A large scale hearing loss screen reveals an extensive unexplored genetic landscape for auditory dysfunction

The developmental and physiological complexity of the auditory system is likely reflected in the underlying set of genes involved in auditory function. In humans, over 150 non-syndromic loci have been identified, and there are more than 400 human genetic syndromes with a hearing loss component. Over 100 non-syndromic hearing loss genes have been identified in mouse and human, but we remain ignorant of the full extent of the genetic landscape involved in auditory dysfunction. As part of the International Mouse Phenotyping Consortium, we undertook a hearing loss screen in a cohort of 3006 mouse knockout strains. In total, we identify 67 candidate hearing loss genes. We detect known hearing loss genes, but the vast majority, 52, of the candidate genes were novel. Our analysis reveals a large and unexplored genetic landscape involved with auditory function

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A Systematic review of radiofrequency ablation for lung tumors

Background: Radiofrequency ablation (RFA) has been increasingly utilized as a non-surgical treatment option for patients with primary and metastatic lung tumors. We performed the present systematic review to assess the safety and efficacy of RFA. Methods: Searches for all relevant studies prior to November 2006 were performed on six databases. Two reviewers independently appraised each study using predetermined criteria. Clinical effectiveness was synthesized through a narrative review, with full tabulation of results of all included studies. Results: A total of 17 of the most recent updates from each institution were included for appraisal and data extraction. All were case series and were classified as level-4 evidence. The mean number of lesions treated ranged from 1 to 2.8, and the mean size ranged from 1.7 cm to 5.2 cm. The overall procedure-related morbidity rate ranged from 15.2% to 55.6% and mortality from 0% to 5.6%. The most commonly reported complication was pneumothorax (4.5-61.1%). Most pneumothoraces were self-limiting and only 3.3-38.9% (median = 11%) required chest drain insertion. The local recurrence of tumors at the site of RFA ranged from 3% to 38.1% (median = 11.2%). The median progression-free interval ranged from 15 months to 26.7 months (median = 21 months), and 1-, 2- and 3-year survival rates were 63-85%, 55-65% and 15-46%, respectively. Conclusions: Only observational studies were available for evaluation, which demonstrated some promising safety profiles of RFA.10 page(s

Radiofrequency ablation of lung tumors : feasibility and safety

Background: Percutaneous image-guided radiofrequency ablation is being promoted as a novel technique with a low morbidity rate in the treatment of inoperable lung tumors. The purpose of this study was to assess the incidence and risk factors of various complications after radiofrequency ablation of pulmonary neoplasms. Methods: The clinical and treatment-related data regarding 129 consecutive percutaneous radiofrequency ablation treatment sessions for 100 patients with inoperable lung tumors were collected prospectively. Univariate and multivariate analyses were conducted to identify significant risk factors associated with postprocedural overall morbidity, pleuritic chest pain, hemoptysis, pneumothorax, pleural effusions, and chest drain requirement. Results: There was no postprocedural mortality. The overall morbidity rate was 43% (n = 55 of 129). The most common adverse effect was pneumothorax, occurring in 32% (n = 41 of 129) of treatment sessions. Other significant complications included pleuritic chest pain (18%, n = 23 of 129), hemoptysis (7%, n = 9 of 129), pleural effusions (12%, n = 15 of 129), and chest drain insertion (20%, n = 26 of 129). Both univariate and multivariate analyses identified more than two lesions ablated per session as a significant risk factor for overall morbidity, pneumothorax, and chest drain insertion, but not for pleuritic pain, hemoptysis, and pleural effusions. Length of the ablation probe trajectory greater than 3 cm was an additional independent risk factor for overall morbidity and pneumothorax. Hilar location of lung tumor/s was the only independent risk factor associated with the increased incidence of hemoptysis. Conclusions: Radiofrequency ablation for lung tumors can be considered as a safe and technically feasible procedure with acceptable incidence of complications.6 page(s

Laparoscopic repair of large hiatal hernia : impact on dyspnoea

Introduction This study aims to examine the impact of laparoscopic repair of large hiatal hernia on dyspnoea severity, respiratory function and quality of life. Methods From 2004 to 2008, 30 consecutive patients with large para-oesophageal hernia defined as >50% of stomach in the intra-thoracic cavity and minimum followup of 2 years were included in this study. All patients had a formal respiratory function test 1 week prior and 3 months after their laparoscopic hiatal hernia repair. Patients rated symptom severity and completed a quality-of-life questionnaire [Gastrointestinal Quality of Life Index (GIQLI)] pre-operatively, and post-operatively at 3 months, 6 months and yearly thereafter. Results There was no hospital mortality, and the morbidity rate was 10%. In 26 patients with pre-operative dyspnoea, 22 had complete resolution while the remaining 4 had improvement of dyspnoea severity post-operatively. The mean dyspnoea severity index reduced from 2.4 to 1.3 (P<0.001). Overall, there was 1%, 3% and 3% postoperative increase in forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) values for the whole group, none of which reached statistical significance. For patients with resolution or improvement of dyspnoea after laparoscopic repair, no significant change of respiratory function parameters was demonstrated. GIQLI score improved from a pre-operative value of 85.7 to 107.9 post-operatively (P<0.001). Conclusions We failed to show a significant change in post-operative respiratory function despite clearly demonstrated improvement of respiratory symptoms. Alternative explanations for reduction of dyspnoea severity should be sought.7 page(s

Emitting species in chemiluminescence reactions with acidic potassium permanganate : a re-evaluation based on new spectroscopic evidence

The reaction of acidic potassium permanganate with a wide range of compounds is known to produce a broad red emission, and there is strong evidence for an excited manganese(II) emitting species. Nevertheless, numerous researchers have proposed other emitters for reactions with acidic potassium permanganate, particularly for systems where fluorescent compounds were present, either as enhancers or reaction products. We have examined many reactions of this type and found that, in most cases, the same red emission was produced. There were, however, some exceptions, including the oxidation of dihydralazine, certain thiols and sulphite (each in the presence of an enhancer).<br /

Discovery of (10<i>R</i>)‑7-Amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-<i>2H</i>‑8,4-(metheno)pyrazolo­[4,3‑<i>h</i>]­[2,5,11]-benzoxa­diaza­cyclo­tetradecine-3-carbonitrile (PF-06463922), a Macrocyclic Inhibitor of Anaplastic Lymphoma Kinase (ALK) and c-ros Oncogene 1 (ROS1) with Preclinical Brain Exposure and Broad-Spectrum Potency against ALK-Resistant Mutations

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of <b>8k</b> (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity