Uric Acid as a Potential Peripheral Biomarker for Disease Features in Huntington's Patients.

Oxidative stress has long been implicated in the pathophysiology and progression of Huntington's disease (HD). Uric acid (UA) is a naturally occurring antioxidant that is present in the brain and periphery. Growing evidence has implicated UA as a molecular biomarker for several neurodegenerative diseases, most notably Parkinson's disease (PD). In this study, we investigated UA levels in clinical samples from HD patients and normal controls (NCs) and assessed potential relationships between UA levels and disease and clinical data. UA levels were measured in plasma (n = 107) and saliva (n = 178) samples from premanifest (pre-HD) and manifest HD patients and control subjects. Gender effects of UA levels were observed in both biofluids, with male patients showing higher UA levels compared to female patients. Comparisons of UA levels across diagnostic groups, separated by gender, revealed that both plasma and salivary UA levels were significantly lower in female pre-HD and manifest HD patients compared to NCs. Salivary levels of UA were also significantly lower in male manifest HD patients versus controls, but not in plasma. Correlations of peripheral UA levels to clinical data also showed differences according to gender. In male HD patients, both plasma and salivary UA levels were significantly negatively correlated with total functional capacity (TFC), while positive correlations were observed with total motor score (TMS). Female HD patients showed a significant positive correlation between plasma UA levels and TMS, while salivary UA levels from female patients were significantly correlated to disease burden. Finally, in a separate cohort, we show that UA levels are decreased in postmortem prefrontal cortical samples (n = 20) from HD subjects compared to matched controls. These findings suggest that decreased levels of UA in the brains of HD patients can be reflected in peripheral fluids, with salivary measures of UA particularly offering significant promise as a potentially relevant, non-invasive biomarker of disease symptoms and burden. Our findings further highlight the impact of sexual dimorphism in HD pathophysiology

Finishing a whole-genome shotgun: Release 3 of the Drosophila melanogaster euchromatic genome sequence

BACKGROUND: The Drosophila melanogaster genome was the first metazoan genome to have been sequenced by the whole-genome shotgun (WGS) method. Two issues relating to this achievement were widely debated in the genomics community: how correct is the sequence with respect to base-pair (bp) accuracy and frequency of assembly errors? And, how difficult is it to bring a WGS sequence to the accepted standard for finished sequence? We are now in a position to answer these questions. RESULTS: Our finishing process was designed to close gaps, improve sequence quality and validate the assembly. Sequence traces derived from the WGS and draft sequencing of individual bacterial artificial chromosomes (BACs) were assembled into BAC-sized segments. These segments were brought to high quality, and then joined to constitute the sequence of each chromosome arm. Overall assembly was verified by comparison to a physical map of fingerprinted BAC clones. In the current version of the 116.9 Mb euchromatic genome, called Release 3, the six euchromatic chromosome arms are represented by 13 scaffolds with a total of 37 sequence gaps. We compared Release 3 to Release 2; in autosomal regions of unique sequence, the error rate of Release 2 was one in 20,000 bp. CONCLUSIONS: The WGS strategy can efficiently produce a high-quality sequence of a metazoan genome while generating the reagents required for sequence finishing. However, the initial method of repeat assembly was flawed. The sequence we report here, Release 3, is a reliable resource for molecular genetic experimentation and computational analysis

Angiographic Findings and Outcome in Diabetec Patients Treated With Thrombolytic Therapy for Acute Myocardial Infarction: The GUSTO-I Experience

OBJECTIVES: This study sought to determine whether diabetes mellitus, in the setting of thrombolysis for acute myocardial infarction, affects 1) early infarct-related artery patency and reocclusion rates; and 2) global and regional ventricular function indexes. We also sought to assess whether angiographic or baseline clinical variables, or both, can account for the known excess mortality after myocardial infarction in the diabetic population. BACKGROUND: Mortality after acute myocardial infarction in patients with diabetes is approximately twice that of nondiabetic patients. It is uncertain whether this difference in mortality is due to a lower rate of successful thrombolysis, increased reocclusion after successful thrombolysis, greater ventricular injury or a more adverse angiographic or clinical profile in diabetic patients. METHODS: Patency rates and global and regional left ventricular function were determined in patients enrolled in the GUSTO-I Angiographic Trial. Thirty-day mortality differences between those with and without diabetes were compared. RESULTS: The diabetic cohort had a significantly higher proportion of female and elderly patients, and th

Measuring Granger Causality between Cortical Regions from Voxelwise fMRI BOLD Signals with LASSO

Functional brain network studies using the Blood Oxygen-Level Dependent (BOLD) signal from functional Magnetic Resonance Imaging (fMRI) are becoming increasingly prevalent in research on the neural basis of human cognition. An important problem in functional brain network analysis is to understand directed functional interactions between brain regions during cognitive performance. This problem has important implications for understanding top-down influences from frontal and parietal control regions to visual occipital cortex in visuospatial attention, the goal motivating the present study. A common approach to measuring directed functional interactions between two brain regions is to first create nodal signals by averaging the BOLD signals of all the voxels in each region, and to then measure directed functional interactions between the nodal signals. Another approach, that avoids averaging, is to measure directed functional interactions between all pairwise combinations of voxels in the two regions. Here we employ an alternative approach that avoids the drawbacks of both averaging and pairwise voxel measures. In this approach, we first use the Least Absolute Shrinkage Selection Operator (LASSO) to pre-select voxels for analysis, then compute a Multivariate Vector AutoRegressive (MVAR) model from the time series of the selected voxels, and finally compute summary Granger Causality (GC) statistics from the model to represent directed interregional interactions. We demonstrate the effectiveness of this approach on both simulated and empirical fMRI data. We also show that averaging regional BOLD activity to create a nodal signal may lead to biased GC estimation of directed interregional interactions. The approach presented here makes it feasible to compute GC between brain regions without the need for averaging. Our results suggest that in the analysis of functional brain networks, careful consideration must be given to the way that network nodes and edges are defined because those definitions may have important implications for the validity of the analysis

Granger Causality Analysis of Steady-State Electroencephalographic Signals during Propofol-Induced Anaesthesia

Changes in conscious level have been associated with changes in dynamical integration and segregation among distributed brain regions. Recent theoretical developments emphasize changes in directed functional (i.e., causal) connectivity as reflected in quantities such as ‘integrated information’ and ‘causal density’. Here we develop and illustrate a rigorous methodology for assessing causal connectivity from electroencephalographic (EEG) signals using Granger causality (GC). Our method addresses the challenges of non-stationarity and bias by dividing data into short segments and applying permutation analysis. We apply the method to EEG data obtained from subjects undergoing propofol-induced anaesthesia, with signals source-localized to the anterior and posterior cingulate cortices. We found significant increases in bidirectional GC in most subjects during loss-of-consciousness, especially in the beta and gamma frequency ranges. Corroborating a previous analysis we also found increases in synchrony in these ranges; importantly, the Granger causality analysis showed higher inter-subject consistency than the synchrony analysis. Finally, we validate our method using simulated data generated from a model for which GC values can be analytically derived. In summary, our findings advance the methodology of Granger causality analysis of EEG data and carry implications for integrated information and causal density theories of consciousness

Clinical outcomes according to permanent discontinuation of clopidogrel or placebo in the CHARISMA trial

SummaryBackgroundLate discontinuation of clopidogrel after an acute coronary syndrome or stent placement may be associated with a clinical rebound effect.AimsTo describe the characteristics and evolution of patients non-compliant to study drug in the prospective, randomized, double-blind CHARISMA trial.MethodsOf 15,603 patients aged 45 or older years with established atherothrombotic disease (coronary artery disease, stroke, peripheral arterial disease) or multiple cardiovascular risk factors, 2999 permanently interrupted (withdrawers) study drug (clopidogrel or placebo) during follow-up. The primary endpoint was first occurrence since randomization of myocardial infarction, stroke or cardiovascular death.ResultsWithdrawers displayed a higher risk profile and rates of death/myocardial infarction/stroke (13.5% versus 5.6%; hazard ratio [HR]: 3.18; 95% confidence interval [CI]: 3.05–3.32; p<0.001) and severe bleeding (4.9% versus 0.7%; odds ratio [OR]: 7.42; 95% CI: 5.67–9.70; p<0.001) versus non-withdrawers. Death/myocardial infarction/stroke occurred after an average of 228 days (95% CI: 197–258) and was less frequent in patients assigned to clopidogrel versus placebo (9.7% versus 11.9%; HR: 0.80; 95% CI: 0.64–1.00; p=0.051); the rate of severe bleeding was the same (4.0% versus 4.3%; OR: 0.92; 95% CI: 0.65–1.32; p=0.66). Among withdrawers, initial clopidogrel treatment was an independent correlate of survival (HR: 0.74, 95% CI: 0.59–0.93; p=0.011), but not severe bleeding (OR: 0.94; 95% CI: 0.65–1.35; p=0.74). Kaplan-Meier curves for the primary endpoint suggested no rebound effect or disease reactivation after discontinuation of clopidogrel compared with placebo.ConclusionsPatients who stopped medication had increased rates of ischaemic and bleeding events and mortality. Patients initially on clopidogrel had fewer ischaemic events than those on placebo; discontinuation was not associated with any clinically detectable rebound effect

Comparative Genomics of Gardnerella vaginalis Strains Reveals Substantial Differences in Metabolic and Virulence Potential

Gardnerella vaginalis is described as a common vaginal bacterial species whose presence correlates strongly with bacterial vaginosis (BV). Here we report the genome sequencing and comparative analyses of three strains of G. vaginalis. Strains 317 (ATCC 14019) and 594 (ATCC 14018) were isolated from the vaginal tracts of women with symptomatic BV, while Strain 409-05 was isolated from a healthy, asymptomatic individual with a Nugent score of 9.Substantial genomic rearrangement and heterogeneity were observed that appeared to have resulted from both mobile elements and substantial lateral gene transfer. These genomic differences translated to differences in metabolic potential. All strains are equipped with significant virulence potential, including genes encoding the previously described vaginolysin, pili for cytoadhesion, EPS biosynthetic genes for biofilm formation, and antimicrobial resistance systems, We also observed systems promoting multi-drug and lantibiotic extrusion. All G. vaginalis strains possess a large number of genes that may enhance their ability to compete with and exclude other vaginal colonists. These include up to six toxin-antitoxin systems and up to nine additional antitoxins lacking cognate toxins, several of which are clustered within each genome. All strains encode bacteriocidal toxins, including two lysozyme-like toxins produced uniquely by strain 409-05. Interestingly, the BV isolates encode numerous proteins not found in strain 409-05 that likely increase their pathogenic potential. These include enzymes enabling mucin degradation, a trait previously described to strongly correlate with BV, although commonly attributed to non-G. vaginalis species.Collectively, our results indicate that all three strains are able to thrive in vaginal environments, and therein the BV isolates are capable of occupying a niche that is unique from 409-05. Each strain has significant virulence potential, although genomic and metabolic differences, such as the ability to degrade mucin, indicate that the detection of G. vaginalis in the vaginal tract provides only partial information on the physiological potential of the organism