New knowledge on critical osteoclast formation and activation pathways from study of rare genetic diseases of osteoclasts: focus on the RANK/RANKL axis.

Functional, biochemical and genetic studies have over the past decade identified many causative genes in the osteoclast diseases osteopetrosis and Paget's disease of bone. Here, we outline all osteoclast diseases and their genetic associations and then focus specifically on those diseases caused by mutations in the critical osteoclast molecule Receptor Activator of Nuclear factor Kappa B (RANK). Both loss and gain-of-function mutations have been found in humans leading to osteopetrosis and high bone turnover phenotypes, respectively. Osteopetrosis-associated RANK mutations are widely distributed over the RANK molecule. It is likely that some negatively affect ligand binding, whereas others preclude appropriate association of RANK with downstream signalling molecules. In the Paget-like disorders, familial expansile osteolysis, early onset Paget's disease and expansile skeletal hyperphosphatasia, heterozygous insertion mutations are found in the RANK signal peptide. These prevent signal peptide cleavage, trapping the protein translated from the mutated allele in the endoplasmic reticulum. Whole animal studies replicate the hyperactive osteoclast phenotype associated with these disorders and present only with heterozygous expression of the mutation, suggesting an as yet unexplained effect of the mutant allele on normal RANK function. We discuss the cell biological studies and animal models that help us to understand the nature of these different RANK defects and describe how careful dissection of these conditions can help understand critical pathways in osteoclast development and function. We highlight areas that require further study, particularly in light of the pharmacological interest in targeting the RANK signalling pathway to treat diseases caused by excessive bone resorption.

Sedentary Behavior and Body Weight and Composition in Adults: A Systematic Review and Meta-analysis of Prospective Studies.

BACKGROUND: The cumulative effect of too much sedentary behavior may contribute to weight gain and obesity. OBJECTIVE: The aim of this study was to conduct a systematic review and meta-analysis of prospective cohorts and randomized controlled studies to determine the association between sedentary behavior and body weight and obesity in adults. DATA SOURCES AND STUDY SELECTION: Relevant studies were identified from searches of the MEDLINE, Embase, AMED and PubMed databases up to May 2017, and by manual searches of in-text citations. Studies that evaluated the association in adults between sedentary behavior and body weight or obesity, while controlling for physical activity, were included. Overall, 31 publications met the eligibility criteria, including 23 prospective cohort studies with data that could be extracted for a quantitative meta-analysis, and a single randomized controlled trial. RESULTS: There were no significant associations between sedentary behavior and any measure of body weight or obesity, with the exception of waist circumference. For the latter outcome, over a 5-year follow-up period, each 1 h per day increase-from baseline to follow-up-in sedentary behavior was associated with a 0.02 mm [95% confidence interval (CI) 0.01-0.04; p = 0.001) increase in waist circumference. The odds ratio of becoming overweight or obese was 1.33 (95% CI 1.11-1.60; p = 0.001) in the highest compared with lowest categories of sedentary behavior. CONCLUSIONS: Meta-analysis of data from prospective cohort studies showed small, inconsistent and non-significant associations between sedentary behavior and body weight.

Effects of carvedilol on blood pressure in patients with mild to moderate hypertension. A dose response study.

Carvedilol 12.5, 25 and 50 mg was administered once daily for 4 weeks to patients with mild to moderate hypertension. The purpose of the study was to investigate the antihypertensive action of carvedilol when administered once daily and to investigate the pharmacokinetics of carvedilol in patients with mild to moderate hypertension. Measurable decreases in blood pressure (BP) occurred within 1 hour after the first dose. Peak decreases in supine diastolic blood pressure (DBP) were 9.0 +/- 6.8, 15.5 +/- 6.7, 14.7 +/- 10.6 and 22.5 +/- 7.6mm Hg (+/- SD) for the placebo, 12.5, 25 and 50mg carvedilol groups, respectively, and occurred between 3 and 7 hours after the dose. Administration of carvedilol once daily for 4 weeks kept supine DBP below baseline levels for 24 hours. Trough supine DBP after 4 weeks of treatment were 0.6 +/- 6.5, 7.3 +/- 7.9, 8.8 +/- 7.4 and 12.1 +/- 3.8mm Hg (+/- SD) below baseline. Serum levels of carvedilol were proportional to the dose. Peak serum levels were 39 +/- 27, 75 +/- 38 and 161 +/- 131 mu/L for carvedilol 12.5, 25 and 50mg. The kinetics of carvedilol did not change with repeated administration. Carvedilol was well tolerated; 2 patients experienced dizziness associated with postural hypotension after administration of the 50mg dose. Carvedilol 12.5, 25 and 50mg effectively reduced BP for 24 hours when administered once daily.

The costs of rheumatoid arthritis: an international long-term view.

OBJECTIVES: To review the literature on the measurable direct and indirect costs of rheumatoid arthritis (RA) in industrialized countries from a societal perspective and to develop a template for international use. METHODS: A literature search using MEDLINE and other sources identified 153 relevant published articles, press releases, and so forth on the costs of RA and rheumatism from the major Organization for Economic Cooperation and Development (OECD) countries in English and other languages. Sixty-eight publications provide some economic data for analysis and are included in the bibliography. Twelve publications provide sufficiently detailed and robust information for inclusion in country overview tables. The concept of varied costs at different disease stages measured by years since diagnosis and Health Assessment Questionnaire (HAQ) scores is used to guide rational decisions in the allocation of scarce health care resources. RESULTS: Direct costs increase overproportionately during the course of the disease. The most important driver of direct costs is hospitalization, especially in moderate and severe RA. Costs of medication represent a comparatively small proportion of direct costs. Indirect costs caused by work disability can be substantially higher than direct costs, particularly in working-age patients. The total costs of RA to society, and the different cost components such as direct and indirect costs, are broadly comparable in industrialized countries by their order of magnitude. Major confounding factors for international comparison are different study methodologies and patient samples. CONCLUSIONS: The cost template developed in this article can be used to estimate the likely costs of RA to society for industrialized countries. It probably will underestimate indirect costs because of their incomplete coverage in the studies examined. A long-term perspective is needed for chronic diseases such as RA to assess the future effects of early interventions. Treatment in the early stages of RA that effectively reduces long-term disability has the potential to save substantial costs to society.

Indomethacin in the treatment of proximal tubular acidosis.

Treatment of a 7-week-old black male who had proximal tubular acidosis with large doses of bicarbonate did not achieve correction of the acidosis and was accompanied by diarrhea. Addition of indomethacin therapy (2 mg/kg/day) was followed by correction of the acidosis and allowed a decrease in the dosage of alkali.

Anabolic steroids: performance enhancers?

Physicians must discourage steroid use in those who have not yet begun and must treat those patients already on anabolic steroids. Physicians cannot encourage anabolic steroid use by their patients or by themselves. Anabolic steroids are bad for the user.