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ISLAMIC MEDICAL EDUCATION RESOURCES-03

0106-CONTROL

Lecture for year 2 Medical Students on 15th June 2001 by Professor Omar Hasan Kasule Sr.

A. CONTROL IN ANATOMY

CENTRAL CONTROL

There is centralised master control of physiological functions mediated by the pituitary gland,  the hypothalamus, and the CNS. This control has a genetic basis in the form of DNA. DNA has 6x10E9 bits of information called codons. These represent 10E7 genes. Each gene codes for one protein molecule (Bowman p 4.1). Command and control in physiology relate very well to the concept of tauhid. For efficiency there must be a controlling center otherwise contradictions from many un coordinated centers of control will lead to failure. An orderly and harmonious universe cannot have more than one master.

 

CELL GROWTH

Integrity of DNA: Cellular DNA is subjected to constant mutation pressure. The mutations result in base substitution, deletion, insertion or rearrangement. Mutated cells may be eliminated by the immunological surveillance system on the basis that they are abnormal or thay may be repaired and return to normal function. Repair processes preserve the integrity of DNA. The integrity is further preserved by the conservative replication of DNA. Preserving DNA integrity ensures that control of metabolic processes is constant.

 

Normal cell growth: The phases of cell growth are: G0 (quiescent stage), M (variable phase), G1 (gap 1), S (DNA replication) , G2 (gap 2) which is a quiescent stage, M, Mitotic activity is controlled through the endocrine system (growth factor & growth inhibitoy factors). The reticulo-endothelial system regulates the optimal number of cells (proliferation, replacement, hyperplasia). Embryonic tissues, skin, blood, and intestinal mucosa have an abnormal rate of multiplication but within the range of the normal (Bowman p 38.1). Embryonic cells continually divide. They follow the cell cycle from mitosis to mitosis and are eventually destroyed. Parenchymal cells of all glandular organs such as the liver, the kidney, and the pancreas are quiescent or stable cells. They have a low level of replication in ordinary conditions. They can replicate rapidly on injury. Non-dividing (permanent) cells are the neural, skeletal muscle, and cardiac muscle cells.

 

Abnormal cell growth: Hypertrophy is increase in the size of cells resulting ion increase or organ size. It could be physiological or pathological. Atrophy is shrinkage in the size of cells by loss of cell substance. It is caused by decreased work-load, loss of innervation, decreased blod supply, inadequate nutrition, loss of endocrine stimulation, and aging.  In metaplasia there is a change from one adult cell type to another both being normal cells. Dysplasia is disorganisation of cells. Hyperplasia is excessive growth in response to a stimulus and is reversible when the stimulus is removed. In neoplasia, control mechanisms are deficient leading to excessive proliferation. Neoplasia has genetic, physical, chemical, humoral, immune, and viral infectious causes. In benign neoplasia the cells are well differentiated, are slow-growing, are encapsulated, and are not invasive. In malignant hyperplasia, the cells are not encapsulated, the edges are not well defined, they are undifferentiated, with increased mitotic activity and metastases. Malignant tumors are classified according to the tissue: epithelian (carcinoma and adenocarcinoma, papilloma, adenoma, melanoma), connective tissue (sarcoma, osteoclastoma), nervous tissue (ganglioneuroma, neuroblastoma, neurofibroma, neurofribrosarcoma), blood (leukemia, myeloma). Tumors cause injury by pressure, erosion, chemicals, (eh phaechromocytoma).

 

Control of cell growth: Growth factor is involved in cell growth. It binds to cell receptors causing activation of the protein phosphorylation cascade which leads to entry into the cell cycle. Cyclins are proteins that modulate the above process. Gorwth is limited by contact inhibition.

 

PRE-NATAL and POST NATAL GROWTH

Control of embryogenesis: The time-table and pre-determinism of the growth process result in a constant and predictable outcome. None of the phenomena of growth exceeds its expectations. There are correlations among physical, intellectual, moral, & social growth. The shaping in the uterine stage is according to Allah’s wish; He makes it as He likes 3:6. The uterine stage is for a limited period (22:5). The process goes through pre-determined stages (22:5, 23:14, 39:6). Growth in definite stages, twuur (71:4).

 

Post-natal growth: The 5 stages: intra-uterine, Infancy and childhood, tufuula), youth, sinn al shudd, middle age, sinn al rishd, old age, shaikhukhat/ ardhal al ‘umr (16:70).

 

Rationale of staged growth: The staged and relatively slow growth and change  is necessary to allow interaction with and learning from the environment since the fetal stage and the later period of childhood are learning and adaptation processes to the environment. Relations established among organs and tissues in the embryological period correlate with later physiology and pathology. Embryological blood supply and innervation persist even when organs migrate to new positions. Some embryological organs and tissues disappear after serving their function.

 

Growth and decline: It is a constant law that phenomena of growth and renewal co-exist with those of degeneration and decay. The overall result is determined by which of the two phenomena is dominant at a particular time. Human cells are growing and are increasing by mitosis but at the same time old and effete cells are broken down. The human body declines and degenerates toward old age, ardhal al umr (p 16:70, 22:5, 36:78). This overall physical decline occurs despite daily renewal of cells.

 

Concept of life-span or half-life: Every living things has a maximum life-span. This applies to cells, sub-cellular organelles, tissues and whole organisms. In biology life-span is expressed as half-life which is a mesasure of the time taken for a 50% decay. Half-lfe (T1/2) for albumin is 15-20 days, platelets 8-14 days, erythrocytes 120 days. Erythrocytes are replaced at the rate of 2 million a second. Exponential decay is a constant of nature and is considered one of the sunan. The exponential distribution.

 

 

B. CONTROL IN PHYSIOLOGY, BIOCHEMISTRY, PHARMACOLOGY

BALANCE AS THE OBJECTIVE OF CONTROL

The various control mechanisms in the body aim at maintaining an optimal balance. If the balance is disturbed, patho-physiological disturbances occur.

 

PHENOMENA OF BALANCE

FLUID BALANCE: The following distribution systems are involved in fluid balance: distributiion between tissues, distribution between the intra-cellular fluid (ICF) and extra-cellular fluid (ECF), and the acid-base balance. The organs involved in integrated homeostatic control are the kidneys, the alimentary system, the respiratory system, and the cardio-vascular system. Both neuronal and endocrine controls are involved in these organs.  Water is 66% of adult body weight; if adipose tissue is excluded this proportion becomes 73.2%. The ratio of water distribution between ICF and ECF is 1:2 for adults and 1:1.5 for infants. The extracellular fluid compartment consists of: interstitial fluid, lymph,  blood plasma, and transcellular fluids such as CSF, synovial fluid, acqueus humor, endo and periluymph, peritoneal fluid, perocardial fluid, pleural fluid, and alimentary secretions. Osmotic pressure is the main determinant of fluid distribution. A tight water balance is maintained between water losses and water intake. Water loss of 1.1 liters a day is accounted for as follows: vapour in expired air 0.4 L/.day, skin evaporation 0.4L/day, sweat 0.1-0.8 L/day, feces 0.2l/day and urine 1 l/day. Water intake is 0.8 l/day from diet, 0.4 l/day as metabolic water, and the balance from fluid intake. 

 

ELECTROLYTE BALANCE: The chemical composition of the extra-cellular fluid compartment is maintained constant. Differential concentrations across permeable membranes are temporary. Electrolytes are transported across the membranes to restore the balance and remove the chemical or electrical gradient. (a) Sodium balance: The daly dietary intake is 2.5 - 15 g as Sodium Chloride. It is lost in feces 0.3 g /day and in sweat which can be up to 20 g/day in hot climates. The lymphatic system removes excess sodium from tissues and returns it to the circulation. Excess sodium leads to fluid retention. 

 

IRON BALANCE: Total iron in the body is 2-6 g. It is lost at a rate of 0.5 mg/day as part of cells being shed off. The dietary intake is 15-20 mg of which only 0.5-2.0 mg is absorbed. Menstrual iron loss is 17.5 mg in 35 ml, 0.6 mg/day. Pregnancy and chronic bleeding increase iron needs.

 

ACID-BASE BALANCE: There are 3 mechanisms for balance of H+. (i) buffer systems based on carbon dioxide and ionisable proteins (ii) regulation of carbon dioxide elimination by the lungs (iii) electrolyte secretion by the kidneys. The following equations show the equilibrium equations for the buffer systems (a) : CO2 + H2O <-- H2CO3   <-- H+   +  HCO3- (b)       HbO2 + CO2 + H2O HHb + HCO3-  + O2 (c) Protein+ <-- H+  + HCO3-. Acidosis (metabolic and respiratory) and alkalosis (metabolic & respiratory) are conditions of imbalance that are rapidly corrected by the body. Respiratory acidosis arises due to accumulation of carbon dioxide that arises in hypoventilation. Respiratory alkalosis airses when there is low carbon dioxide pressure in the alveoli in cases of hyperventilation. Metabolic acidosis arises in cases of lactic acidosis. Metabolic alkalosis arises when bicarbonates are ingested. The kidney plays a role in acid-base balance by regulating the excretion or reabsorption of HCO3- and H+.

 

ENTROPY (DISORDER) AND EQUILIBRIUM: Energy is needed for maintenance, reproduction, and other functions under the rubric 'catabolic'. ATP is the link between energy-producing and energy-utlising systems. There is inter-conversion between various forms of energy. There is also exchange of energy with the external environment. Entropy is the degree of disorder or randomness in the system. All processes chemical or biological tend toward maximum disorder, entropy. Equilibrium is achieved when disorder is maximum. The relation between change in free energy available for work, G, enthalpy (change in heat content), H, and change in entropy can be described mathematically.

 

HEAT  ENERGY BALANCE: The first law of thermodynamics state sthat energy can not be created or destroyed (law of conservation of energy). It can only be interchanged from one form to another.  The chemical energy of glucose covalent bonds can be converted to the chemical energy of ATP. The chemical energy of ATP can be converted to mechanical energy of muscle contraction. The law of conservation of energy applies to human metabolic processes. According to the 1st law of thermodynamics, there is energy balance in a closed system. The energy output = external work + energy storage + heat. Metabolic rate = energy per unit time. Efficiency = work done/total energy expended. Heat balance is controlled basically by physico-chemical factors.  Heat is produced by: metabolism (catabolic break-down of macro molecules), food intake (specific dynamic action of food), and muscle activity. The amount of heat produced by metablism can be measured by direct calorimetry or indirectly by measuring oxygen and carbon dioxide consumption/production. About 85% of all heat produced is from 5 organs only: liver, muscle, brain, heart, and kidneys. Metabolic rate is more related to surface area than to weight. Other factors of metabolic rate are: age (lowest in infants and elderly), hormonal status (thyroid, anterior pituitary, adrenaline), habitat, amount of brown fat, mental state (anxiety), shivering, food intake, work and exercise, and body temperature. Heat is lost by radiation, conduction, vaporisation of sweat, respiration, urination, and defecation. Heat can be gained or lost by conduction, convection, and radiation.

 

TEMPERATURE BALANCE: There are mechanisms to make sure that the body temperature stays within the acceptable range (Ganong p 230). Pathogenesis of fever (Ganong p. 231). Humans are homoimothermic (ie bofy temperature is within a narrow range). Poikilothermic animals such as reptiles and amphibia have body temperatures that vary with external temperature. Heterothermic animals are able to suspend the homoimothermic state and go into hibernation. Normal human body temperature is 37 degrees centigrade. There are regional differences: rectum is 0.3  and the axilla is 0.6 degrees below the mouth. The temperature of blood leaving the liver is 0.2 degrees higher  than blood entering the liver. Testes are 1 degree below rectal temperature since spermatogenesis is inhibited below 36 degrees. A circadian rhythm has been described with temperatures being lowest in the morning and highest in the afternoons and evenings. The temperature rises on ovulation, work, and exercise.

BALANCE BETWEEN COAGULATION AND FIBRINOLYSIS: The processes of coagulation and fibrinolysis are kept in finely tuned balance. Hemostasis refers to control of blood coagulation which stops bleeding from injured blood vessels. It has three components: platelets which plug the injury, the coagulation process, and the contraction of the vascular smooth muscles that cuts off blood supply to the injured area. Coagulation is the process of stopping bleeding; its eventual product is the clot that plugs the injured blood vessel. The change of prothrombin to thrombin is a result of a series of events (a cascade) triggered by contact with a 'foreign' substance; the amplification factor in the cascade could be as much as a million. Thrombin causes the change of fibrinogen to fibrin that is the basis of the clot. The fibrinolytic system acts opposite to the coagulation system. It is triggerred at the same time as the coagulation system by damage to tissues. Plasminogen is activated to change to plasmin (fibrinolysin). Anti-plasmin in serum and platelets controls the small amounts of plasmin that are formed spontaneously. Urokinase and similar substances in tears, sweat, milk, and other secretions are plasminogen activators. Once a clot is formed fibrin is covered and plasmin does not reach the inside.

 

BALANCE OF SYMPATHETIC AND PARASYMPATHETIC SYSTEMS: Balance between sympathetic NS (flight or fight) vs parasympathetic (resting function or quiet activity). The balance is responsible for control of: HR, BP, GIT motility, bladder control, sweat glands, erector pilli muscles, smooth muscles of blood vessels

 

BALANCE BETWEEN LEFT AND RIGHT BRAIN HEMISPHERES: The left and right brain hemispheres are connected by the corpus collosum. There is continuous communication between the right and the left brains. There is clear dominance by either hemispehere.Injuries to one hemisphere or to the joining corpus collosum lead to specific clinical manifetations. It is interesting that many functions depend on the balance between the two hemispheres. Whe one hemisphere is injured, the othert ione seems to take over some of the functions that would otherwise be lost.

 

EQUILIBRIUM OF CHEMICAL REACTIONS: Equilibrium reactions: Hassel-bach law. Enzyme kinetics. Cytochromes are found in all cells except RBC and skeletal nmuscles. They catalyse the oxidation of various compounds. Structure closely follows function. Little changes lead to big differences.

 

BALANCE BETWEEN ANABOLISM AND CATABOLISM: The 4 processes in protein synthesis: transcription, post-transcription, modification, translation, post-translation modification..

 

PHENOMENA OF CONTROL IN PHYSIOLOGY, BIOCHEMISTRY, PHARMACOLOGY

CONTROL OF THE HEART BEAT: The heart rate is a balance between opposing effects of the sympathetic and para-sympathetic nervous systems. If both were eliminated the heart would beat at an intrinsic rythm of 110/minute. If the sympathetic system alone were eliminated, the heart rhythm would be 60-70/minute. If the parasympathetic system were eliminated the rythm would be 160/minute. The cardio-regulatory and cardio-inhibitory centers in the medulla are under cortical control. Baro-receptors in the carotid sinus, the aortic arch,, and the wall of the left ventricle have control on the heart rate. Heart rate decreases in sl;eep and increases on exercise, fever, and stimulation. Sinus bradycardia is found in athletes and sinus tachycardia is found in infants. The electrical activity of the heart and the cardiac conduction system (SAN, AVN, internodal pathway) ahev a role in controlling the heart rate. The electrical impulse starts from SAN through the inter-nodal tract to the bundle of His, the purkinje network, to the ventricular muscle. The speed of conduction is controlled and is variable. Atrial systole is before ventricular systole. Concept of pacemakers as automatic cells. There is a hierarchy among pacemakers.

 

CONTROL OF VOMITING: The stimuli for vomiting are from: intra-cranial pressure receptors, GIT receptors (chemical or pressure), labrynth, and the cerebral cortex (chemo-receptor trigger zone). The vomiting center is in the medulla oblongata. Nausea is sensation of anticipation of vomiting. Salivation is the first act. Deep inspiration is followed by increased intra-abdominal pressure. The epiglottis is closed and the soft palate is raised. Abdominal muscles contract in a co-ordinated way.

 

CONTROL OF SWALLOWING:

 

CONTROL OF COUGHING: Sneezing is due to mechanical and chemical irritation. The hiccup is involuntary rapid inspiration of the diaphragm with the glottis closed. Yawning is prolonged inspiration with the mouth open and the pharynx dilated. It is due to fatigue and psych0-social factors.

 

CONTROL OF GAGGING:

 

CONTROL OF POSTURE: Integration in the brain and spinal cord. Motor cortex. Cortico-spinal and cortico-bulbar. The extrapyramidal system. Postural reflexes,

 

CONTROL OF MICTURITION:

 

CONTROL OF DEFECATION: Distention of the sigmoid colon leading to awareness of need for defecation. The presence of stool in the rectum relaxes the internal anal sphincter. The external anal sphincter is under voluntary control. Contraction of abdominal muscles helps expel the stool.

 

CONTROL OF LACTATION:

 

CONTROL OF PARTURITION: (Bowman p. 20.53)

 

CONTROL OF CELL MEMBRANE PERMEABILITY: passive diffussion, cellular-facilitated diffussion, active transport

 

CONTROL OF GENETIC EXPRESSION: Every human has 23 chromosomes pairs. The mammalian geneome has 4 x 10E9 base-pairs of DNA. About 0.3% of human DNA is in the mitochondria outside the nucleus. The DNA content does not correlate with the complexity of the organism. Each cell has the same DNA but expression of some genes is inhibited by histone. This is the basis for cellular specialisation. Regulation of gene expression enables the organism to adpt to the environment. Molecules regulate gene expression for example all body cells have genes for insulin but only pancreatic cells produce it.  An operon is a complete regulatory unit of clustered genes. It consists of structural genes and regulatory genes. Introns are intervening sequences that do not code for any protein.  Inducer molecules turn on te transcription of a structural gene whereas co-repressor s are molecules that inhibit induction.

 

CONTROL OF HORMONAL RECEPTORS: surface membrane, cytoplasmic, intranuclear. Endocrine hormones are elaborated in endocrine glands and ae released into the blood stream to exert their action on certain other tissues. Some chemicals such as serotonin and histamine are referred to as local hormines. Neurotrasnmitters such as acetyle choline

 

PHENOMENA OF PERIODICITY IN PHYSIOLOGY, BIOCHEMISTRY, PHARMACOLOGY

CYCLICITY: Many phenomena in human biology go though a full circle and repeat themselves. Nothing illustrates this better than the origin and fate of the human body. Earth is the origin of all the physical elements of the human body and to it all return. Humans were created from dust, khalq al insan min turab ( 3:59, 18:37, 20:55, 22:5, 30:20, 35:11, 40:67, 71:17). They return to the earth on death and burial (‘awdat al insan ila al turab): 13:5, 16:59, 17:49, 20:55, 23:35, 23:82, 27:68, 37:16, 37:53, 50:3, 56:47, 37:16, 78:40. Humans also go through a social cycle. They start in weakness as infants. They become strong as young adults before becoming weak again in old age (30:54). The cell cycle has 4 phases: G0, G1, G2, and S. The mature human female has several cyclical phenomena: ovarian, uterine, cervical, and vaginal cycles. The human menstrual cycle differs from the estrus cycle in animals.

 

CIRCADIAN RYTHMS: Circadian rythms in biology also illustrate cyclicity. ACTH secretion has a circadian rhythm. Wake and sleep alternate. The body temperature changes cyclically between day and night. Melatonin secretion is also cyclical

 

PHENOMENA OF CONSTANCY and PREDICTABILITY IN PHYSIOLOGY, BIOCHEMISTRY, PHARMACOLOGY

DIAGNOSTIC TESTS: the principle is that there is consistency and predictability. Indirect measures of phenomena. Concept of normative distribution. The central tendency. Methods of direct visualisation of sample eg histology, slides, electron microscopy, x-ray, cat scan, MRI. Serology: agglutination, precipitation, electropheresis, radioiimunoassay. Measure products of metabolism & their homeostatic levels: primary, intermediate, and final.

 

DRUG ACTION: Three stages can be defined for drug action. The pharmaceutical phase is the disintegration of the drug. The pharmaco-kinetic phase is the absorption, distribution, metabolism, and excretion of the drug. The pharmaco-dynamic phase involves drug-receptor intercations. Drugs act at the following levels: molecular, subcellular structures, cells, tissues and organs, intact organism, and interaction between organisms. The targest of drug action are: enzymes, transport systems, and receptors. Drugs act by specific interference with metabolic processes (Bowman p 2.29). Almost all drugs act by interference with cell division or cell growth either in humans or in the pathigens or neoplasms. The agents interfere with synthesis or function of DNA, RNA, arrest of metaphase or arrest of telophase. The non-specific mechanisms that determine drug action are: osmotic properties, acidity, basicity, osidising and reducing agents, protein precipitation, physical barriers, adsorbents, surfactants. Chemical bonds (covalent and electri-static) are intimately bound with drug action. Recptor action may be agonist or antagonist. Structure determines receptor action. Antibiotics act by inhibiting protein synthesis in micro-organisms but not in humans.

Professor Omar Hasan Kasule Sr. June 2001