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101.
Apoptosis associated oligonucleosomal fragmentation of DNA can result from the activation of endonucleases that exhibit different pH optima and are either sensitive or insensitive to divalent cations. DNA fragmentation due to activation of cation sensitive endonucleases occurs in the absence of a change in intracellular pH whereas intracellular acidification is a feature of apoptosis characterized by activation of cation insensitive acidic endonuclease. We have reported earlier that somatostatin (SST) induced DNA fragmentation and apoptosis is signaled in a receptor subtype selective manner uniquely via human somatostatin receptor subtype 3 (hSSTR3). In the present study we investigated the pH dependence and cation sensitivity of endonuclease induced in hSSTR3 expressing CHO-K1 cells by the SST agonist octreotide (OCT) and its effect on intracellular pH. We show that OCT induced apoptosis is associated with selective stimulation of a divalent cation insensitive acidic endonuclease. The intracellular pH of of cells undergoing OCT induced apoptosis was 0.9 pH units lower than that of control cells. The effect of OCT on endonuclease and pH was inhibited by orthovanadate as well as by pretreatment with pertussis toxin, suggesting that hSSTR3 initiated cytotoxic signaling is protein tyrosine phosphatase mediated and is G protein dependent. These findings suggest that intracellular acidification and activation of acidic endonuclease mediate wild type p53 associated apoptosis signaled by hormones acting via G protein coupled receptors.  相似文献   
102.
The Galileo spacecraft has been orbiting Jupiter since 7 December 1995, and encounters one of the four galilean satellites-Io, Europa, Ganymede and Callisto-on each orbit. Initial results from the spacecraft's magnetometer have indicated that neither Europa nor Callisto have an appreciable internal magnetic field, in contrast to Ganymede and possibly Io. Here we report perturbations of the external magnetic fields (associated with Jupiter's inner magnetosphere) in the vicinity of both Europa and Callisto. We interpret these perturbations as arising from induced magnetic fields, generated by the moons in response to the periodically varying plasma environment. Electromagnetic induction requires eddy currents to flow within the moons, and our calculations show that the most probable explanation is that there are layers of significant electrical conductivity just beneath the surfaces of both moons. We argue that these conducting layers may best be explained by the presence of salty liquid-water oceans, for which there is already indirect geological evidence in the case of Europa.  相似文献   
103.
104.
PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.  相似文献   
105.
BACKGROUND: The duration of action of muscle relaxants is poorly correlated to the rate of decay of their plasma concentration. The plasma concentration of mivacurium may rapidly decrease below its active concentration because of the extensive hydrolysis of mivacurium. By inflating a tourniquet on one upper limb for 3 min after the administration of atracurium, mivacurium or vecuronium, we studied the influence of the initial decline of their plasma concentration on their effect. METHODS: In 50 patients anaesthetised with thiopental, isoflurane and fentanyl, the effect of bolus doses of 0.15 or 0.25 mg.kg-1 mivacurium (MIV 15, MIV 25), 0.3 or 0.5 mg.kg-1 atracurium (ATR 30, ATR 50) and 0.06 or 0.1 mg.kg-1 vecuronium (VEC 06, VEC 10) were measured on both arms (evoked response of the adductor pollicis to train-of-four stimulation every 12 s), a tourniquet being applied on one arm just before and during 3 min after the muscle relaxant bolus. RESULTS: Tourniquet inflation of 3 min almost abolished the neuromuscular effect of mivacurium. In the vecuronium groups and in the ATR 50 group, tourniquet inflation did not modify the maximum degree of depression of the twitch response. Also, the duration of action of vecuronium was unaffected by the tourniquet. In the ATR 30 group, times to return of the twitch response to 25% (duration 25%) and 75% (duration 75%) of control response were significantly shorter in the cuffed arm, 23 min vs 27 min, and 41 min vs 45 min, respectively. In the ATR 50 group, only duration 25% was significantly shorter in the cuffed arm (41 min vs 45 min). CONCLUSION: The results suggest that the rate of decline of the plasma concentration of mivacurium is so rapid, that a very low and almost clinically ineffective concentration is present as soon as 3 min after its administration. The results also indicate that the recovery from a mivacurium-induced neuromuscular blockade is not influenced by the rate of decay of its plasma concentration in patients with genotypically normal plasma cholinesterase.  相似文献   
106.
Concurrent infection is a risk factor for abdominal wound dehiscence. We reviewed our experience with fascial dehiscence to determine the incidence and to identify prognostic factors for associated intra-abdominal infection. Over a 7-year period, 107 patients with abdominal wound dehiscence were identified. Seventeen were managed nonoperatively, and 90 underwent exploratory laparotomy, 43 of whom had no intra-abdominal pathology and 47 of whom had intra-abdominal infections. Demographic factors, comorbid diseases, and potential indicators of systemic infection did not distinguish patients with intra-abdominal infection from those without. Patients with an intra-abdominal infection were more likely to have undergone an emergency operation (74% vs 48%; P < 0.02), an operation on the colon (55% vs 25%; P < 0.005), or an operation with a higher wound classification (P < 0.02). Mortality was higher in patients with intra-abdominal infection than in those without (44% vs 20%; P < 0.02). Wound dehiscence after emergent operations, and operations with a higher wound classification, especially those involving the colon, should raise concern for intra-abdominal infection. Thorough abdominal exploration should be performed at the time of dehiscence repair. Before nonoperative management is chosen, intra-abdominal infection should be excluded.  相似文献   
107.
Scaling of posturally stabilizing long latency (LL) reflexes in tibialis anterior muscles induced by "toe-up" rotational perturbations is abnormal in standing patients with Parkinson's disease. To investigate the contribution of dopaminergic pathways to abnormal scaling, we studied LL reflexes in 22 patients with selective hypodopaminergic syndromes: 10 psychiatric patients taking chronic neuroleptic medication (7 with mild parkinsonism), 8 patients with young-onset Parkinson's disease, and 4 patients with MPTP-induced parkinsonism. Results were compared with those of 10 healthy controls. Stimuli consisted of (a) 10 serial (predictable) perturbations of 4 degrees amplitude, (b) 10 serial (predictable) perturbations of 10 degrees amplitude, and (c) 20 randomly mixed (unpredictable) perturbations of either 4 or 10 degrees amplitude. In normal subjects, LL reflex amplitudes were adapted to match predictable variations in stimulus size, whereas under unpredictable conditions a "default" response emerged that anticipated the 10 degrees perturbation. LL reflex scaling under predictable conditions was intact in patients with neuroleptic-induced parkinsonism and young-onset Parkinson's disease, but the large default LL response under unpredictable conditions was absent. In patients with MPTP-induced parkinsonism, LL reflex scaling was absent during both predictable and unpredictable conditions. We conclude that abnormal scaling of posturally stabilizing LL reflexes is related to decreased supraspinal dopaminergic influence.  相似文献   
108.
C5a is a 74-amino-acid glycoprotein whose receptor is a member of the rhodopsin superfamily. While antagonists have been generated to many of these receptors, similar efforts directed at family members whose natural ligands are proteins have met with little success. The recent development of hexapeptide analogs of C5a has allowed us to begin elucidation of the molecular events that lead to activation by combining a structure/activity study of the ligand with receptor mutagenesis. Removal of the hexapeptide's C-terminal arginine reduces affinity by 100-fold and eliminates the ability of the ligand to activate the receptor. Both the guanidino side chain and the free carboxyl of the arginine participate in the interaction. The guanidino group makes the energy-yielding contact with the receptor, while the free carboxylate negates "electrostatic" interference with Arg-206 of the receptor. It is the apparent movement Arg-206 induced by this set of interactions that is responsible for activation, since conversion of Arg-206 to alanine eliminates the agonist activity of the hexapeptides. Surprisingly, activation is a nearly energy-neutral event and may reflect the binding process rather than the final resting site of the ligand.  相似文献   
109.
Decades of practice and research suggest that nurse practitioners (NPs) provide cost-effective and high-quality care. Managed care's emphasis on prevention and cost savings led some policy makers to view NPs as a way to meet the need for primary care providers. However, access to and utilization of NPs has increasingly been controlled by managed care organizations (MCOs) through their selection of providers for primary care panels. This study employed qualitative methodology to examine NPs' experiences with MCOs. Three focus groups, comprising 27 NPs in New York and Connecticut, revealed NPs' mixed reactions to managed care and a range of sentiments regarding NPs' efforts to be listed as primary care providers. The results reflected NPs' concerns about their perceived "invisibility," as well as their sense of "invincibility" in the ways in which NPs are responding to the barriers posed by MCOs. They identified barriers to, as well as ways to facilitate, being listed by MCOs, and described the importance of NPs working individually and collectively in negotiating with MCOs.  相似文献   
110.
OBJECTIVE: To document injury rates in professional rugby players in the Rugby Super 12 competition and to act as a pilot study for future studies of rugby injuries. DESIGN: Prospective longitudinal study encompassing the 1997 Super 12 rugby season. SETTING: A New Zealand Super 12 rugby squad. PATIENTS AND PARTICIPANTS: 25 professional rugby players (replacement players were used for unavailable players, so although 30 different players were used during the season, there were only 25 in the squad at any one time). OUTCOME MEASURES: An "injury" was defined as something that prevented a player from taking part in two training sessions, from playing the next week, or something requiring special medical treatment (suturing or special investigations). An injury was "significant" if it prevented the player from being able to play one week after sustaining it (that is, if it made the player miss the next match). RESULTS: The overall injury rate was 120/1000 player hours. The rate of significant injuries was 45/1000 player hours. Those playing the position of "forward" had a higher overall injury rate than other players, but there was no difference in significant injury rate between the forwards and the backs. Injuries that caused players to miss game time occurred almost exclusively during the pre-season program or in the final third of the season. The majority of injuries were musculo-tendinous sprains or strains. The phase of play responsible for the majority of injuries was the tackle. The most frequently injured body part was the head and face. No catastrophic injuries occurred during the study period. CONCLUSIONS: Injury rates increase with increasing grade of rugby, injury rates in the Super 12 competition being higher than in first grade rugby. There is very little quality data on rugby injuries, and the few studies available use different methods of data collection and injury definition. There is a pressing need for the collection of accurate ongoing epidemiological data on injuries in rugby.  相似文献   
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