Higher prevalence of GPIIIa PlA2 polymorphism in siblings of patients with premature coronary heart disease

BACKGROUND: The Pl(A2) polymorphism of GPIIIa has been associated with unstable coronary syndromes in some studies, but the association has remained debated. None of the previous studies have focused on families at high risk. Risk factors tend to cluster within kindreds with high prevalence of premature coronary heart disease (CHD). Therefore, a heightened prevalence of the Pl(A2) polymorphism among siblings of patients with CHD would support the hypothesis that Pl(A2) is linked, directly or indirectly, to CHD. OBJECTIVES: To measure the prevalence of the Pl(A2) polymorphism among siblings of patients with CHD before the age of 60 years and to seek an association between the Pl(A2) polymorphism and established atherosclerotic and thrombogenic risk factors. METHODS: From January 1994 to April 1996, we genotyped 116 asymptomatic siblings (60 Caucasians, 56 Afro-Caribbeans) of patients with CHD manifestations before the age of 60 years for the Pl(A) polymorphism (also called HPA-1). A control cohort was used for comparison, consisting of individuals that were matched for race and geographic area but were free of CHD (n = 268, 168 Caucasians and 100 Afro-Caribbeans). In addition, we have characterized the sibling cohort for other atherogenic and thrombogenic risk factors. RESULTS: The prevalence of Pl(A2)-positive individuals (Pl(A2)[+], Pl(A1/A2) heterozygotes plus Pl(A2/A2) homozygotes) in the sibling cohort was high: 41.4%. When analyzed separately, the prevalence of Pl(A2)(+) siblings was 53.3% among Caucasians and 28.6% among Afro-Caribbeans. There was no association between Pl(A2) and other established atherogenic or thrombogenic risk factors. Interestingly, the clustering of other risk factors was lesser among Pl(A2)(+) siblings than their Pl(A1) counterparts. CONCLUSIONS: This study supports the hypothesis that the prevalence of Pl(A2)(+) individuals is high in kindreds with premature CHD. Hence, like the established risk factors that tend to cluster in families with premature CHD and contribute strongly to the accelerated atherosclerotic process affecting these individuals, the Pl(A2) polymorphism of GPIIIa may represent an inherited risk that promotes the thromboembolic complications of CHD. That these asymptomatic Pl(A2)(+) siblings had overall less established risk factors than their Pl(A1) counterparts might represent an explanation for why they remained asymptomatic despite their Pl(A2) positivity.     

A phase II study of biochemotherapy for the treatment of metastatic malignant melanoma

The use of interleukin-2 (IL-2) and interferon-alpha (IFNalpha) in combination with chemotherapy for the treatment of advanced malignant melanoma has generated considerable interest. In particular, the relatively high number of durable complete responses has suggested this may be a significant advance in the treatment of malignant melanoma. We report our experience at the University of Colorado in 43 patients, including many with poor prognostic factors. Patients received cisplatin 20 mg/m2 on days 1-4, vinblastine 1.6 mg/m2 on days 1-4, dacarbazine 800 mg/m2 on day 1, IL-2 9 x 10(6) IU/m2 per day intravenously over 24h on days 1-4 and IFNalpha 5 x 10(6) IU/m2 per day subcutaneously on days 1-5 every 3 weeks. The median follow-up for all patients was 34 months. Responses were seen in 20 patients (47%, 95% confidence interval 31-62%) and comprised five complete responses (CRs) (12%) and 15 partial responses (PRs) (35%). Two patients achieving a CR remain disease free at 45 and 47 months follow-up. In addition three patients who obtained a surgical CR and another with only minor residual changes on computed tomography scan have not progressed at 27, 30, 40 and 27 months, respectively. Toxicity was manageable, but all patients had at least one grade 3 or 4 toxicity, predominantly hypotension and neutropenia. There were no treatment-related deaths. In conclusion, the response rate and duration is within the range previously reported for biochemotherapy. The results of ongoing randomized studies are awaited to better define the value of biochemotherapy in the treatment of advanced melanoma.     

Local hypothermia and optimal temperature for stroke therapy in rats

Background Local hypothermia induced by intravascular infusion of cold saline solution effectively reduces brain damage in stroke. We further determined the optimal temperature of local hypothermia in our study. Methods Seventy-eight adult male Sprague Dawley rats (260-300 g) were randomly divided into 3 groups: group A, ischemia/reperfusion without cold saline infusion (n=-26) (control group); group B, infusion with 20℃ saline before reperfusion (n=26); group C: infusion with 10~C saline before reperfusion (n=26). In each group, we chose 15 rats for monitoring physical indexes and the temperature of the brain (cortex and striatum) and body (anus), measurement of brain infarction volume, assessment of neurological deficits and the survival rate of reperfusion at 48 hours. Another 8 rats from each group was chosen for examining brain edema, another 3 from each group for histological observation by electron microscopy (EM) and light microscopy (LM) at 48 hours after reperfusion. Results There was no significant difference among the 3 groups for physical indexes during the examination (F(2,45)=0.577, P=0.568; F(2, 45)= 0.42, P=0.78 for blood pressure and blood gas analysis, respectively). The brain temperature was significantly reduced in the group C compared to the other groups (F(2, 45)=37.074, P=0.000; F(2, 45)=32.983, P=0.000, for cortex and striatum temperature respectively), while the difference in rectal temperature between group A and B or C after reperfusion was not significant (F(2, 45)= 0.17115, P=0.637). And the brain infarct volume was significantly reduced in group C (from 40%±10% in group A, 26%±8% in group B, to 12%±6% in group C, F<(2,45)=43.465, P=0.000) with the neurological deficits improving in group C (X2=27.626, P=0.000). The survival rate at 48 hours after 10℃ and 20℃ saline reperfusion was increased by 132.5% and 150%, respectively, as compared to the control group (X2=10.489, P=0.005). The extent of the brain edema showed no significant difference (F(2, 21)=0.547, P=0.587) after cold saline infusion compared to the control group. No obvious vascular injury was found by electron or light microscopy in either infusion group.Conclusions Regional hypothermia with 10~C cold saline infusion can significantly decrease the infarction volume, improve the neurological deficits, and 10~C seems to be the optimal temperature in inducing a cerebral protection effect during stroke. This procedure could be adopted as a further treatment for acute stroke patients.     

Effects of single and repeated doses of theophylline on aspects of performance,electrophysiology and subjective assessments in healthy human subjects

The effects of both single and repeated doses of theophylline were evaluated on a battery of nine performance tests, the EEG, the EMG and on subjective assessments of mood and side-effects. The subjects were 20 healthy adults who participated in both phases of this randomized, double-blind, placebo controlled, crossover study. The single dose of 400 mg and the repeated doses of 300 mg b.d. for 4 weeks were intended to attain therapeutic serum concentrations. The Sternberg Additive Factors Method for assessing information processing revealed enhanced performance in both phases of this study, while the Horizontal Addition Test showed improved performance in the single dose phase only. The remaining seven performance tests failed to show significant differences between theophylline and placebo. Single doses of theophylline did not significantly alter mood, but marked adverse effects were encountered in the repeated dose phase, possibly related to unpleasant side-effects. Both EEG and EMG findings indicative of stimulation were associated with a single dose of theophylline, but substantial tolerance developed during 4 weeks of therapy. These findings demonstrate CNS stimulation by both single and repeated doses of theophylline with the occurrence of adverse side-effects during repeated administrations.     

Anticancer role of dendritic cells (DC) in human and experimental cancers--a review.

The bone marrow-derived dendritic cells (DL/LC) are antigen-presenting accessory cells functioning as part of the immune system. In addition, DC/LC in epithelial tissues may have the capacity to be involved in cellular interactions which may have regulatory functions. Such properties can also be noted when LC/DC interact with cancer cells in tumors. The present review summarizes reports which suggest that the outcome of a primary tumor in patients depends on the presence or absence of DC/LC in the tumor. The evidence showing that the presence of DC/LC in primary tumors indicates that a good prognosis may be reached are presented and discussed. Based on these observations and the ability of immunomodulators to enhance the activity of DC/LC and the ability of these cells to enter into tumors, it is suggested that the molecular basis of DC/LC activity against primary tumors cells should be investigated. It is possible that activation of DC/LC, thereby enhancing their ability to enter primary tumors, and the abrogation of the ability of DC/LC-resistant tumors to destroy or prevent DC/LC from entering the tumor, could be developed as an effective anti-cancer approach.