Ethical considerations in a cancer phase I trial require a design allowing determination of the maximum tolerated dose with a minimum number of patients treated at low ineffectual or high overly toxic doses. It would also be advantageous to complete the phase I trial in as short a period of time and with as few patients as possible to allow further resources for later studies in which patients are treated at the optimal dose. Several dose escalation schemes are compared. These are the Fibonacci, two two-stage schemes, and a proposed scheme which uses knowledge of all toxicity grades. Estimates of the maximum tolerated dose are obtained and compared using the dose escalation schemes alone, a logit model, and a proposed mean response model. Confidence intervals using the delta method are obtained from the logit and mean response models. The proposed scheme and the two-stage schemes have the advantage of requiring fewer patients, particularly at low doses. Confidence intervals obtained from the mean response model have better coverage than those from the logit model. Data from a cancer phase I trial of dipyridamole and acivicin is presented to illustrate the methods. 相似文献
Cholecystokinin (CCK) and bombesin (BBS) are neuropeptides of the brain and gut which have been shown to inhibit intake of ethanol. CCK octapeptide and BBS tetradecapeptide were injected intraperitoneally in both single doses and combinations of doses to determine interactions of the two peptides in the control of consumption of ethanol. Water-deprived rats were given access to 5% w/v ethanol for 30 min, followed by a 30-min access to water, daily. One minute before presentation of ethanol, rats were injected with either saline or one of ten peptide solutions (three of CCK alone, three of BBS alone, and four combinations of both). Results from the injections of single peptides were used to determine predicted inhibitions of the peptide combinations, assuming perfect additivity of doses. None of the actual values of inhibition of intake of ethanol by peptide combinations differed significantly from its predicted additive value. Endogenous CCK-like and BBS-like peptides may suppress intake of ethanol by an additive mechanism of inhibition. 相似文献
BACKGROUND: It has been established that individuals who score high on measures of psychopathy demonstrate difficulty when performing tasks requiring the interpretation of other's emotional states. The aim of this study was to elucidate the relation of emotion and cognition to individual differences on a standard psychopathy personality inventory (PPI) among a nonpsychiatric population. METHODS: Twenty participants completed the PPI. Following survey completion, a mean split of their scores on the emotional-interpersonal factor was performed, and participants were placed into a high or low group. Functional magnetic resonance imaging data were collected while participants performed a recognition task that required attention be given to either the affect or identity of target stimuli. RESULTS: No significant behavioral differences were found. In response to the affect recognition task, significant differences between high- and low-scoring subjects were observed in several subregions of the frontal cortex, as well as the amygdala. No significant differences were found between the groups in response to the identity recognition condition. CONCLUSIONS: Results indicate that participants scoring high on the PPI, although not behaviorally distinct, demonstrate a significantly different pattern of neural activity (as measured by blood oxygen level-dependent contrast)in response to tasks that require affective processing. The results suggest a unique neural signature associated with personality differences in a nonpsychiatric population. 相似文献
BACKGROUND: Vitamin D deficiency is a putative, pathogenic cofactor in the increase in osteopenia and osteoporosis seen in patients with Crohn's disease. OBJECTIVE: To determine the frequency of low serum 25-hydroxy-vitamin D3 (25-OHD) levels and the associated alterations in bone mineral density in a cohort of adults with Crohn's disease. METHODS: 25-OHD levels were determined in 242 consecutive patients with Crohn's disease seen in two tertiary inflammatory bowel disease referral centres. Bone mineral density was assessed by dual energy x-ray absorptiometry. RESULTS: Nineteen (8%) patients exhibited vitamin D deficiency (25-OHD less than 25 nmol/L) and 52 (22%) patients exhibited vitamin D insufficiency (25-OHD less than 40 nmol/L). Mean T-scores at the lumbar spine, femoral neck, total hip and ultradistal radius in the group with low 25-OHD did not differ from those of the normal 25-OHD group. Serum alkaline phosphatase and parathyroid hormone levels were higher in the low 25-OHD group than in the normal group. Decreased red blood cell (RBC) folate predicted low 25-OHD in male patients, while smoking, RBC folate and serum iron predicted low 25-OHD in female patients. The rate of low 25-OHD deficiency in the winter was significantly higher than that in the summer (11.9% versus 2.8%, respectively). CONCLUSION: Vitamin D-deficient Crohn's disease patients exhibit biochemical evidence of metabolic bone disease, without detectable differences in bone mineral density. Sunlight exposure, nutrition and smoking status were predictors of vitamin D deficiency in this patient cohort. 相似文献
OBJECTIVE: To demonstrate that the dimension-weighted DSM-IV model for classifying the depressive disorders lacks utility. METHOD: The logical flaws in classifying the depressive disorders with any severity-based model (which underpin both the DSM-IV and ICD-10 systems) are noted. Integral definitional limitations to the DSM-IV definition of key depressive disorders are identified. It is argued that the DSM-IV classificatory system lacks utility for providing information on etiology and preferential management strategies. An alternative subtyping model is considered. RESULTS: It is asserted that, in practice, the DSM-IV model and criteria lack explanatory power and compromise research and clinical practice. CONCLUSIONS: It is hoped that this article evokes wider debate about modelling and classifying the depressive disorders. 相似文献
Employees from a large midwestern automobile manufacturing plant completed a preemployment evaluation which included a personal and family history, physical examination, and wrist ratio determinations obtained by dividing the anteroposterior diameter by the mediolateral diameter of the wrist. Over a 3-year period, 80 of these employees who developed symptoms compatible with carpal tunnel syndrome within 4-12 months of employment were entered into the study and were evaluated with standard electrodiagnostic techniques. The symptoms included nocturnal hand pain, paresthesia and weak grasp. Thirty-nine of the 80 employees had wrist ratios equal to or greater than 0.70. Twenty-four percent of the employees with wrist ratios less than 0.70 had abnormal electrodiagnostic studies compared with 74% of employees with wrist ratios greater than or equal to 0.70. Regression analysis performed on the data revealed a significant positive correlation between distal median motor latency and wrist ratio (P = 0.001). The study suggests the practical value of wrist ratio determination in job placement. 相似文献
Eales' disease is an uncommon idiopathic disorder characterized by retinal perivasculitis and recurrent vitreous hemorrhages in young males. Associated neurological involvement is rare. We report a 38-year-old man who presented with stroke attributed to Eales' disease. 相似文献
The relative importance of ADP, arachidonic acid metabolites and serotonin as thrombogenic factors was evaluated in rats by comparing, after oral administration, the effects of two inhibitors of ADP-induced platelet aggregation (ticlopidine and PCR 4099), three cyclo-oxygenase inhibitors (aspirin, triflusal and indobufen) and a selective serotonin 5HT2 receptor antagonist (ketanserin) on platelet aggregation, in four platelet-dependent thrombosis models and on bleeding time. Platelet aggregation induced by ADP and collagen was completely inhibited by ticlopidine and PCR 4099 whereas only the collagen aggregation was reduced by the cyclo-oxygenase inhibitors. Ketanserin or a depletion of platelet serotonin by reserpine did not affect platelet aggregation. Ticlopidine and PCR 4099 greatly prolonged rat tail transection bleeding time. This is probably related to their known ability to inhibit ADP-mediated platelet aggregation. In contrast, the cyclooxygenase inhibitors did not affect bleeding time at all. Reserpine and ketanserin prolonged bleeding time by interfering with the action of serotonin on the vascular wall. Ticlopidine and PCR 4099 were very potent antithrombotics in all the models. Aspirin, only at a high dose, inhibited poorly thrombus formation on a silk thread in an arterio-venous shunt, suggesting that the inhibition of cyclo-oxygenase was not responsible. Triflusal was inactive in all models while indobufen slightly reduced thrombus formation in the silk thread and metallic coil models. Ketanserin and reserpine reduced thrombus only in the metallic coil model. Thrombus formation was greatly reduced in fawn-hooded rats, which lack ADP in their platelet dense granules because of a genetic storage pool deficiency.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
1 The reproducibility of angiotensin converting enzyme inhibitor induced cough was examined in a double-blind cross over study in patients previously shown to have exhibited this side effect.
2 Ninety-seven patients who had experienced angiotensin converting enzyme inhibitor cough within the last 2 years were challenged with enalapril 20 mg daily for 4 weeks to establish eligibility. Eighty-eight of 97 (91%) patients experienced a repeat of their cough symptoms. Sixty-four patients entered the double-blind part of the study where they were treated with enalapril 20 mg and a renin inhibitor for up to 4 weeks in random order. These periods were separated by a minimum 4 week placebo wash out.
3 Of 59 evaluable patients who received enalapril a second time, 37 (62.7%) experienced cough again. Of 62 patients on the renin inhibitor 16 (25.8%) experienced cough, however as it was not equi-efficacious to enalapril no valid comparison could be made.
4 Angiotensin converting enzyme inhibitor cough is not reproducible within patients, as other factors are involved in the aetiology. Objective testing with blinded assessment together with symptom reporting, would give a more accurate measure of the incidence, and mechanism of this side effect.