Clinical utility of fixed combinations of sitagliptin–metformin in treatment of type 2 diabetes

Adequate glycemic control in type 2 diabetes remains a difficult but achievable goal. The development of new classes of glucose-lowering medications, including in particular the incretin-based therapies, provides an opportunity to utilize combinations of medications which target multiple physiologic abnormalities in type 2 diabetes. Complementary combination therapy with sitagliptin–metformin lowers glucose via enhancement of insulin secretion, suppression of glucagon secretion, and insulin sensitization. Use of this combination in diabetes management will provide a greater degree of glycosylated hemoglobin-lowering than that seen with the use of either drug as monotherapy, is unlikely to cause significant hypoglycemia, and is generally associated with weight loss. The effectiveness, tolerability, and potential cost savings associated with the use of sitagliptin–metformin combination therapy make this an attractive option in diabetes management. The possible beneficial effects of this therapy on beta cell function, as well as its cardiovascular impact, remain inadequately explored but are of significant interest

Heterologous Expression of Secondary Metabolite Genes in Trichoderma reesei for Waste Valorization

Trichoderma reesei (Hypocrea jecorina) was developed as a microbial cell factory for the heterologous expression of fungal secondary metabolites. This was achieved by inactivation of sorbicillinoid biosynthesis and construction of vectors for the rapid cloning and expression of heterologous fungal biosynthetic genes. Two types of megasynth(et)ases were used to test the strain and vectors, namely a non-reducing polyketide synthase (nr-PKS, aspks1) from Acremonium strictum and a hybrid highly-reducing PKS non-ribosomal peptide synthetase (hr-PKS-NRPS, tenS + tenC) from Beauveria bassiana. The resulting engineered T. reesei strains were able to produce the expected natural products 3-methylorcinaldehyde and pretenellin A on waste materials including potato, orange, banana and kiwi peels and barley straw. Developing T. reesei as a heterologous host for secondary metabolite production represents a new method for waste valorization by the direct conversion of waste biomass into secondary metabolites

Effector memory differentiation increases detection of replication-competent HIV-l in resting CD4+ T cells from virally suppressed individuals.

Studies have demonstrated that intensive ART alone is not capable of eradicating HIV-1, as the virus rebounds within a few weeks upon treatment interruption. Viral rebound may be induced from several cellular subsets; however, the majority of proviral DNA has been found in antigen experienced resting CD4+ T cells. To achieve a cure for HIV-1, eradication strategies depend upon both understanding mechanisms that drive HIV-1 persistence as well as sensitive assays to measure the frequency of infected cells after therapeutic interventions. Assays such as the quantitative viral outgrowth assay (QVOA) measure HIV-1 persistence during ART by ex vivo activation of resting CD4+ T cells to induce latency reversal; however, recent studies have shown that only a fraction of replication-competent viruses are inducible by primary mitogen stimulation. Previous studies have shown a correlation between the acquisition of effector memory phenotype and HIV-1 latency reversal in quiescent CD4+ T cell subsets that harbor the reservoir. Here, we apply our mechanistic understanding that differentiation into effector memory CD4+ T cells more effectively promotes HIV-1 latency reversal to significantly improve proviral measurements in the QVOA, termed differentiation QVOA (dQVOA), which reveals a significantly higher frequency of the inducible HIV-1 replication-competent reservoir in resting CD4+ T cells

'A bite before bed': exposure to malaria vectors outside the times of net use in the highlands of western Kenya.

BACKGROUND: The human population in the highlands of Nyanza Province, western Kenya, is subject to sporadic epidemics of Plasmodium falciparum. Indoor residual spraying (IRS) and long-lasting insecticide treated nets (LLINs) are used widely in this area. These interventions are most effective when Anopheles rest and feed indoors and when biting occurs at times when individuals use LLINs. It is therefore important to test the current assumption of vector feeding preferences, and late night feeding times, in order to estimate the extent to which LLINs protect the inhabitants from vector bites. METHODS: Mosquito collections were made for six consecutive nights each month between June 2011 and May 2012. CDC light-traps were set next to occupied LLINs inside and outside randomly selected houses and emptied hourly. The net usage of residents, their hours of house entry and exit and times of sleeping were recorded and the individual hourly exposure to vectors indoors and outdoors was calculated. Using these data, the true protective efficacy of nets (P*), for this population was estimated, and compared between genders, age groups and from month to month. RESULTS: Primary vector species (Anopheles funestus s.l. and Anopheles arabiensis) were more likely to feed indoors but the secondary vector Anopheles coustani demonstrated exophagic behaviour (p < 0.05). A rise in vector biting activity was recorded at 19:30 outdoors and 18:30 indoors. Individuals using LLINs experienced a moderate reduction in their overall exposure to malaria vectors from 1.3 to 0.47 bites per night. The P* for the population over the study period was calculated as 51% and varied significantly with age and season (p < 0.01). CONCLUSIONS: In the present study, LLINs offered the local population partial protection against malaria vector bites. It is likely that P* would be estimated to be greater if the overall suppression of the local vector population due to widespread community net use could be taken into account. However, the overlap of early biting habit of vectors and human activity in this region indicates that additional methods of vector control are required to limit transmission. Regular surveillance of both vector behaviour and domestic human-behaviour patterns would assist the planning of future control interventions in this region

Effectiveness of Small Onshore Seawall in Reducing Forces Induced by Tsunami Bore: Large Scale Experimental Study

Tsunami force and pressure distributions on a rigid wall fronted by a small seawall were determined experimentally in a large-scale wave flume. Six different seawall heights were examined, two of which were exposed to a range of solitary wave heights. The same experiment was done without a seawall for comparison. The measured wave profile contained incident offshore, incident broken, reflected broken, and transmitted wave heights measured using wire resistance and ultrasonic wave gauges. Small individual seawalls increased reflection of the incoming broken bore front and reduced force on the rigid landward wall. These findings agree well with published field reconnaissance on small seawalls in Thailand that showed a correlation between seawalls and reduced damage on landward structures.This is the publisher’s final pdf. The published article is copyrighted by the author(s) and published by Fuji Technology Press. The published article can be found at: http://www.fujipress.jp/JDR/.Keywords: tsunami inundation, tsunami defense strategy, tsunami hazard mitigation, tsunami risk reduction, wave force

Evaluation of Tsunami Loads on Wood Frame Walls at Full Scale

The performance of full-scale light-frame wood walls subjected to wave loading was examined using the Large Wave Flume of the Network for Earthquake Engineering (NEES) Tsunami Facility at Oregon State University. The hydrodynamic conditions (water level and bore speed) and structural response (horizontal force, pressure, and deflection) were observed for a range of incident tsunami heights and for several wood wall framing configurations. The walls were tested at the same cross-shore location with a dry bed condition. For each tsunami wave height tested, the force and pressure profiles showed a transient peak force followed by a period of sustained quasi-static force. The ratio of the transient force to quasi-static force was 2.2. These experimental values were compared to the predicted values using the linear momentum equation, and it was found that the equation predicted the measured forces on the vertical wall within an accuracy of approximately 20% without using a momentum correction coefficient. The experiments also showed that the more flexible 2x4 wall resulted in lower peak forces when compared to the 2x6 walls subjected to similar tsunami heights. However, the 2x6 walls were able to withstand larger waves before failure.Keywords: light-frame wood walls, impact, tsunami mitigation, tsunami forces, tsunami damageKeywords: light-frame wood walls, impact, tsunami mitigation, tsunami forces, tsunami damag

Evaluation of Tsunami Loads on Wood-Frame Walls at Full Scale

The performance of full-scale light-frame wood walls subjected to wave loading was examined using the Large Wave Flume of the Network for Earthquake Engineering (NEES) Tsunami Facility at Oregon State University. The hydrodynamic conditions (water level and bore speed) and structural response (horizontal force, pressure, and deflection) were observed for a range of incident tsunami heights and for several wood wall framing configurations. The walls were tested at the same cross-shore location with a dry-bed condition. For each tsunami wave height tested, the force and pressure profiles showed a transient peak force followed by a period of sustained quasi-static force. The ratio of the transient force to quasi-static force was 2.2. These experimental values were compared with the predicted values using the linear momentum equation, and it was found that the equation predicted the measured forces on the vertical wall within an accuracy of approximately 20% without using a momentum correction coefficient. The experiments also showed that the more flexible 2×4 wall resulted in lower peak forces when compared with 2×6 walls subjected to similar tsunami heights. However, the 2×6 walls were able to withstand larger waves before failure

Molecular Characterization Reveals Diverse and Unknown Malaria Vectors in the Western Kenyan Highlands.

The success of mosquito-based malaria control is dependent upon susceptible bionomic traits in local malaria vectors. It is crucial to have accurate and reliable methods to determine mosquito species composition in areas subject to malaria. An unexpectedly diverse set of Anopheles species was collected in the western Kenyan highlands, including unidentified and potentially new species carrying the malaria parasite Plasmodium falciparum. This study identified 2,340 anopheline specimens using both ribosomal DNA internal transcribed spacer region 2 and mitochondrial DNA cytochrome oxidase subunit 1 loci. Seventeen distinct sequence groups were identified. Of these, only eight could be molecularly identified through comparison to published and voucher sequences. Of the unidentified species, four were found to carry P. falciparum by circumsporozoite enzyme-linked immunosorbent assay and polymerase chain reaction, the most abundant of which had infection rates comparable to a primary vector in the area, Anopheles funestus. High-quality adult specimens of these unidentified species could not be matched to museum voucher specimens or conclusively identified using multiple keys, suggesting that they may have not been previously described. These unidentified vectors were captured outdoors. Diverse and unknown species have been incriminated in malaria transmission in the western Kenya highlands using molecular identification of unusual morphological variants of field specimens. This study demonstrates the value of using molecular methods to compliment vector identifications and highlights the need for accurate characterization of mosquito species and their associated behaviors for effective malaria control

Bidirectional Psychoneuroimmune Interactions in the Early Postpartum Period Influence Risk of Postpartum Depression

More than 500,000 U.S. women develop postpartum depression (PPD) annually. Although psychosocial risks are known, the underlying biology remains unclear. Dysregulation of the immune inflammatory response and the hypothalamic–pituitary–adrenal (HPA) axis are associated with depression in other populations. While significant research on the contribution of these systems to the development of PPD has been conducted, results have been inconclusive. This is partly because few studies have focused on whether disruption in the bidirectional and dynamic interaction between the inflammatory response and the HPA axis together influence PPD. In this study, we tested the hypothesis that disruption in the inflammatory-HPA axis bidirectional relationship would increase the risk of PPD. Plasma pro- and anti-inflammatory cytokines were measured in women during the 3rd trimester of pregnancy and on Days 7 and 14, and Months 1, 2, 3, and 6 after childbirth. Saliva was collected 5 times the day preceding blood draws for determination of cortisol area under the curve (AUC) and depressive symptoms were measured using the Edinburgh Postpartum Depression Survey (EPDS). Of the 152 women who completed the EPDS, 18% were depressed according to EDPS criteria within the 6 months postpartum. Cortisol AUC was higher in symptomatic women on Day 14 (p = .017). To consider the combined effects of cytokines and cortisol on predicting symptoms of PPD, a multiple logistic regression model was developed that included predictors identified in bivariate analyses to have an effect on depressive symptoms. Results indicated that family history of depression, day 14 cortisol AUC, and the day 14 IL8/IL10 ratio were significant predictors of PPD symptoms. One unit increase each in the IL8/IL10 ratio and cortisol AUC resulted in 1.50 (p = 0.06) and 2.16 (p = 0.02) fold increases respectively in the development of PPD. Overall, this model correctly classified 84.2% of individuals in their respective groups. Findings suggest that variability in the complex interaction between the inflammatory response and the HPA axis influence the risk of PPD