PLA2 promotes fusion between PMN-specific granules and complex liposomes

Neutrophil stimulation results in the activation of a variety of phospholipases, including phospholipase A2 (PLA2), which releases arachidonic acid from the 2 position of membrane phospholipids, leaving a lysophospholipid. Because arachidonic acid is known to be a potent fusogen in vitro, we examined the effect of metabolism by PLA2 on the fusion of complex liposomes (liposomes prepared with a phospholipid composition similar to that found in neutrophil plasma membrane). We observed that PLA2 augmented the fusion of complex liposomes with each other as well as with specific granules isolated from human neutrophils, lowering the Ca2+ requirement for fusion by three orders of magnitude. Furthermore, although lysophospholipids inhibited fusion, the incorporation of arachidonic acid into liposome membranes overcame the inhibitory effects of the lysophospholipids. Thus with PLA2 and annexins we were able to obtain fusion of complex liposomes at concentrations of Ca2+ that are close to physiological. Our data suggest that the activation of PLA2 and the generation of arachidonic acid may be the major fusion-promoting event mediating neutrophil degranulation.     

Well differentiated cerebellar tissue within a mature cystic teratoma

OBJECTIVE: Oesophageal self-expanding metal endoprostheses (SEMS, or stents) are recognized as a safe means of palliating dysphagia caused by malignancy. Stent designs that have covered or uncovered walls are now available. The purpose of this study was to compare the outcome of use of these two designs. DESIGN: Thirty consecutive cases were reviewed. All the patients had been referred over a period of 25 months for palliation of dysphagia caused by malignant obstruction. Either a covered or an uncovered stent was placed in each patient. Palliation of dysphagia, 30 day mortality, mean survival time, and the number of endoscopic re-interventions required, were assessed. RESULTS: Uncovered Ultraflex stents were used in 14 patients, and Schneider Wallstents were used in 16 patients. Dysphagia improved by one grade or more in 69% of patients. The 30 day mortality was 27%, with an overall mean survival time of 99 days. There was no significant difference between the two groups for these three parameters. Ten patients needed a total of 28 repeat endoscopic procedures to maintain stent patency, with overall rates for each group of 1.64 procedures per patient, for uncovered stents, compared with 0.31 for covered stents (significant at the P < 0.05 level). The number of repeat procedures increased with survival time. CONCLUSION: The use of covered self-expanding metal oesophageal endoprostheses is associated with a significant reduction in the need for endoscopic reintervention after stent placement.     

Synthesis of isomeric 3-piperidinyl and 3-pyrrolidinyl benzo[5,6]cyclohepta[1,2-b]pyridines: sulfonamido derivatives as inhibitors of Ras prenylation

Blocking farnesylation of oncogenic Ras proteins is a mechanism based therapeutic approach that is of current interest for the development of antitumor agents to treat ras associated tumors. As part of a SAR study on the lead farnesyl protein transferase (FPT) inhibitor I, we report here the synthesis of novel geometric isomers II and III and the FPT inhibition activity of their N-acyl and N-sulfonamido derivatives 15-65. The N-acyl derivatives are markedly less active than the lead inhibitor I thereby demonstrating that the spatial location of the N-acyl group in I is critical for binding of the compound to FPT. In contrast to I, the N-sulfonamido-II series is a novel lead of non-sulfhydryl, nonpeptidic compounds that are dual FPT/GGPT inhibitors. In light of recent reports on the alternative prenylation of N- and K-Ras, dual FPT/GGPT inhibitors may be required to control cell proliferation in tumors containing activated Ras.     

An universal model of health and work output: theoretical structure and testing strategy

The model proposed in this paper presents a broad range of factors to predict individual human work output. The predictors include aerobic capacity, body size, motivation, work pattern, social environment and social network, caloric intake, drug and alcohol use, stress resistance and thermoregulation. Health is a major intervening variable, and its relationship to work output is a special concern of this research. We suggest that this model may be used as a template to explain human productivity in most societies. Its universality can be subjected to rigorous testing in a range of settings from tropical upland swidden horticulturalists to urban workers in a northern industrialized country. Observations are offered on some of those testing sites and on methodological issues implicit in research of this breadth. A major pilot study of urban Chinese workers has already demonstrated the predictive power of the model in one setting.