Alpha-synuclein supports type 1 interferon signalling in neurons and brain tissue.

The protein alpha-synuclein is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinson's disease and dementia with Lewy bodies. However, the normal function of alpha-synuclein in neurons is not clearly defined. We have previously shown that mice lacking alpha-synuclein expression exhibit markedly increased viral growth in the brain, increased mortality and increased neuronal cell death, implicating alpha-synuclein in the neuronal innate immune response. To investigate the mechanism of alpha-synuclein-induced immune responses to viral infections in the brain, we challenged alpha-synuclein knockout mice and human alpha-synuclein knockout dopaminergic neurons with RNA virus infection and discovered that alpha-synuclein is required for neuronal expression of interferon-stimulated genes. Furthermore, human alpha-synuclein knockout neurons treated with type 1 interferon failed to induce a broad range of interferon stimulated genes, implying that alpha-synuclein interacts with type 1 interferon signalling. We next found that alpha-synuclein accumulates in the nucleus of interferon-treated human neurons after interferon treatment and we demonstrated that interferon-mediated phosphorylation of STAT2 is dependent on alpha-synuclein expression in human neurons. Next, we found that activated STAT2 co-localizes with alpha-synuclein following type 1 interferon stimulation in neurons. Finally, we found that brain tissue from patients with viral encephalitis expresses increased levels of phospho-serine129 alpha-synuclein in neurons. Taken together, our results show that alpha-synuclein expression supports neuron-specific interferon responses by localizing to the nucleus, supporting STAT2 activation, co-localizing with phosphorylated STAT2 in neurons and supporting expression of interferon-stimulated genes. These data provide a novel mechanism that links interferon activation and alpha-synuclein function in neurons.

Submaximal effort tolerance as a predictor of all-cause mortality in patients undergoing cardiac rehabilitation.

BACKGROUND: Submaximal effort tolerance is routinely available during cardiac rehabilitation, but its prognostic value in relation to underlying referral diagnosis is not known. HYPOTHESIS: Treadmill effort capacity during submaximal exercise training predicts all-cause mortality after cardiac rehabilitation. METHODS: We followed 600 consecutive patients (450 men and 150 women, mean age 65 years) who were referred to a 12-week outpatient program of cardiac rehabilitation; 37% had a prior myocardial infarction (MI), 44% had a recent percutaneous intervention (PCI), and 39% had history of coronary artery bypass surgery (CABG). RESULTS: There were 48 deaths during a mean follow-up period of 1603 +/- 822 days. By multivariate Cox analysis, exit MET activity was the most significant predictor of all-cause mortality. In this model, each 1 MET increase in exit submaximal effort tolerance was associated with a 34% decrease in mortality (hazard ratio [HR] 0.66, 95% confidence interval 0.56-0.77) alone and 28% decrease after adjustment for age (HR = 0.72, confidence interval 0.60-0.85). Enty MET level also had predictive value. Subgroup analysis revealed that the predictive value of exit METs was limited to patients after recent CABG and with MI. None of the variables predicted death after PCI, in whom mortality was significantly lower than in the other groups. CONCLUSIONS: Submaximal effort tolerance at completion of cardiac rehabilitation, and also at entry, is a strong and age-independent predictor of mortality in patients who have had either recent CABG or MI without intervention, but not in patients after recent PCI.

Randomized, controlled dose-ranging study of the selective adenosine A2A receptor agonist binodenoson for pharmacological stress as an adjunct to myocardial perfusion imaging.

BACKGROUND: Dipyridamole and adenosine cause frequent side effects as a result of nonspecific adenosine receptor stimulation. Selective agonism of the adenosine A2A receptor should result in a similar degree of coronary vasodilation (and thus similar perfusion images) with fewer side effects. METHODS AND RESULTS: In a multicenter, randomized, single-blind, 2-arm crossover trial, 240 patients underwent 2 single photon emission computed tomographic (SPECT) imaging studies in random order, first after pharmacological stress with adenosine and a second study with the selective adenosine A2A receptor agonist binodenoson, using 1 of 4 dosing regimens. Safety, tolerability, and SPECT image concordance between the 2 agents were examined. Exact categorical agreement in the extent and severity of reversible perfusion defects ranged from 79% to 87%, with kappa values from 0.69 to 0.85, indicating very good to excellent agreement between binodenoson and adenosine. The risk of any safety event/side effect was significantly lower with any dose of binodenoson than with adenosine (P< or =0.01) because of a dose-related reduction in subjective side effects, as objective events were infrequent. There was a reduction in the severity of chest pain, dyspnea, and flushing in all binodenoson doses compared with adenosine (P<0.01), and the magnitude of severity reduction was dose-related. CONCLUSIONS: The selective adenosine A2A receptor agonist binodenoson results in an extent and severity of reversible perfusion defects on SPECT imaging similar to nonselective adenosine receptor stimulation, accompanied by a dose-related reduction in the incidence and severity of side effects.

Effect of age and gender on heart rate recovery after submaximal exercise during cardiac rehabilitation in patients with angina pectoris, recent acute myocardial infarction, or coronary bypass surgery.

The effect of exercise training on the heart rate recovery (HRR) response to submaximal effort was examined in 81 patients during 12 weeks of phase II cardiac rehabilitation. Although HRR after submaximal effort was relatively reduced in older patients with heart disease and in women, its increase during exercise training in men and women of all ages was consistent with enhancement of parasympathetic tone during activities of daily living.

Atrial fibrillation in cardiac resynchronization therapy patients: should we ablate the atrioventricular node?

Prevalence of persistent atrial fibrillation in patients undergoing cardiac resynchronization therapy remains high. Several factors, including suboptimal biventricular capture rates, compound the significant mortality and response rates in patients with atrial fibrillation and severe heart failure. Atrioventricular nodal ablation provides the best mean of rate control in this population. In this article, the authors evaluate a recently published trial addressing this issue in a prospective fashion and discuss the results and clinical applications.