Tony Fulford

Effectiveness of an early supplementation scheme of high-dose vitamin A versus standard WHO protocol in Gambian mothers and infants: a randomised controlled trial

BACKGROUND Most developing countries have adopted a standard WHO dosing schedule for vitamin A supplementation. However, in 2002 the International Vitamin A Consultative Group (IVACG) Annecy Accord recommended a new high-dose regimen for mothers and infants. Our aim was to test whether the new high-dose regimen of vitamin A supplementation would increase maternal and infant plasma vitamin A, reduce infant Helicobacter pylori infection and nasopharyngeal pneumococcal carriage, and improve infant gut epithelial integrity. METHODS In an area of moderate vitamin A deficiency in rural Gambia, 220 mother-infant pairs were enrolled in a randomised double-blind trial between September, 2001, and October, 2004, that compared the IVACG high dose with the WHO dose. The primary endpoints were levels of maternal and infant plasma vitamin A, H pylori infection, pneumococcal carriage, and gut epithelial integrity. The trial is registered as ISRCTN 98554309. FINDINGS 197 infants completed follow-up to 12 months (99 high dose and 98 WHO dose). There were no adverse events at dosing. No differences were found in the primary outcomes for high-dose versus WHO schedule: maternal vitamin A concentration at 2 months +0.02 micromol/L (95% CI -0.10 to 0.15); infant vitamin A at 5 months +0.01 micromol/L (-0.06 to 0.08); H pylori infection at 12 months -0.3% (-14.7 to 14.2); maternal pneumococcal carriage at 12 months -2.0% (-13.7 to 9.7); infant pneumococcal carriage at 12 months -4.1% (-15.8 to 7.6); infant gut mucosal damage at 12 months 5.2% (-8.7 to 19.2). There were more clinic attendances by the high-dose group in the first 6 months of life (p=0.018). INTERPRETATION Our results do not lend support to the proposal to increase the existing WHO standard dosing schedule for vitamin A in areas of moderate vitamin A deficiency. Caution is urged for future studies because trials have shown possible adverse effects of higher doses of vitamin A, and potential negative interactions with the expanded programme on immunisation (EPI) vaccines.

The linear effects of alpha-thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease

Serum bilirubin levels and predisposition to gallstones in sickle cell disease (SCD) are influenced by genetic variation in the hepatic uridine diphosphate (UDP)‐glucuronosyltransferase (UGT1A1) gene, but the association is not consistent. This study investigated whether variation in the gene encoding haem oxygenase (HMOX1), a rate‐limiting enzyme upstream of UGT1A in the haem catabolic pathway, and α‐thalassaemia could explain some of the inconsistent effects. The UGT1A1 [TA]n and HMOX1 [GT]n promoter polymorphisms and α globin genotypes were determined in 263 SCD patients (199 HbSS, 5 HbS/β0, 59 HbSC). Detection of gallstones was based on ultrasound of the liver/biliary tree. Regression analysis showed that serum bilirubin levels and the incidence of gallstones were strongly associated with the number of UGT1A1 [TA] repeats in all subjects (P < 0·0001 and P < 0·01, respectively). While HMOX1 genotype had no effect, co‐inheritance of α‐thalassaemia reduced serum bilirubin levels in all SCD patients independently of the number of UGT1A1 [TA] repeats. Each additional [TA] repeat is associated with an increase in mean serum bilirubin levels of 21% and cholelithiasis risk of 87% in SCD.

α-Cell Neogenesis in an Animal Model of IDDM

Currently there is debate regarding the capacity of pancreatic islets to regenerate in adult animals. Because pancreatic endocrine cells are thought to arise from duct cells, we examined the pancreatic ductal epithelium of the diabetic NOD mouse for evidence of islet neogenesis. We have evidence of duct proliferation as well as ductal cell differentiation, as suggested by bromodeoxyuridine-labeling and the presence of glucagon-containing cells within these ducts. In addition, the ductal epithelia in diabetic NOD mice expressed the neuroendocrine markers neuropeptide Y and tyrosine hydroxylase. These ducts also expressed the homeobox gene product, insulin promoter factor 1. Ductal cell proliferation and expression of these markers was not observed in transgenic NOD mice (NOD-E), which do not develop clinical or histopathological symptoms of IDDM. This suggests that the observed ductal cell proliferation and differentiation was a direct result of β-cell destruction and insulin insufficiency in these adult diabetic mice, which further suggests that these events are recapitulating islet ontogeny observed during embryogenesis. It is possible that comparable processes occur in the human diabetic pancreas.

Association between hemolysis and albuminuria in adults with sickle cell anemia

Studies have questioned whether renal dysfunction in sickle cell disease is linked to hemolysis-associated vasculopathy. We have investigated renal function and markers of hemolysis in a cohort of 424 adult African-British patients with sickle cell disease. While significant associations were found in HbSS and HbSβ0 (sickle cell anemia) patients with and without controlling for covariates between hemolytic markers and albuminuria, the associations were not significant in patients with HbSC. Estimated glomerular filtration rate, a marker of renal function, correlated significantly with reticulocyte count and bilirubin. Alpha thalassemia, present in 34% of the sickle cell anaemia patients, had a protective effect against albuminuria in this group. Altogether, the incidence of hyperfiltration was 71% and microalbuminuria 37%, making nephropathy a common complication of sickle cell anemia.

alpha-Cell neogenesis in an animal model of IDDM.

Currently there is debate regarding the capacity of pancreatic islets to regenerate in adult animals. Because pancreatic endocrine cells are thought to arise from duct cells, we examined the pancreatic ductal epithelium of the diabetic NOD mouse for evidence of islet neogenesis. We have evidence of duct proliferation as well as ductal cell differentiation, as suggested by bromodeoxyuridine-labeling and the presence of glucagon-containing cells within these ducts. In addition, the ductal epithelia in diabetic NOD mice expressed the neuroendocrine markers neuropeptide Y and tyrosine hydroxylase. These ducts also expressed the homeobox gene product, insulin promoter factor 1. Ductal cell proliferation and expression of these markers was not observed in transgenic NOD mice (NOD-E), which do not develop clinical or histopathological symptoms of IDDM. This suggests that the observed ductal cell proliferation and differentiation was a direct result of beta-cell destruction and insulin insufficiency in these adult diabetic mice, which further suggests that these events are recapitulating islet ontogeny observed during embryogenesis. It is possible that comparable processes occur in the human diabetic pancreas.

Coverage and timing of children's vaccination: an evaluation of the expanded programme on immunisation in The Gambia.

Objective To evaluate the coverage and timeliness of the Expanded Programme on Immunisation (EPI) in The Gambia. Methods Vaccination data were obtained between January 2005 and December 2012 from the Farafenni Health and Demographic Surveillance System (FHDSS), the Basse Health and Demographic Surveillance System (BHDSS), the Kiang West Demographic surveillance system (KWDSS), a cluster survey in the more urban Western Health Region (WR) and a cross sectional study in four clinics in the semi-urban Greater Banjul area of WR. Kaplan-Meier survival function was used to estimate the proportion vaccinated by age and to assess timeliness to vaccination. Findings BCG vaccine uptake was over 95% in all regions. Coverage of DPT1 ranged from 93.2% in BHDSS to 99.8% in the WR. Coverage decreased with increasing number of DPT doses; DPT3 coverage ranged from 81.7% in BHDSS to 99.0% in WR. Measles vaccination coverage ranged from 83.3% in BHDSS to 97.0% in WR. DPT4 booster coverage was low and ranged from 43.9% in the WR to 82.8% in KWDSS. Across all regions, delaying on previous vaccinations increased the likelihood of being delayed for the subsequent vaccination. Conclusions The Gambia health system achieves high vaccine coverage in the first year of life. However, there continues to be a delay to vaccination which may impact on the introduction of new vaccines. Examples of effectively functioning EPI programmes such as The Gambia one may well be important models for other low income countries struggling to achieve high routine vaccination coverage.

Effect of moderate anaemia on later mortality in rural African children

Severe anaemia in childhood is associated with increased mortality, although evidence relating moderate anaemia to child survival is scarce. We aimed to investigate this association. We did a case-control study of children with moderate anaemia, and compared haemoglobin concentrations measured up to a year before death for 403 children (age range 28 days to 15 years) with those from children who survived (matched for age and sex). Data were obtained from long-term health records (1950-97) of a rural Gambian research centre. Excluding an acute effect in this last week of life, no evidence was recorded of lower haemoglobin concentrations in the children who died than in survivors, or of any general or disease-specific effects of non-severe anaemia (70-110 g/L) on mortality.

The effect of Duffy antigen receptor for chemokines on severity in sickle cell disease

Despite the identical genotypes, the clinical course of sickle cell disease (SCD) is extremely variable, prompting the search for genetic and biological predictors of disease severity.[1][1],[2][2] Raised white blood counts (WBC) have been known to be a marker of disease severity in SCD since the

Early supplementation with high-dose vitamin A in The Gambia – Authors' reply

Young Kwang Chae and Jeong Hyun Yun query whether data from our randomised controlled trial of early high-dose vitamin A supplementation (50 000 I given with the three diphtheria-tetanus-pertussis [DPT] vaccinations at 6 10 and 14 weeks) in Gambian infants can contribute to the ongoing controversy about whether there might be harmful interactions between vitamin A supplementation and killed vaccines particularly in girls. Several notes of caution are necessary. The observations by Benn and colleagues that have raised the concerns relate to excess mortality. Our trial is greatly underpowered for this endpoint. There were two postneonatal deaths in the high-dose group (n=99) and none in the standard WHO dose group (n=98). One male infant died of pneumonia and septicaemia at 7 months and one female of unknown causes at 3 months. This overall post-neonatal infant mortality rate equates to 10 in 1000 which is exceptionally low for this region and reflects the high level of monitoring and clinical care offered to the study participants. This point reduces the usefulness of our data in contributing to the debate. In response to Chae and Yuns query as to whether the vitamin A might have exacerbated DTP-related side-effects we have reanalysed our data in an attempt to identify potentially life-threatening illnesses. In our original paper we restricted the analyses to clinic visits that elicited a treatment. Numerous non-critical conditions such as colds and skin rashes remained. We have now excluded these and repeated the analysis of potentially life-threatening events for the time window between the first DPT vaccination and vitamin A dose at 6 weeks and the first live vaccine (measles at 9 months). We analysed four diseases (malaria diarrhoea pneumonia and septicaemia) separately and combined. There were 73 events in the high-dose group and 79 events in the WHO group. Owing to small numbers of events there were wide confidence intervals and no differences were significant. The closest to significance (pneumonia) was if anything lower in the high-dose group. In summary our trial is under powered to contribute to this important debate but we will be happy to contribute the data to future meta-analyses. (full text)