Efficacy and effectiveness of dihydroartemisinin-piperaquine versus artesunate-mefloquine in falciparum malaria: an open-label randomised comparison.

BACKGROUND: Artemisinin-based combinations are judged the best treatments for multidrug-resistant Plasmodium falciparum malaria. Artesunate-mefloquine is widely recommended in southeast Asia, but its high cost and tolerability profile remain obstacles to widespread deployment. To assess whether dihydroartemisinin-piperaquine is a suitable alternative to artesunate-mefloquine, we compared the safety, tolerability, efficacy, and effectiveness of the two regimens for the treatment of uncomplicated falciparum in western Myanmar (Burma). METHODS: We did an open randomised comparison of 3-day regimens of artesunate-mefloquine (12/25 mg/kg) versus dihydroartemisinin-piperaquine (6.3/50 mg/kg) for the treatment of children aged 1 year or older and in adults with uncomplicated falciparum malaria in Rakhine State, western Myanmar. Within each group, patients were randomly assigned supervised or non-supervised treatment. The primary endpoint was the PCR-confirmed parasitological failure rate by day 42. Failure rates at day 42 were estimated by Kaplan-Meier survival analysis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN27914471. FINDINGS: Of 652 patients enrolled, 327 were assigned dihydroartemisinin-piperaquine (156 supervised and 171 not supervised), and 325 artesunate-mefloquine (162 and 163, respectively). 16 patients were lost to follow-up, and one patient died 22 days after receiving dihydroartemisinin-piperaquine. Recrudescent parasitaemias were confirmed in only two patients; the day 42 failure rate was 0.6% (95% CI 0.2-2.5) for dihydroartemisinin-piperaquine and 0 (0-1.2) for artesunate-mefloquine. Whole-blood piperaquine concentrations at day 7 were similar for patients with observed and non-observed dihydroartemisinin-piperaquine treatment. Gametocytaemia developed more frequently in patients who had received dihydroartemisinin-piperaquine than in those on artesunate-mefloquine: day 7, 18 (10%) of 188 versus five (2%) of 218; relative risk 4.2 (1.6-11.0) p=0.011. INTERPRETATION: Dihydroartemisinin-piperaquine is a highly efficacious and inexpensive treatment of multidrug-resistant falciparum malaria and is well tolerated by all age groups. The effectiveness of the unsupervised treatment, as in the usual context of use, equalled its supervised efficacy, indicating good adherence without supervision. Dihydroartemisinin-piperaquine is a good alternative to artesunate-mefloquine

Beneficial effect of ustekinumab in familial pityriasis rubra pilaris with a new missense mutation in CARD14

Pityriasis rubra pilaris (PRP) represents a group of rare chronic inflammatory skin disorders in which ~1 in 20 affected individuals show autosomal dominant inheritance. In such cases, there may be gain-of-function mutations in CARD14, encoding caspase recruitment domain-containing protein 14 (CARD14) that activates the non-canonical nuclear factor-kappa B (NF-κB) pathway, thereby promoting cutaneous inflammation. Here, we report a mother and son with PRP due to a new missense mutation in CARD14 and describe the beneficial clinical effects of ustekinumab, a monoclonal antibody against interleukins-12 and -23, in both subjects. A 49 year-old female and her 20 year-old son had lifelong, generalised, patchy erythematous scale with a few islands of sparing, as well as minor nail ridging and mild palmoplantar keratoderma, features consistent with generalised PRP. Topical steroids, phototherapy and oral retinoids proved ineffective therapies. Following informed consent, Sanger sequencing of CARD14 in both individuals revealed a new heterozygous single nucleotide transversion in exon 16, c.356T>G, resulting in the missense mutation, p.Met119Arg. Ustekinumab, at a dose of 45mg every 12 weeks, brought about a significant physical and emotional improvement in both the mother and son within a few days of the initial dose, which was sustained on maintenance dosing. This report highlights the therapeutic potential of biologics that downregulate NF-kB signalling in familial PRP with mutations in CARD14. This article is protected by copyright. All rights reserved

The Mucin Family of Proteins: Candidates as Potential Biomarkers for Colon Cancer

Mucins (MUC1-MUC24) are a family of glycoproteins involved in cell signaling and barrier protection. They have been implicated in the progression of numerous malignancies including gastric, pancreatic, ovarian, breast, and lung cancer. Mucins have also been extensively studied with respect to colorectal cancer. They have been found to have diverse expression profiles amongst the normal colon, benign hyperplastic polyps, pre-malignant polyps, and colon cancers. Those expressed in the normal colon include MUC2, MUC3, MUC4, MUC11, MUC12, MUC13, MUC15 (at low levels), and MUC21. Whereas MUC5, MUC6, MUC16, and MUC20 are absent from the normal colon and are expressed in colorectal cancers. MUC1, MUC2, MUC4, MUC5AC, and MUC6 are currently the most widely covered in the literature regarding their role in the progression from normal colonic tissue to cancer

Evaluation of 3 rapid diagnostic tests (CareStart) Malaria 3 line pl.DH (Pan, Pf), OptiMAL-IT pl.DH (Pan, Pf) and CareStart 0 2 line.pl.DH (Pan) for the diagnosis of malaria in Myanmar

Presented at the conference of the American Society of Tropical Medicine and Hygiene 200

Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer

BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.British Journal of Cancer advance online publication, 22 December 2016; doi:10.1038/bjc.2016.402 www.bjcancer.com

Identification of new sources of resistance to dry root rot caused by Macrophomina phaseolina isolates from India and Myanmar in a mungbean mini-core collection

Dry root rot (DRR), caused by Macrophomina phaseolina, is a prevalent disease of mungbean in Myanmar, and an emerging problem in South Asia. The pathogen is a polyphagous necrotroph, survives in the soil for many years that results disease mitigation difficult. Managing DRR in mungbean through an integrated approach has been suggested, and the use of resistant varieties is one of the economical methods. The present study aimed to identify sources of resistance against DRR from a mungbean mini-core collection and to characterize the associated M. phaseolina isolates from India and Myanmar. Evaluation of the 296 mungbean mini-core accessions against the isolate MP1 by paper towel method identified 29 accessions with DRR resistance (disease scores: ≤ 3), and 18 of them with the consistent resistance in the repeated experiment. During the screening of 18 resistant accessions in the glasshouse, nine accessions were found DRR resistance in repeated sick pot experiments with ≤10% disease incidence. A subset of 30 accessions was selected from the mini-core collection based on their in vitro DRR reactions. These accessions were evaluated for DRR resistance in the field in Yezin, Myanmar in 2018 and 2019. Out of the 30 accessions, ten accessions were found DRR resistance with ≤10% disease incidence in both years of evaluations. Pooled analysis of percent disease incidence data of 15 accessions common in both glasshouse and field revealed the stability of accessions VI001509AG, VI001244AG, and VI001400AG for DRR resistance across years and locations. The three resistant accessions along with a susceptible check VC693088 were re-evaluated by paper towel method against nine additional M. phaseolina isolates from India (MP3-MP11). The accessions VI001509AG and VI001400AG were resistant to all nine isolates, while accession VI001244AG was resistant to MP5, MP6, and MP7 isolates. These accessions could be used in mungbean DRR resistance breeding programs

Specific Targeting and Labeling of Colonic Polyps in CPC-APC Mice with Mucin 5AC Fluorescent Antibodies: A Model for Detection of Early Colon Cancer

Poor visualization of polyps can limit colorectal cancer screening. Fluorescent antibodies to mucin5AC (MUC5AC), a glycoprotein upregulated in adenomas and colorectal cancer, could improve screening colonoscopy polyp detection rate. Adenomatous polyposis coli flox mice with a Cdx2-Cre transgene (CPC-APC) develop colonic polyps that contain both dysplastic and malignant tissue. Mice received MUC5AC-IR800 or IRdye800 as a control IV and were sacrificed after 48 h for near-infrared imaging of their colons. A polyp-to-background ratio (PBR) was calculated for each polyp by dividing the mean fluorescence intensity of the polyp by the mean fluorescence intensity of the background tissue. The mean 25 μg PBR was 1.70 (±0.56); the mean 50 μg PBR was 2.64 (±0.97); the mean 100 μg PBR was 3.32 (±1.33); and the mean 150 μg PBR was 3.38 (±0.87). The mean PBR of the dye-only control was 2.22 (±1.02), significantly less than the 150 μg arm (p-value 0.008). The present study demonstrates the ability of fluorescent anti-MUC5AC antibodies to specifically target and label colonic polyps containing high-grade dysplasia and intramucosal adenocarcinoma in CPC-APC mice. This technology can potentially improve the detection rate and decrease the miss rate of advanced colonic neoplasia and early cancer at colonoscopy

Community-based assessment of human rights in a complex humanitarian emergency: the Emergency Assistance Teams-Burma and Cyclone Nargis

<p>Abstract</p> <p>Introduction</p> <p>Cyclone Nargis hit Burma on May 2, 2008, killing over 138,000 and affecting at least 2.4 million people. The Burmese military junta, the State Peace and Development Council (SPDC), initially blocked international aid to storm victims, forcing community-based organizations such as the Emergency Assistance Teams-Burma (EAT) to fill the void, helping with cyclone relief and long-term reconstruction. Recognizing the need for independent monitoring of the human rights situation in cyclone-affected areas, particularly given censorship over storm relief coverage, EAT initiated such documentation efforts.</p> <p>Methods</p> <p>A human rights investigation was conducted to document selected human rights abuses that had initially been reported to volunteers providing relief services in cyclone affected areas. Using participatory research methods and qualitative, semi-structured interviews, EAT volunteers collected 103 testimonies from August 2008 to June 2009; 42 from relief workers and 61 from storm survivors.</p> <p>Results</p> <p>One year after the storm, basic necessities such as food, potable water, and shelter remained insufficient for many, a situation exacerbated by lack of support to help rebuild livelihoods and worsening household debt. This precluded many survivors from being able to access healthcare services, which were inadequate even before Cyclone Nargis. Aid efforts continued to be met with government restrictions and harassment, and relief workers continued to face threats and fear of arrest. Abuses, including land confiscation and misappropriation of aid, were reported during reconstruction, and tight government control over communication and information exchange continued.</p> <p>Conclusions</p> <p>Basic needs of many cyclone survivors in the Irrawaddy Delta remained unmet over a year following Cyclone Nargis. Official impediments to delivery of aid to storm survivors continued, including human rights abrogations experienced by civilians during reconstruction efforts. Such issues remain unaddressed in official assessments conducted in partnership with the SPDC. Private, community-based relief organizations like EAT are well positioned and able to independently assess human rights conditions in response to complex humanitarian emergencies such as Cyclone Nargis; efforts of this nature must be encouraged, particularly in settings where human rights abuses have been documented and censorship is widespread.</p