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Congenital leptin deficiency

The role of leptin was first discovered in studies of severely obese ob ob mice, which harbour mutations in the ob gene resulting in a complete lack of its protein product leptin which is derived from adipose tissue (Zhang et al., 1994). Administration of recombinant leptin reduces the food intake and body weight of leptin-deficient ob ob mice and corrects all their neuroendocrine and metabolic abnormalities (Halaas et al., 1995). In 1997, we reported two severely obese cousins from a highly consanguineous family of Pakistani origin who had undetectable levels of serum leptin and were found to be homozygous for a frameshift mutation in the ob gene (AG133), which resulted in a truncated protein that was not secreted (Montague et al., 1997). We have since identified four further affected individuals from three other families who are also homozygous for the same mutation in the leptin gene. All the families are of Pakistani origin but not known to be related over five generations. A...

Response to leptin therapy

Recently we reported the dramatic and beneficial effects of daily subcutaneous injections of leptin reducing body weight and fat mass in three congenitally leptin-deficient children (Farooqi et al., 1999 2002). The major effect of leptin was on appetite with normalisation of hyperphagia. Leptin therapy reduced energy intake during an 18MJ ad libitum test meal by up to 84 (Farooqi et al., 2002). We were unable to demonstrate a major effect of leptin on basal metabolic rate or free-living energy expenditure, but, as weight loss by other means is associated with a decrease in (BMR) basal metabolic rate, the fact that energy expenditure did not fall in our leptin-deficient subjects is notable. The administration of leptin-permitted progression of appropriately timed pubertal development in the single child of appropriate age and did not cause the early onset of puberty in the younger children (Farooqi et al., 2002). Leptin also reversed the T cell dysfunction and caused a switch from a...

Partial leptin deficiency in heterozygotes

We studied the heterozygous relatives of our leptin deficient subjects (Farooqi et al., 2001). Serum leptin levels in the heterozygous subjects were found to be significantly lower than expected for body fat and they had a higher prevalence of obesity than seen in a control population of similar age, sex and ethnicity (Farooqi et al., 2001). Additionally, percentage body fat was higher than predicted from their height and weight in the heterozygous subjects compared to control subjects of the same ethnicity. These findings closely parallel those in heterozygous ob- and db -mice (Chung et al., 1998). These data provide further support for the possibility that leptin can produce a graded response in terms of body composition across a broad range of plasma concentrations.

Leptin receptor deficiency

The signalling form of the leptin receptor is deleted in db db mice (and disrupted in the fatty Zucker and Koletsky rat models) which are consequently unresponsive to endogenous or exogenous leptin (Tartaglia, 1997). In rodents, the phenotype is comparable to ob ob, with earlier development of hyperglycemia on some backgrounds. A mutation in the leptin receptor has been reported in several obese subjects from a consanguineous family of Kabilian origin (Clement et al., 1998). Affected individuals were homozygous for a mutation that truncates the receptor before the transmembrane domain and the mutated receptor circulates bound to leptin. Although this mutation does not result in a complete null phenotype, there are a number of phenotypic similarities with the leptin-deficient subjects. Leptin receptor deficient subjects were also born of normal birth weight, exhibited rapid weight gain in the first few months of life, with severe hyperphagia and aggressive behaviour when denied food....

Cortisol Awakening Rise and Day Profiles

Activity of the HPA axis displays a pronounced circadian rhythm. Peak levels of cortisol and ACTH can be observed shortly after awakening, followed by decreasing concentrations throughout the day, a quiescent period of minimal secretory activity during the night and rising levels during late sleep. Superimposed on this circadian rhythm, a sharp increase (50-100 ) in both free salivary Cortisol levels and total plasma Cortisol levels can be observed within the first hour after awakening in the majority of people (Dockray et al, 2008 Pruessner et al, 1997). Salivary cortisol levels are considered a reliable measure of HPA axis activity, due to the high correlation between salivary cortisol levels and free unbound cortisol levels in plasma and serum (Hellhammer et al, 2009). Thus, the CAR can be simply assessed by taking four saliva samples (directly after awakening, 30, 45, and 60 min after awakening), with strict reference to awakening time. A major advantage of this non-invasive...

Plasma Leptin

Plasma leptin concentrations are known to reflect body fat content (Niswender and Schwartz, 2003). At the age between 6 and 8 months, plasma concentrations did not significantly differ among rat groups, although the fat content was slightly lower in (tg tg) rats compared with Figure 31.5. (A) Body fat content, and (B) plasma leptin and (C) adiponectin concentrations. The body fat content represents the combined wet weights of perirenal and epididymal fat normalized by body weight (g 100 g body weight (BW)). Fat content did not significantly differ between the CR1 and CR2 phase rats thus data were combined into the CR group. Plasma samples were prepared from trunk blood collected at decapitation. Plasma leptin and adiponectin data was unavailable for (tg tg) rats. Young represents an age of 6 to 8 months, while Old represents an age of 24 to 25 months. The numbers of rats examined were 7 to 24 for body fat content, 3 to 8 for plasma leptin, and 3 to 7 for plasma adiponectin. 3-f ANOVA...


Salivary cortisol can easily be measured in naturalistic studies since samples can be readily collected and stored using Salivettes and other devices. Cortisol remains stable in saliva at room temperature and so can be kept for several days, allowing participants to return collection tubes by mail (Kirschbaum and Hellhammer, 2007). An immense advantage of assessing salivary cortisol is that repeated measures can be obtained, allowing the diurnal rhythm of the hormone to be recorded. The cortisol awakening response, the cortisol slope over the day, and total cortisol over the day have all received attention. For example, one study of 70 patients who had recently experienced an acute coronary syndrome (ACS) involved eight measures of salivary cortisol over a day at home (Molloy et al, 2008). Thirty-eight percent of the sample was identified as having type D personality. Type D personality was not related to the cortisol awakening response, but cortisol output during the day was higher...

Metabolism and Energy Utilization

The metabolic activity of the indigenous gastrointestinal flora has been described as equaling that of the liver (Berg 1996). Among many other abilities, commensals produce short-chain fatty acids (SCFA), synthesize vitamin B12, and deconjugate bile acids. Compared to conventionally raised animals, germfree animals show defects in vitamin synthesis (including, biotin, folate, and vitamins B and K), bile acid transformation, carbohydrate and fatty acid digestion, synthesis of SCFA, xenobiotic transformation, and other signs of metabolic deficiencies (Berg 1996 Midvedt 1999 Savage 1986). Many of these benefits are indeed mediated by the novel enzymatic bioactivity of the indigenous flora. However, recent studies by Backhed et al. reveal that some of the effects of intestinal symbionts on host metabolism maybe due to regulation of host metabolic enzymes (Backhed et al. 2004). Conventionalization of germfree mice led to adipogenesis and increased insulin resistance, revealing a role of...

Formation of 5Androstene317Diol and Testosterone

5-Androstene-3j6,17jS-diol and testosterone are formed from DHEA and androstenedione, respectively, through the action of 17jS-hydroxys-teroid oxidoreductase, which is commonly referred to as 17j6-hydroxysteroid dehydrogenase (17jS-HSD) the reactions are reversible. Five isoforms of the enzyme, encoded by the 17fi-HSD gene, have been described in humans, each having cell-specific expression, substrate specificity, regulatory mechanisms, and reductase or oxidative catalytic activities. They are designated types 1-5 in the chronological order of their isolation. Chromosomal locations, enzymatic activities, and cellular distributions of the human 17fi-HSD isoenzymes vary (see review by An-dersson and Moghrabi38).

Formation of Corticosteroids

In contrast to the mineralocorticoid pathway, the glucocorticoid pathway, leading to formation of cortisol, begins with 17-hydroxyprogesterone. The latter compound is converted to 11-deoxy-cortisol, which is then transformed to cortisol through the action of 21-hydroxylase and 11jS-hydroxylase, respectively. These reactions are analagous to the formation of corticosterone from progesterone. Cortisol has high glucocor-ticoid activity, in contrast to 11-deoxycortisol, which lacks significant amounts of this activity.

Dairy consumption energy intake and body weight

Over the long term, the hypothalamus regulates food intake in response to hormones that enter the brain from the peripheral circulation and whose plasma concentrations are related to adipose tissue mass (Schwartz et al., 2000). The two major hormones that have been implicated in the long-term regulation of food intake are leptin and insulin (Badman and Flier, 2005). However, it has recently been shown that ghrelin, a hormone secreted by specialized cells in the stomach, also meets the criteria for a long-term regulator of food intake (Cummings, 2006). Leptin is a hormone arising from adipose tissue and its plasma concentrations are directly proportional to the adipose tissue mass. Although insulin does not arise from adipose tissue, its concentration in blood at fasting and after food ingestion is influenced by adipose tissue mass. It has been proposed that both insulin (Biddinger and Kahn, 2006) and leptin (Munzberg and Myers, 2005) resistance in the brain lead to increased food...

Oral Properties of MK0677 in the Clinic

Based on the indications of potency, duration of action, oral bioavailability, and selectivity, which are summarized above, compound 44 (L-163,191) as its crystalline mesylate salt was selected for safety assessment studies. Subsequently it entered clinical testing and was given the designation MK-0677 as a potential product candidate. In confirmation of the animal data, MK-0677 was found to raise IGF-1 in man following oral administration. The first published account was by Copinischi et al. (62) who treated nine healthy young men daily for seven days in a crossover comparison of placebo and 5- and 25-mg doses of MK-0677. IGF-1 levels were increased in a dose dependent manner without detectable elevations of GH. Nor was any evidence observed of induced hypercortisolism. Chapman et al. (63) reported results shortly thereafter of a study in which 32 healthy elderly men and women received placebo, or 2, 10, or 25 mg MK-0677 orally, once daily for two separate study periods of 14 and 28...

Risk Factors and Neurocognition

Various hormones are known to have a direct biological influence on the brain while potentially promoting diseases that affect cognitive function. In that regard, low levels of estrogen and androgens (Sherwin, 2003, 2006) and both low and high levels of thyroid hormones (Smith et al, 2002) have been related to poorer cognitive function. Hormone therapy in post-menopausal women may help prevent cognitive decline (Sherwin, 2003). Numerous studies have revealed associations between higher resting cortisol levels and lowered levels of cognitive performance, particularly on tests of learning and memory (Lupien et al, 2005). It has also been noted that stress-induced cortisol elevations are associated with decreased cognitive performance (Kirschbaum et al, 1996). The latter findings reflect a larger literature on the negative relations of stress to cognitive performance and brain structure and function, at least in part via aberrations in cortisol (Sapolsky, 1999 McEwen, 2002)....

Nuclear Receptor Ligands

Specificity and are capable of binding to identical ligands. Examples of this cross-specificity include mineralocorticoid receptor high-affinity binding to cortisol and the ability of both GRs and PRs to bind the synthetic glucocorti-coid antagonist RU486 with relatively high affinity.215,216 For some receptors, such as the retinoid receptors and PPARs, fatty acyl chain length and degree of saturation can also influence binding affinity.158,217 Furthermore, or-thologs within a particular family can selectively recognize distinct ligands, as is the case for PPARs, or exhibit overlapping binding specificity, as is the case for the retinoid receptors

Cardiovascular Effects

Studies have been conducted to examine the effects on GB administration on blood pressure and blood flow. In one study, either GB or placebo was administered in a double-blind, placebo-controlled crossover design to healthy volunteers and forearm blood flow was measured (29). Forearm blood flow was significantly higher during GB therapy than with placebo and mean arterial pressure remained unchanged, thus rendering the forearm vascular resistance significantly lower during active treatment. In a related study, Jezova and colleagues studied the effect of GB (EGb 761) treatment on changes in blood pressure and cortisol release following exposure to stress stimuli (30). The rise in systolic blood pressure following stress stimuli was significantly lower ( 20 mmHg rise in subjects receiving EGb 761 vs an 30 mmHg rise in subjects receiving placebo) in the GB group. Differences in diastolic pressure rise were similar ( 10 mmHg difference between GB and placebo) between the two groups. GB...

Glucocorticoid and Mineralocorticoid Receptors

Mineralocorticoid receptors are primarily involved in the regulation of salt balance. In addition to being activated by the mineralocorti-coid aldosterone, MR binds to and is activated by glucocorticoids. Since MRs are expressed in many tissues that also express GRs, it is probable that MR also activates transcription through GREs.316,317 However, in tissues where MR function is critical, such as in the gut and kidney, glucocorticoids are metabolized via the action of 11j6-hydroxysteroid dehydrogenase, ensuring MR-aldosterone sensitivity.318 Currently, little is known about bona fide MR target genes, other than that loss of the receptor through gene knockout results in severely impaired regulation of salt balance.319 In any event, it is clear that the CNS-related activities of these two receptors ensure appropriate regulation of peptide and steroid hormone production and response from the hypothala-mic-pituitary-adrenal axis.

Physiological Links Between Social Stress and Disease Processes

A large body of evidence points to both biological and behavioral accompaniments of hostility that could account for increased disease risk. Beginning with biological studies, Suarez and colleagues (1998) found that while physiological functions did not differ in high and low hostile men while solving anagrams, when harassment was added to the experiment, high hostiles showed larger blood pressure, heart rate, and forearm blood flow responses during the task as well as slower recovery in blood levels of nore-pinephrine and cortisol. Sloan et al (1994) found decreased vagal tone as indexed by heart rate variability in younger men with high hostility levels. Using T-wave amplitude responses to iso-proterenol, with and without atropine pretreat-ment, to index vagal antagonism of SNS effects on myocardial function, Fukudo et al (1992) found weaker vagal antagonism among high hostile Type A men. Markowitz (1998) and Shimbo and colleagues (2009) have observed increased platelet activation...

Physiological Stimuli For Gh Release In Search Of An Endogenous Ligand For Gh Secretagogues

It seems possible that an endogenous GH secretagogue ligand could be synthesized in some discrete population of neurons within the CNS, possibly even synthesized in neuroendocrine cells controlling GH secretion. However, it is equally possible that it is produced peripherally in response to physiological stimuli. Under what physiological circumstances are plasma levels of GH higher than normal, possibly reflecting the release of an endogenous GH secretagogue ligand Interestingly, the endocrine response to GHRP-6 is in some respects similar to that observed in response to exercise. In humans, infusion of GHRP-6 results in an initial rapid increase in plasma levels of GH, followed by long-lasting elevated fluctuations (25) this profile is in marked contrast to the profile of GH release in response to GHRH infusion, which elicits a rapidly desensitizing response. However, the pituitary response to GHRP-6 desensitizes even more rapidly than that to GHRH, hence the profile of the in vivo...

Biological Processes Linking Positive Well Being and Health

The first is to obtain a single reading or a few measures of biological state, for example, a measure of plasma interleukin (IL-6) or blood pressure, and relate this to positive well-being. This technique is used in epidemi-ological studies (often in large samples) and in smaller studies of convenience, with measures of heart rate, blood pressure, cortisol output, and immune parameters such as natural killer cells cytotoxicity or IL-6 concentration. The results of such studies have been varied, due in part to the range of measures of positive well-being applied, but also because of small samples sizes and failure to control for covariates (Pressman and Cohen, 2005). Many of the biological variables assessed are affected by age, gender, smoking, adiposity, socioeconomic status, and other factors, so failure to control for these variables may generate spurious findings.

Experimental Studies of Biology and Well Being

Experimental studies of biology and well-being are typically involved of the assessment of cardiovascular, neuroendocrine, or immunological responses under controlled laboratory conditions. Two types of experimental studies have been reported. The first has evaluated the biological effects of short-term manipulation of mood state. Pressman and Cohen's (2005) systematic review identified 16 studies with strong methodology that assessed the cardiovascular effects of mood manipulations using procedures such as listening to cheerful music or watching amusing videos. In the majority of studies, positive mood inductions stimulated increased blood pressure (BP) and heart rate compared with neutral conditions, probably because of general activation effects. Nonetheless, Vlachopoulos et al (2009) recently showed that a positive mood induction (amusing movie) led to decreases in arterial stiffness, while the reverse was found for stress induction. Arterial stiffness is an indicator of vascular...

Naturalistic Physiological Monitoring Studies

Naturalistic monitoring has the advantage of assessing effects in ecologically valid real-life situations as people go about their normal activities, rather than in the rarified atmosphere of the laboratory. Naturalistic studies are limited to a few biological variables by technology, but key measures such as cortisol can be assessed from saliva, while ambulatory BP, heart rate, and heart rate variability (HRV) can be assessed relatively unobtrusively. We recorded salivary cortisol eight times over a working day and eight times over a leisure day in the study of 216 Whitehall participants mentioned earlier. We found that salivary cortisol averaged over the day was inversely related to positive affect after controlling for other relevant factors such as age, grade of employment, BMI, and smoking. The effect also remained significant after adjusting for psychological distress, indicating that the potentially beneficial effect of positive affect is distinct from the absence of...

Appraisals and Psychological Stress

Another focal point in stress-related physiological responding is the hypothalamic-pituitary-adrenocortical (HPA) axis. This set of structures plays a major role in the body's stress response (McEwen, 2006, 2008). HPA activation is reflected in increases in levels of several hormones, including the catecholamines (epinephrine and norepinephrine) and cortisol. Cortisol is considered a particularly important stress hormone because of its links to other processes in the overall stress response. For example, elevation of cortisol can suppress diverse aspects of immune functioning (e.g., Choi et al, 2008 Kronfol et al, 1997). That is, as noted earlier, when strong demands are made on behavior (fight-or-flight), immune surveillance takes

Lipid Receptors Peroxisome Proliferator Activated Receptors

The observations that the thiazolidinedione class of Type 2 diabetic non-insulin-dependent diabetes mellitus insulin sensitizers act as direct PPARy ligands implicates PPARy as a NR involved in glucose as well as lipid homeostasis.400 Although adipose tissue and obesity contribute to insulin resistance, the molecular details concerning this relationship remain unclear.401 Several possibilities for the involvement of PPARy activity in insulin and glucose resistance have been suggested, such as regulation of adipocyte size, glucose transporters, and circulating leptin and free fatty acid levels.402-405 Since PPARy activity may directly or indirectly contribute to regulation of several of these parameters, it is likely that this receptor will continue to be targeted in the pharmacological intervention of Type 2 diabetes and obesity.406 Additionally, several studies have implicated PPARy as a regulator of macrophage foam cell generation, a process directly correlated to the incidence of...

Social And Procedural Context

The majority of neuroimaging studies to date may be classified as brain mapping studies, in which investigators are exploring the patterns of activity elicited by a particular psychological process or condition. Brain mapping has been used to investigate virtually every field of study in human psychology and psychiatry, including (for example) attention, perception, memory, learning, emotion, reward, depression and other mood disorders, psychopathy, and Parkinson's and other neurological disorders. Recently, this trend has broadened to include mapping of social processes such as representations of the self and of others' intentions, economic principles such as expected utility and risk, and emotional self-regulation. Another approach particularly relevant here is the mapping of brain regions that correspond with changes in the autonomic and endocrine systems as measured by heart rate (Critchley, 2003), electrodermal responses (Critchley, 2000), pupil dilation (Siegle, 2003), and...

Psychophysiological Pathways

One set of physiological parameters that has received attention concerns the stress hormone Cortisol. In general, problem-focused and approach coping styles are related to lower overall levels of cortisol, more favorable diurnal cortisol rhythms, and faster recovery to normal patterns after a stressor (Mikolajczak et al, 2007 Nicolson, 1992 O'Donnell et al, 2008 Sjogren et al, 2006). A number of qualities that reflect social integration and support have also been linked to favorable cortisol profiles. Use of social support relates to lower daily cortisol levels (O'Donnell et al, 2008). Social isolation (living alone and little contact with friends and family) predicts a greater cortisol response at awakening and greater cortisol output over the day (Grant et al, 2009). Higher levels of religiosity have also been associated with favorable cortisol patterns in women with fibromyalgia, even after controlling for social support (Dedert et al, 2004).

Coping Interventions for Disease Populations

Antoni and his colleagues developed a 10-week cognitive behavioral stress management intervention involving relaxation, cognitive restructuring, and coping skills training for women being treated for non-metastatic breast cancer. This intervention led to improved psychosocial outcomes (Antoni et al, 2006a, b). It also led to greater reductions in cortisol levels through a 12-month follow-up, compared with a control group (Phillips et al, 2008), and

Trier Social Stress Test TSST Paradigm

In particular, psychological stress, or challenge, tests have been frequently used to assess hypothalamic-pituitary-adrenal (HPA) reactivity (e.g., salivary cortisol) in laboratory settings (see Chapter 43). Many hormones may be reliably measured in saliva and such techniques have been used extensively in psychobio-logical research (Kirschbaum and Hellhammer, 2000). Previous research aimed at elucidating the factors responsible for individual differences in HPA reactivity obtained mixed results (e.g., Berger et al, 1987) due, in part, to use of stressors that yielded unreliable stimulation of the HPA axis. Consequently, the Trier social stress test (TSST Kirschbaum et al, 1993) was developed to allow for reliable stimulation of the HPA axis and subsequent measure of both physiological and psychological responses to stress in a controlled laboratory setting. The TSST has now become the .standard protocol for the experimental induction of psychological stress in healthy participants, as...

Mental Harassment in the Context of Hostility and Cardiovascular Risk

The studies conducted by Suarez and colleagues (1989, 1990, 1993, 1998) yielded several, consistent findings. In studies of both men and women, those who scored high in hostility and also experienced mental harassment during the anagram task consistently exhibited increased cardiovascular and or neuroendocrine responses. For example, Suarez and colleagues (1998) demonstrated that increased (and protracted) blood pressure, heart rate, forearm blood flow, forearm vascular resistance, nore-pinephrine, testosterone, and cortisol responses resulted from harassment of those high in hostility. In addition, throughout the series of studies conducted by Suarez and colleagues, these same individuals also reported increased levels of negative affect including anger, anxiety, and depression. In contrast, individuals who were not harassed during the anagram task showed no increases in physiological or emotional arousal. Excessive cardiovascular reactivity has also been demonstrated in studies...

In Vivo Expression of Recombinant Adenoviral Encoded Proteins

Systemically administered Ad vectors can also provide high-level temporary expression of a protein that is secreted into the bloodstream. Much of this work has focused on preclinical applications, as in expression of factor VIII for the treatment of hemophilia A (Connelly et al., 1996) or of erythropoietin to stimulate erythro-poiesis (Setoguchi et al., 1994a), but this property can also be useful in understanding the in vivo roles of secreted proteins. For example, rats treated intravenously with a viral vector directing expression of the rat leptin protein exhibited reduced food intake and weight gain, as well as a disappearance of fat deposits (Chen et al., 1996). Intraperitoneal administration of an Ad vector containing the gene encoding HST-l FGF-4 to mice stimulated platelet production (Sakamoto et al., 1994). This group then used the same viral vector in an in vitro study to demonstrate that the increased platelet count was due to FGF-4 stimulation of megakaryocyte maturation...

Behavior And Reproduction

During the nonbreeding season, many sandpiper species feed and rest in large flocks. Sandpipers also migrate in large flocks of just one species. Some sandpipers migrate distances as great as several thousand miles, having built up large fat deposits to sustain them during the trip.

Other Steroid Hormone Bacterial Conversions

Studies have shown that fecal organisms can modify corticosteroids. The corticosteroids undergo reduction in ring A, and undergo side-chain dehydroxylation separately or sequentially with the reduction (48). Cortisol is converted to 21 -deoxycortisol, tetrahydrocortisol, and tetrahyro-21-deoxycortisol (48). Corticosterone is metabolized to tetrahydrocorticosterone, 21-deoxycorticosterone, and 3-alpha-hydroxy or 3-beta-hydroxy epimers of tetrahydro-21-deoxycorticosterone (48).

Zebrafish For A Model Of Nutritionrelated And Agedependent Chronic Diseases With Oxidative Stress

The increasing prevalence of obesity and other nutrition-related chronic diseases, which usually accompany aging, has prompted considerable efforts to understand their pathogenesis and treatment. One experimental approach is to overexpress, inactivate, or manipulate specific genes that regulate energy metabolism and fat storage. Many such techniques are fully amenable and have been established as routine tools in zebrafish, as well as in Drosophila and C. elegans. In the future, these elegant models will be complementarily helpful in dissecting endocrine problems and metabolic pathways, associated with aging and senescence. Particularly, once zebrafish counterparts of essential signaling molecules, such as Sir2 and FoxOs, involved in regulation of energy metabolism are available, development of model systems appear to be within of our current technologies and fat storage, are obtained, development of new vertebrate aging models appears to be within the scope of our current...

Growth Suppression of Prostate Cancer Cells in Culture by Androgen

The cellular level of AR mRNA was 2-3 fold higher in the LNCaP 104-R1 and 104-R2 cells than in LNCaP 104-S cells. AR protein level increased 10-20 fold during this transition from A-dependent 104-S cells to A-independent 104-R1 or 104-R2 cells. The growth of both 104-R1 and 104-R2 cells, as well as CDXR cells in culture was suppressed by physiological concentrations (

Neuroendocrine Studies

The neuroendocrine circuitries that serve as convergence points between the body weight and reproduction systems have been recently explored.57 Rare mutations in both the leptin gene and its receptor have been identified in patients with hypogonadotropic hypogonadism and morbid obesity.58 Interestingly, the administration of kisspeptin can correct the hypogonadism of leptin deficient animals, suggesting that the kisspeptin GPR54 pathway may serve a converging function between the reproductive and nutritional systems.59

EGCG Modulation of Food Intake and Endocrine Systems

After 7 days of daily ip treatment with EGCG, circulating levels of testosterone are reduced by about 75 in male rats and 17(3-estradiol levels by 34 in female rats. The weights of A-sensitive organs, such as ventral prostate and seminal vesicles and estrogen-sensitive organs, such as the uterus and ovary were reduced by about 50 . Other catechins were not as effective as EGCG. We also found that the serum level of LH is reduced by 40-50 , suggesting that low LH production led to the reduced blood levels of sex hormones. In both male and female rats, we observed significant reduction in blood levels of leptin, IGF-I, and insulin (1, 26). Some of these peptide hormones may modulate the levels of sex hormone and indirectly alter tumor growth in the animals.

Multigenic Models Of Susceptibility

The steroid pathways), the genes originally proposed included three of interest the 17jS-hydroxysteroid dehydrogenase 1 (HSD17B1) gene, the cytochrome P450c17a (CYP17) gene, and the estrogen receptor a (ESR1) gene (Fig. 5.3). These genes were selected not only because of their known function but also because polymorphisms had already been identified that could be functionally relevant. Data have been published on the role of CYP17 and HSD17B1 and breast cancer risk.119 Huang and col-leagues120 have published findings of a similar model with the estrogen-metabolizing genes CYP17, CYP1A1 (which participates in estrogen hydroxylation), and catechol-O-methyltrans-ferase (COMT), which encodes the enzyme responsible for O-methylation, leading to inactiva-tion of catechol estrogen. Several candidate genes for such a model are described in subsequent chapters, and the numerous studies of other polymorphisms are reviewed else-where.121

Growth Hormone Receptors In The

The successful purification of GHRs made possible the development of specific antibodies to measure GHR proteins (4). These have been useful to demonstrate GHRs in peripheral target tissues where GHRs are of low abundance (e.g., within the epiphyseal growth plate). Immunocytochemistry has also been used to confirm that GHRs are indeed expressed in the brain, particularly in fetal and young animals (5), and show a widespread distribution including regions of the CNS not obviously expressing GHR in later life. Similar immunohistochemical studies demonstrated GHR expression in human fetal brain tissue (6). One potential complication is that GHR can also give rise to a GH binding protein (GHBP) either by proteolytic cleavage of the full-length receptor or as a translation product of an alternatively spliced mRNA in rodents (7,8). Because of this, antibody localization studies employing an epitope directed against the extracellular domain of the GHR will also recognize GHBP moieties able...

And Parasympathetic Cardiac Controls

The suprarenal glands can also contribute to vasomotion. Because norepinephrine is released directly into the bloodstream from these endocrine glands, arteriolar constriction in the systemic organs can result. The human fight-or-flight response elicited under stressful or exciting circumstances originates within the hypothalamus and via hormones travels to the pituitary gland and later the adrenal cortex, where the agent cortisol is released into the bloodstream and adrenal medulla. It is in the medulla that cortisol activates the enzyme necessary to convert norepinephrine to epinephrine, which is released into the bloodstream to amplify increased sympathetic activity (2,3). Blood flow to the skin and other internal organs (like the stomach and intestines) is greatly decreased by increasing sympathetic (and decreasing parasympathetic) tonic activity flow to skeletal muscles and the heart increases considerably. This process can be thought of as simply delivering blood to the areas of...

Chemical Classification of Hormones

These are lipids derived from cholesterol. They include the hormones testosterone, estradiol, progesterone, and cortisol (fig. 11.2). Leptin Cortisol (hydrocortisone) Steroid hormones are secreted by only two endocrine glands the adrenal cortex and the gonads (fig. 11.2). The gonads secrete sex steroids the adrenal cortex secretes corticosteroids (including cortisol and aldosterone) and small amounts of sex steroids.

Changes in the skeleton and internal organs

Striking changes occurred in the skull for example, there was a shortening of the snout and jaws and at the same time a reduction of the number of teeth (dog, cat, cattle, pig). The shortened snout and accentuated rounded eyes induced the juvenile appearance of the eternal cub. It also resulted in lower brainpower and smaller brain volume. The skeleton became less resistant than that of wild animals as a consequence of the comfortable life with its lack of movement. For the same reasons, the size of some of the physical organs decreased, for example, the heart (35 lower by weight in the domestic rabbit when compared to its wild ancestor). Of course there are exceptions. The English thoroughbred, trained for several centuries for racing, has a heart about one fifth heavier than that of other horses of the same size. The fat storage mechanism has also been modified by domestication. In wild animals, fat is stored in the surroundings of the

Aging and the Hypothalamic PituitaryGonadal HPG Axis

Both males and females experience an age-related decline in the HPG axis. However, aging in the male system is a more gradual process in humans and in other species. Nonetheless, data show an age-related decline in testis function and decreased circulating androgen levels (for review, see Ottinger 1998). A recent study showed that circadian patterns in adrenal steroids were maintained in aging males for cortisol (Urbanski et al., 2004). Similarly, levels of dehydroepiandrosterone sulfate (DHEAS) also had a circadian pattern and did show an age-related decline.

Functions of the Adrenal Cortex

The predominant glucocorticoid in humans is cortisol (hydrocortisone), which is secreted by the zona fasciculata and perhaps also by the zona reticularis. The secretion of cortisol is stimulated by ACTH from the anterior pituitary (fig. 11.20). Cortisol and other glucocorticoids have many effects on metabolism they stimulate gluconeogenesis (production of glucose from amino acids and lactic acid) and inhibit glucose utilization, which help to raise the blood glucose level and they promote lipolysis (breakdown of fat) and the consequent release of free t Cortisol Remember that Rosemary had high blood levels of cortisol together with low ACTH. She also had a puffy appearance. What disease, due to what cause, is most likely responsible for Rosemary's condition

Sheep Ovis ammon f aries

Almost 14,000-year-old paintings from the La Pileta cave in Spain show sheep and goats in a corral. It takes a long time for wild sheep, which were kept in simple corrals, to become truly domestic animals. The oldest findings of domestic sheep come from the north Iran mountains (Zawi Chemi Shanidar) and date from 9000 B.C. However, there were certainly more areas of domestication in western Asia at that time. In 4000 B.C., domestic sheep were bred throughout the civilized world. At first they gave only meat, milk, and leather, and only later did wool sheep appear, though only with short and rough wool (in Mesopotamia around 3000 B.C.). In the first millenium, sheep spread all over Europe, Africa (except in primeval forest areas), and Asia (to Sulawesi). At that time sheep with white, longer wool were common, with four horns or without horns (known from ancient Egyptian frescos). Sheep from antique Greece and Rome resembled modern breeds. The number of sheep breeds today ranges between...

Determinants of Gene Expression

Stimuli can activate transcription factors, including signals like hormones and cytokines which are themselves responsive to events in the social environment. For example, when epinephrine released from the adrenal medulla encounters a white blood cell, it can bind to a -adrenergic receptor on the cell surface, initiating a signaling cascade that eventually results in activation of the transcription factor cyclic AMP response element binding (CREB) protein. The activated CREB protein can then bind to specific segments of DNA (called cAMP response elements) located in promoters of some genes. Depending on the structure of the promoter and what other molecules are present, CREB could then serve to enhance or suppress transcription of that gene. Thus, CREB and other transcription factors can function as conduits through which the social world modulates activity of the genome. (Other hormones can influence gene expression in the same basic fashion. For example, cortisol can bind to...

Underlying Mechanisms

To identify mechanisms linking chronic stress and differential transcription, we compared the diurnal output cortisol of caregivers and controls. Subjects collected saliva six times daily for a 3-day period, according to a schedule that captures the hormone's diurnal rhythm. Figure 30.4 illustrates that caregivers and controls displayed similar patterns of cortisol secretion over the day. Although caregivers showed higher cortisol than controls 4 h after waking (t 4.19, p 0.029), there were no significant differences at other times of day, and the groups were similar on global indices such as the diurnal rhythm of secretion and total output over the day (p's 0.59). We also considered whether differences were attributable to reduced expression of the GR among caregivers i.e., that glucocorticoid-mediated transcription arose because this group Fig. 30.4 Diurnal cortisol cycles in caregivers and controls. Caregivers showed higher cortisol than controls 4 h after waking (t 4.19, p 0.029),...

Perceived Stress and Social Support

As noted previously, most models of stress distinguish between stressors and their subjective evaluation (appraisals), even if this distinction is blurred in the wording of questions used to assess environmental exposures in specific instruments. Appraisals define the meaning of stressors to individuals, as in their perceptions of the threat or demands posed by a life event or circumstance, as well as individuals' sense of their capacity and resources to cope with a stressor effectively. Appraisal-based measures of stress tap these perceptions, either globally or within particular domains of activity. Compared with life event scales and early family environments, though, less is known about the her-itability of stress appraisals. In a twin study of organizational climate, genetic influences accounted for 22 of the variance in a composite measure of respondents' perceptions of their work environment as supportive (versus unsup-portive) and 27 of the variance in reported annoyance...

Gene Stress Interaction Acute Stressors

Children, genetic influences accounted for 5560 of the variance in salivary cortisol measured at baseline and following performance of a challenging video game and for 44 of baseline-to-task cortisol reactivity (Steptoe et al, 2009). Also, similar heritability was observed for salivary and total cortisol, ACTH, and heart rate responses to the trier social stress test (TSST), a composite stress protocol involving mental arithmetic and public speaking before an audience, in an earlier study of adolescent young adult twins (Federenko et al, 2004). Not surprisingly, one target of molecular studies has been the GR gene (NR3C1). Genotyping four putatively functional NR3C1 polymorphisms, labeled N363S, ER22 23EK, 9p , and an intronic marker of unknown function, Bcll, Wust and colleagues (2004) found TSST-elicited salivary cortisol responses in males to be greatest among carriers of the 363S allele and blunted in participants homozygous for the Bcll GG allele. In a subsequent study, the Bcll...

Ligand Entry Loop Interactions

Figure 9.3 (a) Schematic diagram of the active site of the 17 -hydroxysteroid dehydrogenase 1 (17HSD1)-equilin-oxidized nicotinamide adenine dinucleotide phosphate (NADP+) ternary complex. Residues belonging to the hydrophilic catalytic and recognition ends, as well as residues lining the hy- Figure 9.3 (a) Schematic diagram of the active site of the 17 -hydroxysteroid dehydrogenase 1 (17HSD1)-equilin-oxidized nicotinamide adenine dinucleotide phosphate (NADP+) ternary complex. Residues belonging to the hydrophilic catalytic and recognition ends, as well as residues lining the hy- Figure 9.4 Superposition of the backbones of structures of 17 -hydroxysteroid dehydrogenase 1 (17HSD1) apoenzyme and ternary complex with equilin and oxidized nicotinamide adenine dinucleotide phosphate (NADP+). Substrate-entry loops (residues 286-201) in open and closed forms are shown in thicker cross-sections.

The choice between Thl and Th2 responses in humans nature versus nurture

Neuroendocrine factors have a powerful effect on immune responses. Populations stressed by war or natural disasters have an increased incidence of infections such as tuberculosis and typhus, but under these circumstances it is difficult to estimate the relative contributions of defective public health and of increased host susceptibility to infection. Bernton et al (1995) studied the immunological and endocrine changes in military recruits under conditions of 'mental and physical stress approaching that found in combat', and found raised cortisol levels and reduced DHEA cortisol ratios in these recruits. Testosterone levels, delayed-type hypersensitive responses and T cell mitogenic responses decreased, while IgE levels increased. The authors suggested that stress induced a Th1 to Th2 shift.

The Hypothalamic PituitaryGonadal HPG Axis and Agerelated Changes

Figure 43.1 A summary of the hypothalamic-pituitary-gonadal axis of females. GnRH stimulates gonadatropin release (LH and FSH), which then stimulates ovarian steroid hormone release (estrogen and progesterone). Estrogen either has positive (just prior to ovulation) or negative feedback actions on the hypothalamus and pituitary. Inhibin is also released by the ovary and inhibits FSH release. In rats, the estropause is characterized by continued high estrogen levels and a persistent estrus vaginal cytology until much later in life. On the arrows, the circle refers to the initiator of the signal, and arrows indicate the termination of the signal. Figure 43.1 A summary of the hypothalamic-pituitary-gonadal axis of females. GnRH stimulates gonadatropin release (LH and FSH), which then stimulates ovarian steroid hormone release (estrogen and progesterone). Estrogen either has positive (just prior to ovulation) or negative feedback actions on the hypothalamus and pituitary. Inhibin is also...

GHD in the Newborn Period

Hypopituitarism may present in the newborn in a nonspecific fashion. Signs and symptoms include apnea, cyanosis, pallor, lethargy, jitteriness, and seizures. The differential diagnosis of hypogylcemia includes GHD and hypopituitarism, which could include cortisol deficiency. Prolonged hyperbilirubinemia may be owing to TRH or TSH deficiency, causing hypothyroidism in a neonate with multiple hormone deficiency. Patients with congenital hypopituitarism may have a turbulent neonatal course, generally more characteristic of a full-term infant because of the frequency of neonatal problems in preterm infants. Neonatal glucocorticoid deficiency can present as hyponatremia.

Cushings diseaseCushings syndrome

Diagnosis is by detection of an elevated plasma cortisol with lack of diurnal variation. Because other conditions can produce a similar pattern (e.g. excess alcohol production), a low dose Dexamethasone suppression test should be performed to confirm the diagnosis. Dexamethasone suppresses ACTH production but does not interfere with cortisol assay. Therefore, in a patient who does not have Cushing's syndrome, Dexamethasone, by suppressing ACTH, will suppress cortisol. If cortisol levels are not suppressed, the next step is to measure plasma ACTH (by a radio-immunoassay) and to perform a high dose Dexamethasone suppression test to determine suppression of urinary 17-hydroxy-corticosteroids.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia is the commonest form of virilisation and is due to a genetic enzyme defect which results in deficient secretion of cortisol. This results in reduced negative feedback to the pituitary resulting in a very high ACTH. This produces adrenal hyperplasia and excess androgen production, especially androsterone which is converted to testosterone peripherally. Androsterone is a 17-ketosteroid and testosterone is not. Therefore, virilisation with an elevated urinary 17-keto steroid level suggest adrenal origin, while a normal or only slightly elevated 17-ketosteroid suggests excess testosterone from ovary or testis. Congenital adrenal hyperplasia is treated by glucocorti-coids which supply cortisol requirements and suppress the ACTH. Cosmetic surgery may be required.

The Link Between Birth Weight and Later Health

While most clinical attention has been focused on premature and SGA babies, there is a complementary literature indicating that excessive fetal growth can present a different set of problems. With large-for-gestational age babies (LGA), there is a significant increase in obstetrical complications and need for caesarian delivery (Gregory et al, 1998). In addition, these infants are more likely to continue on the path toward obesity during childhood and adulthood, especially after diabetic pregnancies (Law et al, 1992). Longitudinal studies show they are predisposed to have poorer glucoregu-lation and to develop type 2 diabetes as adults. Here too, basic science studies in animals have provided considerable support for these associations and revealed several critical mediating pathways linking accentuated growth rates and later disease. For example, pregnant dams fed a high caloric diet will gestate offspring with a distinctive insulin response and altered pancreatic size and renal...

Challenges to Fetal Wellbeing Maternal Stress

With many long-lasting ramifications after birth (Weinstock, 1997). The experimental manipulations used to evoke stress range from immobilization or arousing sensory stimuli in rodent models to stressful husbandry conditions in farm animals and social aggression in primates. Even when gestation length and infant birth weight are not affected, many alterations in the infant's behavioral and physiological functioning have been described (Coe et al, 2007). The offspring from stressed pregnancies often appear to be more behaviorally and emotionally reactive. Thus, when challenged, they continue to manifest larger behavioral and hormonal responses to stressful events. In rats and mice, the secretion of hypothalamic-pituitary-adrenal hormones is typically greater, and increased HPA activity often persists into adulthood (Koehl et al, 1999). Basal levels of adrenal hormones are more typically reported to be normal in primates, but there may be alterations in the diurnal hormone rhythm or an...

The Mixed Blessing of Antenatal Corticosteroids

An additional reason for so much interest in the potentially adverse effects of corticosteroids on the fetus is its common use in clinical practice when babies are born premature (Merill and Ballard, 2001). Given the concerns about excess fetal exposure to maternal cortisol, it may seem paradoxical that one of the more important trans-lational findings from animal research to clinical practice was the seminal finding that antenatal corticosteroid treatments are very beneficial in quickly advancing lung maturation (Liggins, 1969). Experiments in sheep showed that rising cortisol levels in the ewe signal the impending parturition and simultaneously accelerate the production of lung surfactant in the immature fetal lamb. The benefits for improving airway functioning in premature infants were soon extended to humans (Liggins and Howie, 1972). While these findings revolutionized the treatment of neonatal respiratory distress syndrome, reduced the likelihood of intraventricular hemorrhage...

How Ovarian Steroids Affect Mammographic Density

The association between ovarian steroids and mammographic density parallels what is known about the effects of ovarian steroids and breast cell proliferation.43 Breast cell proliferation is higher in pre- than postmenopausal women and higher in women in the luteal than in the follicular phase of the menstrual cycle. In short, high estrogen progesterone levels are associated with high amounts of breast cell proliferation.

Early Family Environment

Similar patterns are found when an early family environment is assessed directly. A harsh family upbringing has been related to poor health behaviors (Repetti et al, 2002) to high levels of depression, hostility, and anxiety (Repetti et al, 2002) to preclinical risk factors for physical health disorders, including elevated autonomic and cortisol responses to threatening circumstances (e.g., Roisman et al, 2009 Taylor et al, 2004) to risk factors for disease, including compromised metabolic functioning (Lehman et al, 2005) and C-reactive protein (Taylor et al, 2006b) and to diagnosed health disorders, including ischemic heart disease, some cancers, and depression (Felitti et al, 1998). Socioemotional resources that affect the ability to regulate emotional states effectively and to develop social competencies are implicated in these pathways. For example, offspring from harsh early environments experience difficulty in managing emotions in challenging circumstances (Repetti et al, 2002,...

Neural Regulation of Stress Responses

Socioemotional skills are themselves related to the neural regulation of threat responses and, thus, constitute an indirect route whereby early environment is implicated in the regulation of biological stress responses. In a recent study (Eisenberger et al, 2007), participants completed a signal-contingent daily diary experience sampling procedure over a 9-day period in which each time they were signaled, they rated how supportive their most recent social interaction had been. At the end of this period, participants took part in an fMRI investigation of neural responses to threat, specifically a virtual social rejection task (cyberball) that has previously been shown to evoke psychological distress (Eisenberger et al, 2003). At a third time point, participants experienced laboratory stress challenges (the Trier Social Stress Task (TSST), Kirschbaum et al, 1993) to assess autonomic and neuroendocrine reactivity to social stressors. People who reported frequent supportive interactions...

Impact of Early Environment on Biological Stress Responses

The neural regulation of responses to threat ultimately affects downstream biological stress regulatory systems. What are these systems During times of stress, the body releases the catecholamines epinephrine and norepinephrine with concomitant sympathetic nervous system arousal. Stress may also engage the HPA (hypothalamic-pituitary-adrenocortical) axis, involving the release of corticosteroids including cortisol. These responses have short-term protective effects under stressful circumstances, because they mobilize the body to meet the demands of pressing situations. However, with Stress can also suppress immune functioning in ways that leave a person vulnerable to opportunistic diseases and infections. Corticosteroids such as cortisol have immunosuppressive effects, and stress-related increases in cortisol have been tied to decreased lymphocyte responsivity to mitogenic stimulation and to decreased lymphocyte cytotoxicity. Such immunosuppressive changes may be associated with...

Materials and Methods

Tissue Sample, RT-PCR, and AR Yeast-based Functional Assay. The patient was diagnosed with T3NxMo PCA at age 76, and was first treated with leuprorelin and flutamide. The patient responded to this complete androgen blockade for 17 months, and relapsed thereafter. Using bone scanning, diffuse bone marrow metastases including bilateral posterior iliac metastases were revealed at that time. He was later treated by alternative hormonal (cyproterone acetate, cortisol, medroxyprogesterone) and chemotherapy. The bone marrow sample was aspirated at the site of a hyperfixation area on the right posterior iliac crest, five years after the initial diagnosis, and cytologic examination showed the presence of numerous metastatic PCA cells. Total RNAs were isolated from the bone marrow sample, and an AR fragment (1786 bp, 2311 - 4097) was amplified by RT-PCR, and cloned into a yeast expression plasmid. The AR functional assay has been described (7).

Biological Pathways

A number of biological pathways are thought to link SES to adolescent health. In this section we provide a brief overview of the biological risk markers that are likely to impact adolescents' health into their adult life. Research has primarily focused on risk factors for cardiovascular health, such as blood pressure, cardiac reactivity, and hormonal profiles, for example, cortisol, which can provide information about the potential dysregulation of the hypothalamic-pituitary axis (HPA). In addition, some studies have found links between SES and hormonal profiles among adolescents. Results from a longitudinal study (Evans and Kim, 2007) showed that among 13-year olds, those who had been exposed to greater cumulative exposure to poverty over the course of their life span had higher levels of overnight urinary free cortisol at the follow-up assessment, after controlling for baseline values. Another study found evidence of increased daily salivary cortisol output among both healthy...

Information from Human Studies

Wismer Fries et al (2005) reported that children who had lived in orphanages with limited social contact for an average of 17 months before being adopted showed lower overall urinary vasopressin levels for 4 days and lower urinary oxytocin during a game involving lots of mother-child touching compared with age-matched children who had always lived with their parents. Adult men who experienced early parental separation have also failed to show normal inhibition of cortisol following intranasal oxytocin administration (Meinlschmidt and Heim, 2007), while adult women who had experienced childhood abuse or neglect had lower oxytocin levels in their cerebrospinal fluid (Heim et al, 2008). Together, these studies suggest that central oxytocin and vasopressin pathways may show long-term effects of early life events involving parental attachment. In young unmarried adults, higher plasma oxytocin levels were linked to stronger attachment to their parents and to lower...

Project Title Mentored Patient Oriented Research Career Development Aw

Summary PROPOSAL (Adapted from the applicant's abstract) Major depression is a significant independent risk factor for the development of ischemic heart disease and is a potentially lethal comorbid condition in post-myocardial infarction patients. The pathophysiology that links major depression to the occurrence of heart disease is not known. Preliminary observations indicate that platelet reactivity is increased in depression, which implies that depressed patients may be prone to thrombus formation, hence at increased risk for catastrophic cardiac events. There are considerable data indicating that the serotonergic system is altered in depression, both in the central nervous system (CNS) and in the platelets. In the periphery, the most notable and consistently replicated observation of serotonergic alteration is an increased B max for the serotonin-2A (5-HT2A) receptor on the platelets of depressed individuals. The platelet 5-HT2A receptor plays a central role in platelet reactivity...

Of Physiological Stress Mechanisms in the Oldest

Other aging-specific observations have been found for the hypothalamus-pituitary-adrenal (HPA) axis which produces the stress hormone cortisol. Generally, high cortisol levels are hypothesized to be linking mechanisms between behavioral factors and adverse health outcomes. In an aged population, however, physical frailty could actually exhaust the body's responses to stress potentially resulting in hypoactivity of the HPA axis. This may explain why some studies among older frail persons have in fact observed not only hyperactivity but also hypoac-tivity of the HPA axis among depressed persons (Bremmer et al, 2007 Penninx et al, 2007). Consequently, not considering the possibility of reduced cortisol levels among depressed older persons might lead to erroneous conclusions. Results of the InCHIANTI study among 800 community-dwelling older persons showed that only hypercortisolemic depressed persons showed an increased prevalence of the metabolic syndrome (Vogelzangs et al, 2007b)....

Biological Indicators of Health or Resistance to Disease

Have emerged from analysis of the second group of biomarkers. This category is not disease specific, but instead relates to general indicators of health and resistance to disease, and also includes markers of stress reactivity. These indicators supply information about future risk but do not typically define a specific illness. Although elevations in some markers are associated with reduced risk, such as high density lipoprotein (HDL) cholesterol, most are related to increased risk of future disease. They include the inflammatory markers C-reactive protein and interleukin (IL)-6, the neuroendocrine parameter cortisol, and hemostatic markers such as fibrinogen and von Willebrand factor. Cortisol is involved in immune and metabolic regulation, and elevated levels are linked with abdominal adiposity, insulin resistance, diabetes, CHD, and depression (Dekker et al, 2008 Herbert et al, 2006 Raison et al, 2006). Cortisol also contributes to memory function across the life span, with...

Psychophysiological Stress Testing

Cortisol can take up to 30 min to peak, and inflammatory cytokines such as IL-6 continue to rise for up to 2 h post-stress. There is growing interest in variations in rate of post-stress recovery, since these may be indicative of chronic allostatic load (see Chapter 42). Protocols that are not sufficiently long to measure recovery processes lose data that are potentially significant to health. Recovery rates vary with psychosocial factors and with age. Blood pressure, for instance, may return to baseline within a few minutes of stress termination in young adults, but can remain elevated for more than 1 h in older individuals (Steptoe et al, 2002). It is also important to recognize that stress tasks are not interchangeable, but have distinctive characteristics. Apart from well-known dimensions such as sensory intake rejection, predictability unpredictability, and control-labity uncontrollability, the involvement of social challenges is relevant. Dickerson and Kemeny's (2004)...

Naturalistic and Ambulatory Monitoring of Biological Variables

Naturalistic studies involve sampling biological variables during everyday life. This sampling method is known as ambulatory monitoring when the measurement instruments are carried on the person and operate automatically. Naturalistic studies take many forms, from recordings during challenging tasks such as parachuting or public speaking, to repeated measures of blood pressure or salivary cortisol over an ordinary day. Some of these techniques are extensions of methods used in clinical investigation, such as Holter monitoring of electrocardiogram in patients with coronary artery disease and the use of ambulatory blood pressure monitors for evaluating hypertension. The purpose of these methods in behavioral medicine research is to assess biological activity under natural conditions and thus to circumvent some of the problems with laboratory studies concerning ecological validity. In addition, these

Summary and Limitations

Validity, evaluating biological activity in real life rather than under the artificial conditions of a laboratory or clinic. Associations between psychosocial factors and biological responses may be observed that are not detectable when single measures are taken under clinical or survey conditions. But naturalistic methods also have several drawbacks, in addition to the specific methodological issues described earlier. First, the range of biological markers that can be assessed is relatively small in comparison with the more sophisticated possibilities available in the laboratory setting. Second, the measurement techniques need to be relatively unobtrusive, so as not to interfere with ongoing activities. This is why some pioneering studies of repeated measurements over the day can now be questioned for their representativeness. For instance, much of the early data on circadian rhythms of cortisol secretion involved venepuncture every 1 or 2 h for 24 h or the periodic withdrawal of...

Why look for human obesity genes

The discovery of human obesity genes will undoubtedly lead to health benefits. Firstly some obesity syndromes are very severe, occur at a young age and are associated with other developmental and clinical manifestations. It is clear that knowledge of the underlying genetic defect in these syndromes will be of considerable clinical benefit in terms of recognising other treatable aspects of the particular syndrome and providing more informed genetic counseling. As illustrated by congenital leptin deficiency (see below) the precise identification of some of these syndromes may turn out to have therapeutic relevance.

Sampling Framework Is Specific to the Biological Outcomes

There is no correct sampling interval for physiological outcome measures the sampling strategy will depend on the nature of the specific outcome parameter. Some measurements can be taken only once, usually at the end of each phase of the study, due to timing constraints or expense (e.g., echocardiogram). Other measures are assessed continuously (e.g., ECG) or intermittently (e.g., salivary cortisol, serum cholesterol) during the phases of the study. The measurement of salivary cortisol, for example, presents a specific challenge in terms of the proper sampling interval because there is a latency ( 20 min) between the stressful event and the release of cortisol therefore, the researcher has to map out the measurement intervals carefully. Thus, a saliva sample for assessment of cortisol might be obtained 20 min after stressor offset. If the interval is mis-specified, the effect of the manipulation may be missed entirely.

Obesity as a disease state or adiposity as a continuous variable

Obesity as a clinical condition is currently defined as an excess accumulation of adipose tissue resulting in a BMI greater than 30kg m2. While the diagnosis of obesity by this criterion has clinical relevance with regards to intervention, management, and treatment, from an epidemiological perspective, it may hamper the study of the genetics underlying variation in body fat mass and distribution. For example, BMI exhibits a normal distribution with no clear division between the ''clinically obese'' (BMI 30) and the non-obese. Such a pattern of continuous distribution is not restricted to merely BMI but is found in all obesity-related phenotypes, including anthropo-metric measures (e.g. skin folds, and waist circumference), measures of body composition (e.g. percentage body fat, fat mass), and associated biochemical markers (e.g. leptin). Therefore the division of individuals into ''obese'' versus ''non-obese'' categories has a certain degree of arbitrariness that does not appear to...

Social Interaction Tasks Speech Tasks

The TSST was initially developed to evaluate effects of psychosocial stress on cortisol activity in a laboratory setting (Kirschbaum et al, 1993). Because the time course of Cortisol is relatively slow - a measurement may reflect the state of the body 15-20 min earlier - the researcher has to pay particular attention to the timing of the task and the measurements. Moreover, for a stressor to have a substantial effect on cortisol, it must persist for a longer time than other measures require. The TSST was designed to address these concerns. The 20-min test comprises two stressors, conducted in front of a panel of judges An impromptu speech (explaining why they had been caught shoplifting) and mental arithmetic (other variants of this task, however, are used).

Transduction of the Liver

Leptin is a potent modulator of weight and food intake. Leptin deficient ob ob mice gain considerable weight ( 70 g) compared with lean littermates ( 28 g) at 8 to 12 weeks of age. Morsy et al. (62) compared HDAd with FGAd, with respect to safety and efficacy, for leptin gene therapy in ob ob mice. Intravenous injection of 1-2 X 1011 particles of a FG vector encoding murine leptin (Ad-leptin) into ob ob mice resulted in an increase in serum leptin levels for only the first 4 days, returning to baseline levels 10 days postinjection (Fig. 5A). Increased leptin levels were associated with transient weight loss of 25 followed by weight gain 2 weeks after treatment (Fig. 5B). In contrast, ob ob mice injected with an HDAd-encoding leptin (HD-leptin) resulted in about 2-fold higher serum levels of leptin up to 15 days postinjection (Fig. 5A). However, expression was transient and gradually returned to baseline levels 40 days postinjection. Rapid weight loss to levels approaching that of...

Proopiomelanocortin deficiency

The first-order neuronal targets of leptin action in the brain are anorectic (reducing food intake) pro-opiomelanocortin (POMC) and orexigenic (increasing food intake) neuropeptide-Y Agouti-related protein (NPY AgRP) neurons in the hypothalamic arcuate nucleus, where the signalling isoform of the leptin receptor is highly expressed (Schwartz et al., 2000). Forty percent of POMC neurons in the arcuate nucleus express the mRNA for the long form of the leptin receptor and POMC expression is regulated positively by leptin. POMC is sequentially cleaved by prohormone convertases to yield peptides including a-MSH that have been shown to play a role in feeding behavior.

Methodological Aspects When to Measure Neuroendocrine Markers

Single time point basal measurements in the individual case, however, may be strongly misleading, as hormones are secreted in a marked pulsatile fashion. For example, cortisol is released in hourly pulses with differing amplitudes across the day (Young et al, 2004). Basal hormone assessments do not necessarily reveal information on the integrity and reactivity of neuroendocrine axes. Therefore, a variety of challenge tests have been developed, using either pharmacological agents or real-life stimuli. Pharmacological challenge tests either stimulate or suppress an endocrine axis. For stimulating hormone secretion, hypothalamic releasing hormones and pituitary hormones have been used. The feedback sensitivity of an axis may be estimated by the degree of axis suppression after administering a synthetic version of the natural hormone exerting inhibitory feedback actions (see also Section 2.2). Other physiological stimuli activating endocrine axes may be mimicked by the administration of...

The Hypothalamic PituitaryAdrenal Axis

Cortisol, secreted by the adrenal gland, is a major stress hormone and exerts vital effects on the cardiovascular, immune, and metabolic systems. Cortisol stimulates hepatic gluconeoge-nesis, amino acid, and free fatty acid mobilization and inhibits glucose uptake by muscle and adipose tissues. It furthermore alters immune functions by upregulating the expression of anti-inflammatory proteins and dampening levels of pro-inflammatory substances. However, permanently enhanced HPA axis activity has been linked to health impairments (Charmandari et al, 2004 Puetz, 2008).

The Neuroendocrine Dysfunction

As described earlier, aging is associated with a low-grade inflammation. This manifests itself also at the neuro-endocrine level by a relative sustained increase of cortisol and adrenergic hormone levels in elderly subjects (Valenti, 2004). The stress hormones such as cortisol may contribute to the development of insulin resistance. In case of acute events, such as illnesses, the effect of these stress hormones may be accentuated, contributing to the occurrence of type 2 diabetes. The contributing effect of cortisol on impaired glucose tolerance or type 2 diabetes could be through its ill-defined age-dependent effects on the innate immune response or direct interference with insulin-mediated glucose disposal. The -adrenergic effect of catechol-amines by inhibiting insulin secretion further accentuates the contribution of age-related hormonal changes to insulin resistance in diabetes mellitus. The activation of serine kinase via the catecholamine-mediated cAMP dependent kinase inhibits...

Reproductive biology

Humans mature slowly, so that the onset of puberty is delayed relative to pongids and other catarrhines. In females, the onset of puberty is signaled by menarche, or first menstruation. This is triggered by a critical amount of body fat. The hormone leptin, released by fat, appears to trigger menarche. Reduction of body fat in a cycling female suppresses menstruation.

Linkage studies in common obesity

At present, the strongest evidence for a QTL influencing obesity-related phenotypes in humans comes from the San Antonio Family Heart Study (SAFHS) with a Log Odds Ratio (LOD) score of 7.5 for serum leptin levels on chromosome 2 (Comuzzie et al., 1997). This study used a sample of 459 Mexican-Americans distributed in ten families. In addition, in this population significant linkage has also been detected on chromosome 8 with both leptin (LOD 3.1) (Martin et al., 2002) and BMI (LOD 3.2) (Mitchell etal., 1999), as well as on chromosome 17 (LOD 3.2) for BMI (Comuzzie, 2002). The chromosome 2 QTL localizes very near the POMC locus, which encodes pro-opiomelanocor-tin. Hixson and colleagues detected significant association (P 0.001) between molecular variation in the POMC locus and variation in serum leptin levels among Mexican-Americans (Hixson et al., 1999). The region containing the QTL on chromosome 8 contains the b-3-adrenergic receptor (ADRB3 gene), a strong candidate previously...

The HPA Axis Under Challenge

To investigate the functionality of the HPA axis, various ways to stimulate acute cortisol responses in the laboratory have been developed, including psychological stress protocols (e.g., cognitive tasks or public speaking paradigms (for an overview, see Kudielka et al, 2009) and a wide variety of pharmacological provocations, physical exercise, or intake of standardized meals. While psychological stressors are central stimuli that are processed at higher brain levels, pharmacological challenge tests are specifically tailored to act at certain levels of the HPA system and operate in a dose-dependent manner. The HPA axis is regulated by the negative feedback action of cortisol on receptors in the hippocampus, hypothalamus. and pituitary gland. The dexamethasone suppression test is used to test HPA axis negative feedback efficiency by determining the degree to which endogenous cortisol release is suppressed by intake of oral dexamethasone. This synthetic glucocorti-coid acts primarily...

Hypothalamic PituitaryThyroid Axis

TSH-producing cells in the anterior pituitary are positively regulated by TRH, while TSH-inhibiting substances include dopamine, somato-statin, T3 (triiodothyronine), and cortisol. Given sufficient iodine levels, the biologically inactive form thyroxine (tetraiodothyronine, T4) is released through TSH binding at the thyroid gland. The conversion to bioactive T3 mostly happens in target tissue, such as the liver. T3 influences growth and development, oxygen consumption, and heat production (Joffe, 2002).

Experimental Animal Models

Currently there exist several experimental animal models for the study of diabetes (Mathews, 2002). The most currently used are from rodents. All these animal models mainly reproduce by genetic engineering single specific alterations found in type 2 diabetes. These models try to elucidate one particular pathological aspect of the disease. The most widely used are the leptin-deficient ob ob_ mice, db db+ + mice, KATP-channel mutated, ApoE deficient mice with other deficiencies, several knock-out mice including for RAGE, for specific signaling molecules for IR, for PTP1B.

The Oxytocinergic System

Oxytocin affects species-specific social and reproductive behaviors (for an overview, see Heinrichs and Domes, 2008, Heinrichs et al, 2009). Warm social contact with the partner, sexual arousal, orgasm, and attachment as well as regulation of parturition and lactation have been related to oxytocin actions in women. Oxytocin interacts with the HPA axis and has stress-reducing effects in both men and women During laboratory stress, oxytocin was found to diminish cortisol responses, which is most likely due to a central inhibition of the HPA axis, involving reduced amygdala reactivity.

Recent Advances in Treatment

Pathogenic mechanism of diabetes type 2 has provided a strong rationale for the introduction of thiazolidinedione (TZDs), which are PPARy agonists and which target insulin resistance in part through improvement of postprandial fat storage in adipose tissues (Miles et al., 2003 Boden et al., 2005). Large clinical trials are currently ongoing to test whether these drugs can prevent the progression of beta cell dysfunction in the natural history of diabetes and whether their beneficial effects on cardiovascular function observed in small-scale studies can translate into significant benefits in terms of hard cardiovascular end-points (Kanaya et al., 2003).

Pathogenic Mechanisms

The lipolytic process is mainly regulated by catecholamines in human adipose tissue (18). Furthermore, visceral adipocytes have a higher density of lipolytic -adrenergic receptors than other fat cells, mediating lipolysis by the action of norepinephrine (19). The density of glucocorticoid as well as androgen receptors is also higher (12,20). The effect of cortisol is mainly to increase visceral fat mass by increasing the expression of LPL (21,22), while testosterone has the capacity to decrease fat accumulation by inhibiting LPL (23,24) and enhancing lipolysis by the increasing the expression of P-adren-ergic receptors (25,26). In addition to these intrinsic characteristics of the visceral adipocytes the surroundings of these cells are different from other adipocytes. Blood flow is higher than in other adipose tissues (27), which is of fundamental importance for both lipid uptake and mobilization, and in addition visceral adipose tissue contains more catecholamines and...

Endocrine Aberrations

During recent years of investigation abdominal visceral distribution of adipose tissue has been found to be associated with endocrine disturbances, confirming the original observation by Vague (6). These disturbances include an increased cortisol activity and a blunted secretion of growth hormone (GH) and sex steroids in both men and women (29-34). These endocrine perturbations can theoretically be a consequence of the obese condition but it has also been suggested that the endocrine aberrations can have causal effects (33,35). Cortisol is of interest as it causes accumulation of abdominal visceral adipose tissue (39) and an increased release of FFA. The latter will, in turn, cause reduced insulin binding in the liver and thereby higher circulating levels of insulin, glucose, and blood lipids by the mechanisms discussed above. The role of cortisol in obesity has been controversial during many years. Several authors have found decreased plasma cortisol levels in obese subjects while...

Hypothalamic PituitaryAdrenal Axis HPA Interactions

Briefly, it is now well understood that complex and dynamic interactive communication exists between the cytokines and the HPA and that the regulation of cytokine release, as well as HPA responses to immune insults, is governed in part by positive and negative feedback loops between the two systems (Kariagina et al, 2004). In particular, pro-inflammatory cytokines have been shown to stimulate HPA stress responses, while Th2 cytokines can inhibit this activation. For example, pro-inflammatory cytokines appear to activate corticotropin releasing hormone (CRH) and arginine vasopressin neurons in the par-vocellular paraventricular nucleus within the hypothalamus. This activation results in a downstream HPA cascade in which CRH is released from the hypothalamus, promoting release of corticotrophin (ACTH) from the anterior pituitary gland and resulting in release of the glu-cocorticoids corticosterone and cortisol from the adrenal cortex. There are several postulated mechanisms of action...

Cytokines Stress Negative Affect and Sleep

We investigated the IL-6 response to acute stress and whether the response would habituate to a repetitively applied stressor. As part of the mechanism of the response, we examined whether cortisol reactivity would show a relationship with IL-6 reactivity. Study participants underwent the Trier Social Stress Test three times with an interval of 1 week. Plasma IL-6 and free salivary cortisol were measured immediately before and after stress and at 45 and 105 min of recovery from stress. Cortisol samples were also obtained 15 and 30 min after Fig. 45.1 IL-6 (a and b) and free salivary cortisol (c) measures. IL-6 was measured immediately before stress (rest), during mental arithmetic (stress), and 45 and 105 min after stress. Compared to the non-stressed control group, IL-6 had significantly increased (*) in the stress group 45 and 105 min after stress (a). In the stress group, IL-6 was significantly higher (*) 45 and 105 min after stress than at rest, but IL-6 showed no habituation...

Effects of Behavioral Stressors and Negative Affect on Hemostasis

Different types of speech tasks, mental arithmetic, mirror star tracing task and the Stroop color-word conflict test, are regularly applied as mental stressors in studies. This research suggests that acute stress elicits a significant increase both in procoagulant factors (i.e., FXII, FVII, FVIII, fibrinogen, VWF, platelet activity) and in profibrinolytic t-PA (Table 45.1). However, findings of an increase in coagulation activation markers TAT and D-dimer suggests that the concomitant activation of virtually all hemostasis components with acute stress results in net hypercoagulability compatible with the evolution paradigm of Cannon (von Kanel et al, 2001). We showed that, unlike changes in blood pressure and cortisol, changes in the coagulation system do not adapt in response to the same stressor (i.e., combined speech task and mental arithmetic) applied three times to healthy subjects with an interval of 1 week (von Kanel et al, 2004a) (Fig. 45.5). Apparently, evolution empowered...

Drugs For Dyskinesia Sarizotan

64 dyskinetic PD subjects, sarizotan, at doses ranging from 2 mg BID to 10 mg BID, prolonged the amount of on time without dyskinesia (55). PD symptoms were not worsened, as assessed by amount of off time or UPDRS scores, although some patients did report worsening of parkinsonism as an adverse event. Additional adverse events reported included sedation and nausea. Higher doses have been associated with suppression of the cortisol response to ACTH challenge, but this was not seen in PD. A large multicenter Phase III trial did not demonstrate a difference between sarizotan and placebo and consequently the development of this compound for PD has been abandoned (56).

Etiology and Pathogenesis

Polymorphisms in the promoter region of the serotonin transporter gene (5-HTTLPR) may play a role in the pathogenesis and course of depression and anxiety (Hariri et al., 2003 Sen et al., 2004 Taylor et al., 2005). Geneotype has been related to hippocampal volumes (Taylor et al., 2005) and to amygdala reactivity to environmental stimuli (Hariri et al., 2005). These findings may be related to interactions between the serotonergic system and neurotrophic factors or cortisol response to stresses and may bias an individual's reactivity to stressful life experiences (Hariri et al., 2005 Taylor et al., 2005). Some studies report that genotype significantly predicts the development of depression after stressful life events (Lenze et al., 2005), although others did not find an association (Gillespie et al., 2005). Several studies have suggested that response to antidepressant therapy may be related to serotonin transporter genotype (Murphy et al., 2004). The short (S) allele was associated...

Models of Neural Control of HRV

Self-regulation and adaptability that might provide a unifying framework within which to view the diversity of observed responses across domains (Thayer and Lane, 2000, 2009). In this model a set of neural structures that regulate physiological, behavioral, emotional, and cognitive responses can be indexed via peripheral indices such as cortisol excretion, startle blink magnitude, inflammatory markers, and HRV. This model emphasized the role of HRV as an index of self-regulation and its ability to reflect neural feedback mechanisms between the central nervous system (CNS) and the autonomic nervous system (ANS).

Glucocorticoid remediable aldosteronism GRA

The last stages in the synthesis of the mineralo-corticoid aldosterone and the glucocorticoid cortisol take place in the adrenal cortex, and are catalyzed by two highly homologous enzymes which lie adjacent to each other on chromosome 8. CYP11B1 (11-beta hydroxylase) converts deoxy-cortisol to cortisol (the principal corticosteroid), a process involving 11-hydroxylation, and CYP11B2 (aldosterone synthase) converts deoxycorticoster-one to aldosterone (the principal mineralocorti-coid), a process involving 18-hydroxylation. The CYP11B1 promoter is responsive to plasma levels of adrenocorticotrophic hormone (ACTH) and thus CYP11B1 is constitutively active, regulated by negative feedback of cortisol on the hypotha-lamic pituitary axis. The CYP11B2 promoter responds to the activity of the renin angiotensin system, mediated via the action of angiotensin II on Type I angiotensin II receptors. In some families segregating hypertension, hypokalemia and hyperaldosteronism in an autosomal...

Apparent mineralocorticoid excess AME

Though cortisol is principally a glucocorticoid, the mineralocorticoid receptor exhibits the same affinity for cortisol in vitro as it does for aldoste-rone. Since the plasma concentration of cortisol is over 100 times higher than that of aldoste-rone, the discovery that cortisol could bind to the mineralocorticoid receptor raised the question of how the specificity of that receptor for aldosterone is preserved. This is the role of the short chain dehydrogenase-reductase enzyme 11-betahydroxy-steroid dehydrogenase type 2 (HSD11B2), which is principally expressed in the collecting ducts of the kidney and is responsible for converting cortisol to cortisone (which is inactive at the mineral-ocorticoid receptor Figure 25.3 ). The syndrome of hypertension and hypokalemic alkalosis produced by liquorice intoxication or the drug carbenoxolone (which is very similar biochemically to hyperaldosteronism, but without aldosterone excess) is due to the pharmacological inhibition of HSD11B2 and...

Personality and the NHP Model

Recently, this also has been found to be an indicator, or by-product, of psychological well-being in humans in that higher levels of psychological well-being have also been associated with lower levels of cortisol release (Lindfors and Lundberg, 2002). Environmental enrichment is often used to alleviate stress and promote psychological well-being in captive nonhuman primates. This is particularly important as stress has been clearly associated with a variety of undesirable physiological effects, mostly as the result of compromised immune system functioning (Kelly, 1985 Shapiro et al., 1998).

Inhibitory Effects Associated with Awakenings

In a study where GH secretion was stimulated by the injection of growth hormone releasing hormone (GHRH) at the beginning of the sleep period, it was found that whenever sleep was interrupted by a spontaneous awakening, the ongoing GH secretion was abruptly suppressed (41). This inhibitory effect of awakenings on the GH response to GHRH was further demonstrated in a detailed study where sleeping subjects who had received a GHRH injection were awakened 30 min after the injection and then allowed to re-initiate sleep 30 min later (42). The subjects who were able to resume sleep rapidly showed a secondary smaller GH pulse. A near complete inhibition of the GH response to GHRH was also observed when the injection was given 20 min after a forced awakening around the end of the first third of nocturnal sleep (42). It has been suggested that this inhibitory effect of nocturnal awakenings on the GH secretory response to GHRH could be mediated by an increase in somatostatin release (42). This...

Environmental adversity and reproductive development

Low birth weight (birth weight that is less than expected for gestational age) followed by a postnatal period of adequate nutritional resources is commonly associated with a period of catch-up growth over the first 3 years of life. As predicted by Chisholm and Burbank (2001), it is precisely this population of children that show an advanced age of sexual maturation. This same population shows an increased risk for obesity and metabolic diseases (Barker et al., 1989, 2002 Gluckman and Hanson, 2004a Hales and Barker, 2001 Phillips, 1998). Compared with controls (i.e., children born at weights that are average for gestational age) children showing low birth weight and postnatal catch-up growth reveal evidence for hyperinsulinemia, dyslipidemia, and increased body fat with reduced lean body mass. This condition is also associated with increased leptin levels (Ong et al., 1999 Pulzer et al., 2001). Increased insulin activity is thought to advance adrenarche by stimulating the activity of...

Normative Emotional States

The hippocampus lies adjacent to the amygdala in the medial temporal lobe. Although originally thought to be a key component of the lim-bic system, it is now thought to have a primarily cognitive function and plays a major role in organizing memory mechanisms such as the ability to consciously recall facts and autobiographical events (Gazzaniga et al, 2008). The hippocampus participates in emotional responding in an adjunctive way by assessing the contextual significance of incoming information (Fanselow, 2000). The hippocampus is also an important feedback site for circulating cortisol and has an important influence on regulation of the hypothalamic-pituitary-adrenal axis (Sapolsky, 2000).

Overview of Brain Changes inMDD

The cognitive model of depression (Beck, 1961) posits that stressful life events activate cognitive vulnerability and the depressive state develops, resulting in the depressive phenotype that is characterized by increased negative emotion processing (i.e., negative bias) and impaired emotional control (e.g., emotional responses that are too intense or prolonged). Extensive behavioral evidence supports this model, revealing that depressed individuals (1) focus more on negative stimuli and less on positive stimuli (Mogg et al, 1995 Scher et al, 2005), (2) are less easily distracted from negative emotion processing (Ellenbogen et al, 2002 Lyubomirsky et al, 1998 Siegle et al, 2002 Wenzlaff and Bates, 1998), (3) show heightened stress hormone levels such as cortisol that may have deleterious effects on the brain (Sapolsky, 2000), and (4)

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