Elevated Pontine and Putamenal GABA Levels in Mild-Moderate Parkinson Disease Detected by 7 Tesla Proton MRS

Background: Parkinson disease (PD) is characterized by the degeneration of nigrostriatal dopaminergic neurons. However, postmortem evidence indicates that the pathology of lower brainstem regions, such as the pons and medulla, precedes nigral involvement. Consistently, pontomedullary damage was implicated by structural and PET imaging in early PD. Neurochemical correlates of this early pathological involvement in PD are unknown. Methodology/Principal Finding: To map biochemical alterations in the brains of individuals with mild-moderate PD we quantified neurochemical profiles of the pons, putamen and substantia nigra by 7 tesla (T) proton magnetic resonance spectroscopy. Thirteen individuals with idiopathic PD (Hoehn & Yahr stage 2) and 12 age- and gender-matched healthy volunteers participated in the study. c-Aminobutyric acid (GABA) concentrations in the pons and putamen were significantly higher in patients (N = 11, off medications) than controls (N = 11, p,0.001 for pons and p,0.05 for putamen). The GABA elevation was more pronounced in the pons (64%) than in the putamen (32%). No other neurochemical differences were observed between patients and controls. Conclusion/Significance: The GABA elevation in the putamen is consistent with prior postmortem findings in patients with PD, as well as with in vivo observations in a rodent model of PD, while the GABA finding in the pons is novel. The more significant GABA elevation in the pons relative to the putamen is consistent with earlier pathological involvement of th

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain

The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here

Variation in the Glucose Transporter gene <i>SLC2A2 </i>is associated with glycaemic response to metformin

Metformin is the first-line antidiabetic drug with over 100 million users worldwide, yet its mechanism of action remains unclear1. Here the Metformin Genetics (MetGen) Consortium reports a three-stage genome-wide association study (GWAS), consisting of 13,123 participants of different ancestries. The C allele of rs8192675 in the intron of SLC2A2, which encodes the facilitated glucose transporter GLUT2, was associated with a 0.17% (P = 6.6 × 10−14) greater metformin-induced reduction in hemoglobin A1c (HbA1c) in 10,577 participants of European ancestry. rs8192675 was the top cis expression quantitative trait locus (cis-eQTL) for SLC2A2 in 1,226 human liver samples, suggesting a key role for hepatic GLUT2 in regulation of metformin action. Among obese individuals, C-allele homozygotes at rs8192675 had a 0.33% (3.6 mmol/mol) greater absolute HbA1c reduction than T-allele homozygotes. This was about half the effect seen with the addition of a DPP-4 inhibitor, and equated to a dose difference of 550 mg of metformin, suggesting rs8192675 as a potential biomarker for stratified medicine

Advancing tools to promote health equity across European Union regions : The EURO-HEALTHY project

Population health measurements are recognised as appropriate tools to support public health monitoring. Yet, there is still a lack of tools that offer a basis for policy appraisal and for foreseeing impacts on health equity. In the context of persistent regional inequalities, it is critical to ascertain which regions are performing best, which factors might shape future health outcomes and where there is room for improvement. Under the EURO-HEALTHY project, tools combining the technical elements of multi-criteria value models and the social elements of participatory processes were developed to measure health in multiple dimensions and to inform policies. The flagship tool is the Population Health Index (PHI), a multidimensional measure that evaluates health from the lens of equity in health determinants and health outcomes, further divided into sub-indices. Foresight tools for policy analysis were also developed, namely: (1) scenarios of future patterns of population health in Europe in 2030, combining group elicitation with the Extreme-World method and (2) a multi-criteria evaluation framework informing policy appraisal (case study of Lisbon). Finally, a WebGIS was built to map and communicate the results to wider audiences. The Population Health Index was applied to all European Union (EU) regions, indicating which regions are lagging behind and where investments are most needed to close the health gap. Three scenarios for 2030 were produced - (1) the 'Failing Europe' scenario (worst case/increasing inequalities), (2) the 'Sustainable Prosperity' scenario (best case/decreasing inequalities) and (3) the 'Being Stuck' scenario (the EU and Member States maintain the status quo). Finally, the policy appraisal exercise conducted in Lisbon illustrates which policies have higher potential to improve health and how their feasibility can change according to different scenarios. The article makes a theoretical and practical contribution to the field of population health. Theoretically, it contributes to the conceptualisation of health in a broader sense by advancing a model able to integrate multiple aspects of health, including health outcomes and multisectoral determinants. Empirically, the model and tools are closely tied to what is measurable when using the EU context but offering opportunities to be upscaled to other settings

Tractor decelometric trials by application of the ecological hydraulic oil

In this article, there is resumed the accomplished impact analysis of biodegradable tractor oil HYDROS UNI application in gear - hydraulic circuit of the tractor Zetor Proxima 7441. This analysis was performed by comparative testing with standard mineral oil PP 80 on the basis of decelometric trials. Decelometric trials were carried out with measuring device XL - MeterTM Pro Gamma. The measurements were executed by the 3rd and the 4th unreduced gear. The results show that the oil HYDROS UNI does not affect decelometric characteristics of the tractor Zetor Proxima 7441

In vivo macromolecule signals in rat brain 1 H-MR spectra at 9.4T: Parametrization, spline baseline estimation, and T 2 relaxation times

Purpose: Reliable detection and fitting of macromolecules (MM) are crucial for accurate quantification of brain short-echo time (TE) 1 H-MR spectra. An experimentally acquired single MM spectrum is commonly used. Higher spectral resolution at ultra-high field (UHF) led to increased interest in using a parametrized MM spectrum together with flexible spline baselines to address unpredicted spectroscopic components. Herein, we aimed to: (1) implement an advanced methodological approach for post-processing, fitting, and parametrization of 9.4T rat brain MM spectra; (2) assess the concomitant impact of the LCModel baseline and MM model (ie, single vs parametrized); and (3) estimate the apparent T2 relaxation times for seven MM components. Methods: A single inversion recovery sequence combined with advanced AMARES prior knowledge was used to eliminate the metabolite residuals, fit, and parametrize 10 MM components directly from 9.4T rat brain in vivo 1 H-MR spectra at different TEs. Monte Carlo simulations were also used to assess the concomitant influence of parametrized MM and DKNTMN parameter in LCModel. Results: A very stiff baseline (DKNTMN ≥ 1 ppm) in combination with a single MM spectrum led to deviations in metabolite concentrations. For some metabolites the parametrized MM showed deviations from the ground truth for all DKNTMN values. Adding prior knowledge on parametrized MM improved MM and metabolite quantification. The apparent T2 ranged between 12 and 24 ms for seven MM peaks. Conclusion: Moderate flexibility in the spline baseline was required for reliable quantification of real/experimental spectra based on in vivo and Monte Carlo data. Prior knowledge on parametrized MM improved MM and metabolite quantification