An Investigation of Maintenance and the Correlates of Depression: Rumination, Emotion Regulation, Cognitive Inhibition, Sleep and Diet

Prior research has shown that depression is highly correlated with rumination, difficulties with emotion regulation and cognitive inhibition, and changes in sleep and appetite. Yet, little information exists regarding possible associations between these constructs themselves within depressed individuals. Given the possible link between the ongoing state of depression and these factors, it is important to determine how these factors are related to one another within the depressed state. Therefore, the present study extended previous research by investigating the relationship between rumination, emotion regulation, cognitive inhibition, sleep and diet in the context of depression. Questionnaires related to rumination, emotion regulation, sleep, and personal diet among controls, previously-depressed and currently depressed participants. Participants also completed a go/no-go computer task in which they identified the valance of emotional words. The results revealed that depressed and previously-depressed individuals responded more quickly to emotional words than healthy controls. The individuals with current depressive symptomology also exhibited impairments in the inhibition of negative stimuli. The results also suggested that maladaptive emotional re-activity may be a remnant of previous functioning among those with a past history of depression, as the current sample demonstrated emotion regulation trouble despite their lower levels of depressive symptoms. A number of processes were also found to be related in the context of a depressive episode. These findings highlight the significance of identifying the nature of the relationships between symptoms thought to maintain one's depression, as this could help to develop more effective intervention strategies

IMPAIRED GLUCOSE METABOLISM IN THE ABSENCE OF SKELETAL MUSCLE BRAIN AND MUSCLE ARNT-LIKE-PROTEIN 1 (\u3cem\u3eBMAL1\u3c/em\u3e)

Metabolism is a critical physiological function that works to generate energy for cells, store substrates and maintain homoeostasis. Alterations in normal metabolism can have a severe effect on physiology, leading to metabolic disease. Skeletal muscle is a key metabolic tissue, taking up ~80% of postprandial glucose. Therefore it contributes considerably to glucose metabolism: glucose uptake, oxidation and homeostasis. To address the role of the skeletal muscle clock in insulin sensitivity and glucose tolerance, our lab generated an inducible skeletal muscle specific Bmal1-/- mouse (iMSBmal1-/-). 5 weeks post-recombination we observed impairment in both insulin- and AICAR-stimulated skeletal muscle glucose uptake. RT-PCR and western blot analysis demonstrated a significant decrease in mRNA expression and protein content of the skeletal muscle glucose transporter, Glut4. Glucose uptake may be affected by glucose utilization so we examined aspects of glycolysis in the skeletal muscle. Both mRNA expression and activity of rate limiting enzymes hexokinase 2 (Hk2) and phosphofructokinase 1 (Pfk1) were significantly reduced. Additionally, metabolomics illustrated a reduction in metabolites of the glycolytic pathway further supporting a decrease in glycolytic flux. These changes in skeletal muscle glucose metabolism led to altered overall body metabolic health. iMSBmal1-/- mice presented with glucose intolerance and non-fasting hyperglycemia. Furthermore, changes in body composition were seen from 5-12 weeks post-recombination. These data propose a critical role for skeletal muscle Bmal1 in both skeletal muscle glucose metabolism and overall body metabolic health. The presented findings also illuminate skeletal muscle Bmal1 and circadian rhythms as potential targets for metabolic disease

Cognitive Inhibition, Rumination, and Insomnia in Depressed Suicide-Prone Individuals

The overall goal of this investigation was to broaden our understanding of suicidality among those with depression. Specifically, I sought to clarify the relationship between rumination, cognitive inhibition, insomnia, and suicidal ideation. Prior research has shown that suicide is highly correlated with rumination, cognitive inhibition deficits, and insomnia. Yet, although various studies have examined these factors individually, little information exists regarding possible associations between these constructs within suicidal individuals. Given that these constructs are related to both depressive and suicidal phenomenon, it is important to consider how these factors may interrelate in order to gain a better understanding of the potential mechanisms which lead to suicidality. The aims of the present study were to: (1) examine whether cognitive inhibition deficits exist among those with suicidal ideation; (2) test the hypothesis that rumination mediates the relationship between cognitive inhibition deficits and suicidality; (3) examine whether insomnia serves as a moderating variable in the relationship between cognitive inhibition and suicidality; (4) expand previous research by directly comparing three suicidal mental states (i.e., suicidal ideation, suicidal attempts, and the combination of both); and (5) examine the variables of interest in a more precise sample of suicidal individuals than currently present in the literature. The results indicated cognitive inhibition deficits and an affective bias for negative stimuli among both of the groups with current suicidal ideation. Furthermore, it was hypothesized that the relationship between cognitive inhibition and suicidal ideation would be mediated by depressive rumination, and moderated by insomnia severity. Two moderated mediation path models were evaluated using Structural Equation Modeling. Contrary to expectations, the results did not indicate that there was a good fit between either model and the data. However, individual path analysis revealed that insomnia partially mediated the relationship between cognitive inhibition and rumination. Clinical implications and suggestions for future research are also discussed

Muscle-Specific Loss of \u3cem\u3eBmal1\u3c/em\u3e Leads to Disrupted Tissue Glucose Metabolism and Systemic Glucose Homeostasis

Background: Diabetes is the seventh leading cause of death in the USA, and disruption of circadian rhythms is gaining recognition as a contributing factor to disease prevalence. This disease is characterized by hyperglycemia and glucose intolerance and symptoms caused by failure to produce and/or respond to insulin. The skeletal muscle is a key insulin-sensitive metabolic tissue, taking up ~80 % of postprandial glucose. To address the role of the skeletal muscle molecular clock to insulin sensitivity and glucose tolerance, we generated an inducible skeletal muscle-specific Bmal1 −/− mouse (iMSBmal1 −/−). Results: Progressive changes in body composition (decreases in percent fat) were seen in the iMSBmal1 −/− mice from 3 to 12 weeks post-treatment as well as glucose intolerance and non-fasting hyperglycemia. Ex vivo analysis of glucose uptake revealed that the extensor digitorum longus (EDL) muscles did not respond to either insulin or 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) stimulation. RT-PCR and Western blot analyses demonstrated a significant decrease in mRNA expression and protein content of the muscle glucose transporter (Glut4). We also found that both mRNA expression and activity of two key rate-limiting enzymes of glycolysis, hexokinase 2 (Hk2) and phosphofructokinase 1 (Pfk1), were significantly reduced in the iMSBmal1 −/− muscle. Lastly, results from metabolomics analyses provided evidence of decreased glycolytic flux and uncovered decreases in some tricarboxylic acid (TCA) intermediates with increases in amino acid levels in the iMSBmal1 −/− muscle. These findings suggest that the muscle is relying predominantly on fat as a fuel with increased protein breakdown to support the TCA cycle. Conclusions: These data support a fundamental role for Bmal1, the endogenous circadian clock, in glucose metabolism in the skeletal muscle. Our findings have implicated altered molecular clock dictating significant changes in altered substrate metabolism in the absence of feeding or activity changes. The changes in body composition in our model also highlight the important role that changes in skeletal muscle carbohydrate, and fat metabolism can play in systemic metabolism

Cationic Divalent Metal Sites (M = Mn, Fe, Co) Operating As Both Nitrene-Transfer Agents And Lewis Acids Toward Mediating The Synthesis Of Three- And Five-Membered N-Heterocycles

The tripodal compounds [(TMG3trphen)MII-solv](PF6)2 (M = Mn, Fe, Co; solv = MeCN, DMF) and bipodal analogues [(TMG2biphen)MII(NCMe)x](PF6)2 (x = 3 for Mn, Fe; x = 2 for Co) and [(TMG2biphen)MIICl2] have been synthesized with ligands that feature a triaryl- or diarylmethyl-amine framework and superbasic tetramethylguanidinyl residues (TMG). The dicationic M(II) sites mediate catalytic nitrene-transfer reactions between the imidoiodinane PhI═NTs (Ts = tosyl) and a panel of styrenes in MeCN to afford aziridines and low yields of imidazolines (upon MeCN insertion) with an order of productivity that favors the bipodal over the tripodal reagents and a metal preference of Fe \u3e Co ≥ Mn. In CH2Cl2, the more acidic Fe(II) sites favor formation of 2,4-diaryl-N-tosylpyrrolidines by means of an in situ (3 + 2) cycloaddition of the initially generated 2-aryl-N-tosylaziridine with residual styrene. In the presence of ketone, 1,3-oxazolidines can be formed in practicable yields, involving a single-pot cycloaddition reaction of alkene, nitrene, and ketone (2 + 1 + 2). Mechanistic studies indicate that the most productive bipodal Fe(II) site mediates stepwise addition of nitrene to olefins to generate aziridines with good retention of stereochemistry and further enables aziridine ring opening to unmask a 1,3-zwitterion that can undergo cycloaddition with dipolarophiles (MeCN, alkene, ketone) to afford five-membered N-heterocycles

Re‐evaluation of celluloses E 460(i), E 460(ii), E 461, E 462, E 463, E 464, E 465, E 466, E 468 and E 469 as food additives

Following a request from the European Commission, the EFSA Panel on Food Additives and Nutrient sources added to Food (ANS) was asked to deliver a scientific opinion on the re-evaluation of microcrystalline cellulose (E 460(i)), powdered cellulose (E 460(ii)), methyl cellulose (E 461), ethyl cellulose (E 462), hydroxypropyl cellulose (E 463), hydroxypropyl methyl cellulose (E 464), ethyl methyl cellulose (E 465), sodium carboxy methyl cellulose (E 466) and enzymatically hydrolysed carboxy methyl cellulose (E 469) as food additives. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Scientific Committee on Food (SCF) established an acceptable daily intake (ADI) ‘not specified’ for unmodified and modified celluloses. Celluloses are not absorbed and are excreted intact in the faeces; in addition, microcrystalline cellulose, powdered and modified celluloses could be fermented by the intestinal flora in animals and humans. Specific toxicity data were not always available for all the celluloses evaluated in the present opinion and for all endpoints. Given their structural, physicochemical and biological similarities, the Panel considered it possible to read-across between all the celluloses. The acute toxicity of celluloses was low and there was no genotoxic concern. Short-term and subchronic dietary toxicity studies performed with E 460(i), E 461, E 462, E 463, E 464, E 466 and E 469 at levels up to 10% did not indicate specific treatment related adverse effects. In chronic toxicity studies performed with E 460(i), E 461, E 463, E 464, E 465 and E 466, the no observed adverse effect level (NOAEL) values reported ranged up to 9,000 mg/kg body weight (bw) per day. No carcinogenic properties were detected for microcrystalline cellulose and modified celluloses. Adverse effects on reproductive performance or developmental effects were not observed with celluloses at doses greater than 1,000 mg/kg bw by gavage (often the highest dose tested). The combined exposure to celluloses (E 460–466, E 468 and E 469) at 95th percentile of the refined (brand-loyal) exposure assessment for the general population was up to 506 mg/kg bw per day. The Panel concluded that there was no need for a numerical ADI and that there would be no safety concern at the reported uses and use levels for the unmodified and modified celluloses (E 460(i); E 460(ii); E 461–466; E 468 and E 469). The Panel considered an indicative total exposure of around 660–900 mg/kg bw per day for microcrystalline, powdered and modified celluloses

Temperature as a Circadian Marker in Older Human Subjects: Relationship to Metabolic Syndrome and Diabetes

Background: Circadian rhythms are characterized by approximate 24-hour oscillations in physiological and behavioral processes. Disruptions in these endogenous rhythms, most commonly associated with shift work and/or lifestyle, are recognized to be detrimental to health. Several studies have demonstrated a high correlation between disrupted circadian rhythms and metabolic disease. The aim of this study was to determine which metabolic parameters correlate with physiological measures of circadian temperature amplitude (TempAmp) and stability (TempStab). Methods: Wrist skin temperature was measured in 34 subjects (ages 50 to 70, including lean, obese, and diabetic subjects) every 10 minutes for 7 consecutive days. Anthropometric measures and fasting blood draws were conducted to obtain data on metabolic parameters: body mass index, hemoglobin A1C, triglycerides, cholesterol, high-density lipoprotein, and low-density lipoprotein. A history of hypertension and current blood pressure was noted. Results: Analysis of the data indicated a substantial reduction in TempAmp and TempStab in subjects with metabolic syndrome (three or more risk factors). To determine the impact of individual interdependent metabolic factors on temperature rhythms, stepwise multilinear regression analysis was conducted using metabolic syndrome measurements. Interestingly, only triglyceride level was consistently correlated by the analysis. Triglyceride level was shown to contribute to 33% of the variability in TempAmp and 23% of the variability in TempStab. Conclusion: Our results demonstrate that elevated triglycerides are associated with diminished TempAmp and TempStab in human subjects, and triglycerides may serve as a primary metabolic predictor of circadian parameters