14 research outputs found
The initiator caspase Dronc plays a non-apoptotic role in promoting DNA damage signalling in D. melanogaster
No full textThe phosphorylation of the variant histone H2Ax (denoted γH2Ax; γH2Av in flies) constitutes an important signalling event in DNA damage sensing, ensuring effective repair by recruiting DNA repair machinery. In contrast, the γH2Av response has also been reported in dying cells, where it requires activation of caspase-activated DNases (CADs). Moreover, caspases are known to be required downstream of DNA damage for cell death execution. We show here, for the first time, that the Drosophila initiator caspase Dronc acts as an upstream regulator of the DNA damage response (DDR) independently of executioner caspases by facilitating γH2Av signalling, possibly through a function that is not related to apoptosis. Such a γH2Av response is mediated by ATM rather than ATR, suggesting that Dronc function is required upstream of ATM. In contrast, the role of γH2Av in cell death requires effector caspases and is associated with fragmented nuclei. Our study uncovers a novel function of Dronc in response to DNA damage aimed at promoting DDR via γH2Av signalling in intact nuclei. We propose that Dronc plays a dual role that can either initiate DDR or apoptosis depending upon its level and the required threshold of its activation in damaged cells.This article has an associated First Person interview with the first author of the paper
Poor quality drugs: grand challenges in high throughput detection, countrywide sampling, and forensics in developing countries.
No full textThroughout history, poor quality medicines have been a persistent problem, with periodical crises in the supply of antimicrobials, such as fake cinchona bark in the 1600s and fake quinine in the 1800s. Regrettably, this problem seems to have grown in the last decade, especially afflicting unsuspecting patients and those seeking medicines via on-line pharmacies. Here we discuss some of the challenges related to the fight against poor quality drugs, and counterfeits in particular, with an emphasis on the analytical tools available, their relative performance, and the necessary workflows needed for distinguishing between genuine, substandard, degraded and counterfeit medicines
Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment : Findings from the MAL-ED birth cohort study
No full textFunding Information: Funding The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation (#OPP47075), the Foundation for the NIH and the National Institutes of Health/Fogarty International Center. The Bill & Melinda Gates Foundation did not play any role in the writing of the manuscript nor did the funders of the study have any role in the study design, data collection, data analysis or interpretation of study results. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. Publisher Copyright: © Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Peer reviewe
Reducing childhood illness - fostering growth : an integrated home-based intervention package (IHIP) to improve indoor-air pollution, drinking water quality and child nutrition
No full textChild mortality attributable to pneumonia, diarrhoea and malnutrition accounts globally for the majority of 8.8 million annual deaths. More than half of these deaths are preventable. Available and effective interventions include safe water supply, household water treatment, improved chimney stoves and personal- and home-hygiene and -health messages. In Peru, the current health services reform is focused on shifting responsibilities to peripheral levels; thus, empowering community organisations to manage primary health care services, including health promotion and preventive measures at household level. The current political situation and policy framework to integrate effective preventive interventions that can be delivered at family level, prompted us to test the efficacy of a package of health interventions to reduce childhood illness burden at rural household level.
The goal of this PhD thesis was to assess the efficacy of an Integrated Environmental Home-based-Intervention Package (IHIP), comprised of an improved chimney stoves, access to safe drinking water from solar radiation household water treatment (SODIS), and hygiene education interventions, to reduce morbidity of acute respiratory infections, diarrhoea and poor growth of rural Peruvian children under three years of age. We implemented a community-randomised control field trial (cRCT) in 51 community’s clusters of the San Marcos Province, Cajamarca Region, Peru. The cRCT was divided as follows:
* Set-up, community selection and participatory intervention development: A pilot study was carried out for the selection of the interventions. These were adapted to local customs. The participatory phase is described in detail in Chapters 4 & 5.
* Randomization, enrolment and baseline data collection: Chapter 6 describes the randomisation, enrolment and baseline in detail.
* Carbon monoxide (CO) and Particulate Matter (PM2.5) household air quality assessment: Chapter 7 & 8 describe the efficacy of the OPTIMA-improved stove in improving household air quality in comparison to traditional open fire stoves.
* Morbidity surveillance and field data acquisition: Morbidity data on the daily occurrence of signs and symptoms diarrhoea and respiratory illnesses of children was collected weekly. Anthropometric every two months and microbial data every 6 months. Chapter 9 describes the IHIP impact on morbidity reduction.
* Workshops for a community-driven sustainable dessimination: Chapter 10 describes the community workshops and dissemination processes and dynamics within a socio-ecological framework.
Our community-randomised control trial demonstrated that IHIP reduced 22% per year of child diarrhoea (RR 0.78, 95% CI: 0.49-1.05) and found an odds ratio of 0.71 for diarrhoea prevalence (OR 0.71, 95%, CI: 0.47, 1.06). No effects on the frequency of acute lower respiratory infections (RR 0.99, 95% CI: 0.59, 1.65) or child’s growth rates were found when comparing study arms. We identified three reasons for this moderate diarrhoea reduction: i) hand-washing promotion was universally found in our setting, since it is being promoted by the health care centre; ii) SODIS compliance was moderate: only one third of the beneficiaries were using the method regularly; and iii) the increased awareness for the child’s needs linked to the control intervention, could induce improved child care behaviour. The lack of effect on ALRI, could be linked to insufficient reduction in exposure to household air pollutants and high health service utilisation due to cultural beliefs and health seeking behavoiur. The household air pollution assessment study revealed only moderate reductions of 45% and 27% reduction of PM2.5 and CO, respectively for mothers’ personal exposure. This result was achieved in the best working stoves only. This may most likely not be sufficient to reduce impact on physician-diagnosed pneumonia.
Community participatory meetings and surveys revealed that people’s decisions on adopting household-level environmental and hygiene interventions, was not only based on individual perceptions of their potential gains, but also depended on peer pressure and social network relations. Individual perceptions regarding pollution levels of water and household air (transparent, odourless water vs dirty air environments) influenced perceived gains and the adoption of certain interventions. Access to information and encouragement from health-care providers and programme implementers also increased adoption.
The IHIP had several additional benefits beyond health outcomes. Mother’s expressed that the stoves could reduce cooking time and wood consumption, which translated into cost saving. They also could perform other task while cooking. Regarding the kitchen sink, the mothers expressed it facilitated handwashing, and washing of utensils with detergent, generating a cleaner kitchen environment that fostered home and food hygiene. We believe that the IHIP package motivated families to improve the kitchen living area in general. The high acceptance and sustained use was not only observed in the IHIP families but also in non-participating families that had copied the OPTIMA-improved stove after the community engagement in the desimination activities. We can also conclude that the IHIP package added to the family status, improved quality of life and impacted on their livelihoods, by empowering the beneficiary families.
In conclusion, through this project we envisaged to demonstrate how an integrated package could be implemented at the household level in rural areas of Peru and its effect on health, quality of life and livelihoods. However, behaviour change for keeping maintanence of the interventions and use is necessary to achieve compliance, replication and sustainability
Early Life Child Micronutrient Status, Maternal Reasoning, and a Nurturing Household Environment have Persistent Influences on Child Cognitive Development at Age 5 years : Results from MAL-ED
No full textFunding Information: The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project (MAL-ED) is carried out as a collaborative project supported by the Bill & Melinda Gates Foundation, the Foundation for the NIH, and the National Institutes of Health/Fogarty International Center. This work was also supported by the Fogarty International Center, National Institutes of Health (D43-TW009359 to ETR). Author disclosures: BJJM, SAR, LEC, LLP, JCS, BK, RR, RS, ES, LB, ZR, AM, RS, BN, SH, MR, RO, ETR, and LEM-K, no conflicts of interest. Supplemental Tables 1–5 and Supplemental Figures 1–3 are available from the “Supplementary data” link in the online posting of the article and from the same link in the online table of contents at https://academic.oup.com/jn/. Address correspondence to LEM-K (e-mail: [email protected]). Abbreviations used: HOME, Home Observation for Measurement of the Environment inventory; MAL-ED, The Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development Project; TfR, transferrin receptor; WPPSI, Wechsler Preschool Primary Scales of Intelligence.Peer reviewe
Relationship between growth and illness, enteropathogens and dietary intakes in the first 2 years of life: Findings from the MAL-ED birth cohort study
No full text© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. Background Dietary and illness factors affect risk of growth faltering; the role of enteropathogens is less clear. As part of the Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) study, we quantify the effects of enteropathogen infection, diarrhoea and diet on child growth. Methods Newborns were enrolled and followed until 24 months. Length and weight were assessed monthly. Illnesses and breastfeeding practices were documented biweekly; from 9 to 24 months, non-breast milk intakes were quantified monthly. Routinely collected non-diarrhoeal stools were analysed for a broad array of enteropathogens. A linear piecewise spline model was used to quantify associations of each factor with growth velocity in seven of eight MAL-ED sites; cumulative effects on attained size at 24 months were estimated for mean, low (10th percentile) and high (90th percentile) exposure levels. Additionally, the six most prevalent enteropathogens were evaluated for their effects on growth. results Diarrhoea did not have a statistically significant effect on growth. Children with high enteropathogen exposure were estimated to be 1.21±0.33 cm (p<0.001; 0.39 length for age (LAZ)) shorter and 0.08±0.15 kg (p=0.60; 0.08 weight-for-age (WAZ)) lighter at 24 months, on average, than children with low exposure. Campylobacter and enteroaggregativeEscherichia coli detections were associated with deficits of 0.83±0.33 and 0.85±0.31 cm in length (p=0.011 and 0.001) and 0.22±0.15 and 0.09±0.14 kg in weight (p=0.14 and 0.52), respectively. Children with low energy intakes and protein density were estimated to be 1.39±0.33 cm (p<0.001; 0.42 LAZ) shorter and 0.81±0.15 kg (p<0.001; 0.65 WAZ) lighter at 24 months than those with high intakes. conclusions Reducing enteropathogen burden and improving energy and protein density of complementary foods could reduce stunting
Norovirus infection and acquired immunity in 8 countries: Results from the MAL-ED study
No full text© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. Background. Norovirus is an important cause of childhood diarrhea. We present data from a longitudinal, multicountry study describing norovirus epidemiology during the first 2 years of life. Methods. A birth cohort of 1457 children across 8 countries contributed 7077 diarrheal stools for norovirus testing. A subset of 199 children contributed additional asymptomatic samples (2307) and diarrheal stools (770), which were used to derive incidence rates and evaluate evidence for acquired immunity. Results. Across sites, 89% of children experienced at least 1 norovirus infection before 24 months, and 22.7% of all diarrheal stools were norovirus positive. Severity of norovirus-positive diarrhea was comparable to other enteropathogens, with the exception of rotavirus. Incidence of genogroup II (GII) infection was higher than genogroup I and peaked at 6-11 months across sites. Undernutrition was a risk factor for symptomatic norovirus infection, with an increase in 1 standard deviation of length-for-age z score associated with a 17% reduction (odds ratio, 0.83 [95% confidence interval,. 72-.97]; P =. 011) in the odds of experiencing diarrhea when norovirus was present, after accounting for genogroup, rotavirus vaccine, and age. Evidence of acquired immunity was observed among GII infections only: Children with prior GII infection were found to have a 27% reduction in the hazard of subsequent infection (hazard ratio, 0.727; P =. 010). Conclusions. The high prevalence of norovirus across 8 sites in highly variable epidemiologic settings and demonstration of protective immunity for GII infections provide support for investment in vaccine development
Early childhood cognitive development is affected by interactions among illness, diet, enteropathogens and the home environment: Findings from the MAL-ED birth cohort study
No full text© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. background Millions of children in low-income and middle-income countries (LMICs) are at risk of not reaching their full cognitive potential. Malnutrition and enteric infections in early life are implicated as risk factors; however, most studies on these risks and their associations with cognitive development have failed to adequately account for confounding factors or the accumulation of putative insults. Here, we examine the interaction between infections and illness on cognitive development in LMIC community settings. Methods As part of the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) longitudinal birth cohort study, children from eight LMICs were followed from birth to 24 months to understand the influence of repeated enteric infections on child growth and development. Here, data from six sites were employed to evaluate associations between infection, illness, the home environment, micronutrient intake and status, maternal reasoning, and cognitive development at 24 months. results Higher rates of enteropathogen detection and days with illness were associated with lower haemoglobin concentrations, which in turn were associated with lower cognitive scores at 24 months. Children with lower environmental health/safety scores and lower intakes of vitamin B 6 and folate had more enteropathogen detections and illness. Strength of associations varied by weight-for-age in the first 17 days of life; lower weight infants were more susceptible to the negative effects of enteropathogens and illness. Conclusions Enteropathogens were negatively related to child cognitive development. However, other factors were more strongly associated with child cognition. Targeting of interventions to improve cognitive development should include a focus on reducing frequency of illness, improving the safety and healthfulness of the child's environment, and improving dietary intake
Use of quantitative molecular diagnostic methods to investigate the effect of enteropathogen infections on linear growth in children in low-resource settings: longitudinal analysis of results from the MAL-ED cohort study
No full text© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: Enteropathogen infections in early childhood not only cause diarrhoea but contribute to poor growth. We used molecular diagnostics to assess whether particular enteropathogens were associated with linear growth across seven low-resource settings. Methods: We used quantitative PCR to detect 29 enteropathogens in diarrhoeal and non-diarrhoeal stools collected from children in the first 2 years of life obtained during the Etiology, Risk Factors, and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) multisite cohort study. Length was measured monthly. We estimated associations between aetiology-specific diarrhoea and subclinical enteropathogen infection and quantity and attained length in 3 month intervals, at age 2 and 5 years, and used a longitudinal model to account for temporality and time-dependent confounding. Findings: Among 1469 children who completed 2 year follow-up, 35 622 stool samples were tested and yielded valid results. Diarrhoeal episodes attributed to bacteria and parasites, but not viruses, were associated with small decreases in length after 3 months and at age 2 years. Substantial decrements in length at 2 years were associated with subclinical, non-diarrhoeal, infection with Shigella (length-for-age Z score [LAZ] reduction −0·14, 95% CI −0·27 to −0·01), enteroaggregative Escherichia coli (−0·21, −0·37 to −0·05), Campylobacter (−0·17, −0·32 to −0·01), and Giardia (−0·17, −0·30 to −0·05). Norovirus, Cryptosporidium, typical enteropathogenic E coli, and Enterocytozoon bieneusi were also associated with small decrements in LAZ. Shigella and E bieneusi were associated with the largest decreases in LAZ per log increase in quantity per g of stool (−0·13 LAZ, 95% CI −0·22 to −0·03 for Shigella; −0·14, −0·26 to −0·02 for E bieneusi). Based on these models, interventions that successfully decrease exposure to Shigella, enteroaggregative E coli, Campylobacter, and Giardia could increase mean length of children by 0·12–0·37 LAZ (0·4–1·2 cm) at the MAL-ED sites. Interpretation: Subclinical infection and quantity of pathogens, particularly Shigella, enteroaggregative E coli, Campylobacter, and Giardia, had a substantial negative association with linear growth, which was sustained during the first 2 years of life, and in some cases, to 5 years. Successfully reducing exposure to certain pathogens might reduce global stunting. Funding: Bill & Melinda Gates Foundation
Contribution of 3q26-29 gene cluster to glioma invasion
No full textDiffuse gliomas are the most common and lethal brain tumors. Cell invasion into the surrounding brain tissue is a hallmark feature of glioma. Understanding the mechanism of glioma invasion could lead to the discovery of novel therapeutic strategies to treat affected patients. Earlier gene expression analyses on human glioma biopsies showed that SOX2 is associated with glioma invasiveness. The gene for transcription factor SOX2 localizes to 3q26.3 in the human genome amid oncogene PIK3CA and genes regulating mitochondrial fusion, MFN1 and OPA1. Increasing evidence points to a role for 3q26-29 genes in tumor invasion. We hypothesized that SOX2 regulates the 3q26-29 candidate genes as effectors of glioma cell invasion.
We used SOX2 expressing human glioma cell lines, LN319 and U373 to test our hypothesis in vitro. Lentiviruses expressing shRNAs against PIK3CA, MFN1, OPA1 or SOX2 were used for genetic knockdown. Engineered cells were assayed for invasion and migration using Boyden chamber and wound healing assays, respectively. Chromatin immuno-precipitation and luciferase assays were used to demonstrate protein-DNA interactions and trans-activation of 3q26-29 genes by SOX2.
Our results show that cells downregulated for 3q26-29 genes exhibited enhanced invasion and migration, while shSOX2 and shPIK3CA cells exhibited reduced proliferation rates compared to sh scramble controls. Furthermore, we show that SOX2 knockdown reduced gene and protein expression of PIK3CA, MFN1 and OPA1 except for PIK3CA at the protein level. Chromatin immuno-precipitation assays suggested that SOX2 binds to the upstream region of 3q26-29 gene promoters in the glioma cells.
Preliminary luciferase assays in HEK293 cells suggested that SOX2 trans-activates PIK3CA and OPA1. Preliminary immunofluorescence analysis showed that cells knocked-down for 3q26-29 genes demonstrated altered mitochondrial morphology compared to sh scramble controls. Overall, our results show that SOX2, PIK3CA, MFN1 and OPA1 contribute to glioma invasion and that SOX2 is a potential regulator of the 3q26-29 genes
