Novel mutations in the LRP5 gene in patients with Osteoporosis-pseudoglioma syndrome

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Themed Issue on the Opioid Epidemic: What Have We Learned? Where Do We Go From Here?

No abstract available

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Molecular Targets for Pain Management: More Than Just Mu

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Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

Opioids represent an efficacious therapeutic modality for some, but not all pain states. Singular reliance on opioid therapy for pain management has limitations, and abuse potential has deleterious consequences for patient and society. Our understanding of pain biology has yielded insights and opportunities for alternatives to conventional opioid agonists. The aim is to have efficacious therapies, with acceptable side effect profiles and minimal abuse potential, which is to say an absence of reinforcing activity in the absence of a pain state. The present work provides a nonexclusive overview of current drug targets and potential future directions of research and development. We discuss channel activators and blockers, including sodium channel blockers, potassium channel activators, and calcium channel blockers; glutamate receptor–targeted agents, including N-methyl-D-aspartate, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, and metabotropic receptors. Furthermore, we discuss therapeutics targeted at γ-aminobutyric acid, α2-adrenergic, and opioid receptors. We also considered antagonists of angiotensin 2 and Toll receptors and agonists/antagonists of adenosine, purine receptors, and cannabinoids. Novel targets considered are those focusing on lipid mediators and anti-inflammatory cytokines. Of interest is development of novel targeting strategies, which produce long-term alterations in pain signaling, including viral transfection and toxins. We consider issues in the development of druggable molecules, including preclinical screening. While there are examples of successful translation, mechanistically promising preclinical candidates may unexpectedly fail during clinical trials because the preclinical models may not recapitulate the particular human pain condition being addressed. Molecular target characterization can diminish the disconnect between preclinical and humans' targets, which should assist in developing nonaddictive analgesics.

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Unraveling the Mystery of THC: Cannabinoids and Neuropathic Pain

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Impact of moderate-intensity and vigorous-intensity physical activity on mortality.

Purpose: Physical activity guidelines recommend at least 150 min of moderate-intensity physical activity (MPA), 75 min of vigorous-intensity physical activity (VPA), or combination of MPA and VPA. However, few epidemiological studies have examined whether the general population can derive equal health benefits from MPA or VPA. This study examined the associations of different activity intensities with mortality. Methods: In this prospective cohort study, a total of 83,454 community-dwelling Japanese who answered a questionnaire in 2000-2003 were followed for all-cause mortality through 2012. Subjects were classified into four groups by physical activity guidelines and also by the proportion of VPA to total MVPA, i.e., physically inactive, physically active without any VPA (0% VPA), and active with some VPA (less than 30%) or with more VPA (30% or more). Hazard ratios (HR) of all-cause mortality were calculated with adjustment for potential confounders including PA volume. Results: During 894,718 person-years of follow-up, 8,891 deaths were identified. Compared with physically inactive subjects, the adjusted HRs for all-cause mortality were 0.90 (95% CI: 0.75-1.08), 0.78 (0.68-0.89), and 0.74 (0.64-0.86) among men, and 0.78 (0.62-0.99), 0.66 (0.54-0.79), and 0.64 (0.50-0.81) among women for "0% VPA," "less than 30%," and "30% or more," respectively. In addition, men in the "30% or more" group showed somewhat lower mortality risk than "0% VPA" men (0.81, 0.66-1.01), but women did not. Conclusions: Meeting the guidelines in either pattern of physical activity is important for lowering mortality risk. In addition, compared with subjects who did not engage in any VPA, there was a suggestion that those who participated in VPA may experience lower risks, especially for men. (C) 2017 American College of Sports Medicine

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