Absence of Ret Signaling in Mice Causes Progressive and Late Degeneration of the Nigrostriatal System

Support of ageing neurons by endogenous neurotrophic factors such as glial cell line–derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.</p

Toward Continuous, Noninvasive Assessment of Ventricular Function and Hemodynamics: Wearable Ballistocardiography

Ballistocardiography, the measurement of the reaction forces of the body to cardiac ejection of blood, is one of the few techniques available for unobtrusively assessing the mechanical aspects of cardiovascular health outside clinical settings. Recently, multiple experimental studies involving healthy subjects and subjects with various cardiovascular diseases have demonstrated that the ballistocardiogram (BCG) signal can be used to trend cardiac output, contractility, and beat-by-beat ventricular function for arrhythmias. The majority of these studies has been performed with "fixed" BCG instrumentation-such as weighing scales or chairs-rather than wearable measurements. Enabling wearable, and thus continuous, recording of BCG signals would greatly expand the capabilities of the technique; however, BCG signals measured using wearable devices are morphologically dissimilar to measurements from "fixed" instruments, precluding the analysis and interpretation techniques from one domain to be applied to the other. In particular, the time intervals between the electrocardiogram (ECG) and BCG-namely, the R-J interval, a surrogate for measuring contractility changes-are significantly different for the accelerometer compared to a "fixed" BCG measurement. This paper addresses this need for quantitatively normalizing wearable BCG measurement to "fixed" measurements with a systematic experimental approach. With these methods, the same analysis and interpretation techniques developed over the past decade for "fixed" BCG measurement can be successfully translated to wearable measurements

Long-Term Corticosteroid-Sparing Immunosuppression for Cardiac Sarcoidosis.

Background Long-term corticosteroid therapy is the standard of care for treatment of cardiac sarcoidosis (CS). The efficacy of long-term corticosteroid-sparing immunosuppression in CS is unknown. The goal of this study was to assess the efficacy of methotrexate with or without adalimumab for long-term disease suppression in CS, and to assess recurrence and adverse event rates after immunosuppression discontinuation. Methods and Results Retrospective chart review identified treatment-naive CS patients at a single academic medical center who received corticosteroid-sparing maintenance therapy. Demographics, cardiac uptake of 18-fluorodeoxyglucose, and adverse cardiac events were compared before and during treatment and between those with persistent or interrupted immunosuppression. Twenty-eight CS patients were followed for a mean 4.1 (SD 1.5) years. Twenty-five patients received 4 to 8&nbsp;weeks of high-dose prednisone (&gt;30&nbsp;mg/day), followed by taper and maintenance therapy with methotrexate±low-dose prednisone (low-dose prednisone, &lt;10&nbsp;mg/day). Adalimumab was added in 19 patients with persistently active CS or in those with intolerance to methotrexate. Methotrexate±low-dose prednisone resulted in initial reduction (88%) or elimination (60%) of 18-fluorodeoxyglucose uptake, and patients receiving adalimumab-containing regimens experienced improved (84%) or resolved (63%) 18-fluorodeoxyglucose uptake. Radiologic relapse occurred in 8 of 9 patients after immunosuppression cessation, 4 patients on methotrexate-containing regimens, and in no patients on adalimumab-containing regimens. Conclusions Corticosteroid-sparing regimens containing methotrexate with or without adalimumab is an effective maintenance therapy in patients after an initial response is confirmed. Disease recurrence in patients on and off immunosuppression support need for ongoing radiologic surveillance regardless of immunosuppression regimen

Education, income, and incident heart failure in post-menopausal women: the Women\u27s Health Initiative Hormone Therapy Trials

OBJECTIVES: The purpose of this study is to estimate the effect of education and income on incident heart failure (HF) hospitalization among post-menopausal women. BACKGROUND: Investigations of socioeconomic status have focused on outcomes after HF diagnosis, not associations with incident HF. We used data from the Women\u27s Health Initiative Hormone Trials to examine the association between socioeconomic status levels and incident HF hospitalization. METHODS: We included 26,160 healthy, post-menopausal women. Education and income were self-reported. Analysis of variance, chi-square tests, and proportional hazards models were used for statistical analysis, with adjustment for demographics, comorbid conditions, behavioral factors, and hormone and dietary modification assignments. RESULTS: Women with household incomes $50,000 a year (16.7/10,000 person-years; p \u3c 0.01). Women with less than a high school education had higher HF hospitalization incidence (51.2/10,000 person-years) than college graduates and above (25.5/10,000 person-years; p \u3c 0.01). In multivariable analyses, women with the lowest income levels had 56% higher risk (hazard ratio: 1.56, 95% confidence interval: 1.19 to 2.04) than the highest income women; women with the least amount of education had 21% higher risk for incident HF hospitalization (hazard ratio: 1.21, 95% confidence interval: 0.90 to 1.62) than the most educated women. CONCLUSIONS: Lower income is associated with an increased incidence of HF hospitalization among healthy, post-menopausal women, whereas multivariable adjustment attenuated the association of education with incident HF. Elsevier Inc. All rights reserved

Two decades of forest-related legislation changes in European countries analysed from a property rights perspective

In the last two decades, attention on forests and ownership rights has increased in different domains of international policy, particularly in relation to achieving the global sustainable development goals. This paper looks at the changes in forest-specific legislation applicable to regular productive forests, across 28 European countries. We compare the legal framework applicable in the mid-1990s with that applicable in 2015, using the Property Rights Index in Forestry (PRIF) to measure changes across time and space. The paper shows that forest owners in most western European countries already had high decision-making power in the mid-1990s, following deregulation trends from the 1980s; and for the next two decades, distribution of rights remained largely stable. For these countries, the content and direction of changes indicate that the main pressure on forest-focused legislation comes from environmental discourses (e.g. biodiversity and climate change policies). In contrast, former socialist countries in the mid-1990s gave lower decision-making powers to forest owners than in any of the Western Europe countries; over the next 20 years these show remarkable changes in management, exclusion and withdrawal rights. As a result of these changes, there is no longer a clear line between western and former socialist countries with respect to the national governance systems used to address private forest ownership. Nevertheless, with the exception of Baltic countries which have moved towards the western forest governance system, most of the former socialist countries still maintain a state-centred approach in private forest management. Overall, most of the changes we identified in the last two decades across Europe were recorded in the categories of management rights and exclusion rights. These changes reflect the general trend in European forest policies to expand and reinforce the landowners' individual rights, while preserving minimal rights for other categories of forest users; and to promote the use of financial instruments when targeting policy goals related to the environmental discourse

Risk Factors for Incident Hospitalized Heart Failure With Preserved Versus Reduced Ejection Fraction in a Multiracial Cohort of Postmenopausal WomenClinical Perspective

BACKGROUND: Heart failure is an important and growing public health problem in women. Risk factors for incident hospitalized heart failure with preserved ejection fraction (HFpEF) compared with heart failure with reduced ejection fraction (HFrEF) in women and differences by race/ethnicity are not well characterized. METHODS AND RESULTS: We prospectively evaluated the risk factors for incident hospitalized HFpEF and HFrEF in a multiracial cohort of 42 170 postmenopausal women followed up for a mean of 13.2 years. Cox regression models with time-dependent covariate adjustment were used to define risk factors for HFpEF and HFrEF. Differences by race/ethnicity about incidence rates, baseline risk factors, and their population-attributable risk percentage were analyzed. Risk factors for both HFpEF and HFrEF were as follows: older age, white race, diabetes mellitus, cigarette smoking, and hypertension. Obesity, history of coronary heart disease (other than myocardial infarction), anemia, atrial fibrillation, and more than one comorbidity were associated with HFpEF but not with HFrEF. History of myocardial infarction was associated with HFrEF but not with HFpEF. Obesity was found to be a more potent risk factor for African American women compared with white women for HFpEF (P for interaction=0.007). For HFpEF, the population-attributable risk percentage was greatest for hypertension (40.9%) followed by obesity (25.8%), with the highest population-attributable risk percentage found in African Americans for these risk factors. CONCLUSIONS: In this multiracial cohort of postmenopausal women, obesity stands out as a significant risk factor for HFpEF, with the strongest association in African American women. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00000611

Pro-Survival Role for Parkinson's Associated Gene DJ-1 Revealed in Trophically Impaired Dopaminergic Neurons

A mouse genetic study reveals a novel cell-survival role for the Parkinson's disease-associated gene DJ-1 in dopaminergic neurons that have reduced support from endogenous survival factors

Inactivation of VCP/ter94 Suppresses Retinal Pathology Caused by Misfolded Rhodopsin in Drosophila

The most common Rhodopsin (Rh) mutation associated with autosomal dominant retinitis pigmentosa (ADRP) in North America is the substitution of proline 23 by histidine (RhP23H). Unlike the wild-type Rh, mutant RhP23H exhibits folding defects and forms intracellular aggregates. The mechanisms responsible for the recognition and clearance of misfolded RhP23H and their relevance to photoreceptor neuron (PN) degeneration are poorly understood. Folding-deficient membrane proteins are subjected to Endoplasmic Reticulum (ER) quality control, and we have recently shown that RhP23H is a substrate of the ER–associated degradation (ERAD) effector VCP/ter94, a chaperone that extracts misfolded proteins from the ER (a process called retrotranslocation) and facilitates their proteasomal degradation. Here, we used Drosophila, in which Rh1P37H (the equivalent of mammalian RhP23H) is expressed in PNs, and found that the endogenous Rh1 is required for Rh1P37H toxicity. Genetic inactivation of VCP increased the levels of misfolded Rh1P37H and further activated the Ire1/Xbp1 ER stress pathway in the Rh1P37H retina. Despite this, Rh1P37H flies with decreased VCP function displayed a potent suppression of retinal degeneration and blindness, indicating that VCP activity promotes neurodegeneration in the Rh1P37H retina. Pharmacological treatment of Rh1P37H flies with the VCP/ERAD inhibitor Eeyarestatin I or with the proteasome inhibitor MG132 also led to a strong suppression of retinal degeneration. Collectively, our findings raise the possibility that excessive retrotranslocation and/or degradation of visual pigment is a primary cause of PN degeneration