Pannexin‐1 and P2X7‐Receptor Are Required for Apoptotic Osteocytes in Fatigued Bone to Trigger RANKL Production in Neighboring Bystander Osteocytes

Osteocyte apoptosis is required to induce intracortical bone remodeling after microdamage in animal models, but how apoptotic osteocytes signal neighboring “bystander” cells to initiate the remodeling process is unknown. Apoptosis has been shown to open pannexin‐1 (Panx1) channels to release adenosine diphosphate (ATP) as a “find‐me” signal for phagocytic cells. To address whether apoptotic osteocytes use this signaling mechanism, we adapted the rat ulnar fatigue‐loading model to reproducibly introduce microdamage into mouse cortical bone and measured subsequent changes in osteocyte apoptosis, receptor activator of NF‐κB ligand (RANKL) expression and osteoclastic bone resorption in wild‐type (WT; C57Bl/6) mice and in mice genetically deficient in Panx1 (Panx1KO). Mouse ulnar loading produced linear microcracks comparable in number and location to the rat model. WT mice showed increased osteocyte apoptosis and RANKL expression at microdamage sites at 3 days after loading and increased intracortical remodeling and endocortical tunneling at day 14. With fatigue, Panx1KO mice exhibited levels of microdamage and osteocyte apoptosis identical to WT mice. However, they did not upregulate RANKL in bystander osteocytes or initiate resorption. Panx1 interacts with P2X₇R in ATP release; thus, we examined P2X₇R‐deficient mice and WT mice treated with P2X₇R antagonist Brilliant Blue G (BBG) to test the possible role of ATP as a find‐me signal. P2X₇RKO mice failed to upregulate RANKL in osteocytes or induce resorption despite normally elevated osteocyte apoptosis after fatigue loading. Similarly, treatment of fatigued C57Bl/6 mice with BBG mimicked behavior of both Panx1KO and P2X₇RKO mice; BBG had no effect on osteocyte apoptosis in fatigued bone but completely prevented increases in bystander osteocyte RANKL expression and attenuated activation of resorption by more than 50%. These results indicate that activation of Panx1 and P2X₇R are required for apoptotic osteocytes in fatigued bone to trigger RANKL production in neighboring bystander osteocytes and implicate ATP as an essential signal mediating this process. © 2016 American Society for Bone and Mineral Research.     

Cardiac Disease Burden and Risk of Mortality in Hospitalized Muscular Dystrophy Patients

As treatments of the extra-cardiac complications of muscular dystrophy (MD) improve, males with MD are more likely to develop cardiac disease. The impact of cardiomyopathy or heart failure (HF) and ventricular tachycardia (VT) on hospitalizations and in hospital mortality are not known. We performed an analysis of inpatient admission data for patients with MD using the Pediatric Health Information System database. We selected males who were 6 years or older with diagnosis codes of MD and cardiac disease including cardiomyopathy/HF and VT between 2003 and 2013. We created a logistic regression model to identify predictors of subsequent cardiac arrest or death in MD patients. We also compared hospital charges, lengths of stay and ages among MD patients with or without cardiac disease. Our logistic regression model showed that VT (OR 5.41, 95 % CI 2.83, 10.34) and cardiomyopathy/HF (OR 1.79, 95 % CI 1.05, 3.04) were risk factors for cardiac arrest or death. Of the 84 cardiac arrests or deaths in 3363 MD patients, 49 (58 %) were related to cardiac disease. Nineteen (39 %) of these events occurred in MD patients with VT. The mean hospital charges and the mean length of stay were greater and longer in MD patients with VT compared to those without cardiac disease and those with only cardiomyopathy/HF (p < 0.05). Cardiac disease is a significant burden in hospitalized MD patients. Our results suggest that VT and cardiomyopathy/HF are associated with an increased risk of cardiac arrest or death in MD patients.     

Identifying predictors of resilience at inpatient and 3-month post-spinal cord injury

Objectives

To identify (1) changes in psychosocial factors, (2) relationships between psychosocial factors, and (3) significant predictors of resilience in adults with spinal cord injury (SCI) during inpatient rehabilitation and at 3-month post-discharge.

Design

Cross sectional with convenience sample based on inclusion/exclusion criteria.

Setting

Inpatient rehabilitation hospital and community-based follow-up.

Participants

Individuals with a SCI.

Interventions

Not applicable.

Outcome measures

Demographic, resilience, self-efficacy for managing a chronic health issue, depression, social roles/activity limitations, and pain.

Results

The final sample consisted of 44 respondents (16 women and 28 men). Results of repeated measure analyses of variance indicated no significant changes in variables between inpatient and 3-month follow-up. Bivariate correlations revealed associations between resilience and self-efficacy at inpatient (r = 0.54, P < 0.001), and resilience and depression (r = −0.69, P < 0.001) and self-efficacy (r = 0.67, P < 0.001) at 3-month follow-up. Hierarchical regression analyses a significant model predicting resilience at inpatient stay (R = 0.61; adjusted R² = 0.24, P = 0.023), and at 3-month follow-up (R = 0.83; adjusted R² = 0.49, P = 0.022). Self-efficacy was the strongest predictor at inpatient stay (β = 0.46, P  =  0.006) and depression was strongest at 3-month follow-up (β = −0.80, P = 0.007).

Conclusion

Results suggest that although resilience appears to be stable from inpatient to 3-month follow-up, different factors are stronger predictors of resilience across time. Based on current results, an assessment of self-efficacy during inpatient rehabilitation and an identification of depression at 3-month follow-up may be important factors to help identify those at risk of health issues overtime.     

Fatal Taxus baccata ingestion with perimortem serum taxine B quantification

Introduction: Common yew (Taxus baccata) is a common decorative evergreen shrub with potentially fatal toxicity hallmarked by seizure, arrhythmia and cardiovascular collapse if ingested. Taxine B has been identified as one of the most cardiotoxic taxine alkaloids in Taxus spp, and another alkaloid, 3,5-dimethoxyphenol (3,5-DMP), is used as a marker of ingestion. We present a fatal case of ingestion of yew with perimortem serum and gastric taxine B, and 3,5-DMP concentrations.

Case presentation: A 22-year-old woman was brought to the emergency department (ED) from a nearby botanical garden after she was found apneic and pulseless after a witnessed generalized tonic clonic seizure. The patient was found to have a wide complex rhythm with persistent cardiovascular collapse and expired despite maximal supportive care in the ED. A baggie of plant material was found on the patient, identified as Taxus baccata. Perimortem serum and gastric samples were analyzed to quantify serum and gastric taxine B and 3,5-DMP concentrations.

Results: Perimortem serum showed a 3,5-DMP concentration of 86.9 ng/mL, and taxine B of 80.9 ug/mL.

Conclusion: We report a perimortem serum and gastric taxine B and 3,5-DMP concentrations in a fatal case of T. baccata toxicity.