Bisphosphonate Use Is Protective of Radiographic Knee Osteoarthritis Progression Among those With Low Disease Severity and Being Non-Overweight: Data From the Osteoarthritis Initiative

Antiresorptive medications have been explored for treating knee osteoarthritis (OA); however, little data exist on the effects of today's more potent nitrogen-containing oral bisphosphonates on radiographic disease-progression in patients with varying disease-severity, especially those who are not overweight. The primary objective of this cohort study was to determine if the use of bisphosphonates is protective against 2-year radiographic-progression of knee OA in Osteoarthritis Initiative (OAI) participants, stratified by baseline radiographic disease status. Secondary objectives were to examine effects in non-overweight participants (body mass index [BMI] < 25 kg/m²) and cumulative bisphosphonate exposure effects. We identified female OAI participants aged ≥50 years and excluded those missing baseline radiograph readings, bisphosphonate use information, or all clinical questionnaire information at baseline. Participants reporting bisphosphonate use (69% alendronate) were propensity-matched 1:1 to non–bisphosphonate users and followed until first radiographic knee OA progression (1-unit increase in Kellgren and Lawrence [KL] grade) or data were censored (first missed visit or end of 2-year follow-up). Discrete-time logistic regression models estimated hazard ratios (HRs) between bisphosphonate users versus nonusers, with an interaction term for baseline KL grade (KL <2 or KL ≥2). We identified 1977 eligible women (n = 346 bisphosphonate users). Propensity-matched results indicated that bisphosphonate users with KL grade <2 were protected against progression (HR_KL<2 0.53; 95% CI, 0.35 to 0.79), while bisphosphonate use was not associated with radiographic progression in those with KL grade ≥2 (HR_KL≥2 1.06; 95% CI, 0.83 to 1.35). When restricting analyses to those with BMI <25 kg/m², effects were strengthened (HR_KL<2 0.49 [95% CI, 0.26 to 0.92]; HR_KL≥2 0.69 [95% CI, 0.33 to 1.26]). Duration of bisphosphonate use had no effect on progression, though sample size was limited. Bisphosphonate therapy may be protective against radiographic knee OA progression in early-stage patients, particularly those who are non-overweight, but less so for those with more advanced disease or more weight-bearing joint stress. © 2020 American Society for Bone and Mineral Research (ASBMR).     

Pharmacokinetic,pharmacodynamic and clinical evaluation of saxagliptin in type 2 diabetes

Introduction: Dipeptide peptidase-4 (DPP-4) inhibitors such as saxagliptin are established and efficacious oral therapies in the management of type 2 diabetes. These agents have the potential to confer significant benefits in glycemic control without the risk of weight gain and hypoglycemia, which may be associated with other medications used to treat type 2 diabetes.

Areas covered: This review examines the pharmacokinetics, efficacy and tolerability of saxagliptin for the management of type 2 diabetes.

Expert opinion: Saxagliptin is routinely used in the management of type 2 diabetes as monotherapy, and in combination with other oral agents and insulin. Robust clinical trials have shown consistent improvements in glycated hemoglobin, fasting and postprandial glucose levels, with few adverse effects. The agent is well tolerated with low rates of hypoglycemia in the absence of insulin or sulphonylurea therapy.     

Evaluation of arterial oxygenation during anaesthesia

Canadian Journal of Anesthesia/Journal canadien d'anesthésie - The clinical or physiological signs of hypoxaemia have limited value during anaesthesia. In the absence of surgical bleeding,...     

Loss of ATE1-mediated arginylation leads to impaired platelet myosin phosphorylation,clot retraction,and in vivo thrombosis formation

Protein arginylation by arginyl–transfer RNA protein transferase (ATE1) is emerging as a regulator protein function that is reminiscent of phosphorylation. For example, arginylation of β-actin has been found to regulate lamellipodial formation at the leading edge in fibroblasts. This finding suggests that similar functions of β-actin in other cell types may also require arginylation. Here, we have tested the hypothesis that ATE1 regulates the cytoskeletal dynamics essential for in vivo platelet adhesion and thrombus formation. To test this hypothesis, we generated conditional knockout mice specifically lacking ATE1 in their platelets and in their megakaryocytes and analyzed the role of arginylation during platelet activation. Surprisingly, rather than finding an impairment of the actin cytoskeleton structure and its rearrangement during platelet activation, we observed that the platelet-specific ATE1 knockout led to enhanced clot retraction and in vivo thrombus formation. This effect might be regulated by myosin II contractility since it was accompanied by enhanced phosphorylation of the myosin regulatory light chain on Ser19, which is an event that activates myosin in vivo. Furthermore, ATE1 and myosin co-immunoprecipitate from platelet lysates. This finding suggests that these proteins directly interact within platelets. These results provide the first evidence that arginylation is involved in phosphorylation-dependent protein regulation, and that arginylation affects myosin function in platelets during clot retraction.     

How Does Preeclampsia Predispose to Future Cardiovascular Disease?

Pulmonary hypertension (PH) is a progressive lung disease characterized by elevated pressure in the lung vasculature, resulting in right-sided heart failure and premature death. The pathogenesis of PH is complex and multifactorial, involving a dysregulated autonomic nervous system and immune response. Inflammatory mechanisms have been linked to the development and progression of PH; however, these are usually restricted to systemic and/or local lung tissue. Inflammation within the CNS, often referred to as neuroinflammation involves activation of the microglia, the innate immune cells that are found specifically in the brain and spinal cord. Microglial activation results in the release of several cytokines and chemokines that trigger neuroinflammation, and has been implicated in the pathogenesis of several disease conditions such as Alzheimer’s, Parkinson’s, hypertension, atherosclerosis, and metabolic disorders. In this review, we introduce the concept of neuroinflammation in the context of PH, and discuss possible strategies that could be developed for PH therapy based on this concept.     

MAT2A Inhibition Blocks the Growth of MTAP-Deleted Cancer Cells by Reducing PRMT5-Dependent mRNA Splicing and Inducing DNA Damage

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