Abstract
Respiratory virus infection is a major cause of exacerbation of cystic fibrosis (CF) lung disease and CF patients suffer more severe consequences of virus infection. Our goals are to understand the impact of respiratory viruses on the pathogenesis of CF lung disease. To study the effects of virus infection on the human CF ciliated airway epithelium we used an in vitro model of human ciliated airway epithelium (HAE) and respiratory syncytial virus (RSV) as a virus that commonly infects CF patients. Using non-CF HAE, we show that RSV infects only ciliated cells and causes an acute increase in airway surface liquid height (ASL) height as measured by Texas red-dextran staining of ASL followed by confocal microscopy. This effect was maximum at ~3 days post-inoculation (pi) in non-CF HAE (ctrl,7.71?0.5;RSV,14.8?0.9?m, n=4). Parallel experiments with CF HAE revealed that RSV infection of ciliated cells failed to induce an increase in ASL (CF-ctrl,5.9?0.1;CF-RSV,5.9?0.1?m; n=4). These data suggest that non-CF HAE, but not CF HAE, respond to RSV infection by stimulation of fluid secretion into the airway lumen and is likely mediated by epithelial cell ion transport mechanisms. To determine whether the increase in ASL height after RSV was due to active Cl- secretion, we used bumetanide (100?M) which significantly inhibited RSV-induced ASL height (ctrl,7.3?0.6; RSV,14.4?1.3; RSV+bumetanide,9?0.6; ctrl+bumetanide,5.6?0.1?m; n=4). To determine the specific contribution of CFTR-mediated Cl- secretion to this response we used CFTR172 that also significantly inhibited RSV-induced ASL height (ctrl,6.6?0.3;RSV,11.4?1;RSV+CFTR172, 8 ?0.3; ctrl+CFTR172, 6.8?0.5?m; n=4). Since adenosine triphosphate (ATP) and adenosine (ADO) have been previously shown to regulate Cl- secretion and ASL height in non-CF HAE, we determined the ASL concentration of ATP and ADO 3 days after RSV infection in non-CF HAE and found that both were increased by RSV infection (ATP, ctrl,16?5; RSV,26?3nM; ADO, ctrl,151?25; RSV,245?15nM, n=3) suggesting that the increased ASL after RSV infection was due to the release of nucleotides known to regulate ion transport in airway epithelium. We conclude that RSV infection results in a CFTR-dependent increase in ASL height which is mediated by increased nucleotide levels in the ASL and that this cell response to infection is defective in CF airway epithelial cells. We speculate that increased fluid secretion is a host defense mechanism that attempts to clear virus from the airways and this clearance is diminished in CF airways possibly resulting in prolonged RSV infection of the CF airways.

Abstract
The ?F508 mutation stops the maturation of the CFTR protein and causes its early degradation by the ubiquitin/proteasome system. Small molecules called correctors may rescue ?F508-CFTR from the endoplasmic reticulum and enhance its targeting to the plasma membrane. However, the efficacy of most correctors identified so far is low when they are tested in native airway epithelial cells. We have performed a screening of a small molecule library using a fluorescence-based assay on CFBE41 o- bronchial epithelial cells. A small set of molecules, including corr-194 and corr-207, was found to enhance the activity of ?F508-CFTR after 24 hours of incubation. Such putative correctors were compared to known correctors previously identified, particularly corr-4a (Pedemonte et al., J. Clin. Invest. 115: 2564-2571, 2005), and to low temperature treatment (27 ?C). In CFBE41 o- cells, responsiveness of ?F508 to rescue treatments follows the order: low temperature > corr-194 > corr-207 > corr-4a. Interestingly, we found that some combination of correctors caused a synergic effect. In particular, correction by low temperature was enhanced by corr-4a and by corr-207 but not by corr-194. At the protein level, we found that most treatments increased the intensity of the immature form, band B, of CFTR protein. In particular, corr-194 was the most effective, by causing a > 10-fold increase in band B with a relatively small effect on the mature form, band C. Our results suggest that the various ?F508 correctors act on different targets, probably associated with different steps of the quality control process in the endoplasmic reticulum. Identification of such targets and rational design of correcting maneuvers may help to maximize ?F508 rescue.

Abstract
The analysis of genome wide variation is potentially a powerful tool for identifying markers for complex disease and drug response. For such studies to deliver on their promise it is imperative to ensure optimum study design and robust analysis. The paper will discuss the challenges in the design, analysis, interpretation and clinical utility of large-scale genetics studies aimed at identifying genes involved in the etiology of complex disease and drug response.

Abstract
It is estimated that there are more than 2000 named dermatological diseases. The pattern of dermatological diseases is different from one place to another being influenced by many factors like the environment, and the social and economic status. It has been also estimated that 300 of the dermatological diseases are caused by genetic disorders. Some of them are common and some are rare. The definition of rare in diseases is different. A disease is considered rare in United States, when it occurs in less than 200,000 individuals, while In Europe, a disease is considered as rare when it affects 1 person per 2,000. However a rare disease in a given area might be fairly common in the other areas. Due to large family size and consanguinity, genodermatoses are more common in developing countries. Due to less public health education, there are some myths and misconceptions that surround the genodermatoses, and hence perpetuate the sufferings of affected patients. In this paper, few examples of uncommon genodermatoses like Kinder syndrome, hereditary hypotrichosis simplex, and multiple hereditary trichoepithelioms (MHT) will be presented, together with a proposed strategy to fight this major public health problem. P