Lifestyle risk factors predict disability and death in healthy aging adults

BackgroundAssociations between modifiable health risk factors during middle age with disability and mortality in later life are critical to maximizing longevity while preserving function. Positive health effects of maintenance of normal weight, routine exercise, and nonsmoking are known for the short and intermediate term. We studied the effects of these risk factors into advanced age.MethodsA cohort of 2327 college alumnae aged 60 years or more was followed annually (1986-2005) by questionnaires addressing health risk factors, history, and Health Assessment Questionnaire disability. Mortality data were ascertained from the National Death Index. Low-, medium-, and high-risk groups were created on the basis of the number (0, 1, ≥2) of health risk factors (overweight, smoking, inactivity) at baseline. Disability and mortality for each group were estimated from unadjusted data and regression analyses. Multivariable survival analyses estimated time to disability or death.ResultsThe medium- and high-risk groups had higher disability than the low-risk group throughout the study (P < .001). Low-risk subjects had onset of moderate disability delayed 8.3 years compared with high-risk subjects. Mortality rates were higher in the high-risk group (384 vs 247 per 10,000 person-years). Multivariable survival analyses showed the number of risk factors to be associated with cumulative disability and increased mortality.ConclusionSeniors with fewer behavioral risk factors during middle age have lower disability and improved survival. These data document that the associations of lifestyle risk factors on health continue into the ninth decade.     

Population activity in the human dorsal pathway predicts the accuracy of visual motion detection

A person's ability to detect a weak visual target stimulus varies from one viewing to the next. We tested whether the trial-to-trial fluctuations of neural population activity in the human brain are related to the fluctuations of behavioral performance in a "yes-no" visual motion-detection task. We recorded neural population activity with whole head magnetoencephalography (MEG) while subjects searched for a weak coherent motion signal embedded in spatiotemporal noise. We found that, during motion viewing, MEG activity in the 12- to 24-Hz ("beta") frequency range is higher, on average, before correct behavioral choices than before errors and that it predicts correct choices on a trial-by-trial basis. This performance-predictive activity is not evident in the prestimulus baseline and builds up slowly after stimulus onset. Source reconstruction revealed that the performance-predictive activity is expressed in the posterior parietal and dorsolateral prefrontal cortices and, less strongly, in the visual motion-sensitive area MT+. The 12- to 24-Hz activity in these key stages of the human dorsal visual pathway is correlated with behavioral choice in both target-present and target-absent conditions. Importantly, in the absence of the target, 12- to 24-Hz activity tends to be higher before "no" choices ("correct rejects") than before "yes" choices ("false alarms"). It thus predicts the accuracy, and not the content, of subjects' upcoming perceptual reports. We conclude that beta band activity in the human dorsal visual pathway indexes, and potentially controls, the efficiency of neural computations underlying simple perceptual decisions.     

Reconstruction of the bicuspid aortic valve

Reconstruction of a regurgitant bicuspid aortic valve is a new alternative to aortic valve replacement. With concomitant aortic root dilatation adequate reconstruction is feasible by valve-sparing aortic replacement. Between 10/95 and 02/00, 30 patients underwent reconstruction of a regurgitant bicuspid aortic valve. Additional aortic replacement was performed in 23 cases. Valve reconstruction was performed by plication of the prolapsing leaflet. No patient died peri- or postoperatively. Freedom from aortic valve regurgitation > or = II as well as freedom from reoperation were 100% after 48 months. Reconstruction of a regurgitant bicuspid aortic valve is feasible with encouraging mid-term results. With concomitant dilatation of the ascending aorta, a combination of aortic replacement and valve reconstruction can achieve stable results even in bicuspid valve anatomy.     

Human (HLA-A and HLA-B) and murine (H-2K and H-2D) histocompatibility antigens are cell surface receptors for Semliki Forest virus.

The proteins coded for by the HLA-A and HLA-B loci in man and the H-2K and H-2D loci in mice were identified as cell surface receptors for Semliki Forest virus. This conclusion is based on the following observations: (i) Water-soluble octamers of viral coat proteins inhibit the complement-dependent cytotoxicity of antibodies directed against H-2K and H-2D antigens in mouse cells. (ii) Isolated detergent-soluble HLA-A and HLA-B antigens reconstituted in lipid vesicles inhibit the binding of viral proteins to human cells (as do the water-soluble antigens to a lesser extent). (iii) Reconstituted HLA-A and HLA-B vesicles interact in solution with Semliki Forest virus (or with vesicles containing viral spike proteins), as demonstrated by coprecipitation with antisera. (iv) Complexes between viral spoke proteins and HLA-A and HLA-B antigens or H-2K and H-2D antigens can be isolated from the cell surface by utilizing affinity chromatography or immunoprecipitation.     

Hematologic and immunomodulatory effects of an interleukin-1 receptor antagonist coinfusion during low-dose endotoxemia in healthy humans

Endotoxin is a component of gram-negative bacteria that causes hematologic and immunologic changes through its induction of cytokines. Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of IL-1 that competes with IL-1 for occupancy of cell-surface receptors but possesses no agonist activity. We investigated the ability of human recombinant IL-1Ra to block the effects of low-dose endotoxin. Fourteen healthy male volunteers between 18 and 30 years old were injected intravenously with 3 ng/kg Escherichia coli endotoxin. Concurrent with the injections, nine volunteers received a 3-hour continuous intravenous infusion of IL-1Ra. The other five subjects were given a 3-hour infusion of saline. Volunteers injected with endotoxin experienced a threefold increase in circulating neutrophils over baseline. This neutrophilia was significantly reduced by 48% in subjects administered endotoxin plus IL-1Ra (P = .0253). Ex vivo mitogen-induced peripheral blood mononuclear cell proliferation decreased by greater than 60% at 3 and 6 hours after endotoxin injection (P = .0053). This endotoxin-induced reduction in mitogen response was reversed in subjects coinjected with IL-1Ra (P = .0253). Endotoxin-induced symptoms, fever, and tachycardia were unaffected by IL-1Ra. IL-1 appears to be an important mediator in endotoxemia because some of its hematologic and immunomodulatory effects can be blocked by IL-1Ra.     

Degradation of tissue-type plasminogen activator by human monocyte- derived macrophages is mediated by the mannose receptor and by the low- density lipoprotein receptor-related protein

The balance of tissue-type plasminogen activator (t-PA) production and degradation determines its concentration in blood and tissues. Disturbance of this balance may result in either increased or decreased proteolysis. In the present study, we identified the receptor systems involved in the degradation of t-PA by human monocytes/macrophages in culture. Monocytes were cultured and became macrophages within 2 days. At 4 degrees C, 125I-t-PA bound to macrophages with high (apparent dissociation constant [kd], 1 to 5 nmol/L) and low affinity (kd > 350 nmol/L). At 37 degrees C, the cells internalized and degraded t-PA via the high affinity binding sites, which were partially inhibited by mannan. The low affinity binding sites were 6-aminohexanoic acid- inhibitable and not involved in t-PA degradation. Degradation of t-PA was upregulated during differentiation of monocytes to macrophages. Dexamethasone further upregulated the mannan-inhibitable t-PA degradation. Lipopolysaccharide downregulated both mannan-inhibitable and non-mannan-inhibitable t-PA degradation. Non-mannan-inhibitable degradation was completely blocked by recombinant 39-kD receptor- associated protein (RAP, inhibitor of lipoprotein receptor-related protein [LRP]), whereas mannan-inhibitable degradation was blocked by the addition of a monoclonal antibody against the mannose receptor. No differences between the degradation of t-PA and functionally inactivated t-PA were observed. We conclude that human monocyte-derived macrophages are able to bind, internalize, and degrade t-PA. Degradation of t-PA does not require complex formation with plasminogen activator inhibitors. The macrophages use two independently regulated receptors, namely, the mannose receptor and LRP, for the uptake and degradation of t-PA.     

Current treatment paradigms in rheumatoid arthritis

Rheumatoid arthritis (RA) has traditionally been treated using the pyramid approach, in which non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment and disease-modifying anti-rheumatic drugs (DMARDs) are introduced relatively late in the disease. This approach is no longer valid. Previously regarded as a benign disease, RA is now recognized as causing substantial morbidity and mortality, as do the NSAIDs used in treatment. DMARDs are more effective in controlling the pain and disability of RA than NSAIDs, and are often no more toxic. The current treatment paradigm emphasizes early, consistent use of DMARDs. A 'sawtooth' strategy of DMARD use has been proposed, in which a rising but low level of disability triggers a change in therapy. Determining the most clinically useful DMARD combinations and the optimal sequence of DMARD use requires effectiveness studies, Bayesian approaches and analyses of long-term outcomes. Such approaches will allow optimization of multiple drug therapies in RA, and should substantially improve the long-term outcome for many patients.     

Factors influencing heart rate variability in patients with severe aortic valve disease

Background and hypothesis: Heart rate variability (HRV) is an accepted tool for the assessment of cardiovascular autonomic tone. There are no sufficient data concerning its application to patients with severe aortic valve disease (AVD) requiring cardiac surgery. Methods: It was the aim of this study to examine HRV and its physiologic correlates in patients with severe aortic valve disease requiring cardiac surgery. The correlates of time domain indices of HRV obtained from 24-h Holter electrocardiographic recordings were analyzed in 36 consecutive patients (23 men and 13 women, mean age 62 ± 11 years) with AVD prior to cardiac surgery (aortic stenosis: 17 patients, aortic valve regurgitation: 3 patients, combined aortic valve disease: 16 patients). Results: Low values of HRV were found in the entire study group: SDNN 96.8 ± 30.9 ms, SDNNI 39.3 ± 14.4 ms, SDANN 86 ± 28.9 ms, and RMSSD 30 ± 18.1 ms. In a univariate analysis, there was no significant correlation between the time domain measures of HRV and age, gender, medication, left ventricular ejection fraction, peak aortic pressure gradient, fraction of aortic valve regurgitation, and left ventricular mass assessed by echocardiography. Patients in advanced functional classes of heart failure [New York Heart Association (NYHA) III or IV] had significantly lower values for SDNN (83.8 ± 33.6 vs. 107.3 ± 24.7 ms; p<0.05) and SDANN (72.7 ± 29.4 vs. 96.6 ± 24.3 ms; p<0.05) than patients in NYHA class I or II. Reassessment of HRV 1 week after aortic valve replacement was performed in 17 patients and showed a significant further decrease of SDNN (102.4 ± 29.7 vs. 61.5 ± 23.5 ms; p<0.001), SDNNI (40.7 ± 13.6 vs. 23.4 ± 12.4 ms; p<0.001) and SDANN (91.8 ±29.2 vs. 54.2 ± 22.8 ms;p<0.001). Conclusion: Patients with AVD requiring cardiac surgery reveal reduced time domain indices of HRV. This observation is pronounced in patients with a progressed clinical class of heart failure, whereas hemodynamic and echocardiographic parameters seem to have no significant influence on HRV parameters in this population. In addition, there is evidence of a further reduction of HRV time domain indices 1 week after uncomplicated aortic valve replacement.     

A vaccine manufacturer’s approach to address medical needs related to seasonal and pandemic influenza viruses

Abstract Vaccination is considered to be one of the most effective tools to decrease morbidity as well as mortality caused by influenza viruses.For the prevention of seasonal influenza, Fluarix ™ and FluLaval™ have been marketed since 1987 and 1992, respectively. Both vaccines have consistently been shown to meet or exceed the regulatory criteria for immunogenicity against the three strains H1N1, H3N2 and B, have a good safety profile, and are recommended for vaccinating children and adults of all ages.For the prevention of pandemic influenza, GlaxoSmithKline (GSK) has obtained licensure of a pre‐pandemic vaccine, Prepandrix ™. This split‐virus H5N1 adjuvanted with AS03, a proprietary oil‐in‐water emulsion‐based adjuvant system, has demonstrated broad immunity against drifted H5N1 strains and has been shown to be effective in preventing mortality and viral shedding in animal studies.The influenza vaccine portfolio of GSK addresses specific medical needs related to seasonal or pandemic influenza viruses, which remain an important public health threat worldwide.