Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development

Systematic review of ototoxic pre-surgical antiseptic preparations – what is the evidence?

Abstract Objective There is uncertainty regarding the safety of surgical antiseptic preparations in the ear. A systematic review of the literature was conducted to assess the evidence regarding ototoxicity of surgical antiseptic preparations. Methods A literature search was conducted using the PRISMA methods. Key words included “ototoxicity” “hearing loss”, “antiseptic”, “surgical preparation”, “tympanoplasty”, “vestibular dysfunction”, “chlorhexidine”, “iodine”, “povidone”, “ethanol”, and “hydrogen peroxide” using Medline, Embase, Cochrane Library, Scopus and Web of Science. We included peer-reviewed papers that 1) objectively measured ototoxicity in humans or animals through hearing, vestibular function or histologic examination, 2) studied topically applied surgical antiseptic preparations, 3) were either in English or had an English abstract. We excluded papers that were 1) in vitro studies, 2) ear trauma studies, 3) studies of ototoxic ear drops intended for therapy, or 4) case reports. Studies included in the final review were screened using the PRISMA method. Current systematic review registration number pending: 83,675. Results Fifty-six papers were identified as using PRISMA criteria. After applying our exclusion criteria, 13 papers met overall study criteria. Of these, six papers reported ototoxicity of iodine based solutions, five papers reported ototoxicity of chlorhexidine and ethanol and two papers assessed hydrogen peroxide. All papers reviewed were animal studies. Iodine based solutions show least harm overall, while chlorhexidine and high concentrations of alcohol based solutions showed most harm. The evidence on hydrogen based solutions was inconclusive. Conclusions The overall evidence for anyone antiseptic solution is weak. There is some evidence that iodine, chlorhexidine, hydrogen peroxide and alcohol based antiseptics have ototoxicity. Conclusive evidence for human ototoxicity from any solution is not strong

Mannitol and the blood-labyrinth barrier

Abstract Background Characterization of the blood labyrinth barrier (BLB) is extremely important to determine whether the BLB can be manipulated pharmacologically. However, experiments to investigate the BLB are technically difficult to perform. In this report, we demonstrated a unique method of controlling the BLB, and established the pharmacokinetics of gentamicin in perilymph, cerebrospinal fluid (CSF) and blood with and without mannitol. Study design Controlled animal research project. Methods Permeability of the BLB and the blood brain barrier (BBB) to gentamicin with and without mannitol was studied by collecting 175 samples from 44 guinea pigs using concentrations relevant to human clinical situations. Samples were taken from two groups of 22 animals, with each animal undergoing sampling at a different time after administration of either 10 mg/ml gentamicin (4 mg/kg) (Gardena, CA) alone or gentamicin with 20% mannitol (250 mg/kg) (Mallinckrodt Inc., KY). The sample times varied from 0.5 to 17.5 h post-infusion. Samples were also taken from 4 animals as negative controls after administration of normal saline. Our goal was to simultaneously assess the pharmacokinetics of gentamicin in each of three different fluid samples in the same animal. Thus at the pre-determined post-infusion sampling time, each animal was sampled once for perilymph, CSF, and blood before being euthanized. Each animal contributed to a single time point on the subsequent pharmacokinetic curves with more than one animal per time point. Results Mannitol increased the rate of entry and egress of gentamicin through BLB significantly (p = 0.0044) but the effects on the BBB did not reach statistical significance (p = 0.581). Mannitol did not alter renal clearance of gentamicin from the blood (p = 0.433). The concentration of gentamicin in perilymph and CSF was always significantly lower than in blood. Conclusions Mannitol administration transiently increases the permeability of the BLB. Potential clinical benefits may accrue from selected timing of administration of osmotic agents such as mannitol augmenting the rate of entry and egress of compounds such as gentamicin into and out of perilymph

Clinical predictors of chronic rhinosinusitis: do the Canadian clinical practice guidelines for acute and chronic rhinosinusitis predict CT-confirmation of disease?

Abstract Background The diagnosis of chronic rhinosinusitis (CRS) based on clinical presentation alone remains challenging. To improve the accuracy of clinical diagnosis, the Canadian Rhinosinusitis Guidelines recommend the use of specific symptom and endoscopic criteria. Our study objective was to determine whether symptom and endoscopic criteria, as defined by the Canadian Rhinosinusitis Guidelines, accurately predict CT-confirmed CRS diagnosis. Methods A retrospective cohort study of 126 patients who underwent CT sinuses based on clinical suspicion of possible CRS. The presence of symptom and endoscopic criteria, as defined by the Canadian Rhinosinusitis Guidelines, were compared between patients with and without a CT-confirmed CRS diagnosis using two-tailed Fisher’s exact tests. Positive predictive values and likelihood ratios were determined for each symptom and endoscopic finding. Results Overall, 56.3% of patients had a CT-confirmed diagnosis of CRS. With the exception of nasal polyps, none of the symptom or endoscopic criteria had a statistically significant correlation with positive CT sinuses. For symptom criteria, positive predictive values ranged from 52.4% to 63.4%; likelihood ratios ranged from 0.85 to 1.34. For endoscopic criteria, positive predictive values and likelihood ratios were 71.4% and 1.94 (edema); 63.0% and 1.32 (discharge); and 92.9% and 10.1 (nasal polyps). 35.2% of patients with CT-confirmed CRS had normal endoscopic exams. Conclusion The Canadian Rhinosinusitis Guidelines’ symptom and endoscopic criteria for CRS, with the exception of nasal polyps on endoscopy, do not accurately predict CT-confirmed disease. In addition, a normal endoscopic exam does not rule out CRS