Chronic Insufficient Sleep Has a Limited Impact on Circadian Rhythmicity of Subjective Hunger and Awakening Fasted Metabolic Hormones

Weight gain and obesity have reached epidemic proportions in modern society. Insufficient sleep—which is also prevalent in modern society—and eating at inappropriate circadian times have been identified as risk factors for weight gain, yet the impact of chronic insufficient sleep on the circadian timing of subjective hunger and physiologic metabolic outcomes are not well understood. We investigated how chronic insufficient sleep impacts the circadian timing of subjective hunger and fasting metabolic hormones in a 32-day in-laboratory randomized single-blind control study, with healthy younger participants (range, 20–34 years) randomized to either Control (1:2 sleep:wake ratio, 6.67 h sleep:13.33 h wake, n = 7, equivalent to 8 h of sleep per 24 h) or chronic sleep restriction (CSR, 1:3.3 sleep:wake ratio, 4.67 h sleep:15.33 h wake, n = 8, equivalent to 5.6 h of sleep per 24 h) conditions. Participants lived on a “20 h day” designed to distribute all behaviors and food intake equally across all phases of the circadian cycle over every six consecutive 20 h protocol days. During each 20 h day, participants were provided a nutritionist-designed, isocaloric diet consisting of 45–50% carbohydrate, 30–35% fat, and 15–20% protein adjusted for sex, weight, and age. Subjective non-numeric ratings of hunger were recorded before and after meals and fasting blood samples were taken within 5 min of awakening. Subjective levels of hunger and fasting concentrations of leptin, ghrelin, insulin, glucose, adiponectin, and cortisol all demonstrated circadian patterns; there were no differences, however, between CSR and Control conditions in subjective hunger ratings or any fasting hormone concentrations. These findings suggest that chronic insufficient sleep may have a limited role in altering the robust circadian profile of subjective hunger and fasted metabolic hormones.Clinical Trial RegistrationThe study was registered as clinical trial #NCT01581125

Chronic Insufficient Sleep Has a Limited Impact on Circadian Rhythmicity of Subjective Hunger and Awakening Fasted Metabolic Hormones

Weight gain and obesity have reached epidemic proportions in modern society. Insufficient sleep—which is also prevalent in modern society—and eating at inappropriate circadian times have been identified as risk factors for weight gain, yet the impact of chronic insufficient sleep on the circadian timing of subjective hunger and physiologic metabolic outcomes are not well understood. We investigated how chronic insufficient sleep impacts the circadian timing of subjective hunger and fasting metabolic hormones in a 32-day in-laboratory randomized single-blind control study, with healthy younger participants (range, 20–34 years) randomized to either Control (1:2 sleep:wake ratio, 6.67 h sleep:13.33 h wake, n = 7, equivalent to 8 h of sleep per 24 h) or chronic sleep restriction (CSR, 1:3.3 sleep:wake ratio, 4.67 h sleep:15.33 h wake, n = 8, equivalent to 5.6 h of sleep per 24 h) conditions. Participants lived on a “20 h day” designed to distribute all behaviors and food intake equally across all phases of the circadian cycle over every six consecutive 20 h protocol days. During each 20 h day, participants were provided a nutritionist-designed, isocaloric diet consisting of 45–50% carbohydrate, 30–35% fat, and 15–20% protein adjusted for sex, weight, and age. Subjective non-numeric ratings of hunger were recorded before and after meals and fasting blood samples were taken within 5 min of awakening. Subjective levels of hunger and fasting concentrations of leptin, ghrelin, insulin, glucose, adiponectin, and cortisol all demonstrated circadian patterns; there were no differences, however, between CSR and Control conditions in subjective hunger ratings or any fasting hormone concentrations. These findings suggest that chronic insufficient sleep may have a limited role in altering the robust circadian profile of subjective hunger and fasted metabolic hormones. Clinical Trial Registration The study was registered as clinical trial #NCT01581125

The Incidence, Pattern, and Prognostic Value of Left Ventricular Myocardial Scar by Late Gadolinium Enhancement in Patients With Atrial Fibrillation

Objectives We aimed to identify the frequency, pattern, and prognostic significance of left ventricular (LV) late gadolinium enhancement (LGE) in patients with atrial fibrillation (AF). Background There are limited data on the presence, pattern, and prognostic significance of LV myocardial fibrosis in patients with AF. Late gadolinium enhancement during cardiac magnetic resonance (CMR) is a marker for myocardial fibrosis. Methods We studied a consecutive group of 664 patients without known prior myocardial infarction being referred for radiofrequency ablation of AF. CMR was requested to assess pulmonary venous anatomy. Results Overall, 73% were male, with an average age of 56 years, and an ejection fraction of 55±10%. Left ventricular LGE was found in 88 patients (13%). The endpoint was all-cause mortality, and in this cohort we observed 68 deaths over a median follow-up period of 42 months. On univariable analysis, age (HR 1.05, CI 1.03–1.08, LRχ2 15.2, p=0.0001), diabetes (HR 2.39, CI 1.41–4.09, LRχ210.3, p=0.001), a history of heart failure (HR 1.78, CI 1.09–2.91, LRχ2 5.37, p=0.02), left atrial dimension (HR 1.04, CI 1.01–1.08, LRχ2 6.47, p=0.01), presence of LGE (HR 5.08, CI 3.08–8.36, LRχ2 28.8, p<0.0001), and LGE extent (HR 1.15, CI 1.10–1.21, LRχ2 35.6, p<0.0001) provided the strongest association with mortality. The mortality rate was 8.1% per patient-years in patients with LGE vs. 2.3% patients without LGE. In the best overall multivariable model for mortality, age and the extent of LGE were independent predictors of mortality. Indeed, each 1% increase in LGE associated with a 15% increased risk of death. Conclusions In patients with AF, LV LGE is a frequent finding and is a powerful predictor of mortality

Antimyeloma activity of heat shock protein-90 inhibition

We show that multiple myeloma (MM), the second most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in a clinically relevant orthotopic in vivo model, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors, or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors, such as the geldanamycin analog 17-AAG. This class of agents simultaneously suppresses in MM cells the expression and/or function of multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (eg, IKK/NF-κB, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1α activities). These pleiotropic proapoptotic effects allow hsp90 inhibitors to abrogate bone marrow stromal cell-derived protection on MM tumor cells, and sensitize them to other anticancer agents, including cytotoxic chemotherapy and the proteasome inhibitor bortezomib. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This suggests a more general role for hsp90 in chaperoning tumor- or tissue-type-specific constellations of client proteins with critical involvement in proliferative and antiapoptotic cellular responses, and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM