Next-generation active immunization approach for synucleinopathies: implications for Parkinson’s disease clinical trials

Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that α-synuclein (α-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs^® (AFF)- that do not elicit an α-syn-specific T cell response. This approach allows for the production of long term, sustained, more specific, non-cross reacting antibodies suitable for the treatment of synucleinopathies, such as Parkinson’s disease (PD). In this context, we screened a large library of peptides that mimic the C-terminus region of α-syn and discovered a novel set of AFF that identified α-syn oligomers. Next, the peptide that elicited the most specific response against α-syn (AFF 1) was selected for immunizing two different transgenic (tg) mouse models of PD and Dementia with Lewy bodies, the PDGF- and the mThy1-α-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized α-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn oligomers in axons and synapses, accompanied by reduced degeneration of TH fibers in the caudo-putamen nucleus and by improvements in motor and memory deficits in both in vivo models. Clearance of α-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies.     

Prognostic value of uric acid in patients with acute coronary syndromes

The association between uric acid and cardiovascular disease is incompletely understood. In particular, the prognostic value of uric acid in patients with acute coronary syndromes who undergo percutaneous coronary intervention has not been studied. This study included 5,124 patients with acute coronary syndromes who underwent percutaneous coronary intervention: 1,629 with acute ST-segment elevation myocardial infarction, 1,332 with acute non-ST-segment elevation myocardial infarction, and 2,163 with unstable angina. The primary end point was 1-year mortality. Patients were divided into quartiles according to uric acid level as follows: quartile 1, 1.3 to <5.3 mg/dl; quartile 2, 5.3 to <6.3 mg/dl; quartile 3, 6.3 to <7.5 mg/dl; and quartile 4, 7.5 to 18.4 mg/dl. There were 450 deaths during follow-up: 80 deaths in quartile 1, 77deaths in quartile 2, 72 deaths in quartile 3, and 221 deaths in quartile 4 of uric acid (Kaplan-Meier estimates of 1-year mortality 6.4%, 6.2%, 5.6%, and 17.4%, respectively; unadjusted hazard ratio 3.05, 95% confidence interval 2.54 to 3.67, p <0.001 for fourth vs first quartile of uric acid). After adjustment for traditional cardiovascular risk factors, renal function, and inflammatory status, the association between uric acid and mortality remained significant, with a 12% increase in the adjusted risk for 1-year mortality for every 1 mg/dl increase in the uric acid level. Uric acid improved the discriminatory power of the predictive model regarding 1-year mortality (absolute integrated discrimination improvement 0.008, p = 0.005). In conclusion, elevated levels of uric acid are an independent predictor of 1-year mortality across the whole spectrum of patients with acute coronary syndromes treated with percutaneous coronary intervention.     

Novel treatment concepts for graft-versus-host disease

Acute and chronic graft-versus-host disease (GVHD) are potentially lethal complications after stem cell transplantation (SCT). Steroids are the appropriate first-line treatment for both. However, if patients do not adequately benefit from steroid therapy, mortality is high and standardized treatment algorithms are lacking. This is mainly because of limited data from prospective, randomized clinical trials. In addition, most of the available treatment options only induce clinical benefits in a limited proportion of patients. Thus, there is an urgent clinical need to develop more potent immunosuppressive treatment strategies for patients suffering from acute or chronic steroid-refractory GVHD while maintaining the graft versus tumor effect to avoid a potential rise in relapse-related mortality. The increasing knowledge about host- as well as donor-derived variables favoring GVHD development and the increasing armamentarium of immune-modulatory agents entering preclinical and clinical research will probably allow more effective treatment of GVHD in the future. This review describes novel developments in the treatment of steroid-refractory GVHD, with a special focus on the rationale behind promising pharmacologic compounds or up-coming cellular therapies.     

Observational Study Mortality in Treated Primary Aldosteronism: The German Conn's Registry

In comparison with essential hypertension, primary aldosteronism (PA) is associated with an increased risk of cardiovascular morbidity. To date, no data on mortality have been published. We assessed mortality of patients treated for PA within the German Conn's registry and identified risk factors for adverse outcome in a case-control study. Patients with confirmed PA treated in 3 university centers in Germany since 1994 were included in the analysis. All of the patients were contacted in 2009 and 2010 to verify life status. Subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg served as controls. Final analyses were based on 600 normotensive controls, 600 hypertensive controls, and 300 patients with PA. Kaplan-Meyer survival curves were calculated for both cohorts. Ten-year overall survival was 95% in normotensive controls, 90% in hypertensive controls, and 90% in patients with PA (P value not significant). In multivariate analysis, age (hazard ratio, 1.09 per year [95% CI, 1.03-1.14]), angina pectoris (hazard ratio, 3.6 [95% CI, 1.04-12.04]), and diabetes mellitus (hazard ratio, 2.55 [95% CI, 1.07-6.09]) were associated with an increase in all-cause mortality, whereas hypokalemia (hazard ratio, 0.41 per mmol/L [95% CI, 0.17-0.99]) was associated with reduced mortality. Cardiovascular mortality was the main cause of death in PA (50% versus 34% in hypertensive controls; P<0.05). These data indicate that cardiovascular mortality is increased in patients treated for PA, whereas all-cause mortality is not different from matched hypertensive controls.