Differential Regulation of the Period Genes in Striatal Regions following Cocaine Exposure

Several studies have suggested that disruptions in circadian rhythms contribute to the pathophysiology of multiple psychiatric diseases, including drug addiction. In fact, a number of the genes involved in the regulation of circadian rhythms are also involved in modulating the reward value for drugs of abuse, like cocaine. Thus, we wanted to determine the effects of chronic cocaine on the expression of several circadian genes in the Nucleus Accumbens (NAc) and Caudate Putamen (CP), regions of the brain known to be involved in the behavioral responses to drugs of abuse. Moreover, we wanted to explore the mechanism by which these genes are regulated following cocaine exposure. Here we find that after repeated cocaine exposure, expression of the Period (Per) genes and Neuronal PAS Domain Protein 2 (Npas2) are elevated, in a somewhat regionally selective fashion. Moreover, NPAS2 (but not CLOCK (Circadian Locomotor Output Cycles Kaput)) protein binding at Per gene promoters was enhanced following cocaine treatment. Mice lacking a functional Npas2 gene failed to exhibit any induction of Per gene expression after cocaine, suggesting that NPAS2 is necessary for this cocaine-induced regulation. Examination of Per gene and Npas2 expression over twenty-four hours identified changes in diurnal rhythmicity of these genes following chronic cocaine, which were regionally specific. Taken together, these studies point to selective disruptions in Per gene rhythmicity in striatial regions following chronic cocaine treatment, which are mediated primarily by NPAS2. © 2013 Falcon et al

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

FRAX™ and the assessment of fracture probability in men and women from the UK

SUMMARY: A fracture risk assessment tool (FRAX) is developed based on the use of clinical risk factors with or without bone mineral density tests applied to the UK. INTRODUCTION: The aim of this study was to apply an assessment tool for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density (BMD). The clinical risk factors, identified from previous meta-analyses, comprised body mass index (BMI, as a continuous variable), a prior history of fracture, a parental history of hip fracture, use of oral glucocorticoids, rheumatoid arthritis and other secondary causes of osteoporosis, current smoking, and alcohol intake 3 or more units daily. METHODS: Four models were constructed to compute fracture probabilities based on the epidemiology of fracture in the UK. The models comprised the ten-year probability of hip fracture, with and without femoral neck BMD, and the ten-year probability of a major osteoporotic fracture, with and without BMD. For each model fracture and death hazards were computed as continuous functions. RESULTS: Each clinical risk factor contributed to fracture probability. In the absence of BMD, hip fracture probability in women with a fixed BMI (25 kg/m(2)) ranged from 0.2% at the age of 50 years for women without CRF's to 22% at the age of 80 years with a parental history of hip fracture (approximately 100-fold range). In men, the probabilities were lower, as was the range (0.1 to 11% in the examples above). For a major osteoporotic fracture the probabilities ranged from 3.5% to 31% in women, and from 2.8% to 15% in men in the example above. The presence of one or more risk factors increased probabilities in an incremental manner. The differences in probabilities between men and women were comparable at any given T-score and age, except in the elderly where probabilities were higher in women than in men due to the higher mortality of the latter. CONCLUSION: The models provide a framework which enhances the assessment of fracture risk in both men and women by the integration of clinical risk factors alone and/or in combination with BMD

Evolutionary relationships among barley and <i>Arabidopsis</i> core circadian clock and clock-associated genes

The circadian clock regulates a multitude of plant developmental and metabolic processes. In crop species, it contributes significantly to plant performance and productivity and to the adaptation and geographical range over which crops can be grown. To understand the clock in barley and how it relates to the components in the Arabidopsis thaliana clock, we have performed a systematic analysis of core circadian clock and clock-associated genes in barley, Arabidopsis and another eight species including tomato, potato, a range of monocotyledonous species and the moss, Physcomitrella patens. We have identified orthologues and paralogues of Arabidopsis genes which are conserved in all species, monocot/dicot differences, species-specific differences and variation in gene copy number (e.g. gene duplications among the various species). We propose that the common ancestor of barley and Arabidopsis had two-thirds of the key clock components identified in Arabidopsis prior to the separation of the monocot/dicot groups. After this separation, multiple independent gene duplication events took place in both monocot and dicot ancestors. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00239-015-9665-0) contains supplementary material, which is available to authorized users

Modelling the Cost Effectiveness of Interventions for Osteoporosis: Issues to Consider

Expenditure on treating osteoporotic fractures and on preventative intervention is considerable and is likely to rise in forthcoming years due to the association between fracture risk and age. With funders such as the National Institute for Health and Care Excellence and the Pharmaceutical Benefits Advisory Committee explicitly considering cost-effectiveness analyses within the process of producing guidance, it is imperative that economic models are as robust as possible. This article details issues that need to be considered specifically related to health technology assessments of interventions for osteoporosis, and highlights limitations within the current evidence base. A likely direction of impact on cost effectiveness of addressing the key issues has been included alongside a tentative categorization of the level of these impacts. It is likely that cost-effectiveness ratios presented in previous models that did not address the identified issues were favourable to interventions

Coronary artery to left ventricle fistula

BACKGROUND: Coronary cameral fistulas are an uncommon entity, the etiology of which may be congenital or traumatic. They involve abnormal termination of a coronary artery, usually the right coronary, into a cardiac chamber, usually the right ventricle. CASE PRESENTATION: We describe a case of female patient with severe aortic stenosis and interventricular septal hypertrophy that underwent bioprosthetic aortic valve replacement with concomitant septal myectomy. On subsequent follow-up an abnormal flow traversing the septum into the left ventricle was identified and Doppler interrogation demonstrated a continuous flow, with a predominantly diastolic component, consistent with coronary arterial flow. CONCLUSION: The literature on coronary cameral fistulas is reviewed and the etiology of the diagnostic findings discussed. In our patient, a coronary artery to left ventricle fistula was the most likely explanation secondary to trauma to the septal perforator artery during myectomy. Since the patient was asymptomatic at the time of diagnosis no intervention was recommended and has done well on follow-up

Current and emerging treatment of osteoporosis

The goal of treating a patient with recent fragility fracture should not only be to treat the patient in the acute phase but also to prevent further fractures. Interventions to increase bone mass to preventing further fragility fractures can be classified as non-pharmacological and pharmacological. All European and international guidelines base the need for treatment, not on the diagnosis of osteoporosis (based on the T-score), but on the risk of fracture, which is strongly influenced by the presence of a fragility fracture, especially vertebral or femoral fractures. Before treatment, it is important to make a differential diagnosis between primary and secondary osteoporosis because anti-osteoporotic drug treatment would be useless if the primary illness causing osteoporosis is not treated too. Some studies show that anti-osteoporotic drugs are frequently interrupted within 1 month of their prescription; this happens not so much due to the occurrence of adverse events but mostly because patients have not been sufficiently informed about the importance of taking the drug and because are not receiving personalised treatment. All data confirm that, in older people, vitamin D deficiency is highly prevalent and calcium intake is often not adequate. So, osteoporosis guidelines recommend calcium and vitamin D for all patients in association with antiosteoporotic therapy. We have many drugs for the treatment of patients at high risk of fracture, but we should use drugs based on evidence of their efficacy and safety in older-age subgroups, provided by targeted studies or extrapolated data. In this chapter, we describe efficacy, route of administration, adverse events and recent technical remarks of current antiresorptive and anabolic osteoporosis therapies. Furthermore, we describe emerging therapies, such as Abaloparatide and Romosozumab