171 research outputs found
SPES/SCOPA and MDS-UPDRS: Formulas for converting scores of two motor scales in Parkinson’s disease
AbstractBackgroundMotor impairment in Parkinson’s disease (PD) can be evaluated with the Short Parkinson’s Evaluation Scale/Scales for Outcomes in Parkinson’s disease (SPES/SCOPA) and the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). The aim of this study was to determine equation models for the conversion of scores from one scale to the other.Methods148 PD patients were evaluated with the SPES/SCOPA-motor and the MDS-UPDRS motor examination. Linear regression was used to develop equation models.ResultsScores on both scales were highly correlated (r = 0.88). Linear regression revealed the following equation models (explained variance: 78%):1.MDS-UPDRS motor examination score = 11.8 + 2.4 ∗ SPES/SCOPA-motor score2.SPES/SCOPA-motor score = −0.5 + 0.3 ∗ MDS-UPDRS motor examination score.ConclusionWith the equation models identified in this study, scores from SPES/SCOPA-motor can be converted to scores from MDS-UPDRS motor examination and vice versa
Mouse Studies to Shape Clinical Trials for Mitochondrial Diseases: High Fat Diet in Harlequin Mice
BACKGROUND: Therapeutic options in human mitochondrial oxidative phosphorylation (OXPHOS) diseases have been poorly evaluated mostly because of the scarcity of cohorts and the inter-individual variability of disease progression. Thus, while a high fat diet (HFD) is often recommended, data regarding efficacy are limited. Our objectives were 1) to determine our ability to evaluate therapeutic options in the Harlequin OXPHOS complex I (CI)-deficient mice, in the context of a mitochondrial disease with human hallmarks and 2) to assess the effects of a HFD. METHODS AND FINDINGS: Before launching long and expensive animal studies, we showed that palmitate afforded long-term death-protection in 3 CI-mutant human fibroblasts cell lines. We next demonstrated that using the Harlequin mouse, it was possible to draw solid conclusions on the efficacy of a 5-month-HFD on neurodegenerative symptoms. Moreover, we could identify a group of highly responsive animals, echoing the high variability of the disease progression in Harlequin mice. CONCLUSIONS: These results suggest that a reduced number of patients with identical genetic disease should be sufficient to reach firm conclusions as far as the potential existence of responders and non responders is recognized. They also positively prefigure HFD-trials in OXPHOS-deficient patients
First Myocardial Infarction in Patients with Premature Coronary Artery Disease:Insights into Patient Characteristics and Outcome after Treatment with Contemporary Stents
Diabetic patients treated with novel thin composite-wire strut zotarolimus-eluting stents versus ultrathin strut sirolimus-eluting stents in the BIONYX trial: 2-year results of a prespecified analysis
Comparison of two iterations of the zotarolimus-eluting stents: an analysis of all-comer patients from two consecutive randomised clinical trials
Impact of proton pump inhibitors on efficacy of antiplatelet strategies with ticagrelor or aspirin after percutaneous coronary intervention:Insights from the GLOBAL LEADERS trial
BACKGROUND
Several studies have suggested that proton pump inhibitors (PPIs) may reduce the antiplatelet effects of clopidogrel and/or aspirin, possibly leading to cardiovascular events.
AIMS
We aimed to investigate the association between PPI and clinical outcomes in patients treated with ticagrelor monotherapy or conventional antiplatelet therapy after percutaneous coronary intervention (PCI).
METHODS
This is a subanalysis of the randomized GLOBAL LEADERS trial, comparing the experimental antiplatelet arm (23-month ticagrelor monotherapy following 1-month dual antiplatelet therapy [DAPT]) with the reference arm (12-month aspirin monotherapy following 12-month DAPT) after PCI. Patient-oriented composite endpoints (POCEs: all-cause mortality, myocardial infarction, stroke, or repeat revascularization) and its components were assessed stratified by PPI use as a time-dependent covariate in patients with the experiment or reference antiplatelet arm.
RESULTS
Among 15,839 patients, 2115 patients (13.5%) experienced POCE at 2 years. In the reference arm, the use of PPIs was independently associated with POCE (hazard ratio [HR]: 1.27; 95% confidence interval [CI]: 1.12-1.44) and its individual components, whereas it was not in the experimental arm (HR: 1.04; 95% CI: 0.92-1.19; pinteraction  = 0.035). During the second-year follow-up, patients taking aspirin with PPIs had a significantly higher risk of POCE compared to those on aspirin without PPIs (HR: 1.57; 95% CI: 1.27-1.94), whereas the risk did not differ significantly irrespective of PPI in ticagrelor monotherapy group (HR: 1.03; 95% CI: 0.83-1.28; pinteraction  = 0.008).
CONCLUSIONS
In contrast to conventional antiplatelet strategy, there were no evidence suggesting the interaction between ticagrelor monotherapy and PPIs on increased cardiovascular events, which should be confirmed in further studies.
CLINICAL TRIAL REGISTRATION
URL: https://clinicaltrials.gov
The Variability of the Harlequin Mouse Phenotype Resembles that of Human Mitochondrial-Complex I-Deficiency Syndromes
Background: Despite the considerable progress made in understanding the molecular bases of mitochondrial diseases, no effective treatments have been developed to date. Faithful animal models would be extremely helpful for designing such treatments. We showed previously that the Harlequin mouse phenotype was due to a specific mitochondrial complex I deficiency resulting from the loss of the Apoptosis Inducing Factor (Aif) protein. Methodology/Principal Findings: Here, we conducted a detailed evaluation of the Harlequin mouse phenotype, including the biochemical abnormalities in various tissues. We observed highly variable disease expression considering both severity and time course progression. In each tissue, abnormalities correlated with the residual amount of the respiratory chain complex I 20 kDa subunit, rather than with residual Aif protein. Antioxidant enzyme activities were normal except in skeletal muscle, where they were moderately elevated. Conclusions/Significance: Thus, the Harlequin mouse phenotype appears to result from mitochondrial respiratory chain complex I deficiency. Its features resemble those of human complex I deficiency syndromes. The Harlequin mouse hold
The Warburg Effect Is Genetically Determined in Inherited Pheochromocytomas
The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to as pseudohypoxia. We observed a decrease in electron transport protein expression and activity, associated with increased angiogenesis in SDH- and VHL-related, pseudohypoxic tumors, while stimulation of glycolysis was solely observed in VHL tumors. Moreover, microarray analyses revealed that expression of genes involved in these metabolic pathways is an efficient tool for classification of pheochromocytomas in accordance with the predisposition gene mutated. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas
Region-Specific Expression of Mitochondrial Complex I Genes during Murine Brain Development
Mutations in the nuclear encoded subunits of mitochondrial complex I (NADH:ubiquinone oxidoreductase) may cause circumscribed cerebral lesions ranging from degeneration of the striatal and brainstem gray matter (Leigh syndrome) to leukodystrophy. We hypothesized that such pattern of regional pathology might be due to local differences in the dependence on complex I function. Using in situ hybridization we investigated the relative expression of 33 nuclear encoded complex I subunits in different brain regions of the mouse at E11.5, E17.5, P1, P11, P28 and adult (12 weeks). With respect to timing and relative intensity of complex I gene expression we found a highly variant pattern in different regions during development. High average expression levels were detected in periods of intense neurogenesis. In cerebellar Purkinje and in hippocampal CA1/CA3 pyramidal neurons we found a second even higher peak during the period of synaptogenesis and maturation. The extraordinary dependence of these structures on complex I gene expression during synaptogenesis is in accord with our recent findings that gamma oscillations – known to be associated with higher cognitive functions of the mammalian brain – strongly depend on the complex I activity. However, with the exception of the mesencephalon, we detected only average complex I expression levels in the striatum and basal ganglia, which does not explain the exquisite vulnerability of these structures in mitochondrial disorders
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