A GIP/xenin hybrid in combination with exendin-4 improves metabolic status in db/db diabetic mice and promotes enduring antidiabetic benefits in high fat fed mice.

The current study has determined the ability of exendin-4 to augment the antidiabetic benefits of the recently characterised GIP/xenin hybrid, (DAla2)GIP/xenin-8-Gln. As such, combined activation of metabolic pathways linked to various gut derived hormones has been shown to exert complementary beneficial metabolic effects in diabetes. (DAla2)GIP/xenin-8-Gln and exendin-4 were administered twice daily to high fat fed (HFF) or db/db mice for 28 days and antidiabetic benefits assessed. Persistence of beneficial metabolic effects in HFF mice was also examined. Twice-daily injection of (DAla2)GIP/xenin-8-Gln for 28 days in HFF mice significantly reduced energy intake, body weight, circulating glucose, HbA1c and improved glucose tolerance and insulin sensitivity. Overall pancreatic islet, alpha- and beta-cell areas were reduced, with concurrent reduction in alpha- and beta-cell proliferation that was more apparent in the combined treatment group. Addition of exendin-4 to (DAla2)GIP/xenin-8-Gln therapy did not significantly improve metabolic control. Remarkably, beneficial effects were still evident 14 days following complete cessation of peptide administration. Thus, circulating glucose and insulin, HbA1c concentrations and glucose tolerance were still significantly improved when compared to control HFF mice on day 42, with minimal changes to pancreatic islet architecture. In contrast to HFF mice, combined treatment of db/db mice with (DAla2)GIP/xenin-8-Gln plus exendin-4 was required to induce beneficial effects on key metabolic parameters, which were not observed with either treatment alone. This included improvements in glucose tolerance and insulin sensitivity, but no effect on pancreatic architecture. These studies highlight the clear, and persistent, metabolic advantages of sustained activation of GLP-1 receptors, alongside concurrent activation of related GIP and xenin cell signalling pathways, in diabetes.

Characterisation of Glucose-Dependent Insulinotropic Polypeptide Receptor Antagonists in Rodent Pancreatic Beta Cells and Mice.

Hypersecretion and alterations in the biological activity of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), have been postulated as contributing factors in the development of obesity-related diabetes. However, recent studies also point to weight-reducing effects of GIP receptor activation. Therefore, generating precise experimental tools, such as specific and effective GIP receptor (GIPR) antagonists, is of key significance to better understand GIP physiology. Thus, the primary aim of the current study was to uncover improved GIPR antagonists for use in rodent studies, using human and mouse GIP sequences with N- and C-terminal deletions. Initial in vitro studies revealed that the GIPR agonists, human (h) GIP(1-42), hGIP(1-30) and mouse (m) GIP(1-30), stimulated (P < 0.01 to P < 0.001) insulin secretion from rat BRIN-BD11 cells. Analysis of insulin secretory effects of the N- and C-terminally cleaved GIP peptides, including hGIP(3-30), mGIP(3-30), h(Pro3)GIP(3-30), hGIP(5-30), hGIP(3-42) and hGIP(5-42), revealed that these peptides did not modulate insulin secretion. More pertinently, only hGIP(3-30), mGIP(3-30) and h(Pro3)GIP(3-30) were able to significantly (P < 0.01 to P < 0.001) inhibit hGIP(1-42)-stimulated insulin secretion. The human-derived GIPR agonist sequences, hGIP(1-42) and hGIP(1-30), reduced (P < 0.05) glucose levels in mice following conjoint injection with glucose, but mGIP(1-30) was ineffective. None of the N- and C-terminally cleaved GIP peptides affected glucose homeostasis when injected alone with glucose. However, hGIP(5-30) and mGIP(3-30) significantly (P < 0.05 to P < 0.01) impaired the glucose-lowering action of hGIP(1-42). Further evaluation of these most effective sequences demonstrated that mGIP(3-30), but not hGIP(5-30), effectively prevented GIP-induced elevations of plasma insulin concentrations. These data highlight, for the first time, that mGIP(3-30) represents an effective molecule to inhibit GIPR activity in mice.

Impact of a 6-month family-based weight management programme on child food and activity behaviours: short-term and long-term outcomes of the PEACH™ intervention.

BACKGROUND: The PEACH™ randomized controlled trial measured changes to children's food and activity behaviours following participation in a weight management programme. We have previously reported a 10% reduction in body mass index z-score at intervention end (6-month post-baseline) that was maintained to 24 months with no further intervention for the full study sample. OBJECTIVES: The objective of the study is to report changes in food and activity outcomes in the full sample at (i) the end of the 6-month intervention and (ii) 24-month post-baseline (18-month post-intervention). METHODS: Changes in dietary and activity outcomes were assessed over time (baseline: n = 169, 8.1 ± 1.2 years, body mass index z-score 2.72 ± 0.62). Dietary intake was assessed using the Child Dietary Questionnaire, and times spent active and sedentary were assessed using a study-specific questionnaire. Linear mixed models were used. RESULTS: There were significant time effects for all Child Dietary Questionnaire scores and activity and sedentary behaviours in the expected direction. Significant sex effects were observed for fruit and vegetable and sweetened beverages scores and for time spent in small screen-based activity. CONCLUSIONS: This is one of few child weight management studies to report short-term and long-term behaviour outcomes. It demonstrates that an intervention promoting food and activity behaviours consistent with guidelines can achieve modest changes, mediating improvements in relative weight.

The adaptation and translation of the PEACH™ RCT intervention: the process and outcomes of the PEACH™ in the community trial.

OBJECTIVE: To describe the process and report selected outcomes of translating an effective child weight management initiative (PEACH™) from a randomised controlled trial intervention to a community health programme. STUDY DESIGN AND METHODS: Pre-post study design utilising the reach, effectiveness, adoption, implementation and maintenance (RE-AIM) evaluation framework. Adaptation of PEACH™ required significant promotional activity and consideration of legal, ethical and financial issues. PEACH™ components were revised and an evaluation design based on the RE-AIM framework was developed. Facilitator training workshops were made available to South Australian health or education professionals initially, then opened up to new graduates, interstate dietitians and others interested in professional development. Facilitators completed pretraining and post-training questionnaires and a third questionnaire following programme delivery. Data were collected from families by facilitators and returned to university staff for assessment of change (baseline to programme end) in body mass index (BMI) and waist circumference (WC) z-scores. RESULTS: Changes to organisational and political environments prevented maximum programme reach and adoption. Nonetheless, data indicated that PEACH™ was effective at improving facilitators' confidence (P < 0.05) and children's (n = 37) BMI z-score (-0.17, 95% confidence interval [CI]: 0.03:0.30, P = 0.016), WC z-score (-0.14, 95% CI: -0.02:0.30, P = 0.09) and lifestyle behaviours. Collection of maintenance data was prevented due to time and financial constraints. CONCLUSIONS: Translational research needs to develop ways to effectively and efficiently bridge the gap between behavioural research and practice to improve the adoption of evidence-based approaches to child weight management. Nutrition educators and researchers can drive these nutrition-focussed translational research efforts forward. Funding bodies and health service organisations are encouraged to provide financial and structural support for such activity.

PGC-1α4 gene expression is suppressed by the IL-6-MEK-ERK 1/2 MAPK signalling axis and altered by resistance exercise, obesity and muscle injury.

AIM: PGC-1α4 is a novel regulator of muscle hypertrophy; however, there is limited understanding of the regulation of its expression and role in many (patho)physiological conditions. Therefore, our purpose was to elicit signalling mechanisms regulating gene expression of Pgc1α4 and examine its response to (patho)physiological stimuli associated with altered muscle mass. METHODS: IL-6 knockout mice and pharmacological experiments in C2C12 myocytes were used to identify regulation of Pgc1α4 transcription. To examine Pgc1α4 gene expression in (patho)physiological conditions, obese and lean Zucker rats with/without resistance exercise (RE), ageing mice and muscle regeneration from injury were examined. RESULTS: In IL-6 knockout mice, Pgc1α4mRNA was ~sevenfold greater than wild type. In C2C12 cells, Pgc1α4mRNA was suppressed ~70% by IL-6. Suppression of Pgc1α4 by IL-6 was prevented by MEK-ERK-MAPK inhibition. RE led to ~260% greater Pgc1α4mRNA content in lean rats. However, obese Zucker rats exhibited ~270% greater Pgc1α4mRNA than lean, sedentary with no further augmentation by RE. No difference was seen in IL-6mRNA or ERK-MAPK phosphorylation in Zucker rats. Aged mice demonstrated ~50% lower Pgc1α4mRNA and ~fivefold greater ERK-MAPK phosphorylation than young despite unchanged Il-6mRNA. During muscle regeneration, Pgc1α4 content is ~30% and IL-6mRNA >threefold of uninjured controls 3 days following injury; at 5 days, Pgc1α4 was >twofold greater in injured mice with no difference in IL-6mRNA. CONCLUSION: Our findings reveal a novel mechanism suppressing Pgc1α4 gene expression via IL-6-ERK-MAPK and suggest this signalling axis may inhibit Pgc1α4 in some, but not all, (patho)physiological conditions.

Translational machinery of mitochondrial mRNA is promoted by physical activity in Western diet-induced obese mice.

AIM: Mitochondria-encoded proteins are necessary for oxidative phosphorylation; however, no report has examined how physical activity (PA) and obesity affect mitochondrial mRNA translation machinery. Our purpose was to determine whether Western diet (WD)-induced obesity and voluntary wheel running (VWR) impact mitochondrial mRNA translation machinery and whether expression of this machinery is dictated by oxidative phenotype. METHODS: Obesity was induced with 8-wk WD feeding, and in the final 4 wks, half of mice were allowed VWR. Mitochondrial mRNA translation machinery including initiation factors (mtIF2/3), elongation factor Tu (TUFM) and translational activator (TACO1), and mitochondria-encoded proteins (CytB and ND4) was assessed by immunoblotting. The relation of mitochondrial mRNA translation to muscle oxidative phenotype was assessed using PGC-1α transgenic overexpression (MCK-PGC-1α vs. wild-type mice) and comparing across muscle groups in wild-type mice. RESULTS: mtIF3 and TACO1 proteins were ~45% greater in VWR than sedentary (SED), and TACO1 and mtIF2 proteins were ~60% and 125% greater in WD than normal chow (NC). TUFM protein was ~50% lower in WD-SED than NC-SED, but ~50% greater in WD-VWR compared to NC-SED. CytB and ND4 were ~40% greater in VWR and ND4 was twofold greater with WD. TUFM, TACO1, ND4 and CytB were greater in MCK-PGC-1α compared to wild-type, and mtIF2/3 contents were not different. In oxidative muscle (soleus), mitochondrial translation machinery was elevated compared to mixed (gastrocnemius) or glycolytic (extensor digitorum longus) muscles. CONCLUSION: These data suggest a novel mechanism promoting mitochondrial function by translation of mitochondrial protein following PA. This may act to promote muscle health by PA in obesity.

Diet-induced obesity alters anabolic signalling in mice at the onset of skeletal muscle regeneration.

AIM: Obesity is classified as a metabolic disorder that is associated with delayed muscle regeneration following damage. For optimal skeletal muscle regeneration, inflammation along with extracellular matrix remodelling and muscle growth must be tightly regulated. Moreover, the regenerative process is dependent on the activation of myogenic regulatory factors (MRFs) for myoblast proliferation and differentiation. The purpose of this study was to determine how obesity alters inflammatory and protein synthetic signalling and MRF expression at the onset of muscle regeneration in mice. METHODS: Forty-eight male C57BL/6J mice (3 weeks old) were randomly assigned to either a high-fat diet (HFD, 60% fat) or a lean diet (10% fat) for 12 weeks. At 15 weeks, bupivacaine was injected into the tibialis anterior (TA) of the injured group (n = 5-8/group) and PBS was injected into the control (n = 5-6). The TA was excised 3 or 28 days after injection. RESULTS: We demonstrated impaired muscle regeneration in obese mice. The obese mice had reduced IL-6, MyoD and IGF-1 mRNA abundance compared to the lean mice (P < 0.05). Three days following muscle damage, TNF-α mRNA and protein levels of P-STAT3 and P-Akt were 14-fold, fourfold and fivefold greater in the lean mice respectively. However, there were no differences observed in the obese injured group compared to the uninjured group. Moreover, p70S6K1 was threefold greater in lean injured mice compared to uninjured but was reduced by 28% in the obese injured mice. CONCLUSION: Obese mice have impaired inflammatory and protein synthetic signalling that may negatively influence muscle regeneration.

Dietary intake in Australian children aged 4-24 months: consumption of meat and meat alternatives.

Meat/meat alternatives (M/MA) are key sources of Fe, Zn and protein, but intake tends to be low in young children. Australian recommendations state that Fe-rich foods, including M/MA, should be the first complementary foods offered to infants. The present paper reports M/MA consumption of Australian infants and toddlers, compares intake with guidelines, and suggests strategies to enhance adherence to those guidelines. Mother-infant dyads recruited as part of the NOURISH and South Australian Infants Dietary Intake studies provided 3 d of intake data at three time points: Time 1 (T1) (n 482, mean age 5·5 (SD 1·1) months), Time 2 (T2) (n 600, mean age 14·0 (SD 1·2) months) and Time 3 (T3) (n 533, mean age 24 (SD 0·7) months). Of 170 infants consuming solids and aged greater than 6 months at T1, 50 (29%) consumed beef, lamb, veal (BLV) or pork on at least one of 3 d. Commercial infant foods containing BLV or poultry were the most common form of M/MA consumed at T1, whilst by T2 BLV mixed dishes (including pasta bolognaise) became more popular and remained so at T3. The processed M/MA increased in popularity over time, led by pork (including ham). The present study shows that M/MA are not being eaten by Australian infants or toddlers regularly enough; or in adequate quantities to meet recommendations; and that the form in which these foods are eaten can lead to smaller M/MA serve sizes and greater Na intake. Parents should be encouraged to offer M/MA in a recognisable form, as one of the first complementary foods, in order to increase acceptance at a later age.

Neuroangiostrongyliasis due to Angiostrongylus cantonensis in gang-gang cockatoos (Callocephalon fimbriatum).

CASE REPORT: Four gang-gang cockatoos from an aviary in Sydney displayed severe neurological signs. Three were necropsied and histopathology of the brains and spinal cords revealed migrating nematodes, which were identified as Angiostrongylus cantonensis. The migrating larval nematodes created tracts of malacia in the brain, but elicited little inflammatory cell infiltration. However, adult nematodes that had emerged onto the meningeal surface of the spinal cord evoked a marked non-suppurative reaction. Detailed histological examination of other tissues revealed larvae embedded in arterioles in the gastrointestinal serosa, lung and heart, which were associated with a significant granulomatous response. The latter lesions were consistent with our understanding of the pathogenesis of infection with this parasite, but have not been previously described, probably as a result of limited sampling. CONCLUSIONS: Angiostrongylus cantonensis is still present in the Sydney area and can cause significant disease in exposed animals, including birds. It also highlights potential human health problems.

The impact of diabetes mellitus on two-year mortality following contemporary percutaneous coronary intervention: implications for revascularization practice.

OBJECTIVE: To assess the impact of diabetes on 2-year mortality in current PCI practice. BACKGROUND: In patients with coronary artery disease undergoing revascularization, diabetes mellitus is associated with higher mortality. METHODS: A retrospective analysis was done of all patients undergoing PCI at our tertiary center between January 2000 and December 2004. There were 6,160 PCI procedures performed in 5,759 patients who received at least one stent. Of these patients, 801 (13.9%) were diabetic and 4,958 (86.1%) were nondiabetic. The primary outcome measure of the study was all-cause mortality. All patients were followed up for a period of 2 years. Multivariate logistic regression analysis was used to test for a potential independent association between diabetic status and follow-up mortality. RESULTS: Before adjustment, a trend toward higher mortality was observed in diabetic patients compared to non-diabetics at 1 year (3.2% vs 2.4%) and 2 years (5.1% vs 3.8%), P = 0.12. Independent predictors for mortality were increasing age, renal dysfunction, peripheral vascular disease, NYHA class >2, urgent PCI, treating left main stem lesions, vessel diameter < or = 2.5 mm, and 3-vessel disease. The use of drug-eluting stent was associated with a reduction in mortality. Diabetes was found to have no independent impact on mortality following PCI (odds ratio = 1.08; 95% confidence intervals = 0.73-1.60; P = 0.71). CONCLUSION: The presence of diabetes was not an independent predictor of mortality following PCI. A diabetic patient that does not require insulin treatment and has no evidence of macro- or microvascular diabetic disease could enjoy a PCI outcome similar to nondiabetic subjects.

An abnormal finding in an angiogram.

An 80 year old Chinese gentleman was admitted with NSTEACS characterized by anterior T wave inversion and raised Troponin T. His coronary angiogram showed stenosis of the proximal LAD. He underwent PCI to LAD lesion. The RCA was large and there was large collateral between, RCA and PA (fig 1,2), which was not intervened. He made good recovery and has been asymptomatic for over 2 years. Coronary artery anomalies are found in 1% of the population, RCA is the most commonly involved. Best approach would be to observe the patients, as most of them do not develop any symptoms.

Cost effectiveness of drug eluting coronary artery stenting in a UK setting: cost-utility study.

OBJECTIVE: To assess the cost effectiveness of drug eluting stents (DES) compared with conventional stents for treatment of symptomatic coronary artery disease in the UK. DESIGN: Cost-utility analysis of audit based patient subgroups by means of a simple economic model. SETTING: Tertiary care. PARTICIPANTS: 12 month audit data for 2884 patients receiving percutaneous coronary intervention with stenting at the Cardiothoracic Centre Liverpool between January 2000 and December 2002. MAIN OUTCOME MEASURES: Risk of repeat revascularisation within 12 months of index procedure and reduction in risk from use of DES. Economic modelling was used to estimate the cost-utility ratio and threshold price premium. RESULTS: Four factors were identified for patients undergoing elective surgery (n = 1951) and two for non-elective surgery (n = 933) to predict risk of repeat revascularisation within 12 months. Most patients fell within the subgroup with lowest risk (57% of the elective surgery group with 5.6% risk and 91% of the non-elective surgery group with 9.9% risk). Modelled cost-utility ratios were acceptable for only one group of high risk patients undergoing non-elective surgery (only one patient in audit data). Restricting the number of DES for each patient improved results marginally: 4% of stents could then be drug eluting on economic grounds. The threshold price premium justifying 90% substitution of conventional stents was estimated to be 112 pound sterling (212 USD, 162 pound sterling) (sirolimus stents) or 89 pound sterling (167 USD, 130 pound sterling) (paclitaxel stents). CONCLUSIONS: At current UK prices, DES are not cost effective compared with conventional stents except for a small minority of patients. Although the technology is clearly effective, general substitution is not justified unless the price premium falls substantially.

Effect of completeness of revascularization on clinical outcome in patients with multivessel disease presenting with unstable angina who undergo percutaneous coronary intervention.

We evaluated the current short- and medium-term outcomes of complete revascularization, compared to culprit lesion percutaneous coronary intervention (PCI), in patients with multivessel coronary disease presenting with unstable angina. One hundred fifty-one patients with multivessel coronary disease presented to a tertiary cardiothoracic center with unstable angina/non-ST elevation myocardial infarction (UA/NSTEMI) between January 2000 and September 2001. In group A (n=71), the intended strategy was complete revascularization by multivessel PCI. In group B (n=80), culprit lesion PCI was intended despite the presence of other lesions amenable to PCI (B1) or due to confounding anatomical factors (B2). Clinical variables and endpoints were collected from patient notes, a dedicated database and telephone follow-up, and included recurrent stable and unstable angina, need for repeat PCI or elective coronary artery bypass graft, incidence of non-fatal myocardial infarction (MI) and death. Baseline characteristics were similar in each group. Procedural success was achieved in over 95% of cases in both groups with high stent implantation rates (>96%). There was no observed difference in mortality or incidence of MI between the groups. Compared to group A, more patients in group B1 had residual angina [22.8% (13/57) versus 9.9% (7/71); p=0.041] and required further PCI [17.5% (10/57) versus 7.0% (5/71); p=0.045]. There was a non-significant trend toward fewer readmissions for UA and less long-term antianginal medication in group A [38.0% (27/71) versus 52.6% (30/57); p=0.043]. Complete and culprit lesion revascularization by PCI are safe methods of treating patients with multivessel coronary disease presenting with UA/NSTEMI. Reductions in residual angina, repeat PCI and need for antianginal therapies suggest that complete revascularization should be the strategy of choice when possible.

An echocardiographic assessment of cardiac morphology and common ECG findings in teenage professional soccer players: reference ranges for use in screening.

OBJECTIVE: To assess physiological cardiac adaptation in adolescent professional soccer players. SUBJECTS AND DESIGN: Over a 32 month period 172 teenage soccer players were screened by echocardiography and ECG at a tertiary referral cardiothoracic centre. They were from six professional soccer teams in the north west of England, competing in the English Football League. One was excluded because of an atrial septal defect. The median age of the 171 players assessed was 16.7 years (5th to 95th centile range: 14-19) and median body surface area 1.68 m(2) (1.39-2.06 m(2)). MAIN OUTCOME MEASURES: Standard echocardiographic measurements were compared with predicted mean, lower, and upper limits in a cohort of normal controls after matching for age and surface area. Univariate regression analysis was used to assess the correlation between echocardiographic variables and the age and surface area of the soccer player cohort. ECG findings were also assessed. RESULTS: All mean echocardiographic variables were greater than predicted for age and surface area matched controls (p < 0.001). All variables except left ventricular septal and posterior wall thickness showed a modest linear correlation with surface area (r = 0.2 to 0.4, p < 0.001); however, left ventricular mass was the only variable that was significantly correlated with age (r = 0.2, p < 0.01). Only six players (3.5%) had structural anomalies, none of which required further evaluation. All had normal left ventricular systolic function. Sinus bradycardia was found in 65 (39%). The Solokow-Lyon voltage criteria for left ventricular hypertrophy were present in 85 (50%) and the Romhilt-Estes points score (five or more) in 29 (17%). Repolarisation changes were present in 19 (11%), mainly in the inferior leads. CONCLUSIONS: Chamber dimensions, left ventricular wall thickness and mass, and aortic root size were all greater than predicted for controls after matching for age and surface area. Sinus bradycardia and the ECG criteria for left ventricular hypertrophy were common but there was poor correlation with echocardiographic left ventricular hypertrophy. The type of hypertrophy found reflected the combined endurance and strength based training undertaken.

Cardiac rupture caused by Staphylococcus aureus septicaemia and pericarditis: an incidental finding.

A 35 year old woman with a long history of intravenous drug abuse presented to a local hospital with severe anaemia, fever, raised markers of inflammation, and positive blood cultures for Staphylococcus aureus. She responded to treatment with antibiotics with improvement in her symptoms and markers of inflammation. Four weeks later a "routine" echocardiogram showed a rupture of her left ventricular apex and a large pseudoaneurysm. There had been no deterioration in her symptoms or haemodynamic status to herald this new development. It was successfully repaired surgically and the patient made a good recovery.

Intracoronary ultrasound.

Although contrast angiography is important in the diagnosis and treatment of atherosclerotic disease, it does have limitations. Intracoronary ultrasound more accurately assesses the amount of atherosclerosis and has given us new insights into the pathophysiology of coronary plaque accumulation and remodelling. It also allows the monitoring of therapeutic intervention. Intracoronary ultrasound is a new gold standard. It does not obviate the need for angiography but provides complementary information that enables us to perform optimal interventional procedures.

Setting up a heart emergency centre.

We describe the setting up of a 'heart emergency centre' linked to a pre-existing coronary care unit. The 'heart emergency centre' offers a new and efficient way of providing a fast and effective system for the assessment and management of patients with cardiac emergencies. This set-up can result in significant improvements in 'door to needle' time for thrombolysis, which has been shown to be beneficial both in terms of morbidity and mortality following myocardial infarction.