Power of concordant versus discordant sib pairs at different penetrance levels

Knowing the answers, we used the GAW11 data set to compare the power and efficiency of discordant versus concordant affected sib pairs for qualitative traits at different levels of penetrance. Samples of 200 concordant sib pairs outperformed discordant sib pairs for low penetrance (40%) and 70% penetrance models while at 90% penetrance they performed equally well. Increasing the sample size of discordant sib pairs to twice that of concordant pairs was not enough to reach the power of concordant sib pairs at the 40% and 70% penetrance models. For low penetrance using a combination of concordant and discordant sib pairs resulted in higher power than using discordant sib pairs alone. At 90% penetrance, the power of concordant and discordant sib pairs was similar in the region close to the gene while concordant sib pairs performed better at locations further from the gene.     

Small-molecule inhibitors of Bcl-2 family proteins as therapeutic agents in cancer

This review focuses on the recent patents and use of small-molecule inhibitors (SMIs) of Bcl-2 family proteins as therapeutic agents against cancer. Bcl-2 members are crucial regulators of apoptotic cell death. Apoptosis is an evolutionarily conserved process of programmed cell death that plays an essential role in organism development and tissue homeostasis. Several mechanisms exist allowing cells to escape programmed cell death among them is the overexpression of the antiapoptotic proteins. Cancer cells are often found to overexpress many of these members such as Bcl-2, Bcl-X(L), Mcl-1, Bcl-w and A1/Bfl1 and are usually resistant to a wide range of anti-cancer drugs and treatments. Many groups have been working to develop anti-cancer drugs that block the function of anti-apoptotic Bcl-2 members, thus favoring cell death. Methods include the downregulation of Bcl-2 expression or the use of peptides or small organic molecules to the Bcl-2 binding pocket, preventing its sequestration of proapoptotic proteins such as Bid and Bim. One of the most promising aspects of SMIs in treating cancer is that their targets and mechanisms of action are different from those of cytotoxic drugs and radiation. This makes it feasible to combine SMIs with other treatments, creating a synergistic therapy, without likely development of cross-resistance or increased toxicity. A broad-spectrum or "pan" SMI which targets multiple Bcl-2 family proteins is the goal.     

Arsenic-induced cell proliferation is associated with enhanced ROS generation, Erk signaling and CyclinA expression

Arsenic is a well-established human carcinogen; however molecular mechanisms to arsenic-induced carcinogenesis are complex and elusive. The present study identifies a potential biomarker of arsenic exposure, and redefines arsenic-induced signaling in stimulation of cell proliferation. The effect of arsenic exposure on gene expression was evaluated in PBMC of arsenic-exposed individuals selected from a severely affected district of West Bengal, India. A novel, un-documented biomarker of arsenic exposure, CyclinA was identified by microarray analysis from the study. Non-transformed cell lines HaCat and Int407 when exposed to clinically achievable arsenic concentration showed significant increase of CyclinA substantiating the clinical data. An associated increase in S phase population of cells in cell cycle, indicative of enhanced proliferation was also noticed. On further investigation of the pathway to arsenic-induced proliferation, we observed that arsenic resulted: ROS generation; activated Erk signaling; stimulated AP-1 activity, including immediate early genes, c-Jun and c-Fos. N-Acetyl-l-cysteine, a ROS quencher, blocked the arsenic-induced effects. Our study underlines a previously undefined mechanism by which arsenic imparts its toxicity and results in uncontrolled cell proliferation.     

12. Chromosomal aberrations and sister chromatid exchanges in the symptomatic individuals exposed to arsenic through drinking water in West Bengal, India

In the seven districts of West Bengal, India arsenic in ground water has been found to be above the permissible limit. The concentrations of arsenic is ranging from 200-800 (g/l according to latest reports. More than 200,000 people have already shown different types of arsenical skin lesions in these seven districts of West Bengal. It has been regarded as the biggest arsenic calamity in the world. However, there is     

Does applying the Canadian Cervical Spine rule reduce cervical spine radiography rates in alert patients with blunt trauma to the neck? A retrospective analysis

Background  

A cautious outlook towards neck injuries has been the norm to avoid missing cervical spine injuries. Consequently there has been an increased use of cervical spine radiography. The Canadian Cervical Spine rule was proposed to reduce unnecessary use of cervical spine radiography in alert and stable patients. Our aim was to see whether applying the Canadian Cervical Spine rule reduced the need for cervical spine radiography without missing significant cervical spine injuries.     

Effects of thiourea on pulmonary vascular permeability and on lung and plasma histamine levels in rats

The intraperitoneal administration of thiourea (TU) to mature male rats results in a significant increase in lung vascular permeability to Evans Blue dye (EBD). On the other hand, young, sexually immature rats are resistant to this effect. The increase in lung vascular permeability in response to TU in mature rats is associated with corresponding increases in lung and plasma histamine levels. The correlation of increases in lung and plasma histamine in response to TU is similar to that reported for ammonium salts which produce similar pulmonary edema.     

Dose-related effects of enzyme-generated oxidants on the biochemistry and morphology of the hamster lung

Reactive oxygen species (ROS) have been closely associated with a number of pathological disorders, including interstitial pulmonary fibrosis. While models of ROS-induced fibrosis offer advantages over chemically-induced fibrosis, the biochemical and morphological features of ROS-induced fibrosis have yet to be extensively documented. In this study, we evaluated the effect of initial ROS dose on lung injury and repair. Male hamsters received a single dose of glucose, glucose oxidase and lactoperoxidase via the intratracheal route. From 3 to 14 days post-treatment, a significant dose-related body weight loss was observed. There was a trend towards greater mortality with increasing dose. After 2 weeks, we noted significant, dose-related increases in lung levels of collagen, lipid peroxidation products, nucleic acids, and protein. Similarly, total lung catalase, lactic dehydrogenase and glutathione reductase activities were also elevated significantly above control values in a dose-related fashion. A concurrent, dose-dependent thickening of alveolar septa in ROS-treated lungs was composed of epithelial hyperplasia, hyperemia, edema and accumulations of interstitial fibers and macrophages. Interstitial and alveolar macrophages in ROS-induced lesions were enlarged and contained numerous primary and secondary lysosomes. These results demonstrate that, in the hamster lung, injury induced by enzyme-generated ROS can initiate dose-dependent fibroproliferative changes which eventuate into interstitial fibrosis.