Baseline characteristics of participants in the VITamin D and OmegA-3 TriaL (VITAL).

Evidence for a role of supplemental vitamin D and marine omega-3 fatty acids in preventing cancer and cardiovascular disease (CVD) remains inconclusive and insufficient to inform nutritional recommendations for primary prevention. The VITamin D and Omega-A 3 TriaL (VITAL) is an ongoing nationwide, randomized, double-blind, placebo-controlled clinical trial designed to fill this knowledge gap. The study population consists of 25,874 U.S. adults without cancer or CVD at baseline, who were selected only on age (men aged ≥50 and women aged ≥55), with an oversampling of African Americans (n=5,107). In a 2 × 2 factorial design, participants were randomized to one of four supplement groups: [1] active vitamin D3 (cholecalciferol; 2000 IU/d) and active marine omega-3 fatty acids (Omacor® fish oil, eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA], 1g/d); [2] active vitamin D and omega-3 placebo; [3] vitamin D placebo and active marine omega-3 fatty acids; or [4] vitamin D placebo and omega-3 placebo. The mean length of the randomized treatment period will be 5 years. The randomization was successful, as evidenced by similar distributions of baseline demographic, health, and behavioral characteristics across treatment groups. The similar distribution of known potential confounders across treatment groups strongly suggests that unmeasured or unknown potential confounders are also equally distributed. VITAL is expected to provide important information on the benefit-risk balance of vitamin D and omega-3 fatty acid supplementation when taken for the primary prevention of cancer and CVD.

Stereotactic radiosurgery with neoadjuvant embolization of larger arteriovenous malformations: an institutional experience.

OBJECTIVE: This study investigates the safety and efficacy of a multimodality approach combining staged endovascular embolizations with subsequent SRS for the management of larger AVMs. METHODS: Ninety-five patients with larger AVMs were treated with staged endovascular embolization followed by SRS between 1996 and 2011. RESULTS: The median volume of AVM in this series was 28 cm(3) and 47 patients (48%) were Spetzler-Martin grade IV or V. Twenty-seven patients initially presented with hemorrhage. Sixty-one patients underwent multiple embolizations while a single SRS session was performed in 64 patients. The median follow-up after SRS session was 32 months (range 9-136 months). Overall procedural complications occurred in 14 patients. There were 13 minor neurologic complications and 1 major complication (due to embolization) while four patients had posttreatment hemorrhage. Thirty-eight patients (40%) were cured radiographically. The postradiosurgery actuarial rate of obliteration was 45% at 5 years, 56% at 7 years, and 63% at 10 years. In multivariate analysis, larger AVM size, deep venous drainage, and the increasing number of embolization/SRS sessions were negative predictors of obliteration. The number of embolizations correlated positively with the number of stereotactic radiosurgeries (P < 0.005). CONCLUSIONS: Multimodality endovascular and radiosurgical approach is an efficacious treatment strategy for large AVM.

Effect of tobacco smoking on survival of men and women by social position: a 28 year cohort study.

OBJECTIVE: To assess the impact of tobacco smoking on the survival of men and women in different social positions. DESIGN: A cohort observational study. SETTING: Renfrew and Paisley, two towns in west central Scotland. PARTICIPANTS: 8353 women and 7049 men aged 45-64 years recruited in 1972-6 (almost 80% of the population in this age group). The cohort was divided into 24 groups by sex (male, female), smoking status (current, former, or never smokers), and social class (classes I + II, III non-manual, III manual, and IV + V) or deprivation category of place of residence. MAIN OUTCOME MEASURE: Relative mortality (adjusted for age and other risk factors) in the different groups; Kaplan-Meier survival curves and survival rates at 28 years. RESULTS: Of those with complete data, 4387/7988 women and 4891/6967 men died over the 28 years. Compared with women in social classes I + II who had never smoked (the group with lowest mortality), the adjusted relative mortality of smoking groups ranged from 1.7 (95% confidence interval 1.3 to 2.3) to 4.2 (3.3 to 5.5). Former smokers' mortalities were closer to those of never smokers than those of smokers. By social class (highest first), age adjusted survival rates after 28 years were 65%, 57%, 53%, and 56% for female never smokers; 41%, 42%, 33%, and 35% for female current smokers; 53%, 47%, 38%, and 36% for male never smokers; and 24%, 24%, 19%, and 18% for male current smokers. Analysis by deprivation category gave similar results. CONCLUSIONS: Among both women and men, never smokers had much better survival rates than smokers in all social positions. Smoking itself was a greater source of health inequality than social position and nullified women's survival advantage over men. This suggests the scope for reducing health inequalities related to social position in this and similar populations is limited unless many smokers in lower social positions stop smoking.

Differential role of KIR channel and Na(+)/K(+)-pump in the regulation of extracellular K(+) in rat hippocampus.

Little information is available on the specific roles of different cellular mechanisms involved in extracellular K(+) homeostasis during neuronal activity in situ. These studies have been hampered by the lack of an adequate experimental paradigm able to separate K(+)-buffering activity from the superimposed extrusion of K(+) from variably active neurons. We have devised a new protocol that allows for such an analysis. We used paired field- and K(+)-selective microelectrode recordings from CA3 stratum pyramidale during maximal Schaffer collateral stimulation in the presence of excitatory synapse blockade to evoke purely antidromic spikes in CA3. Under these conditions of controlled neuronal firing, we studied the [K(+)]o baseline during 0.05 Hz stimulation, and the accumulation and rate of recovery of extracellular K(+) at higher frequency stimulation (1-3 Hz). In the first set of experiments, we showed that neuronal hyperpolarization by extracellular application of ZD7288 (11 microM), a selective blocker of neuronal I(h) currents, does not affect the dynamics of extracellular K(+). This indicates that the K(+) dynamics evoked by controlled pyramidal cell firing do not depend on neuronal membrane potential, but only on the balance between K(+) extruded by firing neurons and K(+) buffered by neuronal and glial mechanisms. In the second set of experiments, we showed that di-hydro-ouabain (5 microM), a selective blocker of the Na(+)/K(+)-pump, yields an elevation of baseline [K(+)]o and abolishes the K(+) recovery during higher frequency stimulation and its undershoot during the ensuing period. In the third set of experiments, we showed that Ba(2+) (200 microM), a selective blocker of inwardly rectifying K(+) channels (KIR), does not affect the posttetanus rate of recovery of [K(+)]o, nor does it affect the rate of K(+) recovery during high-frequency stimulation. It does, however, cause an elevation of baseline [K(+)]o and an increase in the amplitude of the ensuing undershoot. We show for the first time that it is possible to differentiate the specific roles of Na(+)/K(+)-pump and KIR channels in buffering extracellular K(+). Neuronal and glial Na(+)/K(+)-pumps are involved in setting baseline [K(+)]o levels, determining the rate of its recovery during sustained high-frequency firing, and determining its postactivity undershoot. Conversely, glial KIR channels are involved in the regulation of baseline levels of K(+), and in decreasing the amplitude of the postactivity [K(+)]o undershoot, but do not affect the rate of K(+) clearance during neuronal firing. The results presented provide new insights into the specific physiological role of glial KIR channels in extracellular K(+) homeostasis.