Determinants of arterial stiffness in COPD

Background

Cardiovascular morbidity and mortality is high in patients with chronic obstructive pulmonary disease (COPD) and arterial stiffness is a potentially modifiable risk factor with added predictive value beyond that obtained from traditional risk factors. Arterial stiffness has been the target of pharmacologic and exercise interventions in patients with COPD, but the effects appear limited to those patients with more significant elevations in arterial stiffness. We aimed to identify predictors of increased arterial stiffness in a cohort with moderate to severe COPD.

Methods

Aortic pulse wave velocity (aPWV) was measured in subjects with moderate to severe COPD enrolled in a multicenter randomized controlled trial. Subjects were categorized into quartiles based on aPWV values and factors affecting high arterial stiffness were assessed. Multivariate models were created to identify independent predictors of high aPWV, and cardiovascular disease (CVD).

Results

153 patients were included. Mean age was 63.2 (SD 8.2) years and mean FEV₁ was 55.4 (SD 15.2) % predicted. Compared to the quartile with the lowest aPWV, subjects in the highest quartile were older, had higher systolic blood pressure (SBP), were more likely to be current smokers, and had greater burden of thoracic aortic calcification. On multivariate analyses, age (adjusted OR 1.14, 95%CI 1.05 to 1.25, p?=?0.003) and SBP (adjusted OR 1.06, 95% CI 1.02 to 1.09, p?=?0.001) were independent predictors of elevated aPWV. Body mass index, therapy with cholesterol lowering medications and coronary calcification were independent predictors of CVD.

Conclusions

Elevated arterial stiffness in patients with COPD can be predicted using age, blood pressure and thoracic aortic calcification. This will help identify subjects for enrollment in clinical trials using aPWV for assessing the impact of COPD therapies on CV outcomes.

Trial registration

Clinicaltrials.gov NCT00857766     

Evidence That Bank Vole PrP Is a Universal Acceptor for Prions

Bank voles are uniquely susceptible to a wide range of prion strains isolated from many different species. To determine if this enhanced susceptibility to interspecies prion transmission is encoded within the sequence of the bank vole prion protein (BVPrP), we inoculated Tg(M109) and Tg(I109) mice, which express BVPrP containing either methionine or isoleucine at polymorphic codon 109, with 16 prion isolates from 8 different species: humans, cattle, elk, sheep, guinea pigs, hamsters, mice, and meadow voles. Efficient disease transmission was observed in both Tg(M109) and Tg(I109) mice. For instance, inoculation of the most common human prion strain, sporadic Creutzfeldt-Jakob disease (sCJD) subtype MM1, into Tg(M109) mice gave incubation periods of ∼200 days that were shortened slightly on second passage. Chronic wasting disease prions exhibited an incubation time of ∼250 days, which shortened to ∼150 days upon second passage in Tg(M109) mice. Unexpectedly, bovine spongiform encephalopathy and variant CJD prions caused rapid neurological dysfunction in Tg(M109) mice upon second passage, with incubation periods of 64 and 40 days, respectively. Despite the rapid incubation periods, other strain-specified properties of many prion isolates—including the size of proteinase K–resistant PrP^Sc, the pattern of cerebral PrP^Sc deposition, and the conformational stability—were remarkably conserved upon serial passage in Tg(M109) mice. Our results demonstrate that expression of BVPrP is sufficient to engender enhanced susceptibility to a diverse range of prion isolates, suggesting that BVPrP may be a universal acceptor for prions.     

Population genetics of Formica aquilonia wood ants in Scotland: the effects of long-term forest fragmentation and recent reforestation

Formica aquilonia wood ants are forest specialists which play a key role in the ecology of forests in Europe. Many of the Scottish populations at the edge of the species distribution range occur in highly fragmented landscapes. We used ten microsatellite loci to study the genetic diversity and structure of populations from two contrasting regions (Inverpolly and the Trossachs) to set the Scottish populations in the context of conspecific populations in mainland Europe. Historically, both study regions have experienced extreme habitat loss and fragmentation over several centuries. Inverpolly has remained fragmented whereas large scale reforestation over the last century has greatly increased the forested area in the Trossachs. Despite the long history of fragmentation, genetic diversity in the Scottish populations was greater than in the populations in mainland Europe. Genetic diversity was similar in the two Scottish regions and no evidence of inbreeding was detected. However, the populations in Inverpolly showed more evidence of genetic bottlenecks, possibly due to more frequent stochastic events such as moorland fires. The ant populations in individual forests were genetically distinct and we detected no contemporary gene flow between forests. The most intensively studied forest where non-native conifer plantations now occupy the matrix between the remaining ancient woodland fragments showed evidence that admixture and gene flow between nests was reducing the past differentiation. This may reflect a dynamic response to the reconnection of previously isolated populations in forest fragments by recent reforestation.     

Low-Dose Curcumin Stimulates Proliferation,Migration and Phagocytic Activity of Olfactory Ensheathing Cells

One of the promising strategies for neural repair therapies is the transplantation of olfactory ensheathing cells (OECs) which are the glial cells of the olfactory system. We evaluated the effects of curcumin on the behaviour of mouse OECs to determine if it could be of use to further enhance the therapeutic potential of OECs. Curcumin, a natural polyphenol compound found in the spice turmeric, is known for its anti-cancer properties at doses over 10 µM, and often at 50 µM, and it exerts its effects on cancer cells in part by activation of MAP kinases. In contrast, we found that low-dose curcumin (0.5 µM) applied to OECs strikingly modulated the dynamic morphology, increased the rate of migration by up to 4-fold, and promoted significant proliferation of the OECs. Most dramatically, low-dose curcumin stimulated a 10-fold increase in the phagocytic activity of OECs. All of these potently stimulated behavioural characteristics of OECs are favourable for neural repair therapies. Importantly, low-dose curcumin gave a transient activation of p38 kinases, which is in contrast to the high dose curcumin effects on cancer cells in which these MAP kinases tend to undergo prolonged activation. Low-dose curcumin mediated effects on OECs demonstrate cell-type specific stimulation of p38 and ERK kinases. These results constitute the first evidence that low-dose curcumin can modulate the behaviour of olfactory glia into a phenotype potentially more favourable for neural repair and thereby improve the therapeutic use of OECs for neural repair therapies.     

Community Mobilisation and Empowerment Interventions as Part of HIV Prevention for Female Sex Workers in Southern India: A Cost-Effectiveness Analysis

Background

Most HIV prevention for female sex workers (FSWs) focuses on individual behaviour change involving peer educators, condom promotion and the provision of sexual health services. However, there is a growing recognition of the need to address broader societal, contextual and structural factors contributing to FSW risk behaviour. We assess the cost-effectiveness of adding community mobilisation (CM) and empowerment interventions (eg. community mobilisation, community involvement in programme management and services, violence reduction, and addressing legal policies and police practices), to core HIV prevention services delivered as part of Avahan in two districts (Bellary and Belgaum) of Karnataka state, Southern India.

Methods

An ingredients approach was used to estimate economic costs in US$ 2011 from an HIV programme perspective of CM and empowerment interventions over a seven year period (2004–2011). Incremental impact, in terms of HIV infections averted, was estimated using a two-stage process. An ‘exposure analysis’ explored whether exposure to CM was associated with FSW’s empowerment, risk behaviours and HIV/STI prevalence. Pathway analyses were then used to estimate the extent to which behaviour change may be attributable to CM and to inform a dynamic HIV transmission model.

Findings

The incremental costs of CM and empowerment were US$ 307,711 in Belgaum and US$ 592,903 in Bellary over seven years (2004–2011). Over a 7-year period (2004–2011) the mean (standard deviation, sd.) number of HIV infections averted through CM and empowerment is estimated to be 1257 (308) in Belgaum and 2775 (1260) in Bellary. This translates in a mean (sd.) incremental cost per disability adjusted life year (DALY) averted of US$ 14.12 (3.68) in Belgaum and US$ 13.48 (6.80) for Bellary - well below the World Health Organisation recommended willingness to pay threshold for India. When savings from ART are taken into account, investments in CM and empowerment are cost saving.

Conclusions

Our findings suggest that CM and empowerment is, at worst, highly cost-effective and, at best, a cost-saving investment from an HIV programme perspective. CM and empowerment interventions should therefore be considered as core components of HIV prevention programmes for FSWs.     

Influence of Corn Residue Harvest Management on Grain,Stover, and Energy Yields

Economic, environmental, and energy independence issues are contributing to rising fossil fuel prices, petroleum supply concerns, and a growing interest in biomass feedstocks as renewable energy sources. Potential feedstocks include perennial grasses, timber, and annual grain crops with our focus being on corn (Zea mays L.) stover. A plot-scale study evaluating stover removal was initiated in 2008 on a South Carolina Coastal Plain Coxville/Rains–Goldsboro–Lynchburg soil association site. In addition to grain and stover yields, carbon balance, greenhouse gas (GHG) emissions and soil quality impact reported elsewhere in this issue, variation in gross energy distribution within various plant fractions — whole plant, below ear shank (bottom), above ear shank (top), cob, as well as leaves and stems of the bottom and top portions (n _{(part, year)}?=?20) was measured with an isoperibol calorimeter. Stalks from above the ear shank were the most energy dense, averaging 18.8 MJ/kg db, and when combined with other plant parts from above the ear shank, the entire top half was more energy dense than the bottom half — 18.4 versus 18.2 MJ/kg db. Gross energy content of the whole plant, including the cob, averaged 18.28?±?0.76 MJ/kg db. Over the 4 years, partial to total removal (i.e., 25 % to 100 %) of above-ground plant biomass could supply between 30 and 168 GJ/ha depending upon annual rainfall. At 168 GJ/ha, the quantity of corn stover biomass (whole plant) available in a 3,254-km² area (32 km radius) around the study site could potentially support a 500-MW power plant.     

Risk of dietary magnesium deficiency is low in most African countries based on food supply data

Background

Dietary mineral deficiencies are widespread in Africa. Our previous studies in Malawi revealed population-level shortfalls in dietary calcium and selenium supply but adequate dietary magnesium (Mg) supply. Here we examine dietary Mg supply throughout Africa.

Methods

Food supply data from 1961 to 2007 were compiled using Food and Agriculture Organization (FAO) Food Balance Sheets (FBSs). Magnesium supply was estimated for each country using regional food Mg composition tables.

Results

Mean Mg supply in 2007 was 649 mg capita ^?1 d^?1, ranging from 188 mg d^?1 in Eritrea to 1,828 mg d^?1 in Burkina Faso. Magnesium supply was greater in West Africa than in other regions, was dominated by sorghum, maize and wheat and was correlated with calorie supply. The World Health Organization (WHO) Estimated Average Requirement (EAR) for Mg (217 mg capita ^?1 d^?1 for adult males) was exceeded in most countries. Using the EAR cut-point method, the risk of dietary Mg deficiency in Africa is <4 % and unlikely to be a major problem, assuming access to sufficient food and that phytic acid does not compromise Mg absorption.

Conclusions

Estimating Mg supply is highly sensitive to concentration data available for the primary staple crops. Given that soil factors profoundly affect crop Mg concentration, there is a need to increase the spatial resolution of food composition tables for the staple crops.     

Anti-antimicrobial Peptides: FOLDING-MEDIATED HOST DEFENSE ANTAGONISTS*

Antimicrobial or host defense peptides are innate immune regulators found in all multicellular organisms. Many of them fold into membrane-bound α-helices and function by causing cell wall disruption in microorganisms. Herein we probe the possibility and functional implications of antimicrobial antagonism mediated by complementary coiled-coil interactions between antimicrobial peptides and de novo designed antagonists: anti-antimicrobial peptides. Using sequences from native helical families such as cathelicidins, cecropins, and magainins we demonstrate that designed antagonists can co-fold with antimicrobial peptides into functionally inert helical oligomers. The properties and function of the resulting assemblies were studied in solution, membrane environments, and in bacterial culture by a combination of chiroptical and solid-state NMR spectroscopies, microscopy, bioassays, and molecular dynamics simulations. The findings offer a molecular rationale for anti-antimicrobial responses with potential implications for antimicrobial resistance.     

The Spontaneously Adhesive Leukocyte Function-associated Antigen-1 (LFA-1) Integrin in Effector T Cells Mediates Rapid Actin- and Calmodulin-dependent Adhesion Strengthening to Ligand under Shear Flow

Integrins in effector T cells are highly expressed and important for trafficking of these cells and for their effector functions. However, how integrins are regulated in effector T cells remains poorly characterized. Here, we have investigated effector T cell leukocyte function-associated antigen-1 (LFA-1) regulation in primary murine effector T cells. These cells have high LFA-1 integrin expression and display high spontaneous binding to intercellular adhesion molecule-1 (ICAM-1) ligand under static conditions. In addition, these cells are able to migrate spontaneously on ICAM-1. Atomic force microscopy measurements showed that the force required for unbinding of integrin-ligand interactions increases over time (0.5–20-s contact time). The maximum unbinding force for this interaction was ∼140 piconewtons at 0.5-s contact time, increasing to 580 piconewtons at 20-s contact time. Also, the total work required to disrupt the interaction increased over the 20-s contact time, indicating LFA-1-mediated adhesion strengthening in primary effector T cells over a very quick time frame. Effector T cells adhered spontaneously to ICAM-1 under conditions of shear flow, in the absence of chemokine stimulation, and this binding was independent of protein kinase B/Akt and protein kinase C kinase activity, but dependent on calcium/calmodulin signaling and an intact actin cytoskeleton. These results indicate that effector T cell integrins are highly expressed and spontaneously adhesive in the absence of inside-out integrin signaling but that LFA-1-mediated firm adhesion under conditions of shear flow requires downstream integrin signaling, which is dependent on calcium/calmodulin and the actin cytoskeleton.     

Seropositivity and geographical distribution of Strongyloides stercoralis in Australia: A study of pathology laboratory data from 2012–2016

BackgroundThere are no national prevalence studies of Strongyloides stercoralis infection in Australia, although it is known to be endemic in northern Australia and is reported in high risk groups such as immigrants and returned travellers. We aimed to determine the seropositivity (number positive per 100,000 of population and percent positive of those tested) and geographical distribution of S. stercoralis by using data from pathology laboratories.MethodologyWe contacted all seven Australian laboratories that undertake Strongyloides serological (ELISA antibody) testing to request de-identified data from 2012–2016 inclusive. Six responded. One provided positive data only. The number of people positive, number negative and number tested per 100,000 of population (Australian Bureau of Statistics data) were calculated including for each state/territory, each Australian Bureau of Statistics Statistical Area Level 3 (region), and each suburb/town/community/locality. The data was summarized and expressed as maps of Australia and Greater Capital Cities.Principal findingsWe obtained data for 81,777 people who underwent serological testing for Strongyloides infection, 631 of whom were from a laboratory that provided positive data only. Overall, 32 (95% CI: 31, 33) people per 100,000 of population were seropositive, ranging between 23/100,000 (95% CI: 19, 29) (Tasmania) and 489/100,000 population (95%CI: 462, 517) (Northern Territory). Positive cases were detected across all states and territories, with the highest (260-996/100,000 and 17–40% of those tested) in regions across northern Australia, north-east New South Wales and north-west South Australia. Some regions in Greater Capital Cities also had a high seropositivity (112-188/100,000 and 17–20% of those tested). Relatively more males than females tested positive. Relatively more adults than children tested positive. Children were under-represented in the data.Conclusions/SignificanceThe study confirms that substantial numbers of S. stercoralis infections occur in Australia and provides data to inform public health planning.