crossclamp and cardiopulmonary bypass times in the valve-sparing group, there were no significant between-group differences in postoperative complications. Thirty-day valve-related complications occurred in 2 (4%) patients undergoing valve replacement and in 3 (3%) undergoing valve-sparing procedures (P = .6). CONCLUSIONS: The analysis of early outcomes revealed that valve-sparing techniques were the most common approach to root replacement in patients with Marfan syndrome in these centers. The complexity of valve-sparing root replacement did not translate into any demonstrable adverse early outcomes. Subsequent analysis will compare the 3-year durability of these two surgical approaches.

Valve-sparing and valve-replacing techniques for aortic root replacement in patients with Marfan syndrome: Analysis of early outcome.

OBJECTIVE: A prospective, international registry study was initiated to provide contemporary comparative data on short-term clinical outcomes after aortic valve-sparing and aortic valve-replacing root operations in patients with Marfan syndrome. The purpose of this initial report is to describe the study design and to compare early outcomes in the first 151 enrolled patients. METHODS: We assessed 30-day outcomes in 151 patients who met strict Ghent diagnostic criteria for Marfan syndrome and underwent aortic root replacement with either valve-replacing (n = 46) or valve-sparing techniques (n = 105) at one of 18 participating centers. In the valve replacement group, a mechanical composite valve graft was used in 39 (85%) patients and a bioprosthetic valve in 7 (15%). In the valve-sparing group, David V procedures were performed in 57 (54%) patients, David I in 38 (36%), David IV in 8 (8%), Florida sleeve in 1 (1%), and Yacoub remodeling in 1 (1%). RESULTS: No in-hospital or 30-day deaths occurred. Despite longer crossclamp and cardiopulmonary bypass times in the valve-sparing group, there were no significant between-group differences in postoperative complications. Thirty-day valve-related complications occurred in 2 (4%) patients undergoing valve replacement and in 3 (3%) undergoing valve-sparing procedures (P = .6). CONCLUSIONS: The analysis of early outcomes revealed that valve-sparing techniques were the most common approach to root replacement in patients with Marfan syndrome in these centers. The complexity of valve-sparing root replacement did not translate into any demonstrable adverse early outcomes. Subsequent analysis will compare the 3-year durability of these two surgical approaches.