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  1. Stress

  2. PSYCHONEUROIMMUNOLOGYThe concept of a stress response: Physical or psychological stress alters the body's neuroendocrine systems. Responses are attempts to successfully cope with stress. When stress is severe or chronic, the altered physiology can cause or exacerbate health problems.Holmes life stress scale: statistical association between stress and numerous illnesses. Negative events are more detrimental than positive ones. [Overhead]Selye's general adaptation syndrome: Endocrine response to acute and chronic stress.Stress and disease: immune system cells both synthesize and respond to ACTH and beta-endorphins.Ader: Conditioned immunosuppression in rodents; conditioned immunoactivation. Pairing exposure to immunoactivators or immunosuppressors with smells.Chronic stress reduces a variety of immune indices in humans. (Glaser & Kiecolt-Glaser)Chronic stress decreases resistance to infectious diseases in mice (Ader).

  3. H. Selye: General Adaptation Syndrome: Stress reaction has 3 stages, Alarm, Resistance and Exhaustion. Stress disorders represent reaction to chronic involvement in stage of resistance, "wearing down."Selye:* Eustress (+) e.g., physical exercise* Distress (-) e.g., environmental pressuresLazarus emphasized coping vs. vulnerability as a key dimension as to whether stress resulted in stress disorders.

  4. StressvNeural Activation - HypothalamusvSecretion of Corticotrophin Releasing Factor (CRF)vPituitary Release of Adrenocorticotrophic Hormone (ACTH)vAdrenal Release of GlucocorticoidsvMetabolic, Immunological, Psychological Responses

  5. Glucocorticoids from adrenal cortex Gluconeogenesis Suppressed inflammation Immunosuppression Feedback to brain (esp Hippocampus)

  6. STRESS AND DISEASE - IaPeptic Ulcers:• For years there was an established relationship between peptic ulcers (and other GI irritative diseases) and psychological stress.• Marshall and Warren “Unidentified curved bacilli in the stomach of pts with gastric and peptic ulceration” (Lancet, 1984)• Very tight causal relation between Helicobacter pylori and peptic ulcer and other irritative GI diseases. • Diagnosis of infection (serology, IGG for H.p.; or endoscopy-biopsy), treat with antibiotics (tetracycline, metronidazole), is eradicating H. pylori infection in much of US populationSo What Happened to the Relationship to Stress?

  7. STRESS AND DISEASE - IbEvidence for a Relationship Between Stress and Ulcers:• Gastric fluids increase acidity in response to anger, hostility, resentment, guilt, frustration.• Stressful situations (surgery, school exams) increase basal gastric acid secretion.• Alleviation of stress can reverse peptic ulcer condition.• Animals exposed to stress develop stomach ulcers.• Ulcer occurs in the absence of H. pylori infection.• Most people still have H. pylori infection and do not have ulcers.• Ulcer patients more likely to exhibit excess stress (Levenstein & Veylan, J. Clin. Gastroenterol., 1995).• Psychological stress impedes ulcer healing.• Other factors also important: sex (choose female), blood type (avoid O), other genetics, cigarettes, coffee, alcohol consumption patterns, possibly diet. These are not correlated with presence or degree of H. pylori infection.• “Psychosomatic” etiology is preferentially discarded as soon as a “biological” explanation becomes available.

  8. STRESS AND DISEASE - IcAside from Impaired Treatment of Pts and Widespread Overprescription of Antibiotics, are there Costs?On the Horizon:• Absence of H. pylori infection may be linked to gastroesophogeal reflux disease (“acid reflux”; Labenz et al., Gastroenterology, 1997)• Reflux disease increases risk for gastric adenocarcinoma, a serious form of malignancy, which has recently also been linked by co-occurrence to absence of H. pylori infection.• H. pylori infection is dropping, especially among SES levels with good medical care.• Stay tuned. And don’t throw out good data just because something more “biological” comes along. Consider the whole patient, both in theory and in practice.

  9. STRESS AND DISEASE IIaCoronary Artery Disease (Leading US cause of death; 1,250,000 heart attacks/year):• Type A behavior? (Time urgency, competitive achievement orientation, anger hostility). Controversial, particularly in details, hostility may be most predictive of CAD.• Stress can increase serum cholesterol levels.Sudden Cardiac Death:• Heart arrhythmias may be associated with chronic stress (animal and human studies)• Clear evidence for stress as cause or contributing factor in many human clinical casesLearned Helplessness (Seligman): Controllable vs. uncontrollable life events; uncontrollable events lead to feelings of helplessness Sense of personal control of one’s life leads to greater self-efficacy, “hardiness”

  10. STRESS AND DISEASE IIbHypertension (incidence: 25-38% of adults); major risk factor for cardiac and brain disorders:• Chronic stress leads to hypertension in animal studies• Human studies suggest greater tendency towards hypertension with stress. Stressful occupations: Air traffic controllers have exceptionally high prevalence of hypertensionCancer:• Rats subjected to stress less likely to reject tumor implants• Women who respond poorly to stress: cervical cancer incidence higher; increased incidence of malignacy in breast biopsies• Depressed mood linked to increased cancer risk

  11. STRESS AND THE IMMUNE SYSTEMStress and disease: immune system cells both synthesize and respond to ACTH and beta-endorphins.Ader: Conditioned immunosuppression in rodents; conditioned immunoactivation. Pairing exposure to immunoactivators or immunosuppressors with smells.Stress Impairs Resistance to Infection in Laboratory Animals(Ader)

  12. STRESS AND THE IMMUNE SYSTEMEvidence that Psychological Stess Affects Human Immune Function(Kiecolt-Glaser & Glaser, 1987)* Men whose wives had died of breast cancer had decreased immune function* Marital disruption is associated with increased morbidity and mortality* Divorced people more likely to die from pneumonia than married people* Women who are separated have 30% more appointments for physical illness* Patients with mental illness have greater numbers of physical illnesses* Medical students have reduced immune function (Natural Killer Cell activity) during final exams

  13. STRESS AND PSYCHIATRIC ILLNESS* Social stressors often associated with depression* Other medical illnesses increase probability of psychiatric disorders by about 1/3* Posttraumatic stress disorder: often see loss of affect, withdrawal, other signs of depression, some violent hostile behavior patterns, etc.* Up to four-fold increase in incidence of psychiatric symptoms in people with high stress levels and poor coping skills vs. people with low stress levels, good coping skills

  14. STRESS AND THE BRAIN • Aging memory disorders - non-Alzheimer or other dementias. Associated with hippocampal neuron loss • Animal model: Chronic stress or glucocorticoid exposure • Stress induces: • Neuron loss in hippocampus (esp. region CA1) (Sapolsky) • Adrenalectomy induces hippocampal granule cell loss (Sloviter) • Individual stress history, indicated by adrenal weight, predicts hippocampal pyramidal cell loss with aging (Landfield) • Mechanism (?) (Sapolsky) • Glucocorticoids disrupt hippocampal glucose utilization. This leaves neurons vulnerable to insults. • Glucocorticoid administration sensitizes the hippocampus to epilepsy or hypoxia • Glucose supplements protect the hippocampus • Likewise, monkeys that died from ulceration had more hippocampal neuron loss than those that did not. • Early Handling protects against stress-induced neuron loss • BOTTOM LINE: STRESS AFFECTS THE BRAIN, AND THE WRONG KIND OF STRESS AFFECTS IT NEGATIVELY. THE ANSWERS ARE FAR FROM ALL IN, AND AS A PHYSICIAN, CONTINUING TO EDUCATE YOURSELF ABOUT THIS WILL BE IMPORTANT.

  15. NEW TOPIC: PAINACUTE PERIPHERAL PAINEpidermal Pain: c-fiber activation by intense physical stimulationInjurious tissue damage --> bradykinin (peptide), which in turn activates c-fibersc-fibers: small, unmyelinated somatosensory fibers that innervate epidermis, striated muscle, joints, etc.* most senstive to local anesthetics* interact with other sensory input to amplify pain sensationOpiate systems in spinal cord react to diminish this type of pain within a few minutes.This system subserves acute pain.

  16. ACUTE PERIPHERAL PAINAnti-opiates such as naloxone may increase pain, revealing effects of the body’s opiate systems. Placebo (“sugar pill”) administration may sometimes cause activation of opiate systems if subjects believe the pills are painkillers. Naloxone-sensitive pain reduction. Psychological activation of endogenous opiate systems.However, acute pain can modify central systems on a longer term basis. It is now commonly recommended that both peripheral “local” anesthetization and global anesthetic administration be used in conjunction with pain-inducing surgical procedures. Repetitious activation of C fibers builds up the electrical response of neurons to which they project in the spinal cord. This resembles LTP, a process thought to be involved in memory.

  17. Shep Siegel Opiate Tolerance stuff here if time allows

  18. CHRONIC PAIN Chronic Pain: Basis is often much less clear. Incidence: more than 40% of the population will experience pain at some time in their lives.Chronic pain is not merely persistent acute pain. It may occur in the absence of obvious peripheral or visceral pathology.All pain has both sensory and affective-evaluative components. Focusing exclusively on either of these alone is equally misguided.With chronic pain there is not a linear relationship between nociception and pain experience. In chronic pain syndromes, there are qualitative differences in the affective-evaluative perception of pain.Prevalence of chronic pain increases with age

  19. Sources of Chronic PainChronic Benign Pain: Any pain resulting from nonmalignant causes that is not allieviated by appropriate medical, pharmacotherapy, or surgical treatment.Example: Fibromyalgia, widespread aching, local tenderness, absence of laboratory evidence of inflammation. American College of Rheumatology defines as involving 3 or more segments of the body and at least 11 of 18 “tender points.” (e.g., trapezius, rib juctions, buttocks, knees) Steroids and NSAIDS have no more effect than placebo. (Placebos benefit 50% of patients, at least short-term.) Ketamine (NMDA receptor antagonist) appears to be effective in 50% of patients. Some think fibromyalgia is one extreme on a continuum of widespread chronic pain syndromes. Higher incidence in females.Opiates remain the most effective medications for managing chronic pain.

  20. Behavioral Approaches to Chronic Pain ManagementIt was historically thought that chronic pain patients exaggerated trivial pain problems--not made of “the right stuff.” This is not therapeutically helpful. Goal is restoration of functional life. Chronic pain can have secondary consequences: depressive illness, marital discord, job problems social withdrawal, sleep disorders.Biofeedback therapies combine feedback from detectors such as muscle EMG electrodes with techniques such as muscle relaxation to affect muscle function. Biofeedback can be effective for muscle contraction headaches, for symptoms of chronic stress such as anxiety, and for blood pressure disorders such as hypertension.Controlling pain behavior through operant conditioning and other behavioral approaches has also had success. The approach focuses upon modifying pain-related behavior separately from the treatment of the pain itself.Exercise and conditioning (e.g. stretching) is a very important mitigator of increased chronic pain with aging. Mild joint and limb pain is very common in sedentary (inactive) aging people.