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مقدمة في العلاج المعرفي السلوكي : المهارات والتطبيقات
إن الحديث عن العلاج السلوكي المعرفي كما لو كان علاجا نفسيا وحيدا يعتبر شيء مضلل، فالعلاج السلوكي المعرفي المعاصر ليس بناء واحدا، ولكن حركة واسعة ما زالت ف طور النمو والتطور ومليئة بالتناقضات، يقوم المدخل الذي تتبناه في هذا الكتاب على نموذج بيك Beck من الستينات والسبعينات ولقد ساد هذا المدخل في المملكة المتحدة خلال الثلاثين عاما الماضية ومن ثم نحن نرى أنفسنا في المجال الرئيس في العلاج السلوكي المعرفي في هذا البلد ومع ذلك قد يختلف المنظرون والإكلينيكيون الآخرون بطرق رئيسية وفرعية، كبيرة وصغيرة مع بعض المداخل التي نقدمها هنا.
BOOK
Hyperphosphatemia increases inflammation to exacerbate anemia and skeletal muscle wasting independently of FGF23-FGFR4 signaling
Elevations in plasma phosphate concentrations (hyperphosphatemia) occur in chronic kidney disease (CKD), in certain genetic disorders, and following the intake of a phosphate-rich diet. Whether hyperphosphatemia and/or associated changes in metabolic regulators, including elevations of fibroblast growth factor 23 (FGF23) directly contribute to specific complications of CKD is uncertain. Here, we report that similar to patients with CKD, mice with adenine-induced CKD develop inflammation, anemia, and skeletal muscle wasting. These complications are also observed in mice fed high phosphate diet even without CKD. Ablation of pathologic FGF23-FGFR4 signaling did not protect mice on an increased phosphate diet or mice with adenine-induced CKD from these sequelae. However, low phosphate diet ameliorated anemia and skeletal muscle wasting in a genetic mouse model of CKD. Our mechanistic in vitro studies indicate that phosphate elevations induce inflammatory signaling and increase hepcidin expression in hepatocytes, a potential causative link between hyperphosphatemia, anemia, and skeletal muscle dysfunction. Our study suggests that high phosphate intake, as caused by the consumption of processed food, may have harmful effects irrespective of pre-existing kidney injury, supporting not only the clinical utility of treating hyperphosphatemia in CKD patients but also arguing for limiting phosphate intake in healthy individuals.
Journal Article
The interplay between sex, time of day, fasting status, and their impact on cardiac mitochondrial structure, function, and dynamics
Mitochondria morphology and function, and their quality control by mitophagy, are essential for heart function. We investigated whether these are influenced by time of the day (TOD), sex, and fed or fasting status, using transmission electron microscopy (EM), mitochondrial electron transport chain (ETC) activity, and mito-QC reporter mice. We observed peak mitochondrial number at ZT8 in the fed state, which was dependent on the intrinsic cardiac circadian clock, as hearts from cardiomyocyte-specific BMAL1 knockout (CBK) mice exhibit different TOD responses. In contrast to mitochondrial number, mitochondrial ETC activities do not fluctuate across TOD, but decrease immediately and significantly in response to fasting. Concurrent with the loss of ETC activities, ETC proteins were decreased with fasting, simultaneous with significant increases of mitophagy, mitochondrial antioxidant protein SOD2, and the fission protein DRP1. Fasting-induced mitophagy was lost in CBK mice, indicating a direct role of BMAL1 in regulating mitophagy. This is the first of its kind report to demonstrate the interactions between sex, fasting, and TOD on cardiac mitochondrial structure, function and mitophagy. These studies provide a foundation for future investigations of mitochondrial functional perturbation in aging and heart diseases.
Journal Article
Developmental Exposure to Second-Hand Smoke Increases Adult Atherogenesis and Alters Mitochondrial DNA Copy Number and Deletions in apoE−/− Mice
Cardiovascular disease is a major cause of morbidity and mortality in the United States. While many studies have focused upon the effects of adult second-hand smoke exposure on cardiovascular disease development, disease development occurs over decades and is likely influenced by childhood exposure. The impacts of in utero versus neonatal second-hand smoke exposure on adult atherosclerotic disease development are not known. The objective of the current study was to determine the effects of in utero versus neonatal exposure to a low dose (1 mg/m(3) total suspended particulate) of second-hand smoke on adult atherosclerotic lesion development using the apolipoprotein E null mouse model. Consequently, apolipoprotein E null mice were exposed to either filtered air or second-hand smoke: (i) in utero from gestation days 1-19, or (ii) from birth until 3 weeks of age (neonatal). Subsequently, all animals were exposed to filtered air and sacrificed at 12-14 weeks of age. Oil red-O staining of whole aortas, measures of mitochondrial damage, and oxidative stress were performed. Results show that both in utero and neonatal second-hand smoke exposure significantly increased adult atherogenesis in mice compared to filtered air controls. These changes were associated with changes in aconitase and mitochondrial superoxide dismutase activities consistent with increased oxidative stress in the aorta, changes in mitochondrial DNA copy number and deletion levels. These studies show that in utero or neonatal exposure to second-hand smoke significantly influences adult atherosclerotic lesion development and results in significant alterations to the mitochondrion and its genome that may contribute to atherogenesis.
Journal Article
FGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes
Fibroblast growth factor (FGF) 21, a hormone that increases insulin sensitivity, has shown promise as a therapeutic agent to improve metabolic dysregulation. Here we report that FGF21 directly targets cardiac myocytes by binding β-klotho and FGF receptor (FGFR) 4. In combination with high glucose, FGF21 induces cardiac myocyte growth in width mediated by extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. While short-term FGF21 elevation can be cardio-protective, we find that in type 2 diabetes (T2D) in mice, where serum FGF21 levels are elevated, FGFR4 activation induces concentric cardiac hypertrophy. As T2D patients are at risk for heart failure with preserved ejection fraction (HFpEF), we propose that induction of concentric hypertrophy by elevated FGF21-FGFR4 signaling may constitute a novel mechanism promoting T2D-associated HFpEF such that FGFR4 blockade might serve as a cardio-protective therapy in T2D. In addition, potential adverse cardiac effects of FGF21 mimetics currently in clinical trials should be investigated.
Journal Article
Mitochondrial DNA damage and vascular function in patients with diabetes mellitus and atherosclerotic cardiovascular disease
Objective
Prior studies demonstrate mitochondrial dysfunction with increased reactive oxygen species generation in peripheral blood mononuclear cells in diabetes mellitus. Oxidative stress-mediated damage to mitochondrial DNA promotes atherosclerosis in animal models. Thus, we evaluated the relation of mitochondrial DNA damage in peripheral blood mononuclear cells s with vascular function in patients with diabetes mellitus and with atherosclerotic cardiovascular disease.
Approach and results
We assessed non-invasive vascular function and mitochondrial DNA damage in 275 patients (age 57 ± 9 years, 60 % women) with atherosclerotic cardiovascular disease alone (N = 55), diabetes mellitus alone (N = 74), combined atherosclerotic cardiovascular disease and diabetes mellitus (N = 48), and controls age >45 without diabetes mellitus or atherosclerotic cardiovascular disease (N = 98). Mitochondrial DNA damage measured by quantitative PCR in peripheral blood mononuclear cells was higher with clinical atherosclerosis alone (0.55 ± 0.65), diabetes mellitus alone (0.65 ± 1.0), and combined clinical atherosclerosis and diabetes mellitus (0.89 ± 1.32) as compared to control subjects (0.23 ± 0.64, P < 0.0001). In multivariable models adjusting for age, sex, and relevant cardiovascular risk factors, clinical atherosclerosis and diabetes mellitus remained associated with higher mitochondrial DNA damage levels (β = 0.14 ± 0.13, P = 0.04 and β = 0.21 ± 0.13, P = 0.002, respectively). Higher mitochondrial DNA damage was associated with higher baseline pulse amplitude, a measure of arterial pulsatility, but not with flow-mediated dilation or hyperemic response, measures of vasodilator function.
Conclusions
We found greater mitochondrial DNA damage in patients with diabetes mellitus and clinical atherosclerosis. The association of mitochondrial DNA damage and baseline pulse amplitude may suggest a link between mitochondrial dysfunction and excessive small artery pulsatility with potentially adverse microvascular impact.
Journal Article
Magical contracts, numinous capitalism
Much of US social reality is constructed through contractual rituals, typically thought to be words that create enforceable relations. Such relations are backed by the power of the state and are said to exist on some plane above the empirical. Politically, we speak of a social contract. Economically, contracts lie at the heart of markets, and thus of a commercial society. But just how do individuals use words that construct a suprasensible reality which third parties must respect? Why do some words become ‘binding’, and not others? Such questions have long vexed legal scholars who have been candid, if not comfortable, with the ‘metaphysical’ character of contract law and its complex, and shifting, invocation of a suprasensible social order. It is often said that this social order is founded on the autonomous individual with the power to bind herself (liberalism). Contracts thus not only articulate social relations, they legitimate such relations as something done by and among the parties. As contract law and jurisprudence develop, however, the individual becomes ever more clearly subordinate, i.e. the imaginary of the individual as an autonomous agent who somehow ‘makes’ the contract, who acts upon the social with her words, becomes increasingly difficult to sustain. The magic of contract still works; commercial society still knits itself. But the belief that individuals make the law, rather than the other way around, comes to seem naïve. By extension, the social must still be legitimate (what alternative is there?), but its legitimacy is hardly, if at all, derived from its liberal character. Instead, liberalism emerges as the way law presents itself, and the individual with whom we thought we began emerges as a somewhat disingenuous representation of contemporary law.
Journal Article
Perinatal Tobacco Smoke Exposure Increases Vascular Oxidative Stress and Mitochondrial Damage in Non-Human Primates
Epidemiological studies suggest that events occurring during fetal and early childhood development influence disease susceptibility. Similarly, molecular studies in mice have shown that in utero exposure to cardiovascular disease (CVD) risk factors such as environmental tobacco smoke (ETS) increased adult atherogenic susceptibility and mitochondrial damage; however, the molecular effects of similar exposures in primates are not yet known. To determine whether perinatal ETS exposure increased mitochondrial damage, dysfunction and oxidant stress in primates, archived tissues from the non-human primate model Macaca mulatta (M. mulatta) were utilized. M. mulatta were exposed to low levels of ETS (1 mg/m³ total suspended particulates) from gestation (day 40) to early childhood (1 year), and aortic tissues were assessed for oxidized proteins (protein carbonyls), antioxidant activity (SOD), mitochondrial function (cytochrome oxidase), and mitochondrial damage (mitochondrial DNA damage). Results revealed that perinatal ETS exposure resulted in significantly increased oxidative stress, mitochondrial dysfunction and damage which were accompanied by significantly decreased mitochondrial antioxidant capacity and mitochondrial copy number in vascular tissue. Increased mitochondrial damage was also detected in buffy coat tissues in exposed M. mulatta. These studies suggest that perinatal tobacco smoke exposure increases vascular oxidative stress and mitochondrial damage in primates, potentially increasing adult disease susceptibility.
Journal Article
The Capacitance of Pristine Ice Crystals and Aggregate Snowflakes
A new method of accurately calculating the capacitance of realistic ice particles is described: such values are key to accurate estimates of deposition and evaporation (sublimation) rates in numerical weather models. The trajectories of diffusing water molecules are directly sampled, using random “walkers.” By counting how many of these trajectories intersect the surface of the ice particle (which may be any shape) and how many escape outside a spherical boundary far from the particle, the capacitances of a number of model ice particle habits have been estimated, including hexagonal columns and plates, “scalene” columns and plates, bullets, bullet rosettes, dendrites, and realistic aggregate snowflakes. For ice particles with sharp edges and corners this method is an efficient and straightforward way of solving Laplace’s equation for the capacitance. Provided that a large enough number of random walkers are used to sample the particle geometry (∼104) the authors expect the calculated capacitances to be accurate to within ∼1%. The capacitance for the modeled aggregate snowflakes (C/Dmax = 0.25, normalized by the maximum dimension Dmax) is shown to be in close agreement with recent aircraft measurements of snowflake sublimation rates. This result shows that the capacitance of a sphere (C/Dmax = 0.5), which is commonly used in numerical models, overestimates the evaporation rate of snowflakes by a factor of 2. The effect of vapor “screening” by crystals growing in the vicinity of one another has also been investigated. The results clearly show that neighboring crystals growing on a filament in cloud chamber experiments can strongly constrict the vapor supply to one another, and the resulting growth rate measurements may severely underestimate the rate for a single crystal in isolation (by a factor of 3 in this model setup).
Journal Article