Gerard Conrad Blobe, MD, PhD

• Professor of Medicine
• Professor of Pharmacology and Cancer Biology
• Associate of the Duke Initiative for Science & Society
• Member of the Duke Cancer Institute

https://medicine.duke.edu/faculty/gerard-conrad-blobe-md-phd

Application of Ancillary Studies onCytologic Materials Almost all ancillary studies treatment room buy isordil pills in toronto. Most routinely performed include cell block for immunocytochemistry and flow cytometry for immunophenotyping treatment yeast uti buy isordil 40mg visa. Various special and ancillary techniques are as follows: v Special stains: these are performed on wet-fixed smears in treatment 1 isordil 10 mg free shipping. When there is a clinical suspicion of infection symptoms 20 weeks pregnant isordil 40 mg purchase online, usually an additional aspirate is obtained and it is delivered into a sterile culture tube medications causing hair loss discount isordil 40mg amex. Epithelioid cells have elongated (oblong/slipper shaped) nuclei and abundant pale cytoplasm. The background shows lymphocytes and eosinophilic granular caseous necrotic material. Ziehl-Neelsen stain for acid-fast bacilli may show positivity for the tubercle bacilli. High nuclear cytoplasmic ratio; nuclei are enlarged, hyperchromatic with irregular nuclear membranes. Then smears are prepared by gently touching or pressing freshly exposed surface (without smearing) onto a glass slide. The advantage of the imprint smear is that the cell distribution recapitulates tissue architecture to some extent, thereby aids in interpretation. Imprint cytology is used for the intraoperative diagnosis of malignancy as a complement to frozen-section, and is also valuable as an adjunct to histopathology in the typing of lymphomas. Crush Smear Cytology In crush smear cytology, the tissue particles are crushed to prepare smears. Biopsy Sediment Cytology In biopsy sediment cytology, the smears are prepared from sediment obtained by centrifugation of fixatives/fluids in which surgical biopsy specimens are received by the laboratory. This method may be useful in the rapid diagnosis of bone tumors because histological sections of bone needs many days for processing due to necessity of decalcification. Hematopoiesis (hemopoiesis) is the continuous, regulated process of blood cell production or formation. Hematopoietic (hemopoietic) system: It consists of all organs and tissues involved in hematopoiesis, and these are divided into myeloid tissue and lymphoid tissue. Extramedullary hematopoiesis: t Normally, the cells of the myeloid lineage arise in the central bone marrow (medullary cavity). If the increased demand of blood cells is not met with compensatory hyperactivity of marrow alone, hematopoietic islands appear in liver and spleen (resulting in hepatosplenomegaly) and even in lymph nodes. The above division of hematopoietic elements as myeloid and lymphoid tissue is mainly for understanding their pathology. It is not always possible to draw clear demarcation between the diseases affecting them. Sites of Hematopoiesis Different sites of hematopoiesis during various phases of life are shown in Table 11. Terminology Used in Hematopoiesis the meaning of the terms used with reference to hematopoiesis is shown in Table 11. Normal Development of Blood Cells (Hematopoiesis) the hematopoietic system is a hierarchy of cells in which pluripotent hematopoietic stem cells proliferate and differentiate. Note: Apart from blood cells, the stem cells may be able to differentiate into diverse tissue types. This change in the differentiation of a cell from one type to another is known as transdifferentiation, and the capacity of a cell to transdifferentiate into diverse lineages is referred to as developmental plasticity. Multipotent progenitor cells: these are of two types namely-early progenitor with myeloid potential and early progenitor with lymphoid potential. Early progenitor with myeloid potential further divide to produce mainly two types of multipotent progenitor cells with restricted differentiation. Early progenitor with lymphoid potential cell in turn gives rise to three progenitor cells. Morphologically, the progenitor (both multipotent and unipotent) cells and stem cells cannot be distinguished from one another on morphological appearance or cytochemistry except by immunological techniques. The next step in hematopoiesis is maturation of unipotent progenitor cells to precursor cells. The earliest morphologically recognizable precursor cell of each lineage is termed by adding the suffix "blast" to the type of lineage. Mature Cells the precursor cells finally give rise to mature blood cells, which are released from the marrow into the circulation. Terminology Pluripotent Multipotent Unipotent Ability to generate all mature hematopoietic cells Ability to produce a limited range of differentiated cell lineages appropriate to their location Restricted ability to differentiate and generate one specific cell type Regulation of Hematopoiesis the growth of different hematopoietic cells is regulated by a number of hematopoietic growth factors, which in general are called cytokines. Etiological classification: the etiological classification of anemia is presented in Box 11. Red cell indices are useful in morphological characterization and diagnosis of anemias. They are either directly measured or automatically calculated by specialized instruments. Speed of onset of anemia: Rapidly progressive anemia causes more symptoms than that of gradual onset. Severity of anemia: Mild anemia produces no symptoms compared to significant symptoms in severe anemia. In anemia, the lowered oxygen content of the circulating blood leads to tissue hypoxia. Due to tissue hypoxia: n Nonspecific symptoms: Weakness, malaise and easy fatigability due to hypoxia of muscles. Due to compensatory mechanisms: n Cardiac features: Dyspnea on mild exertion, palpitation, tachycardia and cardiac murmur occur due to compensatory mechanisms. The resulting increase in the cardiac output may cause congestive cardiac failure. Describe the peripheral blood smear and bone marrow findings and list the laboratory investigations in iron deficiency anemia. Describe the etiology, clinical features and the laboratory diagnosis of iron deficiency anemia. The total body iron content is divided into functional and storage compartments (Table 11. Iron in the body is extensively recycled between the functional and storage pools. The remaining functional iron is found in myoglobin and iron-containing enzymes (catalase, cytochromes and peroxidases). Free iron is highly toxic, because it can result in tissue damage due to its capacity to form free radicals. Therefore, iron is bound to protein and stored in the body in two forms namely-ferritin and hemosiderin. The storage iron can be readily mobilized whenever there is increase in the requirements of iron, as may occur after blood loss. Very small amounts of ferritin circulate in the serum, the value normally being 15­300 µg/L. Serum ferritin level is usually below 12 µg/L in iron deficiency and it is very high (as high as 5000 µg/L may be observed) in conditions associated with iron overload. Hemosiderin appears as golden yellow granules in the cytoplasm of the cells when stained with routine Hematoxylin and Eosin. Daily requirements: the daily requirement in adult males is 5­10 mg/day and in females 20 mg/day. Dietary sources: the diet contains iron either in the form of heme contained in animal products and/or nonheme iron in vegetables. Iron Absorption Site of absorption: Iron is absorbed from the duodenum and proximal jejunum. Iron in nonheme form is mostly in the Fe3+ (ferric) state and is reduced to Fe2+ (ferrous) iron by ferrireductases, such as duodenal cytochrome b. Heme iron is moved across the brush border of the cytoplasmic membrane of the enterocyte through heme transporters into the cytoplasm. Iron (heme or nonheme) that enters the cytoplasm of the enterocyte may be either transported to the blood or stored as mucosal iron. Fe2+ iron destined for transport from cytoplasm to the circulation is carried out by ferroportin1. This process is coupled by the iron oxidase like hephaestin (which is expressed predominantly in the enterocyte) which oxidizes Fe2+ iron to Fe3+ form. Pool Total Functional Hemoglobin Myoglobin and enzymes Storage Ferritin, hemosiderin Men 3450 2000­2500 350­400 500­1000 Women 2450 1750 300 400 Transport of Iron Iron is transported in plasma by the iron transport protein transferrin, which is synthesized in the liver. The major function of plasma transferrin is to deliver iron to erythroid precursors for the synthesis of hemoglobin. In normal individuals, transferrin is about 33% saturated with iron, with an average serum iron levels of 120 µg/dL in men and 100 µg/dL in women. Iron Excretion Iron metabolism is unique as it is very efficiently utilized and reutilized by the body. Regulation of Iron Balance Iron is essential for cellular metabolism; at the same time excess of it is highly toxic. Hepcidin synthesized in the liver is the central regulator of iron homeostasis and it controls absorption and storage. Hepcidin inhibits iron transfer from the enterocyte to plasma by binding to ferroportin. Pathogenesis of Iron Deficiency Anemia It is due to decreased synthesis of heme and can be divided into three stages: v Stage 1 (Iron depletion): Iron adequate to maintain normal hemoglobin level and only serum ferritin decreased. Describe the peripheral blood picture and bone marrow finding in iron deficiency anemia. Absence of bone marrow iron: "Gold standard" test, demonstrated by negative Prussian blue reaction. Central nervous system: Pica-unusual craving for substances with no nutritional value such as clay or chalk. Iron deficiency anemia n Thalassemia major and minor n Anemia of chronic disorders n Others: Alcohol, lead poisoning and drugs n Sideroblastic anemia (rare cause) Various differentiating features of microcytic hypochromic anemias are presented in Table 11. Patterson-Kelly or Plummer-Vinson syndrome: Microcytic hypochromic anemia, atrophic glossitis and esophageal webs. First fingernails become thin and flat-platonychia, then brittle and finally spoon-shaped. Megaloblastic anemias are common among anemias due to impaired red cell production. Other disorders may be associated with macrocytosis but megaloblastic hematopoiesis is most commonly due to deficiency of vitamin B12 or folic acid. Vitamin B12 Metabolism Human beings are totally dependent on animal products in the diet for vitamin B12 requirement. Due to this adequate storage, if there is any dietary deficiency or malabsorption of vitamin B12, its clinical manifestations appear only after about 2 to 4 years. Vitamin B12 is a complex compound known as cobalamin and daily requirement is about 2 to 3 µg. In the stomach, peptic digestion at low pH is required for release of vitamin B12 from binding protein in the food. The released vitamin B12 binds with salivary protein called haptocorrin, which is secreted in salivary juices. As the haptocorrin-B12 complexes pass into the second part of the duodenum, pancreatic proteases release vitamin B12 from haptocorrin. These ileal enterocytes express a receptor on their surfaces for the intrinsic factor. Deficiency of vitamin B12 causes increased levels of methylmalonic acid in plasma and urine. This results in the formation of abnormal fatty acids which get incorporated into neuronal lipids. Consequently, this predisposes to myelin breakdown and is probably responsible for neurologic complications of vitamin B12 deficiency. Folic Acid Metabolism Humans are entirely dependent on dietary sources for their folic acid requirement. Green vegetables, yeast, legumes, fruits and animal proteins are the richest sources and most normal diets contain sufficient amounts of folic acid. Polyglutamates are sensitive to heat (thermolabile); boiling, steaming or frying and cooking destroys most of the folic acid. Intestinal conjugases split the polyglutamates into monoglutamates that are readily absorbed in the proximal jejunum. During intestinal absorption, they are modified to 5 methyltetrahydrofolate, the normal transport form of folic acid. The nuclear maturation lags behind the cytoplasmic maturation and results in abnormally large nucleated erythroid precursors named as megaloblasts. Ineffective erythropoiesis: Megaloblast precursors undergo intramedullary destruction. Impaired absorption · Gastric: Deficiency of gastric acid or pepsin or intrinsic factor ­ Pernicious anemia ­ Post-gastrectomy · Intestinal ­ Loss of absorptive surface Malabsorption syndromes Diffuse intestinal disease. Increased demand: Pregnancy, hyperthyroidism, disseminated cancer Folic Acid Deficiency 1. Impaired absorption · Malabsorption states: Nontropical and tropical sprue · Diffuse infiltrative diseases of the small intestine. Increased demand: Pregnancy, infancy, disseminated cancer, markedly increased hematopoiesis 5. Write short note on the laboratory findings/peripheral smear findings in megaloblastic anemia. Diagnostic Tests for Vitamin B12 Deficiency Serum vitamin B12 levels: decreased v Serum methylmalonic acid v Urinary excretion of methylmalonic acid v Schilling test for vitamin B12 absorption (refer page 302). Stomach shows damage to parietal cells, dense infiltration by lymphocytes and plasma cells chronic atrophic gastritis failure of production of intrinsic factor.

Arsenicals may also be found naturally in soil and ground water (in countries medications migraine headaches isordil 5mg on line, such as Bangladesh medications 3 times a day purchase isordil cheap, Chile medications pancreatitis buy discount isordil 40 mg online, and China) as a result of naturally occurring arsenic-rich rock formations medications definition buy 10 mg isordil amex, from coal burning or from use of arsenical pesticides medications 142 isordil 10mg buy fast delivery. Toxic effects: these include: v v Acute arsenic poisoning is almost always due to accidental or homicidal ingestion. Ingested of large quantities of arsenic causes severe abdominal pain, diarrhea; cardiac arrhythmias, shock and respiratory distress syndrome; and acute encephalopathy. These effects may be due to the interference with mitochondrial oxidative phosphorylation. Chronic exposure to arsenic: Chronic arsenic intoxication affects many organ systems. Cancers of the skin, respiratory tract (lung carcinoma) and gastrointestinal tract may develop due to industrial and agricultural exposure. This may be followed by the development of basal and squamous cell carcinomas (but not melanomas). Arsenic can cause encephalopathy and peripheral neuropathy (paresthesias, motor palsies and painful neuritis). Cadmium Sources: Cadmium is a plasticizer and a pigment and is relatively a modern toxic agent. It is used in manufacturing alloys, producing rechargeable nickel-cadmium batteries and electroplating other metals. Cadmium oxide fumes are released during welding of steel parts previously plated with a cadmium anticorrosive. Cadmium can contaminate soil and plants directly or through fertilizers and irrigation water. Both plant- and animal-derived foodstuffs may contain substantial amount of cadmium. In the kidney, initially it produces proteinuria due to tubular damage (rather than glomerular damage) that may progress to end-stage renal disease. Chromium Chromium (Cr) is used in several industries, such as metal plating and some types of manufacturing. Chronic exposure is highly genotoxic and increases the risk of lung cancer and other tumors. Nickel Nickel is used in electronics, coins, steel alloys, batteries and food processing. The most frequent effect of exposure to nickel is contact dermatitis ("nickel itch") and can develop due to contact with metals containing nickel, such as coins and costume jewelery. Exposure to nickel increases the risk of lung cancer and cancer of the nasal cavities. Tobacco is the most common exogenous cause of human cancers and is responsible for about 90% of lung cancers. Apart from death due to various types of cancers, tobacco can cause deaths from cardiovascular and metabolic diseases, deaths from nonmalignant lung diseases and perinatal deaths. Life expectancy is reduced by cigarette smoking and overall mortality is proportional to the amount (dose dependent) and duration of smoking commonly quantitated as "pack-years. Betel quid/pan is a type of tobacco chewing that contains several ingredients, such as areca nut, slaked lime, and tobacco which are wrapped in a betel leaf. Oral cancers are found on the buccal and gingival surfaces in the sites where tobacco products are held in contact with the mucosa for long periods. Constituents of Tobacco Smoke Tobacco contains more than 2,000 substances (potentially noxious) and more than 60 have been identified as carcinogens and few of them along with the type of injury produced by these agents are listed in Table 9. It does not directly cause tobacco-related diseases, but is strongly addictive and is responsible for tobacco addiction. Nicotine binds to nicotinic acetylcholine receptors in the brain, and release catecholamines from sympathetic neurons. This is responsible for the acute ill effects of smoking namely increase in heart rate, blood pressure, cardiac contractility and output. Respiratory System the most common diseases caused by cigarette smoking involve the respiratory system mainly lung. The risk of developing lung cancer depends on the intensity of exposure and is usually expressed in terms of number of "pack years". In nonsmokers, passive environmental smoke inhalation is also associated with risk of lung cancer than those who are not exposed to passive smoke. Chronic bronchitis, emphysema and chronic obstructive pulmonary disease: Contents in tobacco smoke directly irritate the tracheobronchial mucosa, producing inflammation and increased production of mucus (bronchitis). Cigarette smoke also recruits leukocytes to the lung, and increases the local production of elastase. Children living along with adult smokers are susceptible to increased respiratory illnesses and asthma. Other Systems Apart from lung cancer, tobacco smoking is a risk factor for many other malignant and nonmalignant disorders of many organ systems. All forms of tobacco usecigarette, cigar and pipe smoking, and tobacco chewing are associated with oral cancer. Tobacco consumption interacts with alcohol in multiplying the risk of oral, laryngeal and esophageal cancer. Smoking is a risk factor for atherosclerotic peripheral vascular disease and cerebrovascular disease (ischemic stroke, intracranial hemorrhage). If smoking is combined other risk factors, such as hypertension (elevated blood pressure) and hypercholesterolemia (raised blood cholesterol levels), this multiplies the risk of atherosclerosis and myocardial infarction. The cigarette smoking is a strong risk factor for atherosclerotic aortic aneurysms. Maternal smoking: Increases the risk of spontaneous abortions and preterm births and results in intrauterine growth retardation (fetal tobacco syndrome). It may be due to nicotine-related insulin resistance and beta cell apoptosis, increased central obesity and altered metabolism of estrogens and androgens in smokers. However, excessive amounts of alcohol can cause marked physical and psychologic damage. After consumption, ethanol is directly absorbed in the stomach and small intestine. Then it is distributed to all the tissues and fluids of the body which is directly proportional to its level in the blood. Less than 10% of the alcohol is excreted directly in the urine, sweat, and breath. Chronic alcoholism: It is defined as regular intake of sufficient alcohol to injure an individual socially, psychologically or physically. Alcoholism is more common in men, but the number of female alcoholics is gradually increasing. It may lead to death either directly or due to accidents caused by drunken driving and alcohol-related homicides and suicides, and as a consequence of cirrhosis of the liver. Alcohol level in blood: the amount of alcohol exhaled is proportional to the blood level. The legal definition of drunk driving is an alcohol concentration of 80 mg/dL in the blood. In most individual, this alcohol concentration may be observed after consumption of three standard drinks [for example, three (12 ounce) bottles of beer, 15 ounces of wine, or 4­5 ounces of 80-proofdistilled spirits]. When the alcohol level reach 200 mg/dL, drowsiness develops, 300 mg/dL level stupor, and with more than this level, coma with respiratory arrest may develop. For most individuals, daily consumption should be <45 g alcohol and any quantity more than this should be discouraged and consumption of 100 g or more/day may be dangerous [10 g alcohol = 1 oz, or 30 mL, of 86 proof (43%) spirits]. Factors affecting alcohol levels in blood: Apart from amount of alcohol consumed other factors also affect the alcohol levels in blood: the rate of metabolism affects the alcohol level in blood. Chronic alcoholics develop tolerance to alcohol and they metabolize alcohol at a higher rate than normal. Hence, chronic alcoholics show lower peak levels of alcohol than others for the same amount of alcohol consumed. In a normal individual, intellectual behavioral changes can be observed at low alcohol concentrations (below 50 mg/dL). Levels above 80 mg/dL are usually associated with slower reaction times and gross incoordination. Most individuals become comatose at levels above 300 mg/dL, and at concentrations above 400 mg/dL, death from respiratory arrest/failure is common. Chronic alcoholism can affect any organs and tissues, but main affects are found in the liver and stomach. It can produce alcoholic liver disease which includes (i) fatty change (steatosis), (ii) alcoholic hepatitis, and (iii) cirrhosis (refer Chapter 19). Cirrhosis is associated with portal hypertension and also is a risk factor for hepatocellular carcinoma. Violent retching may cause tears at the esophageal­gastric junction (Mallory­Weiss syndrome). Nervous system: General cortical atrophy of the brain is common in chronic alcoholics. Most of the characteristic brain diseases in alcoholics are probably due to nutritional deficiency. Wernicke encephalopathy: It is due to nutritional thiamine deficiency which is common in chronic alcoholics. It is characterized by mental confusion, ataxia, abnormal ocular motility and polyneuropathy. Its most common complaints include numbness, paresthesias, pain, weakness, and ataxia. Cardiovascular effects: Chronic alcoholism produces diverse effects on the cardiovascular system. Thus, it may provide significant protection against coronary artery disease(atherosclerosis) and its consequence, myocardial infarction. Pancreatitis: Excess alcohol intake increases the risk of both acute and chronic pancreatitis (refer Chapter 19). Chronic calcifying pancreatitis in alcoholism produces severe pain, pancreatic insufficiency and pancreatic stones. Effects on fetus: Infants born to mothers who consume alcohol (even in low amounts) during pregnancy (especially during the first trimester) can show a cluster of abnormalities that together constitute the fetal alcohol syndrome. These abnormalities in the newborn consists of microcephaly, growth retardation and facial abnormalities (dysmorphology, neurologic dysfunction), and other congenital anomalies. However, about 6% of the v infants of alcoholic mothers develop the full syndrome. More commonly it is associated with less severe abnormalities, such as mental retardation (reduction of mental functions in older children), intrauterine growth retardation and minor dysmorphic features. Carcinogenesis: Chronic alcohol consumption is associated with an increased incidence of cancers of the oral cavity, esophagus, larynx, liver (increased in patients with alcoholic cirrhosis), and probably, breast in females than in the general population. The risk is markedly more if there is concurrent smoking or the use of smokeless tobacco. Malnutrition: Alcohol provides substantial energy, but is often consumed at the expense of food (empty calories). Thus, chronic alcoholism may be associated with malnutrition and deficiencies, particularly of the B vitamins (such as thiamine deficiency). It may be due to dietary deficiency of folic acid and decreased absorption of folate by the small intestine in alcoholics. In patients with alcoholic cirrhosis, the spleen is often enlarged by portal hypertension. Transient thrombocytopenia may develop after acute alcohol intoxication and may produce bleeding. Endocrine system: Male alcoholics may develop feminization and loss of libido and potency. They may also develop gynecomastia (enlargement of breasts), loss of body hair and a female distribution of pubic hair (female escutcheon). But many of the changes (especially testicular atrophy) may occur even without any liver disease. Alcohol has a direct toxic effect on the testes and causes male sexual impairment. Bone: Chronic alcoholism, especially in postmenopausal women predisposes to osteoporosis. Interestingly, it may be noted that moderate consumption of alcohol may be protective against osteoporosis. Male alcoholics are likely to have high incidence of aseptic necrosis of the head of the femur. Immune system: Chronic alcoholics may be prone to many infections (particularly pneumonias) with micro-organisms that are unusual in the general population. It develops due to inadequate intake of protein and calories and is characterized by emaciation with obvious muscle wasting and loss of body fat. Edema: In kwashiorkor, marked protein deprivation causes hypoalbuminemia leading to generalized or dependent edema. This consists of alternating zones of hyperpigmentation, and hypopigmentation, producing "flaky paint" appearance. Other features: the other features that differentiate kwashiorkor from marasmus are as follows: n Presence of enlarged, fatty liver. Cachexia occurs most commonly in patients with cancers of gastrointestinal, pancreatic and lung. Characterized by extreme weight loss, fatigue, muscle atrophy, anemia, anorexia and edema. Metabolic Changes in Starvation Starvation is a gradual process in which there is decrease in the metabolic rate as storage carbohydrate reserves are metabolized. During fasting, insulin independent tissues, such as the brain, blood cells and renal medulla continue to utilize glucose.

The rough inflamed pericardial surfaces produce a characteristic loud pericardial friction rub on auscultation treatment diabetic neuropathy buy cheap isordil line. Purulent or Suppurative Pericarditis It is usually accompanied by purulent exudate that resembles pus (full of neutrophils) in the pericardial cavity medicine wheel teachings buy isordil 5mg with mastercard. Etiology: It is due to infection caused by microbial (pyogenic bacteria) invasion of the pericardial space medicine ok to take during pregnancy buy isordil cheap. The various routes of infection are as follows: v Direct extension of infections from neighboring structures: Examples include empyema of the pleural cavity treatment lyme disease 40 mg isordil buy amex, lobar pneumonia medicine net cheap isordil 10 mg, mediastinal infections, etc. Microscopy the pericardium shows acute inflammatory infiltrate and may extend into surrounding structures to produce mediastinopericarditis. Outcome: Complete resolution is uncommon and organization by scarring is the usual outcome. The intense inflammatory response and the scarring may lead to constrictive pericarditis. Clinical features: During active phase, they are similar to fibrinous pericarditis. However, the frank infection can produce more marked systemic symptoms such as fever and rigors. Hemorrhagic Pericarditis this type of pericarditis shows an exudate composed of blood mixed with a fibrinous or suppurative effusion. Etiology: Its causes include: v Spread of a malignant neoplasm to the pericardial space is the most common cause. Cytologic examination of pericardial fluid removed through a pericardial tap often shows neoplastic cells. Most common tumors that involve the pericardium and cause malignant pericardial effusions are breast and lung carcinomas. Metastases may be grossly found as irregular excrescences or may be grossly inapparent, especially in the case of leukemia. Tuberculous (Caseous Pericarditis) Etiology: Caseous pericarditis unless otherwise proved is due to tuberculosis. Pericardial involvement in tuberculosis may occur by direct spread from tuberculous foci within the tracheobronchial nodes. Complications: Caseous pericarditis may progress to a disabling, fibrocalcific, chronic constrictive pericarditis. Chronic Constrictive Pericarditis In chronic pericarditis, if delicate adhesions or dense, fibrotic scars occurs, it can cause obliteration of the pericardial space. When this process is severe, the heart may be completely encased by dense, fibrous or fibrocalcific scar. In such case, the heart cannot expand normally during diastole and there will be reduction in the cardiac output. Definition: Chronic constrictive pericarditis is a chronic fibrosing disease of the pericardium (scarring of the pericardial sac) that compresses the heart and limits the ability of the chambers in the heart to fill with blood. Etiology: Causes include prior radiation therapy to the mediastinum, cardiac surgery, sequalae of a purulent or tuberculous infection of pericardium. The visceral and parietal layers of pericardium become fused by a dense, rigid mass of fibrous tissue. The scarred pericardium may be thickened (up to 3 cm) in such a way that it narrows the orifices of the venae cavae. Because of the dense fibrous scar neither cardiac hypertrophy nor dilation can occur. The fibrous scar can be up to a centimetre in thickness and obliterates the pericardial cavity/space. Sometimes calcification may be observed and in extreme cases it can resemble a plaster mold (concretio cordis). Thus, its clinical features are due to a combination of right-sided venous distention and low cardiac output (similar to the clinical features in restrictive cardiomyopathy). Cardiac output may be reduced at rest and the heart is not capable of increase its output in response to increased systemic demands. Treatment consists of surgical resection of the shell of constricting fibrous tissue (total pericardiectomy). The pericarditis after healing produces fibrosis in the form of mesh-like stringy adhesions between the visceral and parietal surfaces. This may completely obliterate the pericardial sac; but has no effect on cardiac function. Adhesive Mediastinopericarditis Etiology: It may follow infectious pericarditis, previous cardiac surgery, or mediastinal irradiation. Pathophysiology: In this type of pericarditis, the pericardial sac is obliterated, and the external aspect of the parietal layer of pericardium is adherent to surrounding structures. During each systolic contraction, the heart pulls both the parietal pericardium and the attached surrounding structures. Clinical features: Theses include, systolic retraction of the rib cage and diaphragm, pulsus paradoxus, etc. The increased workload may occasionally lead to severe cardiac hypertrophy and dilation. Pericardial Effusion and Hemopericardium Normally, the pericardial sac contains less than 50 mL of pericardial fluid. Definition: Pericardial effusions are defined as accumulations of excess fluid within the pericardial cavity. If the accumulated fluid is serous fluid it is termed pericardial effusion, if pus termed purulent pericarditis and if blood is accumulated it is termed as hemopericardium. Pericardial Effusions Etiology: Various types and the causes of pericardial effusions include are presented in Table 16. Rate of accumulation of fluid: If the pericardium is slowly distended (longstanding) with fluid, the pericardium has time to dilate. This allows chronic pericardial effusions to accommodate even up to 2 L of fluid without any significant hemodynamic consequences or interference with cardiac function. Clinically, chronic effusions of less than 500 mL may produce only a characteristic globular enlargement of the heart shadow on chest radiograph. However, if the fluid accumulation is rapid, even 150­200 mL of fluid or blood [e. Type of pericardial effusion Causes Serous effusion (low protein content and Congestive heart failure, hypoalbuminemia of any few cells) cause. Tamponade refers to external compression of the heart chambers such that filling is impaired. Pathophysiology: Rapid accumulation of fluid in the pericardial cavity raise the pericardial pressure. When the pressure increase exceeds central venous pressure, the return of blood to the heart is limited. This in turn reduces cardiac output and blood pressure, and leads to pulsus paradoxus (an abnormal decrease in systolic pressure with inspiration). Consequences: Hemodynamic consequences can range from a minimal symptom to sudden cardiovascular collapse and death. Acute cardiac tamponade is almost always fatal unless the pericardial pressure is relieved by aspirating/removing offending pericardial fluid, via needle pericardiocentesis or surgery. Site: About 90% of myxomas arise in the atria, more common in the left atrium in the region of the fossa ovalis in the atrial septum. Vary from globular hard masses with hemorrhage to soft, translucent, papillary, or villous lesions having a gelatinous appearance. The pedunculated type may be mobile during systole into the atrioventricular valve producing intermittent obstruction. Obstructive lung diseases consist of four diseases namely (i) emphysema, (ii) chronic bronchitis, (iii) asthma and (iv) bronchiectasis. Definition: Emphysema is a chronic lung disease characterized by abnormal irreversible (permanent) dilatation of the airspaces distal to the terminal bronchiole. Recent evidences show that small airway fibrosis is present which contributes to airflow obstruction. Emphysema is classified according to its anatomic distribution (location of the lesions) within the lobule into four major types: (i) centriacinar, (ii) panacinar, (iii) paraseptal and (iv) irregular. Centriacinar (centrilobular) emphysema n Dilatation involve the central or proximal parts of the acini (formed by respiratory bronchioles), whereas distal alveoli are spared. Thus, both emphysematous and normal airspaces are present within the same acinus and lobule. Panacinar (panlobular) emphysema n All the airspaces beyond terminal bronchiole are more or less uniformly/equally dilated. Distal acinar (paraseptal) emphysema n Dilatation affects the distal airspace at the periphery of the lobule and the proximal portion is normal. Irregular (scar or cicatricial) emphysema n Acinus is irregularly involved and may be asymptomatic. Clear-cut association between heavy cigarette smoking and development of emphysema is observed. Inhaled cigarette smoke and other toxic substances produce damage to the lung and produces inflammation. This leads to destruction of the lung parenchyma (emphysema) and disease of the airway (bronchiolitis and chronic bronchitis). Inflammatory mediators and leukocytes n Inflammatory mediators: Many inflammatory mediators are released in the lung. This leads to local release of proteases by inflammatory cells and damaged epithelial cells. The Pi locus is polymorphic, and individuals homozygous for the Z allele, have markedly decreased serum levels of 1-antitrypsin. In these patients with absence of 1-antitrypsin activity, there is excessive digestion of elastic tissues which produce emphysema. Oxidative stress: Contents of tobacco smoke, damage to the alveoli (apoptosis) and inflammatory cells produce oxidants. Airway infection: Though not involved in initiation of emphysema bacterial and/or viral infections, may exacerbate the existing inflammatory process and chronic bronchitis. Small airways obstruction in emphysema: It is due to: v Loss of elastic tissue in the walls of alveoli that surround respiratory bronchioles. There is destruction of alveolar walls and loss of attachments of the alveoli to the outer wall of small airways. Clinical Course Manifestations appear late until at least one-third of the functioning pulmonary parenchyma is damaged. Clinical examination: Barrel-shaped chest, dyspnea with prolonged expiration, and breathes through pursed lips. Complications: (i) Cor pulmonale, (ii) congestive heart failure due to secondary pulmonary hypertension and pneumothorax. Cause of death: (i) Respiratory acidosis and coma, (ii) right-sided heart failure and (iii) massive collapse of the lungs secondary to pneumothorax. It may result from alveolar tears in pulmonary emphysema, which occurs during coughing. Centriacinar emphysema: · Involves proximal parts of acini (spares alveoli) · Severe in upper lobes · Smokers · Seen as most common type clinically Panacinar emphysema: · Involves all the airspaces beyond terminal bronchiole (entire acinus) · More common and severe in lower lobes · Associated with 1-antitrypsin deficiency Panacinar emphysema: Prefix "pan" refers to the entire acinus but not to the entire lung. Distal acinar (paraseptal) emphysema: Involves distal air spaces and are prone to spontaneous rupture pneumothorax. It is defined on clinical basis in contrast to emphysema which is defined on the basis of morphologic and radiologic features. Hypersecretion of mucus: n Hyperplasia/hypertrophy of the submucosal glands in large airways (trachea and bronchi): Develops in response to inhaled environmental irritants and proteases released from neutrophils. Both the submucosal gland hypertrophy and the increase in goblet cells are thought to be protective metaplastic response against air pollutants. Role of Inflammation Inhalants producing chronic bronchitis cause damage to cells and cause acute as well as chronic inflammation (neutrophils, lymphocytes and macrophages). Chronic inflammation and accompanying fibrosis involving small airways can produce chronic airway obstruction. Infection may be secondary rather than primary and probably important in maintaining and producing acute exacerbations. Infection may cause direct damage to airway epithelium and interferes with ciliary action of the respiratory epithelium defective clearance of bacteria by leukocytes. It is useful for detecting the increase in the size and number of the mucus glands. Chronic bronchitis: Persistent productive cough for at least 3 months in at least two consecutive years, in the absence of any other identifiable cause. Chronic bronchitis: Cigarette smoking is the most important etiological risk factor. Chronic bronchitis: Microscopically shows: · Hyperplasia of submucosal glands · Increase in goblet cells · Squamous metaplasia · Fibrosis of bronchiolar walls Chronic bronchitis: Reid index (normal 0. Reid index: Ratio of mucus gland layer thickness to the thickness of wall between epithelium and cartilage. Definition: Asthma is a chronic inflammatory disorder of the bronchial tree (airways) in which breathing is periodically rendered difficult by widespread narrowing of the bronchi (reversible bronchoconstriction). It is clinically characterized by recurrent episodes of wheezing, breathlessness, tightness of the chest and cough. Non-atopic/intrinsic (without evidence of allergen sensitization) According to the agents or events that trigger bronchoconstriction: 1. Triggering environmental allergens: It includes dusts, pollens, animal dander and foods. Skin test with the causative allergen results in an immediate wheal-andflare reaction. Aspirin inhibits cyclooxygenase pathway of arachidonic acid metabolism produces leukotrienes (bronchoconstrictor) causes asthma. Occupational Asthma Triggering occupational agents: v Fumes (epoxy resins, plastics).

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