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11.
NPC 15437 is a prototype member of a new class of synthetically derived protein kinase C (PKC) inhibitors. PKC activity and binding of phorbol ester to the enzyme were inhibited by NPC 15437, with IC50 values of 19 +/- 2 microM and 23 +/- 4 microM, respectively. No inhibition of cAMP-dependent or calcium/calmodulin-dependent protein kinases was observed at concentrations of NPC 15437 up to 300 microM. To investigate the mechanism by which NPC 15437 exerts its effects, a kinetic analysis of the inhibition with respect to three activators of the enzyme, phosphatidylserine, calcium, and phorbol ester, was performed. NPC 15437 was a competitive inhibitor of the activation of PKC by phorbol ester (Ki = 5 +/- 3 microM). Stimulation of PKC alpha by phosphatidylserine was competitively inhibited by NPC 15437 (Ki = 12 +/- 4 microM). The inhibition was mixed with respect to activation by calcium. These results suggest that NPC 15437 is a selective inhibitor of PKC, interacting at the regulatory region of the enzyme. NPC 15437 inhibited PKC in intact cells, dose-dependently antagonizing the phorbol ester-induced phosphorylation of a 47-kDa protein in human platelets. 相似文献
12.
13.
Lesley A Ricci Daniel F Connor Randall Morrison Richard H Melloni 《Neuropsychopharmacology》2007,62(3):218-225
BACKGROUND: Risperidone has been shown to be clinically effective for the treatment of aggressive behavior in children, yet no information is available regarding whether risperidone exhibits aggression-specific suppression in preclinical studies that use validated developmentally immature animal models of escalated aggression. Previously, we have shown that exposure to low doses of the psychostimulant cocaine-hydrochloride (.5 mg/kg intraperitoneally) during the majority of pubertal development (postnatal days [P]27-57) generates animals that exhibit a high level of offensive aggression. This study examined whether risperidone exerts selective aggression-suppressing effects by using this pharmacologic animal model of highly escalated offensive aggression. METHODS: Experimental hamsters were tested for offensive aggression after the acute administration of risperidone (.05-1.0 mg/kg, intraperitoneally). RESULTS: Risperidone dose-dependently reduced the highly aggressive phenotype, with a significant reduction observed at .1-.2 mg/kg for most aggressive responses measured. Experimental animals treated with higher doses of risperidone (.3-1.0 mg/kg) showed significant reductions in aggression and social interest toward intruders, indicating more general behavioral inhibition. CONCLUSIONS: These studies provide evidence that risperidone exerts specific aggression-suppressing effects in a developmentally immature animal model of escalated aggression. 相似文献
14.
Jamieson M. Bourque Eric J. Velazquez Robert H. Tuttle Linda K. Shaw Christopher M. O’Connor Salvador Borges-Neto 《Journal of nuclear cardiology》2007,14(2):165-173
Background Left ventricular ejection fraction (LVEF) is a significant predictor of morbidity and death. The nuclear summed rest score
(SRS) measures myocardial perfusion defects and provides prognostic information, but its effects on long-term outcomes are
not fully established. Moreover, information regarding the potential interaction between these 2 covariates is limited. The
purpose of this study was to determine whether the mortality risk associated with LVEF is the same across all values of SRS
in a population undergoing evaluation for ischemic heart disease.
Methods and Results We examined 3,187 patients who underwent cardiac catheterization and perfusion single photon emission computed tomography
imaging with a maximum follow-up of 8.1 years and median follow-up of 3.1 years. Cox proportional hazards modeling showed
that increasing nuclear SRS and decreasing LVEF were independently associated with a higher long-term mortality rate, with
a clinically significant interaction between them (P=.032). Patients with a normal LVEF and a high SRS (greater perfusion abnormality) have a prognosis similar to those with
a reduced LVEF.
Conclusions Resting perfusion studies provide prognostic information for long-term survival and significantly impact the interpretition
of mortality risk associated with changes in LVEF. Patient prognostication, risk stratification, and future research using
these variables should take this interaction into account.
Supported by a grant from the Tom & Lynn Royster Foundation. Durham, NC, and a National Institutes of Health Research Fellowship
Grant (T5 GM08679-04), Bethesda, Md. 相似文献
15.
Ribavirin disposition in high-risk patients for acquired immunodeficiency syndrome 总被引:13,自引:0,他引:13
O L Laskin J A Longstreth C C Hart D Scavuzzo C M Kalman J D Connor R B Roberts 《Clinical pharmacology and therapeutics》1987,41(5):546-555
Ribavirin is a broad-spectrum antiviral drug that has in vitro activity against human immunodeficiency virus. To determine the kinetics of ribavirin, 17 symptom-free homosexual men with lymphadenopathy were studied. Single doses of ribavirin, 600, 1200, or 2400 mg, were given orally or intravenously. The plasma ribavirin concentration-time profiles were well fitted by a three-compartment open model. Ribavirin followed linear kinetics over the dose range studied. The mean 1-hour postinfusion concentrations after intravenous ribavirin, 600, 1200, and 2400 mg, were 8.0, 19.7, and 37.1 mumol/L, respectively. The mean +/- SD plasma beta-phase half-life, terminal-phase (gamma) half-life, and volume of distribution at steady state were 2.0 +/- 1.1 hours, 35.5 +/- 14.0 hours, and 647 +/- 258 L, respectively. The mean ribavirin renal clearance and total body clearance were 99 +/- 30 and 283 +/- 37 ml/min, respectively. After an oral dose of 600, 1200, and 2400 mg, the mean peak plasma ribavirin concentrations (which occurred 1.5 hours after administration) were 5.1, 9.9, and 12.6 mumol/L, respectively. The mean absorption half-life and bioavailability of ribavirin were 0.5 hour and 45%. Ribavirin had no plasma protein binding and the drug accumulated within red blood cells. In conclusion, ribavirin is incompletely absorbed from the gastrointestinal tract, its renal excretion accounts for approximately one third of the drug's elimination, and drug accumulation (greater than threefold) will result with repetitive dosing at the 6- to 8-hour dosing interval currently used. 相似文献
16.
The results of a survey of children attending an Accident and Emergency (A & E) Department following ingestion of alcohol are reported. Data were analysed to indicate age and sex of children, date and time of attendance, method of transport to hospital, whether accompanied to hospital and if so by whom, and whether admitted or discharged. Trends in children's consumption of alcohol, as observed by the author, are discussed. 相似文献
17.
Immunocytochemical and electrophysiological differentiation of rat cerebellar granule cells in explant cultures 总被引:5,自引:0,他引:5
We have used a combination of immunocytochemical and electrophysiological measurements to monitor the differentiation of cerebellar granule cells in vitro. We present immunocytochemical evidence showing that several characteristic features of developing rat cerebellar tissue were retained in postnatal explant cultures. Most notably the cultures expressed radiating GFAP-positive (Bergmann) glia processes, proliferating NSE-negative neuroblasts, and migrating NSE-positive granule cells. The latter were subdivided into 3 developmental stages--i.e., immature, intermediate, and mature granule cells, based upon cell differences in location from the explant, intensity of NSE staining, excitability, and the amplitude of voltage-dependent conductances. Immature cells were identifiable during the first week in culture and were located up to 140 micron from the explant. These cells stained lightly for NSE and displayed conductances of insufficient magnitude to generate action potentials. Intermediate cells were present after 1-2 weeks in culture and were located up to 500 micron from the explant. These cells were also NSE positive and were characterized by the presence of soma action potentials. Intermediate cells displayed 3 large voltage-dependent conductances: a transient, TTX-sensitive inward current; a delayed, TEA-sensitive outward current; and a transient, 4AP-sensitive outward current. Mature cells were present after 1 month in culture and, like intermediate cells, were no more than 500 micron from the explant. However, mature cells stained more intensely for NSE, and the somata of these cells were devoid of voltage-dependent conductances (although axonal currents were usually present). These results indicate that granule cells undergo a stereotypic sequence of differentiation in postnatal explant cultures. These stages may correspond to developmental changes in granule cells during migration into the (internal) granular cell layer in vivo. 相似文献
18.
Connor RC Smolker RA Richards AF 《Proceedings of the National Academy of Sciences of the United States of America》1992,89(3):987-990
In Shark Bay, Western Australia, male bottlenose dolphins (Tursiops sp.) cooperate in pairs and triplets to sequester and control the movements of females. We refer to this behavior as "herding" and to the male pairs and triplets as alliances. During a 25-month study (1987-1989) on the social relationships of males, we documented herding in 10 alliances. Males preferentially herded nonpregnant females likely to be in estrus. Alliance members associated with one another consistently when not herding females. Each alliance associated preferentially with one or two other alliances. Occasionally, two alliances combined and took females from another alliance or defended females against such efforts. This study documents multiple-level male alliances within a social group outside of humans. 相似文献
19.
20.
Gillingham MB Connor WE Matern D Rinaldo P Burlingame T Meeuws K Harding CO 《Molecular genetics and metabolism》2003,79(2):114-123
Current dietary therapy for long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency consists of fasting avoidance, and limiting long-chain fatty acid (LCFA) intake. This study reports the relationship of dietary intake and metabolic control as measured by plasma acylcarnitine and organic acid profiles in 10 children with LCHAD or TFP deficiency followed for 1 year. Subjects consumed an average of 11% of caloric intake as dietary LCFA, 11% as MCT, 12% as protein, and 66% as carbohydrate. Plasma levels of hydroxypalmitoleic acid, hydroxyoleic, and hydroxylinoleic carnitine esters positively correlated with total LCFA intake and negatively correlated with MCT intake suggesting that as dietary intake of LCFA decreases and MCT intake increases, there is a corresponding decrease in plasma hydroxyacylcarnitines. There was no correlation between plasma acylcarnitines and level of carnitine supplementation. Dietary intake of fat-soluble vitamins E and K was deficient. Dietary intake and plasma levels of essential fatty acids, linoleic and linolenic acid, were deficient. On this dietary regimen, the majority of subjects were healthy with no episodes of metabolic decompensation. Our data suggest that an LCHAD or TFP-deficient patient should adhere to a diet providing age-appropriate protein and limited LCFA intake (10% of total energy) while providing 10-20% of energy as MCT and a daily multi-vitamin and mineral (MVM) supplement that includes all of the fat-soluble vitamins. The diet should be supplemented with vegetable oils as part of the 10% total LCFA intake to provide essential fatty acids. 相似文献