A Chemogenetic Approach for the Optical Monitoring of Voltage in Neurons

Optical monitoring of neuronal voltage using fluorescent indicators is a powerful approach for the interrogation of the cellular and molecular logic of the nervous system. Herein, a semisynthetic tethered voltage indicator (STeVI1) based upon nile red is described that displays voltage sensitivity when genetically targeted to neuronal membranes. This environmentally sensitive probe allows for wash-free imaging and faithfully detects supra- and sub-threshold activity in neurons

Capture the fracture: a best practice framework and global campaign to break the fragility fracture cycle

Summary The International Osteoporosis Foundation (IOF) Capture the Fracture Campaign aims to support implementation of Fracture Liaison Services (FLS) throughout the world. Introduction FLS have been shown to close the ubiquitous secondary fracture prevention care gap, ensuring that fragility fracture sufferers receive appropriate assessment and intervention to reduce future fracture risk. Methods Capture the Fracture has developed internationally endorsed standards for best practice, will facilitate change at the national level to drive adoption of FLS and increase awareness of the challenges and opportunities presented by secondary fracture prevention to key stakeholders. The Best Practice Framework (BPF) sets an international benchmark for FLS, which defines essential and aspirational elements of service delivery. Results The BPF has been reviewed by leading experts from many countries and subject to beta-testing to ensure that it is internationally relevant and fit-for-purpose. The BPF will also serve as a measurement tool for IOF to award ‘Capture the Fracture Best Practice Recognition’ to celebrate successful FLS worldwide and drive service development in areas of unmet need. The Capture the Fracture website will provide a suite of resources related to FLS and secondary fracture prevention, which will be updated as new materials become available. A mentoring programme will enable those in the early stages of development of FLS to learn from colleagues elsewhere that have achieved Best Practice Recognition. A grant programme is in development to aid clinical systems which require financial assistance to establish FLS in their localities. Conclusion Nearly half a billion people will reach retirement age during the next 20 years. IOF has developed Capture the Fracture because this is the single most important thing that can be done to directly improve patient care, of both women and men, and reduce the spiralling fracture-related care costs worldwide.</p

Osteopenia: A Diagnostic and Therapeutic Challenge

We discussed whether we are able to select a subgroup of patients with osteopenia having a high fracture risk, in which anti-osteoporotic drug treatment can be advocated. We concluded that in individuals in whom, based on clinical risk factors, a dual-energy x-ray absorptiometry (DXA) was performed in which osteopenia was diagnosed, anti-osteoporotic treatment should be prescribed in those patients with prevalent vertebral fractures, and in patients chronically using glucocorticoids, in a dosage of 7.5 mg per day or more. Although recent developments with regard to high-resolution imaging techniques (eg, peripheral quantitative computed tomography) seem to be promising, until now they do not provide substantial more reliable information than DXA in the prediction of fractures. We think that more data are urgently needed, since safe and effective drugs are available, but there is uncertainty to which patients with osteopenia these drugs should be prescribed

The relative efficacy of nine osteoporosis medications for reducing the rate of fractures in post-menopausal women

<p>Abstract</p> <p>Background</p> <p>In the absence of head-to-head trials, indirect comparisons of randomized placebo-controlled trials may provide a viable option to assess relative efficacy. The purpose was to estimate the relative efficacy of reduction of fractures in post-menopausal women, and to assess robustness of the results.</p> <p>Methods</p> <p>A systematic literature review of multiple databases identified randomized placebo-controlled trials with nine drugs for post-menopausal women. Odds ratio and 95% credibility intervals for the rates of hip, non-vertebral, vertebral, and wrist fractures for each drug and between drugs were derived using a Bayesian approach. A drug was ranked as the most efficacious if it had the highest posterior odds ratio, or had the highest effect size.</p> <p>Results</p> <p>30 studies including 59,209 patients reported fracture rates for nine drugs: alendronate (6 studies), denosumab (1 study), etidronate (8 studies), ibandronate (4 studies), raloxifene (1 study), risedronate (7 studies), strontium (2 study), teriparatide (1 study), and zoledronic acid (1 study). The drugs with the highest probability of reducing non-vertebral fractures was etidronate and teriparatide while the drugs with the highest probability of reducing vertebral, hip or wrist fractures were teriparatide, zoledronic acid and denosumab. The drugs with the largest effect size for vertebral fractures were zoledronic acid, teriparatide and denosumab, while the drugs with the highest effect size for non-vertebral, hip or wrist fractures were alendronate or risedronate. Estimates were consistent between Bayesian and classical approaches.</p> <p>Conclusion</p> <p>Teriparatide, zoledronic acid and denosumab have the highest probabilities of being most efficacious for non-vertebral and vertebral fractures, and having the greatest effect sizes. The estimates from indirect comparisons were robust to differences in methodology.</p

Glycerol Hypersensitivity in a Drosophila Model for Glycerol Kinase Deficiency Is Affected by Mutations in Eye Pigmentation Genes

Glycerol kinase plays a critical role in metabolism by converting glycerol to glycerol 3-phosphate in an ATP dependent reaction. In humans, glycerol kinase deficiency results in a wide range of phenotypic variability; patients can have severe metabolic and CNS abnormalities, while others possess hyperglycerolemia and glyceroluria with no other apparent phenotype. In an effort to help understand the pathogenic mechanisms underlying the phenotypic variation, we have created a Drosophila model for glycerol kinase deficiency by RNAi targeting of dGyk (CG18374) and dGK (CG7995). As expected, RNAi flies have reduced glycerol kinase RNA expression, reduced phosphorylation activity and elevated glycerol levels. Further investigation revealed these flies to be hypersensitive to fly food supplemented with glycerol. Due to the hygroscopic nature of glycerol, we predict glycerol hypersensitivity is a result of greater susceptibility to desiccation, suggesting glycerol kinase to play an important role in desiccation resistance in insects. To evaluate a role for genetic modifier loci in determining severity of the glycerol hypersensitivity observed in knockdown flies, we performed a preliminary screen of lethal transposon insertion mutant flies using a glycerol hypersensitive survivorship assay. We demonstrate that this type of screen can identify both enhancer and suppressor genetic loci of glycerol hypersensitivity. Furthermore, we found that the glycerol hypersensitivity phenotype can be enhanced or suppressed by null mutations in eye pigmentation genes. Taken together, our data suggest proteins encoded by eye pigmentation genes play an important role in desiccation resistance and that eye pigmentation genes are strong modifiers of the glycerol hypersensitive phenotype identified in our Drosophila model for glycerol kinase deficiency

Evidence-based guidelines for the pharmacological treatment of postmenopausal osteoporosis: a consensus document by the Belgian Bone Club

Several drugs are available for the management of postmenopausal osteoporosis. This may, in daily practice, confuse the clinician. This manuscript offers an evidence-based update of previous treatment guidelines, with a critical assessment of the currently available efficacy data on all new chemical entities which were granted a marketing authorization. Osteoporosis is widely recognized as a major public health concern. The availability of new therapeutic agents makes clinical decision-making in osteoporosis more complex. Nation-specific guidelines are needed to take into consideration the specificities of each and every health care environment. The present manuscript is the result of a National Consensus, based on a systematic review and a critical appraisal of the currently available literature. It offers an evidence-based update of previous treatment guidelines, with the aim of providing clinicians with an unbiased assessment of osteoporosis treatment effect

Lipid droplets: a classic organelle with new outfits

Lipid droplets are depots of neutral lipids that exist virtually in any kind of cell. Recent studies have revealed that the lipid droplet is not a mere lipid blob, but a major contributor not only to lipid homeostasis but also to diverse cellular functions. Because of the unique structure as well as the functional importance in relation to obesity, steatosis, and other prevailing diseases, the lipid droplet is now reborn as a brand new organelle, attracting interests from researchers of many disciplines

Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder

Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes.National Institute of Health/[R01MH075007]/NIH/Estados UnidosNational Institute of Health/[R01MH095454]/NIH/Estados UnidosNational Institute of Health/[P30NS062691]/NIH/Estados UnidosNational Institute of Health/[T32MH073526]/NIH/Estados UnidosNational Institute of Health/[K23MH074644-01]/NIH/Estados UnidosNational Institute of Health/[K08MH086786]/NIH/Estados UnidosUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM