Exenatide extended-release; clinical trials, patient preference, and economic considerations

Type 2 diabetes remains an escalating world-wide problem, despite a range of treatments. The revelation that insulin secretion is under the control of a gut hormone, glucagon-like peptide 1 (GLP-1) led to a new paradigm in the management of type 2 diabetes, medicines that directly stimulate, or that prolong the actions of the endogenous GLP-1, at its receptors. Exenatide is an agonist at the GLP-1 receptors, and was initially developed as a subcutaneous twice daily medication, ExBID. The clinical trials with ExBID established a role for exenatide in the treatment of type 2 diabetes. Subsequently, once weekly exenatide (ExQW) was shown to have advantages over ExBID, and there is now more emphasis on the development of ExQW. ExQW alone reduces glycosylated haemoglobin (HbA1c) and body weight, and is well tolerated. ExQW has been compared to sitagliptin, pioglitazone and metformin, and shown to have a greater ability to reduce HbA1c than these other medicines. The only preparation of insulin, which ExQW has been compared to, is insulin glargine, and the ExQW has some favourable properties in this comparison, notably causing weight loss, compared to the gain with insulin glargine. ExQW has been compared to another GLP-1 receptor agonist, liraglutide, and ExQW is non-inferior to liraglutide in reducing HbA1c. The small amount of evidence available, shows that subjects with type 2 diabetes, prefer ExQW to ExBID, and that adherence was high to these in the clinical trial setting. Healthcare and economic modelling suggests that ExQW will reduce diabetic complications and be cost-effective, compared to other medications, with long term use. Little is known about whether subjects with type 2 diabetes prefer ExQW to other medicines, and whether adherence is good to ExQW in practice, and these important topics require further study.

Age-related trends in urinary excretion of bisphenol A in Australian children and adults : evidence from a pooled sample study using samples of convenience

Bisphenol A (BPA or 4,4’-(propane-2,2-diyl)diphenol) is a chemical intermediate in the production of polycarbonate and epoxy resins, and used in a wide range of applications. BPA has attracted significant attention in the past decade due to its frequency of detection in human populations worldwide, demonstrated animal toxicity and potential impact on human health, particularly during critical periods of development. The aim of this study was to perform a preliminary assessment of age-related trends in urinary concentration and to estimate daily excretion of BPA in Australian children (aged (>0 – <5 years) and adults (≥15 – <75 years). This was achieved using 79 samples pooled by age and gender, created from 868 individual samples of convenience collected as part of routine, community-based pathology testing. Total BPA was analyzed using online-SPE-LC-MS/MS and detected in all samples with a range of 0.65 – 265 ng/ml. No significant differences were observed between males and females. A urine flow model was constructed from published values and used to provide an estimate of daily excretion per unit bodyweight for each pooled sample. The daily excretion estimates ranged from 26.2 – 18200 ng/kg-d for children; and 20.1 – 165 ng/kg-d for adults. Urinary concentrations and estimated excretion rates were inversely associated with age, and estimated daily excretion rates in infants and young children were significantly higher than in adults (geometric mean: 107 and 47.0 ng/kg-d, respectively). Higher excretion of BPA in children may be explained by their higher food consumption relative to body weight compared to adults and adolescents, and may also reflect alternative exposure pathways and sources. Keywords: bisphenol A, biomonitoring, children, urine flow, Australia

High dietary diversity is associated with obesity in Sri Lankan adults : an evaluation of three dietary scores

Background Dietary diversity is recognized as a key element of a high quality diet. However, diets that offer a greater variety of energy-dense foods could increase food intake and body weight. The aim of this study was to explore association of diet diversity with obesity in Sri Lankan adults. Methods Six hundred adults aged > 18 years were randomly selected by using multi-stage stratified sample. Dietary intake assessment was undertaken by a 24 hour dietary recall. Three dietary scores, Dietary Diversity Score (DDS), Dietary Diversity Score with Portions (DDSP) and Food Variety Score (FVS) were calculated. Body mass index (BMI) ≥ 25 kg.m-2 is defined as obese and Asian waist circumference cut-offs were used diagnosed abdominal obesity. Results Mean of DDS for men and women were 6.23 and 6.50 (p=0.06), while DDSP was 3.26 and 3.17 respectively (p=0.24). FVS values were significantly different between men and women 9.55 and 10.24 (p=0.002). Dietary diversity among Sri Lankan adults was significantly associated with gender, residency, ethnicity, education level but not with diabetes status. As dietary scores increased, the percentage consumption was increased in most of food groups except starches. Obese and abdominal obese adults had the highest DDS compared to non obese groups (p<0.05). With increased dietary diversity the level of BMI, waist circumference and energy consumption was significantly increased in this population. Conclusion Our data suggests that dietary diversity is positively associated with several socio-demographic characteristics and obesity among Sri Lankan adults. Although high dietary diversity is widely recommended, public health messages should emphasize to improve dietary diversity in selective food items.

Genome analysis reveals insights into physiology and longevity of the Brandt’s bat Myotis brandtii

Bats account for one-fifth of mammalian species, are the only mammals with powered flight, and are among the few animals that echolocate. The insect-eating Brandt’s bat (Myotis brandtii) is the longest-lived bat species known to date (lifespan exceeds 40 years) and, at 4–8 g adult body weight, is the most extreme mammal with regard to disparity between body mass and longevity. Here we report sequencing and analysis of the Brandt’s bat genome and transcriptome, which suggest adaptations consistent with echolocation and hibernation, as well as altered metabolism, reproduction and visual function. Unique sequence changes in growth hormone and insulin-like growth factor 1 receptors are also observed. The data suggest that an altered growth hormone/insulin-like growth factor 1 axis, which may be common to other long-lived bat species, together with adaptations such as hibernation and low reproductive rate, contribute to the exceptional lifespan of the Brandt’s bat.

Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats

The mechanisms involved in alcohol use disorders are complex. It has been shown that ghrelin is an important signal for the control of body weight homeostasis, preferably by interacting with hypothalamic circuits, as well as for drug reward by activating the mesolimbic dopamine system. The ghrelin receptor (GHS-R1A) has been shown to be required for alcohol-induced reward. Additionally, ghrelin increases and GHR-R1A antagonists reduce moderate alcohol consumption in mice, and a single nucleotide polymorphism in the GHS-R1A gene has been associated with high alcohol consumption in humans. However, the role of central ghrelin signaling in high alcohol consumption is not known. Therefore, the role of GHS-R1A in operant self-administration of alcohol in rats as well as for high alcohol consumption in Long-Evans rats and in alcohol preferring [Alko alcohol (AA)] rats was studied here. In the present study, the GHS-R1A antagonist, JMV2959, was found to reduce the operant self-administration of alcohol in rats and to decrease high alcohol intake in Long-Evans rats as well as in AA rats. These results suggest that the ghrelin receptor signaling system, specifically GHS-R1A, is required for operant self-administration of alcohol and for high alcohol intake in rats. Therefore, the GHS-R1A may be a therapeutic target for treatment of addictive behaviors, such as alcohol dependence.

Design Pressure Test 2013 Workshop

Design Pressure Test 2013 was a full-day intensive design immersion creative event run on Saturday 3 August 2013, at the QUT Faculty of Creative Industries J Block Design Lab Workshop in Brisbane, Australia, for 25 self-selected high-achieving junior and middle school (year 5-9) students, as part of the Queensland Academies ‘Young Scholars’ Program. Facilitated by tertiary interior design, fashion design and industrial design educators, technicians and six tertiary interior design and fashion design students, the workshop explored design process, environmental impact, the material properties and structural integrity of cardboard, construction techniques, and the production and evaluation of furniture design prototypes. This action research study aimed to facilitate an awareness in young people, of the role and scope of design within our society, the environmental ramifications of design decisions, and the value of design thinking skills in generating strategies to solve basic to complex challenges. It also aimed to investigate the value of collaboration between junior and middle school students, tertiary design educators and students and industry professionals in design awareness, and inspiring post-secondary pathways and idea generation for education. During the creative event, students utilised mathematics skills and developed sketching, making, communication, presentation and collaboration skills to improve their design process, while considering social, cultural and environmental opportunities. Through a series of hands-on collaborative design experiments, participants explored in teams of five, the opportunities available using cardboard as a material – inspiring both functional and aesthetic design solutions. Underpinned by the State Library of Queensland Design Minds Website ‘inquire, ideate and implement’ model of design thinking, the experiments culminated in the development of a detailed client brief, the design and fabrication of a furniture item for seating, and then a team presentation of prototypes to a panel of judges from the professions of architecture, interior design and industrial design, viewed also by parents. The final test for structural integrity was measured by the hoisting down of an adult body weight onto the fabricated seat. The workshop was filmed for the television program ‘Totally Wild’ for dissemination nationally (over 200,000 viewing audience) of the value of design and the Design Minds model to a wider target youth audience.

Mice lacking β-Adrenergic receptors have increased bone mass but are not protected from deleterious skeletal effects of ovariectomy

Activation of β2-adrenergic receptors inhibits osteoblastic bone formation and enhances osteoclastic bone resorption. Whether β-blockers inhibit ovariectomy-induced bone loss and decrease fracture risk remains controversial. To further explore the role of β-adrenergic signaling in skeletal acquisition and response to estrogen deficiency, we evaluated mice lacking the three known β-adrenergic receptors (β-less). Body weight, percent fat, and bone mineral density were significantly higher in male β-less than wild-type (WT) mice, more so with increasing age. Consistent with their greater fat mass, serum leptin was significantly higher in β-less than WT mice. Mid-femoral cross-sectional area and cortical thickness were significantly higher in adult β-less than WT mice, as were femoral biomechanical properties (+28 to +49%, P < 0.01). Young male β-less had higher vertebral (1.3-fold) and distal femoral (3.5-fold) trabecular bone volume than WT (P < 0.001 for both) and lower osteoclast surface. With aging, these differences lessened, with histological evidence of increased osteoclast surface and decreased bone formation rate at the distal femur in β-less vs. WT mice. Serum tartrate-resistance alkaline phosphatase-5B was elevated in β-less compared with WT mice from 8–16 wk of age (P < 0.01). Ovariectomy inhibited bone mass gain and decreased trabecular bone volume/total volume similarly in β-less and WT mice. Altogether, these data indicate that absence of β-adrenergic signaling results in obesity and increased cortical bone mass in males but does not prevent deleterious effects of estrogen deficiency on trabecular bone microarchitecture. Our findings also suggest direct positive effects of weight and/or leptin on bone turnover and cortical bone structure, independent of adrenergic signaling.

Intermittent Fugu parathyroid hormone 1 (1–34) is an anabolic bone agent in young male rats and osteopenic ovariectomized rats

Human parathyroid hormone (hPTH) is currently the only treatment for osteoporosis that forms new bone. Previously we described a fish equivalent, Fugu parathyroid hormone 1 (fPth1) which has hPTH-like biological activity in vitro despite fPth1(1–34) sharing only 53% identity with hPTH(1–34). Here we demonstrate the in vivo actions of fPth1(1–34) on bone. In study 1, young male rats were injected intermittently for 30 days with fPth1 [30 μg–1000 μg/kg body weight (b.w.), (30fPth1–1000fPth1)] or hPTH [30 μg–100 μg/kg b.w. (30hPTH–100hPTH)]. In proximal tibiae at low doses, the fPth1 was positively correlated with trabecular bone volume/total volume (TbBV/TV) while hPTH increased TbBV/TV, trabecular thickness (TbTh) and trabecular number (TbN). 500fPth1 and 1000fPth1 increased TbBV/TV, TbTh, TbN, mineral apposition rate (MAR) and bone formation rate/bone surface (BFR/BS) with a concomitant decrease in osteoclast surface and number. In study 2 ovariectomized (OVX), osteopenic rats and sham operated (SHAM) rats were injected intermittently with 500 μg/kg b.w. of fPth1 (500fPth1) for 11 weeks. 500fPth1 treatment resulted in increased TbBV/TV (151%) and TbTh (96%) in the proximal tibiae due to increased bone formation as assessed by BFR/BS (490%) and MAR (131%). The effect was restoration of TbBV/TV to SHAM levels without any effect on bone resorption. 500fPth1 also increased TbBV/TV and TbTh in the vertebrae (L6) and cortical thickness in the mid-femora increasing bone strength at these sites. fPth1 was similarly effective in SHAM rats. Notwithstanding the low amino acid sequence homology with hPTH (1–34), we have clearly established the efficacy of fPth1 (1–34) as an anabolic bone agent.

Physical activity guidelines and preschooler's obesity status

Aim The benefits of promoting physical activity (PA) in counteracting the high prevalence of childhood obesity have become increasingly important in the past decade. The aim of this study was to examine the association between compliance of daily PA recommendations and the risk of being overweight or obese in preschool-aged children. Methods The sample comprised 607 children aged 4–6 years, recruited from kindergartens located in the metropolitan area of Porto, Portugal. Preschooler’s body mass index was classified according to International Obesity Task Force. PA was assessed during 7 consecutive days by accelerometer. Children were classified as meeting or not meeting PA recommendations based on two guidelines: (i) at least 3 h per day of total PA (TPA); and (ii) at least 1 h per day of moderate to vigorous PA (MVPA). Results The prevalence of overweight and obesity was 23.5 and 10.6% in girls and 17.2 and 8.9% in boys. In all, 90.2 and 97.3% of girls met the 1 h MVPA and 3 h TPA recommendations, respectively. In all, 96.2 and 99.4% boys met the 1 h MVPA and 3 h TPA recommendations, respectively. Boys were significantly more likely to achieve the 1 h MVPA and 3 h TPA recommendations than girls (P0.001). Not meeting the 1 h MVPA guideline was associated with obesity status (OR: 3.8; IC: 1.3–10.4), in girls, but not boys. No other statistically significant associations were found. Discussion These findings suggest that over 90% of children met the recommended guidelines. There is an association with low levels of MVPA and higher obesity status among preschool girls. Further, longitudinal studies are needed to confirm these data.

Reactive stepping behaviour in response to forward loss of balance predicts future falls in community-dwelling older adults

Background: a fall occurs when an individual experiences a loss of balance from which they are unable to recover. Assessment of balance recovery ability in older adults may therefore help to identify individuals at risk of falls. The purpose of this 12-month prospective study was to assess whether the ability to recover from a forward loss of balance with a single step across a range of lean magnitudes was predictive of falls. Methods: two hundred and one community-dwelling older adults, aged 65–90 years, underwent baseline testing of sensorimotor function and balance recovery ability followed by 12-month prospective falls evaluation. Balance recovery ability was defined by whether participants required either single or multiple steps to recover from forward loss of balance from three lean magnitudes, as well as the maximum lean magnitude participants could recover from with a single step. Results: forty-four (22%) participants experienced one or more falls during the follow-up period. Maximal recoverable lean magnitude and use of multiple steps to recover at the 15% body weight (BW) and 25%BW lean magnitudes significantly predicted a future fall (odds ratios 1.08–1.26). The Physiological Profile Assessment, an established tool that assesses variety of sensori-motor aspects of falls risk, was also predictive of falls (Odds ratios 1.22 and 1.27, respectively), whereas age, sex, postural sway and timed up and go were not predictive. Conclusion: reactive stepping behaviour in response to forward loss of balance and physiological profile assessment are independent predictors of a future fall in community-dwelling older adults. Exercise interventions designed to improve reactive stepping behaviour may protect against future falls.

Radiosensitizing effect of electrochemotherapy in a fractionated radiation regimen in radiosensitive murine sarcoma and radioresistant adenocarcinoma tumor model

Radiosensitizing Effect of Electrochemotherapy in a Fractionated Radiation Regimen in Radiosensitive Murine Sarcoma and Radioresistant Adenocarcinoma Tumor Model. Electrochemotherapy can potentiate the radiosensitizing effect of bleomycin, as shown in our previous studies. To bring this treatment closer to use in clinical practice, we evaluated the interaction between electrochemotherapy with bleomycin and single-dose or fractionated radiation in two murine tumor models with different histology and radiosensitivity. Radiosensitive sarcoma SA-1 and radioresistant adenocarcinoma CaNT subcutaneous tumors grown in A/J and CBA mice, respectively, were used. The anti-tumor effect and skin damage around the treated tumors were evaluated after electrochemotherapy with bleomycin alone or combined with single-dose radiation or a fractionated radiation regimen. The anti-tumor effectiveness of electrochemotherapy was more pronounced in SA-1 than CaNT tumors. In both tumor models, the tumor response to radiation was not significantly influenced by bleomycin alone or by electroporation alone. However, electrochemotherapy before the first tumor irradiation potentiated the response to a single-dose or fractionated radiation regimen in both tumors. For the fractionated radiation regimen, normal skin around the treated tumors was damaged fourfold less than for the single-dose regimen. Electrochemotherapy prior to single-dose irradiation induced more damage to the skin around the treated tumors and greater loss of body weight compared to other irradiated groups, whereas electrochemotherapy combined with the fractionated radiation regimen did not. Electrochemotherapy with low doses of bleomycin can also be used safely for radiosensitization of different types of tumors in a fractionated radiation regimen, resulting in a good anti-tumor effect and no major potentiating effect on radiation-induced skin damage. © 2009 by Radiation Research Society.

Coffee for morning hunger pangs. An examination of coffee and caffeine on appetite, gastric emptying, and energy intake

Coffee is one of the most widely consumed beverages in the world and has a number of potential health benefits. Coffee may influence energy expenditure and energy intake, which in turn may affect body weight. However, the influence of coffee and its constituents – particularly caffeine – on appetite remains largely unexplored. The objective of this study was to examine the impact of coffee consumption (with and without caffeine) on appetite sensations, energy intake, gastric emptying, and plasma glucose between breakfast and lunch meals. In a double-blind, randomised crossover design. Participants (n = 12, 9 women; Mean ± SD age and BMI: 26.3 ± 6.3 y and 22.7 ± 2.2 kg•m−2) completed 4 trials: placebo (PLA), decaffeinated coffee (DECAF), caffeine (CAF), and caffeine with decaffeinated coffee (COF). Participants were given a standardised breakfast labelled with 13C-octanoic acid and 225 mL of treatment beverage and a capsule containing either caffeine or placebo. Two hours later, another 225 mL of the treatment beverage and capsule was administered. Four and a half hours after breakfast, participants were given access to an ad libitum meal for determination of energy intake. Between meals, participants provided exhaled breath samples for determination of gastric emptying; venous blood and appetite sensations. Energy intake was not significantly different between the trials (Means ± SD, p > 0.05; Placebo: 2118 ± 663 kJ; Decaf: 2128 ± 739 kJ; Caffeine: 2287 ± 649 kJ; Coffee: 2016 ± 750 kJ); Other than main effects of time (p < 0.05), no significant differences were detected for appetite sensations or plasma glucose between treatments (p > 0.05). Gastric emptying was not significantly different across trials (p > 0.05). No significant effects of decaffeinated coffee, caffeine or their combination were detected. However, the consumption of caffeine and/or coffee for regulation of energy balance over longer periods of time warrant further investigation.

Design and test of a custom instrumented leg press for injury and recovery intervention

There is an increasing desire and emphasis to integrate assessment tools into the everyday training environment of athletes. These tools are intended to fine-tune athlete development, enhance performance and aid in the development of individualised programmes for athletes. The areas of workload monitoring, skill development and injury assessment are expected to benefit from such tools. This paper describes the development of an instrumented leg press and its application to testing leg dominance with a cohort of athletes. The developed instrumented leg press is a 45° reclining sled-type leg press with dual force plates, a displacement sensor and a CCD camera. A custom software client was developed using C#. The software client enabled near-real-time display of forces beneath each limb together with displacement of the quad track roller system and video feedback of the exercise. In recording mode, the collection of athlete particulars is prompted at the start of the exercise, and pre-set thresholds are used subsequently to separate the data into epochs from each exercise repetition. The leg press was evaluated in a controlled study of a cohort of physically active adults who performed a series of leg press exercises. The leg press exercises were undertaken at a set cadence with nominal applied loads of 50%, 100% and 150% of body weight without feedback. A significant asymmetry in loading of the limbs was observed in healthy adults during both the eccentric and concentric phases of the leg press exercise (P < .05). Mean forces were significantly higher beneath the non-dominant limb (4–10%) and during the concentric phase of the muscle action (5%). Given that symmetrical loading is often emphasized during strength training and remains a common goal in sports rehabilitation, these findings highlight the clinical potential for this instrumented leg press system to monitor symmetry in lower-limb loading during progressive strength training and sports rehabilitation protocols.

Canagliflozin : something new for type 2 diabetes, but is it safe and efficacious?

Evaluation of Inagaki N, Kondo K, Yoshinari T, et al. Efficacy and safety of canagliflozin in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, 12-week study. Diabetes Obes Metab 2013. [Epub ahead of print] and Cefalu WT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomized, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-50 INTRODUCTION Inhibition of the sodium-glucose cotransporter 2 (SGLT2), to promote the excretion of glucose, is a new paradigm in the treatment of type 2 diabetes. AREAS COVERED Canagliflozin is an SGLT2 inhibitor, which has been the subject of two recent clinical trials, which are evaluated. EXPERT OPINION Studies with canagliflozin, in subjects with type 2 diabetes, have shown that its use is associated with reductions in HbA1c and body weight and small reductions in blood pressure and triglycerides, while increasing high-density lipoprotein cholesterol and low-density lipoprotein cholesterol. As monotherapy in Japanese subjects, or in comparison with glimepiride in CANTATA-SU (CANagliflozin Treatment and Trial Analysis versus SUlphonylurea), canagliflozin causes a low incidence of hypoglycemia, and this is an advantage over glimepiride. However, one of the disadvantages with canagliflozin, which was also highlighted in CANTATA-SU, is that canagliflozin can cause urogenital infections, which are not observed with other antidiabetic drugs. The Federal Drug Administration has recently approved canagliflozin for use in type 2 diabetes, while directing that a clinical outcome safety trial be undertaken. We are concerned that canagliflozin has been approved for use in type 2 diabetes prior to a clinical outcome study of efficacy being undertaken and without the outcome of further safety testing.