Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart

Multiple brief periods of ischemia in the mammalian heart elicits protection against morphologic and functional damage caused by longer-duration ischemia. Preconditioning-induced protection against post-ischemic contractile dysfunction has been reported to be depressed with aging of the adult heart. This study was undertaken to determine whether aging of the adult myocardium reduces the preconditioning-induced attenuation of necrosis observed with ischemia. Isolated, perfused hearts obtained from Fischer 344 rats of either 3 (young) or 22 (aged) months of age were paced and instrumented for determination of developed left ventricular pressure. Necrosis was determined with triphenyltetrazolium. In the absence of preconditioning, young and aged adult hearts made globally ischemic for 45 min developed necrosis involving 53+/-6% and 49+/-6% of the myocardium, respectively. Contractile function (+dP/dt(max)) at 90 min of reperfusion was depressed by 80% in young and 52% in aged hearts, compared to values obtained prior to preconditioning. Preconditioning with two 5 min ischemia/5 min reperfusion cycles significantly reduced necrosis development and enhanced reperfusion contractile function in young hearts. However, in aged adult hearts, the preconditioning did not significantly reduce the development of necrosis or enhance reperfusion contractile function. These data suggest that aging reduces the effectiveness of preconditioning in providing cardioprotection against ischemic-induced myocardial necrosis.     

A C-Peptide-Based Model of Pancreatic Insulin Secretion in Extremely Preterm Neonates in Intensive Care

Background:

Model-based glycemic control relies on sufficiency of underlying models to describe underlying patient physiology. In particular, very preterm infant glucose-insulin metabolism can differ significantly from adults, and is relatively unstudied. In this study, C-peptide concentrations are used to develop insulin-secretion models for the purposes of glycemic control in neonatal intensive care.

Methods:

Plasma C-peptide, insulin, and blood glucose concentrations (BGC) were retrospectively analyzed from a cohort of 41 hyperglycemic very preterm (median age 27.2 [26.2-28.7] weeks) and very low birth-weight infants (median birth weight 839 [735-1000] g). A 2-compartment model of C-peptide kinetics was used to estimate insulin secretion. Insulin secretion was examined with respect to nutritional intake, exogenous and plasma insulin concentration, and BGC.

Results:

Insulin secretion was found to be highly variable between patients and over time, and could not be modeled with respect to age, weight, or protein or dextrose intake. In 13 of 54 samples exogenous insulin was being administered, and insulin secretion was lower. However, low data numbers make this result inconclusive. Insulin secretion was found to increase with BG, with a stronger association in female infants than males (R² = .51 vs R² = .13, and R² = .26 for the combined cohort).

Conclusions:

A sex-based insulin secretion model was created and incorporated into a model-based glycemic control framework. Nutritional intake did not predict insulin secretion, indicating that insulin secretion is a complex function of a number of metabolic factors.     

Achieving the optimal epinephrine effect in wide awake hand surgery using local anesthesia without a tourniquet

Background

In our experience, for all surgeries in the hand, the optimal epinephrine effect from local anesthesia—producing maximal vasoconstriction and visualization—is achieved by waiting significantly longer than the traditionally quoted 7 min from the time of injection.

Methods

In this prospective comparative study, healthy patients undergoing unilateral carpal tunnel surgery waited either 7 min or roughly 30 min, between the time of injection of 1 % lidocaine with 1:100,000 epinephrine and the time of incision. A standardized incision was made through dermis and into the subcutaneous tissue followed by exactly 60 s of measuring the quantity of blood loss using sterile micropipettes.

Results

There was a statistically significant reduction in the mean quantity of bleeding in the group that waited roughly 30 min after injection and before incision compared to the group that waited only 7 min (95 % confidence intervals of 0.06 + −0.03 ml/cm of incision, compared to 0.17 + −0.08 ml/cm, respectively) (P = 0.03).

Conclusions

Waiting roughly 30 min after injection of local anesthesia with epinephrine as oppose to the traditionally taught 7 min, achieves an optimal epinephrine effect and vasoconstriction. In the hand, this will result in roughly a threefold reduction in bleeding—making wide awake local anesthesia without tourniquet (WALANT) possible. This knowledge has allowed our team to expand the hand procedures that we can offer using WALANT. The benefits of WALANT hand surgery include reduced cost and waste, improved patient safety, and the ability to perform active intraoperative movement examinations.     

Antimitochondrial Antibody-Negative Primary Biliary Cirrhosis

Objectives : We reviewed our experience with patients who had biochemical and histological features of primary biliary cirrhosis in the absence of antimitochondrial antibodies (AMA) to better understand this variant of the syndrome. Methods : During the period between 1976 to 1992, 597 patients with clinical and histological features of primary biliary cirrhosis were seen at the Mayo Clinic. Thirty-five (5.8%) of these patients were negative for antimitochondrial antibody and had normal cholangiographic studies. The records of these patients were reviewed for this study. Results : No difference was found between the two groups with respect to age, gender, or biochemical features. IgM and γ-globulin levels were higher in the antimitochondrial antibody-positive than the antimitochondrial antibody-negative patients. What is more important, 96% of the AMA-negative patients who could be tested were positive for antinuclear antibody or anti-smooth-muscle antibodies. These tests were positive in only 56% of the antimitochondrial antibody-positive group (p < 0.05). The response of five of these patients to ursodeoxycholic acid appeared comparable to the response seen in antimitochondrial antibody-positive patients. Conclusions : Patients with histological features of primary biliary cirrhosis, whether antimitochondrial antibody positive or negative, are quite comparable with respect to clinical and biochemical features. Other autoantibodies, such as antinuclear or anti-smooth-muscle antibodies, are more common in the antimitochondrial antibody-negative group. These two conditions might be part of a spectrum that has been termed "autoimmune cholangitis" and that is characterized by chronic cholestasis, histological features of chronic nonsuppurative destructive cholangitis, and the presence of any of a variety of serum autoantibodies.     

Building skill in heart failure self-care among community dwelling older adults: Results of a pilot study

Objective

Most of the day-to-day care for heart failure (HF) is done by the patient at home and requires skill in self-care. In this randomized controlled trial (RCT) we tested the efficacy of a community-based skill-building intervention on HF self-care, knowledge and health-related quality of life (HRQL) at 1- and 3-months.

Methods

An ethnically diverse sample (n = 75) of patients with HF (53% female; 32% Hispanic, 27% Black; mean age 69.9 ± 10 years) was randomized to the intervention group (IG) or a wait-list control group (CG). The protocol intervention focused on tactical and situational HF self-care skill development delivered by lay health educators in community senior centers. Data were analyzed using mixed (between–within subjects) ANOVA.

Results

There was a significant improvement in self-care maintenance [F(2, 47) = 3.42, p = .04, (Cohen's f = .38)], self-care management [F(2, 41) = 4.10, p = .02, (Cohen's f = .45) and HF knowledge [F(2, 53) = 8.00, p = .001 (Cohen's f = .54)] in the IG compared to the CG.

Conclusions

The skill-building intervention improved self-care and knowledge but not HRQL in this community-dwelling sample.

Practice implications

Delivering an intervention in a community setting using lay health educators provides an alternative to clinic- or home-based teaching that may be useful across diverse populations and geographically varied settings.     

Perennial grasslands enhance biodiversity and multiple ecosystem services in bioenergy landscapes

Agriculture is being challenged to provide food, and increasingly fuel, for an expanding global population. Producing bioenergy crops on marginal lands—farmland suboptimal for food crops—could help meet energy goals while minimizing competition with food production. However, the ecological costs and benefits of growing bioenergy feedstocks—primarily annual grain crops—on marginal lands have been questioned. Here we show that perennial bioenergy crops provide an alternative to annual grains that increases biodiversity of multiple taxa and sustain a variety of ecosystem functions, promoting the creation of multifunctional agricultural landscapes. We found that switchgrass and prairie plantings harbored significantly greater plant, methanotrophic bacteria, arthropod, and bird diversity than maize. Although biomass production was greater in maize, all other ecosystem services, including methane consumption, pest suppression, pollination, and conservation of grassland birds, were higher in perennial grasslands. Moreover, we found that the linkage between biodiversity and ecosystem services is dependent not only on the choice of bioenergy crop but also on its location relative to other habitats, with local landscape context as important as crop choice in determining provision of some services. Our study suggests that bioenergy policy that supports coordinated land use can diversify agricultural landscapes and sustain multiple critical ecosystem services.In agricultural landscapes, balancing the provisioning of food and energy with maintenance of biodiversity and ecosystem functions is a global challenge. To avoid impacts on food production, attention is increasingly being focused on the potential for marginal lands to support bioenergy production (1). Marginal lands, those suboptimal for food production, may consist of relatively small areas within generally productive landscapes or larger regions where conditions generally limit crop productivity. However, there is increasing recognition that these lands are already performing a variety of useful functions, and their conversion to bioenergy cropping could reduce these services. For example, in the north central United States, rising commodity prices are predicted to bring marginal croplands—including Conservation Reserve Program lands—into annual crop production with negative impacts on wildlife habitat and water quality (2, 3). With 2013 corn plantings at recent record highs (4) and new reports of grassland and wetland conversion to cropland (5, 6), this may be occurring already.An alternative to annual cropping is conversion of marginal croplands to perennial, cellulosic crops for bioenergy. Although current US biofuel production centers on grain ethanol derived from annual monocultures of maize (Zea mays), this situation could change with full implementation of the 2007 US Energy Independence and Security Act (7), which calls for increased production of cellulosic biofuels. In the Midwest United States, perennial grasses and forbs grown on marginal lands could provide up to 25% of national targets for cellulosic biofuel, with substantial greenhouse gas (GHG) benefits (8). Moreover, increasing the area of perennial cover on the landscape is predicted to positively affect a diverse array of organisms and ecological functions (9–11), leading to important synergies that have not yet informed the ongoing bioenergy debate. Here we provide the most comprehensive empirical evaluation of this hypothesis to date, reporting data that elucidate the impacts of different bioenergy cropping systems on a wide variety of organisms and the ecosystem functions they perform.Previous studies have examined the ability of select bioenergy crops to support specific taxa (12) or individual services such as energy production (13) or GHG mitigation (14), without consideration of the tradeoffs or synergies that can arise when considering entire suites of organisms and ecosystem functions. We report on a unique multidisciplinary study of matched sets of organisms and ecosystem services and show that perennial grass energy crops (switchgrass, Panicum virgatum, and mixed prairie plantings) synergistically enhance diversity of a variety of organisms and levels of the services they provide. We further quantify the importance of landscape context on service provisioning, suggesting that policy supporting intentional design of bioenergy landscapes could increase sustainability of both food and energy production.     

Comprehensive Sterilization of Malaria Vectors Using Pyriproxyfen: A Step Closer to Malaria Elimination

One of the main challenges to malaria elimination is the resilience of vectors, such as Anopheles arabiensis, that evade lethal exposure to insecticidal control measures or express resistance to their active ingredients. This study investigated a novel technology for population control that sterilizes mosquitoes using pyriproxyfen, a juvenile hormone analogue. Females of An. arabiensis were released in a semifield system divided into four equal sections, and each section had a mud hut sheltering a tethered cow providing a blood source for mosquitoes. In all sections, the inner mud hut walls and roofs were lined with black cotton cloth. In one-half of the sections, the cloth was dusted with pyriproxyfen. An overwhelming 96% reduction in adult production was achieved in pyriproxyfen-treated sections compared with control sections. This unprecedented level of control can be exploited to design new vector control strategies that particularly target existing behaviorally resilient and insecticide-resistant populations.     

Novel mutation in MAPT exon 13 (p.N410H) causes corticobasal degeneration

In order to determine the frequency of microtubule-associated protein tau gene (MAPT) mutations and rare variants in CBD, we performed a systematic sequence analysis of MAPT coding and 3′ untranslated region (3′UTR) in a large cohort of autopsy-confirmed CBD patients (N = 109). This identified a novel MAPT mutation in exon 13, p.N410H, in a case that is neuropathologically indistinguishable from sporadic CBD. On immunoblot, the p.N410H mutation carrier had the same insoluble tau profile as seen in CBD. Additionally, tau expression analysis in brain tissue found a significant increase in the 4R/3R tau mRNA ratio (P = 0.04), indicating that p.N410H disrupts tau isoform homeostasis. Biochemically, recombinant tau protein with p.N410H showed a marked increase in tau filament formation compared to wild-type tau (P < 0.001), had a 19.2 % decrease in rate of microtubule assembly (P < 0.05), and a 10.3 % reduction in the extent of total microtubule polymerization (P < 0.01). Sequence analysis of the complete MAPT 3′UTR in autopsy-confirmed CBD cases further identified two rare variants with nominally significant association with CBD. An ATC nucleotide insertion (“MAPTv8”) was found in 4.6 % of CBD patients compared to 1.2 % of controls (P = 0.031, OR = 3.71), and rs186977284 in 4.6 % CBD patients, but only 0.9 % of controls (P = 0.04, OR = 3.58). Rs186977284 was also present in 2.7 % of a large cohort of autopsy-confirmed PSP patients (N = 566) and only 0.9 % of an additional control series (P = 0.034, OR = 3.08), extending the association to PSP. Our findings show that mutations in MAPT can cause CBD and MAPT non-coding variants may increase the risk of complex 4R tauopathies.     

Aggregation-prone c9FTD/ALS poly(GA) RAN-translated proteins cause neurotoxicity by inducing ER stress

The occurrence of repeat-associated non-ATG (RAN) translation, an atypical form of translation of expanded repeats that results in the synthesis of homopolymeric expansion proteins, is becoming more widely appreciated among microsatellite expansion disorders. Such disorders include amyotrophic lateral sclerosis and frontotemporal dementia caused by a hexanucleotide repeat expansion in the C9ORF72 gene (c9FTD/ALS). We and others have recently shown that this bidirectionally transcribed repeat is RAN translated, and the “c9RAN proteins” thusly produced form neuronal inclusions throughout the central nervous system of c9FTD/ALS patients. Nonetheless, the potential contribution of c9RAN proteins to disease pathogenesis remains poorly understood. In the present study, we demonstrate that poly(GA) c9RAN proteins are neurotoxic and may be implicated in the neurodegenerative processes of c9FTD/ALS. Specifically, we show that expression of poly(GA) proteins in cultured cells and primary neurons leads to the formation of soluble and insoluble high molecular weight species, as well as inclusions composed of filaments similar to those observed in c9FTD/ALS brain tissues. The expression of poly(GA) proteins is accompanied by caspase-3 activation, impaired neurite outgrowth, inhibition of proteasome activity, and evidence of endoplasmic reticulum (ER) stress. Of importance, ER stress inhibitors, salubrinal and TUDCA, provide protection against poly(GA)-induced toxicity. Taken together, our data provide compelling evidence towards establishing RAN translation as a pathogenic mechanism of c9FTD/ALS, and suggest that targeting the ER using small molecules may be a promising therapeutic approach for these devastating diseases.