Christopher Barrett Bowling, MD

• Associate Professor of Medicine
• Associate Professor in Population Health Sciences

https://medicine.duke.edu/faculty/christopher-barrett-bowling-md

The treatment protocol is of four different types 0g infection order on line omnicef, all of which involve the use of synthetic steroid derivatives that have long biological half-lives antibiotic 1g buy generic omnicef canada. The first three protocols involve estrogen 1 progestin combinations taken for 3 weeks antimicrobial nail solution buy 300mg omnicef with mastercard, followed by no treatment for 1 week antibiotic resistance markers in plasmids purchase discount omnicef. Triphasic type: fixed dose estrogen 1 three different doses of progestin (stepwise increase at 1-week intervals); and 4 virus images order 300 mg omnicef. Among these antibiotic gentamicin cheap omnicef 300 mg without a prescription, the combination pill is the most widely used and is probably the most effective at a success rate of. The rationale for varying the dose of progestin was that reducing the total amount of steroid would reduce the risk of myocardial infarction, hypertension, and stroke, all of which were subsequently shown not to be altered by varying the dose of progestin. The rationale for the progestinonly protocol was to eliminate the risk of endometrial cancer and breast cancer associated with estrogen; however, some of the health benefits of estrogen. Folliculogenesis did not occur during treatment, but there was no evidence of increased atresia; when electing to bear a child, former pill users experienced normal menstrual cyclicity, pregnancy, and lactation. Long-term observations indicated that pill users experienced menopause within the normal age range and had no health problems that could be attributed to the long-term use of the pill, although recent epidemiological studies suggest that combination pill users may be at increased risk of developing breast cancer prior to age 45. Postcoital pharmacologic prevention of implantation can be achieved by oral administration of a synthetic estrogen (25 mg diethylstilbestrol) twice daily for 5 days. This "morning after pill" treatment stimulates fallopian tube contractions during the period of conceptus travel toward the uterus, such that the conceptus is propelled into the uterus prematurely and is resorbed, or is trapped within the fallopian tube because of spastic contraction of the isthmus. Although effective, the high-dose estrogen produces nausea, vomiting, and menstrual problems. Alternatively, oral administration of a combination pill (50 g ethinylestradiol 1 0. This treatment does not involve an alteration in fallopian tube activity, but the treatment may serve to convert the endometrium into a less-receptive tissue for blastocyst implantation. Synopsis this case study describes a consanguineous family consisting of four sisters with the diagnosis of primary infertility, despite normal maturity and more than 12 months of unprotected sexual intercourse. One of the infertile sisters, who was 32 years old and served as a proband for this study, underwent further clinical and molecular investigations. The role of the zona pellucida is to support early development of the oocyte, facilitate gamete recognition during fertilization, prevent polyspermia, and protect early embryos prior to implantation. The parents of the affected women were first cousins, both with heterozygous genotype (1 / 2). Of their seven offspring who underwent genetic testing, four were infertile (homozygous affected genotype 2 / 2), one produced a child (heterozygous genotype 1 / 2), and the remaining two did not attempt to have children (homozygous affected genotype 2 / 2). Synopsis A 14-year-old boy with an unremarkable past medical history was brought to his primary care physician for concerns of delayed pubertal development. Family history was significant for late pubertal development in his mother and father. Physical examination revealed Tanner stage 1 pubic hair and prepubertal-sized testes (see case reference for a diagram of Tanner stages). Delayed puberty is defined as the absence of testicular enlargement in boys, or the absence of breast development in girls, at an age that is 2 to 2. Treatment with growth hormone, anabolic steroids, or aromatase inhibitors is not recommended to induce the appearance of secondary sexual characteristics; however, low-dose sex steroids may be administered electively to alleviate the psychosocial difficulties associated with short stature and pubertal delay. Synopsis A 15-year-old female presented to her primary care physician with absent breast development, primary amenorrhea, and intermittent lower abdominal pain. The patient was enrolled in a study and, at 17 years old, was found to have Tanner stage 1 breast development, Tanner stage 4 pubic hair, severe facial acne, and a body mass index of 16. Ultrasonography revealed a small uterus, no endometrial stripe, and significantly enlarged multicystic ovaries. A trial of exogenous estrogens was started, but after 5 months of high-dose estrogen therapy, her breasts remained at Tanner stage 1. Synopsis A 6-year-old girl presented to her pediatrician with unexpected breast development for her age. Her height was in the 97th percentile for her age, and her body mass index was 17. She had Tanner stage 3 breast development and Tanner stage 2 pubic hair development. Her presentation suggested the diagnosis of progressive central precocious puberty. In an attempt to elucidate the idiopathic etiologies of progressive central precocious puberty, there have been numerous efforts to identify genes associated with central precocious puberty. Many cases of idiopathic precocious puberty may not require any treatment because of their lack of progression. Bhasin, Targeting the skeletal muscleetabolism axis in prostate-cancer therapy, N. Describe functions and properties of the major cell types and organs associated with the human immune system. The "Communication within the Immune Response" section will enable the student to a. Describe how immune cells communicate through cytokines and cell surface molecules. Describe the function of the major histocompatibility complex in the immune response. Describe the importance of the exogenous and endogenous pathways in antigen presentation. Explain the function of Toll-like receptors and their importance in the host immune response. Describe why and how phagocytes migrate to and from the circulation to the tissues. The "B-cell Development and Antibody Diversity" section will enable the student to a. The "T-cell Development and T-cell Receptor Diversity" section will enable the student to a. The "Adaptive Immune Response: Specific Antibody Response" section will enable the student to a. Explain the mechanism and importance of somatic hypermutation on antibody diversity. The "Adaptive Immune Response: Cell-Mediated Immune Response" section will enable the student to a. Describe the major cell types and their role in generating a cell-mediated immune response. This system is the basis for the immune response that serves to protect us from our encounters with the outside world. The general characteristics of this immune response are specificity, adaptability, and memory. One successful outcome of our immune response to an organism or its products is immunity. For the immune response to be able to induce this resistance to disease, an elaborate multilayer interaction between many different immune mechanisms must come into play each time the host encounters the specific organism. Characteristics of this immune response therefore must include diversity and the ability to adapt, so as to respond to several different N. Immunity therefore can be thought of as the ability to "remember" organisms previously encountered and react promptly to prevent disease associated with that specific organism. Memory of a previous interaction between host and microbe is a unique characteristic of the immune response. This immunologic memory allows for a rapid and specific response against an organism. Finally, the need for control of the immune response is key to an appropriate response. So we can think of the essential steps to an appropriate immune response as (1) recognition of an invading microbe as nonself, (2) activation of the key specific effector cells and molecules for the response, (3) mediation of an appropriate response to remove the microbe, and (4) modulation of the response once the microbe is no longer present. Any substance, from molecule to organism, that is capable of being recognized by the immune system, is called an antigen. The degree to which an antigen induces an immune response is termed antigenicity or immunogenicity [1]. As mentioned previously, the immune system is a complex multilayered network of molecules, cells, and tissues that interact on a local and a systemic level. One can think of the immune response as beginning on an external surface of the host with the epithelium providing a mechanical barrier. The physiologic environment of the skin with its population of normal flora organisms and low pH presents a formidable barrier to colonization by potential pathogenic organisms. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms. The skin and respiratory tract secrete antimicrobial peptides such as the -defensins. Enzymes such as lysozyme and phospholipase A in saliva, tears, and breast milk are also antibacterials. In the stomach, gastric acid and proteases serve as powerful chemical defenses against ingested pathogens. Collectively, these initial nonspecific immune mechanisms of dealing with potential pathogens and altered or infected host cells have traditionally been termed the innate immune response. The innate immune response is characterized by its rapid nonspecific recognition and response to potential pathogens and for its activation of the adaptive immune response. The adaptive immune response is an orchestrated interaction of specialized cells and soluble molecules that initiate a specific response against a targeted threat. Unlike the innate response, adaptive immunity requires a period of time before it can mount a finely tuned specific response to the targeted organism, but in doing so, it also generates a memory component that gives the immune system the ability to remember the best way to deal with that specifically targeted organism. It is this memory component that allows the host to mount a vigorous, rapid targeted response should it encounter that specific organism again Table 33. This differentiation into the different immune cells is driven by various cytokines, small proteins important for cell signaling, released by a number of different cell types such as the bone marrow stromal cells and other mature immune cells. The production of all these immune cells from the different lineages is under tight control and is dictated by the needs of the host. Such physiologic states such as stress or infection can greatly increase any or all immune cells needed for the host to regain homeostasis. The term hematopoiesis describes the process of the generation of cells in the blood. This process begins in the early embryo and continues throughout the life of an individual. Since most mature blood cells are short-lived, new blood cells continually arise from hematopoietic stem cells and become committed to either the myeloid or lymphoid lineage of development. The granulocytes, which arise from the myeloid lineage, are a group of immune cells characterized by the presence of intracellular granules and named according to appearance under various histological stains. Hence, basophils possess basic staining granules, eosinophils possess eosin-staining granules, and neutrophils have neutral staining granules. Neutrophils are the most numerous of the leukocytes in a healthy host and are actively motile cells that play a major role in the ingestion and killing of invading microorganisms. Neutrophils are rapidly produced in the bone marrow and have a half-life of only 6 to 8 hours after entering the peripheral blood. Eosinophils, basophils, and mast cells are granulocytes that play a special role in the immune response associated with epithelial surfaces of the respiratory, gastrointestinal, and urogenital tracts. Mast cells play an important role in inflammation by releasing the contents of their granules that contain numerous inflammatory mediators. Produced by the bone marrow, monocytes circulate in the bloodstream for about 1 to 3 days before moving into tissues throughout the body. Once in the tissues, monocytes mature into macrophages and then engulf and digest cellular debris. If organisms are also present, they can stimulate other immune cells to respond to the potential pathogen. Macrophages (M) have various names depending on the tissue they reside in: liver-Kupffer cells, kidney-mesangial cells, lung-alveolar macrophages; or brain-microglial cells. T-cell subclass that releases necessary cytokines for cell stimulation and proliferation. Create pores that permit transfer of proteins which promote apoptosis of infected cells. Attack parasites too large for phagocytosis, possess granules that contain toxic proteins, adhere to foreign organisms via C3b, release proteins and enzymes that damage foreign organism membranes, kill with active oxygen burst. Recognize and endocytose foreign carbohydrate antigens that are not found in vertebrate animals. Neutrophils are attracted to sites of complement activation by C5a, a chemotactic peptide from C5. T cells play a central role in the initiation, propagation, and control of antigen-specific immune responses. There are two different subsets of B cells-B1 cells and B2 cells-that differ in their developmental origin, cell surface marker expression, and their immune function. B1 cells predominate in the developing fetus, spontaneously secrete antibodies, and operate under a differentiation program that is unique from that of conventional B2 cells, which become the predominant cells in adults. Upon stimulation with antigen, B cells develop into plasma cells, which function as antibody secreting "factories" or memory cells, which are maintained by the immune system to be able to respond quickly following a subsequent exposure to the same antigen. They are the most effective and efficient at presenting antigens to other cells of the immune system. As with the lymphocytes, dendritic cells are composed of several subsets that express different cell surface molecules and signaling proteins.

The mechanism of action of statins in bone metabolism may involve inhibition of prenylation of signaling proteins found on osteoclast cell membrane (Chapter 35) antibiotic 625 generic 300 mg omnicef visa. Independent of the hypocholesterolemic effect antibiotics variceal bleed generic omnicef 300 mg online, statins have beneficial anti-inflammatory properties flagyl antibiotic for sinus infection order omnicef 300mg visa, presumably linked to their inhibition of isoprenoid biosynthesis treatment for dogs going blind buy 300mg omnicef overnight delivery. Patients with severe forms of inherited mevalonate kinase deficiency exhibit mevalonic aciduria antibiotics in food buy cheap omnicef 300 mg on line, failure to thrive infection line up arm best order for omnicef, developmental delay, anemia, hepatosplenomegaly, gastroenteropathy, and dysmorphic features during neonatal development. Cholesterol delivered to the cells via low-density lipoprotein (Chapter 18) is converted to oxygenated sterol derivatives in the mitochondria, followed by their release into the cytoplasm. Oxygenated sterols are then translocated to the nucleus by binding to oxysterol-binding protein. These compounds are commonly known as statins and are used pharmacologically in cholesterol reduction, which can reduce the risk for coronary artery disease and stroke (Chapter 18). Naturally occurring statins are found in a dietary supplement known as cholestin, which is obtained from rice fermented in red yeast. The farnesyl pyrophosphate generated in this pathway is also used in the farnesylation of proteins. The farnesyl group is attached to a protein via a thioether linkage involving a cysteine residue found in the C terminus. Proteins attached to a geranyl-geranyl group (a 20-C isoprene unit) have also been identified. The modification of proteins by these lipid moieties increases their hydrophobicity and may be required for these proteins to interact with other hydrophobic proteins and for proper anchoring in the cell membrane. The importance of farnesylation of proteins is exemplified by the fact that inhibition of mevalonate synthesis results in a blockage of cell growth. Lanosterol 314 Essentials of Medical Biochemistry concerted 1,2-methyl group and hydride shifts along the squalene chain. Conversion of Lanosterol to Cholesterol Transformation of lanosterol to cholesterol is a complex, multistep process catalyzed by enzymes of the endoplasmic reticulum (microsomes). A cytosolic sterol carrier protein is also required and presumably functions as a carrier of steroid intermediates from one catalytic site to the next but may also affect activity of the enzymes. The reactions consist of removal of the three methyl groups attached to C4 and C14, migration of the double bond from the 8,9- to the 5,6-position, and saturation of the double bond in the side chain. Conversion of lanosterol to cholesterol occurs principally via 7-dehydrocholesterol and to a minor extent via desmosterol. The importance of cholesterol biosynthesis in embryonic development and formation of the central nervous system is reflected in patients with disorders in the pathway for the conversion of lanosterol to cholesterol. Clinical manifestations of this disorder include skeletal abnormalities, chondrodysplasia punctata, craniofacial anomalies, cataracts, and skin abnormalities. Clinical manifestations of affected individuals include craniofacial abnormalities, microcephaly, congenital heart disease, malformation of the limbs, psychomotor retardation, cerebral maldevelopment, and urogenital anomalies. Measurement of 7-dehydrocholesterol in amniotic fluid during the second trimester or in neonatal blood specimens has been useful in the identification of the disorder. The inability of de novo fetal synthesis of cholesterol combined with its inadequate transport from the mother to the fetus appears to be involved in the multiple abnormalities of morphogenesis. However, it is not known whether long-term dietary cholesterol supplementation can improve cognitive development, particularly since cholesterol is not transported across the bloodrain barrier. An appreciation of the relationship between cellular cholesterol metabolism and a family of signaling molecules that participate in embryonic development is emerging. These signaling molecules are known as hedgehog proteins, which were initially identified in Drosophila. The vertebrate counterparts of hedgehog proteins participate in embryonic development, including the formation of the neural tube and its derivatives, the axial skeleton, and the appendages. The hedgehog protein is a selfsplicing protein that undergoes an autocatalytic proteolytic processing, giving rise to an N-terminal and a C-terminal product. Cholesterol is covalently attached to the carboxy terminal end of the N-terminal cleavage product. Both the autocatalytic proteolysis and intramolecular cholesterol transferase activities are located in the C-terminal portion of the hedgehog protein. The covalent modification of the Nterminal segment of the hedgehog protein is necessary for proper localization on the cell membrane at target sites to initiate downstream events. Thus, perturbations of cholesterol biosynthesis due to mutations or pharmacological agents can lead to defects in embryonic development. Utilization of Cholesterol Cholesterol is utilized in the formation of membranes (Chapter 9), steroid hormones (Chapters 28, 30, and 32), and bile acids. Under steady-state conditions, the cholesterol content of the body is kept relatively constant by balancing synthesis and dietary intake with utilization. However, secretion of bile acids by the liver is many times greater (150 g/day) than the rate of synthesis because of their enterohepatic circulation (Chapter 11). Cholesterol is also secreted into bile, and some is lost in feces as cholesterol and as coprostanol, a bacterial reduction product (about 0. Conversion of cholesterol to steroid hormones and of 7-dehydrocholesterol to vitamin D, and elimination of their inactive metabolites are of minor significance in the disposal of cholesterol, amounting to approximately 50 mg/day. A small amount of cholesterol (about 80 mg/day) is also lost through shedding the outer layers of the skin. In human bile, about 45% is chenodeoxycholic acid, 31% cholic acid, and 24% deoxycholic acid (a secondary bile acid formed in the intestine). Early studies in rodents showed the preferred substrate to be newly synthesized cholesterol. Formation is initiated by 7-hydroxylation, the committed and rate-limiting step catalyzed by microsomal 7-hydroxylase. Reactions that follow are oxidation of the 3-hydroxyl group to a 3-keto group, isomerization of the 5 double bond to the 4-position, conversion of the 3-keto group to a 3-hydroxyl group, reduction of the 4 double bond, 12-hydroxylation in the case of cholic acid synthesis, and oxidation of the side chain. Since the substrates for bile acid formation are water insoluble, they require sterol carrier proteins for synthesis and metabolism. At the alkaline pH of bile and in the presence of alkaline cations (Na1, K1), the acids and their conjugates are present as salts (ionized forms), although the terms bile acids and bile salts are used interchangeably. The formation and excretion of bile is an exocrine function of hepatocytes, which is unique to the liver. In the rat, they show similar patterns of diurnal variation, with highest activities during the dark period. In the intestines, bile acids may regulate cholesterol biosynthesis, in addition to their role in cholesterol absorption. In humans, the presence of excess cholesterol does not increase bile acid production proportionally, although it suppresses endogenous cholesterol synthesis and increases excretion of fecal neutral steroids. When loss of bile occurs owing to drainage through a biliary fistula, administration of bile acid-complexing resins. The latter two methods are used to reduce cholesterol levels in hyper-cholesterolemic patients (Chapter 18). Cholesterol is solubilized in bile by the formation of micelles with bile acids and lecithin. Cholesterol gallstones can form as a result of excessive secretion of cholesterol or of insufficient amounts of bile acids and lecithin relative to cholesterol in bile. Inadequate amounts of bile acids result from decreased hepatic synthesis, decreased uptake from the portal blood by hepatocytes, or increased loss from the gastrointestinal tract. With ingestion of food, cholecystokinin (Chapter 11) is released into the blood and causes contraction of the gallbladder, whose contents are then rapidly emptied into the duodenum by way of the common bile duct. In the duodenal wall, the bile duct fuses with the pancreatic duct at the ampulla of Vater. Bile functions include absorption of lipids and the lipid-soluble vitamins A, D, E, and K by the emulsifying action of bile salts (Chapter 11), neutralization of acid chyme, and excretion of toxic metabolites. Minor quantities of the secondary bile acid, ursodeoxycholic (ursodiol) acid, are also produced in the intestine. It is structurally identical to chenodeoxycholic acid (chenodiol) except for orientation of the 7-hydroxyl group. Synthetic ursodiol is used in the therapy of cholelithiasis (discussed later) and primary biliary cirrhosis. They are taken up by the liver, promptly reconjugated with taurine and glycine, and resecreted into bile. Both ileal absorption and hepatic uptake of bile acids may be mediated by Na1-dependent (carrier) transport mechanisms. About 90% of the bile acids are extracted during a single passage of portal blood through the liver. The bile acid pool in the enterohepatic circulation is 2 g and circulates about twice during the digestion of each meal. Bile Acid Metabolism and Clinical Medicine In liver disorders, serum levels of bile acids are elevated, and their measurement is a sensitive indicator of liver disease. Bile acids are not normally found in urine owing to efficient uptake by the liver and excretion into the intestines. In hepatocellular disease and obstructive jaundice, however, their urinary excretion increases. Effects associated with hyperbile acidemia include pruritus, steatorrhea, hemolytic anemia, and further liver injury. The main cause of cholelithiasis (presence or formation of gallstones) is precipitation of cholesterol in bile. Elevated biliary concentrations of bile pigments (bilirubin glucunorides) can also lead to formation of concretions known as pigment stones (Chapter 27). Since biliary cholesterol is solubilized by bile acids and lecithin, an excess of cholesterol along with decreased amounts of bile acids and lecithin causes bile to become supersaturated with cholesterol with the risk of forming cholesterol stones. The limits of solubility of cholesterol in the presence of bile salts and lecithin have been established by using a ternary phase diagram. If the mole ratio of bile salts and phospholipids to cholesterol is less than 10:1, the bile is considered to be lithogenic (stone forming), but this ratio is not absolute. The pattern of food intake in Western nations consists of excess fat, cholesterol, and an interval of 124 hours between the evening meal and breakfast. This leads to a fasting gallbladder bile that is saturated or supersaturated with cholesterol. In individuals who have gallstones, the problems associated with production of lithogenic bile appear to reside in the liver and not in the gallbladder. Under these conditions, the ratio of cholesterol to bile acids secreted by the liver is increased. The gallbladder provides an environment where concentration of the lithogenic bile triggers formation of gallstones. A genetic predisposition to formation of cholesterol gallstones is common in certain groups. In general, the incidence of gallstones in women is three times higher than in men, and this proportion increases with age. Obesity and possibly multiparity are also associated with formation of gallstones. Cholelithiasis is frequently treated by surgical removal of the gallbladder (cholecystectomy). Oral treatment with ursodeoxycholic (ursodiol) and chenodeoxycholic (chenodiol) acids has effectively solubilized gallstones in a number of patients. The increased bile acid to cholesterol ratio in the bile apparently aids in solubilizing the stones already present. However, the effect of chenodiol is transient, and therapy may have to be long term. In addition, the treatment appears to be promising only in patients who have radiolucent gallstones and functioning gallbladders. Since chenodiol raises serum transaminase levels, the significance of which is not clear, the measurement of other liver function tests may be necessary. Two other nonsurgical treatments undergoing clinical evaluation are extracorporeal shock-wave lithotripsy to fragment gallstones and direct infusion into the gallbladder with the solvent methyl tert-butyl ether to dissolve cholesterol stones. Oral treatment with ursodiol in conjunction with extracorporeal shock-wave lithotripsy is more effective than lithotripsy alone. Rosenberg, Case 20-2003: A nine-year-old girl with hepatosplenomegaly and pain in the thigh, N. Synopsis A nine-year-old girl was admitted to the hospital with an enlarged liver and spleen (hepatosplenomegaly), skeletal pain, and a history of epistaxis. Imaging and histologic bonemarrow biopsy, aspirate specimen analysis, and bone scan studies revealed a pathologic infiltrative process of histiocytes (tissue macrophages) into the organs. She was treated with recombinant -glucocerebrosidase, which was specifically targeted to macrophages. It is an autosomal recessive disease, and its most common form is non-neuropathic type 1 disease. The therapy consists of administering macrophagetargeted missing enzyme -glucocerebrosidase. The recombinant glucocerebrosidase is targeted to macrophages by its mannose-terminated oligosaccharide side chain. The recognition sites on the carbohydrate receptor sites of the macrophage internalize the mannoseterminated enzyme. Synopsis An 11-month-old daughter of a nonconsanguineous couple was referred to an outpatient neurology clinic for developmental delay. At 8 months old, the patient could no longer sit herself up, reach for objects, or feed herself, and she appeared less alert. On examination at 11 months old, she was found to have multiple abnormalities, most notably an exaggerated startle response, increased muscle tone due to spasticity and rigidity, and the developmental skills of a 6-month-old infant. Metabolic screening tests revealed very low activity of leukocyte hexosaminidase A, consistent with the diagnosis of Tayachs disease. As the disease progressed, she developed muscle spasms, seizures, and sleep and respiratory difficulties. An autopsy revealed gross, microscopic, and ultrastructural findings consistent with a storage disease limited to the neurons. The approach to evaluating developmental delay and spasticity in a child begins with consideration of nonprogressive causes and metabolic or degenerative causes.

Morphology of Vascular Changes in Hypertension Large and Medium Vessel Disease: AtheroscleosisHypertension is one of the major modifiable risk factor for atherogenesis antibiotic with metallic taste generic omnicef 300 mg amex. Hyaline arteriolosclerosis: It is seen in the arterioles in patients with benign hypertension antibiotic resistance crisis cheap 300 mg omnicef otc. It may be also show fibrinoid deposits and necrosis of vessel wall (necrotizing arteriolitis) antibiotic resistance rise buy cheapest omnicef and omnicef, particularly in the kidney antibiotics z pack dosage buy omnicef 300 mg line. Blood vessels in malignant hypertension:Hyperplastic arterioscleosis (onionskin appaerance)Fibrinoid necrosisnecrotizing arteriolitis virus-20 300 mg omnicef mastercard. Hyaline arteriolosclerosis in benign hypertension: the arteriolar wall is thickened antibiotics for uti levaquin buy generic omnicef 300 mg on line, hyalinized, and the lumen is narrowed; B. Hyperplastic arteriolosclerosis in malignant hypertension: Shows onion-skinning with obliteration of arteriolar lumen Vasculitis: Inflammation and damage of the blood vessel. The lumen of the involved vessel is usually narrowed may lead to ischemia of the tissues supplied. General CharacteristicsPrimary or secondary: Vasculitis may be primary or secondary component of another primary disease. Classification May be classified in many ways such as: 1) According to size of the vessel involved Table 9. Direct invasion of vascular walls by infectious pathogens (infectious vasculitis). Infections can also indirectly induce noninfectious vasculitis by generating immune complexes or triggering cross-reactivity. Noninfectious Vasculitis Mechanism: Main immunological mechanisms of noninfectious vasculitis are: (1) Immune complex mediated, (2) antineutrophil cytoplasmic antibody-mediated, and (3) antindothelial cell antibody-mediated. Immune Complex-mediated Vascular Injury Immune complex-mediated tissue vasculitis is characterized by deposition immune complexes in the vessel walls. C5a) chemotactic for neutrophils phagocytose the immune complexes release their contents damage the vessel wall. Antiendothelial Cell Antibodies They can produce endothelial cell injury and lysis through either complement-mediated cytotoxicity or antibody-dependent cellular cytotoxicity. Giant cell arteritis:Medium and large-sized arteriesGranulomatous inflammationFragmentation of internal elastic laminaImmunologicallymediated chronic inflammation. Giant-Cell (Temporal) Arteritis Definition: Giant-cell (temporal/cranial) arteritis is a chronic, typically granulomatous inflammation of medium- and large-sized arteries. MorphologyGross: Involved segment of the artery show nodular thickening of the intima reduces the size of lumen ischemia. Giant cell arteritis: Biopsy of the involved artery is theManifest after the age of 50. MorphologyVessels involved: Vessels of the skin, kidneys, heart, liver, peripheral nerves, and gastrointestinal tract. Fibrinoid necrosis Thrombosis infarction of the tissues supplied by the involved vessel. Polyarteritis nodosa does not involve: Pulmonary artery and spares small blood vessels. Consequences of vasculitis: Thrombosis impaired perfusion lead to ulcerations, infarcts, ischemic atrophy, or hemorrhages in the distribution of affected vessels. Acute necrotizing granulomatous inflammation in the upper respiratory tract (ear, nose, sinuses, throat) or the lower respiratory tract (lung) or both. It may present with persistent pneumonitis and bilateral nodular and cavitary infiltrates. Renal lesion in the form of focal and segmental necrotizing, often crescentic, glomerulonephritis. Probably represents a form of T cellediated hypersensitivity reaction to an exogenous (inhaled infectious or other environmental agent) or endogenous antigen. Morphology Mainly involves three organs but may be widespread involving any organ such as eyes, skin, kidney, and other organs. Upper respiratory tract lesions: They range from inflammatory sinusitis to ulcerative lesions in the nose, palate, or pharynx. Lower respiratory tract: Lung shows multiple, bilateral, nodular cavitary infiltrates. Necrotizing granulomas: It consists of geographic patterns of central necrosis surrounded by a zone of fibroblastic proliferation with giant cells, reminiscent of mycobacterial or fungal infections. Course: If not treated, it is usually rapidly fatal and majority die within 1 year. Most of these lesions are present from birth and Willebrand factor increase in size as the child grows. Hemangioma:Consists of large, dilated vascular channels; compared with small vascular spaces in Unencapsulated benign tumor. Morphology: Gross:Red-blue, soft, spongy masses and measure 1 to 2 cm in diameter. They are found in the skin, on the mucosal surfaces and visceral organs such as the spleen, liver, and pancreas. Typically it occurs when there is an imbalance between the demand and supply (perfusion) of oxygenated blood. Decreased/Impaired Coronary Blood Flow Coronary arterial occlusion is the main cause of myocardial ischemia. Coronary Atherosclerosis It narrows one or more of the epicardial coronary arteries decreases the coronary blood flow in about 90% of cases. Extent and severity of pre-existing (fixed) atherosclerotic occlusionNumber of coronaries affected/involved: Atherosclerosis may affect one, two or all three coronaries. Sudden cardiac death due to fatal ventricular arrhythmia Effects of myocardial ischemia: 1. Vulnerable plaque Vulnerable plaque:Central necrotic core with many foam cells and abundant extracellular lipidFibrous cap is thin with few smooth muscle cells or groups of inflammatory cellsLess likely to undergo rupture. Vulnerable plaque: They have core with many foam cells and abundant extracellular lipid. The fibrous cap is thin with few smooth muscle cells or groups of inflammatory cells and increased inflammation. Fixed obstruction of 75% or more: It results in critical stenosis precipitates ischemia by exerciseproduces symptom as chest pain-stable angina. Fixed obstruction of 90% and above: It leads to inadequate coronary blood flow even at rest-unstable angina. Sudden morphological changes in atheromatous plaque: It is known as acute plaque change (refer page 280-281) and is followed by thrombosis, produces unstable angina, myocardial infarction and sudden cardiac death in most of the patients. Other Causes of Coronary Artery Occlusion (Other Nonatheromatous Causes-refer page 280) Coronary emboli from thrombi in left side of the heart Coronary vasospasm Diminished availability of blood or oxygen:Lowered systemic blood pressure. Variants of Angina Pectoris Stable Angina It is the most common and is also known as typical angina pectoris. Cause: Coronary atherosclerosis and it develops when myocardial oxygen demand increases with increased physical activity or emotional excitement. Pain:Site: Chest pain in the substernal region, which may radiate to the left arm, jaw, and epigastrium. Stable angina: Most common type of angina pectoris, substernal chest pain induced by exercise. Unstable or Crescendo Angina Unstable angina: Cause: It is caused by the disruption/rupture of an atherosclerotic plaque complicated by 1. Multivessel disease Characteristics: It is of prolonged duration and occurs with minimal physical activity or 3. Consequence: May progress to myocardial infarction and is also referred to as preinfarction angina. Myocardial infarction: Commonly known as Definition: Myocardial infarction is a coagulative type of necrosis of cardiac muscle and is "heart attack" and is the most important form of due to prolonged severe ischemia. It can develop at younger age in patients with major risk factors of atherosclerosis (hyperlipidemia, hypertension, diabetes and cigarette smoking). Sex: Males have significantly higher risk than females mainly during the reproductive period. Other risk factors: Refer under risk factors for atherosclerosis (refer pages 255-257). Coronary Atherosclerosis Coronary artery occlusion in 90% of cases, myocardial infarction is due to atherosclerotic narrowing of one or more coronary arteries. It may be due to: Vasospasm without coronary atherosclerosis Emboli: the source of which may be:Left atrium in association with atrial fibrillationLeft-sided mural thrombusVegetations of infective endocarditisIntracardiac prosthetic materialParadoxical emboli: the emboli from the right side of the heart or the peripheral veins, which travel through a patent foramen ovale to the coronary arteries. Ischemia due to other causes:VasculitisHematologic disorders like sickle cell diseaseAmyloid deposition in vascular wallsVascular dissectionLowered systemic blood pressure. Acute plaque change: It is the sudden change/event occurring in an atheromatous plaque. The initial event in pathogenesis of myocardial infarction is sudden change in the atheromatous plaques. These as acute plaque changes convert partially occlusive atherosclerotic plaque to produce sudden ischemia. Rupture, fissuring of plaqueexposes highly thrombogenic plaque constituents sudden thrombus formationsudden occlusion of lumen. Erosion/ulceration of plaqueExposes highly thrombogenic subendothelial basement membraneSudden thrombus formationSudden occlusion of lumen. Acute plaque change: Sudden morphological changes occurring in an atheromatous plaque. Hemorrhage into the central core of plaqueincreases the plaque sizesudden occlusion of lumen. Factors that trigger acute plaque change:Intrinsic: Plaque composition and structure (namely vulnerable plaque). Formation of microthrombi: Acute plaque changes exposes thrombogenic subendothelial collagenplatelets adhere to the siteplatelet activation and aggregationformation of microthrombi on the atheromatous plaque partial or complete occlusion of the affected coronary artery. Vasospasm: Activated platelets, endothelial cell and inflammatory cells release mediatorscause vasospasm at the sites of atheromafurther narrowing of the lumen. Activation of the coagulation pathway: Tissue factor released at the site of acute plaque changeactivates coagulation systemincrease the size of the thrombus. Complete occlusion of vessel: Within minutes, the thrombus may completely occlude the lumen of the vessel. Myocardial necrosis: Complete occlusionresults in ischemic coagulative necrosis of the area supplied by the particular coronary artery. Consequence of Myocardial Ischemia these include functional, biochemical and morphological changes. Morphological changes can be divided into reversible and irreversible damage/injury. Functional disturbances: Loss of contractility within 60 secondscan precipitate acute heart failure. Morphological changes: They are seen at ultrastructural level such as mitochondrial swelling, glycogen depletion and myofibrillar relaxation. Irreversible injury: A develops only after prolonged, severe myocardial ischemia of more than 20 to 40 minutes Biochemical changes: They cause leakage of cytoplasmic proteins into the blood. Morphological changes: Coagulative necrosis of cardiac muscle fibers usually complete within 6 hours of the onset of myocardial ischemia. Zones damaged: First necrosis in the subendocardial zonelater transmural infarct Q. Usually associated with chronic coronary atherosclerosis, acute plaque change, and superimposed thrombosis. Occurs due to plaque disruption followed by a coronary thrombus, which undergoes lysis or prolonged, severe reduction in systemic blood pressure. Depending on the anatomic region involved: Anterior, posterior, lateral, septal and their combination like posterolateral. Left circumflex coronary artery occlusion (150%): Infarcts involve the lateral wall of left ventricle except at the apex. Triphenyl tetrazolium chloride (a histochemical stain) can grossly identify infarct within 2 to 3 hours after onset. Appears pale reddish-blue area (due to stagnated, trapped blood)progressively becomes sharply defined, yellow-tan, and soft. After 3 to 5 days: Mottled with a central pale, yellowish, necrotic region with well-demarcated border of hyperemic zone (due to granulation tissue). By 10 days to 2 weeks: Appears soft and rimmed by a hyperemic zone of highly vascularized granulation tissue. Posterolateral infarct develops following occlusion of the left circumflex artery; B. Anterior infarct develops following occlusion of the anterior descending branch of left coronary. Coronal section of left ventricle with acute myocardial infarct (124 hr old) involving anterior wall of left ventricle and anterior portion of interventricular septum; B. The changes include mitochondrial amorphous matrix densities, focal disruption of sarcolemma and clumping and margination of nuclear chromatin. Other changes include:Wavy fibers: They represents noncontractile, stretched, buckled dead myofibrils at the periphery of the infarct. These include: (1) preserved cell outlines of myocardial cell, (2) deeply eosinophilic cytoplasm and (3) pyknotic nuclei. Macrophages phagocytose and remove the necrotic myocardial cells and neutrophil fragments at the border of infarct. After about 12 to 18 hours, the infarcted myocardium shows myocardial fibers with eosinophilia; C.

Squamous cell carcinoma of lung:Most common lung cancer in smokersMost common lung cancer in males infection tooth cheap 300mg omnicef otc. Well differentiated: these tumors show keratinization in the form of keratin/squamous pearls ntl discount 300mg omnicef amex. They appear as small round nests of brightly eosinophilic aggregates of keratin surrounded by concentric (onion skin) layers of squamous cells virus 72 hour order online omnicef. Poorly differentiated: these tumors may show only intercellular bridges without any foci of keratinization antibiotics zone of inhibition order discount omnicef line. Grades of squamous cell carcinoma: Well differentiated Moderately differentiated Poorly differentiated antibiotic jobs purchase generic omnicef from india. It can also be diagnosed by cytological examination of bronchoalveolar lavage fluid antimicrobial keratolytic purchase omnicef online from canada, or fine-needle aspiration. Morphology Adenocarcinoma of lung:Overall most common type of cancerMost common lung cancer in non-smokers and females. Gross Site: Usually more peripherally located (in contrast to squamous cell carcinoma), and tend to be smaller. Cut section: They appear grayish white and glistening (depending on the amount of mucus). Microscopy Patterns: Two morphologic signs of glandular differentiation are: 1) formation of tubules or papillae and 2) secretion of mucin. Depending on the relative prominence of these features, adenocarcinomas can be subdivided into acinar, papillary, and solid (adeno) carcinomas with mucin production. Differentiation: Well-differentiated adenocarcinoma form glandular pattern or with papillary structures. Poorly differentiated adenocarcinomas to solid masses with only occasional mucin-producing glands and cells. Spread: They grow more slowly than squamous cell carcinomas but metastasize widely and earlier. Adenocarcinoma is situ:Tumor 3 cm or less in diameterLepidic growth patternNo stromal invasion. Characteristically, they grow along pre-existing alveolar walls without destruction of alveolar architecture. This growth pattern is known as lepidic, where the neoplastic cells resemble butterflies sitting on a fence. Small cell carcinoma of lung: There is no known preinvasive phase or carcinoma in situ. Highly malignant epithelial tumor and is strongly associated with cigarette smoking. Adenocarcinoma in situ (Bronchioloalveolar carcinoma) of lung Morphology Gross Site: It may arise not only in major bronchi (central) but also in the peripheral portion of the lung. Cut section: It is soft, friable, and white and shows extensive hemorrhage and necrosis. Small cell carcinoma:Small cellsSalt and pepper chromatinNuclear moldingHigh mitotic countExtensive necrosisNeurosecretory granules. Electron Microscopy the tumor cell shows membrane-bound neurosecretory granules similar to the neuroendocrine cells. These tumors are most commonly associated with ectopic hormone production and paraneoplastic syndromes. Behavior: All small cell carcinomas are high grade and are most aggressive lung tumors. They widely metastasize and are incurable by surgery but are markedly sensitive to chemotherapy. Large Cell Carcinoma Large cell carcinoma is an undifferentiated malignant epithelial tumor of lung. The tumor cells do not have the characteristic of small-cell, glandular or squamous cell carcinoma. Inset shows nuclear moulding Small cell carcinoma of lung:May be central or peripheralMost commonly associated with paraneoplastic syndromes. Microscopically they have combined histology of two or more of the above histological types. Example: squamous cell carcinoma and adenocarcinoma or of small-cell and squamous cell carcinoma. Total obstruction may lead to atelectasis (collapse of the lung) distal to obstruction. Compression or invasion of the superior vena cava: It produces marked dilation of the veins of the head, neck, and arms and cyanosis results in a characteristic clinical complex is known as superior vena cava syndrome. Tumor at the apex of lung may invade the neural structures around the trachea and the cervical sympathetic plexus. They may produce severe pain in the distribution of the ulnar nerve and Horner syndrome (enophthalmos, ptosis, miosis, and anhidrosis) on the same side as the tumor. Horner syndrome: Enophthalmos, lid lag (ptosis), miosis and anhydrosis on the same side of lung cancer. Horner syndrome: Caused Tumor may spread into the tracheal, bronchial, hilar and mediastinal nodes. It may also due to compression of sympathetic nerve plexus spread to lymph nodes in the neck (scalene node) and clavicular region. Involvement of by apical tumor of the lung supraclavicular node (Virchow node) may call attention to primary. Lymphatic Spread Hematogenous Spread Common sites of metastases are to adrenals (in more than 50%), liver, brain and bone. Investigations Radiologic examination of the chest Cytologic examination of sputum, bronchial washings or brushings or fine needle aspiration. In general, the adenocarcinoma and squamous cell carcinomas remain localized and have slightly better prognosis than undifferentiated carcinomas. Squamous cell carcinoma of lung: Hypercalcemia due to parathormone or parathyroid related peptide. Paraneoplastic Syndromes Lung cancer may occasionally be associated with paraneoplastic syndromes. Hypertrophic pulmonary osteoarthropathy: It is associated with clubbing of the fingers. Lambert-Eaton myasthenic syndrome: Muscle weakness due to autoantibodies directed against the neuronal calcium channel. Both carcinomas and sarcomas from any site may spread to the lungs via the blood or lymphatics or by direct invasion. Local spread into the lungs occurs in carcinoma of esophagus, carcinomas and mediastinal lymphomas. Radiologically, when large nodules are seen in the lungs, they are known as cannon ball metastases. Other patterns: They may also present as solitary nodule, endobronchial, pleural, pneumonic consolidation, or mixtures of any of these patterns. Sources of Metastases to Lung Common: Carcinoma of gastrointestinal tract, breast, thyroid, kidney, pancreas and liver Other tumors: Osteogenic sarcoma, neuroblastoma, Wilms tumor, melanoma, lymphomas and leukemias. The microscopic appearance of metastases usually resembles that of the primary tumor. Definition: It is defined as a white patch or plaque, not less than 5 mm in diameter, that Leukoplakia: White mucosal patch or plaque that can undergo malignant transformation. Leukoplakia: Until otherwise proved by microscopic examination, all leukoplakias must be considered precancerous. If any white patches in the oral cavity can be given a specific diagnosis, it is not a leukoplakia. Most common sites are buccal mucosa, floor of the mouth, ventral surface of the tongue, palate, and gingiva. ErythroplakiaLess common and appears as a red, velvety area within the oral cavity. Intermediate forms, which have the characteristics of both leukoplakia and erythroplakia, are termed speckled leukoerythroplakia. List the differences between Features of Leukoplakia and Erythroplakia erythroplakia and leukoplakia. Age and Gender Both leukoplakia and erythroplakia may be found in adults of any age, but they are usually seen between 40 to 70 years. Etiology Both have multifactorial origin and are associated with use of tobacco (cigarettes, pipes, cigars, and chewing tobacco). Erythroplakia:Epithelium shows erosions with dysplasia, carcinoma in situ, or frank carcinoma. Toluidine blue:Basic metachromatic dye with high affinity forHairy leukoplakia is a distinctive oral lesion and is seen in immunocompromised patients. Hairy LeukoplakiaMicroscopy: It shows hyperparakeratosis and acanthosis with "balloon cells" in the upper spinous layer of the epithelium. Tobacco products and smoking: Any irritating smoked product increases the risk for tumors of the oral cavity. Smoking: It may be in the form of cigarette, beedi, cigar, or pipe smoking, or reverse smoking (smoking a cheroot with the burning end inside the mouth is practiced in certain regions of India). Smokeless tobacco: It is in the form of betel quid/pan that contains several ingredients such as areca nut, slaked lime, and tobacco, which are wrapped in a betel leaf. It is commonly used in India and Southeast Asia, and is associated with marked increaseTongue>lipIn India: Buccal mucosa > anterior tongue > lower alveolus. Patients with head and neck squamous cell carcinoma are at increased risk for second primary malignancy. Risk factors associated with Oral cancers are found on the buccal and gingival surfaces in the sites where tobacco cancer of the head and neck. Alcohol consumption: It is another important etiologic factor and act synergistically with smoking and areca nut/ tobacco as either a cocarcinogen (increasing the risk) or a promoter (decreasing the lag time). Other risk factors:PlummerinsonRadiation exposure and solar actinic radiation (sunlight). Squamous cell carcinoma of oral cavity: Risk factors include tobacco and alcohol use. Inherited Genomic Instability Family history of head and neck cancer is a risk factor, and is thought to be due to inherited genomic instability. Field cancerization: Phenomenon of susceptibility of the oral mucosa for multiple primary cancer. It involves sequential activation of oncogenes and inactivation of tumor suppressor genes in a clonal population of cells. Common sites are lower lip, the ventral surface of the tongue, floor of the mouth, buccal mucosa, soft palate, and gingiva. GrossEarly stages: It appears either as raised, firm, pearly plaques or as irregular, roughened, or verrucous areas of mucosal thickening. Verrucous carcinoma showing exophytic growth, swollen and voluminous rete pegs extending into the deeper tissues Spread 1. Lymph node: the involved site of lymphnode depends on the location of the primary tumor. Carcinomas of the base of the tongue and oropharynx metastasize to the deep retropharyngeal lymph nodes. Verrucous carcinoma (Ackerman tumor):Distinct variant of wellVerrucous carcinoma (Ackerman tumor) is a variant of well-differentiated squamous cell differentiated squamous carcinoma. Spread: May infiltrate the soft tissues of the cheek, mandible or maxilla, and invade perineurial spaces. Regional lymph node metastases are exceedingly rare, and distant metastases have not been reported. IncidenceParotid gland-65% to 80% and ~ 15% to 30% parotid tumors are malignantSubmandibular gland-10% and ~ 40% are malignant. About 50% of minor salivary gland and 70% to 90% of sublingual tumors are malignant. Clinical PresentationParotid gland neoplasms produce swellings in front of and below the ear. Pleomorphic adenoma:Most common tumor of major salivary gland mainly parotidLess common in submandibular and sublingual glandRare in minor glands. SiteMajor salivary gland: Common site and constitute about 60% of tumors in the parotid. It was called as mixed tumor, because of the mixture of epithelial and mesenchymal components. However, it is now considered that the tumor neoplastic cells (epithelial and those which appear mesenchymal), are of either myoepithelial or ductal reserve cell origin. Neoplastic cells show varying mixture of epithelial tissue component intermingled with cells showing mesenchymal differentiation. The ducts are lined by both epithelial (cuboidal to columnar) cells and surrounded by myoepithelial components (a layer of deeply chromatic, small myoepithelial cells). Pleomorphic adenoma: Encapsulated but pseudopodia (finger-like projections) into the surrounding gland. Clinical FeaturesPleomorphic adenomas present as painless, slow-growing, mobile, discrete tumors in the parotid or submandibular areas or in the buccal cavity. Pleomorphic adenoma:The tumors tend to protrude focally from the main tumor into adjacent tissues. Carcinoma Ex Pleomorphic AdenomaRarely, a carcinoma may arise in pleomorphic adenomas-referred to as a carcinoma ex pleomorphic adenoma or a malignant mixed tumor. Sex: It is the only salivary glands tumor that is more common in males than in females.

Inactivation of the same X chromosome persists in all the cells derived from each precursor cell antibiotic half life purchase omnicef 300mg with visa. Genetic sex is determined by: Y chromosome Barr body: Attached to inner aspect of nuclear membrane and represents inactivated X-chromosome nbme 7 antimicrobial resistance discount omnicef 300mg without a prescription. The inactive X can be seen in the interphase nucleus as a darkly staining small mass in contact with the nuclear membrane antibiotic eye ointment for dogs 300 mg omnicef visa. Y chromosome: Irrespective of the number of X chromosomes antibiotics for uti gonorrhea purchase omnicef uk, the presence of a single Y determines the male sex antibiotic alternatives order genuine omnicef line. KaryotypingThe chromosomal constitution of a cell or individual is known as the karyotype antibiotic 300mg order omnicef in india. The normal human karyotypes contain 22 pairs of autosomal chromosomes and one pair of sex chromosomes. This includes both the number and appearance (photomicrograph) of complete set of chromosomes. Karyotyping requires cells to be in a state of division and arresting this cell division at the metaphase of cell cycle. Source of chromosome: To produce karyotype, it is necessary to obtain cells capable of growth and division. The more commonly used cell for chromosomal study is circulating lymphocyte obtained from the blood sample cultured in a media. Staining: There are many staining methods using specific dyes to identify individual chromosomes. Classification of Chromosomes in Karyotyping There are various systems used for study the morphology of the chromosomes. Denver system of classification: In this system, the chromosomes are grouped from A to G according to the length and position of the centromere of the chromosomes. According to this, the chromosomes are identified based on the various banding patterns. Each chromosome shows a characteristic banding pattern (light and dark bands) which will help to identify them. Long and short arm of chromosome are calledSex chromosome constitution respectively: q and p. Bands and sub-bands: Each region is further subdivided into bands and sub-bands, and these are ordered numerically as well. Uses of KaryotypingFor diagnosis: Diagnosis of genetic disorders including prenatal diagnosis. Structural chromosomal aberrations Both may involve either the autosomes or the sex chromosomes. Numerical Chromosomal Aberrations Total number of chromosomes may be either increased or decreased. The deviation from the normal number of chromosomes is called as numerical chromosomal aberrations. Aneuploidy: It is defined as a chromosome number that is not a multiple of 23 (the normal haploid number-n). Polyploidy: this term used when the chromosome number is a multiple greater than two of the haploid number (multiples of haploid number 23). Mosaicism: It is the presence of two or more populations of cells with different chromosomal complement in an individual. Structural Chromosomal Aberration Aberration of structure of one or more chromosomes may occur during either mitosis or meiosis. Transfer of the segments leads to one very large chromosome and one extremely small one. The small one is because of fusion of short arms of both chromosomes which lack a centromere and is lost in subsequent divisions. Inversion: It involves two breaks within a single chromosome, the affected segment inverts with reattachment of the inverted segment. Two types of inversions are: Structural chromosomal aberrations:TranslocationInversionIsochromosomeRing chromosomeDeletionInsertion. If a centromere divides in a plane transverse to the long axis, it results in pair of isochromosomes. Ring chromosomes are formed by a break at both the ends of a chromosome with fusion of the damaged ends. Loss of significant amount of genetic material will result in phenotypic abnormalities. Ring chromosomes do not behave normally in meiosis or mitosis and usually result in serious consequences. Insertion: It is a form of nonreciprocal translocation in which a fragment of chromosome is transferred and inserted into a nonhomologous chromosome. This fragment is inserted into another chromosome following one break in the receiving chromosome, to insert this fragment. Lysosomal storage disorders:Lysosomal enzymes are used for the intracellular digestion/degradation of many complexInheritedMutation in genes biological macromolecules. This can lead to the accumulation of the partially degraded insoluble substrate within the lysosomes. The inherited disorders results from mutations in genes that encode lysosomal hydrolases are known as lysosomal storage disorders. General FeaturesLysosomal disorders are transmitted as autosomal recessive disorder. Classification of lysosomal storage disorders: They are classified according to the biochemical nature of the metabolite accumulated within the lysosomes. Write short note on Niemannglycogenoses, sphingolipidoses (lipidoses), sulfatidoses, and mucopolysaccharidoses Pick disease. Niemann-Pick Disease 246 Exam Preparatory Manual for Undergraduates-General and Systemic Pathology Classification of Niemann-Pick DiseaseType A: It is a severe infantile form with almost complete deficiency of sphingomyelinase. It is characterized by extensive neurologic involvement, massive visceromegaly, marked accumulations of sphingomyelin in liver and spleen, and progressive wasting and death Neimann-Pick disease type occurring by 3 years of age. A and B:Diagnosis and detectionType B: It usually presents with hepatosplenomegaly and generally without involvement of carriers by estimation of central nervous system. Morphology Deficiency of sphingomyelinase enzyme blocks degradation of the lipid-sphingomyelin accumulates inside the lysosomes of cells of the mononuclear phagocyte system. Microscopically, the neurons show vacuolation and ballooning, which in time leads to cell death and loss of brain substance. Symptoms include progressive motor and mental deterioration, blindness, and increasing dementia. Write short note on GaucherMost common lysosomal storage disorder due to mutation in the gene that encodes disease. Gaucher disease:Autosomal recessiveDeficiency of enzyme glucocerebrosidaseAccumulation of glucocerebroside, mainly in lysosomes of macrophage. Write short note on enzymeType I or the chronic non-neuronopathic form: deficiency in Gaucher disease and Niemann-Pick disease. Morphology Light microscopy: Gaucher cells are hallmark of this disorder and its characteristics are:Enlarged, phagocytic cells (sometimes up to 100 m in diameter) distended with massive amount of glucocerebrosides. Electron microscopy: the fibrillary cytoplasm appears as elongated, distended lysosomes, containing the stored lipid arranged in parallel layers of tubular structures. Clinical Features Type IManifests in adult life and follows a progressive course. About 95% of these individuals have trisomy 21 (extra copy of chromosome 21), resulting in chromosome count of 47 instead of normal 46. Down syndrome: Caused by Robertsonian translocation and Mosaicism has no relation with maternal age. Etiology and PathogenesisMaternal age: Older mothers (above 45 years of age) have much greater risk. Mechanism of trisomy 21: the three copies of chromosome 21 in somatic cells cause Down syndrome. It may be due to:Nondisjunction in the first meiotic division of gametogenesis and is responsible for trisomy 21 in most (95%) of the patients. The hands are broad and short and show a Simian crease (a single transverse crease across the palm). Clinically, it may present with easy fatigability, difficulty in walking, abnormal gait, restricted neck mobility, torticollis, etc. Write short note on Klinefelter Definition: Klinefelter syndrome (testicular dysgenesis) is characterized by two or more syndrome. This complement of chromosomes results from nondisjunction during the meiotic divisions in one of the parents. Klinefelter syndrome: AnMost of the patients are tall and thin with relatively important genetic cause of long legs (eunuchoid body habitus). The testis may show atrophy of seminiferous tubules containing pink, hyaline, collagenous ghosts. It is characterized by hypogonadism and is the most common sex chromosome abnormality in females. Important diagnostic features are:Adult women with short stature (less than 5 ft tall), primary amenorrhea and sterility. Mckeberg medial sclerosis: It is characterized by deposition of calcium in muscular arteries seen in old age (above 50 years). Atherosclerosis: Primarily a disease of intima characterized by lesions Definition: Atherosclerosis is primarily a progressive disease of intima involving large and called atheroma. It is characterized by focal lipid-rich intimal lesions called atheromas (atheromatous or atherosclerotic plaques). Epidemiology: Atherosclerosis is a worldwide disease seen in both developed and developing the word atherosclerosis countries. Hyperlipidemia: Increase in the serum lipids mainly cholesterol (hypercholesterolemia) is a major modifiable risk factor. Atherosclerosis: Major modifiable risk factors include hyperlipidemia, hypertension, cigarette smoking and diabetes. Serum cholesterol is strongly related to the dietary intake of saturated fat (in the absence of genetic disorders of lipid metabolism). Risk of atherosclerosis increases with increasing serum cholesterol concentrations and lowering serum cholesterol concentrations reduces the risk. This can be achieved either by dietary modification or by treatment with cholesterol-lowering drugs. Transunsaturated fats produced by artificial hydrogenation of polyunsaturated oils (used in baked goods and margarine). Diet which lower blood cholesterol: Diets low in cholesterol and/or with higher ratios of polyunsaturated fats. This may be the reason for the increased incidence and severity of atherosclerosis in men compared to women. There is a strong dose-linked relationship between cigarette smoking and ischemic heart disease. The incidence of myocardial infarction and other atherosclerotic vascular diseases (strokes, gangrene of the lower extremities) is more in diabetics than in nondiabetics. Clinical manifestation of atherosclerosis is usually observed after middle age and the lesions progressively rise with each decade. Sex: Premenopausal women have lower incidence of atherosclerosis-related diseases compared to males of the same age group. However, hormone replacement therapy has no role in the prevention of coronary heart disease. Familial predisposition is usually multifactorial, due to genetic, environmental and lifestyle factors. Genetic abnormalities: Most common inherited modifiable risk factors (hypertension, Achilles tendon xanthoma: hyperlipidemia, and diabetes mellitus) are polygenic. Hyperhomocysteinemia: It is a rare autosomal recessive inborn error and results in elevated circulating homocysteine premature and severe atherosclerosis. Metabolic syndrome: It is associated with central obesity, insulin resistance and is known risk factors for atherosclerosis. It competes with plasminogen in clots and decreases the ability to form and clear clots. Raised procoagulant levels: these procoagulants include: thrombin (procoagulant and proinflammatory action), platelet activation and raised fibrinogen increased risk. Stressful lifestyle: Certain personality associated with competitive, stressful life ("type A" personality) is associated with an increased risk of coronary disease. Alcohol consumption: It is associated with reduced rates of coronary artery disease. Regular exercise (brisk walking, cycling or swimming for 20 minutes two or three times a week) has a protective effect. Excess alcohol consumption is associated with hypertension and cerebrovascular disease. Pathogenesis of Atherosclerosis There are several theories proposed for pathogenesis of atherosclerosis and few of them are: A. Insudation hypothesis: According to this, the focal accumulation of lipid in a vessel wall is due to insudation (transport) of plasma lipoproteins across an intact endothelium. Encrustation hypothesis: this hypothesis states that small mural thrombi are formed at the site of endothelial damage. Monoclonal hypothesis: the monoclonal concept postulates that single clone (monoclonal) of smooth muscle migrate from the underlying media into the intima and then proliferate. Pathogenesis of atherosclerosis: Presently favored theory is reaction to injury hypothesis. Write short note on reactionto-injury hypothesis of atheroscleAccording to this theory, atherosclerosis develops as a chronic (inflammatory and healing) rogenesis. Migration of monocytes into the arterial intima and are transformed into macrophages.

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