Neuromuscular electrical stimulation prevents muscle wasting in critically ill comatose patients

This is the author accepted manuscript. The final version is available from Portland Press via the DOI in this recordFully sedated patients, being treated in the intensive care unit (ICU), experience substantial skeletal muscle loss. Consequently, survival rate is reduced and full recovery after awakening is compromised. Neuromuscular electrical stimulation (NMES) represents an effective method to stimulate muscle protein synthesis and alleviate muscle disuse atrophy in healthy subjects. We investigated the efficacy of twice-daily NMES to alleviate muscle loss in six fully sedated ICU patients admitted for acute critical illness [n=3 males, n=3 females; age 63 ± 6 y; APACHE II (Acute Physiology and Chronic Health Evaluation II) disease-severity-score: 29 ± 2]. One leg was subjected to twice-daily NMES of the quadriceps muscle for a period of 7 ± 1 day whereas the other leg acted as a non-stimulated control (CON). Directly before the first and on the morning after the final NMES session, quadriceps muscle biopsies were collected from both legs to assess muscle fibre-type-specific cross-sectional area (CSA). Furthermore, phosphorylation status of the key proteins involved in the regulation of muscle protein synthesis was assessed and mRNA expression of selected genes was measured. In the CON leg, type 1 and type 2 muscle-fibre-CSA decreased by 16 ± 9% and 24 ± 7% respectively (P<0.05). No muscle atrophy was observed in the stimulated leg. NMES increased mammalian target of rapamycin (mTOR) phosphorylation by 19 ± 5% when compared with baseline (P<0.05), with no changes in the CON leg. Furthermore, mRNA expression of key genes involved in muscle protein breakdown either declined [forkhead box protein O1 (FOXO1); P<0.05] or remained unchanged [muscle atrophy F-box (MAFBx) and muscle RING-finger protein-1 (MuRF1)], with no differences between the legs. In conclusion, NMES represents an effective and feasible interventional strategy to prevent skeletal muscle atrophy in critically ill comatose patients

How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRR’s Rehabilitation Engineering Research Centers

Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a “total approach to rehabilitation”, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970’s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

Using magnetoencephalography to investigate brain activity during high frequency deep brain stimulation in a cluster headache patient

PURPOSE: Treatment-resistant cluster headache can be successfully alleviated with deep brain stimulation (DBS) of the posterior hypothalamus [1]. Magnetoencephalography (MEG) is a non-invasive functional imaging technique with both high temporal and high spatial resolution. However, it is not known whether the inherent electromagnetic (EM) noise produced by high frequency DBS is compatible with MEG. MATERIALS AND METHODS: We used MEG to record brain activity in an asymptomatic cluster headache patient with a DBS implanted in the right posterior hypothalamus while he made small movements during periods of no stimulation, 7 Hz stimulation and 180 Hz stimulation. RESULTS: We were able to measure brain activity successfully both during low and high frequency stimulation. Analysis of the MEG recordings showed similar activation in motor areas in during the patient's movements as expected. We also observed similar activations in cortical and subcortical areas that have previously been reported to be associated with pain when the patient's stimulator was turned on or off [2,3]. CONCLUSION: These results show that MEG can be used to measure brain activity regardless of the presence of high frequency deep brain stimulation

Climate Policy Under Fat-Tailed Risk: An Application of Dice

Uncertainty plays a significant role in evaluating climate policy, and fat-tailed uncertainty may dominate policy advice. Should we make our utmost effort to prevent the arbitrarily large impacts of climate change under deep uncertainty? In order to answer to this question, we propose a new way of investigating the impact of (fat-tailed) uncertainty on optimal climate policy: the curvature of the optimal carbon tax against the uncertainty. We find that the optimal carbon tax increases as the uncertainty about climate sensitivity increases, but it does not accelerate as implied by Weitzman's Dismal Theorem. We find the same result in a wide variety of sensitivity analyses. These results emphasize the importance of balancing the costs of climate change against its benefits, also under deep uncertainty. © 2013 Springer Science+Business Media Dordrecht

Adipokine Imbalance in the Pericardial Cavity of Cardiac and Vascular Disease Patients

Aim Obesity and especially hypertrophy of epicardial adipose tissue accelerate coronary atherogenesis. We aimed at comparing levels of inflammatory and atherogenic hormones from adipose tissue in the pericardial fluid and circulation of cardiovascular disease patients. Methods and Results Venous plasma (P) and pericardial fluid (PF) were obtained from elective cardiothoracic surgery patients (n = 37). Concentrations of leptin, adipocyte fatty acid-binding protein (AFABP) and adiponectin (APN) were determined by enzyme-linked immunosorbent assays (ELISA). The median concentration of leptin in PF (4.3 (interquartile range: 2.8-9.1) mu g/L) was comparable to that in P (5.9 (2.2-11) mu g/L) and these were significantly correlated to most of the same patient characteristics. The concentration of A-FABP was markedly higher (73 (28-124) versus 8.4 (5.2-14) mu g/L) and that of APN was markedly lower (2.8 (1.7-4.2) versus 13 (7.2-19) mg/L) in PF compared to P. APN in PF was unlike in P not significantly related to age, body mass index, plasma triglycerides or coronary artery disease. PF levels of APN, but not A-FABP, were related to the size of paracardial adipocytes. PF levels of APN and A-FABP were not related to the immunoreactivity of paracardial adipocytes for these proteins. Conclusion In cardiac and vascular disease patients, PF is enriched in A-FABP and poor in APN. This adipokine microenvironment is more likely determined by the heart than by the circulation or paracardial adipose tissue.published_or_final_versio

Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia.

Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International Licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material.The activation of microglia, resident immune cells of the central nervous system, and inflammation-mediated neurotoxicity are typical features of neurodegenerative diseases, for example, Alzheimer's and Parkinson's diseases. An unexpected role of caspase-3, commonly known to have executioner role for apoptosis, was uncovered in the microglia activation process. A central question emerging from this finding is what prevents caspase-3 during the microglia activation from killing those cells? Caspase-3 activation occurs as a two-step process, where the zymogen is first cleaved by upstream caspases, such as caspase-8, to form intermediate, yet still active, p19/p12 complex; thereafter, autocatalytic processing generates the fully mature p17/p12 form of the enzyme. Here, we show that the induction of cellular inhibitor of apoptosis protein 2 (cIAP2) expression upon microglia activation prevents the conversion of caspase-3 p19 subunit to p17 subunit and is responsible for restraining caspase-3 in terms of activity and subcellular localization. We demonstrate that counteracting the repressive effect of cIAP2 on caspase-3 activation, using small interfering RNA targeting cIAP2 or a SMAC mimetic such as the BV6 compound, reduced the pro-inflammatory activation of microglia cells and promoted their death. We propose that the different caspase-3 functions in microglia, and potentially other cell types, reside in the active caspase-3 complexes formed. These results also could indicate cIAP2 as a possible therapeutic target to modulate microglia pro-inflammatory activation and associated neurotoxicity observed in neurodegenerative disorders

Involvement of a Natural Fusion of a Cytochrome P450 and a Hydrolase in Mycophenolic Acid Biosynthesis

Mycophenolic acid (MPA) is a fungal secondary metabolite and the active component in several immunosuppressive pharmaceuticals. The gene cluster coding for the MPA biosynthetic pathway has recently been discovered in Penicillium brevicompactum, demonstrating that the first step is catalyzed by MpaC, a polyketide synthase producing 5-methylorsellinic acid (5-MOA). However, the biochemical role of the enzymes encoded by the remaining genes in the MPA gene cluster is still unknown. Based on bioinformatic analysis of the MPA gene cluster, we hypothesized that the step following 5-MOA production in the pathway is carried out by a natural fusion enzyme MpaDE, consisting of a cytochrome P450 (MpaD) in the N-terminal region and a hydrolase (MpaE) in the C-terminal region. We verified that the fusion gene is indeed expressed in P. brevicompactum by obtaining full-length sequence of the mpaDE cDNA prepared from the extracted RNA. Heterologous coexpression of mpaC and the fusion gene mpaDE in the MPA-nonproducer Aspergillus nidulans resulted in the production of 5,7-dihydroxy-4-methylphthalide (DHMP), the second intermediate in MPA biosynthesis. Analysis of the strain coexpressing mpaC and the mpaD part of mpaDE shows that the P450 catalyzes hydroxylation of 5-MOA to 4,6-dihydroxy-2-(hydroxymethyl)-3-methylbenzoic acid (DHMB). DHMB is then converted to DHMP, and our results suggest that the hydrolase domain aids this second step by acting as a lactone synthase that catalyzes the ring closure. Overall, the chimeric enzyme MpaDE provides insight into the genetic organization of the MPA biosynthesis pathway

Core components for effective infection prevention and control programmes: new WHO evidence-based recommendations

Abstract Health care-associated infections (HAI) are a major public health problem with a significant impact on morbidity, mortality and quality of life. They represent also an important economic burden to health systems worldwide. However, a large proportion of HAI are preventable through effective infection prevention and control (IPC) measures. Improvements in IPC at the national and facility level are critical for the successful containment of antimicrobial resistance and the prevention of HAI, including outbreaks of highly transmissible diseases through high quality care within the context of universal health coverage. Given the limited availability of IPC evidence-based guidance and standards, the World Health Organization (WHO) decided to prioritize the development of global recommendations on the core components of effective IPC programmes both at the national and acute health care facility level, based on systematic literature reviews and expert consensus. The aim of the guideline development process was to identify the evidence and evaluate its quality, consider patient values and preferences, resource implications, and the feasibility and acceptability of the recommendations. As a result, 11 recommendations and three good practice statements are presented here, including a summary of the supporting evidence, and form the substance of a new WHO IPC guideline