SUMMARYWhat is known and objective: A novel class of antidiabetic drugs -SGLT2 (Na + /glucose cotransporter type 2) inhibitors -target renal reabsorption of glucose and promote normal glucose levels, independent of insulin production or its action at receptors. We review this new mechanistic approach and the reported efficacy and safety of clinical testing of lead compounds. Methods: Information was obtained from various bibliographic sources, including PubMed and others, on the basic science and the clinical trials of SGLT2 inhibitors. The information was then summarized and evaluated from the perspective of contribution to a fuller understanding of the potential and current status of the lead clinical candidates. Results and discussion: Diabetes mellitus is a spectrum of disorders that involves inadequate insulin function resulting in adverse health sequelae due to acute and chronic hyperglycaemia. Current antidiabetic pharmacotherapy primarily addresses either insulin production at the pancreatic b-cells or insulin action at insulin receptors. These drugs have less than full clinical effectiveness and sometimes therapy-limiting adverse effects. The third major component of glucose balance, namely elimination, has not been a significant therapeutic target to date. SGLT2 inhibitors are a novel approach. What is new and conclusion: A sufficient number of clinical trials have been conducted on sufficiently chemically diverse SGLT2 inhibitors to reasonably conclude that they have efficacy (HbA1c reductions of 0Á4-1%), and thus far, the majority of adverse effects have been mild and transitory or treatable, with the caveat of possible association with increased risk of breast cancer in women and bladder cancer in men. WHAT IS KNOWN AND OBJECTIVEDiabetes mellitus (DM) is a metabolic disorder of inadequate glycaemic control, defined by the American Diabetes Association as a haemoglobin A1C (HgA1c) level ≥6Á5%.

Background and Purpose: Cannabidiol (CBD) is a non-euphorigenic component of Cannabis sativa that prevents the development of paclitaxel-induced mechanical sensitivity in a mouse model of chemotherapy-induced peripheral neuropathy (CIPN).We recently reported that the CBD structural analogue KLS-13019 shows efficacy in an in vitro model of CIPN. The present study was to characterize the behavioural effects of KLS-13019 compared to CBD and morphine in mouse models of CIPN, nociceptive pain and reinforcement.Experimental Approach: Prevention or reversal of paclitaxel-induced mechanical sensitivity were assessed following intraperitoneal or oral administration of CBD, KLS-13019 or morphine. Antinociceptive activity using acetic acid-induced stretching and hot plate assay, anti-reinforcing effects on palatable food or morphine selfadministration and binding to human opioid receptors were also determined.

SUMMARYWhat is known and Objective: The deleterious effect of vitamin D deficiency on bone health has long been known. More recent studies suggest a deleterious effect of low vitamin D (hypovitaminosis D) on general health. And specific studies propose an association between hypovitaminosis D and the aetiology and progression of type 2 diabetes (T2DM). Given a commonly assumed lack of toxicity of vitamin D, routine measurement of plasma vitamin D and supplementation is rapidly becoming accepted general practice. Comment: Authoritative practice guidelines have raised the level of vitamin D that is to be considered minimal for optimum health. This recommendation was based on a wealth of information and definitive evidence for skeletal benefits of vitamin D, but there was a lack of compelling evidence that hypovitaminosis D is causally related to extra-skeletal health outcomes such as diabetes. Hence, vitamin D supplementation for the purpose of achieving a level consistent with good health is evidence based, but measurement and supplementation for the purpose of preventing or treating T2DM is not. What is new and Conclusion: Although the maintenance of adequate vitamin D levels is desirable for all patients, we conclude that routine measurement of vitamin D level in every patient or initiating high-dose supplementation for the purpose of preventing or treating T2DM is not evidence based. WHAT IS KNOWN AND OBJECTIVEThe following scenario is becoming increasingly common. A healthy young adult goes to their family physician for an annual examination. The physical is normal, and all laboratory test results are within normal limits -except for vitamin D, which is 27 ng/mL instead of the recommended minimum of 30 ng/mL.

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed >600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.