Cost-effectiveness of a family-based GP-mediated intervention targeting overweight and moderately obese children

Objective
 To assess from a societal perspective the incremental cost-effectiveness of a family-based GP-mediated intervention targeting overweight and moderately obese children. The intervention was modelled on the LEAP (live, eat and play) trial, a randomised controlled trial conducted by the Centre for Community Child Health, Melbourne, Australia in 2002–2003. This study was undertaken as part of the assessing cost-effectiveness (ACE) in obesity project which evaluated, using consistent methods, 13 interventions targeting unhealthy weight gain in children and adolescents.
Method
A logic pathway was used to model the effects of the intervention compared to no intervention on body mass index (BMI) and health outcomes (disability-adjusted life years—DALYs). Disease costs and health benefits were tracked until the cohort of eligible children reached the age of 100 years or death. Simulation-modelling techniques were used to present a 95% uncertainty interval around the cost-effectiveness ratio. The intervention was also assessed against a series of filters (‘equity’, ‘strength of evidence’, ‘acceptability’, ‘feasibility’, sustainability’ and ‘side-effects’) to incorporate additional factors that impact on resource allocation decisions.
Results
The intervention, as modelled, reached 9685 children aged 5–9 years with a BMI z-score of ≥3.0, and cost $AUD6.3M (or $AUD4.8M excluding time costs). It resulted in an incremental saving of 2300 BMI units which translated to 511 DALYs. The cost-offsets stemming from the intervention totalled $AUD3.6M, resulting in a net cost per DALY saved of $AUD4670 (dominated; $0.1M) (dominated means intervention costs more for less effect).
Conclusion
Compared to a ‘no intervention’ control group, the intervention was cost-effective under current assumptions, although the uncertainty intervals were wide. A key question related to the long-term sustainability of the small incremental weight loss reported, based on the 9-month follow-up results for LEAP.

Copper and zinc mediated oligomerisation of Aß peptides

The accumulation of senile plaques composed primarily of aggregated amyloid β-peptide (Aβ), is the major characteristic of Alzheimer’s disease. Many studies correlate plaque accumulation and the presence of metal ions, particularly copper and zinc. The metal binding sites of the amyloid Aβ peptide of Alzheimer’s disease are located in the N-terminal region of the full-length peptide. In this work, the interactions with metals of a model peptide comprising the first 16 amino acid residues of the amyloid Aβ peptide, Aβ(1–16), were studied. The effect of Cu²⁺ and Zn²⁺ binding to Aβ(1–16) on peptide structure and oligomerisation are reported. The results of ESI-MS, gel filtration chromatography and NMR spectroscopy demonstrated formation of oligomeric complexes of the peptide in the presence of the metal ions and revealed the stoichiometry of Cu²⁺ and Zn²⁺ binding to Aβ(1–16), with Cu²⁺ showing a higher affinity for binding the peptide than Zn²⁺.

The effect of nitric oxide donor sodium nitroprusside on glucose uptake in human primary skeletal muscle cells

Nitric oxide (NO) has been implicated as an important signaling molecule in the insulin-independent, contraction-mediated glucose uptake pathway and may represent a novel strategy for blood glucose control in patients with type 2 diabetes (T2DM). The current study sought to determine whether the NO donor, sodium nitroprusside (SNP) increases glucose uptake in primary human skeletal muscle cells (HSkMC) derived from both healthy individuals and patients with T2DM. Vastus lateralis muscle cell cultures were derived from seven males with T2DM (aged 54 ± 2 years, BMI 31.7 ± 1.2 kg/m², fasting plasma glucose 9.52 ± 0.80 mmol/L) and eight healthy individuals (aged 46 ± 2 years, BMI 27.1 ± 1.5 kg/m², fasting plasma glucose 4.69 ± 0.12 mmol/L). Cultures were treated with both therapeutic (0.2 and 2 μM) and supratherapeutic (3, 10 and 30 mM) concentrations of SNP. An additional NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) was also examined at a concentration of 50 μM. Glucose uptake was significantly increased following both 30 and 60 min incubations with the supratherapeutic SNP treatments (P = 0.03) but not the therapeutic SNP doses (P = 0.60) or SNAP (P = 0.54). There was no difference in the response between the healthy and T2DM cell lines with any treatment or dose. The current study demonstrates that glucose uptake is elevated by supratherapeutic, but not therapeutic doses of SNP in human primary skeletal muscle cells derived from both healthy volunteers and patients with T2D. These data confirm that nitric oxide donors have potential therapeutic utility to increase glucose uptake in humans, but that SNP only achieves this in supratherapeutic doses. Further study to delineate mechanisms and the therapeutic window is warranted.

Effect of the glycemic index of carbohydrates on day-long (10 h) profiles of plasma glucose, insulin, cholecystokinin and ghrelin

Background: Low glycemic index (GI) carbohydrates have been linked to increased satiety. The drive to eat may be mediated by postprandial changes in glucose, insulin and gut peptides.
Objective: To investigate the effect of a low and a high GI diet on day-long (10 h) blood concentrations of glucose, insulin, cholecystokinin (CCK) and ghrelin (GHR).
Design: Subjects (n¼12) consumed a high and a low GI diet in a randomized, crossover design, consisting of four meals that were matched for macronutrients and fibre, and differed only in carbohydrate quality (GI). Blood was sampled every 30–60 min and assayed for glucose, insulin, CCK and GHR.
Results: The high GI diet resulted in significantly higher glucose and insulin mean incremental areas under the curve (IAUC, P¼0.027 and P¼0.001 respectively). CCK concentration was 59% higher during the first 7 h of the low GI diet (394±95 pmol/l min) vs the high GI diet (163±38 pmol/l min, P¼0.046), but there was no difference over 10 h (P¼0.224). GHR concentration was inversely correlated with insulin concentration (Pearson correlation 0.48, P¼0.007), but did not differ significantly between the low and high GI diets.
Conclusions: Mixed meals of lower GI are associated with lower day-long concentrations of glucose and insulin, and higher CCK after breakfast, morning tea and lunch. This metabolic profile could mediate differences in satiety and hunger seen in some, but not all, studies.

Do maternally derived antibodies and early immune experience shape the adult immune response?

1. Immunological imprinting by maternally derived antibodies has been proposed to have both positive and negative consequences for offspring immunity in early and adult life. However, few studies of maternal effects on immunity have followed individuals past the juvenile stages.

2. Using laboratory Japanese quail, we developed a novel method of directly manipulating yolk antibodies of neonates, and then followed individuals through a series of immune challenges until they were of reproductive age.

3. Our method of directly injecting purified antibodies into the yolk sac of newly hatched chicks successfully elevated the plasma titres of specific anti-KLH IgY in neonates. This allows us to test whether differences in neonatal anti-KLH IgY affect immunity at the juvenile and adult stages of life.

4. We found little evidence for an effect of maternal antibodies on juvenile stage immune response, in contrast to results from previous studies. Adult immune response depended largely on the magnitude of the juvenile immune response regardless of the identity of the antigen in the juvenile immune challenge, and did not depend on neonatal IgY titres. Our results are consistent with a priming effect of early immune experience on adult stage immune responsiveness, but we found no evidence of carryover effects of yolk-derived antibodies on adult immunity.

5. This study employs new methodology for investigation of maternal antibodies and presents results suggesting that further studies of maternal effects on immunity will require careful consideration of the numerous ways maternally derived yolk components can impact the different types of immune response.

A population-based study of the effect of the HFE C282Y and H63D mutations on iron metabolism

The C282Y and H63D mutations in the HFE gene are important causes of hemochromatosis. In the elderly, these mutations might be associated with increased morbidity because of the lifelong accumulation of iron. In a population-based sample of the elderly, we determined the value of genotyping for HFE mutations to screen for subclinical hemochromatosis. HFE genotype frequencies were determined in a random group of 2095 subjects (55 years and over). In this random group, we selected within the six genotype groups a total of 342 individuals and measured their serum transferrin saturation, iron and ferritin levels. We also estimated the heritability and parameters needed to evaluate screening, including the sensitivity, specificity, positive and negative predictive values (PPV, NPV) of HFE genotypes. Iron parameters were significantly increased in subjects homozygous, heterozygous or compound heterozygous. The effect of the mutations was more pronounced in men than in women. For the H63D mutation, an allele dose effect was observed. The HFE gene explained about 5% of the variability in serum iron indices. The PPV for hemochromatosis for the C282Y homozygous was 100% in men and 67% in women. The NPV of the wild-type allele was 97% for both men and women. The sensitivity of both mutations was 70% for men and 52% for women and the specificity was 62% for men and 64% for women. Our study shows that the HFE C282Y and H63D are determinants of iron parameters in the elderly and will be effective in detecting individuals at high risk of hemochromatosis. However, when screening based on these two mutations, some individuals with subclinical hemochromatosis will be missed.

The effect of acute exercise on undercarboxylated osteocalcin in obese men

Summary : The purpose of this study was to examine if the reduction in glucose post-exercise is mediated by undercarboxylated osteocalcin (unOC). Obese men were randomly assigned to do aerobic or power exercises. The change in unOC levels was correlated with the change in glucose levels post-exercise. The reduction in glucose post-acute exercise may be partly related to increased unOC.

Introduction : Osteocalcin (OC) in its undercarboxylated (unOC) form may contribute to the regulation of glucose homeostasis. As exercise reduces serum glucose and improves insulin sensitivity in obese individuals and individuals with type 2 diabetes (T2DM), we hypothesised that this benefit was partly mediated by unOC.

Methods : Twenty-eight middle-aged (52.4 ± 1.2 years, mean ± SEM), obese (BMI = 32.1 ± 0.9 kg m⁻²) men were randomly assigned to do either 45 min of aerobic (cycling at 75% of VO2peak) or power (leg press at 75% of one repetition maximum plus jumping sequence) exercises. Blood samples were taken at baseline and up to 2 h post-exercise.

Results : At baseline, unOC was negatively correlated with glucose levels (r = −0.53, p = 0.003) and glycosylated haemoglobin (HbA1c) (r = −0.37, p = 0.035). Both aerobic and power exercises reduced serum glucose (from 7.4 ± 1.2 to 5.1 ± 0.5 mmol L⁻¹, p = 0.01 and 8.5 ± 1.2 to 6.0 ± 0.6 mmol L⁻¹, p = 0.01, respectively). Aerobic exercise significantly increased OC, unOC and high-molecular-weight adiponectin, while power exercise had a limited effect on OC and unOC. Overall, those with higher baseline glucose and HbA1c had greater reductions in glucose levels after exercise (r = −0.46, p = 0.013 and r = −0.43, p = 0.019, respectively). In a sub-group of obese people with T2DM, the percentage change in unOC levels was correlated with the percentage change in glucose levels post-exercise (r = −0.51, p = 0.038).

Conclusions : This study reports that the reduction in serum glucose post-acute exercise (especially aerobic exercise) may be partly related to increased unOC.r exercises. The change in unOC levels was correlated with the change in glucose levels post-exercise. The reduction in glucose post-acute exercise may be partly related to increased unOC.

Differential response to resistance training in CHF according to ACE genotype

Background : The Angiotensin Converting Enzyme (ACE) gene may influence the risk of heart disease and the response to various forms of exercise training may be at least partly dependent on the ACE genotype. We aimed to determine the effect of ACE genotype on the response to moderate intensity circuit resistance training in chronic heart failure (CHF) patients.

Methods : The relationship between ACE genotype and the response to 11 weeks of resistance exercise training was determined in 37 CHF patients (New York Heart Association Functional Class = 2.3 ± 0.5; left ventricular ejection fraction 28 ± 7%; age 64 ± 12 years; 32:5 male:female) who were randomised to either resistance exercise (n = 19) or inactive control group (n = 18). Outcome measures included VO_2peak power output and muscle strength and endurance. ACE genotype was determined using standard methods.

Results : At baseline, patients who were homozygous for the I allele had higher VO_2peak (p = 0.02) and peak power (p = 0.003) compared to patients who were homozygous for the D allele. Patients with the D allele, who were randomised to resistance training, compared to non-exercising controls, had greater peak power increases (ID p < 0.001; DD p < 0.001) when compared with patients homozygous for the I allele, who did not improve. No significant genotype-dependent changes were observed in VO_2peak, muscle strength, muscle endurance or lactate threshold.

Conclusion : ACE genotype may have a role in exercise tolerance in CHF and could also influence the effectiveness of resistance training in this condition.

Effect of L-arginine infusion on glucose disposal during exercise in humans

Purpose: We have previously shown that local infusion of a nitric oxide synthase (NOS) inhibitor attenuates increases in leg glucose uptake during exercise in humans. We have also shown that infusion of the NOS substrate, L-arginine (L-Arg), increases glucose clearance, although the mechanisms involved were not determined. A potential mechanism for NO-mediated glucose disposal is via interactions with NOS and the energy sensor AMPactivated protein kinase (AMPK). The aim of this study was to determine the mechanism(s) by which L-Arg infusion increases glucose disposal during exercise in humans by examining total NOS activity and AMPK signaling.

Methods: Seven males cycled for 120 min at 64% T 1% V˙ O2peak, during which the [6,6-2H]glucose tracer was infused. During the final 60 min of exercise, either saline alone (Control, CON), or saline containing L-Arg HCl (L-Arg, 30 g at 0.5 gIminj1) was coinfused in a double-blind, randomized, counterbalanced order.

Results: L-Arg increased the glucose rate of disappearance and glucose clearance rate during exercise; however, this was accompanied by a 150% increase in plasma insulin concentration from 65 to 75 min (P G 0.05) that remained significantly elevated until 90 min of exercise. Skeletal muscle AMPK signaling, nNOSK phosphorylation by AMPK, and total NOS activity increased to a similar extent in the two trials.

Conclusions: The increase in glucose disposal after L-Arg infusion during exercise is likely due to the significantly higher plasma insulin concentration.

Inhibitory effect of antidepressant drugs on contact hypersensitivity reaction

Background: Contact hypersensitivity (CS) reaction in the skin is T-cell mediated immune reaction which plays a major role in the pathogenesis and chronicity of various inflammatory skin disorders and, like other delayed-type hypersensitivity (DTH) reactions, affords immunity against tumor cells and microbes. CS response is a self-limiting reaction, and interleukin (IL)-10 is considered to be a natural suppressant of cutaneous inflammatory response. Recently, it has been demonstrated that major depression is related to activation of the inflammatory response and elevation of some parameters of cell-mediated immunity. It has been suggested that such activation of the immune system may play a role in etiology of depression. If this immunoactivation is involved in etiology of depression, one would expect that antidepressant agents may have negative immunoregulatory effects. To the best of our knowledge, the effect of antidepressants on contact hypersensitivity has not been studied.

Methods: The aim of the present study was to establish the effect of prolonged desipramine or fluoxetine treatment on CS reaction to picryl chloride.

Results: Antidepressants significantly suppressed CS reaction, fluoxetine by 53% whereas desipramine by 47% compared to positive control. Moreover, desipramine and fluoxetine decreased relative weight of auxillary lymph nodes. Desipramine decreased also relative weight of inguinal lymph nodes and spleens whereas desipramine and fluoxetine increased production of IL-10 in comparison to positive control.

Conclusion: The observed effect of antidepressant drugs on CS reaction is consistent with the hypothesis that T-cell mediated immunity is targeted by antidepressants.

Density-dependent mortality is mediated by foraging activity for prey fish in whole-lake experiments

1. Whereas the effects of density-dependent growth and survival on population dynamics are well-known, mechanisms that give rise to density dependence in animal populations are not well understood. We tested the hypothesis that the trade-off between growth and mortality rates is mediated by foraging activity and habitat use. Thus, if depletion of food by prey is density-dependent, and leads to greater foraging activity and risky habitat use, then visibility and encounter rates with predators must also increase.

2. We tested this hypothesis by experimentally manipulating the density of young rainbow trout (Oncorhynchus mykiss) at risk of cannibalism, in a replicated single-factor experiment using eight small lakes, during an entire growing season.

3. We found no evidence for density-dependent depletion of daphnid food in the near-shore refuge where most age-0 trout resided. Nonetheless, the proportion of time spent moving by individual age-0 trout, the proportion of individuals continuously active, and use of deeper habitats was greater in high density populations than in low density populations. Differences in food abundance among lakes had no effect on measures of activity or habitat use.

4. Mortality of age-0 trout over the growing season was higher in high density populations, and in lakes with lower daphnid food abundance. Therefore, population-level mortality of age-0 trout is linked to greater activity and use of risky habitats by individuals at high densities. We suspect that food resources were depleted at small spatial and temporal scales not detected by our plankton sampling in the high density treatment, because food-dependent activity and habitat use by age-0 trout occurs in our lakes when food abundance is experimentally manipulated

Oxygen dependency of hydrogen sulfide-mediated vasoconstriction in cyclostome aortas

Hydrogen sulfide (H₂S) has been proposed to mediate hypoxic vasoconstriction (HVC), however, other studies suggest the vasoconstrictory effect indirectly results from an oxidation product of H₂S. Here we examined the relationship between H₂S and O₂ in isolated hagfish and lamprey vessels that exhibit profound hypoxic vasoconstriction. In myographic studies, H₂S (Na₂S) dose-dependently constricted dorsal aortas (DA) and efferent branchial arteries (EBA) but did not affect ventral aortas or afferent branchial arteries; effects similar to those produced by hypoxia. Sensitivity of H₂S-mediated contraction in hagfish and lamprey DA was enhanced by hypoxia. HVC in hagfish DA was enhanced by the H₂S precursor cysteine and inhibited by amino-oxyacetate, an inhibitor of the H₂S-synthesizing enzyme, cystathionine β-synthase. HVC was unaffected by propargyl glycine, an inhibitor of cystathionine λ-lyase. Oxygen consumption (ṀO₂) of hagfish DA was constant between 15 and 115 mmHg P_O2 (1 mmHg=0.133 kPa), decreased when P_O2 <15 mmHg, and increased after P_O2 exceeded 115 mmHg. 10 μmol l^–1 H₂S increased and ⩾100μ mol l^–1 H₂S decreased ṀO₂. Consistent with the effects on HVC, cysteine increased and amino-oxyacetate decreased Ṁ_O2. These results show that H₂S is a monophasic vasoconstrictor of specific cyclostome vessels and because hagfish lack vascular NO, and vascular sensitivity to H₂S was enhanced at low P_O2, it is unlikely that H₂S contractions are mediated by either H₂S–NO interaction or an oxidation product of H₂S. These experiments also provide additional support for the hypothesis that the metabolism of H₂S is involved in oxygen sensing/signal transduction in vertebrate vascular smooth muscle.

Post-exercise muscle glycogen repletion in the extreme : effect of food absence and active recovery

Glycogen plays a major role in supporting the energy demands of skeletal muscles during high intensity exercise. Despite its importance, the amount of glycogen stored in skeletal muscles is so small that a large fraction of it can be depleted in response to a single bout of high intensity exercise. For this reason, it is generally recommended to ingest food after exercise to replenish rapidly muscle glycogen stores, otherwise one's ability to engage in high intensity activity might be compromised. But what if food is not available? It is now well established that, even in the absence of food intake, skeletal muscles have the capacity to replenish some of their glycogen at the expense of endogenous carbon sources such as lactate. This is facilitated, in part, by the transient dephosphorylation-mediated activation of glycogen synthase and inhibition of glycogen phosphorylase. There is also evidence that muscle glycogen synthesis occurs even under conditions conducive to an increased oxidation of lactate post-exercise, such as during active recovery from high intensity exercise. Indeed, although during active recovery glycogen resynthesis is impaired in skeletal muscle as a whole because of increased lactate oxidation, muscle glycogen stores are replenished in Type IIa and IIb fibers while being broken down in Type I fibers of active muscles. This unique ability of Type II fibers to replenish their glycogen stores during exercise should not come as a surprise given the advantages in maintaining adequate muscle glycogen stores in those fibers that play a major role in fight or flight responses.

Effect of sodium selenite-enriched reperfusion solutions on rat cardiac ischemia reperfusion injury

Cardiac surgery often generates oxidative stress leading to ischemia reperfusion injury (I-R). Antioxidants have been shown to prevent this injury and have been added to cardioplegic solutions to assist in recovery. In this study, we tested the effectiveness of sodium selenite in protecting against ischemia reperfusion injury and investigated the mechanisms behind this protection. Hearts from male Wistar rats were subjected to ischemia reperfusion using the Langendorf model. Krebs-Henseleit perfusion solutions were supplemented with 0,0.1, 0.5, 1.0, and 10μM sodium selenite. Hearts were perfused for 30 min and then subjected to 22.5 min of global ischemia followed by 45 min reperfusion. Heart rate, ischemic contracture, end diastolic pressure, and developed ventricular pressure were monitored. At the completion of the experiment, hearts were homogenized and tissue extracts were assayed for glutathione peroxidase (GSH-Px) and thioredoxin reductase (Thx-Red) activity. Sodium selenite, at a concentration of 0.5 μM, demonstrated a protective effect on the recovery of cardiac function following I-R, as evidenced by a lower end diastolic pressure and enhanced recovery of rate pressure product. There was no beneficial effect observed in hearts perfused with 0.1 μM sodium selenite-supplemented buffer, whereas poorer functional recovery was observed in hearts perfused with 10 μM sodium selenite-supplemented buffer. The beneficial effect of sodium selenite was not mediated through increased activity of GSH-Px or Thx-Red. This study demonstrates that the addition of sodium selenite to reperfusion solutions, at an optimal concentration of 0.5 μM, assists in cardiac recovery following ischemia reperfusion.

Mediated and direct effects of general control beliefs on obsessive compulsive symptoms

Although control-related cognitions have often been implicated in discussions of obsessive compulsive disorder (OCD), empirical investigations of the relationship between control constructs and OCD symptoms have been relatively limited. This article investigated the hypothesis that OCD symptoms may be linked with a higher desire for control (DC), but a lower sense of control (SC) over the self and environment, leading to motivation for compulsive symptoms. It also investigated whether this effect was direct, or mediated through other OCD-related cognitions. This hypothesis was investigated in a nonclinical population, using path analyses controlling for depression. It was found that higher levels of DC and lower levels of SC were associated with higher levels of OCD-related beliefs, and with symptoms via higher OCD-related beliefs. SC was also directly linked with higher OCD symptoms. Control beliefs regarding both the internal (emotions) and external (threat) environment were related to OCD symptoms. Implications for therapy and research are discussed.