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Vitamin K-dependent protein C is an important regulator of blood coagulation. After its activation on the endothelial cell surface by thrombin bound to thrombomodulin, it cleaves and inactivates procoagulant cofactors Va and VIIIa, protein S and intact factor V working as cofactors. Until recently, genetic defects of protein C or protein S were, together with antithrombin III deficiency, the established major causes of familial venous thromboembolism, but they were found in fewer than 5-10% of patients with thrombosis. In 1993, inherited resistance to activated protein C (APC) was described as a major risk factor for venous thrombosis. It is found in up to 60% of patients with venous thrombosis. In more than 90% of cases, the molecular background for the APC resistance is a single point mutation in the factor V gene, which predicts substitution of an arginine (R) at position 506 by a glutamine (Q). Mutated factor V (FV:Q506) is activated by thrombin or factor Xa in normal way, but impaired inactivation of mutated factor Va by APC results in life-long hypercoagulability. The prevalence of the FV:Q506 allele in the general population of Western countries varies between 2 and 15%, whereas it is not found in several other populations with different ethnic backgrounds. Owing to the high prevalence of FV:Q506 in Western populations, it occasionally occurs in patients with deficiency of protein S, protein C, or antithrombin III. Individuals with combined defects suffer more severely from thrombosis, and often at a younger age, than those with single defects, suggesting severe thrombophilia to be a multigenetic disease. [ABSTRACT FROM AUTHOR]

Objective This study examines whether neighbourhood deprivation increases the risk of hospitalization for childhood asthma, after accounting for individual-level maternal socio-demographic characteristics. Design An open cohort of all singleton children aged 2-11 years was followed between January 1, 1995 and December 31, 2006. Childhood residential addresses were geocoded and classified according to the level of neighbourhood deprivation. Data were analysed by multilevel logistic regression, with individual-level characteristics (sex, age, maternal marital status, family income, maternal educational attainment, maternal immigration status, maternal urban/rural status, mobility, maternal asthma history and maternal smoking) at the first level and level of neighbourhood deprivation at the second level. Results During the study period, among a total of 866 860 children, 17 682 (2.0%) were hospitalized with childhood asthma. Age-adjusted hospital rates for childhood asthma increased with increasing level of neighbourhood deprivation. In the study population, 1.9% and 2.3% of children in the least and most deprived neighbourhoods, respectively, were affected by childhood asthma. Hospital rates of childhood asthma increased with increasing neighbourhood-level deprivation across all individual-level maternal socio-demographic categories, including marital status, educational attainment, urban/rural status, maternal history of asthma and smoking. The odds ratio ( OR) for those living in high-deprivation neighbourhoods vs. those living in low-deprivation neighbourhoods was 1.23 (95% confidence interval, 1.16-1.30). High neighbourhood deprivation remained significantly associated with childhood asthma risk after adjustment for maternal socio-demographic characteristics ( OR=1.08, p = 0.016). Conclusions This study is the largest so far on neighbourhood influences on childhood asthma. Our results suggest that neighbourhood characteristics affect the risk of hospitalization for childhood asthma independent of maternal socio-demographic characteristics. [ABSTRACT FROM AUTHOR]

BACKGROUND: Spousal caregivers of cancer patients suffer psychological and physical burdens that may affect their risk of subsequently developing coronary heart disease and stroke. METHODS AND RESULTS: Cancer patients were identified in the Swedish Cancer Registry, and information on their spouses was retrieved from the Swedish Multi-Generation Register. Follow-up of caregivers was performed from the date of the first diagnosis of cancer in their spouses through 2008. Standardized incidence ratios were calculated for spousal caregivers of cancer patients compared with those without an affected spouse. After the cancer diagnosis in wives, the risks of coronary heart disease, ischemic stroke, and hemorrhagic stroke in husbands were 1.13 (95% confidence interval [CI], 1.10-1.16), 1.24 (95% CI, 1.21-1.27), and 1.25 (95% CI, 1.18-1.32), respectively. The corresponding risks in wives with an affected husband were 1.13 (95% CI, 1.10-1.16), 1.29 (95% CI, 1.26-1.32), and 1.27 (95% CI, 1.19-1.34). The increases were consistent over time and were more pronounced if the spouse was affected by a cancer with a high mortality rate, such as pancreatic and lung cancers. CONCLUSIONS: Spousal caregivers of cancer patients have increased risks of coronary heart disease and stroke that persist over time. Clinical attention should be paid to spousal caregivers, especially those caring for cancer patients with high mortality rates. [ABSTRACT FROM AUTHOR]

Background- This nationwide study sought to determine age- and gender-specific familial risks in siblings hospitalized for venous thromboembolism (VTE). Methods and Results- The Swedish Multigeneration Register on 0- to 75-year-old subjects was linked to the Hospital Discharge Register for the years 1987-2007. Standardized incidence ratios were calculated for individuals whose siblings were hospitalized for VTE compared with those whose siblings were not affected. Among a total of 45 362 hospitalized cases with VTE, 2393 affected siblings were identified, with a familial standardized incidence ratio of 2.45 (95% confidence interval [CI], 1.66 to 3.61). Gender-specific differences in incidence rates were observed. The familial risks were significantly increased from the age of 10 to 69 years, with a familial standardized incidence ratio of 4.77 (95% CI, 1.96 to 10.83) at ages 10 to 19 years, which decreased to 2.08 (95% CI, 1.35 to 3.20) at ages 60 to 69 years, although the absolute risk increased with age. The familial standardized incidence ratios for siblings with 2 and >=3 affected probands were 51.87 (95% CI, 31.47 to 85.00) and 53.69 (95% CI, 25.59 to 108.50), respectively. Spouses had low familial risks (standardized incidence ratio=1.07; 95% CI, 1.04 to 1.10; observed spouse cases=3900). Conclusions- Familial factors, although influenced by age and gender, are important risk factors for VTE. The present study shows that VTE is aggregated in families and suggests that uncovering the sources of familial aggregation (genetic and nongenetic) may be worthwhile. Moreover, in a small fraction of siblings, the familial risk was very high, suggesting segregation of rare but strong genetic risk factors. [ABSTRACT FROM AUTHOR]

Objective: Based on a potential role for serotonin receptors in fibromyalgia, we investigated the efficacy and tolerability of treatment with tropisetron, a highly selective, competitive inhibitor of the 5-HT3 receptor. Methods: In this prospective, multicenter, double-blind, parallel-group, dose-finding study, 418 patients suffering from primary fibromyalgia (ACR criteria) were randomly assigned to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily, respectively. The duration of treatment was 10 days. The clinical response was measured by changes in pain-score, visual analog scale (VAS), and the number of painful tender-points. Results: Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) when compared with placebo (26.2%) (p=0.033). The absolute reduction in pain-score was -13.5% for 5 mg tropisetron, -13.0% for 10 mg tropisetron, and -6.3% for placebo (p<0.05). The effects of 15 mg tropisetron were similar to placebo, thus suggesting a bell-shaped dose-response curve. Compared with placebo, treatment with 5 mg tropisetron led to a significant improvement (p<0.05) in VAS, while a clear trend in terms of clinical benefit was seen with 10 mg tropisetron. The number of painful tender-points was also reduced significantly (p=0.002) in the 5 mg tropisetron group. Of interest, during the 12-month follow-up period, pain intensity of responders on 5 mg and 10 mg tropisetron was still markedly below baseline. The treatment was well tolerated, with gastro-intestinal complaints being the most frequently reported side effects, in keeping with the known safety profile for 5-HT3 receptor antagonists. Conclusions: This study demonstrates the efficacy of short-term treatment with 5 mg tropisetron once daily in primary fibromyalgia. Treatment was well tolerated and prolonged clinical benefits were seen. [ABSTRACT FROM AUTHOR]

Objective: Based on a potential role for serotonin receptors in fibromyalgia, we investigated the efficacy and tolerability of treatment with tropisetron, a highly selective, competitive inhibitor of the 5-HT3 receptor. Methods: In this prospective, multicenter, double-blind, parallel-group, dose-finding study, 418 patients suffering from primary fibromyalgia (ACR criteria) were randomly assigned to receive either placebo, 5 mg, 10 mg or 15 mg tropisetron once daily, respectively. The duration of treatment was 10 days. The clinical response was measured by changes in pain-score, visual analog scale (VAS), and the number of painful tender-points. Results: Treatment with 5 mg tropisetron resulted in a significantly higher response rate (39.2%) when compared with placebo (26.2%) (p =0.033). The absolute reduction in pain-score was -13.5% for 5 mg tropisetron, -13.0% for 10 mg tropisetron, and -6.3% for placebo (p <0.05). The effects of 15 mg tropisetron were similar to placebo, thus suggesting a bell-shaped dose-response curve. Compared with placebo, treatment with 5 mg tropisetron led to a significant improvement (p <0.05) in VAS, while a clear trend in terms of clinical benefit was seen with 10 mg tropisetron. The number of painful tender-points was also reduced significantly (p =0.002) in the 5 mg tropisetron group. Of interest, during the 12-month follow-up period, pain intensity of responders on 5 mg and 10 mg tropisetron was still markedly below baseline. The treatment was well tolerated, with gastro-intestinal complaints being the most frequently reported side effects, in keeping with the known safety profile for 5-HT3 receptor antagonists. Conclusions: This study demonstrates the efficacy of short-term treatment with 5 mg tropisetron once daily in primary fibromyalgia. Treatment was well tolerated and prolonged clinical benefits were seen. [ABSTRACT FROM AUTHOR]

Background: Protein S is an important regulatory protein of the coagulation cascade. The risk for venous thrombosis associated with protein S deficiency has been uncertain because all previous risk estimates used phenotypic evaluation alone, which can be ambiguous.Objective: To quantitate the risk for thrombosis associated with a characterized protein S gene mutation that causes a Gly295-->Val substitution and protein S deficiency.Design: Retrospective study of a single extended family.Setting: University hospital referral center.Participants: A 122-member protein S-deficient family, in which 44 members had a recently characterized gene defect.Measurements: Comprehensive history of thrombosis, history of exposure to acquired risk factors for thrombosis, levels of total and free protein S antigen, and genotype for the mutation causing the Gly295-->Val substitution.Results: Kaplan-Meier analysis of thrombosis-free survival showed that the probability of remaining free of thrombosis at 30 years of age is 0.5 (95% CI, 0.33 to 0.66) for carriers of the Gly295-->Val mutation compared with 0.97 (CI, 0.93 to 1.0) for normal family members (P < 0.001). In a multivariate Cox regression model that included smoking and obesity, the mutation was a strong independent risk factor for thrombosis (hazard ratio, 11.5 [CI, 4.33 to 30.6]; P < 0.001). For free (but not total) protein S antigen levels, the distributions of persons with and persons without the mutation did not overlap.Conclusions: Protein S deficiency, as defined by the presence of a causative gene mutation or a reduced level of free protein S antigen, is a strong independent risk factor for venous thrombosis in a clinical affected family. [ABSTRACT FROM AUTHOR]