Inhibition of drug-induced Fas ligand transcription and apoptosis by Bcl-XL.

Fas/Fas ligand system triggers apoptosis in many cell types. Bcl-XL overexpresion antagonizes Fas/Fas ligand-mediated cell death. The mechanism by which Bcl-XL influences Fas-mediated cell death is unclear. We have found that microtubule-damaging drugs (e.g. Paclitaxel) induce apoptosis in a Fas/FasL-dependent manner. Inhibition of Fas/FasL pathway by anti-FasL antibody, mutant Fas or a dominant negative FADD blocks paclitaxel-induced apoptosis. Paclitaxel induced apoptosis through activation of both caspase-8 and caspase-3. Overexpression of Bcl-XL leads to inhibition of paclitaxel-induced FasL expression and apoptosis. Bcl-XL prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes) by inhibiting the activation of calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT for it to move to the nucleus. The loop domain in Bcl-XL can suppress the anti-apoptotic function of Bcl-XL and may be a target for regulatory post-translational modifications. Upon phosphorylation, Bcl-XL loses its ability to bind with calcineurin. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, paclitaxel and other drugs that disturb microtubule function kill cells, at least in part, through the induction of FasL, and Bcl-XL-mediated resistance to these agents is related to failure to induce FasL expression.

Phosphatidylinositol 3,4,5-trisphosphate directs association of Src homology 2-containing signaling proteins with gelsolin.

Podosomes are adhesion structures in osteoclasts and are structurally related to focal adhesions mediating cell motility during bone resorption. Here we show that gelsolin coprecipitates some of the focal adhesion-associated proteins such as c-Src, phosphoinositide 3-kinase (PI3K), p130(Cas), focal adhesion kinase, integrin alpha(v)beta(3), vinculin, talin, and paxillin. These proteins were inducibly tyrosine-phosphorylated in response to integrin activation by osteopontin. Previous studies have defined unique biochemical properties of gelsolin related to phosphatidylinositol 3,4,5-trisphosphate in osteoclast podosomes, and here we demonstrate phosphatidylinositol 3,4,5-trisphosphate/gelsolin function in mediating organization of the podosome signaling complex. Overlay and GST pull-down assays demonstrated strong phosphatidylinositol 3,4,5-trisphosphate-PI3K interactions based on the Src homology 2 domains of PI3K. Furthermore, lipid extraction of lysates from activated osteoclasts eliminated interaction between gelsolin, c-Src, PI3K, and focal adhesion kinase despite equal amounts of gelsolin in both the lipid-extracted and unextracted experiment. The cytoplasmic protein tyrosine phosphatase (PTP)-proline-glutamic acid-serine-threonine amino acid sequences (PEST) was also found to be associated with gelsolin in osteoclast podosomes and with stimulation of alpha(v)beta(3)-regulated phosphorylation of PTP-PEST. We conclude that gelsolin plays a key role in recruitment of signaling proteins to the plasma membrane through phospholipid-protein interactions and by regulation of their phosphorylation status through its association with PTP-PEST. Because both gelsolin deficiency and PI3K inhibition impair bone resorption, we conclude that phosphatidylinositol 3,4,5-trisphosphate-based protein interactions are critical for osteoclast function.

Incidence and risk of work-related fracture injuries: experience of a state-managed workers' compensation system.

Incidence rates of occupational fractures at various anatomic sites and associated risk factors have not been well documented. We identified 3490 work-related fractures from a West Virginia Workers Compensation database that occurred between July 1, 1994, and June 30, 1995. The annual incidence rate was 55 per 10,000 workers, which is substantially higher than the work-related fracture rates reported previously. The incidence rate of fracture was highest in the agricultural sector, followed by the mining, construction, and manufacturing sectors (202.0, 165.2, 116.7, and 88.0 per 10,000 workers, respectively). The age-specific gender distribution comparing fracture and non-fracture injuries showed a bimodal distribution, with greater proportions of female employees at the younger and older age groups. Fracture of the phalanges was the most common, followed by fractures of the foot bone and carpal bone (15.8, 9.5, and 7.9 per 10,000 workers, respectively). In a multiple logistic regression analysis, age, gender, occupation, caught in-between objects, fall, struck by or against object, and vehicle collision were significant independent predictors of fracture (all sites combined). We believe work-related fractures to be a bigger problem than previously reported. The association among gender, age, occupation, and causes of fractures identified in this study will be useful in developing gender- and occupation-specific prevention intervention.

Epidemiology of work-related burn injuries: experience of a state-managed workers' compensation system.

BACKGROUND: Population-based incidence rates of work-related burn injuries and associated risk factors specific to anatomic sites and degree of burn are not known. METHODS: Using a state-managed workers' compensation database, we estimated incidence rates of work-related burn injuries and identified high-risk occupations and associated exposures. RESULTS: The annual incidence rate of occupational burn was 26.4 per 10,000 workers, with the highest rate observed in the manufacturing sector for males and in the service sector for females. Welders, cooks, laborers, food service workers, and mechanics had higher incidence rates of burn injury compared with other occupations. Wrist and hand burns accounted for a majority of burn injuries, with females experiencing greater incidence of these distal upper extremity burns (8.9 in females and 6.7 in males per 10,000 workers, respectively). Third-degree burns (incidence rate, 1.3 per 10,000 workers) were also most frequently observed in the upper extremities compared with other anatomic sites. The majority of wrist and hand burns were caused by hot liquids/ objects, whereas the majority of eye burns were associated with chemical exposures. Younger cooks and food service workers were at greater risk of burn than older coworkers. CONCLUSION: Specific occupations are associated with degree of burn, anatomic site, and exposures. This information will be useful for targeted intervention among high-risk occupations and work groups.

Patterns of prescriptions and drug use in two tertiary hospitals in Delhi.

The study was carried out to assess prescribing trends in outpatients at Dr. R.P. Centre for Ophthalmic Sciences (RPC) and other OPD's of All India Institute of Medical Sciences (AIIMS) and Safdarjung hospitals, two premier hospitals in Delhi. Prescriptions of 500 patients were audited and analysed under heads of average number of drugs per patient, percentages of drugs prescribed by generic name, antibiotics, injections, drugs from WHO recommended essential drug list, availability of drugs etc. using WHO basic drug indicators. Prescription analysis showed that 75 to 95% drugs were prescribed from essential drug list. The average number of drugs per prescription was 1.42 to 4.07. Percentage of antibiotics prescribed varied from 14.39% to 22.28%. The use of injections was from nil to 4.4%. Availability of drugs was however, not satisfactory. Though maximum drugs were prescribed from essential drug list, the results indicate that there is a considerable scope for improving prescribing habits according to rational drug use and to provide a feed back to hospital authority for making maximum number of drugs available to the patients.