Relevance of Undetectably Rare Resistant Malaria Parasites in Treatment Failure: Experimental Evidence from Plasmodium chabaudi

Resistant malaria parasites are frequently found in mixed infections with drug-sensitive parasites. Particularly early in the evolutionary process, the frequency of these resistant mutants is extremely low and below the level of molecular detection. We tested whether the rarity of resistance in infections impacted the health outcomes of treatment failure and the potential for onward transmission of resistance. Mixed infections of different ratios of resistant and susceptible Plasmodium chabaudi parasites were inoculated in laboratory mice and dynamics tracked during the course of infection using highly sensitive genotype-specific quantitative polymerase chain reaction (qPCR). Frequencies of resistant parasites ranged from 10% to 0.003% at the onset of treatment. We found that the rarer the resistant parasites were, the lower the likelihood of their onward transmission, but the worse the treatment failure was in terms of parasite numbers and disease severity. Strikingly, drug resistant parasites had the biggest impact on health outcomes when they were too rare to be detected by any molecular methods currently available for field samples. Indeed, in the field, these treatment failures would not even have been attributed to resistance

Warmer temperatures reduce the vectorial capacity of malaria mosquitoes

The development rate of parasites and pathogens within vectors typically increases with temperature. Accordingly, transmission intensity is generally assumed to be higher under warmer conditions. However, development is only one component of parasite/pathogen life history and there has been little research exploring the temperature sensitivity of other traits that contribute to transmission intensity. Here, using a rodent malaria, we show that vector competence (the maximum proportion of infectious mosquitoes, which implicitly includes parasite survival across the incubation period) tails off at higher temperatures, even though parasite development rate increases. We also show that the standard measure of the parasite incubation period (i.e. time until the first mosquitoes within a cohort become infectious following an infected blood-meal) is incomplete because parasite development follows a cumulative distribution, which itself varies with temperature. Including these effects in a simple model dramatically alters estimates of transmission intensity and reduces the optimum temperature for transmission. These results highlight the need to understand the interactive effects of environmental temperature on multiple host-disease life-history traits and challenge the assumptions of many current disease models that ignore this complexity

Bench to Bed Evidences for Pharmacokinetic and Pharmacodynamic Interactions Involving Oseltamivir and Chinese Medicine

Oseltamivir (OA), an ethyl ester prodrug of oseltamivir carboxylate (OC), is clinically used as a potent and selective inhibitor of neuraminidase. Chinese medicines have been advocated to combine with conventional drug for avian influenza. The current study aims to investigate the potential pharmacokinetic and pharmacodynamic interactions of a Chinese medicine formula, namely, Yin Qiao San and Sang Ju Yin (CMF1), commonly used for anti-influenza in combination with OA in both rat and human, and to reveal the underlined mechanisms. It was found that although Cmax, AUC and urinary recovery of OC, as well as metabolic ratio (AUCOC/AUCOA), were significantly decreased in a dose-dependent manner following combination use of CMF1 and OA in rat studies (P<0.01), such coadministration in 14 healthy volunteers only resulted in a trend of minor decrease in the related parameters. Further mechanistic studies found that although CMF1 could reduce absorption and metabolism of OA, it appears to enhance viral inhibition of OA (P<0.01). In summary, although there was potential interaction between OA and CMF1 found in rat studies, its clinical impact was expected to be minimal. The coadministration of OA and CMF1 at the clinical recommended dosages is, therefore, considered to be safe

IL-17A both initiates, via IFNγ suppression, and limits the pulmonary type-2 immune response to nematode infection

Nippostrongylus brasiliensis is a well-defined model of type-2 immunity but the early lung-migrating phase is dominated by innate IL-17A production. In this study, we confirm previous observations that Il17a-KO mice infected with N. brasiliensis exhibit an impaired type-2 immune response. Transcriptional profiling of the lung on day 2 of N. brasiliensis infection revealed an increased Ifng signature in Il17a-KO mice confirmed by enhanced IFNγ protein production in lung lymphocyte populations. Depletion of early IFNγ rescued type-2 immune responses in the Il17a-KO mice demonstrating that IL-17A-mediated suppression of IFNγ promotes type-2 immunity. Notably, later in infection, once the type-2 response was established, IL-17A limited the magnitude of the type-2 response. IL-17A regulation of type-2 immunity was lung-specific and infection with Trichuris muris revealed that IL-17A promotes a type-2 immune response in the lung even when infection is restricted to the intestine. Together our data reveal IL-17A as a major regulator of pulmonary type-2 immunity such that IL-17A supports early development of a protective type-2 response by suppression of IFNγ but subsequently limits excessive type-2 responses. A failure of this feedback loop may contribute to conditions such as severe asthma, characterised by combined elevation of IL-17 and type-2 cytokines

IL-13 deficiency exacerbates lung damage and impairs epithelial-derived type 2 molecules during nematode infection

Acknowledgements This work was supported by the Wellcome Trust (203128/Z/16/Z, 110126/Z/ 15/Z, and 106898/A/15/Z) and the Medical Research Council UK (MR/ K01207X/2). TE Sutherland was supported by Medical Research Founda- tion UK joint funding with Asthma UK (MRFAUK-2015-302). We thank Andrew McKenzie (Cambridge) for providing the Il13 tm3.1Anjm mice. We further thank the Flow Cytometry, Bioimaging, Genomic Technologies, BioMS, and Bio- logical Services core facilities at the University of Manchester.Peer reviewedPublisher PD

The effectiveness of dietary approaches to stop hypertension (DASH) counselling on estimated 10-year cardiovascular risk among patients with newly diagnosed grade 1 hypertension : a randomised clinical trial

The Dietary Approaches to Stop Hypertension (DASH) has been shown to lower blood pressure in the West. However, the real-life impact of DASH on reducing cardiovascular (CV) risk in routine clinical setting has not been studied. Methods A parallel-group, open-labelled, physician-blinded, randomised controlled trial was conducted in January–June 2013 and followed up for 6- and 12-months in primary care settings in Hong Kong. Patients newly diagnosed with grade 1 hypertension (aged 40–70 years) who had no concomitant medical conditions requiring dietary modifications were consecutively recruited. Subjects were randomised to standard education (usual care) (n = 275), or usual care plus dietitian-delivered DASH-based dietary counselling in a single one-to-one session (intervention) (n = 281). Primary outcomes were the changes in estimated 10-year CV risk. Results Outcome data were available for 504 (90.6%) and 485 (87.2%) patients at 6 and 12 months, respectively. There was no difference in the reduction of 10-year CV risk between the two groups at 6 months (−0.13%, 95% confidence interval [95% CI] −0.50% to 0.23%, p = 0.477) and 12 months (−0.08%, 95% CI −0.33% to 0.18%, p = 0.568). Multivariate regression analyses showed that male subjects, younger patients, current smokers, subjects with lower educational level, and those who dined out for main meals for ≥4 times in a typical week were significantly associated with no improvements in CV risk. Conclusions The findings may not support automatic referral of newly diagnosed grade 1 hypertensive patients for further one-to-one dietitian counselling on top of primary care physician's usual care. Patients with those risk factors identified should receive more clinical attention to reduce their CV risk

Maternal γδ T cells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner.

Immune development is profoundly influenced by vertically transferred cues. However, little is known about how maternal innate-like lymphocytes regulate offspring immunity. Here, we show that mice born from γδ T cell-deficient (TCRδ-/-) dams display an increase in first-breath-induced inflammation, with a pulmonary milieu selectively enriched in type 2 cytokines and type 2-polarized immune cells, when compared with the progeny of γδ T cell-sufficient dams. Upon helminth infection, mice born from TCRδ-/- dams sustain an increased type 2 inflammatory response. This is independent of the genotype of the pups. Instead, the offspring of TCRδ-/- dams harbors a distinct intestinal microbiota, acquired during birth and fostering, and decreased levels of intestinal short-chain fatty acids (SCFAs), such as pentanoate and hexanoate. Importantly, exogenous SCFA supplementation inhibits type 2 innate lymphoid cell function and suppresses first-breath- and infection-induced inflammation. Taken together, our findings unravel a maternal γδ T cell-microbiota-SCFA axis regulating neonatal lung immunity

Phase I Study of Cetuximab, Irinotecan, and Vandetanib (ZD6474) as Therapy for Patients with Previously Treated Metastastic Colorectal Cancer

BACKGROUND: To determine the maximum tolerated dose (MTD) and safety, and explore efficacy and biomarkers of vandetanib with cetuximab and irinotecan in second-line metastatic colorectal cancer. METHODS: Vandetanib (an orally bioavailable VEGFR-2 and EGFR tyrosine kinases inhibitor) was combined at 100 mg, 200 mg, or 300 mg daily with standard dosed cetuximab and irinotecan (3+3 dose-escalation design). Ten patients were treated at the MTD and plasma angiogenesis biomarkers (VEGF, PlGF, bFGF, sVEGFR1, sVEGFR2, IL-1β, IL-6, IL-8, TNF-α, SDF1α) were measured before and after treatment. RESULTS: Twenty-seven patients were enrolled at 4 dose levels and the MTD. Two dose-limiting toxicities (grade 3 QTc prolongation and diarrhea) were detected at 300 mg of vandetanib with cetuximab and irinotecan resulting in 200 mg being the MTD. Seven percent of patients had a partial response, 59% stable disease and 34% progressed. Median progression-free survival was 3.6 months (95% CI, 3.2-5.6) and median overall survival was 10.5 months (95% CI, 5.1-20.7). Toxicities were fairly manageable with grade 3 or 4 diarrhea being most prominent (30%). Vandetanib and cetuximab treatment induced a sustained increase in plasma PlGF and a transient decrease in plasma sVEGFR1, but no changes in plasma VEGF and sVEGFR2. CONCLUSIONS: Vandetanib can be safely combined with cetuximab and irinotecan for metastatic colorectal cancer. Exploratory biomarker analyses suggest differential effects on certain plasma biomarkers for VEGFR inhibition when combined with EGFR blockade and a potential correlation between baseline sVEGFR1 and response. However, while the primary endpoint was safety, the observed efficacy raises concern for moving forward with this combination. TRIAL REGISTRATION: Clinicaltrials.gov NCT00436072

Comparative effectiveness of dipeptidyl peptidase-4 (DPP-4) inhibitors and human glucagon-like peptide-1 (GLP-1) analogue as add-on therapies to sulphonylurea among diabetes patients in the Asia-Pacific region: a systematic review

The prevalence of diabetes mellitus is rising globally, and it induces a substantial public health burden to the healthcare systems. Its optimal control is one of the most significant challenges faced by physicians and policy-makers. Whereas some of the established oral hypoglycaemic drug classes like biguanide, sulphonylureas, thiazolidinediones have been extensively used, the newer agents like dipeptidyl peptidase-4 (DPP-4) inhibitors and the human glucagon-like peptide-1 (GLP-1) analogues have recently emerged as suitable options due to their similar efficacy and favorable side effect profiles. These agents are widely recognized alternatives to the traditional oral hypoglycaemic agents or insulin, especially in conditions where they are contraindicated or unacceptable to patients. Many studies which evaluated their clinical effects, either alone or as add-on agents, were conducted in Western countries. There exist few reviews on their effectiveness in the Asia-Pacific region. The purpose of this systematic review is to address the comparative effectiveness of these new classes of medications as add-on therapies to sulphonylurea drugs among diabetic patients in the Asia-Pacific countries. We conducted a thorough literature search of the MEDLINE and EMBASE from the inception of these databases to August 2013, supplemented by an additional manual search using reference lists from research studies, meta-analyses and review articles as retrieved by the electronic databases. A total of nine randomized controlled trials were identified and described in this article. It was found that DPP-4 inhibitors and GLP-1 analogues were in general effective as add-on therapies to existing sulphonylurea therapies, achieving HbA1c reductions by a magnitude of 0.59–0.90% and 0.77–1.62%, respectively. Few adverse events including hypoglycaemic attacks were reported. Therefore, these two new drug classes represent novel therapies with great potential to be major therapeutic options. Future larger-scale research should be conducted among other Asia-Pacific region to evaluate their efficacy in other ethnic groups