ISMAUK International Stress Management Association UK Promoting wellbeing

ISMAUK International Stress Management Association UK Promoting wellbeing and stress prevention Our Purpose and Mission ISMA UK is a registered charity with a multidisciplinary professional membership that includes the UK and the Republic of Ireland. It exists to promote sound knowledge and best practice in the prevention and reduction of human stress. It sets professional standards for the benefit of individuals and organisations using the services of its members.

Adaptive responses to disease: a necessary evil? Lessons from transgenic models Katia P. Karalis Biomedical Research Foundation of the Academy of Athens, Greece Children’s Hospital, Boston, USA

Disturbing Forces II Stressors (Physical, Emotional) Harmony Equilibrium Balance II Homeostasis Counteracting Reestablishing Forces II Adaptive Response Specific “Nonspecific” General Stress Syndrome, Diseases of Adaptation

Load=Stressor Load deformation curve Distress, Dyshomeostasis =Allostasis=Cacostasis Fracture point Yield point Stress, Homeostasis, Eustasis Plastic region Elastic region Deformation=Adaptive response

Human Stressors Natural catastrophies Life transitions Unnatural catastrophies Starvation, Excessive exercise Socioeconomic status Job loss, Downsizing, Loss of control Bereavement/Caretaking Addictions/ Toxic substances Inflammations (Traumatic, Infectious, Autoimmune, Allergic) Anxiety, Depression, Personality disorder

Stress James Tighe Stress in itself isn't necessarily harmful. Everyone needs goals and challenges. But too much can be damaging. We explain how to spot when stress is becoming unmanageable and suggest ways to deal with it. bbc. co. uk Health

Sources of peripheral CRH Hypothalamus CRH leukocytes Nerve fibers ? Pituitary ACTH Inflammatory sites Adrenals glucocorticoid

The HPA axis STRESS Locus coeruleus Hypothalamus CRH VP + + Anterior pituitary ACTH Adrenal cortex Glucocorticoid

Crh-/- mice are products of full gestation. Litter size does not indicate implantation or gestational problems. Crh-/- mice need in utero treatment with glucocorticoid for normal lung development and survival.

CRH is necessary for the normal development of the adrenal cortex.

Sites of CRH synthesis BRAIN SPINAL CORD IMMUNE SYSTEM GI TRACT PLACENTA T-lymphocyte LUNG

GLUCOCORTICOID INFLAMMATION EPINEPHRINE CRH

CRH AND INFLAMMATION CRH INFLAMMATION ACTH GC EPI PERIPHERAL CRH

The HPA axis STRESS Locus coeruleus Hypothalamus CRH VP + Anterior pituitary + ACTH Adrenal cortex EPI - PERIPHERAL CRH Glucocorticoid INFLAMMATION

Inflamed muscle following turpentine Saline Turpentine A B C D Crh+/+ Crh-/-

Dual effects of CRH on the immune /inflammatory response * suppressive, by central CRH *stimulatory, by peripheral CRH

Crh+/+ Crh-/- control 7 d DSS+ 4 d

Non-resolving inflammation…… part of inadequate “stress” response ? ? reflects compromised ability to return to homeostasis?

Crh-/- DSS-treated mice do not survive the disease Cummmulative Survival 1. 8. 6. 4 Crh+/+ Crh-/- . 2 0 2 P<0. 0001 by Logrank test 4 6 days 8 10 12 14 %Loss of Body weight 0 100 90 80 70 60 1 2 3 4 5 6 7 8 9 10 11 12 13 <--------------> DSS treatment Experimental day

Crh+/+ Crh-/-

Metabolic response of the Crh-/- mice to inflammatory stimuli Crh +/+ saline Crh+/+ turpentine Crh -/- saline Crh-/- turpentine 100 90 80 70 60 1 2 3 4 5 6 7 8 9 10 11 12 13 <--------------> DSS treatment Body weight (% of control) Crh-/- 108 * * 104 100 * # # # 96 92 1 2 3 4 5 6 Day following the injection

The “stress response” is associated with changes in food behavior what is the role of CRF in this process? ? ?

METABOLISM IMMUNE SYSTEM Stress neuropeptides/ hormones

High fat diet -> an experimental manipulation to induce obesity and reveal altered eating behavior

Eating behavior of Crh-/- mice on HFD WT CRHKO * 31 body weight 25 % weight gain 30 29 28 27 26 20 * 15 10 5 25 week 0 160 30 1 2 3 4 0 weekly food intake (g) 32 140 120 * 100 80 60 40 20 0 WT CRHKO week 1 2 3 4

Decreased adiposity in HFD-fed Crh-/- mice 40 serum leptin (ng/ml) fat pad weight (g) 2. 5 35 2 30 25 1. 5 20 * 1 15 * 10 0. 5 5 0 0 WT CRHKO 50 40 * 30 20 200 150 10 50 0 0 WT CRHKO 250 * TLR 4 m. RNA (AU) 250 MCP-1 m. RNA (AU) TNFα m. RNA (AU) 60 WT 200 150 100 * 50 0 WT CRHKO

Is the response to high fat diet a “stress” response?

CRH +/glucocorticoid Insulin

inflammation tissue repair CRH neuronal function developmental aspects appetite regulation obesity adipocyte biology

Anatomy of the intestinal immune system

Crh+/+ turpentine Crh -/- saline Crh-/- turpentine 0. 30 * # 0. 25 0. 15 * Crh-/- controls Crh+/+ controls 4 3 2 Crh+/+ TNBS 1 Crh-/- TNBS 0 24 h * # 48 h basal LPS * 7 0. 10 5 3 0. 05 1 2 3 4 5 Days following the injection 1 0. 20 * * 5 average daily food intake Food intake (gr)/mouse weight (gr) Crh +/+ saline Food intake (g) Crh deficiency is associated with “paradoxically” normal anorectic response to inflammatory stimuli -1 Crh+/+ Crh-/- Crh/Tnf Tnfa-/-a -/-

Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 betahydroxysteroid dehydrogenase type 1 deficient mice. Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR. Diabetes. (2004) 53: 931 -8

Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity. Kershaw EE, Morton NM, Dhillon H, Ramage L, Seckl JR, Flier JS. Diabetes. (2005) 54(4): 1023 -31

Disturbing Forces II Stressors (Physical, Emotional) Harmony Equilibrium Balance II Homeostasis Counteracting Reestablishing Forces II Adaptive Response Specific “Nonspecific” General Stress Syndrome, Diseases of Adaptation

THE ADAPTIVE RESPONSE= STRESS SYNDROME Phenomenology a. CNS Functions - Facilitation-arousal, alertness, vigilance, cognition attention, aggression - Inhibition – vegetative functions (reproduction, feeding, growth) - Counteregulatory feedback b. Peripheral Functions ● Oxygenation – nutrition cardiovascular tone, respiration, metabolism (catabolism, inhibition of reproduction and growth) ● Detoxification ● Counteregulatory feedback (immunosuppression)

Human Stressors Natural catastrophies Life transitions Unnatural catastrophies Starvation, Excessive exercise Socioeconomic status Job loss, Downsizing, Loss of control Bereavement/Caretaking Addictions/ Toxic substances Inflammations (Traumatic, Infectious, Autoimmune, Allergic) Anxiety, Depression, Personality disorder

METABOLISM IMMUNE SYSTEM Stress neuropeptides/ hormones

INNATE IMMUNITY * First line of defence against infections * Exists before infection-“in-built”, present from birth * Evolutionary “ancient” part of host defence, similar mechanisms in plants and animals-arose before the split of the two kingdoms. * Serves 3 important functions: 1. Early response to microbes, prevents infection and its spread, may eliminate pathogens. 2. Effector mechanisms are often used by adaptive immunity to destroy microbes. 3. Stimulates adaptive immunity and influences the nature of host T and B cell responses against different types of pathogens.

Pattern Recognition Receptors: Toll-like receptors (TLRs) ØTolls were originally identified in Drosophila as rapidly induced genes which confer protection against fungal infections. Ø First human homologue identified was TLR 4, with a major role in the recognition of Gram (–) bacteria by leukocytes (TLR 4 -/- mice are unresponsive to LPS). Ø Induces NF-k. B activation and proinflammatory cytokine secretion signals DANGER!!!

Stress, Inflammation and the Metabolic Syndrome • Stress Concepts • Stress Mechanisms • Effects of the Stress System on the Organism

Συμπάσχει η ψυχή τω σώματι νοσούντι και τεμνομένω, το δε σώμα τη ψυχή The soul suffers when the body is diseased or traumatized, while the body suffers when the soul is ailing Aristotle

“Both sleep and wakefulness, when immoderate, are detrimental” Hippocrates (489 -360 BCE)

Αναπνευστική αλυσίδα στα μιτοχόνδρια Κυτταρόπλασμα Εξωτερική μεμβράνη H+ H+ H+ e- I H+ Q e- H+ H+ e- Cyt. c H+ e- III IV H+ H+ H+ NADH+H+ Succinate Fumarate NAD+ ½ O 2 +2 H+ Μεσομεμβρανικό διάστημα Εσωτερική μεμβράνη II H+ H+ ATP synthase H 2 O ADP+Pi H+ Στρώμα ATP Most dioxygen (O 2) use by the cell occurs in the mitochondria. Hence this organelle (and the eye lense) faces the highest concentrations of toxic oxygen reduction products. Between 1 - 3% of the oxygen in the mitochondria is reduced to O 2 • – instead of water (Boveris 1973, Sohal 1996) mainly by leaking electrons from complex III (Turrens 1997, Genova 2003)

Mitochondrial DNA Human mitochondrium: 16. 5 kb (nuclear genome is 3 Gb) Encodes: 13 protein subunits involved in respiration, 22 t. RNAs and two ribosomal RNAs. Mitochondrial DNA is more susceptible to oxidation than nuclear DNA. There is an inverse correlation of oxidized mitochondrial DNA [8 -oxo. G] with maximal life span of an organism, but this correlation is not seen with nuclear DNA (that is bound to histone proteins and can be repaired by DNA repair enzymes). Ηigh frequency of mitochondrial DNA mutations Bladder, head, neck and lung primary tumors

Antioxidants

If antioxidant systems do not work. . ROS do not get inactivated, they can react with macromolecules and • enhance lipid peroxidation • cause DNA damage • induce protein/nucleic acid modifications

Damaged end products include • • • Oxidized proteins Oxidized lipids Oxidized low-density lipoproteins Oxidized carbohydrates Oxidized nuclei acid bases Enzymatic markers of oxidative stress ex: myeloperoxidase (MPO)

The oxidized or nitrated products of ROS Cause compromised biological activity leading to metabolic dysregulation and changes in cellular functions implicated in the pathogenesis of diseases including Inflammation Atherosclerosis Cancer Metabolic syndrome Congestive heart disease ………….

Oxidative stress: A ROS-antioxidant imbalance when the net amount of ROS exceeds the antioxidant capacity

Oxidative stress due to: • Increase ROS generation • Depression of the antioxidant systems • Combination of both

Overview of generation and antioxidant enzymatic detoxification of ROS generating enzymes include NADPH Oxidase, uncoupled nitric oxide synthase, cyclooxygenase, lipoxygenase and CYP 450 monoxygenases.

Levels of ROS are critical (1) • Low levels: important for normal cellular signaling pathways, modulate growth and apoptosis of endothelium, vascular and cardiac muscle Critical during development and during adaptive changes leading to hypertrophy and remodeling

Levels of ROS are critical (2) • High levels : generated in many disease states including atherosclerosis and hypertension, contribute to endothelial dysfunction and to risk of cardiovascular consequences

ROS and disease

Oxidative stress and Cardiovascular diseases • ROS and superoxide are increased in arteries in several major cardiovascular diseases “Are ROS important for the pathophysiology of atherosclerosis, stroke, hypertension, and other. . ? ”

Sources of ROS in CVD • Leukocytes release ROS Kill bacteria vascular damage • Ischemia -> Reperfusion -> Generation of ROS Excessive superoxide inactivates NO and contributes to endothelial dysfunction, a risk factor for endothelial disease

Superoxide in CVD • Mainly due to increased generation rather than inactivation • Oxidative stress is usually associated with compensatory increases in SODs (caution: heart failure and aging show opposite regulation)

Coronary artery disease and oxidative stress • Oxidation of apo-B containing lipoproteins may play crucial role in atherogenicity • Oxidative stress markers such as 8 -iso. PGF 2 alpha, nitrotyrosine, ox. LDL, MPO, erythrocyte GPX 1, predict independently early risk for CVD and myocardial infarction more …………. .

• Endothelial dysfunction-mediated oxidative stress in pts with CVD could predict the risk of cardiovascular events • Endothelial dysfunction in obesity appears to be mediated by oxidative stress • Hypertension related to endothelial dysfunction is mediated partly by oxidative stress (antioxidants ameliorate hypertension and alter markers of oxidative stress while ACE improves markers of oxidative stress) • Hypertensive pts have reduced SOD activity and inadequate antioxidant capacity in mononuclear cells

Oxidative stress and the metabolic syndrome • May play an important role in manifestations related to the MS • It is associated with adiposity and insulin resistance ? ? Is it an early event in the pathology of these chronic diseases, a consequence or an innocent bystander? ? ?

Does oxidative stress contribute to insulin resistance? Improved insulin sensitivity in T 2 D patients or insulin-resistant pts treated with a-lipoic acid or other antioxidants Metformin, the insulin sensitizing agent, decreases markers of oxidative stress

Evidence…. . Patients with MS have - elevated oxidative damage - decreased antioxidant protection • low serum vitamin C and a-tocopherol, • decreased SOD activity, • altered lipid peroxidation byproducts, • protein carbonyls, • xanthine oxidase activity • increased 8 -iso-PGF 2 alpha

……. . - Stepwise increases in ox. LDL found in normal weight, overweight, obese individuals - Pts with increased ox. LDLs have increased risk to develop MS - Increased oc. LDL was associated with elevated CRP and insulin, while lower adiponectin and HDL

Oxidative stress and diabetes • Prevalence of insulin resistance among obese individuals associated with 8 -iso-PGF 2 alpha levels (Framingham Offspring Study) • T 2 D have elevated lipid, protein, DNA oxidation correlated with levels of glycemic control and evidence of increased susceptibility to LDL oxidation, increased 8 -oxod. G correlated with the levels of glycated Hb …………………. .

Oxidative stress and aging Harman 1950 s: FREE RADICAL THEORY OF AGING 1970 s: MITOCHONDRIAL FREE RADICAL THEORY OF AGING Accumulation of oxidatively damaged proteins and DNA with normal aging -> progressive failure of cellular machinery-> organ aging-> age-related disease

Findings from Caenorhabditis elegans

Lack of Peroxisomal Catalase Causes a Progeric Phenotype in Caenorhabditis elegans JBC (2004) 279, 19996– 20001,

Findings in mice….

Mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase g accumulate mt. DNA mutations and display features of accelerated aging Science (2005) 309, 481 -4

Science (2005) 308, 1909 -11

Kang GS, Gillespie PA, Gunnison A, Moreira AL, Tchou-Wong KM, Chen LC. Long-Term Inhalation Exposure to Nickel Nanoparticles Exacerbated Atherosclerosis in a Susceptible Mouse Model. Environ Health Perspect. 2010 Sep 23. [Epub ahead of print] New York University School of Medicine. Oxidative STRESS Inflammatory STRESS Endoplasmic reticulum STRESS Lung and Cardiovascular system

Stress Signaling in the Methionine-Choline-Deficient Model of Murine Fatty Liver Disease. Gastroenterology. 2010 Aug 1. [Epub ahead of print] Soon RK Jr, Yan JS, Grenert JP, Maher JJ University of California, San Francisco, California. • Methionine-choline-deficient (MCD) diets cause severe fatty liver disease and have the potential to cause many types of cellular stress. • MCD feeding causes an integrated stress response in the liver rather than a classic unfolded protein response.

Gillespie CF, Phifer J, Bradley B, Ressler KJ. Risk and resilience: genetic and environmental influences on development of the stress response. Depress Anxiety. 2009; 26(11): 984 -92 Dpt of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Exposure to stressful events during development has consistently been shown to produce long-lasting alterations in the hypothalamic-pituitaryadrenal (HPA) axis, which may increase vulnerability to disease, including posttraumatic stress disorder and other mood anxiety disorders. Recently reported genetic association studies indicate that these effects may be mediated, in part, by gene-environment interactions involving polymorphisms within two key genes, CRHR 1 and FKBP 5. …………a large and growing body of preclinical research suggests that increased activity of the amygdala-HPA axis induced by experimental manipulation of the amygdala mimics several of the physiological and behavioral symptoms of stress-related psychiatric illness in humans. Notably, interactions between the developing amygdala and HPA axis underlie critical periods for emotional learning, which are modulated by developmental support and maternal care. These translational findings lead to an integrated hypothesis: high levels of early life trauma lead to disease through the developmental interaction of genetic variants with neural circuits that regulate emotion, together mediating risk and resilience in adults.

Yau SY, Lau BW, So KF. Adult hippocampal neurogenesis: a possible way how physical exercise counteracts stress. Cell Transplant. 2010 Sep 30. [Epub ahead of print] It was considered that neurogenesis only occurred during the embryonic and developmental stage. This view has greatly changed since the discovery of adult neurogenesis in two brain regions: the hippocampus and the olfactory bulb. Recently, it is suggested that altered hippocampal neurogenesis is related to pathophysiology of mood disorders and mechanism of antidepressant treatments. Accumulating knowledge about the effects of physical exercise on brain function suggests a special role of adult hippocampal neurogenesis in cognitive and mental health, even though the functional significance of adult neurogenesis is still debated. The beneficial effects of running correlating with increased adult neurogenesis may provide a hint that new born neurons may be involved, at least in part, in the counteractive mechanism of physical exercise on stress-related disorders, like depression.

Quartana PJ, Burns JW. Emotion suppression affects cardiovascular responses to initial and subsequent laboratory stressors. Br J Health Psychol. 2010 Sep; 15(Pt 3): 511 -28. Epub 2009 Oct 16. Dpt of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine We examined the effects of experimentally induced anger and general negative emotion in the context of expressive and experiential suppression on cardiovascular responses to initial and subsequent laboratory stressors. Effortful suppression of negative emotion has immediate and delayed consequences for stress-induced cardiovascular reactivity. Theoretical and clinical significance of these findings are discussed.

Maternal separation as a model of brain-gut axis dysfunction. O'Mahony SM, Hyland NP, Dinan TG, Cryan JF. Psychopharmacology (Berl). 2010 Oct 1. [Epub ahead of print] Alimentary Pharmabiotic Centre, Biosciences Institute, Univ College Cork, Ireland RESULTS: In this review, we describe the components of the brain-gut axis individually and how they are altered by maternal separation. The separated phenotype is characterized by alterations of the intestinal barrier function, altered balance in enteric microflora, exaggerated stress response and visceral hypersensitivity, which are all evident in IBS.

Elsenbruch S, Rosenberger C, Bingel U, Forsting M, Schedlowski M, Gizewski Patients with irritable bowel syndrome have altered emotional modulation of neural responses to visceral stimuli. Gastroenterology. 2010. Epub 2010 Jun 22. Inst of Medical Psychology and Behavioral Immunobiology, University Clinic of Essen During rectal stimulation, IBS patients demonstrated more pronounced stress-induced modulation of neural activation in multiple brain regions, including the insula, midcingulate cortex, and ventrolateral prefrontal cortex.

Long MD, Drossman DA. Inflammatory bowel disease, irritable bowel syndrome, or what? : A challenge to the functional-organic dichotomy. Am J Gastroenterol. 2010 Aug; 105(8): 1796 -8. Many patients with inflammatory bowel disease (IBD) in clinical remission continue to have symptoms of pain and diarrhea despite minimal or no ongoing inflammation. These patients may be considered to have an overlap of IBD and irritable bowel syndrome (IBD-IBS). ………… We propose an alternate biopsychosocial model whereby mutual effects of peripheral and central factors influence symptom generation in both IBD and IBS. Understanding this model has important implications for treatment of patients with IBD-IBS.

Lackner JM, Brasel AM, Quigley BM, Keefer L, Krasner SS, Powell C, Katz LA, Sitrin MD. The ties that bind: perceived social support, stress, and IBS in severely affected patients. Neurogastroenterol Motil. 2010 Aug; 22(8): 893 -900. Epub 2010 May. Div of Gastroenterology, University at Buffalo School of Medicine, SUNY, NY

Hepatology. 2010 Aug; 52(2): 774 -88. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Neuschwander-Tetri BA. Division of Gastroenterology and Hepatology, Saint Louis University, St. Louis, MO 63110, USA. tetriba@slu. edu Abstract A significant body of evidence now forces us to rethink the causes of NASH. Once thought to be a disease caused by triglyceride accumulation in hepatocytes with subsequent oxidant stress and lipid peroxidation causing inflammation and fibrosis, new data from animal studies and a limited number of human studies now provide convincing evidence that triglyceride accumulation does not cause insulin resistance or cellular injury in the liver. The lipotoxic liver injury hypothesis for the pathogenesis of NASH suggests that we need to focus our therapeutic efforts on reducing the burden of fatty acids going to the liver or being synthesized in the liver. This can be accomplished by improving insulin sensitivity at the level of adipose tissue to prevent inappropriate peripheral lipolysis and by preventing unnecessary de novo lipogenesis in the liver. Excess carbohydrates are the major substrates for de novo lipogenesis, and thus, reducing carbohydrate consumption through dietary changes and increasing muscle glucose uptake through exercise remain important cornerstones of treatment and prevention of lipotoxic liver injury, a disease hitherto called NASH.

Adv Exp Med Biol. 2010; 685: 34 -44. Clinical features and pathogenesis of Alzheimer's disease: involvement of mitochondria and mitochondrial DNA. Mancuso M, Orsucci D, Lo. Gerfo A, Calsolaro V, Siciliano G. Department of Neuroscience, Neurological Clinic, University of Pisa Alzheimer's disease (AD) is a neurodegenerative disorder which results in the irreversible loss of cortical neurons, particularly in the associative neocortex and hippocampus. AD is the most common form of dementia in the elderly people. Apart from the neuronal loss, the pathological hallmarks are extracellular senile plaques containing the peptide beta-amyloid (AP) and neurofibrillary tangles. The Af cascade hypothesis remains the main pathogenetic model, as suggested by familiar AD, mainly associated to mutation in amyloid precursor protein and presenilin genes. The remaining 95% of AD patients are mostly sporadic late-onset cases, with a complex aetiology due to interactions between environmental conditions and genetic features of the individual. Mitochondria play a central role in the bioenergetics of the cell and apoptotic cell death. Morphological, biochemical and genetic abnormalities of the mitochondria in several AD tissues have been reported. Impaired mitochondrial respiration, particularly COX deficiency, has been observed in brain, platelets and fibroblasts of AD patients. Somatic mutations in mitochondrial DNA (mt. DNA) could cause energy failure and increased oxidative stress. No causative mutations in the mt. DNA have been detected and studies on mt. DNA polymorphisms are controversial, but the "mitochondrial cascade hypothesis" here revised, could explain many of the biochemical, genetic and pathological features of sporadic AD.

PM R. 2010 May; 2(5): 442 -50. Physiological and psychological fatigue in extreme conditions: overtraining and elite athletes. Purvis D, Gonsalves S, Deuster PA. Dpts of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, USA. This article will review relevant mechanisms and markers associated with overtraining syndrome (OTS), and discuss signs and symptoms, differential diagnosis, and current assessment tools for fatigue within the context of overtraining. The findings are drawn from original research and review articles referenced by Pub. Med and Science. Direct databases. Sources were selected for their contributions to the current knowledge of biological, psychological, and molecular mechanisms. Data were reviewed for relevance to OTS and then evaluated against criteria that included significant OTS outcomes and findings. Information was systematically analyzed to identify patterns, dependencies, connections, and causal factors. Comparative analysis was confounded by inconsistent metrics, terminology, and variable methodology; potential biomarkers, treatment and prevention approaches, and future research directions are identified. Diagnosing OTS is difficult because underlying cause(s) are unknown; one must exclude other factors that degrade performance and mood status. Many studies are confounded by inadequate experimental designs, poor measures of performance, and different methods for characterizing OTS is complex because the demands of excessive training in combination with other biologic, psychological, and social stressors are difficult to quantify. However, changes in mood are always noted. Interrelations among dietary patterns; social, psychological and physiological profiles; and the neuroendocrine, immune, and central nervous systems are complex and not adequately elucidated.

Inflammation Insulin resistance TLRs ? ? ? CRH CYTOKINES ACTH ? GC LEPTIN ? Decreased food intake / Body weight loss-cachexia

CRH +/glucocorticoid

Neurotherapeutics. 2010 Jul; 7(3): 232 -40. Improving the prediction of response to therapy in autism. Bent S, Hendren RL. Department of Psychiatry, University of California, San Francisco, California 94121, USA. stephen. bent@ucsf. edu Autism is a heterogeneous disorder involving complex mechanisms and systems occurring at diverse times. Because an individual child with autism may have only a subset of all possible abnormalities at a specific time, it may be challenging to identify beneficial effects of an intervention in double-blind, randomized, controlled trials, which compare the mean responses to treatments. Beneficial effects in a small subset of children may be obscured by the lack of effect in the majority. We review the evidence for several potential model systems of biochemical abnormalities that may contribute to the etiology of autism, we describe potential biomarkers or treatment targets for each of these abnormalities, and we provide illustrative treatment trials using this methodology. Potential model systems include immune over and under reactivity, inflammation, oxidative stress, free fatty acid metabolism, mitochondrial dysfunction, and excitotoxicity. Including potential biomarkers and targeted treatments in clinical trials for autism provides a potential method for limiting the heterogeneity of enrolled subjects, which may improve the power of studies to identify beneficial effects of treatments while also improving the understanding of the disease.