High circulating levels of endogenous ouabain in the offspring of hypertensive and normotensive individuals

OBJECTIVE: Impaired diastolic function and left ventricular hypertrophy can occur early in the natural history of essential hypertension. High circulating levels of endogenous ouabain (EO) have been described in essential hypertension and have also been associated with left ventricular hypertrophy. The aim of this study was to investigate whether these cardiac modifications are related to plasma EO levels in the offspring of hypertensive families. METHODS: The study involved 41 subjects with (FAM+) and 45 subjects without (FAM-) a family history of hypertension. Arterial blood pressure, left ventricular geometry and function, and plasma EO levels were measured in each subject. RESULTS: Plasma EO levels were higher in the FAM+ subjects (221.5 +/- 10.95 versus 179.6 +/- 9.58 pmol/l, P = 0.004), and directly correlated with both systolic (r = 0.417, P < 0.0001) and diastolic blood pressure (r = 0.333, P = 0.002). Plasma EO was inversely related to an index of cardiac diastolic function determined as the ratio between the early and late peak flow velocity (r = -0.286, P = 0.012) and isovolumetric relaxation time (IVRT) (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, correlated with the IVRT (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, whereas the other echocardiographic parameters were similar to FAM-. CONCLUSIONS: Among the offspring of families with a positive history of hypertension, circulating EO levels and blood pressure are increased. Plasma EO levels are related to alterations of some indexes of diastolic heart function in these individuals.     

Cytohesin-1, a cytosolic guanine nucleotide-exchange protein for ADP-ribosylation factor

Cytohesin-1, a protein abundant in cells of the immune system, has been proposed to be a human homolog of the Saccharomyces cerevisiae Sec7 gene product, which is crucial in protein transport. More recently, the same protein has been reported to be a regulatory factor for the αLβ2 integrin in lymphocytes. Overexpression of human or yeast ADP-ribosylation factor (ARF) genes rescues yeast with Sec7 defects, restoring secretory pathway function. ARFs, 20-kDa guanine nucleotide-binding proteins initially identified by their ability to stimulate cholera toxin ADP-ribosyltransferase activity and now recognized as critical components in intracellular vesicular transport, exist in an inactive cytosolic form with GDP bound (ARF-GDP). Interaction with a guanine nucleotide-exchange protein (GEP) accelerates exchange of GDP for GTP, producing the active ARF-GTP. Both soluble and particulate GEPs have been described. To define better the interaction between ARF and Sec7-related proteins, effects of cytohesin-1, synthesized in Escherichia coli, on ARF activity were evaluated. Cytohesin-1 enhanced binding of ³⁵S-labeled guanosine 5′-[γ-thio]triphosphate [³⁵S]GTP[γS] or [³H]GDP to ARF purified from bovine brain (i.e., it appeared to function as an ARF-GEP). Addition of cytohesin-1 to ARF3 with [³⁵S]GTP[γS] bound, accelerated [³⁵S]GTP[γS] release to a similar degree in the presence of unlabeled GDP or GTP[γS] and to a lesser degree with GDP[βS]; release was negligible without added nucleotide. Cytohesin-1 also increased ARF1 binding to a Golgi fraction, but its effect was not inhibited by brefeldin A (BFA), a drug that reversibly inhibits Golgi function. In this regard, it differs from a recently reported BFA-sensitive ARF-GEP that contains a Sec7 domain.     

The ARVD/C Genetic Variants Database: 2014 Update

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiac disease characterized by myocardial atrophy, fibro‐fatty replacement, and a high risk of ventricular arrhythmias that lead to sudden death. In 2009, genetic data from 57 publications were collected in the arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) Genetic Variants Database (freeware available at http://www.arvcdatabase.info ), which comprised 481 variants in eight ACM‐associated genes. In recent years, deep genetic sequencing has increased our knowledge of the genetics of ACM, revealing a large spectrum of nucleotide variations for which pathogenicity needs to be assessed. As of April 20, 2014, we have updated the ARVD/C database into the ARVD/C database to contain more than 1,400 variants in 12 ACM‐related genes (PKP2, DSP, DSC2, DSG2, JUP, TGFB3, TMEM43, LMNA, DES, TTN, PLN, CTNNA3) as reported in more than 160 references. Of these, only 411 nucleotide variants have been reported as pathogenic, whereas the significance of the other approximately 1,000 variants is still unknown. This comprehensive collection of ACM genetic data represents a valuable source of information on the spectrum of ACM‐associated genes and aims to facilitate the interpretation of genetic data and genetic counseling.     

Risk of Exclusion From Stroke Rehabilitation in the Oldest Old

Objective

To investigate whether oldest-old age (≥85y) is an independent predictor of exclusion from stroke rehabilitation.

Prediction of Falls in Subjects Suffering From Parkinson Disease,Multiple Sclerosis,and Stroke

Objective

To compare the risk of falls and fall predictors in patients with Parkinson disease (PD), multiple sclerosis (MS), and stroke using the same study design.

Quantitative assessment of the effects of 6 months of adapted physical activity on gait in people with multiple sclerosis: a randomized controlled trial

Purpose: The purpose of this study is to quantitatively assess the effect of 6 months of supervised adapted physical activity (APA i.e. physical activity designed for people with special needs) on spatio-temporal and kinematic parameters of gait in persons with Multiple Sclerosis (pwMS).

Methods: Twenty-two pwMS with Expanded Disability Status Scale scores ranging from 1.5 to 5.5 were randomly assigned either to the intervention group (APA, n?=?11) or the control group (CG, n?=?11). The former underwent 6 months of APA consisting of 3 weekly 60-min sessions of aerobic and strength training, while CG participants were engaged in no structured PA program. Gait patterns were analyzed before and after the training using three-dimensional gait analysis by calculating spatio-temporal parameters and concise indexes of gait kinematics (Gait Profile Score – GPS and Gait Variable Score – GVS) as well as dynamic Range of Motion (ROM) of hip, knee, and ankle joints.

Results: The training originated significant improvements in stride length, gait speed and cadence in the APA group, while GPS and GVS scores remained practically unchanged. A trend of improvement was also observed as regard the dynamic ROM of hip, knee, and ankle joints. No significant changes were observed in the CG for any of the parameters considered.

Conclusions: The quantitative analysis of gait supplied mixed evidence about the actual impact of 6 months of APA on pwMS. Although some improvements have been observed, the substantial constancy of kinematic patterns of gait suggests that the full transferability of the administered training on the ambulation function may require more specific exercises.

• Implications for rehabilitation

• Adapted Physical Activity (APA) is effective in improving spatio-temporal parameters of gait, but not kinematics, in people with multiple sclerosis.

• Dynamic range of motion during gait is increased after APA.

• The full transferability of APA on the ambulation function may require specific exercises rather than generic lower limbs strength/flexibility training.

     

Liver injury with novel oral anticoagulants: assessing post-marketing reports in the US Food and Drug Administration adverse event reporting system

Aim

We assessed the hepatic safety of novel oral anticoagulants (NOACs) analyzing the publicly available US-FDA adverse event reporting system (FAERS).

Methods

We extracted reports of drug-induced liver injury (DILI) associated with NOACs, including acute liver failure (ALF) events. Based on US marketing authorizations, we performed disproportionality analyses, calculating reporting odds ratios (RORs) with 95% confidence interval (CI), also to test for event- and drug-related competition bias, and case-by-case evaluation for concomitant medications.

Results

DILI reports represented 3.7% (n = 146) and 1.7% (n = 222) of all reports for rivaroxaban and dabigatran, respectively. No statistically significant association was found for dabigatran, in primary and secondary analyses. Disproportionality signals emerged for rivaroxaban in primary analysis (ALF: n = 25, ROR = 2.08, 95% CI 1.34, 3.08). In a large proportion of DILI reports concomitant hepatotoxic and/or interacting drugs were recorded: 42% and 37% (rivaroxaban and dabigatran, respectively), especially statins, paracetamol and amiodarone. Among ALF reports, fatal outcome occurred in 49% of cases (44% and 51%, rivaroxaban and dabigatran, respectively), whereas rapid onset of the event (<1 week) was detected in 46% of patients (47% and 44%, respectively).

Conclusions

The disproportionality signal for rivaroxaban calls for further comparative population-based studies to characterize and quantify the actual DILI risk of NOACs, taking into account drug- and patient-related risk factors. As DILI is unpredictable, our findings strengthen the role of (a) timely pharmacovigilance to detect post-marketing signals of DILI through FAERS and other data sources, (b) clinicians to assess early, on a case-by-case basis, the potential responsibility of NOACs when they diagnose a liver injury.