Cortical thinning associated with mild cognitive impairment in Parkinson's disease

The aim of this study was to investigate patterns of cortical atrophy associated with mild cognitive impairment in a large sample of nondemented Parkinson's disease (PD) patients, and its relation with specific neuropsychological deficits. Magnetic resonance imaging (MRI) and neuropsychological assessment were performed in a sample of 90 nondemented PD patients and 32 healthy controls. All underwent a neuropsychological battery including tests that assess different cognitive domains: attention and working memory, executive functions, memory, language, and visuoperceptual‐visuospatial functions. Patients were classified according to their cognitive status as PD patients without mild cognitive impairment (MCI; n = 43) and PD patients with MCI (n = 47). Freesurfer software was used to obtain maps of cortical thickness for group comparisons and correlation with neuropsychological performance. Patients with MCI showed regional cortical thinning in parietotemporal regions, increased global atrophy (global cortical thinning, total gray matter volume reduction, and ventricular enlargement), as well as significant cognitive impairment in memory, executive, and visuospatial and visuoperceptual domains. Correlation analyses showed that all neuropsychological tests were associated with cortical thinning in parietotemporal regions and to a lesser extent in frontal regions. These results provide neuroanatomic support to the concept of MCI classified according to Movement Disorders Society criteria. The posterior pattern of atrophy in temporoparietal regions could be a structural neuroimaging marker of cognitive impairment in nondemented PD patients. All of the neuropsychological tests reflected regional brain atrophy, but no specific patterns were seen corresponding to impairment in distinct cognitive domains. © 2014 International Parkinson and Movement Disorder Society     

Molecular Imaging of Tumor-Associated Angiogenesis Using a Novel Magnetic Resonance Imaging Contrast Agent Targeting αvβ3 Integrin

Background

The recent introduction of biological anticancer therapy has renewed the interest in functional imaging of tumor-associated angiogenesis (TAA) as a tool to monitor early therapy response. The present study evaluated imaging of TAA using P1227, a novel, small molecular magnetic resonance imaging (MRI) probe targeting α_vβ₃ integrin.

Methods

HT29 human colorectal cancers were grown in athymic mice. Dynamic MRI was performed using a three-dimensional VIBE sequence up to 110 min after injection of P1227 or gadolinium–tetraazacyclododecane tetraacetic acid (Gd–DOTA). Specificity was assessed by using P1227 1 h after intravenous administration of the α_vβ₃ inhibitor cilengitide. Regions of interest were drawn encompassing the tumor rim and normal muscle. Imaging data were compared with microvessel density and α_vβ₃ expression.

Results

Using P1227, specific enhancement of the angiogenic tumor rim, but not of normal muscle, was observed, whereas Gd–DOTA enhanced tumor and normal muscle. After administering cilengitide, enhancement with P1227, but not with DOTA, was significantly suppressed during the first 20 min. When using P1227, a significant correlation was observed between normalized enhancement of the tumor rim and immunohistochemical α_vβ₃ integrin expression.

Conclusions

Molecular MRI using a small monogadolinated tracer targeting α_vβ₃ integrin and moderate magnetic field strength holds promise in assessing colorectal TAA.     

Meningitis caused by Pseudallescheria boydii treated with voriconazole.

Meningitis caused by Pseudallescheria boydii is an uncommon infection of the CNS that usually has a poor prognosis and a difficult treatment. We describe a case of chronic meningitis caused by P. boydii in an immunocompetent host that was successfully treated with voriconazole, a new antifungal agent.     

Mimicking natural evolution in metallo-beta-lactamases through second-shell ligand mutations

Metallo-beta-lactamases (MBLs) represent the latest generation of beta-lactamases. The structural diversity and broad substrate profile of MBLs allow them to confer resistance to most beta-lactam antibiotics. To explore the evolutionary potential of these enzymes, we have subjected the Bacillus cereus MBL (BcII) to a directed evolution scheme, which resulted in an increased hydrolytic efficiency toward cephalexin. A systematic study of the hydrolytic profile, substrate binding, and active-site features of the evolved lactamase reveal that directed evolution has shaped the active site by means of remote mutations to better hydrolyze cephalosporins with small, uncharged C-3 substituents. One of these mutations is found in related enzymes from pathogenic bacteria and is responsible for the increase in that enzyme's hydrolytic profile. The mutations lowered the activation energy of the rate-limiting step rather than improved the affinity of the enzyme toward these substrates. The following conclusions can be made: (i) MBLs are able to expand their substrate spectrum without sacrificing their inherent hydrolytic capabilities; (ii) directed evolution is able to mimic mutations that occur in nature; (iii) the metal-ligand strength is tuned by second-shell mutations, thereby influencing the catalytic efficiency; and (iv) changes in the position of the second Zn(II) ion in MBLs affect the substrate positioning in the active site. Overall, these results show that the evolution of enzymatic catalysis can take place by remote mutations controlling reactivity.     

NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both inflammatory processes and oxidative stress may contribute to MPTP- and PD-related neurodegeneration. However, whether inflammation may cause oxidative damage in MPTP and PD is unknown. Here we show that NADPH-oxidase, the main reactive oxygen species (ROS)-producing enzyme during inflammation, is up-regulated in SNpc of human PD and MPTP mice. These changes coincide with the local production of ROS, microglial activation, and DA neuronal loss seen after MPTP injections. Mutant mice defective in NADPH-oxidase exhibit less SNpc DA neuronal loss and protein oxidation than their WT littermates after MPTP injections. We show that extracellular ROS are a main determinant in inflammation-mediated DA neurotoxicity in the MPTP model of PD. This study supports a critical role for NADPH-oxidase in the pathogenesis of PD and suggests that targeting this enzyme or enhancing extracellular antioxidants may provide novel therapies for PD.     

Relationship of lipid oxidation with subclinical atherosclerosis and 10-year coronary events in general population

Objectives

To assess 1) the association of lipid oxidation biomarkers with 10-year coronary artery disease (CAD) events and subclinical atherosclerosis, and 2) the reclassification capacity of these biomarkers over Framingham-derived CAD risk functions, in a general population.

Methods

Within the framework of the REGICOR study, 4782 individuals aged between 25 and 74 years were recruited in a population-based cohort study. Follow-up of the 4042 who met the eligibility criteria was carried out. Plasma, circulating oxidized low-density lipoprotein (oxLDL) and oxLDL antibodies (OLAB) were measured in a random sample of 2793 participants.End-points included fatal and non-fatal acute myocardial infarction (AMI) and angina. Carotid intima-media thickness (IMT) in the highest quintile and ankle-brachial index <0.9 were considered indicators of subclinical atherosclerosis.

Results

Mean age was 50.0 (13.4) years, and 52.4% were women. There were 103 CAD events (34 myocardial infarction, 43 angina, 26 coronary deaths), and 306 subclinical atherosclerosis cases. Oxidized LDL was independently associated with higher incidence of CAD events (HR = 1.70; 95% Confidence Interval: 1.02–2.84), but not with subclinical atherosclerosis. The net classification index of the Framingham-derived CAD risk function was significantly improved when ox-LDL was included (NRI = 14.67% [4.90; 24.45], P = 0.003). No associations were found between OLAB and clinical or subclinical events. The reference values for oxLDL and OLAB are also provided (percentiles).

Conclusions

OxLDL was independently associated with 10-year CAD events but not subclinical atherosclerosis in a general population, and improved the reclassification capacity of Framingham-derived CAD risk functions.     

Synthesis and Anticholinesterase Activity Evaluation of Asymmetric Azines

Pharmaceutical Chemistry Journal - Azines or di-imines are compounds containing R1R2C=N-N=CR3R4 fragment in its structure. These compounds have received special attention due to their importance as...     

Are the Effects of High-Intensity Exercise Training Different in Patients with COPD Versus COPD+Asthma Overlap?

Purpose

This study aimed to investigate whether patients with chronic obstructive pulmonary disease (COPD) presenting asthma overlap (ACO) benefit similarly in comparison to patients with only COPD after a 12-week high-intensity exercise training (ET) program.

Methods

Subjects with a diagnosis of COPD alone or ACO were evaluated and compared before and after a high-intensity ET program composed of walking and cycling plus strengthening exercises of the upper and lower limbs (3 days/week, 3 months, 36 sessions). Assessments included spirometry, bioelectrical impedance, 6-min walk test (6MWT), London Chest Activity of Daily Living Scale (LCADL), Hospital anxiety and depression Scale, modified Medical Research Council Scale (mMRC), Saint George Respiratory Questionnaire (SGRQ), and respiratory and peripheral muscle strength [manovacuometry and 1-repetition maximum test (quadriceps femoris, biceps and triceps brachialis), respectively]. ACO was defined according to Sin et al. (Eur Respir J 48(3):664-673, 2016).

Results

The sample was composed of 74 subjects (57% male, age 67 ± 8 years, BMI 26 (21–32) kg/m², FEV₁ 47 ± 17%predicted), and 12 (16%) of them were classified as presenting ACO. Both groups improved pulmonary function, 6MWT, peripheral and inspiratory muscle strength, LCADL, and SGRQ after ET (p < 0.005 for all). There were no significant interactions between ACO and COPD on ET effects (p > 0.05 for all). Likewise, there was no difference in the proportion of patients achieving the minimum clinical important difference for 6MWT and mMRC.

Conclusion

High-intensity exercise training generates similar benefits in patients with COPD regardless of whether presenting asthma overlap or not.