Discussion 8

April 23rd, 2007

Ryan KlimczakQuickTime™ and a

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Growing old successfully:

Approximately 25% role of genetics in determining longevity (twin/family studies)

Environmental affect on longevity (caloric restriction)

EpigeneticsEpigenetics (‘above the genome’): Circumstance in which gene function is altered stably but without fundamental change, e.g.,by mutation, deletion, rearrangement, in primaryDNA structure.

EpigenesisEpigenesis typically (always?) occurs via alterations in chromatin structure (e.g., modification in histone structure) or secondary changes in DNA, e.g., DNA methylation). DNA methylation, for example, is associated with a reduction in gene expression.

Barker HypothesisPrenatal events establish lifelong physiological patterns that may manifest as disease processes in later life

Dutch famine

Aging of the Urinary Tract

Nephron & Renal Circulation

Table 19-1Major Functions of the Kidney

•Water and electrolyte regulation•Metabolic products excretion•Hydrogen ion excretion and maintenance of blood pH

Endocrine functions:•Renin-angiotensin secretion (blood pressure)•Vitamin D activation (Ca++ metabolism)•Erythropoietin secretion (hematopoiesis)

2. Renal Tubules divided into:• Proximal Tubule, mostly reabsorption of water & solutes• Loop of Henle, mostly reabsorption of water & salt • Distal Tubule, mostly water & salt (under influence of aldosterone) reabsorption and acidification of urine• Collecting Duct, water reabsorption under the influence of ADH (antidiuretic hormone from posterior pituitary)

1. Glomerulus: Tufts of capillaries between afferent and efferent renal arterioles. Filtration is through a fenestrated endothelium separated from the basal membrane by podocytes. Filtrate is the same as plasma but without proteins.

Distal and Collecting Tubules function is regulated by ADH (antidiuretic hormone)

• secreted by neuroendocrine hypothalamus• stored and released from the posterior pituitary

Juxtaglomerular Apparatus: • located between afferent artery and distal tubule• secretes the enzyme renin• renin acts on the liver protein angiotensinogen to form angiotensin I, and angiotensin is transformed into angiotensin II in the lungs• angiotensin II is a very potent hypertensive substance; it also stimulates the release of aldosterone from the adrenal cortex

Regulation of Kidney function:

PosteriorHypophysis

OxytocinVasopressinAntidiuretic Hormone (ADH)

Fig. 1.11 Diagramme des principales hormones hypophysiotropes de l'hypothamalus et des hormones du lobe posterieur de l'hypophyse.

smooth musclesof uterus

mammaryglandrenal

collectingducts

Hypothalamus, Posterior Hypophysis, and their Hormones Hypothalamus

Table 19-2 Common Renal Problems in the Elderly

•Renal Failure•Impaired drug excretion (Think about kidney when giving a drug)•Urinary tract infections•Hypertension•Miscellaneous disorders:

TuberculosisNephritisDiabetes, etc.

Table 19-3 Some Signs of Renal Failure

•Generalized edema

•Acidosis

•Increased circulating non-protein nitrogen (urea)

•Increased circulating urinary retention products (e.g. creatinine, uric acid)

Table 19-4 Selected Causes of Acute Renal Failure

PRE-RENAL: (problems BEFORE the kidney)•Loss of body fluids•Inadequate fluid intake•Surgical shock or myocardial infarction

RENAL: (problems IN the kidney)•Drug toxicity (Think about kidney when giving a drug)•Immune reactions•Infectious diseases•Thrombosis

POST-RENAL: (problems AFTER the kidney)•Urinary tract obstruction

Functions of the bladder• Filling with urine from the kidneys• Micturition: emptying of bladder by muscle contraction and opening of sphincters.• Principle muscle: Detrusor muscle (bladder’s body): when it contracts, the bladder empties• Sphincters: Internal (involuntary; smooth muscle) and external (voluntary to some degree; skeletal muscle)

Table 19-10 Neural Control of Micturition

Muscle (Ty pe) Parasympathetic

Nerves (Cholinergic)

Sympathetic Nerves

(Adrenergic) Somatic Nerves

Detrusor (smooth muscle)

Contraction +++

Relaxation +

No effect

Internal sphincter (smooth muscle)

No effect Contraction

++ No effect

External sphincter (striated muscle)

No effect No effect Relaxation

++

For Micturition:1. Internal and external sphincters have to relax

2. Bladder has to contract (detrosor muscle)

Storage:

Table 19-7Physiologic Requirements for Continence

No involuntary bladder contractions

Appropriate bladder sensation

Closed bladder outlet

Low pressure accommodation of urine

Motivation to be continent

Adequate cognitive function

Adequate mobility and dexterity

Normal lower urinary tractfunction

Emptying:

Table 19-7Physiologic Requirements for Continence

Normal bladder contraction

Lack of anatomic obstruction

Coordinated sphincter relaxation & bladder contraction

Absence of environmental/iatrogenic barriers

Figure 19-6: Mnemonic device for

causes of acute urinary incontinence

Table 19-8 Age-Related Changes Contributing to

Incontinence

In FemalesEstrogen deficiency

Weak pelvic floor and bladder outletDecreased urethral muscle tone

Atrophic vaginitis

In MalesIncreased prostatic sizeImpaired urinary flowUrinary retention

Detrusor muscle instability

Table 19-9 Management of Urinary Incontinence Type Management Stress Exercises

Alpha-adrenergic agonistsEstrogenSurgery

Urge Bladder relaxantsSurgery

Overflow alpha-adrenergic antagonistsCatheterization

Functional Habit trainingScheduled toiletingHygienic devices

•Weakness of pelvic muscles

•Inability to avoid voiding when bladder full

• overdistended, non-contractile blood

• cognitive, emotional problems

Questions

• What are the major parts of the kidney and what control mechanisms act at each part?

• What are the muscles involved in micturition? • What are the requirements for continence?• What are some causes of incontinence?• How might these be treated?

Evidence for Decline in Immune Function with Aging

Aged Individuals have:

1) Increased incidence of INFECTIONS:For example: pneumonia, influenza, tuberculosis, meningitis, urinary tract infections

2) Increased incidence of AUTOIMMUNE DISEASE:

For example: rheumatoid arthritis, lupus, hepatitis, thyroiditis (graves-hyper/hashimotos-hypo), multiple sclerosis(Predisposition toward these diseases is related to Human Leukocyte Antigens HLA genes)

3) Increased CANCER INCIDENCE: For Example: prostate, breast, lung, throat/neck/head,

stomach/colon/bladder, skin, leukemia, pancreatic

4) TOLERANCE to organ transplants: Kidneys, skin, bone marrow, heart (valves), liver,

pancreas, lungs

Function of Immune System is PROTECTION against:

1. Bacteria

2. Virus

3. Fungus/ multicellular parasites

4. Cancer

5. Toxins

6. ( 5,000 daltons--protein/lipid/CHO/nucleic acids)

Tissues and Organs Important for Immune Function

•Cells derived from stem cells: liver, bone marrow

• Cells are stored, multiply, interact, and mature in: thymus, spleen, lymph nodes, blood

•Transport: lymphatic vessels

•Important Cell types: Lymphocytes, neutrophils, macrophages, natural killer cells

Accessory Organs

•Appendix, tonsils, intestines

A) T cells: stored & mature in thymus-migrate throughout the body

-Killer Cells Perform lysis (infected cells)Cell mediated immune response

-Helper CellsEnhance T killer or B cell

activity -Suppressor CellsReduce/suppress immune

activityMay help prevent auto immune

disease

Lymphocytes

B)B-Cells: stored and mature in spleen

• secrete highly specific Ab to bind foreign substance (antigen: Ag), form Ab-Ag complex

• responsible for humoral response• perform antigen processing and presentation

• differentiate into plasma cells (large Ab secretion)

Lymphocytes (cont.)

Other cell types

• Neutrophils- found throughout body, in blood. Phagocytosis of Ab-Ag CX

• Macrophages- throughout body, blood, lymphatics

– Phagocytose non-specifically and specifically (non Ab coated Ag)

– perform Ag processing and presentation– secrete lymphokines/ cytokines to stimulate T

helpers • Natural Killer Cells-in blood throughout body

– destroy cancer cells

ComplementSeries of enzymes which are sequentially

activated and result in lysis of cell membrane of infected cell at bacterium

Complement binding and activation

~35 enzymes and factors involved in cascade

5 classes of Ig

IgG: 150,000 m.w.most abundant in blood, cross

placental barrier,fix complement, induce

macrophage engulfment

IgA: associated with mucus and secretory glands, respiratory tract, intestines, saliva, tears, milk

variable size

IgM: 900,000 m.w.2nd most abundant , fix

complement,induce macrophage engulfment,

primary immune response

5 Classes of Ig

IgD: Low level in blood, surface receptor on B- cell

IgE: Binds receptor on mast cells (basophils)

secretes histamine, role in allergic

reactions

Increased histamine leads to vasodilation, which leads to increase blood vessel permeability. This induces lymphocyte immigration swelling and redness.

Thymus involution

Experimental Evidence for Age Related Decrease in Immune

Function

Dependent on T & B cell function

Sheep RBC (Antigen) 1st into human

Table 15-2: Some Aging Related Effects on B-Cells

• Decreased number of circulating and peripheral blood B cells

• Alteration in B-cell repertoire (diversity)

• Decreased generation of primary and secondary memory B cells

• General decline in lymphoproliferative capacity

Table 15-14: Some Aging-Related Effects on T-cells

•General decline in cell mediated immunological function•T-cell population is hyporesponsive•Decrease T cell diversity

•Increase in proportion of memory and activated T-cells while naïve T-cells decrease

Table 15-16 Influence of Aging on Macrophages

and Granulocytes

General functional impairment of macrophages and granulocytes

Table 15-15 Aging-Related Changes in Natural Killer (NK) Cells

General decline in cell function

Good correlation between mortality risk and NK cell number—ie cancer

Impairment of cytotoxic capacity per NK cell

Table 15-13 Aging-Related Shifts in Antibodies

General decrease in humoral responsiveness:Decline in high affinity protective antibody production

Increased auto-antibodies:Organ specific and non-organ specific antibodies directed to self

Table 15-10 Some Aging-Related Shifts in Cytokines

CYTOKINES - influence proliferation, differentiation, and survival of lymphoid cells; has numerous actions on other body cells

•Increased proinflammatory cytokines IL-1, IL-6, TNF-•Increased cytokine production imbalance

Table 15-17 Major Diseases Associated with Aging in Immune Function

Increased tumor incidence and cancer

Increased incidence of infectious diseases caused by:

E. ColiStreptococcus pneumoniaMycobacterium tuberculosisPseudomonas aeruginosaHerpes virusGastroenteritis, bronchitis, and

influenza

Reappearance of latent viral infection

Autoimmune diseases and inflammatory reactions:ArthritisDiabetesOsteoporosis

Dementia

Table 15-9 Hallmarks of ImmunosenescenceAtrophy of the thymus: decreased size decreased cellularity (fewer thymocytes and epithelial cells) morphologic disorganization

Decline in the production of new cells from the bone marrow

Decline in the number of cells exported by the thymus gland

Decline in responsiveness to vaccines

Reduction in formation and reactivity of germinal center nodules in lymph nodes where B-cells proliferate

Decreased immune surveillance by T lymphocytes and NK cells

Questions

• What are aging related changes in B cells? • T cells? • Cytokines? • Antibodies?• Natural killer cells?• What disease is someone more likely to get if

they have fewer/less functional NK cells?