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71.
Effects of insulin on diacylglycerol-protein kinase C signaling in rat diaphragm and soleus muscles and relationship to glucose transport 总被引:2,自引:0,他引:2
Insulin was found to provoke rapid increases in diacylglycerol (DAG) content and [3H]glycerol incorporation into DAG and other lipids during incubations of rat hemidiaphragms and soleus muscles. Insulin also rapidly increased phosphatidic acid and total glycerolipid labeling by [3H]glycerol, suggesting that insulin increases DAG production at least partly through stimulation of the de novo pathway. Increased DAG production may activate protein kinase C (PKC) as reported previously in the rat diaphragm. We also observed apparent insulin-induced translocation of PKC from cytosol to membrane in the rat soleus muscle. The importance of insulin-induced increases in DAG-PKC signaling in the stimulation of glucose transport in rat diaphragm and soleus muscles was suggested by 1) PKC activators phorbol esters and phospholipase C stimulation of [3H]-2-deoxyglucose (DOG) uptake and 2) PKC inhibitors staurosporine and polymixin B inhibition of insulin effects on [3H]-2-DOG uptake. Although phorbol ester was much less effective than insulin in the diaphragm, phospholipase C provoked increases in [3H]-2-DOG uptake that equaled or exceeded those of insulin. In the soleus muscle, phorbol ester, like phospholipase C, was only slightly but not significantly less effective than insulin. Similar variability in effectiveness of phorbol ester has also been noted previously in rat adipocytes (weak) and BC3H1 myocytes (strong), whereas DAG, added exogenously or generated by phospholipase C treatment, stimulates glucose transport to a degree that is quantitatively more comparable to that of insulin in each of the four tissues. Differences in effectiveness of phorbol ester and DAG could not be readily explained by postulating that the latter acts independently of PKC, because DAG provoked the apparent translocation of the enzyme from cytosol to membranes in rat adipocytes, and effects of DAG on [3H]-2-DOG uptake were blocked by inhibitors of PKC in both rat adipocytes and BC3H1 myocytes. Collectively, our findings provide further support for the hypothesis that insulin increases DAG production and PKC activity, and these processes are important in the stimulation of glucose transport in rat skeletal muscle and other tissues. 相似文献
72.
D. J. King M. Blomqvist S. J. Cooper M. M. Doherty M. J. Mitchell R. C. Montgomery 《Psychopharmacology》1992,107(2-3):175-179
Sixty-two DSM III chronic schizophrenic inpatients were selected for a double-blind, placebo controlled, multi-centre, relapse prevention study of remoxipride, a selective dopamine (D2)-receptor antagonist. After a 1 month placebo washout, 23 patients had relapsed and were withdrawn. Of the remaining patients 19 were randomised to remoxipride (150–300 mg daily) and 20 to placebo. Their median age was 58 years, 26 were male, and the median duration of illness was 33 years. After 24 weeks a further total of 8 remoxipride and 17 placebo patients had been withdrawn. Excluding three patients withdrawn for reasons other than relapse, the comparative relapse rates were 37% and 75%, respectively (P=0.015). Efficacy analyses using clinical global impression (P=0.04) and change in BPRS scores (P=0.016) were in favour of remoxipride. Extrapyramidal symptoms were minimal in both groups. Treatment emergent adverse events were similar in the two groups. Remoxipride is therefore of potential value as a safe drug which is both effective and well tolerated in the long term management of chronic schizophrenic patients. 相似文献
73.
James Gordon Maria Felice Ghilardi Scott E. Cooper Claude Ghez 《Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale》1994,99(1):97-111
This study examined the variability in movement end points in a task in which human subjects reached to targets in different locations on a horizontal surface. The primary purpose was to determine whether patterns in the variable errors would reveal the nature and origin of the coordinate system in which the movements were planned. Six subjects moved a hand-held cursor on a digitizing tablet. Target and cursor positions were displayed on a computer screen, and vision of the hand and arm was blocked. The screen cursor was blanked during movement to prevent visual corrections. The paths of the movements were straight and thus directions were largely specified at the onset of movement. The velocity profiles were bell-shaped, and peak velocities and accelerations were scaled to target distance, implying that movement extent was also programmed in advance of the movement. The spatial distributions of movement end points were elliptical in shape. The major axes of these ellipses were systematically oriented in the direction of hand movement with respect to its initial position. This was true for both fast and slow movements, as well as for pointing movements involving rotations of the wrist joint. Using principal components analysis to compute the axes of these ellipses, we found that the eccentricity of the elliptical dispersions was uniformly greater for small than for large movements: variability along the axis of movement, representing extent variability, increased markedly but nonlinearly with distance. Variability perpendicular to the direction of movement, which results from directional errors, was generally smaller than extent variability, but it increased in proportion to the extent of the movement. Therefore, directional variability, in angular terms, was constant and independent of distance. Because the patterns of variability were similar for both slow and fast movements, as well as for movements involving different joints, we conclude that they result largely from errors in the planning process. We also argue that they cannot be simply explained as consequences of the inertial properties of the limb. Rather they provide evidence for an organizing mechanism that moves the limb along a straight path. We further conclude that reaching movements are planned in a hand-centered coordinate system, with direction and extent of hand movement as the planned parameters. Since the factors which influence directional variability are independent of those that influence extent errors, we propose that these two variables can be separately specified by the brain. 相似文献
74.
The types of animal models that are used for assessing lung preservation, and the types of interventions that are likely to prove of value, must be carefully selected. For example, the events of warm ischemia are not necessarily the same as those that occur during cold preservation. Warm ischemia has often been used as a means of accelerating the degree of ischemic injury, but the events may not be qualitatively the same. Nonetheless, the use of different types of lung injury models contributes to our overall understanding of mechanisms of lung injury associated with transplantation. Pathologic studies of lung injury ischemia and reperfusion may not prove helpful, as they may be nonspecific and insensitive. To compare results of different preservation methods, a standardized animal model would be most helpful if a universally accepted one could be identified. This would include standard measurements of lung function, standard techniques of transplantation, and follow-up studies of several days' duration after transplantation. Such a model could serve as the ultimate test of preservation methods following its development in a variety of the animal models. It must be emphasized that whereas animal models generally begin with a normal lung that is preserved, the clinical situation differs because the donor lungs may be far from normal at the outset due to the effects of brain death, hemodynamic instability, infection, trauma, and a host of other factors. Thus, the limits of safe preservation in a clinical situation may well be significantly less than the safe preservation time demonstrated in the laboratory.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
75.
E E Vokes A P Lyss J E Herndon B Cooper M C Perry V Vinciguerra K Mason-Coughlin M R Green 《Annals of oncology》1992,3(9):727-732
This randomized phase II study was designed to evaluate the activity of intravenous 6-thioguanine (6-TG) as a single agent and the combination of cisplatin and 5-fluorouracil (5-Fu) modulated by oral leucovorin (PFL) in patients with advanced non-small cell lung cancer (NSCLC). Eligible patients had measurable or evaluable stage III B or IV NSCLC, had no received prior chemotherapy and had a performance status of 0-2. Patients were randomized to treatment with intravenous 6-TG at 55 mg/m2 administered over 30 minutes for 5 consecutive days and repeated every 35 days, or PFL chemotherapy with cisplatin 100 mg/m2 on day 1, 5-FU 800 mg/m2/day as a continuous intravenous infusion over 5 days and oral leucovorin administered at 100 mg every 4 hours during the entire duration of the cisplatin and 5-FU infusions. PFL was repeated every three weeks. Ninety-five eligible patients were randomized, 46 to 6-TG and 49 to PFL. Response rates were 4% for 6-TG (95% confidence interval 0.5%-14.8%, 1 partial, and 1 complete response) and 29% (16.6%-43.3%) for PFL (all partial). The median time to treatment failure was 2 and 4 months, respectively, and the median survival times were 6 and 10 months, respectively. Toxicities with 6-TG were, generally, mild to moderate but severe or life-threatening granulocytopenia was observed in 21% of patients. With PFL, mucositis was dose-limiting, and 78% of patients had severe or life-threatening mucositis. This led to dose reduction of 5-FU and leucovorin during subsequent cycles or treatment termination in 82% of patients.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
76.
This pilot study compared abdominal massage with laxative treatment in the management of constipation in 32 profoundly disabled, institutionalised adults. A randomised cross-over design was used. After an initial 16-day baseline measurement phase without any treatment, there followed two seven-week treatment phases separated by a one-week washout period. Each subject received seven weeks of massage and seven weeks on his or her previous laxative regimen. Primary outcome measures were gastro-intestinal and segmental transit times, measured at the end of the baseline phase and of each treatment phase. Secondary measures included stool frequency, size and consistency, the requirement for enemas and an assessment of patient well-being.The median value of total colonic transit time was 183 hours for the baseline phase and 159 hours for all treatment phases. There was no evidence of any statistically significant treatment differences between laxative and massage therapy for right, left or rectosigmoid segments either separately or in total. Analysis of secondary outcome measures also failed to find any treatment preferences.These results reveal the grossly abnormal colonic transit times of the study population at all times. The effects of laxative and massage therapy within this environment were not demonstrably different. 相似文献
77.
78.
79.
The in-vitro activity of PD 131628, the active metabolite of the prodrug PD 131112, was compared with that of ciprofloxacin and members of other groups of antimicrobial agents against 701 recent clinical isolates and strains with known mechanisms of resistance. The MIC90s of PD 131628 against the Enterobacteriaceae were between 0.008 and 0.5 mg/L; PD 131628 was one- to four-fold more active than ciprofloxacin against these strains and was four-fold more active than ciprofloxacin against Pseudomonas aeruginosa. Against the Gram-positive species tested, PD 131628 was two- to four-fold more active than ciprofloxacin, inhibiting all strains of Staphylococcus aureus and Streptococcus pneumoniae with 0.5 mg/L or less. PD 131628 was very active against Neisseria spp., Haemophilus influenzae and Moraxella catarrhalis, with MIC90s ranging from 0.004 to 0.008 mg/L. Organisms with decreased susceptibility to other quinolones had decreased susceptibility to PD 131628, but there was no cross-resistance between this class of antimicrobial and other classes. The protein binding of PD 131628 was at most 25% across a broad range of concentrations. The addition of 70% human serum had little effect on the MICs, but caused a two- to eight-fold increase in MBCs. 相似文献
80.
H(1)-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. 总被引:1,自引:0,他引:1
Andrew J Goudie Jason C G Halford Terry M Dovey Gillian D Cooper Joanna C Neill 《Neuropsychopharmacology》2003,28(12):2209; author reply 2210-2209; author reply 2211