Impact of intestinal permeability, inflammation status and parasitic infections on infant growth faltering in rural Bangladesh.

A longitudinal study of 298 rural Bangladeshi infants found evidence of growth faltering starting at 3 months of age. Anthropometric status declined substantially in the first 2 years of life, with weight-for-height (WHZ) falling from - 0.49 to - 1.75, weight-for-age (WAZ) from - 1.18 to - 2.87 and height-for-age (HAZ) from - 1.00 to - 1.88. Higher concentrations of the acute-phase protein alpha-1-acid glycoprotein (AGP) and higher gut mucosal damage (as signified by raised lactulose:mannitol (L:M) ratios) were both associated with chronic malnutrition as indicated by poorer HAZ and WAZ scores (P = 0.011 and 0.005 for AGP and 0.039 and 0.019 for L:M ratio, respectively). Higher Hb levels were related to improved z-scores, while elevation of Giardia-specific IgM titre (GSIgM) was associated with poor WAZ and WHZ (P = 0.015 and 0.039, respectively). IgG did not show any significant association with z-scores and the L:M ratio did not correlate with any of the inflammation markers or Giardia infection. The prevalence of geohelminth infections was low (only 4 % in the total study period). However, the level of GSIgM indicated high endemicity of Giardia infection from early in life, although very few cysts were detected from stool samples. These findings suggest that rural Bangladeshi infants are being exposed to high levels of infection with concomitant gut damage and growth faltering.

Body composition by 2H dilution in Gambian infants: comparison with UK infants and evaluation of simple prediction methods.

Gambian infants show growth faltering, but the underlying body composition is unknown. The present study aimed to compare body composition in Gambian and UK infants using 2H dilution; and to evaluate accuracy of bioelectrical impedance analysis (BIA) and creatinine excretion for estimating lean mass (LM), using 2H as the reference. Body composition was measured in thirty Gambian infants, aged 3-18 months, using (1) anthropometry, (2) 2H, (3) BIA (equation of Fjeld et al. Pediatr Res (1990), 27, 98-102) and (4) 5 h urinary creatinine excretion. Compared with UK reference data, Gambian infants were light, short and had reduced BMI and skinfolds. The subscapular skinfold standard deviation score (SDS) was greater than the triceps SDS (P < 0.01), indicating central fat preservation. Both LM and fat mass were reduced in Gambian infants, with or without adjustment for length. However, whereas the Gambia-UK difference in LM increased with age, that in fat mass decreased. Average creatinine excretion was similar to that expected (95.5 (sd 23.2) % recovery), but LM estimates showed unacceptable error in individuals. BIA using Fjeld's equation overestimated total body water and LM (P < 0.001), hence a new equation was developed, with standard error of 0.47 kg LM. In conclusion, Gambian infants characterised by growth faltering had LM deficits that increased with age. However, adiposity increased with age, and showed indications of a more central distribution than in the reference infants. A new BIA equation for LM prediction is presented; however, creatinine excretion is not recommended for LM estimation in this population.

Pathways leading to early growth faltering: an investigation into the importance of mucosal damage and immunostimulation in different socio-economic groups in Nepal.

Early childhood growth retardation persists in developing countries despite decades of nutritional interventions. Adequate food is necessary, but not sufficient, to ensure normal growth where there is ubiquitous exposure to infection. Pathways associated with infection, small intestinal mucosal damage and chronic immunostimulation remain largely undemonstrated in countries other than The Gambia. We conducted a longitudinal study of one squatter and one middle-class group (n 86, 3-18 month olds) to assess these relationships in Nepal. Growth, mucosal damage index (MDI; urinary lactose:creatinine ratio adjusted for body weight), morbidity reports, and blood concentrations of albumin, alpha-1-acid glycoprotein, IgG and Hb, were recorded monthly. Growth status worsened dramatically from 6 to 18 months, with squatters more stunted (height-for-age Z-score (HAZ), P<0.001) and underweight (weight-for-age Z-score (WAZ), P=0.009) than middle class. IgG increased with age, was elevated in squatter children, and negatively related to WAZ (P=0.034). MDI showed significant negative associations with growth performance, explaining 9 and 19% of height and weight deficits (DeltaHAZ, P=0.004; DeltaWAZ, P<0.001). Unexpectedly, these associations were weaker in squatter children, namely in the group which showed poorer growth, elevated morbidity, greater pathogen exposure (IgG) and higher MDI (P<0.001). In Nepal, as in The Gambia, children exhibit poor growth, mucosal damage and immunostimulation. The relative impact of pathways associated with infection and undernutrition may, however, differ across socio-economic groups: in poorer children, the impact of mucosal damage and immunostimulation could be masked by nutritional constraints. This has important implications for public health interventions.

A double-blind, placebo-controlled, glutamine-supplementation trial in growth-faltering Gambian infants.

BACKGROUND: Growth faltering during infancy is a characteristic of life in developing countries. Previous studies have shown that small-intestine mucosal enteropathy, accompanied by endotoxemia and a persistent systemic inflammatory response, accounts for up to 64% of the growth faltering in Gambian infants. OBJECTIVE: The objective was to test whether glutamine, with its putative trophic effects on enterocytes, immune cells, and intestinal integrity, can accelerate the repair of the intestine, lower immunostimulation, and reduce growth faltering. DESIGN: Ninety-three infants aged 4-10 mo from the West Kiang region of The Gambia were studied in a double-blind, double-placebo, controlled trial. Glutamine (0.25 mg/kg body wt) or a placebo that contained an isonitrogenous, isoenergetic mix of nonessential amino acids was orally administered twice daily throughout the 5-mo rainy season. Anthropometric measurements were made monthly during the supplementation period and for 6 mo after supplementation. Intestinal permeability was measured monthly (by determining the ratio of lactulose to mannitol), and finger-prick blood samples were collected for the analysis of plasma proteins on 3 occasions. RESULTS: Gambian infants showed a seasonal deterioration in growth and persistently elevated acute phase protein concentrations and intestinal permeability. Oral supplementation with glutamine did not improve growth (x +/- SE: weight gain, 60 +/- 19 and 69 +/- 20 g/mo; length gain, 1.01 +/- 0.05 and 0.95 +/- 0.03 cm/mo) or intestinal permeability [lactulose:mannitol ratio: 0.29 (95% CI: 0.23, 0.35) and 0.26 (95% CI: 0.21, 0.32)] in the glutamine and placebo groups, respectively. It also had no effect on infant morbidity or on plasma concentrations of immunoglobulins or acute phase proteins. CONCLUSION: Glutamine supplementation failed to improve growth or intestinal status in malnourished Gambian infants.

Sixty-year follow-up in an untreated patient with Kienböck disease.

Kienböck disease can be treated either conservatively or by various operations. We describe the findings of the progression of Kienböck disease over 60 years in an 84-year-old man who had had no surgical treatment. This is the longest follow-up ever reported to our knowledge of a patient with avascular necrosis of the lunate.

Impact of anti-Giardia and anthelminthic treatment on infant growth and intestinal permeability in rural Bangladesh: a randomised double-blind controlled study.

In order to test the impact of Giardia and geohelminthic infection on infant growth faltering in Bangladesh, a randomised double-blind placebo controlled intervention of 36 weeks' duration was conducted in a rural community located 40 km northwest of Dhaka. Infants aged between 3 and 15 months were randomly assigned to either anti-Giardia and anthelminthic treatment, anti-Giardia treatment only, or a control. Weight and supine length were recorded every 4 weeks. Every 12 weeks intestinal permeability (lactulose/mannitol ratio), haemoglobin, plasma albumin, alpha-1-acid glycoprotein, IgG and Giardia-specific IgM (GSIgM) and eggs of the three common geohelminths and G. intestinalis cysts were determined. Data on 222 fully compliant infants were analysed. No significant differences in intestinal permeability, biochemical or anthropometric variables were found between the intervention groups, although there were associations between improvement in small intestinal mucosal function and better weight-for-age and weight-for-height (length) Z-scores. GSIgM titres indicated high endemicity with rapid re-infection of Giardia among infants; over 95% of infants were positive throughout the study, whereas the stool examination showed very few infants with either geohelminth eggs or Giardia cysts.

Age-related association of small intestinal mucosal enteropathy with nutritional status in rural Gambian children.

Small bowel enteropathy (assessed by the lactulose (L) : mannitol (M) permeability test) is a major factor in infant growth faltering and malnutrition in The Gambia. However, little is known about its persistence and nutritional effect beyond 2 years of age. This was addressed by two cross-sectional studies of intestinal permeability and nutritional status in 162 residents, aged 2-60 years, living in three villages in rural Gambia. L:M ratio was found to be highest in the youngest children and although there was a significant improvement with age (P<0.0001), values were always greater than the range found in UK counterparts. M recovery (mean value 5.68 (se 0.12) %) was at all times between one-third and one-half of expected UK values and showed no improvement with age. Gut barrier function, assessed by L uptake, improved with age (P<0.001) and fell within the UK normal range beyond age 10 years. Both the L:M permeability ratio and L recovery were significantly associated with height-for-age z-scores and -0.22 respectively, P<0.001), a relationship that persisted throughout childhood and into adulthood. Change in height-for-age z-score between the two visits was also related to the L:M ratio P=0.018). The close within-subject correlation of permeability variabilities between the two visits suggests a long-term persistence of enteropathy within individuals. It appears that the small bowel enteropathy previously described in Gambian infants persists through to adulthood. Although the lesion improves with age, the relationship between attained height and L:M permeability raises the possibility that enteropathy may continue to limit growth throughout childhood and puberty.

Intestinal inflammation measured by fecal neopterin in Gambian children with enteropathy: association with growth failure, Giardia lamblia, and intestinal permeability.

OBJECTIVES: Investigate whether fecal neopterin concentration (a potential marker of gut inflammation) in Gambian children with enteropathy was associated with growth failure. Secondary outcome measures tested the associations between Giardia lamblia infestation, fecal neopterin and lactulose mannitol absorption ratio(L:M), a measure of intestinal permeability. METHODS: Seventy-two children had height and weight measured every 6 to 8 weeks until 15 months of age in a rural Gambian village. L:M ratio, a measure of small intestinal permeability and fecal neopterin were measured at these times. Stool was examined by immunofluorescence and light microscope for Giardia cysts. RESULTS: Long-term height and weight gains were negatively associated with mean subject fecal neopterin concentration (r = -0.29 and -0.36, respectively; P < 0.001). There was no correlation between fecal neopterin and intestinal permeability or history of diarrhea. Of 72 children studied, 19 had Giardia cysts in stool and 38 had negative stool examinations. Infected children had a mean of 0.7 days of diarrhea/week (95% confidence interval [CI], 0.31-1.03) versus 0.8 days/week (95% CI, 0.71-0.85) in uninfected children. No difference in growth was detected between those with positive or negative fecal smears. Mean L:M ratio was the same in both groups (0.31; 95% CI, 0.26-0.34). CONCLUSIONS: Consistent with the theory that intestinal inflammation in tropical infants may impair growth, fecal neopterin concentrations were inversely associated with growth. Factors other than Giardia are causing enteropathy and growth failure in Gambian infants.

Chronic T cell-mediated enteropathy in rural west African children: relationship with nutritional status and small bowel function.

Previous studies from The Gambia have shown that poor childhood growth is resistant to all but the most intense nutritional intervention and highly dependent on small bowel permeability related to enteropathy. We thus aimed to characterize the mucosal inflammatory response in rural Gambian children in relation to intestinal permeability and nutritional status. Small bowel biopsies were taken from 38 rural Gambian children (age, 0.5-3 y) with a range of nutritional and clinical states (median weight z score, -4.6; range, 0.5 to -6.4), 75% of whom had diarrhea. Morphometry was performed with immunohistochemical analysis for a range of lineage and activation markers, including proinflammatory and regulatory cytokines, and related to current clinical status and gut permeability. Comparison was made with 19 age-matched U.K. controls. All Gambian children, regardless of nutritional status, had evidence of chronic cell-mediated enteropathy with crypt hyperplasia, villous stunting, and high numbers of intraepithelial lymphocytes. CD25+ cells were 20-fold higher than in U.K. controls. Although small bowel architecture was independent of nutritional status, T cell numbers rose and B cell numbers fell with worsening nutrition, and mucosal cytokine production became biased toward a proinflammatory response, with progressive decrease of transforming growth factor-beta expression. Tropical enteropathy predates the onset of marasmus and is characterized by a cell-mediated TH1 response. Protein-energy malnutrition is associated with reduction of regulatory immune responses in the mucosal microenvironment, potentially impairing the mechanisms of oral tolerance.