Cadmium-induced oxidative cellular damage in human fetal lung fibroblasts (MRC-5 cells).

Epidemiological evidence suggests that cadmium (Cd) exposure causes pulmonary damage such as emphysema and lung cancer. However, relatively little is known about the mechanisms involved in Cd pulmonary toxicity. In the present study, the effects of Cd exposure on human fetal lung fibroblasts (MRC-5 cells) were evaluated by determination of lipid peroxidation, intra-cellular production of reactive oxygen species (ROS), and changes of mitochondrial membrane potential. A time- and dose-dependent increase of both lactate dehydrogenase leakage and malondialdehyde formation was observed in Cd-treated cells. A close correlation between these two events suggests that lipid peroxidation may be one of the main pathways causing its cytotoxicity. It was also noted that Cd-induced cell injury and lipid peroxidation were inhibited by catalase and superoxide dismutase, two antioxidant enzymes. By using the fluorescent probe 2',7'-dichlorofluorescin diacetate, a significant increase of ROS production in Cd-treated MRC-5 cells was detected. The inhibition of dichlorofluorescein fluorescence by catalase, not superoxide dismutase, suggests that hydrogen peroxide is the main ROS involved. Moreover, the significant dose-dependent changes of mitochondrial membrane potential in Cd-treated MRC-5 cells, demonstrated by increased fluorescence of rhodamine 123 examined using a laser-scanning confocal microscope, also indicate the involvement of mitochondrial damage in Cd cytotoxicity. These findings provide in vitro evidence that Cd causes oxidative cellular damage in human fetal lung fibroblasts, which may be closely associated with the pulmonary toxicity of Cd

Multifrequency Strategies for the Identification of Gamma-Ray Sources

More than half the sources in the Third EGRET (3EG) catalog have no firmly established counterparts at other wavelengths and are unidentified. Some of these unidentified sources have remained a mystery since the first surveys of the gamma-ray sky with the COS-B satellite. The unidentified sources generally have large error circles, and finding counterparts has often been a challenging job. A multiwavelength approach, using X-ray, optical, and radio data, is often needed to understand the nature of these sources. This chapter reviews the technique of identification of EGRET sources using multiwavelength studies of the gamma-ray fields.Comment: 35 pages, 22 figures. Chapter prepared for the book "Cosmic Gamma-ray Sources", edited by K.S. Cheng and G.E. Romero, to be published by Kluwer Academic Press, 2004. For complete article and higher resolution figures, go to: http://www.astro.columbia.edu/~muk/mukherjee_multiwave.pd

A systematic approach to therapeutic target selection in oesophago-gastric cancer

Objective The success of personalised therapy depends on identification and inhibition of the oncogene(s) on which that tumour is dependent. We aimed to determine whether a receptor tyrosine kinase (RTK) array could be used to select the most effective therapeutic strategies in molecularly heterogeneous oesophago-gastric adenocarcinomas. Design Gene expression profiling from oesophago-gastric tumours (n=75) and preinvasive stages (n=57) identified the active signalling pathways, which was confirmed using immunohistochemistry (n=434). RTK arrays on a cell line panel (n=14) determined therapeutic targets for in vitro cytotoxic testing. Feasibility of this personalised approach was tested in tumour samples (n=46). Results MAPK was the most frequently activated pathway (32/75 samples (42.7%)) with progressive enrichment in preinvasive disease stages (p<0.05) and ERK phosphorylation in 148/434 (34.3%) independent samples. Cell lines displayed a range of RTK activation profiles. When no RTKs were activated, tyrosine kinase inhibitors (TKIs) and a Mek inhibitor were not useful (MKN1). In lines with a dominant phosphorylated RTK (OE19, MKN45 and KATOIII), selection of this TKI or Mek in nM concentrations induced cytotoxicity and inhibited Erk and Akt phosphorylation. In cells lines with complex activation profiles (HSC39 and OE33), a combination of TKIs or Mek inhibition (in nM concentrations) was necessary for cytotoxicity and inhibition of Erk and Akt phosphorylation. Human tumours demonstrated diverse activation profiles and 65% of cases had two or more active RTKs. Conclusions The MAPK pathway is commonly activated in oesophago-gastric cancer following activation of a variety of RTKs. Molecular phenotyping can inform a rational choice of targeted therapy

Superconductivity in Cu_xTiSe_2

Charge density waves (CDWs) are periodic modulations of the conduction electron density in solids. They are collective states that arise from intrinsic instabilities often present in low dimensional electronic systems. The layered dichalcogenides are the most well-studied examples, with TiSe_2 one of the first CDW-bearing materials known. The competition between CDW and superconducting collective electronic states at low temperatures has long been held and explored, and yet no chemical system has been previously reported where finely controlled chemical tuning allows this competition to be studied in detail. Here we report how, upon controlled intercalation of TiSe_2 with Cu to yield Cu_xTiSe_2, the CDW transition is continuously suppressed, and a new superconducting state emerges near x = 0.04, with a maximum T_c of 4.15 K found at x = 0.08. Cu_xTiSe_2 thus provides the first opportunity to study the CDW to Superconductivity transition in detail through an easily-controllable chemical parameter, and will provide new insights into the behavior of correlated electron systems.Comment: Accepted to Nature Physic

Multi-component assessment of chronic obstructive pulmonary disease: an evaluation of the ADO and DOSE indices and the global obstructive lung disease categories in international primary care data sets

Acknowledgements We thank Sian Williams of the International Primary Care Respiratory Group for her help and encouragement with the project. The OPCRD database was made available courtesy of the Respiratory Effectiveness Group and RIRL and the data were kindly prepared for analysis by Julie von Ziegenweidt. Funding The International Primary Care Respiratory Group (IPCRG) provided funding for this research project as an UNLOCK group study for which the funding was obtained through an unrestricted grant by Novartis AG, Basel, Switzerland. The latter funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Database access for the OPCRD was provided by the Respiratory Effectiveness Group (REG) and Research in Real Life; the OPCRD statistical analysis was funded by REG. The Bocholtz Study was funded by PICASSO for COPD, an initiative of Boehringer Ingelheim, Pfizer and the Caphri Research Institute, Maastricht University, The Netherlands.Peer reviewedPublisher PD

Children grow and horses race: is the adiposity rebound a critical period for later obesity?

BACKGROUND: The adiposity rebound is the second rise in body mass index that occurs between 3 and 7 years. An early age at adiposity rebound is known to be a risk factor for later obesity. The aim here is to clarify the connection between the age at rebound and the corresponding pattern of body mass index change, in centile terms, so as to better understand its ability to predict later fatness. DISCUSSION: Longitudinal changes in body mass index during adiposity rebound, measured both in original (kg/m(2)) and standard deviation (SD) score units, are studied in five hypothetical subjects. Two aspects of the body mass index curve, the body mass index centile and the rate of body mass index centile crossing, determine a child's age at rebound. A high centile and upward centile crossing are both associated separately with an early rebound, while a low centile and/or downward centile crossing correspond to a late rebound. Early adiposity rebound is a risk factor for later fatness because it identifies children whose body mass index centile is high and/or crossing upwards. Such children are likely to have a raised body mass index later in childhood and adulthood. This is an example of Peto's "horse racing effect". The association of centile crossing with later obesity is statistical not physiological, and it applies at all ages not just at rebound, so adiposity rebound cannot be considered a critical period for future obesity. Body mass index centile crossing is a more direct indicator of the underlying drive to fatness. SUMMARY: An early age at adiposity rebound predicts later fatness because it identifies children whose body mass index centile is high and/or crossing upwards. Such children are likely to have a raised body mass index later. Body mass index centile crossing is more direct than the timing of adiposity rebound for predicting later fatness

A decade of experience with injuries to the gallbladder

Article deposited according to publisher policy posted on SHERPA/RoMEO, 05/08/2010.YesFunding provided by the Open Access Authors Fund

Treatments for irritable bowel syndrome: patients' attitudes and acceptability

<p>Abstract</p> <p>Background</p> <p>Irritable Bowel Syndrome, a highly prevalent chronic disorder, places significant burden on the health service and the individual. Symptomatic distress and reduced quality of life are compounded by few efficacious treatments available. As researchers continue to demonstrate the clinical efficacy of alternative therapies, it would be useful to gain a patient-perspective of treatment acceptability and identify patient's attitudes towards those modalities considered not acceptable.</p> <p>Methods</p> <p>Six hundred and forty-five participants identified from an earlier IBS-prevalence study received a postal questionnaire to evaluate preferences and acceptability of nine forms of treatment. Proportions accepting each form of treatment were calculated and thematic analysis of qualitative data undertaken.</p> <p>Results</p> <p>A total of 256 (39.7%) of 645 potential respondents completed the questionnaire (mean age 55.9 years, 73% female). Tablets were most acceptable (84%), followed by lifestyle changes (diet (82%), yoga (77%)). Acupuncture (59%) and suppositories (57%) were less acceptable.</p> <p>When explaining lack of acceptability, patient views fell into four broad categories: dislike treatment modality, do not perceive benefit, general barriers and insufficient knowledge. Scepticism, lack of scientific rationale and fear of CAM were mentioned, although others expressed a dislike of conventional medical treatments. Past experiences, age and health concerns, and need for proof of efficacy were reported.</p> <p>Conclusion</p> <p>Most patients were willing to accept various forms of treatment. However, the reservations expressed by this patient-population must be recognised with particular focus directed towards allaying fears and misconceptions, seeking further evidence base for certain therapies and incorporating physician support and advice.</p