Q.1. Why two classes of etiology’s theory is considered obsolete?
Ans. Some single gene disorders on one hand and infections on the other gave rise two one disease—once cause concept.
Two types of etiological types suggested were genetic and acquired; recent data supports role of genetic factors in acquired diseases like hypertension and DM similarly even infectious are prove to genetic susceptibility, e.g. lower repiratory tract infections in cystic fibrosis.
Q.2. Does pathogenesis involve knowing the earliest molecular event in a disease?
Ans. Yes but not only this. Pathogenesis means the full course of immmunological, biochemical and morphological processes besides the initial infectious or molecular cause. It involves the whole process from the first stimulus to ultimate manifestation of a disease. Some of the processes in many diseases like the mechanism of manifestation of alteration in genes’structure are still a subject of research.
Q.3. Why is morphological diagnosis of tumors not enough for management?
Ans. Tumor behavior also depends on its genetic profile. So studies in molecular biology of tumors which may be morphologically similar but behave differently in therapeutic response are required, e.g. slymphomas.
Q.4. What was the most pioneering concept put forth by Rudolph Virchow?
Ans. Virchow, called the father of modern pathology, put forth the cell theory. All forms of organ injury starts with molecular or structural cell injury. Though cells interact with each other and extracellular matrix ECM. ECM also maintains cells in themselves.
Q.5. What are the two types of pathogenesis identified?
Ans. Casual and formal pathogenesis. Causal pathogenesis tells why a pathogen causes a disease. This considers the environmental factors, host’s bodily disposition (suscep-tibility without regard to adaptability) and the interplay of nonspecific immune responses in producing resistance to
some diseases. Formal pathogenesis describes the struc-tural changes observed during clinical course of a disease which culminate in the altered structural and functional state of diseased organ/body.
Q.6. Define health and disease.
Ans. WHO defines health as a condition of complete bodily, mental and social well-being. Disease is defined as a dysfunction in life-processing that alter the body or a part of body in a manner that the affected individual requires help for subjective, clinical or social reasons.
Q.7. In what way is the type of clinical course of a disease defined as regards to its development.
Ans. Peracute diseases are fulminant and usually lead to death in several days. Acute diseases are usually intense and last for a few days or weeks. Recuperation is possible. Subacute diseases are insidious in onset, clinical course lasting for weeks with doubtful recuperation. Chronic diseases are mild and progress in stages over months. Primary chronic di-seases begin without a manifest acute phase. Clinical course is episodic. Recuperation is not possible. Secondary chronic disorders occur subsequent to acute inflammation that fails to heal because of complications. Recuperation in secondary chronic diseases occurs with persisting struc-tured damage and functional deficits after the disease and subsides. The social and functional adaptability is thus res-tricted. Recurrence is resurgence of what is basically a chronic disease after a gap. Remission is temporary dis-appearance of symptoms of a disease. Death (Exitus letalis
= lethal end)
Q.8. Will it be correct to say that homeostasis is a conti-nuously changing state?
Ans. Yes, but upto some extent only. The normal cell is confined to a fairly narrow range of function because of:
1. Genetic programming of metabolism, differentiation and specialization.
2. Constraints because of neighboring cells.
3. Availability of metabolic substracts.
The narrow range of functioning is the steady state or homeostasis. Within this narrow range there is
conti-nuous change—in one of different metabolites and other substances in the cell.
Q.9. What are the triggers for muscle hypertrophy and for changes in gene expression in cardiac muscle fibers in myocardial hypertrophy?
Ans. Two groups:
1. Mechanical triggers (stretch).
2. Trophic triggers.
The trophic triggers are chiefly growth factors (IGF-α) and vasoactive amines (angiotension II, DC-adrenergic orga-nists). The latter are produced by nonmyocyte cells and myocytes themselves.
Q.10. What ultimately regulates the size of myocardial cells?
Ans. From the above discussion it is clear that environmental cues are important. Nutrients (blood supply to heart muscle) is also a limiting factor.
Q.11. Why don not heart muscles enlarge unlimitedly in response to increase burden?
Ans. There’s a limit upto which heart muscle fibers can resond to increase in their size. Any increase in burden after that leads to cardiac failure. Various factors are implicated but not confirmed. These are—limited blood supply, limited oxidative capacity adaptability of mitochondria, changes in number and type of proteins, degradation of proteins and changes in myofibril cytoskeleton. Various ultrastructural manifestations include the myocardial fibers degeneration.
There may also be apoptosis or nucleosis of myocardial fibers.
Q.12. Give two examples of physiological atrophy.
Ans. Physiologic decrease in cell size that may ultimately culmi-nate in cell death can lead to decrease in entire tissue or even organ. Physiologically this is seen in (1) embryonic growth—thyroglossal of duct atrophy. (2) in uterus after parturition.
Q.13. When is atrophy accompanied by osteoporosis?
Ans. Atrophy of disuse may be accompanied by osteoporosis of disuse.
Q.14. In which conditions is cachexia seen?
Ans. Marked muscle wasting or cachexia may be seen in protein energy malnutrition of (1) marasmus type or (2) chronic inflammatory states (because of secretion of TNF) or (3) cancer.
Q.15. What are the causes of widening of sulci and narro-wing of gyri in above 50 years persons?
Ans. Aging and compromised blood supply because of atheros-clerosis. Aging typically causes cell loss in tissues containing permanent cells: particularly in brain and heart.
Q.16. What are the other causes of atrophy?
Ans. Besides disuse, malnutrition and aging, denervation, ischemia, loss of endocrine stimulation and pressure by expanding mass can cause atrophy.
Q.17. What are the ultrastructural changes seen in atrophy?
Ans. Ultrastructural changes in atrophy represent a new balance between compromised conditions and size of cell upto the limit of its viability. Atrophied muscle fibers have fewer structural and functional components like myofibrils, mito-chondria and endoplasmic reticulum.
Q.18. Can atrophy lead to cell death?
Ans. If the conditions are compromised limitlessly, cell death may result in atrophied tissue. Examples include ischemic necrosis and apoptosis in developing embryo.
Q.19. What are the mechanisms involved in atrophy?
Ans. 1. Proteolysis by lysosomal hydrolases and ubiquitin pro-teasome pathway.
2. Autophagy by autophagic vacuoles.
Lysosomes and proteasomes: Cytosomal hydrolases like cathepsins degrade protein molecules from the inter-cellular environment, surface of cells, environment. Ubi-quitin conjugates cytosolic and nuclear proteins and binds to large proteolytic organelles called protea-somes–leading to proteolysis. Ubiquitin proteasome pathway is involved in cancer cachexia and proteolysis by glucocorticoids and thyroxine. Insulin inhibits this.
TNF also stimulates this.
Autophagy : Small membrane bound vacuoles within cell with fragments of organelles form and then fuse with
lysosomes the latter throwing their proteolytic enzymes in the autophagic vacuoles. Some residual bodies—
vascuoles with digested material may remain.
Lipofuscin or aging pigment is a form of these residual bodies causing brown coloration of organs in which it accumulates brown atrophy.
Q.20. What are the equivocal signs of death?
Ans. These are cardiac arrest, lack of pulse, cessation of breathing, areflexia and decreasing body temperature. This is referred to as clinical death.
Q.21. What are the criteria for brain death?
Ans. A patient is regarded as biologically dead where brain death has been diagnosed according to following criteria:
1. An isoelectric or flat electroencephalogram for 24 hours.
2. Two angiographic studies performed ½ an hour apart demonstrating absent cerebral circulation.
3. Irreversible absence of spontaneous respiration.
4. Aflexia (loss of corneal and papillary reflexes).
Q.22. What are the unequivocal signs of death?
Ans. Livores: After cardiac arrest, gravity causes blood in venous system to collect in lowest part of body. This produces reddish violet skin spots that can be mobilized by applying local process.
Regor mortis: Postmortem rigidity begins 3 to 6 hours after death.
Nystem’s law: Rigor mortis begins at head and spreads towards feet. Later subsides in the same manner. Occurs due to lack of ATP and subsequent coagulation of active and myosin filaments.
Antolysis or decomposition: Because of activiation of lysosomal intrinsic protease and extrinsic protease from intestinal bacteria which digest the organic components of body. Failure of tissue respiration causes lysosomal protease activation.
Q.23. The above three types of signs of death can be simu-lated in which condition?
Ans. In any condition causing reduced vital functions like barbi-turate intoxication.(apparent death).
Q.24. Define average life expectancy, morbidity and morta-lity and lethamorta-lity.
Ans. Average life expectancy: Time period in which 50 percent of certain population group have died. The population group can be, e.g. women.
Morbidity: Number of persons per year per 100,000 popu-lation who suffer from a disease.
Mortality: Number of persons per year per 100,000 popu-lation who have died of a disease.
Lethality: Quotient obtained by dividing the number of persons who have died of a certain disease by the number of persons who have contracted that disease.
Q.25. Define epidemic autopsy, clinical autopsy and insu-rance autopsy.
Ans. Epidemic autopsy: Performed in equivocal cases involving chemical suspicious of infectious disease.
Clinical autopsy: Performed on patients who died in hospital usually a part of hospital quality assurance program.
Requires consent of next of kin.
Insurance autopsy: Done when required by insurance companies when:
1. Sudden death from uncertain or unnatural causes.
2. Occupational exposure to certain pathogens.
The procedure is ordered by ensurer. This type of insurance autopsy to resolve insurance claim is almost never refused by next of kin.
Q.26. What are the two main classes of nuclei seen in cell cycle?
Ans. Interphase nucleus: Characterized by a nucleolus contai-ning RNA, loosely structured, genetically active euchroma-tin and densely structured heterochromaeuchroma-tin (genetically inactive)
Mitotic nucleus: Characterised by visible chromosomes.
Q.27. What is the structure of chromosomes in metaphase?
Ans. Two strands of chromatids joined at centromere.
– short arm – p (for petit) – long arm – q.
Q.28. What is a karyogram?
Ans. Chromosomes of a cell are shown to be arranged in a karyo-gram. This is a short formula or description of chromosomes using the following criteria:
– Total number of chromosomes.
– Sex chromosome status.
– Applicable aberrations.
Q.29. Based on a computer model, which part of DNA corresponds to software and which one to hardware?
Ans. The software is the program and base sequence containing and instructions for:
1. Copying the program—DNA replication.
2. Repairing program defect—DNA repair.
3. Using subprograms to create protein (Structure and functional).
The replication process and machinery, transcription pro-cess and machinery and translation propro-cess and machinery can be compared to hardware—computer itself.
Q.30. What is a nucleosome?
Ans. Nucleosome consists of:
1. A histone molecule with 2, H2A, H2B, H3 and H4 poly-peptides each.
2. One histolne H1 polypeptide 3. Limker DNA
4. DNA proper.
Diameter of a nucleosome in a solenoid model is 11 cm.
A DNA double helix diameter is 2 mm.
Q.31. What are the dimensions or diameter (average) of a chromatid?
Ans. Each chromatid is a supercoil of around 700 mm diameter with each coil of single DNA strand and histone molecules (polynucleosome) being of around 30 mm diameter.
Q.32. Give an example of congenital DNA repair defect.
Ans. Xeroderma pigmentosum.
It is rare. It is hereditary (because of an endonuclease defect).
Pathogentic chain reaction: Ultraviolet radiation
↓
DNA damage in skin cells
↓
Increased DNA defects in skin cells Sequelae:
1. Skin atrophy (→Thinning of skin)→ an adaptive reaction of excessive cornification and hyperpigmentation is induced.
Mitotic dysfunction in skin cells: Skin cancers. Clinically the→following lesions are seen:
• Dry scaly skin (Xeroderma) with mottled hyper-pigmentation.
• It is a precusor of skin cancer. Later multiple skin tumors such as basal cell Ca, squamous cell Ca and malignant melanoma develop.
Q.33. What are the types of UV radiation?
Ans. Three wavelength ranges exist in UV portion of solar spectrum:
1. UVA → 280 to 400 mm
2. UVB → 280 to 320 mm→ to cause cutaneous cancers.
3. UVC → 200 to 280 mm filtered by ozone layer.
Q.34. Causation of skin cancers by UV radiation depends upon which factors?
Ans. 1. Type of UV rays.
2. Intensity of exposure.
3. Quantity of light absorbing protective mantle of melanin in skin. Fair shinned Europeans who do not tan their bodies and live near equator, e.g. Queensland Australia, have the highest incidence of cutaneous cancers.
Q.35. What the subcellular level effects of UV rays?
Ans. 1. Inhibition of cell division.
2. Induction of mutations → carcinogenicity of UV rays is attributed to formation of dipyrimidine dimmers in DNA.
3. Cell death.
4. Inactivation of enzymes.
Q.36. What is NER and discuss its role in UV radiation caused cutaneous tumors?
Ans. NER or nucleotide excision repair is the mechanism of repair of DNA damage such as formation of dispyrimidine dimmers by UV rays in chin cells. Steps of NER are:
1. Recognition of DNA lesion.
2. Incision of damaged portion on both sides of lesion.
3. Removal of damaged nucleotide.
4. Synthesis of normal nucleotide patch.
5. It is ligation to DNA.
In mammalian cells upto 30 or more proteins are involved.
It is postulated that in excessive sunlight UV ray damage, NER is overwhelmed leading to large transcriptional errors and thus cancer.
Q.37. How does UVB radiation cause skin cancers in XP?
Ans. There are basically two mechanisms:
1. Inherited inability to repair UVB damaged DNA.
XP is a heterogenous disease with at least 7 variants each caused by a defect in one of several genes involved in NER. There is extreme photosensitivity and 2000 fold increased risk of skin cancers in sun exposed skin.
2. UVB also causes mutations in oncogenes and tumor suppressor genes.
Mutant forms of P53 and RAS are +. The mutations occur mainly at dipyrimidine sequences. In animal models, P53 mutations occur early than appearance of tumors.
In XP, there may also be neurological abnormalities.
Q.38. What does the size of nucleus in a cell depend upon?
Ans. 1. Size of cell.
2. DNA content of nucleus.
3. Functional state of nucleus.
Q.39. In what conditions does nuclear polyploidy occur?
Ans. Multiple complement chromosomes in a cells is called polyploidy. It occurs when:
1. Proliferating cells double their DNA in synthesis phase and just before mitosis become tetraploid.
2. Where mitosis fails to occur after the synthesis phase or is followed by several additional synthesis phases.
This occurs in some endocrine gland cells like thyroid.
3. As a morphological sign of stress induced adaptative reactive as in.
Barbiturate above: Increased liver metabolism results in liver cells polyploidy.
Cardiac valvular defects: Mycocardium works harder and produces polyploidy.
Haploid cells are normally seen only while spermio-genesis and oospermio-genesis.
Q.40. What is nuclear aneuploidy and what is its morpholo-gical sequela?
Ans. Variation from normal euploid complement (Haploid or Diploid) of chromosomes in which individual chromosomes do not exist in their normal quantities. Morphological sequela of aneuploidy are:
1. Variability in size of nucleus (nuclear polymorphism) larger cell nucleus indicates cellular activity and smaller nucleus indicates cellular inactivity.
2. Variability in nuclear chromatin content. (Nuclear poly-chromasia).
Both polymorphism and ploychromasia are important criteria characterizing a malignant tumor.
Q.41. What are the nuclear criteria of malignancy?
Ans. 1. Nuclear polymorphism and nuclear polychromasia.
2. Proliferation measured by mitotic count in a field of vision.
3. Dyskaryosis.
Q.42. What are the chromatin changes seen in nuclear chro-matin in different disease states?
Ans. 1. Meterochromatin condensation: Checker board type of chromatin condensation indicates arrested transcription.
2. Dyskaryosis: Irregular pattern of heterochromatin con-densation and fine aggregates gives cancer cells a salt and pepper appearance.
3. Perinuclear hyperchromatosis: Chromatin condensation along inner nuclear membrane. Early sign of cell death (apoptosis). Later it leads to total chromatin clumping or nuclear pyknosis.
4. Karyolysis: Fading of nucleus due to chromatin dissolu-tion. Late sign of induced cell death.
5. Karyorrhexis: Nuclear burst due to chromatin fragmen-tation. Late sign of programmed cell death.
Q.43. What are the different types of nuclear inclusions seen?
Ans. 1. Cytoplasmic inclusions: Migration of portions of cyto-plasm in nucleus, associated with dysfunctional cell divi-sion in telephase causes a rounded lucency in nucleus
→ frosted glass nucleus.
For example papillary thyroid carcinoma.
2. Paraplasmic inclusions: Migration of portions of paraplasm in nucleus due to imagination of nuclear membrane or dysfunctional telophase.
3. Glycogen inclusions: Seen as nuclear defects after alcohol fixation—Diabetes.
4. Fatty inclusions: Following paraffin fixation, cause lipid defects in nucleus. Typical of tumors in the form of fatty tissue—Liposarcoma.
5. Immunoglobulin inclusions: PAS-positive globules (Fahey-Dutcher bodies). Malignant lymphocytic tumors like—
Lympholoplasmacytic lymphoma.
6. Viral inclusion: Viral proteins arranged in paracystalline configuration.
Q.44. What is the most frequent type of metaplasia seen?
Ans. Metaplasia or an adaptive response to stress in which one mature cell type (epithelial or mesenchymal) is converted to another mature cell type is most commonly of columnar to squamous epithelial type. The commonest form occurs in smokers’ respiratory columnar ciliated mucous secreting epithelium is replaced by more resistant stratified squa-mous epithelium with loss of mucous secreting function.
The change may be focal or wide. Stones in excretory ducts of salivary glands, pancreas or bile ducts may also cause a change from columnar to stratified squamous epithelium.
Q.45. What is the role of Vitamin A in maintaining respiratory epithelium?
Ans. Vitamin A deficiency (retinoic acid deficiency) may cause squamous metaplasia of respiratory epithelium and excess of Vitamin A is protective against keratinization.
Q.46. Is squamous metaplasia beneficial?
Ans. It is a double edged sword as in case of respiratory epi-thelium important function of mucous secretion is lost. Also malignant cancer can arise in metaplasmic tissue and most common cancer of respiratory epithelium is of squamous type. All this with standing, stratified squamous epithelium is more rugged and causes increased resistance to noxious stimuli.
Q.47. Can metaplasia from squamous to columnar epithe-lium occur?
Ans. Yes. Barrett’s esophagus is a condition in which lower eso-phagus after increased exposure to acid reflux from sto-mach converts from stratified squamous to glandular colum-nar type of epithelium cancer arising in this setting is most commonly adenocarcinoma.
Q.48. In connective tissue metaplasia also clearly are adap-tive response?
Ans. Connective tissue formation of the type which is not indi-genous to its site is not clearly adoptive. Example is forma-tion of bone in soft tissue in myositis ossificans in fractures.
Fat and cartilage can form sometimes too.
Q.49. What is the role of stem cells in metaplasia?
Ans. Metaplasia results from reprogramming of stem cells pre-sent in the tissue or of undifferentiated mesenchymal cells in connective tissue. Precursor cells develop differently there is no change in the phenotype of differentiated, mature cells.
Q.50. What are the mechanisms involved in altered pre-cursor cells development in metaplasia?
Ans. Many tissue specific and differentiation genes are involved in coding for growth factors, cytokines and E (M compo-nents which signal for altered development of precursor cells, e.g. bone morphogenic proteins, members of TGF-B superfamily, induce chondrogenic and osteogenic ex-pression in stem cells. While suppressing differentiating into muscle or fat these growth factors act as external triggers induce specific transcription factors that lead the cascade of phenotype specific genes towards a full-developed (of different type) cell. Why the normal pathways are disrupted is not known?
Examples:
Examples: Vitamin Vitamin AA→→ Retinoic acid regulates cell growth, Retinoic acid regulates cell growth,
Examples: Vitamin Vitamin AA→→ Retinoic acid regulates cell growth, Retinoic acid regulates cell growth,