SummaryThere is increasing evidence that longevity and stress resistance are connected, but the mechanism is unclear. We report that mitochondria are regulated in response to oxidative stress and calorie restriction through a shared mechanism involving peroxisome proliferator-activated receptor-γ γ γ γ co-activator 1α α α α (PGC-1α α α α ). We demonstrate that PGC-1α α α α subcellular distribution is regulated, and its transcriptional activity is promoted through SIRT1-dependent nuclear accumulation. In addition, the duration of PGC-1α α α α activity is regulated by glycogen synthase kinase beta (GSK3β β β β ), which targets PGC-1α α α α for intranuclear proteasomal degradation. This mechanism of regulation permits the rapidity and persistence of PGC-1α α α α activation to be independently controlled. We provide evidence that this pathway of PGC-1α α α α regulation occurs in vivo in mice, both in the oxidative stress response and with calorie restriction. Our data show how mitochondrial function may be adapted in response to external stimuli, and support the concept that such adaptation is critically involved in cellular survival and in lifespan extension by calorie restriction.
Background Immune thrombocytopenia (ITP) is an autoimmune disease characterized by low platelet counts and increased risk of bleeding. In preparation for an upcoming guideline, the ITP Emergency Management Guideline Panel, including clinical experts in hematology, emergency medicine, research methodology, and patient representatives, identified the need for a standardized definition of a critical ITP bleed. The goal of the definition was to distinguish critical bleeds from bleeds that may not require urgent treatment, typically in the context of severe thrombocytopenia. Methods The panel met in person and virtually to achieve consensus on the criteria for critical bleeding events among patients with ITP. Existing ITP bleeding scores and published definitions of major bleeds in patients receiving anticoagulation informed the definition of a critical ITP bleed. The Platelet Immunology Scientific Standardization Committee (SSC) of the International Society on Thrombosis and Haemostasis endorsed the definition. Results A critical ITP bleed was defined as: (a) a bleed in a critical anatomical site including intracranial, intraspinal, intraocular, retroperitoneal, pericardial, or intramuscular with compartment syndrome; or (2) an ongoing bleed that results in hemodynamic instability or respiratory compromise. Conclusion The definition of a critical ITP bleed was developed by the ITP Emergency Management Guideline Panel and endorsed by the Platelet Immunology SSC. It incorporates both anatomic and physiologic risk and pertains to patients with confirmed or suspected ITP who typically have severe thrombocytopenia (platelet count below 20 × 109/L).
Objective: Central diabetes insipidus can occur in the setting of primary or metastatic tumors that disrupt the hypothalamic-pituitary axis. Usual treatment consists of water intake to replace ongoing fluid losses and desmopressin administration aimed at decreasing the urine output to enable maintenance of eunatremia without polyuria. Marked derangement in plasma sodium concentration can occur when high-volume intravenous fluid administration is required during chemotherapy to prevent nephrotoxicity, particularly if obligate fluid intake exceeds the total daily fluid intake necessary to maintain eunatremia. Methods: We developed a protocol for a rapidly titratable low-dose continuous intravenous arginine vasopressin infusion to maintain eunatremia in patients with central diabetes insipidus during periods of obligate fluid intake. Results: We successfully maintained eunatremia in 2 patients with central nervous system lymphoma who underwent several cycles of obligate intravenous fluid administration with 5% dextrose in 0.45% sodium chloride for chemotherapy. Conclusion: Obligate fluid administration can result in dangerous and severe fluctuations in plasma sodium concentration in patients with central diabetes insipidus receiving conventional desmopressin therapy. The use of a rapidly titratable low-dose continuous vasopressin infusion successfully maintained eunatremia in this setting. This protocol can be replicated to prevent the wide and potentially dangerous fluctuations in plasma sodium concentration that can occur in patients with central diabetes insipidus who require high-volume intravenous fluid administration. This protocol has not been assessed among patients with impaired renal function and, thus, may not be generalizable to this population. (AACE Clinical Case Rep. 2018;4:e487-e492)
Hypoglycemia is an acute complication of diabetes management that has been linked to increased morbidity and mortality. In this study, we analyzed whether recurrent hypoglycemia is related to fragmentation of care. The Chicago HealthLNK Data Repository (HDR) consists of merged, de-duplicated and de-identified electronic health records from 6 institutions and employs a hashing and matching algorithm to create a unique ID for each patient (pt) so that pt care can be tracked across different institutions without sharing protected health information. The HDR contains pt demographic and clinical information. Hypoglycemia was identified using a validated algorithm using ICD-9 codes. Fragmentation was defined as an emergency department or inpatient hypoglycemia encounter at >1 institution over the 7-year study period 2006-2012. Of 187,644 patients (pts) with a diabetes diagnosis (250.x), 9,741 (5.2%) pts were identified as having hypoglycemia, representing 18,443 unique encounters, with a mortality rate of 27.7%. 1,035 pts (10.6% of all pts with hypoglycemia) had ≥ 4 hypoglycemic encounters and accounted for 40.3% (n=7,434) of all hypoglycemia encounters. Having any hypoglycemia was associated with race (p<0.001), younger age (p <0.001), and insurance status (p<0.001). Of the 9,741 pts with hypoglycemia, 304 (3.1%) had fragmented care. In 1,035 pts with ≥4 hypoglycemia encounters, 96 pts (9.3%) had fragmented care, and in 1822 pts with 2-3 hypoglycemia encounters, 208 (11.4%) had fragmented care (p=0.074). Hypoglycemic pts with fragmented care relative to those with non-fragmented care had a higher percentage of Medicare (57.9% vs 46% p < 0.001), Medicaid (16.8% vs 9.3% p < 0.001), and self-pay (11.5% vs 4.6% p <0.001). Pts with any hypoglycemia (N=9,741) had greater mortality (2,696 deaths, 27.7%) than those without any hypoglycemia (20,188 deaths, 11.4%, p < 0.00001). In comparing those with ≥ 4 episodes vs 2-3, those with ≥ 4 episodes had fewer complications (39.7% vs. 54.3% p < 0.001) and less mortality (16.0% vs. 30.6% p <0.001). Limitations of this study include use of EHR data and a previously validated algorithm that may misclassify diagnoses/encounters. Overall, hypoglycemia was associated with increased mortality. Pts who had ≥ 4 hypoglycemic encounters represented only 10.6% of patients with hypoglycemic encounters, but accounted for 40.3% of all hypoglycemic encounters, therefore likely contributing to higher healthcare costs. Increased frequency of hypoglycemia encounters was not associated with fragmentation of care. Our findings need to be validated in other large data sets.
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