Moffat Nyirenda

Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.

Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11beta-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11beta-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (treated 5.3+/-0.3; control 4.3+/-0.2 mmol/ liter, P = 0.04), reactive hyperglycemia (treated 8.7+/-0.4; control 7.5+/-0.2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1+/-0.4; control 3.8+/-0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11beta-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.

Improving responsiveness of health systems to non-communicable diseases

In almost all countries, development of health systems that are responsive to the challenge of prevention and treatment of non-communicable diseases (NCDs) is a priority. NCDs consist of a vast group of conditions, but in terms of premature mortality, emphasis has been on cardiovascular disease, cancer, diabetes, and chronic respiratory diseases—diseases that were also the focus of the UN high-level meeting on NCDs, held in 2011. In 1990, there were 26·6 million deaths worldwide from NCDs (57·2% of 46·5 million total deaths), increasing in 2010 to 34·5 million (65·5% of 52·8 million deaths) as the leading cause of death in all regions apart from sub-Saharan Africa and south Asia. Similarly, the global burden of NCDs has increased from 43% (1·08 billion of the total 2·50 billion) in 1990, to 54% (1·34 billion of 2·49 billion) of the total number of disability-adjusted life-years in 2010. The global economic burden of NCDs is large, estimated at US

A Choline-Deficient Diet Exacerbates Fatty Liver but Attenuates Insulin Resistance and Glucose Intolerance in Mice Fed a High-Fat Diet

6·3 trillion in 2010, rising to

Influence of maternal obesity on the long-term health of offspring

13 trillion in 2030. A 10% rise in NCDs leads to a 0·5% decrease in gross domestic product. The projected cumulative global loss of economic output due to NCDs for 2011–30 is estimated at

Association of HIV and ART with cardiometabolic traits in sub-Saharan Africa: a systematic review and meta-analysis

46·7 trillion, with around

A cleaner burning biomass-fuelled cookstove intervention to prevent pneumonia in children under 5 years old in rural Malawi (the Cooking and Pneumonia Study): a cluster randomised controlled trial

21·3 trillion (46%) in low-income and middle-income countries. The growing burden of NCDs in low-income and middle-income countries will compound the poverty and economic hardship created by communicable diseases and hold back development. Yet, few such countries have the fi scal strength to meet the future health, economic, and social burden that NCDs will impose, which raises concerns of economic instability, arrested development, and government fragility—with implications for global security as well as foreign policy. An ageing society, alongside improving health care, means that health systems have to manage not only diseases such as heart disease, stroke, and cancer, but also individuals with multiple chronic disorders. Multimorbidity disproportionately aff ects those who are poorest. Furthermore, around 9 million people in lowincome and middle-income countries now benefi t from antiretroviral treatment (ART), with remarkably im proved survival, but with new comorbidities such as diabetes or cardiovascular disease. Health systems also have to manage patients with new comorbid disease patterns, in which infectious diseases combine with NCDs. Management of people with NCDs and multimor bidity will be particularly challenging in low-income and middle-income countries with weak health systems characterised by fragmented health-care services, which are still designed to respond to single episodes of care, or the long-term prevention and control of infectious diseases such as HIV, tuberculosis, and neglected tropical diseases. These health systems are ill prepared to manage changing disease patterns with a growing burden of NCDs and multimorbidity. To achieve the World Health Assembly target of 25% reduction in preventable deaths from NCDs by 2025, health systems need to be transformed to provide person-centred care with improved outreach and selfmanagement to eff ectively manage risk factors, illness episodes, and multimorbidity over many years. Along with outreach and community-based services, health facilities in low-income and middle-income countries need to be strengthened to develop reliable individual records that enable assessment and management of risks of individuals under their care. Yet, in many such countries, long-term care and risk management that includes follow-up at clinic and repeat prescriptions are a new idea for many patients and health staff . However, existing service delivery platforms can be used to address chronicity, the emerging NCD epidemic, and multi morbidity. Resource constrains imposed by the worldwide economic crisis means that sustaining increases in global health fi nancing will be a challenge. There is an imperative to fi nd solutions that create synergies among investments in low-income and middle-income coun tries for diff erent diseases, especially HIV and tuber culosis, which have substantially benefi ted from international fi nancing and have clear links with NCDs. In this paper we provide examples of how HIV and tuberculosis investments have been used to strengthen health systems and opportunities to integrate NCD prevention and control with HIV and other programmes. We describe the importance of building health services that profi le the risks of NCDs and multimorbidity in their population. Finally, we propose a stepwise approach to scale up health systems by building on existing programmes to tackle NCDs and multimorbidity.

Prenatal Programming of Metabolic Syndrome in the Common Marmoset Is Associated With Increased Expression of 11β-Hydroxysteroid Dehydrogenase Type 1

Liver fat accumulation is proposed to link obesity and insulin resistance. To dissect the role of liver fat in the insulin resistance of diet-induced obesity, we altered liver fat using a choline-deficient diet. C57Bl/6 mice were fed a low-fat (10% of calories) or high-fat (45% of calories) diet for 8 weeks; during the final 4 weeks, diets were either choline deficient or choline supplemented. In choline replete animals, high-fat feeding induced weight gain, elevated liver triglycerides (171%), hyperinsulinemia, and glucose intolerance. Choline deficiency did not affect body or adipose depot weights but amplified liver fat accumulation with high-fat diet (281%, P < 0.01). However, choline deficiency lowered fasting plasma insulin (from 983 ± 175 to 433 ± 36 pmol/l, P < 0.01) and improved glucose tolerance on a high-fat diet. In mice on 30% fat diet, choline deficiency increased liver mRNA levels of the rate-limiting enzyme in phosphatidylcholine synthesis and of enzymes involved in free fatty acid esterification, without affecting those of de novo lipogenesis or fatty acid oxidation. We conclude that liver fat accumulation per se does not cause insulin resistance during high-fat feeding and that choline deficiency may shunt potentially toxic free fatty acids toward innocuous storage triglyceride in the liver.

Prenatal programming of hepatocyte nuclear factor 4α in the rat: a key mechanism in the ‘foetal origins of hyperglycaemia’?

In addition to immediate implications for pregnancy complications, increasing evidence implicates maternal obesity as a major determinant of offspring health during childhood and later adult life. Observational studies provide evidence for effects of maternal obesity on her offsprings risks of obesity, coronary heart disease, stroke, type 2 diabetes, and asthma. Maternal obesity could also lead to poorer cognitive performance and increased risk of neurodevelopmental disorders, including cerebral palsy. Preliminary evidence suggests potential implications for immune and infectious-disease-related outcomes. Insights from experimental studies support causal effects of maternal obesity on offspring outcomes, which are mediated at least partly through changes in epigenetic processes, such as alterations in DNA methylation, and perhaps through alterations in the gut microbiome. Although the offspring of obese women who lose weight before pregnancy have a reduced risk of obesity, few controlled intervention studies have been done in which maternal obesity is reversed and the consequences for offspring have been examined. Because the long-term effects of maternal obesity could have profound public health implications, there is an urgent need for studies on causality, underlying mechanisms, and effective interventions to reverse the epidemic of obesity in women of childbearing age and to mitigate consequences for offspring.

Trends in marriage and time spent single in sub-Saharan Africa: a comparative analysis of six population-based cohort studies and nine Demographic and Health Surveys

Background Sub-Saharan Africa (SSA) has the highest burden of HIV in the world and a rising prevalence of cardiometabolic disease; however, the interrelationship between HIV, antiretroviral therapy (ART) and cardiometabolic traits is not well described in SSA populations. Methods We conducted a systematic review and meta-analysis through MEDLINE and EMBASE (up to January 2012), as well as direct author contact. Eligible studies provided summary or individual-level data on one or more of the following traits in HIV+ and HIV-, or ART+ and ART- subgroups in SSA: body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TGs) and fasting blood glucose (FBG) or glycated hemoglobin (HbA1c). Information was synthesized under a random-effects model and the primary outcomes were the standardized mean differences (SMD) of the specified traits between subgroups of participants. Results Data were obtained from 49 published and 3 unpublished studies which reported on 29 755 individuals. HIV infection was associated with higher TGs [SMD, 0.26; 95% confidence interval (CI), 0.08 to 0.44] and lower HDL (SMD, −0.59; 95% CI, −0.86 to −0.31), BMI (SMD, −0.32; 95% CI, −0.45 to −0.18), SBP (SMD, −0.40; 95% CI, −0.55 to −0.25) and DBP (SMD, −0.34; 95% CI, −0.51 to −0.17). Among HIV+ individuals, ART use was associated with higher LDL (SMD, 0.43; 95% CI, 0.14 to 0.72) and HDL (SMD, 0.39; 95% CI, 0.11 to 0.66), and lower HbA1c (SMD, −0.34; 95% CI, −0.62 to −0.06). Fully adjusted estimates from analyses of individual participant data were consistent with meta-analysis of summary estimates for most traits. Conclusions Broadly consistent with results from populations of European descent, these results suggest differences in cardiometabolic traits between HIV-infected and uninfected individuals in SSA, which might be modified by ART use. In a region with the highest burden of HIV, it will be important to clarify these findings to reliably assess the need for monitoring and managing cardiometabolic risk in HIV-infected populations in SSA.

Chronic disease outcomes after severe acute malnutrition in Malawian children (ChroSAM): a cohort study

Summary Background WHO estimates exposure to air pollution from cooking with solid fuels is associated with over 4 million premature deaths worldwide every year including half a million children under the age of 5 years from pneumonia. We hypothesised that replacing open fires with cleaner burning biomass-fuelled cookstoves would reduce pneumonia incidence in young children. Methods We did a community-level open cluster randomised controlled trial to compare the effects of a cleaner burning biomass-fuelled cookstove intervention to continuation of open fire cooking on pneumonia in children living in two rural districts, Chikhwawa and Karonga, of Malawi. Clusters were randomly allocated to intervention and control groups using a computer-generated randomisation schedule with stratification by site, distance from health centre, and size of cluster. Within clusters, households with a child under the age of 4·5 years were eligible. Intervention households received two biomass-fuelled cookstoves and a solar panel. The primary outcome was WHO Integrated Management of Childhood Illness (IMCI)-defined pneumonia episodes in children under 5 years of age. Efficacy and safety analyses were by intention to treat. The trial is registered with ISRCTN, number ISRCTN59448623. Findings We enrolled 10 750 children from 8626 households across 150 clusters between Dec 9, 2013, and Feb 28, 2016. 10 543 children from 8470 households contributed 15 991 child-years of follow-up data to the intention-to-treat analysis. The IMCI pneumonia incidence rate in the intervention group was 15·76 (95% CI 14·89–16·63) per 100 child-years and in the control group 15·58 (95% CI 14·72–16·45) per 100 child-years, with an intervention versus control incidence rate ratio (IRR) of 1·01 (95% CI 0·91–1·13; p=0·80). Cooking-related serious adverse events (burns) were seen in 19 children; nine in the intervention and ten (one death) in the control group (IRR 0·91 [95% CI 0·37–2·23]; p=0·83). Interpretation We found no evidence that an intervention comprising cleaner burning biomass-fuelled cookstoves reduced the risk of pneumonia in young children in rural Malawi. Effective strategies to reduce the adverse health effects of household air pollution are needed. Funding Medical Research Council, UK Department for International Development, and Wellcome Trust.