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International Stress Management Association UK Promoting wellbeing and stress pr evention 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. ISMAUK

International Stress International Stress Management Association UK Promoting wellbeing and stress preventionManagement Association UKPromoting wellbeing

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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.

ISMAUK

Adaptive responses to disease: a necessary evil?

Lessons from transgenic models

Katia P. KaralisBiomedical Research Foundation of

the Academy of Athens, Greece

Children’s Hospital, Boston, USA

General Stress Syndrome,

Diseases of Adaptation

DisturbingForces

HarmonyEquilibrium

Balance

CounteractingReestablishing

ForcesIIIIII

Stressors HomeostasisAdaptiveResponse

(Physical, Emotional)

Specific“Nonspecific”

Load=Stressor

Elastic region

Deformation=Adaptive response

Plastic region

Yield point

Fracture point

Load deformation curve

Stress, Homeostasis, Eustasis

Distress, Dyshomeostasis =Allostasis=Cacostasis

Human Stressors

Natural catastrophiesLife transitionsUnnatural catastrophiesStarvation, Excessive exerciseSocioeconomic statusJob loss, Downsizing, Loss of controlBereavement/CaretakingAddictions/ Toxic substancesInflammations (Traumatic, Infectious, Autoimmune,

Allergic)Anxiety, Depression, Personality disorder

                                                                                               

                 

     

StressJames 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

ACTH

leukocytes

Nerve fibers?

CRHHypothalamus

Pituitary

Adrenals

Inflammatory sites

glucocorticoid

Glucocorticoid

The HPA axis

ACTH

Hypothalamus

Adrenal cortex

Anterior pituitary

CRH VP+ +

-

-

STRESS

Locus coeruleus

Crh-/- mice are products of full gestation.Litter size does not indicate implantation orgestational 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

IMMUNE SYSTEM

T-lymphocyte

PLACENTA

SPINAL CORD

GI TRACT

LUNG

EPINEPHRINE CRH

INFLAMMATION

GLUCOCORTICOID

CRH AND INFLAMMATION

INFLAMMATIONACTH

CRH

GC PERIPHERAL CRH

EPI

Glucocorticoid

The HPA axis

ACTH

Hypothalamus

Adrenal cortex

Anterior pituitary

CRH VP+ +

-

-

STRESS

Locus coeruleus

INFLAMMATION

PERIPHERAL CRH

EPI

C

A B

D

Inflamed muscle following turpentine

Crh+/+

Crh-/-

Saline Turpentine

Dual effects of CRH on the immune/inflammatory response

* suppressive, by central CRH

*stimulatory, by peripheral CRH

control 7d DSS 7d DSS+ 4d

Crh+/+

Crh-/-

Non-resolving inflammation……

part of inadequate “stress” response ??

reflects compromised ability to return to homeostasis?

0

.2

.4

.6

.8

1

Cum

mm

ulati

ve S

urvi

val

0 2 4 6 8 10 12 14days

P<0.0001 by Logrank test

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13

Experimental day

%Lo

ss o

f Bod

y w

eigh

t

Crh+/+

Crh-/-

<--------------------------->DSS treatment

Crh-/- DSS-treated mice do not survive the disease

80

85

90

95

100

105

110

7nthdayDSS

1st dayH2O

2nd dayH2O

3rd dayH2O

4th dayH2O

5th dayH2O

Days

% A

nim

al

Bo

dy W

eig

ht

Crh+/+

Crh-/-

1 2 3 4 5 6

92

96

100

104

108 *

*

##

#

*

Body

wei

ght (

% o

f con

trol

)

Day following the injection

Crh +/+ salineCrh+/+ turpentine Crh -/- salineCrh-/- turpentine

Metabolic response of the Crh-/- mice to inflammatory stimuli

60

70

80

90

100

1 2 3 4 5 6 7 8 9 10 11 12 13

Crh-/-

<--------------------------->DSS treatment

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

25

26

27

28

29

30

31

32

bo

dy

we

igh

t

0 1 2 3 4week

% w

eig

ht

ga

in

0

5

10

15

20

25

30

WT CRHKO

*

*

0

20

40

60

80

100

120

140

160

1 2 3 4

we

ekl

y fo

od

inta

ke (

g)

WT

CRHKO

week

*

Eating behavior of Crh-/- mice on HFD

*

*

0

5

10

15

20

25

30

35

40

WT CRHKO

seru

m le

ptin

(n

g/m

l)

0

0.5

1

1.5

2

2.5

WT CRHKO

fat

pa

d w

eig

ht

(g)

0

10

20

30

40

50

60

WT CRHKO

TN

mR

NA

(A

U)

0

50

100

150

200

250

WT CRHKO

MC

P-1

mR

NA

(A

U)

*

*

0

50

100

150

200

250

WT CRHKO

TL

R4

mR

NA

(A

U)

*

Decreased adiposity in HFD-fed Crh-/- mice

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

CRH +/-glucocorticoid

Insulin

inflammation

tissue repair

CRH

neuronal functiondevelopmental aspects

appetite regulation

obesityadipocyte biology

Anatomy of the intestinal immune system

Crh deficiency is associated with “paradoxically” normal anorectic response to inflammatory stimuli

Crh/Tnf-/-

basal LPS

-1

1

3

5

7

Crh+/+ Crh-/- Tnf

aver

age

dai

ly

foo

d in

take

1 2 3 4 5

0.05

0.10

0.15

0.20

0.25

0.30

**

*

*

* #

* #

Fo

od

in

take

(g

r)/m

ou

se w

eig

ht

(gr)

Days following the injection

Crh +/+ salineCrh+/+ turpentine Crh -/- salineCrh-/- turpentine

0

1

2

3

4

5

24h 48h

Foo

d in

tak

e (g

)

Crh+/+ controls

Crh+/+ TNBS

Crh-/- controls

Crh-/- TNBS

                   

Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid 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

General Stress Syndrome,

Diseases of Adaptation

DisturbingForces

HarmonyEquilibrium

Balance

CounteractingReestablishing

ForcesIIIIII

Stressors HomeostasisAdaptiveResponse

(Physical, Emotional)

Specific“Nonspecific”

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 – nutritioncardiovascular tone, respiration,metabolism (catabolism, inhibitionof reproduction and growth)

● Detoxification● Counteregulatory feedback (immunosuppression)

Human Stressors

Natural catastrophiesLife transitionsUnnatural catastrophiesStarvation, Excessive exerciseSocioeconomic statusJob loss, Downsizing, Loss of controlBereavement/CaretakingAddictions/ Toxic substancesInflammations (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.

Tolls were originally identified in Drosophila as rapidly induced genes which confer protection against fungal infections.

First human homologue identified was TLR4, with a major role in the recognition of Gram (–) bacteria by leukocytes (TLR4-/- mice are unresponsive to LPS).

Induces NF-kB activation and pro-inflammatory cytokine secretion signals DANGER!!!

Pattern Recognition Receptors: Toll-like receptors (TLRs)

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)

Οξειδωτικό στρες και μιτοχόνδρια

Κυτταρόπλασμα

Εξωτερική μεμβράνη

Εσωτερική μεμβράνη

Στρώμα

Μεσομεμβρανικό διάστημα

II

QIII IV

Cyt. c

ATPsynthase

H+

NADH+H+

NAD+

Succinate

Fumarate

e- e-

e- e-

H2O

ATPADP+Pi

½ O2 +2H+

Αναπνευστική αλυσίδα στα μιτοχόνδρια

H+H+

H+H+

H+ H+H+ H+ H+

H+

H+

H+

H+

I

H+

Most dioxygen (O2) 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 O2

•– instead of water (Boveris 1973, Sohal 1996) mainly by leaking electrons from complex III (Turrens 1997, Genova 2003)

O2•– + Fe3+ → Fe2+ + O2

Fe2+ + H2O2 → Fe3+ + OH- +OH• (αντίδραση Fenton)

Ποιά είναι η μοίρα του O2•– ;

Mitochondrial DNA Human mitochondrium: 16.5 kb (nuclear genome is 3 Gb) Encodes: 13 protein subunits involved in respiration,

22 tRNAs and two ribosomal RNAs.  Mitochondrial DNA is more susceptible to oxidation than nuclear DNA.  

There is an inverse correlation of oxidized mitochondrial DNA [8-oxoG] 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

Αντιοξειδωτικά, γενικά χαρακτηριστικά:

Ουσίες με αναγωγικές ιδιότητες, καλοί δότες ηλεκτρονίων.

Εξουδετερώνουν τη δράση ελευθέρων ριζών (scavengers of free radicals)

Τα μικρού μοριακού βαρους αντιοξειδωτικά βρίσκονται σε υψηλες συγκεντρώσεις (mM)

Οι αντιοξειδωτικές πρωτεϊνες δρουν σε σχέση με τα μικρού μοριακού βάρους αντιοξειδωτικά

Σχεδόν όλα τα αντιοξειδωτικά βρίσκονται σε ανηγμένη κατάσταση παίρνοντας ηλεκτρόνια από το NAD(P)H

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

InflammationAtherosclerosisCancerMetabolic syndromeCongestive 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. ROSgenerating enzymes include NADPH Oxidase, uncoupled nitric oxide synthase,cyclooxygenase, lipoxygenase and CYP450 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-PGF2alpha, nitrotyrosine, oxLDL, MPO, erythrocyte GPX1, 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 T2D 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-PGF2alpha

……..

- Stepwise increases in oxLDL found in normal weight, overweight, obese individuals

- Pts with increased oxLDLs have increased risk to develop MS

- Increased ocLDL 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-PGF2alpha levels (Framingham Offspring Study)

• T2D have elevated lipid, protein, DNA oxidation correlated with levels of glycemic control and evidence of increased susceptibility to LDL oxidation, increased 8-oxodG correlated with the levels of glycated Hb

…………………..

Oxidative stress and aging

Harman1950s: FREE RADICAL THEORY OF AGING

1970s: 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,

ΣυνοπτικάΗ γήρανση στον καινοραβδίτη εξαρτάται από:

1. Μεταβολικές παραμέτρους2. Απόκριση στο οξειδωτικο στρες3. Συνδυασμό και των δύο

Ο σηματοδοτικός δρόμος του DAF-2 αντιστοιχεί στον αντίστοιχο του υποδοχέα της ινσουλίνης και καταλήγει στο DAF-16, παράγοντα πουκαθορίζει την επαγωγή διαφόρων πρωτεϊνών (αντιοξειδωτικά, συνοδοί αναδίπλωσης, κα) που επιμηκύνουν το χρόνο ζωής.

Ανεξάρτητα από την ινσουλίνη (DAF-2), τη ρύθμιση του DAF-16 επηρρεάζουν και άλλοι παράγοντες όπως η διαθεσιμότητα τροφής, η θερμοκρασία, κλπ (SIRT1, JNK1, HSF-1).

Γονίδια που επιμηκύνουν τη ζωή του καινοραβδίτη έχουν ισχυρή αντικαρκινική δράση

Findings in mice….

Mice expressing a proofreading-deficient version of the mitochondrial DNA polymerase accumulate mtDNA mutations and display features of accelerated aging

Science (2005) 309, 481-4

Science (2005) 308, 1909-11

Soon RK Jr, Yan JS, Grenert JP, Maher JJ

Stress Signaling in the Methionine-Choline-Deficient Model of Murine Fatty Liver Disease.

Gastroenterology. 2010 Aug 1. [Epub ahead of print]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-pituitary-adrenal (HPA) axis, which may increase vulnerability to disease, including posttraumatic stress disorder and other mood and 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, CRHR1 and FKBP5.

…………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.

O'Mahony SM, Hyland NP, Dinan TG, Cryan JF. Maternal separation as a model of brain-gut axis dysfunction.

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.

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. [email protected]

AbstractA 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, LoGerfo 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 (mtDNA) could cause energy failure and increased oxidative stress. No causative mutations in the

mtDNA have been detected and studies on mtDNA 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 PubMed and ScienceDirect 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. 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.

CRH

GC

Inflammation

LEPTIN

ACTH

CYTOKINES

?

?

TLRs

???

Decreased food intake / Body weight loss-cachexia

Insulin resistance

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, San Francisco,

California 94121, USA. [email protected]

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.