Grandparental morbidity and mortality patterns are associated with infant birth weight in the Lifeways cross-generation cohort study 2001-2010.

The association of infants' birth weight with maternal cardiovascular morbidity (CVD) and mortality substantiates the foetal origins hypothesis. Few studies to date have investigated grandparent-infant risk association. We prospectively examined this relationship in the Lifeways three-generation familial cohort, contrasting lineage and gender differences to understand mechanisms of intergenerational risk transmission. In 2001, a cohort of 1082 families was established at antenatal stage. A total of 539 families (n = 539 infants) had both a participating grandparent (n = 1054) and information on infants' gestational age. At baseline, grandparents provided their diagnosed CVD status and 79% also underwent a cardiovascular risk factors assessment. In 2005, general practitioners provided an update for 61% grandparents. In 2010, a search of civil register confirmed 77 grandparental deaths in 539 families. Grandchildren's birth weight and grandparental cardiovascular risk factors associations were examined with linear regressions. Grandparental CVD associations were analysed using ANCOVA. Cox proportional hazard ratios (HR) were calculated for all-cause mortality associations. Models were adjusted for infants', mothers' and grandparents' demographic, anthropometric and socio-behavioural characteristics, as appropriate. The paternal grandfathers' (PGF) systolic blood pressure (mmHg) [ß (95% CI) = 6.6 (0.8 - 12.5); P = 0.03] and paternal grandmothers' serum triglycerides (mmol/l) [ß (95% CI) = 78.8 (7.0 - 150.7); P = 0.03] were linearly predictive of infants' birth weight, which was not observed for maternal grandparents. Mean birth weight for infants of maternal grandmothers with diabetes {-272.7 [(-499.7) - (-45.6)] g; P = 0.02} or stroke {-292.1 [(-544.5) - (-39.6)] g; P = 0.02} was lower than those without diabetes or stroke, a pattern not observed for paternal grandparents. Whereas PGFs' mortality was significantly associated with infants' high birth weight (≥4000 g) [HR (95% CI) = 4.9 (1.2 - 19.9); P = 0.03], maternal grandparents' mortality showed a converse pattern with infants' low birth weight (<2500 g) [HR (95% CI) = 1.7 (0.4 - 8.2); P = 0.7], although not statistically significant. These findings suggest that intergenerational transmission of risk differs in maternal and paternal lines.

The effect of nicotine in vitro on the integrity of tight junctions in Caco-2 cell monolayers.

Ulcerative colitis is characterised by impairment of the epithelial barrier and tight junction alterations resulting in increased intestinal permeability. UC is less common in smokers with smoking reported to decrease paracellular permeability. The aim of this study was thus to determine the effect of nicotine, the major constituent in cigarettes and its metabolites on the integrity of tight junctions in Caco-2 cell monolayers. The integrity of Caco-2 tight junctions was analysed by measuring the transepithelial electrical resistance (TER) and by tracing the flux of the fluorescent marker fluorescein, after treatment with various concentrations of nicotine or nicotine metabolites over 48 h. TER was significantly higher compared to the control for all concentrations of nicotine 0.01-10 microM at 48 h (p<0.001), and for 0.01 microM (p<0.001) and 0.1 microM and 10 microM nicotine (p < 0.01) at 12 and 24 h. The fluorescein flux results supported those of the TER assay. TER readings for all nicotine metabolites tested were also higher at 24 and 48 h only (p < or = 0.01). Western blot analysis demonstrated that nicotine up-regulated the expression of the tight junction proteins occludin and claudin-1 (p < or = 0.01). Overall, it appears that nicotine and its metabolites, at concentrations corresponding to those reported in the blood of smokers, can significantly improve tight junction integrity, and thus, decrease epithelial gut permeability. We have shown that in vitro, nicotine appears more potent than its metabolites in decreasing epithelial gut permeability. We speculate that this enhanced gut barrier may be the result of increased expression of claudin-1 and occludin proteins, which are associated with the formation of tight junctions. These findings may help explain the mechanism of action of nicotine treatment and indeed smoking in reducing epithelial gut permeability.

A human flora-associated rat model of the breast-fed infant gut.

OBJECTIVES: Bacterial colonization of the infant gut may have important influences on the development of gastrointestinal, respiratory, and allergic disease. Early diet is a major determinant of the gut microflora. It is very difficult to carry out studies in human infants that can investigate the interaction of diet, flora, and mucosa. In this study we have developed an infant human flora-associated (IHFA) rat model to allow such investigation. METHODS: Germ-free infant rats were infected with fecal bacteria from exclusively breast-fed infants and were maintained on a modified infant formula for 8 weeks. The fecal and cecal contents were collected and compared with feces of breast-fed infants for bacterial populations, bacterial metabolites, and enzymes and for the ability to inhibit adhesion of pathogenic bacteria to human mucosal cells. RESULTS: The IHFA cecum and feces were dominated by lactic acid bacteria, Bifidobacterium, and lactobacilli, which were representative of the infant feces. The fecal short-chain fatty acid profile was dominated by acetic and lactic acid in a similar manner to human infant feces. Other bacterial metabolites were similar to those of the human infant. Rat intestinal samples were able to inhibit the adhesion of pathogens to mucosal cells, but to a lesser extent than the human samples. CONCLUSIONS: This IHFA infant model of the intestinal flora of the breast-fed infant is considered valid for studying the effect of diet on bacterial colonization and metabolism.

Dietary compensation in response to covert imposition of negative energy balance by removal of fat or carbohydrate.

Compensatory changes in energy intake (EI) and macronutrient metabolism in response to modest covert underfeeding were tested by whole-body calorimetry in eight lean men. Each was studied on three occasions comprising a controlled stabilization day followed by manipulation and outcome days in a whole-body calorimeter. On the manipulation day EI was fixed, and calculated to maintain energy balance (CONTROL) or to provide 85% of CONTROL BY removing energy as carbohydrate (CHOred) or as fat (FATred). On the outcome day, ad libitum EI was allowed at fixed mealtimes. CHOred and FATred manipulations generated significantly different energy balances (-1.10 (SE 0.13) MJ, P = 0.000; -1.10 (SE 0.12) MJ, P = 0.000) and fat balances (-0.61 (SE 0.23) MJ, P = 0.03; -1.09 (SE 0.20) MJ, P = 0.000), but not carbohydrate balances (-0.39 (SE 0.22) MJ, NS; 0.11 (SE 0.23) MJ, NS) by the end of the manipulation day compared with CONTROL. On the outcome day, EI was significantly higher than CONTROL after CHOred (+1.58 (SE 0.33) MJ, P = 0.004) and FATred (+1.21 (SE 0.49) MJ, P = 0.022) with no differences between treatments. Overall 48 h energy balances averaged close to zero at -0.14, +0.34, +0.04 MJ on CONTROL, CHOred and FATred respectively. Total 48 h energy intakes on CHOred and FATred averaged 101 (SE 1.7)% and 99 (SE 2.5)% of CONTROL, thus demonstrating accurate detection of a mild energy deficit and efficient next-day compensation. Despite significant differences in macronutrient oxidation rates, the energy homeostatic mechanism appeared to be independent of specific macronutrient deficits.