Exercise training enhanced myocardial endothelial nitric oxide synthase (eNOS) function in diabetic Goto-Kakizaki (GK) rats

Objective

Exenatide belongs to a new therapeutic class in the treatment of diabetes (incretin mimetics), allowing glucose-dependent glycaemic control in Type 2 diabetes. Randomised controlled trial data suggest that exenatide is as effective as insulin glargine at reducing HbA_1c in combination therapy with metformin and sulphonylureas; with reduced weight but higher incidence of adverse gastrointestinal events. The objective of this study is to evaluate the cost effectiveness of exenatide versus insulin glargine using RCT data and a previously published model of Type 2 diabetes disease progression that is based on the United Kingdom Prospective Diabetes Study; the perspective of the health-payer of the United Kingdom National Health Service.

Methods

The study used a discrete event simulation model designed to forecast the costs and health outcome of a cohort of 1,000 subjects aged over 40 years with sub-optimally-controlled Type 2 diabetes, following initiation of either exenatide, or insulin glargine, in addition to oral hypoglycaemic agents. Sensitivity analysis for a higher treatment discontinuation rate in exenatide patients was applied to the cohort in three different scenarios; (1) either ignored or (2) exenatide-failures excluded or (3) exenatide-failures switched to insulin glargine. Analyses were undertaken to evaluate the price sensitivity of exenatide in terms of relative cost effectiveness. Baseline cohort profiles and effectiveness data were taken from a published randomised controlled trial.

Results

The relative cost-effectiveness of exenatide and insulin glargine was tested under a variety of conditions, in which insulin glargine was dominant in all cases. Using the most conservative of assumptions, the cost-effectiveness ratio of exenatide vs. insulin glargine at the current UK NHS price was -£29,149/QALY (insulin glargine dominant) and thus exenatide is not cost-effective when compared with insulin glargine, at the current UK NHS price.

Conclusion

This study evaluated the relative cost effectiveness of insulin glargine versus exenatide in the management of Type 2 diabetes using a published model. Given no significant difference in glycaemic control and applying the additional effectiveness of exenatide over insulin glargine, with respect to weight loss, and using the current UK NHS prices, insulin glargine was found to be dominant over exenatide in all modelled scenarios. With current clinical evidence, exenatide does not appear to represent a cost-effective treatment option for patients with Type 2 diabetes when compared to insulin glargine.     

A Household-Based Study of Contact Networks Relevant for the Spread of Infectious Diseases in the Highlands of Peru

Background

Few studies have quantified social mixing in remote rural areas of developing countries, where the burden of infectious diseases is usually the highest. Understanding social mixing patterns in those settings is crucial to inform the implementation of strategies for disease prevention and control. We characterized contact and social mixing patterns in rural communities of the Peruvian highlands.

Methods and Findings

This cross-sectional study was nested in a large prospective household-based study of respiratory infections conducted in the province of San Marcos, Cajamarca-Peru. Members of study households were interviewed using a structured questionnaire of social contacts (conversation or physical interaction) experienced during the last 24 hours. We identified 9015 reported contacts from 588 study household members. The median age of respondents was 17 years (interquartile range [IQR] 4–34 years). The median number of reported contacts was 12 (IQR 8–20) whereas the median number of physical (i.e. skin-to-skin) contacts was 8.5 (IQR 5–14). Study participants had contacts mostly with people of similar age, and with their offspring or parents. The number of reported contacts was mainly determined by the participants’ age, household size and occupation. School-aged children had more contacts than other age groups. Within-household reciprocity of contacts reporting declined with household size (range 70%-100%). Ninety percent of household contact networks were complete, and furthermore, household members'' contacts with non-household members showed significant overlap (range 33%-86%), indicating a high degree of contact clustering. A two-level mixing epidemic model was simulated to compare within-household mixing based on observed contact networks and within-household random mixing. No differences in the size or duration of the simulated epidemics were revealed.

Conclusion

This study of rural low-density communities in the highlands of Peru suggests contact patterns are highly assortative. Study findings support the use of within-household homogenous mixing assumptions for epidemic modeling in this setting.     

Household risk factors for Trypanosoma cruzi seropositivity in two geographic regions of Ecuador

Few studies on the relationship between environmental factors and Trypanosoma cruzi transmission have been conducted in Ecuador. We conducted a cross-sectional study of household risk factors for T. cruzi seropositivity in 2 distinct geographical regions of Ecuador. Exposure information was collected via household surveys, and subjects were tested for serological evidence of T. cruzi infection. In total, 3,286 subjects from 997 households were included. In the coastal region, factors associated with seropositivity were living in a house with a palm roof (odds ratio [OR] = 2.63, 95% confidence interval, [1.61. 4.27]), wood walls (OR = 5.75 [2.04, 16.18]), or cane walls (OR = 2.81 11.31, 6.04]), and the presence of firewood in the peridomicile (OR = 2.48 [1.54, 4.01]). Accumulation of trash outside the home was associated with a reduced risk of seropositivity (OR = 0.25 [0.12, 0.51]). In the Andean region, living in a house with adobe walls was the only factor predictive of T. cruzi seropositivity. In conclusion, risk factors for T. cruzi transmission in Ecuador varied by geographic region, probably because of differing behavior of the triatomine vector species in each region. An understanding of the transmission dynamics of T. cruzi in a particular area is necessary for the development of effective Chagas disease control strategies in those areas.     

Hybridism between Biomphalaria cousini and Biomphalaria amazonica and its susceptibility to Schistosoma mansoni

Molecular techniques can aid in the classification of Biomphalaria species because morphological differentiation between these species is difficult. Previous studies using phylogeny, morphological and molecular taxonomy showed that some populations studied were Biomphalaria cousini instead of Biomphalaria amazonica. Three different molecular profiles were observed that enabled the separation of B. amazonica from B. cousini. The third profile showed an association between the two and suggested the possibility of hybrids between them. Therefore, the aim of this work was to investigate the hybridism between B. cousini and B. amazonica and to verify if the hybrids are susceptible to Schistosoma mansoni. Crosses using the albinism factor as a genetic marker were performed, with pigmented B. cousini and albino B. amazonica snails identified by polymerase chain reaction-restriction fragment length polymorphism. This procedure was conducted using B. cousini and B. amazonica of the type locality accordingly to Paraense, 1966. In addition, susceptibility studies were performed using snails obtained from the crosses (hybrids) and three S. mansoni strains (LE, SJ, AL). The crosses between B. amazonica and B. cousini confirmed the occurrence of hybrids. Moreover, hybrids can be considered potential hosts of S. mansoni because they are susceptible to LE, SJ and AL strains (4.4%, 5.6% and 2.2%, respectively). These results indicate that there is a risk of introducing schistosomiasis mansoni into new areas.     

Optimization of microCT imaging and blood vessel diameter quantitation of preclinical specimen vasculature with radiopaque polymer injection medium

Vascular networks within a living organism are complex, multi-dimensional, and challenging to image capture. Radio-angiographic studies in live animals require a high level of infrastructure and technical investment in order to administer costly perfusion mediums whose signals metabolize and degrade relatively rapidly, diminishing within a few hours or days. Additionally, live animal specimens must not be subject to long duration scans, which can cause high levels of radiation exposure to the specimen, limiting the quality of images that can be captured. Lastly, despite technological advances in live-animal specimen imaging, it is quite difficult to minimize or prevent movement of a live animal, which can cause motion artifacts in the final data output. It is demonstrated here that through the use of postmortem perfusion protocols of radiopaque silicone polymer mediums and ex-vivo organ harvest, it is possible to acquire a high level of vascular signal in preclinical specimens through the use of micro-computed tomographic (microCT) imaging. Additionally, utilizing high-order rendering algorithms, it is possible to further derive vessel morphometrics for qualitative and quantitative analysis.     

Enhancement by LDL of transfer of L-4F and oxidized lipids to HDL in C57BL/6J mice and human plasma

The apoA-I mimetic peptide L-4F [(Ac-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2) synthesized from all L-amino acids] has shown potential for the treatment of a variety of diseases. Here, we demonstrate that LDL promotes association between L-4F and HDL. A 2- to 3-fold greater association of L-4F with human HDL was observed in the presence of human LDL as compared with HDL by itself. This association further increased when LDL was supplemented with the oxidized lipid 15S-hydroxy-5Z, 8Z, 11Z, 13E-eicosatetraenoic acid (15HETE). Additionally, L-4F significantly (P = 0.02) promoted the transfer of 15HETE from LDL to HDL. The transfer of L-4F from LDL to HDL was demonstrated both in vitro and in C57BL/6J mice. L-4F, injected into C57BL/6J mice, associated rapidly with HDL and was then cleared quickly from the circulation. Similarly, L-4F loaded onto human HDL and injected into C57BL/6J mice was cleared quickly with T(1/2) = 23.6 min. This was accompanied by a decline in human apoA-I with little or no effect on the mouse apoA-I. Based on these results, we propose that i) LDL promotes the association of L-4F with HDL and ii) in the presence of L-4F, oxidized lipids in LDL are rapidly transferred to HDL allowing these oxidized lipids to be acted upon by HDL-associated enzymes and/or cleared from the circulation.     

Sex, subdivision, and domestic dispersal of Trypanosoma cruzi lineage I in southern Ecuador

Background

Molecular epidemiology at the community level has an important guiding role in zoonotic disease control programmes where genetic markers are suitably variable to unravel the dynamics of local transmission. We evaluated the molecular diversity of Trypanosoma cruzi, the etiological agent of Chagas disease, in southern Ecuador (Loja Province). This kinetoplastid parasite has traditionally been a paradigm for clonal population structure in pathogenic organisms. However, the presence of naturally occurring hybrids, mitochondrial introgression, and evidence of genetic exchange in the laboratory question this dogma.

Methodology/Principal Findings

Eighty-one parasite isolates from domiciliary, peridomiciliary, and sylvatic triatomines and mammals were genotyped across 10 variable microsatellite loci. Two discrete parasite populations were defined: one predominantly composed of isolates from domestic and peridomestic foci, and another predominantly composed of isolates from sylvatic foci. Spatial genetic variation was absent from the former, suggesting rapid parasite dispersal across our study area. Furthermore, linkage equilibrium between loci, Hardy-Weinberg allele frequencies at individual loci, and a lack of repeated genotypes are indicative of frequent genetic exchange among individuals in the domestic/peridomestic population.

Conclusions/Significance

These data represent novel population-level evidence of an extant capacity for sex among natural cycles of T. cruzi transmission. As such they have dramatic implications for our understanding of the fundamental genetics of this parasite. Our data also elucidate local disease transmission, whereby passive anthropogenic domestic mammal and triatomine dispersal across our study area is likely to account for the rapid domestic/peridomestic spread of the parasite. Finally we discuss how this, and the observed subdivision between sympatric sylvatic and domestic/peridomestic foci, can inform efforts at Chagas disease control in Ecuador.     

Stimulation of gastric secretion by acute lateral hypothalamic lesions and its reversal by intracisternal injection of bombesin

Lateral hypothalamic (LH) but not lateral thalamic (LT) electrolytic lesions markedly increased gastric secretion (volume and acidity) in rats within 2 h of production of the lesions and pylorus ligation. Intracisternal injection of bombesin inhibited gastric secretion (volume and acidity) and reduced to control levels the enhanced acid output produced by the LH lesions. These data demonstrate that acute LH lesions stimulate gastric secretion, and that bombesin exerts a potent gastric antisecretory influence, probably through interaction with LH-related stimulatory pathways.     

Movement of Aedes aegypti following a sugar meal and its implication in the development of control strategies in Durán,Ecuador

We evaluated how the presence of sugar sources impacted the distribution of Aedes aegypti in different habitats in Durán , Ecuador. Land cover and normalized difference vegetation index maps were used to guide a random point sampling routine to select study grids (30 m × 30 m) in low vegetation (LV) and high vegetation (HV). Five individual plants, at one home in the LV and HV grid, were treated with a different colored, non‐attractive, 60% sucrose solution to determine mosquito feeding and movement. Sugar alone is not attractive to mosquitoes, so spraying vegetation with a dyed sugar solution can be used for visual determination of sugar feeding. Outdoor collections using BG sentinel traps and indoor collections using aspirators were conducted at the treatment home and with collection points at 20, 40, and 60 m surrounding the treatment home for three consecutive days. A total of 3,245 mosquitoes in two genera, Aedes and Culex, was collected. The proportion of stained Ae. aegypti females was 56.8% (510/898) and 0% for males. For Culex, 63.9% (248/388) females and 36.1% (140/388) males were collected stained. Aedes aegypti and Culex spp. were found up to 60 m stained in both LV and HV grids. Significantly more stained females Ae. aegypti were found inside homes compared to females and males of Culex spp. in both habitats. This study identifies that outdoor sugar feeding is a common behavior of Ae. aegypti and can be targeted as a control strategy in urban habitats in Latin America.