Search

Summary: One of the most affected cognitive impairments in children who experienced heavy burdens of diarrhea is semantic fluency, the same impairment that is most affected in Alzheimer’s dementia. These findings are leading us into provocative genetic studies that may elucidate the evolution of such genetic polymorphisms as the APOE alleles. Alternatively, diarrhea could launch the cognitive deficits that might later progress in neurodegenerative diseases. In addition, they suggest that semantic fluency could provide a simple mean to assess cognitive impairment in impoverished settings so as to determine preventive measures. [Copyright &y& Elsevier]

Summary: Our group and others have reported a series of studies showing that heavy burdens of diarrheal diseases in the formative first two years of life in children in urban shantytowns have profound consequences of impaired physical and cognitive development lasting into later childhood and schooling. Based on these previous studies showing that apolipoprotein E4 (APOE4) is relatively common in favela children, we review recent data suggesting a protective role for the APOE4 allele in the cognitive and physical development of children with heavy burdens of diarrhea in early childhood. Despite being a marker for cognitive decline with Alzheimer’s and cardiovascular diseases later in life, APOE4 appears to be important for cognitive development under the stress of heavy diarrhea. The reviewed findings provide a potential explanation for the survival advantage in evolution of the thrifty APOE4 allele and raise questions about its implications for human development under life-style changes and environmental challenges. [Copyright &y& Elsevier]

Background & Aims: Prolonged episodes of acute diarrhea (ProD; duration 7–13 days) or persistent diarrhea (PD; duration ≥14 days) are important causes of undernutrition, yet the epidemiology and nutritional impact of ProD are poorly understood. Methods: We conducted a 10-year cohort study of 414 children from a Brazilian shantytown who were followed from birth; data were collected on diarrhea, enteric pathogens, and anthropometry. Results: During 1276 child-years of observation, we recorded 3257 diarrheal episodes. ProD was twice as common as PD (12% and 5% of episodes, respectively); ProD and PD together accounted for 50% of all days with diarrhea. ProD was more common in infants whose mothers had not completed primary school (relative risk [RR], 2.1; 95% confidence interval: 1.02–2.78). Early weaning was associated with earlier onset of ProD (Spearman ρ = 0.309; P = .005). Infants with ProD were twice as likely to develop PD in later childhood (log rank, P = .002) compared with infants with only acute diarrhea (AD; duration <7 days), even after controlling for confounders. Children''s growth was more severely stunted before their first episode of ProD, compared with AD (mean height-for-age Z score (HAZ) −0.81 vs −0.51, respectively, P < .05, unpaired t test). Following ProD, HAZ (ΔHAZ = −0.232) and weight-for-age (ΔWAZ = −0.26) significantly decreased (P < .005 in paired t tests). ProD was associated with Cryptosporidium and Shigella infections. Conclusions: ProD accounts for significant morbidity and identifies children at risk of a vicious cycle of diarrhea and malnutrition. Further studies are needed to address the recognition and control of ProD and its consequences in resource-limited settings and assess its role in PD pathogenesis. [Copyright &y& Elsevier]

Abstract: Vitamin A (retinol), a fat-soluble vitamin, is an essential nutrient for the normal functioning of the visual system, epithelial cell integrity and growth, immunity, and reproduction. Our group has investigated the effect of high doses of oral vitamin A on early childhood diarrhea in our prospective community-based studies from Northeast Brazil and found a beneficial role in reducing the mean duration but not incidence of diarrheal episodes. In this study, we explored the role of retinol supplementation in intestinal cell lines following Clostridium difficile toxin A (TxA) challenge. C. difficile is the most common anaerobic pathogen borne with antibiotic-borne diarrhea and pseudomembranous colitis. Since retinol is critical for the integrity of tight junctions and to modulate the cell cycle, we have focused on changes in transepithelial electrical resistance (TEER) in Caco-2, a more differentiated intestinal cell line, and on models of cell proliferation, migration and viability in IEC-6 cells, an undifferentiated crypt cell line, following TxA injury. In this model, retinol therapy reduced apoptosis, improved cell migration and proliferation, and prevented the reduction in TEER, following C. difficile TxA challenge in a glutamine-free medium. These results suggest the role of retinol in protecting intestinal epithelial barrier function from C. difficile TxA enterotoxic damage. [Copyright &y& Elsevier]

Abstract: Apolipoprotein E (apoE) is synthesized mainly in the liver and in the brain and is critical for cholesterol metabolism and recovery from brain injury. However, although apoE mRNA increases at birth, during suckling, and after fasting in rat liver, little is known about its role in early postnatal development. Using an established postnatal malnutrition model and apoE knock-out (ko) mice, we examined the role of apoE in intestinal adaptation responses to early postnatal malnutrition. Wild-type and apoE-ko mice were separated from their lactating dams for defined periods each day (4 hours on day 1, 8 hours on day 2, and 12 hours thereafter). We found significant growth deficits, as measured by weight gain or tail length, in the apoE-ko mice submitted to a malnutrition challenge, as compared with malnourished wild type, especially during the second week of postnatal development (P < .05). In addition, apoE-ko animals failed to show growth catch-up after refeeding, compared with wild-type malnourished controls. Furthermore, we found shorter crypts and reduced villus height and area in the apoE-ko malnourished mice, compared with controls, after refeeding. Insulinlike growth factor 1 expression was also blunted in the ileum in apoE-ko mice after refeeding, compared with wild-type controls, which exhibited full insulinlike growth factor 1 expression along the intestinal crypts, villi, and in the muscular layer. Taken together, these findings suggest the importance of apoE in coping with a malnutrition challenge and during the intestinal adaptation after refeeding. [Copyright &y& Elsevier]

Objective: In this study, we postulated the beneficial role of oral alanyl-glutamine, a more stable glutamine derivative to decrease 5-fluorouracil (5-FU)–induced mucositis in mice.Methods: We measured different morphologic parameters to assess structural changes over time in the small bowel, including crypt depth, villus height, villus area, mitotic and apoptotic indices at the crypt level using terminal deoxyuridine triphosphate nick end labeling, and hematoxylin–eosin staining of ileal tissue. In addition, we analyzed the effect of different alanyl-glutamine concentrations on animal weight curves after 5-FU treatment.Results: Neither glutamine nor alanyl- glutamine prevented the 5-FU intestinal structural damage or apoptosis in crypt enterocytes at 24 h after 5-FU challenge. However, we found that alanyl-glutamine, but not glutamine, speeds intestinal recovery when compared with 5-FU–treated controls (P < 0.05), predominantly by enhancing mitotic activity and crypt length.Conclusion: Our findings provide important data to support clinical studies of oral alanyl-glutamine in 5-FU–induced mucositis. [Copyright &y& Elsevier]

Highlights: [•] A nerve pro-inflammatory effect of gabapentin treatment was identified. [•] Gabapentin increased carrageenan-induced paw edema and peritoneal cell migration. [•] Concern of gabapentin widespread use in systemic inflammatory diseases was raised. [Copyright &y& Elsevier]

Abstract: Objective: This study investigated the role of L-arginine supplementation to undernourished and Cryptosporidium parvum–infected suckling mice. Methods: The following regimens were initiated on the fourth day of life and injected subcutaneously daily. The C. parvum–infected controls received L-arginine (200 mmol/L) or phosphate buffered saline. The L-arginine–treated mice were grouped to receive NG-nitro-arginine methyl ester (L-NAME) (20 mmol/L) or phosphate buffered saline. The infected mice received orally 106 excysted C. parvum oocysts on day 6 and were euthanized on day 14 at the infection peak. Results: L-arginine improved weight gain compared with the untreated infected controls. L-NAME profoundly impaired body weight gain compared with all other groups. Cryptosporidiosis was associated with ileal crypt hyperplasia, villus blunting, and inflammation. L-arginine improved mucosal histology after the infection. L-NAME abrogated these arginine-induced improvements. The infected control mice showed an intense arginase expression, which was even greater with L-NAME. L-arginine decreased the parasite burden, an effect that was reversed by L-NAME. Cryptosporidium parvum infection increased urine NO3 −/NO2 − concentrations compared with the uninfected controls, which was increased by L-arginine supplementation, an effect that was also reversed by L-NAME. Conclusion: These findings show a protective role of L-arginine during C. parvum infection in undernourished mice, with involvement of arginase I and nitric oxide synthase enzymatic actions. [Copyright &y& Elsevier]

Abstract: Objective: The effect of zinc and glutamine on brain development was investigated during the lactation period in Swiss mice. Methods: Malnutrition was induced by clustering the litter size from 6–7 pups/dam (nourished control) to 12–14 pups/dam (undernourished control) following birth. Undernourished groups received daily supplementation with glutamine by subcutaneous injections starting at day 2 and continuing until day 14. Glutamine (100mM, 40–80 μL) was used for morphological and behavioral studies. Zinc acetate was added in the drinking water (500mg/L) to the lactating dams. Synaptophysin and myelin basic protein brain expressions were evaluated by immunoblot. Zinc serum and brain levels and hippocampal neurotransmitters were also evaluated. Results: Zinc with or without glutamine improved weight gain as compared to untreated, undernourished controls. In addition, zinc supplementation improved cliff avoidance and head position during swim behaviors especially on days 9 and 10. Using design-based stereological methods, we found a significant increase in the volume of CA1 neuronal cells in undernourished control mice, which was not seen in mice receiving zinc or glutamine alone or in combination. Undernourished mice given glutamine showed increased CA1 layer volume as compared with the other groups, consistent with the trend toward increased number of neurons. Brain zinc levels were increased in the nourished and undernourished-glutamine treated mice as compared to the undernourished controls on day 7. Undernourished glutamine-treated mice showed increased hippocampal gamma-aminobutyric acid and synaptophysin levels on day 14. Conclusion: We conclude that glutamine or zinc protects against malnutrition-induced brain developmental impairments. [Copyright &y& Elsevier]