The effect of neuronal conditional knock-out of peroxisome proliferator-activated receptors in the MPTP mouse model of Parkinson's disease

This study was supported by Parkinson’s Disease Foundation (IRGP 09-11 (P.T.)), the Royal Society (2006/R1 (P.T.)), the Wellcome Trust (WT080782MF (P.T.)), the Biotechnology and Biological Sciences Research Council (P.T. and H.L.M.), the National Institutes of Health (DK057978) (R.M.E.), and by grants from the Leona M. and Harry B. Helmsley Charitable Trust (R.M.E.), the Glenn Foundation for Medical Research (R.M.E.), and the Ellison Medical Foundation (R.M.E.). R.M.E. is an investigator at the Howard Hughes Medical Institute and March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. The authors would like to thank Lynne J. Hocking, University of Aberdeen, for her assistance with the statistics. We are grateful to the staff of the Medical Research Facility for their help with the animal care and the microscopy core facility at the University of Aberdeen for the use of microscopy equipment.Peer reviewedPublisher PD

Challenges and Outcomes of Posterior Wall Isolation for Ablation of Atrial Fibrillation

BACKGROUND: The left atrial posterior wall (PW) often contains sites required for maintenance of atrial fibrillation (AF). Electrical isolation of the PW is an important feature of all open surgeries for AF. This study assessed the ability of current ablation techniques to achieve PW isolation (PWI) and its effect on recurrent AF. METHODS AND RESULTS: Fifty-seven consecutive patients with persistent or high-burden paroxysmal AF underwent catheter ablation, which was performed using an endocardial-only (30) or a hybrid endocardial-epicardial procedure (27). The catheter ablation lesion set included pulmonary vein antral isolation and a box lesion on the PW (roof and posterior lines). Success in creating the box lesion was assessed as electrical silence of the PW (voltage <0.1 mV) and exit block in the PW with electrical capture. Cox proportional hazards models were used for analysis of AF recurrence. PWI was achieved in 21 patients (36.8%), more often in patients undergoing hybrid ablation than endocardial ablation alone (51.9% versus 23.3%, P=0.05). Twelve patients underwent redo ablation. Five of 12 had a successful procedural PWI, but all had PW reconnection at the redo procedure. Over a median follow-up of 302 days, 56.1% of the patients were free of atrial arrhythmias. No parameter including procedural PWI was a statistically significant predictor of recurrent atrial arrhythmias. CONCLUSIONS: PWI during catheter ablation for AF is difficult to achieve, especially with endocardial ablation alone. Procedural achievement of PWI in this group of patients was not associated with a reduction in recurrent atrial arrhythmias, but reconnection of the PW was common

Acute safety, effectiveness, and real-world clinical usage of ultra-high density mapping for ablation of cardiac arrhythmias: results of the TRUE HD study

AIMS: The objective of this study was to verify acute safety, performance, and usage of a novel ultra-high density mapping system in patients undergoing ablation procedure in a real-world clinical setting. METHODS AND RESULTS: The TRUE HD study enrolled patients undergoing catheter ablation with mapping for all arrhythmias (excluding de novo atrial fibrillation) who were followed for 1 month. Safety was determined by collecting all serious adverse events and adverse events associated with the study devices. Performance was determined as the composite of: ability to map the arrhythmia/substrate, complete the ablation applications, arrhythmia termination (where applicable), and ablation validation. Use of mapping system in the ablation validation workflow was also evaluated. Among the 519 patients who underwent a complete (504) or attempted (15) procedure, 21 (4%) serious ablation-related complications were collected, with 3 (0.57%) potentially related to the mapping catheter. Four hundred and twenty treated patients resulted in a successful procedure confirmed by arrhythmia-specific validation techniques (83.3%; 95% confidence interval: 79.8-86.5%). A total of 1419 electroanatomical maps were created with a median acquisition time of 9:23 min per map. Of these, 372 maps in 222 (44%) patients were collected for ablation validation purposes. Following validation mapping, 162/222 (73%) patients required additional ablation. CONCLUSION: In the TRUE HD study mapping was associated with rates of acute success and complications consistent with previously published reports. Importantly, a low percentage of events (0.57%) was attributed to the mapping catheter. When performed, validation mapping was useful for identifying additional targets for ablation in the majority of patients

A peroxisome proliferator-activated receptor-δ agonist provides neuroprotection in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease

Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.Peer reviewedPublisher PD

Trade-offs between antibacterial resistance and fitness cost in the production of metallo-b-lactamases by enteric bacteria manifest as sporadic emergence of carbapenem resistance in a clinical setting

Meropenem is a clinically important antibacterial reserved for treatment of multiresistant infections. In meropenem-resistant bacteria of the family Enterobacterales, NDM-1 is considerably more common than IMP-1, despite both metallo-β-lactamases (MBLs) hydrolyzing meropenem with almost identical kinetics. We show that bla(NDM-1) consistently confers meropenem resistance in wild-type Enterobacterales, but bla(IMP-1) does not. The reason is higher bla(NDM-1) expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness of bla(NDM-1)-positive Enterobacterales. In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encoded bla(NDM-1) having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost, but, consequently, the isolates were not meropenem resistant. However, we identified a Klebsiella pneumoniae isolate from this same clinical case carrying the same bla(NDM-1) plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of a ramR mutation reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting

Scabies Mite Peritrophins Are Potential Targets of Human Host Innate Immunity

The gut of most invertebrates is lined by a protective layer of chitin and glycoproteins, often designated as a peritrophic matrix. Previous research suggests that it forms a barrier that may protect the midgut epithelium from abrasive food particles and pathogens. Parasitic invertebrates ingesting vertebrate plasma have evolved additional strategies to protect themselves from hazardous host molecules consumed during feeding. An important part of the immediate defense in vertebrate plasma is complement-mediated killing. The Complement system is a complex network of more than 35 proteins present in human plasma that results in killing of foreign cells including the gut epithelial cells of a feeding parasite. Recently we found that scabies mites, who feed on skin containing plasma, produce several proteins that inhibit human complement within the mite gut. The mites excrete these molecules into the upper epidermis where they presumably also inhibit complement activity. Mite gut antigens that initially trigger the complement cascade have not been identified previously. Obvious possible targets of complement attack within the mite gut could be peritrophins. Our study describes the first peritrophin identified in scabies mites and indicates a possible role in complement activation

MPP+-induced toxicity in the presence of dopamine is mediated by COX-2 through oxidative stress

Accumulating evidence suggests that endogenous dopamine may act as a neurotoxin and thereby participate in the pathophysiology of Parkinson’s disease (PD). Cyclooxygenase-2 (COX-2) has been implicated in the pathogenesis of PD due to its ability to generate reactive oxygen species (ROS). Inhibition of COX-2 leads to neuroprotection by preventing the formation of dopamine-quinone. In this study, we examined whether dopamine mediates 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in primary ventral mesencephalic (VM) neurons, an in vitro model of PD, and if so, whether the protective effects of COX-2 inhibitors on dopamine mediated MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis result from the reduction of ROS. Reserpine, a dopamine-depleting agent, significantly reduced VM neurotoxicity induced by MPP+, whereas dopamine had an additive effect on MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis. However, inhibition of COX-2 by a selective COX-2 inhibitor (DFU) or ibuprofen significantly attenuated MPP+-induced VM cell toxicity and VM dopaminergic cell apoptosis, which was accompanied by a decrease in ROS production in VM dopaminergic neurons. These results suggest that dopamine itself mediates MPP+-induced VM neurotoxicity and VM dopaminergic cell apoptosis in the presence of COX-2