The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up.

AIMS/HYPOTHESIS: The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study was designed to establish whether weaning to a highly hydrolysed formula in infancy subsequently reduces the risk of type 1 diabetes. METHODS: The study population comprises newborn infants who have first-degree relatives with type 1 diabetes and meet the increased risk HLA inclusion, but not exclusion criteria. The study is being performed in 15 countries in three continents. First-degree relatives of patients with type 1 diabetes were identified from diabetes clinics, diabetes registries, and from other endocrinology or obstetrics offices and websites. HLA typing was performed at birth from cord or heel stick blood, and the results sent to the study's Data Management Unit within 2 weeks for communication of eligibility to the clinical study centre. All mothers recruited were encouraged to breastfeed. The intervention lasted for 6 to 8 months, and weaning formulas based on hydrolysed casein and standard cow's milk were compared. RESULTS: TRIGR recruited 5,606 infants, of whom 2,160 were enrolled as eligible participants, 6% more than the target of 2,032. Of those enrolled, 80% were exposed to the study formula. The overall retention rate over the first 5 years is 87%, with protocol compliance at 94%. The randomisation code will be opened when the last recruited child turns 10 years of age, i.e. in 2017. CONCLUSIONS/INTERPRETATION: The TRIGR experience demonstrates the feasibility and successful implementation of an international dietary intervention study. TRIGR is the first ever primary prevention trial for type 1 diabetes and, if completed successfully, will provide a definite answer to the research question. TRIAL REGISTRATION: ClinicalTrials.gov NCT00179777 FUNDING: The study was funded by the National Institute of Child Health and Development (NICHD) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH) (grant numbers HD040364, HD042444 and HD051997), Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation International and the Commission of the European Communities (specific RTD programme 'Quality of Life and Management of Living Resources', contract number QLK1-2002-00372 'Diabetes Prevention'. Other funding came from the EFSD/JDRF/Novo Nordisk Focused Research Grant, Academy of Finland, Dutch Diabetes Research Foundation and Finnish Diabetes Research Foundation).

Concurrent nematode infection and pregnancy induce physiological responses that impair linear growth in the murine foetus.

This study examined concurrent stresses of nematode infection and pregnancy using pregnant and non-pregnant CD1 mice infected 3 times with 0, 50 or 100 Heligmosomoides bakeri larvae. Physiological, energetic, immunological and skeletal responses were measured in maternal and foetal compartments. Resting metabolic rate (RMR) was elevated by pregnancy, but not by the trickle infection. Energy demands during pregnancy were met through increased food intake and fat utilization whereas mice lowered their body temperature during infection. Both infection and pregnancy increased visceral organ mass and both altered regional bone area and mineralization. During pregnancy, lumbar mineralization was lower but femur area and mineralization were higher. On the other hand, infection lowered maternal femur bone area and this was associated with higher IFN-gamma in maternal serum of heavily infected pregnant mice. Infection also reduced foetal crown-rump length which was associated with higher amniotic fluid IL-1 beta.

Tissue mineral distributions are differentially modified by dietary protein deficiency and a murine nematode infection.

This study was designed to investigate whether mineral concentrations in the spleen, serum, and liver were modified by challenge infection with a gastrointestinal nematode, by infection dose, or by protein deficiency despite adequate dietary intakes of minerals. BALB/c mice fed protein-sufficient (PS, 24%) or protein-deficient (PD, 3%) diets were infected with 100 L3 of Heligmosomoides bakeri, drug-treated, and then re-infected with either 0, 100, or 200 L3. Protein deficiency and infection, but not dose, independently modified tissue mineral distributions. H. bakeri infection lowered serum iron concentrations in both diet groups. Despite this, PD mice had elevated iron and calcium concentrations and Ca/Zn ratio in the spleen as well as Fe/Zn ratio in liver, but they had reduced calcium, zinc, copper, and sulfur concentrations, and Cu/Zn ratio in the liver. Infection reduced calcium and iron concentrations and the Ca/Zn ratio in the spleen. We suggest that tissue mineral distribution is a consequence of Th2 immune and inflammatory responses induced by infection in PS mice and the switch to predominant Th1 inflammation in PD, nematode-infected mice.

Mechanisms underlying reduced expulsion of a murine nematode infection during protein deficiency.

Balb/c mice infected with the gastrointestinal nematode Heligmosomoides bakeri were fed protein sufficient (PS, 24%) or deficient (PD, 3%) diets to investigate whether diet, infection or dose of larval challenge (0, 100 or 200 larvae) influenced gut pathophysiology and inflammation. Among the PS mice, worms were more posteriorad in the intestine of mice infected with 200 compared with 100 larvae, suggesting active expulsion in the more heavily infected mice. This was consistent with the positive correlation between worm numbers and fluid leakage in PS mice; similar patterns were not detected in the PD mice. Infection also induced villus atrophy, which was more pronounced in PS than in PD mice. Our cytokine screening array indicated that infection in PD mice elevated a wide range of pro-inflammatory cytokines and chemokines. Whereas serum leptin concentrations were higher in PD mice, monocyte chemotactic protein-5 (MCP-5) in serum increased with increasing larval dose and concentrations were lower in PD than PS mice. We suggest that elevated MCP-5 together with villus atrophy may contribute to the apparent dose-dependent expulsion of H. bakeri from PS mice but that delayed expulsion in PD mice appeared related to a predominant Th1 cytokine profile that may be driven by leptin.

Oral polyamine administration modifies the ontogeny of hexose transporter gene expression in the postnatal rat intestine.

Gastrointestinal mucosal polyamines influence enterocyte proliferation and differentiation during small intestinal maturation in the rat. Studies in postnatal rats have shown that ornithine decarboxylase (ODC) protein and mRNA peak before the maximal expression of brush-border membrane (BBM) sucrase-isomaltase (SI) and the sugar transporters sodium-dependent glucose transporter 1 (SGLT1) and glucose transporter 2 (GLUT2). This study was undertaken to test the hypothesis that the oral administration of spermidine in postnatal rats upregulates the expression of ODC, thereby enhancing the expression of SI and SGLT1 in the brush-border membrane as well as basolateral membrane-facilitative GLUT2 and Na(+)-K(+)-ATPase. Northern and Western blot analyses were performed with antibodies and cDNA probes specific for SI, SGLT1, GLUT2, alpha(1)- and beta(1)-subunits of Na(+)-K(+)-ATPase, and ODC. Postnatal rats fed 6 mumol spermidine daily for 3 days from days 7 to 9 were killed either on postnatal day 10 (Sp10) or day 13 following a 3-day washout period (Sp13). Sp10 rats showed a precocious increase in the abundance of mRNAs for SI, SGLT1, and GLUT2 and Na(+)-K(+)-ATPase activity and alpha(1)- and beta(1)-isoform gene expression compared with controls. ODC activity and protein and mRNA abundance were also increased in Sp10 animals. The increased expression of these genes was not sustained in Sp13 rats, suggesting that these effects were transient. Thus, 3 days of oral polyamine administration induces the precocious maturation of glucose transporters in the postnatal rat small intestine, which may be mediated by alterations in ODC expression.

Re-feeding rapidly restores protection against Heligmosomoides bakeri (Nematoda) in protein-deficient mice.

This study determined whether the timing of re-feeding of protein-deficient mice restored functional protection against the gastrointestinal nematode, Heligmosomoides bakeri. Balb/c mice were fed a 3% protein-deficient (PD) diet and then transferred to 24% protein-sufficient (PS) diet either on the day of primary infection, 10 days after the primary infection, on the day of challenge infection, or 7 days after the challenge infection. Control mice were fed either the PD or PS diet. Onset of challenge, but not primary, infection caused short-term body weight loss, anorexia and reduced feed efficiency. Weight gain was delayed in mice when re-feeding commenced on the day of challenge infection; alkaline phosphatase (ALP) was also elevated in these mice on day 28 post-challenge. In contrast, other re-feeding groups attained similar body weights to PS mice within 4 days and had similar ALP at day 28. Serum leptin was higher in PD than PS mice and positively associated with food intake. As expected, worm survival was prolonged in mice fed the PD diet. However, egg production and worm burdens were similar in all re-feeding groups to the PS mice, indicating that protein re-feeding during either the primary or challenge infection rapidly restored normal parasite clearance.

Orthostatic hypotension and the risk of myocardial infarction in the home-dwelling elderly.

OBJECTIVES: We investigated the prognostic significance of orthostatic hypotension on the risk of myocardial infarction (MI) amongst the elderly. DESIGN: Prospective population-based study. SETTING: Home-dwelling population. SUBJECTS: Orthostatic testing was performed between 8 a.m. and 2 p.m., irrespective of having had meals, on 792 persons, representing 82% of all home-dwelling persons aged > or =70 years living in five municipalities around the city of Oulu. MAIN OUTCOME MEASURES: Occurrence of cases of MI were recorded during mean 3.58 (SD 1.09) years follow-up period, from national mortality statistics and local hospital discharge registers. RESULTS: Ninety cases of MI, of which 40 were fatal after initial hospitalization, occurred during the follow-up period. Orthostatic diastolic blood pressure (BP) drop 1 min after standing up was associated with subsequent MI, but systolic BP reactions had no predictive value. According to the Cox regression model, the strongest predictor of the occurrence of subsequent MI was found in regard to > or =8 mmHg drop in diastolic BP 1 min after standing up; adjusted for history of MI, diabetes mellitus, chest pain, use of calcium antagonist, beta-blocker, nitrate and diuretic medication, hazard ratio of MI being 2.00 (1.11-3.59). CONCLUSIONS: Orthostatic testing offers a novel means to assess the risk of MI amongst elderly persons. Diastolic BP drop immediately after standing up identifies elderly subjects at a high risk of subsequent MI.

Ambient air quality and occurrence of multiple sclerosis relapse.

Infectious viruses and bacteria can trigger multiple sclerosis (MS) exacerbations. Seasonally changing concentrations of ambient air pollutants are known to predispose to transmissible infections, to induce systemic immune responses and to enhance existing peripheral inflammation. Ambient air quality and monthly MS relapse occurrence in south-western Finland were compared by multivariate logistic regression. The odds ratio of the risk of a relapse onset was over fourfold (4.143, p < 0.001) when the concentration of inhalable particulate matter (PM(10)) was at the highest quartile. Inhalable airborne particulate matter concentrations were connected to relapse occurrence. Poor air quality may enhance the seasonal changes in MS relapse occurrence by an increased susceptibility to transmissible infections.

Dietary pectin, but not cellulose, influences Heligmosomoides polygyrus (Nematoda) reproduction and intestinal morphology in the mouse.

Dietary texture has been reported to influence parasite establishment and survival, but to what degree this relationship is modified by either the type or quantity of dietary fibre is unknown. Using a 2 x 4 factorial design, we explored the relationship between fibre type (soluble pectin vs insoluble = cellulose) and fibre quantity (0, 5, 10 and 20% by dry weight) on parasitic outcomes in BALB/c mice infected with 100 Heligmosomoides polygyrus (Nematoda) larvae. Pectin, but not cellulose, exerted a significant effect on parasite egg production. Following in vitro culture of female worms, increasing levels of dietary pectin were associated with increasing release of eggs. Yet this pattern was not observed in vivo, where per capita egg production peaked at the 10% pectin concentration, but was very low in mice fed 20% pectin. Parasite establishment was elevated in mice fed 20% pectin, but was unaffected by cellulose concentration. Neither type nor quantity of fibre affected H. polygyrus survival or spatial distribution along the gastrointestinal tract. To what degree differences in parasite establishment and reproduction could be attributed to the marked effects of pectin on gut morphology (increased intestinal length, villus length, mucosa thickness and villus/crypt ratio) requires further exploration. Our data indicate that cellulose is preferable to pectin as the source of fibre for experimental diets as cellulose did not affect H. polygyrus establishment, reproduction or survival during a 4-week primary infection.

Recent decline in heavy outdoor work activity predicts occurrence of fractures among the home-dwelling elderly.

The contribution of reduced physical activity of a defined duration to the risk of fall-related fractures and serious soft tissue injuries is not known. We conducted a prospective population-based study among the home-dwelling elderly to examine the association between a recent decline in physical activity and the occurrence of fall-related fractures and soft tissue injuries. The study population consisted of representative sample of home-dwelling older adults who conducted heavy outdoor work activity at least once a week at baseline (n = 284; 136 men, 148 women) and among whom in 93 persons (33%) heavy outdoor work activity was found to have declined during the 2 1/2 years follow-up. Fall-related fractures (n = 24) and serious soft tissue injuries (n = 49) were recorded from the time of the follow-up examination until the end of a further follow-up period lasting 3 1/2 years on average. A decline in heavy outdoor work activity did not predict the occurrence of soft tissue injuries (Mantel-Cox 0.795, p = 0.373), but a greater proportion of those with a decline (n = 14, 15%) than of others (n = 10, 5%) suffered fractures (Mantel-Cox 10.231, p = 0.001). Other risk factors for fractures were female sex (p = 0.03), slow choice reaction time (p = 0.02) and dependency as regards at least one basic activity of daily living (p = 0.01). According to the Cox proportional hazard model, the adjusted hazard ratio of fracture as regards a decline in heavy outdoor work activity was 2.7 (95% CI 1.14-6.62). A recent decline in heavy outdoor work activity predicts the occurrence of fractures, but not the occurrence of serious soft tissue injuries. Early recognition of a decline in physical activity may help in prevention of fractures among the elderly.

Men, masculinity and food: interviews with Finnish carpenters and engineers.

This study explores how Finnish men from two occupational groups describe food in their everyday life. The concept of masculinity is used in interpreting men's food-related behaviours and beliefs. Data are drawn from semi-structured interviews in the 1990s with twenty carpenters and twenty engineers involved in the building trade. The paper presents analyses of the similarities and differences in how the men talked about meat; vegetables; beer and wine as parts of meals; food as energy, health and pleasure; and cooking. The results show variation both between and within occupational groups. The men did not stress the role of meat, but rather emphasised the role of vegetables. The carpenters tended to favour meat whereas the engineers had a more positive attitude to vegetables. Eating was described as an everyday routine needed to refuel the body and stay healthy. In addition, the engineers talked about the pleasures of eating. The men described cooking as optional or exceptional. The carpenters seemed to more actively embrace hegemonic masculinity and reject what is feminine than the engineers, who have reformulated their definition of masculinity to encompass concerns with health. This study suggests that both masculinity and occupational class play a role in male food-related practices and preferences.

Gastrointestinal nematodes, nutrition and immunity: breaking the negative spiral.

Nutritionists have long understood that intestinal nematode parasites have deleterious effects on host nutritional status, but only recently has the importance of malnutrition as a predisposing factor to intestinal nematodes been recognized. Here we review experimental and field studies on the effects of protein, energy, zinc, vitamin A, and iron deficiencies on gastrointestinal (GI) nematodes of humans, livestock, and laboratory rodents, and draw certain conclusions about the state of our current understanding. In general, malnutrition promotes the establishment, survival, and fecundity of these parasites, but the magnitude of the effect depends on factors such as host species, parasite species, particular infection protocol used, magnitude of the infection, severity of the nutritional deficiency, and presence of single or multiple infections and single or multiple nutritional deficiencies. We highlight the Th2 arm of the immune system as a component of primary importance in the association between malnutrition and GI nematode infections. We summarize what is known about underlying mechanisms that may account for the observed patterns. Finally, we suggest future research directions.

Butylated hydroxytoluene (BHT) induction of pulmonary inflammation: a role in tumor promotion.

Chronic pulmonary inflammatory diseases predispose towards lung cancer by unknown mechanisms. Butylated hydroxytoluene (BHT) administration to mice causes lung injury and a subsequent inflammatory response, and when administered chronically to certain inbred strains following carcinogen treatment, increases lung tumor multiplicity. We hypothesize that inflammation promotes lung tumor growth in this model system and have begun to examine this hypothesis by assessing inflammatory parameters in inbred strains that vary in their susceptibility to promotion. Positive correlations were found between susceptibilities to tumor promotion and BHT induction of alveolar macrophage and lymphocyte infiltration into alveolar airspaces, and increased vascular permeability (P < .03, P < .04, and P < .005, respectively). The amounts of pulmonary cyclooxygenase (COX)-1 and COX-2 did not strongly correlate with promotion. Because persistent elevation of macrophage content is the hallmark of a chronic inflammatory response, the alveolar macrophage population was depleted by adding chlorine to the drinking water prior to carcinogenesis. This treatment reduced lung tumor multiplicity following 2-stage carcinogenesis (P < .05). These correlations between inflammatory and tumorigenic responses to BHT, along with decreased tumorigenesis after macrophage depletion, are consistent with a role of inflammation in promotion. Inflammatory mediators may provide targets for early diagnosis and chemoprevention.

Teaching subjects with type 2 diabetes how to incorporate sugar choices into their daily meal plan promotes dietary compliance and does not deteriorate metabolic profile.

OBJECTIVE: To determine whether teaching free-living subjects with type 2 diabetes how to incorporate added sugars or sweets into their daily meal plan results in a greater consumption of calories (fat or sugar) and deteriorates their glycemic or lipid profiles but improves their perceived quality of life. RESEARCH DESIGN AND METHODS: In an 8-month randomized controlled trial, 48 free-living subjects with type 2 diabetes were taught either a conventional (C) meal plan (no concentrated sweets) or one permitting as much as 10% of total energy as added sugars or sweets (S). Mean individual nutrient intake was determined using the average of six 24-h telephone recalls per 4 months. Metabolic control and quality of life were evaluated every 2 months. Quality of life was assessed using the Medical Outcome Survey and the Diabetes Quality of Life questionnaire. RESULTS: The S group did not consume more calories (fat or sugar) and in fact ate significantly less carbohydrate (-15 vs. 10 g) and less starch (-7 vs. 8 g) and had a tendency to eat fewer calories (-77 vs. 81 kcal) than the C group. Weight remained stable, and there was no evidence that consuming more sugar worsened metabolic profile or improved their perceived quality of life. CONCLUSIONS: Giving individuals with type 2 diabetes the freedom to include sugar in their daily meal plan had no negative impact on dietary habits or metabolic control. Health professionals can be reassured and encouraged to teach the new "sugar guidelines," because doing so may result in a more conscientious carbohydrate consumption.

Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin.

We examined serum total osteocalcin (TOC), carboxylated osteocalcin (COC), and their ratio (COC/TOC) by one-step two-site immunofluorescent assays in 87% (n = 792) of all home-dwelling persons of 70 years or older living in a defined area in northern Finland. Other baseline subject-related risk factors of fractures were assessed by postal questionnaires, interviews, clinical examinations, and tests. During a 5-year follow-up period, all falls and fractures (n = 106) were recorded by regular phone calls and by examining all the medical records yearly. Serum TOC and COC concentrations increased with advancing age and were higher in women than in men, but corresponding differences were not found in the case of COC/TOC. The adjusted relative risk of fracture was elevated in association with low (< or =-1 SD from the mean) COC; hazard ratio (HR, 95% CI) 2.00 (1.20-3.36) and low COC/TOC; HR 5.32 (3.26-8.68), the relative risk being highest in the population older than 80 years; and HR 7.02 (2.42-20.39). The predictive value of low COC/TOC lasted 3 years. The multivariable-adjusted relative risk of hip fracture (n = 26) in regard to low COC/TOC ratio was 3.49 (1.12-10.86), as compared with the persons who did not suffer hip fractures. Our results suggest that serum COC concentrations and, more strongly, COC/TOC, predict the occurrence of fractures in older community-dwelling adults. The risk of fracture associated with low COC/TOC equals the hip fracture risk previously verified for concomitant high serum undercarboxylated OC concentrations and low bone mineral density.

Fracture risk associated with a fall according to type of fall among the elderly.

The kinetic energy and direction of a fall contribute to the occurrence of fracture. However, the fracture risk associated with different types of fall, different amounts of energy and different landing directions is poorly understood. We recorded all falls and fall-related fractures over 7 years in an aged semi-rural home-dwelling population (n = 980), using intensive fall recording. The falls were classified according to type and place of occurrence into slip falls (SLFs), trip falls (TRFs), other extrinsic falls on the level (OEFs), intrinsic falls on the level (IFs), stair falls (STFs), falls from an upper level (ULFs) and nondefined falls (NDFs) occurring indoors or outdoors. Incidences of falls and fractures were calculated for the whole follow-up period. The population was clinically examined to assess general risk factors of fracture, after which the risk of fracture was determined in the first fall according to the different fall types. Comparison was made with intrinsic falling on the level. The overall incidences of indoor and outdoor falls were 328 (95% CI 314-345) and 198 (186 210) per 1000 person-years (PY), respectively, and those of fractures 23 (19-27) and 11 (8-4) per 1000 PY, respectively. Indoor SLFs, TRFs, OEFs, IFs, STFs, ULFs and NDFs occurred relatively evenly throughout the study period. The crude and adjusted relative fracture risks were greater in SLFs, OEFs and STFs compared with IFs. Indoor falls and fractures are more common than those occurring outdoors in aged home-dwelling persons. The kinetic energies produced in SLFs, OEFs and STFs may be higher than those generated in IFs, leading to increased risk of fracture.

Predictors of coronary heart diseases among children and adolescents in families with premature coronary heart diseases in central eastern Finland.

OBJECTIVE: To describe coronary heart disease (CHD) predictors in children and adolescents (aged from 7 to 16 years) in families with premature CHD. DESIGN: A cross-sectional cohort study. SETTING: Part of a family-oriented preventive intervention programme concerning CHD risk factors in central eastern Finland (FOPIC study). SUBJECTS: 473 participants in families with premature CHD and 371 in control families. MAIN OUTCOME MEASURES: Traditional CHD predictors. RESULTS: Offspring in families with premature CHD had significantly higher concentrations of total cholesterol (TC, 4.7 vs 4.5 mmol/l, p < 0.01) and low-density lipoprotein cholesterol (LDL-C, 2.8 vs 2.6 mmol/l, p < 0.01) than the control children, and higher diastolic blood pressure (DBP, p < 0.01). According to this cross-sectional screening of children in high-CHD-risk families in the Kainuu region, 75% of those with adverse cholesterol values could be found. After adjusting for confounding factors, associations between TC, LDL-C, body mass index, DBP and the offspring of families with a history of premature CHD found. CONCLUSIONS: The results indicated strong associations between CHD predictors and offspring with a family history of premature CHD. The findings confirm the usability of familial premature CHD in screening for early prevention in primary health care.