Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple co-morbidities1. Here, we investigate a role for senescent cells in age-related bone loss by multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC “suicide” transgene encoding an inducible caspase 8 expressed specifically in senescent cells2–4) or pharmacological (i.e., “senolytic” compounds5,6) means to eliminate senescent cells. We also inhibited the production of the pro-inflammatory secretome of senescent cells using a JAK inhibitor (JAKi)3,7. In old (20–22-months) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2–4 months resulted in higher bone mass and strength and better bone microarchitecture compared to vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular bone) or higher (cortical bone) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent cell-conditioned medium impaired osteoblast mineralization and enhanced osteoclast progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. As eliminating senescent cells and/or inhibiting their pro-inflammatory secretome also improves cardiovascular function4, enhances insulin sensitivity3, and reduces frailty7, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis but also for multiple age-related co-morbidities.
BackgroundAcinetobacter species have become increasingly common in the intensive care units (ICU) over the past two decades, causing serious infections. At the American University of Beirut Medical Center, the incidence of multi-drug resistant Acinetobacter baumannii (MDR-Ab) infections in the ICU increased sharply in 2007 by around 120%, and these infections have continued to cause a serious problem to this day.MethodsWe conducted a seven-year prospective cohort study between 2007 and 2014 in the ICU. Early in the epidemic, a case-control study was performed that included MDR-Ab cases diagnosed between 2007 and 2008 and uninfected controls admitted to the ICU during the same time.ResultsThe total number of patients with MDR-Ab infections diagnosed between 2007 and 2014 was 128. There were also 99 patients with MDR-Ab colonization without evidence of active infection between 2011 and 2014. The incidence of MDR-Ab transmission was 315.4 cases/1000 ICU patient-days. The majority of infections were considered hospital-acquired (84%) and most consisted of respiratory infections (53.1%). The mortality rate of patients with MDR-Ab ranged from 52% to 66%.ConclusionMDR-Ab infections mostly consisted of ventilator-associated pneumonia and were associated with a very high mortality rate. Infection control measures should be reinforced to control the transmission of these organisms in the ICU.
CCSs treated with GHT gain height compared with the untreated controls. GHT may improve lipid profiles and quality of life and does not appear to increase the risk of diabetes or the development of secondary tumors, although close monitoring for such complications remains warranted due to uncertainty in the current evidence.
Context Reduced bone material strength index (BMSi) and increased cortical porosity (CtPo) have emerged as potentially contributing to fracture risk in type 2 diabetes mellitus (T2DM) patients. Objective Determine whether BMSi or CtPo are related to other diabetic complications. Design Cross-sectional observational study. Setting Subjects recruited from a random sample of southeast MN residents. Participants 171 T2DM patients (mean age, 68.8 years) and 108 age-matched non-diabetic controls (mean age, 67.3 years). Main Measures BMSi measured using microindentation, skin advanced glycation end-products (AGEs) measured using autofluorescence, high-resolution peripheral quantitative computed tomography at the distal radius and tibia, assessment of diabetic microvascular complications including urine microalbuminuria, retinopathy, neuropathy, and vascular disease (ankle brachial index, and transcutaneous oxygen tension [TcPO2]). All analyses were adjusted for age, sex, and body mass index. Results Skin AGEs were negatively correlated with BMSi in both T2DM (r= -0.30, p < 0.001) and control (r= -0.23, p = 0.020) subjects. In relating diabetic complications to CtPo, we found that T2DM patients with clinically significant peripheral vascular disease (TcPO2 ≤ 40 mm Hg) had higher (+21.0%, p = 0.031) CtPo at the distal tibia as compared to controls; in these subjects, CtPo was negatively correlated with TcPO2 at both the distal tibia (r = -0.39, p = 0.041) and radius (r = -0.41, p = 0.029). Conclusions Our findings demonstrate that bone material properties are related to AGE accumulation regardless of diabetes status, while CtPo in T2DM patients is linked to TcPO2, a measure of microvascular blood flow.
Chronic hypoparathyroidism is characterized by low serum calcium, increased serum phosphorus, and inappropriately low or decreased serum parathyroid hormone. This rare disorder is associated with a variety of complications. The prevalence, incidence, mortality, financial burden, and epidemiology of complications of this disorder are not well understood. This narrative review summarizes current information on the epidemiology and complications of chronic hypoparathyroidism. The reported prevalence of chronic hypoparathyroidism ranges from 6.4–37/100,000, and the incidence is reported to be 0.8–2.3/100,000/year. Mortality is not increased in studies from Denmark or South Korea but was increased in studies from Scotland and Sweden. The financial burden of this disorder is substantial because of increased health care resource utilization in two studies but not well quantitated. Recognized complications include hypercalciuria, nephrocalcinosis, kidney stones, and chronic kidney disease; low bone turnover and possibly upper extremity fractures; cardiac and vascular calcifications; basal ganglia calcifications, cataracts, infections, neuropsychiatric complications, and difficulties with pregnancy. This review concludes that chronic hypoparathyroidism is a rare disorder associated with significant morbidity that may not increase overall mortality but is associated with a substantial financial burden. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population.
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