Instability of personal human metabotype is linked to all-cause mortality.

Disruption of metabolic homeostasis is an important factor in many diseases. Various metabolites have been linked to higher risk of morbidity and all-cause mortality using metabolomics in large population-based cohorts. In these studies, baseline metabolite levels were compared across subjects to identify associations with health outcomes, implying the existence of 'healthy' concentration ranges that are equally applicable to all individuals. Here, we focused on intra-individual changes in metabolite levels over time and their link to mortality, potentially allowing more personalized risk assessment. We analysed targeted metabolomics data for 134 blood metabolites from 1409 participants in the population-based CARLA cohort at baseline and after four years. Metabotypes of the majority of participants (59%) were extremely stable over time indicated by high correlation between the subjects' metabolite profiles at the two time points. Metabotype instability and, in particular, decrease of valine were associated with higher risk of all-cause mortality in 7.9 years of follow-up (hazard ratio (HR) = 1.5(95%CI = 1.0-2.3) and 0.2(95%CI = 0.1-0.3)) after multifactorial adjustment. Excluding deaths that occurred in the first year after metabolite profiling showed similar results (HR = 1.8(95%CI = 1.1-2.8)). Lower metabotype stability was also associated with incident cardiovascular disease (OR = 1.2(95%CI = 1.0-1.3)). Therefore, changes in the personal metabotype might be a valuable indicator of pre-clinical disease.

Educational status and differences in left ventricular mass and ejection fraction - The role of BMI and parameters related to the metabolic syndrome: A longitudinal analysis from the population-based CARLA cohort.

BACKGROUND AND AIMS: Higher ventricular mass has been reported in non-white US-Americans with low educational status and in socially isolated people. To assess the impact of education on cardiac mass and function in the general population and to identify mediators. METHODS AND RESULTS: Data from a German population-based sample were used (CARLA cohort, n = 1779 at baseline, n = 1436 at the four-year follow-up). Ventricular mass indexed on height (LVMI) and ejection fraction, using Teichholz's formula (EFTZ), were measured. Education was assessed using the ISCED classification. Mediator analyses were performed using the R-macro 'mediation' to compute the average direct effect and the average causal mediated effect after confounder adjustment. Sensitivity analyses for unobserved confounders were performed. Considered mediators were BMI, waist-to-hip ratio, HbA1c, and systolic and diastolic blood pressures. We found differences in LVMI and EFTZ, both at baseline and follow-up, between educational levels in women (lowest vs highest educational level: 15.6 g, 95% CI: -25.7, -5.6), but not in men. Similarly, women (lowest vs highest educational level at baseline: 3.3%, 95% CI: 0.8-5.7), but not men, of higher educational levels had a higher EFTZ of comparable magnitude at baseline and follow-up. Of the considered mediators, BMI explained 55.9% at baseline and 54.1% at follow-up of the educational effect, while other potential mediators had no significant effect. Relations remained constant between baseline and follow-up. CONCLUSIONS: Women with low educational levels tend to have a higher ventricular mass and lower EF, which can be explained by a higher BMI in this group.

Educational level and chronic inflammation in the elderly--the role of obesity: results from the population-based CARLA study.

This study aimed to assess the mediating role of anthropometric parameters in the relation of education and inflammation in the elderly. Cross-sectional data from the population-based CARdio-vascular Disease, Living and Ageing in Halle study were used after excluding subjects with a plasma level of high-sensitive C-reactive protein (hsCRP) above 10 mg L(-1) (916 men/760 women remaining). Education was categorized in accordance with International Standard Classification of Education. As inflammation parameters, the soluble tumour necrosis factor type 1 (sTNF-R1), hsCRP and interleukin 6 (IL-6) were taken into account. Anthropometric parameters were the body mass index (BMI), waist-to-hip ratio (WHR) and waist-to-height ratio (WHeR). We used covariate adjusted mixed models to assess associations. Effect measures were the natural indirect effect (NIE), controlled direct effect and total effect (TE). Education was associated with sTNF-R1, hsCRP and IL-6 in men, and sTNF-R1 and hsCRP in women. Anthropometric parameters correlated with all inflammation parameters after covariate adjustment. BMI and WHeR were strong mediators of educational differences in sTNF-R1 (percentage of NIE of TE: 28% in men; 33% in women) and hsCRP (percentage of NIE of TE: 35% in men; 52% in women), while WHR was the weakest mediator. General obesity mediates roughly one-third of the association of education with chronic inflammation in the elderly.

Inflammation and echocardiographic parameters of ventricular hypertrophy in a cohort with preserved cardiac function.

OBJECTIVE: To investigate the association between inflammation and selective echocardiographic parameters (EP) characteristic for ventricular hypertrophy in cross-sectional and longitudinal population-based analyses. METHODS: Baseline (711 men, 659 women: 45-83 years) and 4-year follow-up data (622 men, 540 women) of the prospective, population-based CARdio-vascular disease, Living and Ageing in Halle (CARLA)study after exclusion of participants with cardiacvascular diseases were analysed. Inflammation parameters: soluble tumour necrosis factor receptor 1 (sTNF-R1), high-sensitivity C reactive protein (hsCRP) and interleukin 6 (IL-6). EPs: left ventricular mass (LVM), left atrial systolic dimension (LADS), interventricular septum diameter (IVSD), posterior wall dimension (PWD), left ventricular diastolic diameter (LVDD), ejection fraction according to Teichholz (EF). For the longitudinal analyses baseline to follow-up differences were considered. Effect sizes were determined by using multiple linear regression and mixed models. Missing values were replaced by means of multiple imputations. RESULTS: Men had higher sTNF-R1 levels; means of hsCRP and IL-6 were similar in men and women. In multiple regression models, sTNF-R1 was associated with LADS (1.4 mm/1000 pg/mL sTNF-R1, 95% CI 0.6 to 2.1) in men. Respecting confounder hsCRP was associated with LVM (5.2 g/10 mg/L hsCRP, 95% CI 1.6 to 8.8), IVSD (0.2 mm/10 mg/L hsCRP, 95% CI 0 to 0.3) and PWD (0.2 mm/10 mg/L hsCRP, 95% CI 0.1 to 0.3) in women, while there were no relevant effects in analysis of IL-6 in both sexes. The baseline to follow-up change in EPs was not relevantly associated with sTNF-R1, hsCRP or IL-6. CONCLUSIONS: STNF-R1, hsCRP and IL-6 were inadequate predictors for structural changes of the heart at follow-up, while weak cross-sectional associations are restricted to certain EPs and depend on sex.

Validation of the German Diabetes Risk Score within a population-based representative cohort.

AIM: To validate the German Diabetes Risk Score within the population-based cohort of the Cardiovascular Disease - Living and Ageing in Halle (CARLA) study. METHODS: The sample included 582 women and 719 men, aged 45-83 years, who did not have diabetes at baseline. The individual risk of every participant was calculated using the German Diabetes Risk Score, which was modified for 4 years of follow-up. Predicted probabilities and observed outcomes were compared using Hosmer-Lemeshow goodness-of-fit tests and receiver-operator characteristic analyses. Changes in prediction power were investigated by expanding the German Diabetes Risk Score to include metabolic variables and by subgroup analyses. RESULTS: We found 58 cases of incident diabetes. The median 4-year probability of developing diabetes based on the German Diabetes Risk Score was 6.5%. The observed and predicted probabilities of developing diabetes were similar, although estimation was imprecise owing to the small number of cases, and the Hosmer-Lemeshow test returned a poor correlation (chi-squared = 55.3; P = 5.8*10⁻¹²). The area under the receiver-operator characteristic curve (AUC) was 0.70 (95% CI 0.64-0.77), and after excluding participants ≥66 years old, the AUC increased to 0.77 (95% CI 0.70-0.84). Consideration of glycaemic diagnostic variables, in addition to self-reported diabetes, reduced the AUC to 0.65 (95% CI 0.58-0.71). A new model that included the German Diabetes Risk Score and blood glucose concentration (AUC 0.81; 95% CI 0.76-0.86) or HbA(1c) concentration (AUC 0.84; 95% CI 0.80-0.91) was found to peform better. CONCLUSIONS: Application of the German Diabetes Risk Score in the CARLA cohort did not reproduce the findings in the European Prospective Investigation into Cancer and Nutrition (EPIC) Potsdam study, which may be explained by cohort differences and model overfit in the latter; however, a high score does provide an indication of increased risk of diabetes.

Derivation of nutrient guidelines for streams in Victoria, Australia.

Human induced increases to nutrient concentrations in streams have led to many agencies developing strategies and criteria for nutrient reduction. National or statewide guidelines are generally inappropriate, due to the natural variability in stream ecosystems within political boundaries. This study used an extant aquatic macroinvertebrate-based regionalisation for the state of Victoria, Australia, as the basis for defining regions of relatively homogeneous environmental character. This enabled the selection of ecologically-based regional reference sites and subsequent characterisation of the nutrient status of these sites. Using an extensive biological and nutrient data base for streams across the State, we calculated 50th and 75th percentile concentrations for reference sites within each region. Using these percentiles in conjunction with 'impact and recovery' studies, we defined nutrient guidelines for each region. Although the nutrient data largely supported the biological regionalisation, patterns in the nutrient data did require some minor modifications for the nutrient regions. Relatively unimpacted regions with reference sites in very good-to excellent-condition were assigned guidelines largely based on the 75th percentiles. The more impacted regions, where 'best available' reference sites were of poorer quality, were assigned guidelines based largely on the 50th percentiles. Professional judgement and known extents of impacts across each region provided important contributions to the decision-making process. The derived guideline concentrations are comparable to several cited in the literature and are proposed for use in monitoring, assessment and restoration targets.

The effects of the menstrual cycle, pregnancy and early lactation on haematology and plasma biochemistry in the baboon (Papio hamadryas).

The changes in the haematology and clinical biochemistry associated with the different stages of the menstrual cycle, gestation and lactation in the baboon (Papio hamadryas) were evaluated in a prospective longitudinal study. Serial EDTA and heparin blood samples were collected from 12 baboons. Haemoglobin concentration, haematorcrit, red blood cell and white blood cell counts were decreased in the luteal compared to the follicular phase (P<0.001); the reverse effect was observed for platelet count, total protein and albumin concentrations. The changes in plasma concentrations of sodium, potassium, urea, creatinine and cholesterol and plasma osmolality were characterized by reductions (P<0.01) in early pregnancy which were maintained throughout gestation. Plasma concentrations of total protein, albumin and alkaline phosphatase, as well as haemoglobin, haematocrit and red cell count were reduced (P<0.001) from mid-gestation. Platelet count and plasma calcium concentration fell continuously throughout gestation (P<0.001). Plasma triglycerides were lower and plasma iron was higher (P<0.01) in gestation compared to the phases of the menstrual cycle and lactation. By 1 week post partum, all parameters except haemaglobin had returned to pre-conception levels.

Low-dose nitro-L-arginine administration in baboon (Papio hamadryas) pregnancy.

1. The purpose of the present study was to examine the effect of nitric oxide (NO) inhibition on mean arterial pressure (MAP), endothelin (ET) and the renin-aldosterone system in pregnancy in the non-human primate (baboon). 2. Twenty pregnant baboons (Papio hamadryas) were examined prospectively after the administration of an oral NO inhibitor in different phases of pregnancy. Haemodynamic responses to NO inhibition, evidence of pre-eclampsia and the renin-aldosterone system were examined under anaesthesia. 3. Oral NL-nitro-L-arginine (NOLA; 5 or 10 mg/kg) was given for 1 week in early (6-8 weeks gestation), middle (14-16 weeks gestation) and late (22-24 weeks gestation) pregnancy and while non-pregnant. Mean arterial pressure, heart rate, haematology, biochemistry, ET, plasma renin activity (PRA) and aldosterone were measured. Foetal effects of NOLA were also examined by ultrasound and neonatal measurements. 4. Nitric oxide inhibition led to an increase in MAP in non-pregnant animals (9 mmHg) and in middle and later pregnancy (6 and 7 mmHg, respectively). Mean arterial pressure in early pregnancy was not affected. A reduction in PRA occurred after NO inhibition in all stages of pregnancy. Significant proteinuria occurred only in late pregnancy. 5. Nitric oxide is involved in the maintenance of lower blood pressure in late pregnancy and inhibition leads to an increase in blood pressure and proteinuria in the baboon. Nitric oxide insufficiency may contribute to the clinical manifestations of human pre-eclampsia. Nitric oxide was not involved in the normal vasodilation of early primate pregnancy.

Biochemistry and haematology values for the baboon (Papio hamadryas): the effects of sex, growth, development and age.

A retrospective study evaluated the influence of sex and age on plasma biochemistry and haematology parameters in a captive-bred colony of baboons. Over 1,140 ETDA and heparin blood samples were obtained from 160 clinically normal baboons between the ages of 11 months and 11 years. Data for these blood tests were analysed for the effects of sex, age and sex age interactions. Sex, age and sex age interactions were detected for many plasma biochemistry and haematological parameters. The reference range values for platelets, white-blood cells and mean corpuscular volume and plasma chloride, glucose, total protein and iron were higher (P < 0.01) and red blood cell, plasma sodium, potassium, total CO2, creatinine, urea, total bilirubin, albumin, alkaline phosphate, gamma glutamyl transpeptidase and phosphate were lower (P < 0.01) in the female compared to the male population. Sex age interactions (P < 0.05) were seen with haemoglobin, white blood cells, haematocrit, mean corpuscular volume, sodium, creatinine, urea, calcium, phosphate, total bilirubin, total protein alkaline phosphatase, the liver enzymes and triglycerides. Plasma alkaline phosphatase was highest ( > 800 micro/l) in young juveniles of both sexes; creatinine was higher in older ( > 4 years) compared to younger baboons of the same sex (P < 0.05). Plasma cholesterol and triglycerides were greater (P < 0.01) in young baboons compared to older animals.

Hemodialysis: an appropriate therapy in myeloma-induced renal failure.

To determine whether vigorous treatment with dialysis is of benefit to patients with myeloma-induced renal failure at presentation, we retrospectively reviewed outcomes in a group of patients diagnosed with multiple myeloma between January 1986 and September 1993. Increased age (P = 0.003), presence of renal impairment (P = 0.006), and failure to enter plateau phase (P < 0.001) were independently associated with shortened survival. However, there was no difference in outcome between patients with severe renal failure, those treated with dialysis, and those with milder renal impairment (median survival, 22 months in both groups), nor was reversibility of renal failure associated with any survival advantage. The lack of correlation between severity or reversibility of the renal failure and survival suggests that there may be characteristics of some patients or their underlying myeloma that are responsible both for renal impairment and for adverse prognosis. In this study, neither age, clinical stage, labeling index, nor response to treatment was able to account for the difference in outcome between patients with and without renal failure. The prolongation of life achieved in the dialysis patients such that their median survival was identical with that of the group with milder renal impairment was considered to represent a significant benefit to these patients and to justify the offer of dialysis to all patients requiring it.

Changes of extracellular matrix in a baboon (Papio hamadryas) model of insulin dependent diabetes: studies using electron microscopy and X-ray diffraction techniques.

Extracellular matrix plays an important role in many physiological functions and its abnormalities are thought to play a key role in the pathogenesis of diabetic complications. In this paper we used the techniques of electron microscopy, immunostaining and X-ray diffraction to document some of the early events in the changes of extracellular matrix in a model of insulin dependent diabetes in baboons. Our results show that thickening of basement membrane and enlargement of mesangium are demonstrable in the glomeruli of prepubertal diabetic baboons within 2 years from the onset of diabetes. Concomitant with this was the accumulation of type IV collagen and laminin in the mesangium. By contrast, even the very sensitive technique of X-ray diffraction failed to demonstrate changes in the equatorial direction of collagen molecules of the skin and tendon. We conclude that changes of glomerular extracellular matrix are demonstrable early in insulin dependent diabetes even in prepubertal baboons. These can be used as endpoints in evaluating the efficacy of pharmacological agents such as aminoguanidine in preventing diabetic complications.

Cyclical changes in the renin-angiotensin-aldosterone system during the menstrual cycle of the baboon (Papio hamadryas).

This study characterizes the renin-angiotensin-aldosterone system during the normal menstrual cycle in the baboon. Ten animals received a daily dose of an ACE inhibitor or placebo in a randomized blind cross-over design. Data were obtained during the mid-follicular and early luteal phases of normal non-pregnant menstrual cycles. All examinations and blood collections were performed with ketamine sedation: 7-kg by im injection. Blood pressure was recorded by sphygmomanometer. Serum ACE activity was measured by spectrophotometry. Aldosterone (ALDO), angiotensin I (AI), and angiotensin II (AII) were measured by radioimmunoassay. Plasma renin activity (PRA) was measured by AI generation. The renin-angiotensin-aldosterone system was found to be activated in the follicular phase and suppressed during the luteal phase of the normal non-pregnant menstrual cycle in the baboon.

Reproductive and neonatal outcomes in captive bred baboons (Papio hamadryas).

Baboons are widely used in biomedical research. Although it is widely held that Papio hamadryas breed well in captivity, each established colony has a different reproductive success often hypothesised to be due to husbandry practices. The National Baboon Colony in Australia is a unique colony that houses Papio hamadryas to mimic that structure seen in the wild. In this article; we have analysed their reproductive parameters and neonatal outcomes. The success of the colony husbandry practices was demonstrated by lack of maternal mortality, low foetal morbidity, and known maternal and paternal linage.

A baboon (Papio hamadryas) model of insulin-dependent diabetes.

Over a period of four years, streptozocin has been used to induce diabetes in 10 baboons, all of whom are insulin dependent. We describe our experience with their husbandry, induction of diabetes, insulin therapy, metabolic control and growth rate. Streptozocin dosage of 60 mg/kg readily induces hyperglycemia with minimal hepatic or renal toxicity. Using a once daily injection of mixed short and intermediate acting insulins at a dosage of 2-4 U/kg, it is possible to maintain a degree of metabolic control similar to that attained in patients.

Fetotoxicity of angiotensin-converting enzyme inhibition in primate pregnancy: a prospective, placebo-controlled study in baboons (Papio hamadryas).

OBJECTIVES: Serious concerns have been raised about angiotensin-converting enzyme inhibition in pregnancy. The central question remains: does toxicity of angiotensin-converting enzyme inhibition pertain to pregnant humans? STUDY DESIGN: A prospective, placebo-controlled study was performed to investigate the effect of angiotensin-converting enzyme inhibition on pregnancy outcome in the baboon. Subjects (N = 12) received active and placebo treatments sequentially in a crossover protocol. Data were analyzed with two-sample t tests, analysis of variance, Fisher's exact test, or Kaplan-Meier survival analysis, where appropriate. RESULTS: Chronic administration of enalapril (7.5 mg per day) from before conception achieved moderate but sustained angiotensin-converting enzyme inhibition as determined by repeated measures of renin-angiotensin system parameters (serum angiotensin-converting enzyme activity, plasma renin activity and plasma angiotensin I, angiotensin II, and aldosterone concentrations). Serum angiotensin-converting enzyme activity was significantly reduced throughout (< 10 nmol.ml-1.min-1, p < 0.01), with significant increases in plasma renin activity and angiotensin I (p < 0.01). Angiotensin II and aldosterone were maintained unchanged compared with placebo. There was a significant incidence of fetal death or intrauterine growth retardation in fetuses exposed to enalapril (eight of 13, zero on placebo, p < 0.01). When the definition of adverse pregnancy outcome was restricted to fetal death alone (four of 13) the difference remained significant (p < 0.05). Maternal arterial pressure was unchanged before conception, but a small and significant fall (10 to 15 mm Hg, p < 0.01) was detected throughout pregnancy. There was no fetal malformations. CONCLUSION: The study provides definitive evidence for serious consequences of angiotensin-converting enzyme inhibition in pregnancy of high-order primates.