Effects of obesity treatments on bone mineral density, bone turnover and fracture risk in adults with overweight or obesity

AbstractBackground:New evidence suggests that obesity is deleterious for bone health, and obesity treatments could potentially exacerbate this.Materials and methods:This narrative review, largely based on recent systematic reviews and meta-analyses, synthesizes the effects on bone of bariatric surgery, weight loss pharmaceuticals and dietary restriction.Results and conclusions:All three obesity treatments result in statistically significant reductions in hip bone mineral density (BMD) and increases in bone turnover relative to pre-treatment values, with the reductions in hip BMD being strongest for bariatric surgery, notably Roux-en Y gastric bypass (RYGB, 8%–11% of pre-surgical values) and weakest for dietary restriction (1%–1.5% of pre-treatment values). Weight loss pharmaceuticals (orlistat or the glucagon-like peptide-1 receptor agonist, liraglutide) induced no greater changes from pre-treatment values than control, despite greater weight loss. There is suggestive evidence that liraglutide may increase bone mineral content (BMC) – but not BMD – and reduce fracture risk, but more research is required to clarify this. All three obesity treatments have variable effects on spine BMD, probably due to greater measurement error at this site in obesity, suggesting that future research in this field could focus on hip rather than spine BMD. Various mechanisms have been proposed for BMD loss with obesity treatments, notably reduced nutritional intake/absorption and insufficient exercise, and these are potential avenues for protection against bone loss. However, a pressing outstanding question is whether this BMD reduction contributes to increased fracture risk, as has been observed after RYGB, and whether any such increase in fracture risk outweighs the risks of staying obese (unlikely).</jats:sec

Comparison of Very Low Energy Diet Products Available in Australia and How to Tailor Them to Optimise Protein Content for Younger and Older Adult Men and Women

Very low energy diets (VLED) are efficacious in inducing rapid weight loss but may not contain adequate macronutrients or micronutrients for individuals with varying nutritional requirements. Adequate protein intake during weight loss appears particularly important to help preserve fat free mass and control appetite, and low energy and carbohydrate content also contributes to appetite control. Therefore, the purpose of this study was to compare the nutritional content (with a focus on protein), nutritional adequacy and cost of all commercially-available VLED brands in Australia. Nutritional content and cost were extracted and compared between brands and to the Recommended Dietary Intake (RDI) or adequate intake (AI) of macronutrients and micronutrients for men and women aged 19–70 years or >70 years. There was wide variability in the nutritional content, nutritional adequacy and cost of VLED brands. Most notably, even brands with the highest daily protein content, based on consuming three products/day (KicStart™ and Optislim®, ~60 g/day), only met estimated protein requirements of the smallest and youngest women for whom a VLED would be indicated. Considering multiple options to optimise protein content, we propose that adding pure powdered protein is the most suitable option because it minimizes additional energy, carbohydrate and cost of VLEDs

Architecture of Pol II(G) and molecular mechanism of transcription regulation by Gdown1.

Tight binding of Gdown1 represses RNA polymerase II (Pol II) function in a manner that is reversed by Mediator, but the structural basis of these processes is unclear. Although Gdown1 is intrinsically disordered, its Pol II interacting domains were localized and shown to occlude transcription factor IIF (TFIIF) and transcription factor IIB (TFIIB) binding by perfect positioning on their Pol II interaction sites. Robust binding of Gdown1 to Pol II is established by cooperative interactions of a strong Pol II binding region and two weaker binding modulatory regions, thus providing a mechanism both for tight Pol II binding and transcription inhibition and for its reversal. In support of a physiological function for Gdown1 in transcription repression, Gdown1 co-localizes with Pol II in transcriptionally silent nuclei of early Drosophila embryos but re-localizes to the cytoplasm during zygotic genome activation. Our study reveals a self-inactivation through Gdown1 binding as a unique mode of repression in Pol II function

Limited diversity associated with duplicated class II MHC-DRB genes in the red squirrel population in the United Kingdom compared with continental Europe

The red squirrel (Sciurus vulgaris) population in the United Kingdom has declined over the last century and is now on the UK endangered species list. This is the result of competition from the eastern grey squirrel (S. carolinensis) which was introduced in the 19th century. However, recent evidence suggests that the rate of population decline is enhanced by squirrelpox disease, caused by a viral infection carried asymptomatically by grey squirrels but to which red squirrels are highly susceptible. Population genetic diversity provides some resilience to rapidly evolving or exotic pathogens. There is currently no data on genetic diversity of extant UK squirrel populations with respect to genes involved in disease resistance. Diversity is highest at loci involved in the immune response including genes clustered within the major histocompatibility complex (MHC). Using the class II DRB locus as a marker for diversity across the MHC region we genotyped 110 red squirrels from locations in the UK and continentalEurope. Twenty four Scvu-DRB alleles at two functional loci; Scvu-DRB1 and Scvu- DRB2, were identified. High levels of diversity were identified at both loci in the continental populations. In contrast, no diversity was observed at the Scvu-DRB2 locus in the mainland UK population while a high level of homozygosity was observed at the Scvu-DRB1 locus. The red squirrel population in the UK appears to lack the extensive MHC diversity associated with continental populations, a feature which may have contributed to their rapid decline

Peptide YY ablation in mice leads to the development of hyperinsulinaemia and obesity

Aims/hypothesis. Obese people exhibit reduced circulating peptide YY (PYY) levels, but it is unclear whether this is a consequence or cause of obesity. We therefore investigated the effect of Pyy ablation on energy homeostasis. Methods. Body composition, i.p. glucose tolerance, food intake and hypothalamic neuropeptide expression were determined in Pyy knock-out and wild-type mice on a normal or high-fat diet. Results. Pyy knock-out significantly increased bodyweight and increased fat mass by 50% in aged females on a normal diet. Male chow-fed Pyy −/− mice were resistant to obesity but became significantly fatter and glucose-intolerant compared with wild-types when fed a high-fat diet. Pyy knock-out animals exhibited significantly elevated fasting or glucose-stimulated serum insulin concentrations vs wild-types, with no increase in basal or fasting-induced food intake. Pyy knock-out decreased or had no effect on neuropeptide Y expression in the arcuate nucleus of the hypothalamus, and significantly increased proopiomelanocortin expression in this region. Male but not female knock-outs exhibited significantly increased growth hormone-releasing hormone expression in the ventromedial hypothalamus and significantly elevated serum IGF-I and testosterone levels. This sex difference in activation of the hypothalamo–pituitary somatotrophic axis by Pyy ablation may contribute to the resistance of chow-fed male knock-outs to late-onset obesity. Conclusions/interpretation. PYY signalling is important in the regulation of energy balance and glucose homeostasis, possibly via regulation of insulin release. Therefore reduced PYY levels may predispose to the development of obesity, particularly with ageing or under conditions of high-fat feeding

Mary's Powers of Imagination

One common response to the knowledge argument is the ability hypothesis. Proponents of the ability hypothesis accept that Mary learns what seeing red is like when she exits her black-and-white room, but they deny that the kind of knowledge she gains is propositional in nature. Rather, she acquires a cluster of abilities that she previously lacked, in particular, the abilities to recognize, remember, and imagine the color red. For proponents of the ability hypothesis, knowing what an experience is like simply consists in the possession of these abilities. Criticisms of the ability hypothesis tend to focus on this last claim. Such critics tend to accept that Mary gains these abilities when she leaves the room, but they deny that such abilities constitute knowledge of what an experience is like. To my mind, however, this critical strategy grants too much. Focusing specifically on imaginative ability, I argue that Mary does not gain this ability when she leaves the room for she already had the ability to imagine red while she was inside it. Moreover, despite what some have thought, the ability hypothesis cannot be easily rescued by recasting it in terms of a more restrictive imaginative ability. My purpose here is not to take sides in the debate about physicalism, i.e., my criticism of the ability hypothesis is not offered in an attempt to defend the anti-physicalist conclusion of the knowledge argument. Rather, my purpose is to redeem the imagination from the misleading picture of it that discussion of the knowledge argument has fostered

Enhanced transport of plant-produced rabies single chain antibody-RVG peptide fusion protein across an in cellulo blood-brain barrier device

The biomedical applications of antibody engineering are developing rapidly and have been expanded to plant expression platforms. In this study, we have generated a novel antibody molecule in planta for targeted delivery across the blood–brain barrier (BBB). Rabies virus (RABV) is a neurotropic virus for which there is no effective treatment after entry into the central nervous system. This study investigated the use of a RABV glycoprotein peptide sequence to assist delivery of a rabies neutralizing single-chain antibody (ScFv) across an in cellulo model of human BBB. The 29 amino acid rabies virus peptide (RVG) recognizes the nicotinic acetylcholine receptor (nAchR) at neuromuscular junctions and the BBB. ScFv and ScFv-RVG fusion proteins were produced in Nicotiana benthamiana by transient expression. Both molecules were successfully expressed and purified, but the ScFv expression level was significantly higher than that of ScFv-RVG fusion. Both ScFv and ScFv-RVG fusion molecules had potent neutralization activity against RABVin cellulo. The ScFv-RVG fusion demonstrated increased binding to nAchR and entry into neuronal cells, compared to ScFv alone. Additionally, a human brain endothelial cell line BBB model was used to demonstrate that plant-produced ScFv-RVGP fusion could translocate across the cells. This study indicates that the plant-produced ScFv-RVGP fusion protein was able to cross the in celluloBBB and neutralize RABV

Grounding, Analysis, and Russellian Monism

Few these days dispute that the knowledge argument demonstrates an epistemic gap between the physical facts and the facts about experience. It is much more contentious whether that epistemic gap can be used to demonstrate a metaphysical gap of a kind that is inconsistent with physicalism. In this paper I will explore two attempts to block the inference from an epistemic gap to a metaphysical gap – the first from the phenomenal concept strategy, the second from Russellian monism – and suggest how the proponent of the knowledge argument might respond to each of these challenges. In doing so, I will draw on recent discussions of grounding and essence in the metaphysics literature