10 In '10 Unit 2

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1. Myotubular Myopathy

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1. defect in lipid phosphatase resulting in embryonic muscle tissue. Females are carriers, 80% of affected individuals have mutation in MTM1 gene that encodes myotubularin protein --> lipid phosphatase. Muscle biopsy shows a centrally located nucleus in skeletal muscle that resembles the fetal stage of muscle development. Floppy Male infant. Characterized by neonatal low muscle tone w/ delayed developmental milestones. Fatal in first 2 years of life due to respiratory failure. Currently no cure.

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2. Duchenne's muscular dystrophy

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2. mutation in gene for dystrophin. Dystrophin links laminin to actin filaments to reinforce and stabilize the sarcolemma during muscle contraction. It's an X-linked recessive disorder (Xp21) with a mutation in the gene that encodes dystrophin that results in progressive muscular weakness where actin is not longer anchored to the extracellular matrix. With the disruption of the sarcolemma, then Ca+2 can't enter the muscle cell, then necrosis happens in the muscle fiber. Primarily affects males, onset 3-5 years old, no cure, unable to walk by 12, require respirator to breathe by age 20. Laboratory findings: Increased serum creatin kinase levels.

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3. Botulism

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3. inhibits Ach release at NMJ. Food poisoning caused by Clostridium botulinum (BOTOX). Characterized by muscle paralysis, vomiting, nausea and visual disorders. If untreated, fatal. Treatment is hospitalization, antibiotics, antitoxin

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4. Myashenia gravis

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4. Autoimmune disease affecting ACh receptors. Alpha-ACh receptor antibodies are produced. These antibodies then bind and block access of ACh to its receptor thereby blocking the normal nerve-muscle interaction. Progression of this disease is associated with a decrease in the number of NMJs. Characterized by extreme muscle weakness, ptosis (droooping of the upper eye lid) & diplopia (single object seen as two). Treat with AChase inhibitors.

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5. Rhabdomyosarcoma

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5. cancer arising from striated muscle. Most common type of childhood sarcoma. There are 3 types: Embryonal (most common, occurse most often in the head, neck, genital or urinary reasons), Alveolar (common during teens; occurs in arms, legs, chest, abdomen, genital or anal regions), and Anaplastic - rare in children. Symptoms: lump or swelling that continually increases in size, eye bulging, headache, problems urinating or with BMs, blood in urine, bleeding in nose, throat, vagina, or rectum; histology is positive for IF desmin. Treatment is surgery, radiation therapy, chemotherapy, and new: high dose chemo with stem cell transplant.

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6. Central core disease (group of disorders)

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6. mutation in ryanodine receptor. Autosomal dominant/recessive. Onset is congenital, symptoms: poor muscle tone and weakness in infants; delay in attainment of motor milestones, skeletal deformities (joint dislocation & scoliosis). Pts are susceptible to malignant hyperthermia with some anesthetics. H&E appearance shows a faint central abnormality in myofibers; Myosin ATPase stain reveals central round areas devoid of staining.

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7. Nemaline myopathy

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7. Defect in nebulin; histology: nemaline rods. Congential, hereditary. Nebulin is an elongated, inelastic protein that is attached to the Z lines and runs parallel to the thin filaments. It helps a-actinin anchor thin filaments to the Z lines and is thought to regulate the length of the thin filaments during muscle development. Characterized by delayed motor development, muscle weakness in arms, legs, trunk, throat, and face muscles (usually non-progressive). Trunk muscle weakness leads to respiratory issues if therapy and/or intervention does not occur. Histology: thread-like rods, nemaline rods, that are positive for actin and a-actinin.

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8. Desmin-related myopathy

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8. Mutation in desmin results in loss of sarcomeric structure. Desmin is an Intermediate Filament that attaches the sarcomeres to each other at the level of the Z lines, and to the plasma membranes, signaling is done through the desmosomes. Autosomal recessive and dominant forms exist. Because of a mutation in desmin, the sarcomere doesn't get intermediate filament rods, but instead forms intracytoplasmic desmin aggregates in skeletal and cardiac muscle. Histology: sarcomeres are misaligned, a loss of Z-lines and loss of the normal striated appearance, muscle cells die by apoptosis and necrosis, desmin inclusion bodies are seen in skeletal and cardiac muscles. Characterized by weakness and atrophy of distal muscle of legs, arms, trunk and neck. Respiratory issues occur due to trunk muscle weakness and loss. 60% of pts also have cardiac involvement.

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9. Myocardial infarction

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9. necrotic death of myocytes. Irreversible necrosis of cardiac muscle cells due to prolonged ischemia (>20 min). Detect lactic dehydrogenase-1 and creatine kinase in serum. Fatal if extensive damage occurs to the cardiac muscle. Treatment: bypass surgery. MI is an example of a localized injury. The cells are replaced with a fibrous CT and leads to loss of cardiac function. MI is confirmed by the presence of marker proteins, TnI and TnT of the troponin complex in the bloodstream 3-12 hours following an MI. TnI levels remain elevated for 2 weeks.

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10. Pompe's Disease (Acid maltase deficiency)

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10. Hinders glycogen breakdown to glucose. Loss of acid maltase in the muscle leads to the inability to process carbs. Affects the storage and breakdown of glycogen in the lysosomes. If acid maltase is absent, glycogen accumulates and is not converted to glucose. Onset in infants and usually fatal by 2. (Child and adult onset is rare.) Characterized by slow progressive weakness in respiratory muscles, hips, upper leg and arms, shoulders; cardiac involvement in some childhood forms.

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1. Naegleria fowleri infection

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1. "brain-eating amoeba". Invades the CNS via the nose, olfactory mucosa and cribiform plate. Initially results in significant necrosis of and hemorrhaging in the olfactory bulbs. From there the amoebae climb along nerve fibers through the floor of the cranium via the cribiform plate and into the brain. The amoebae consume brain cells via a sucker apparatus. Causes primary amoebic menoingoencephalitis (PAM). PAM is a syndrom affecting the CNS, characterized by changes in olfactory perception (taste and smell) followed by vomitting, nausea, fever, headache, and the rapid onset of coma and death in two weeks.

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2. Sinusitis

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Maxillary sinus most often involved in adults, ethmoid sinus in children. Some causes: blockage of drainage via paralysis of cilicary elevator or viral/bacterial upper respiratory infection or deviated septum. Results in fever, nasal congestion, pain over sinus. Sinues become congested with mucous and bacterial growth.

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3. Cystic Fibrosis (CF)

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3. (See ppt and Box 19.2) It affects the viscosity of the secretion of the exocrine glands. Also, nasal polyps are associated with CF. Nasal polyps in a child warrant a sweat test to rule out CF. What is another name for CF? Mucoviscidosis. If involves production of a defective CF transmembrane conductance regulator CFTR for chloride ions. The CFTR CL- is degraded in the Golgi apparatus due to defective protein folding. Loss of CFTR Cl- causes decreased Na+ and Cl- reabsoption in sweat glands. In other epithelial cells (ie bronchus epithelium, pancreatic duct cells), Na+ reabsorption from the lumen is increased causing movement of water into the cell. This results in a thick mucouse secretion. Some ciliary dyskinesia present, expressed as infertility in males (95%).

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4. RDS - Respiratory Distress Syndrome

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4. in newborns/infants. Decreased synthesis of surfactant resulting in decreased surfactant in the fetal lungs. Causes: prematuringy, maternal diabetes, C-section - lack of stress-induced increase in cortisol from a vaginal delivery. Grossly: purple-red lungs, Microscopically: Collapsed alveoli lined by hyaline membranes. Formerly called hyaline membrane disease. Due to an inadequate supply of surfactant at birth which can be related to deficient surfactant production or failure of Type II pneumocytes to develop and mature. Signs include: cyanosis and labored breathing, caused by inability of pulmonary alveoli to expand or remain open after inspiration. The lungs require more pressure to inflate. Widespread atelectasis occurs initially and progresses, resulting in massive intrapulmonary shunting. The lack of O2 damages endothelial cells and pneumocytes and this results in exudation of a fibrinous matrix from the blood. This matrix accumulates and creates a thick 'hyaline membrane' lining the alveoli. These hyaline membrane are formed within half an hour after birth. Some healing or regeneration of Type II cells can occur within 36-72 hours. Type II cells then give rise to Type I alveolar cells. see ppt

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5. alpha1-Antitrypsin Deficiency leading to Emphysema

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5. Emphysema is a condition of the lung characterized by permanent enlargement of the air spaces distal to the terminal bronchioles. This enlargement is caused by chronic obstruction of airflow, most often because of the narrowing of the bronchioles and is accompanied by destruction of the alveolar wall. Thus a significant area for gas exchange is lost in this disease. Elastic fibers (elastin) are in the in the interalveolar septum. Elastin is degraded by elastase (a protease) that is secreted by neutrophils. a-1-Antitrypsin is produced in the liver and it inactivates neutrophil elastase. If a-1 antitrypsin is deficient, then elastase degrades the elastic fibers in the septum which are replaced with CT which leads to emphysema.

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6. ARDS - Adult Respiratory Distress Syndrome

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6. He said to see ppt, there is only a slide with no writing. Any ideas?

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7. Atelectasis

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7. "collapse" - loss of lung volume due to inadequate expansion of the air spaces

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8. Early Stages of Acute Pneumonia

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8. Alveoli fill with exudates containing wbcs and rbcs, referred to as hepatization,because the lung resembles the liver. The lung has enlarged capillaries giving it a red color. The lung lacks alveoli or alveoli that are functional because they are swollen or filled with neutrophils, rbcs, and fibrin. See Box 19.3b

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9. Mesothelioma

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9. A malignant tumor that originates in the mesothelial lining or the serous membranes (pleura, peritoneum, pericardium). 90% of malignant mesotheliomas are pleural mesotheliomas. Pleural mesothelioma is associated with long time exposure (25-40yrs) to asbestos. Pleural mesothelioma can spread to pericardium and diaphragm and can invade the subpleural lung tissue and metastasize to any organ. Imaging of the thorax detects thickening of the pleura and/or asbestos plaques. No etiologic relationship with smoking. Symptoms include pleural effusion (abnormal liquid in the pleural space), chest pain, dyspnea. (see ppt for gross image)

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10. Bronchiectasis

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10. Permanent or chronic dilation of the bronchi and bronchioles, due to destruction of cartilage and elastic tissue by an infection; Causes: CF, TB, obstruction by a carcinoma, primary ciliary dyskineasia; most common in the lower lobes (see ppt for gross image)

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1. Atherosclerosis

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1. A disease of large and muscular (medium-sized) arteries that results in the progressive accumulation within the intima of smooth muscle cells, lipids and CT. An initial structural abnormality of this is the FATTY STREAK: an elevated lesion in the INTIMA that contains accumulations of intracellular and extracellular lipid. Macrophages filled with lipid (Foam cells) accumulate. Smooth m. cells also contain lipid. Fibrous cap contains: foam cells, smooth muscle cells, and lymphocytes. The nectrotic core consists of lipid-laden macrophages. see ppt and Boxes, 13.2, 13.3, and fig 13.12(p.376)

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2. Marfan Syndrome

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2. Fibrillin disorder, faulty tunica media, mitral valve disorders (prolapse or redundant)note 3 CV structures affected in ppt. most common cause of death in Marfan syndrome is aortic dissection. Changes in chordae tendinae.

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3. Vessel Aneurysms

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3. A localized of diffuse dilation of an artery with a diameter at least 50% greather than the normal size of the artery; due to weakening of the vessel wall, followed by dilation and a tendency to rupture: 2 causes are atherosclerosis and bacterial/fungul infection; most common aneurysm in men > 55 is the abdominal aortic aneurysm

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4. Thrombosis

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4. a thrombus is an intravascular mass attached to the vessel wall and is composed of varying proportions of coagulation factors, rbcs and platelets. Can be caused by endothelial cell injury, esp arterial thrombi.

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5. Embolism

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5. a detached mass (ie. Clot, fat, gas) carried by the blood to a distant site. These lodge in various places: atrium, microbasculature, throughout the body, pulmonary system.

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6. Hypertension

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6. In most cases, the size of the lumen of the small muscular arteries and arterioles is reduced, which leads to increased vascular resistance. Restriction in the luminal size may also result from active contraction of the smooth muscle in the vessel wall, an increase in the amount of smooth muscle in the wall or both. Smooth muscles cells multiply. See Box 13.1 Multiplication of smooth m. occurs and tunica media increases in thickness, smooth m cells accumulate lipid; intimal thickness occurs in fat-free diet; cardiac m cells also increase in size and number . An interesting note in Box 13.1 "Prolonged reduction of blood pressure in pts with ventricular hypertrophy as a result of chronic hypertension can actually reduce the degree of hypertrophy."

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7. Aschoff Body

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7. the typical lesion of rheumatic myocarditis. The body has a central region of degenerated collagen surrounded by lymphocytes, plasma cells, neutrophils and histiocytes. Amongst these cells the ANITSCHKOW cell is found; this cell is a large, cardiac histiocyte and may be multinucleated (has a ribbon-like nucleus and eosinophilic cytoplasm). It has a ribbon-like or caterpillar-like nucleus and the nucleus is quite evident, like an owl's eye.

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8. Raynaud's phenomenon

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8. reversible ischmeia of peripheral arterioles usually involving fingers and toes; it is a vasospasm involving arterioles; it is associated with another illness or secondary to another disease and the most common is an autoimmune disease. (from ppt: a phenomenon seen as the result of skin arterioles contracting or going into vasospasm, usually involves fingers and towe, associated with another disease, usually an autoimmune disease.)

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9. Lymphedema

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9. a defect in the transport of lymph because of abnormal lymphatic vessel development or damaged lymphatic vessels; accumulation of fluid and proteins in the ECM or interstitial spaces leads to lymphedema; chylothorax (an accumulation of high fat containing lymph or chyle in the thorax) can be the result of abnormal development of lymphatic vessels or it can be the result of obstruction, trauma. How fast can chyle accumulate in the thorax or pleural cavity if the thoracic duct is lacerated by accident or lung surgery? 75-200 mL/hour

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10. Giant Cell arteriris (GCA)

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10. GCA is also called temporal arteritis, cranial arteritis, and granulomatous arteritis. GCA is a systemic inflammatory vasculitis of unknown etiology that affects medium- and large sized arteries. It is a disease of the over 50 age group and can result in a wide variety of systemic, neurologic, and ophthalmolocic complications. Visual loss is one of the most significant causes of morbidity in GCA. Permanent visual impairment may occur in as many as 60% of patients. GCA typically involves inflammation of the aortic arch and its branches, but almost any artery of the body as well as some veins may be affected occasionally. The inflammation tends to involve the arteris in a segmental or patchy manner, although long portions of arteris may be involved. The likely determinant of arterial susceptibility to GCA is the presence and/or quantity of internal elastic lamina within the vessel wall. For example, intracranial cerebral vasculature is not affected in GCA because these vessels lack an interanl elastic lamina. The extracranial vertebral arteries, superficial temporal arteries, posterior ciliary arteries, and ophthalmic arteries are the most commonly involved arteries. Internal Elastic Lamina fragments as neutrophils accumulate. Mononuclear giant cells are part of the infiltrate.

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1. Peptic ulcer

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1. Open sores in the lining of the stomach, small intestine, and/or esophagus; can result in internal bleeding and if it penetrates the organ wall, peritonitis; scar tissue. Majority are due to bacterial infection or medication.

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2. Pernicious anemia

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2. Disruption of formation of RBC in bone marrow due to deficiency in vitamin B12. Can be caused by autoimmune gastritis which produces antibodies against the H+/K+ATPase which degreases HCL in gastic juice (achlorhydria) and there is also a lack of synthesis of intrinsic factor

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3. Zollinger-Ellison syndrome

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3. Gastrin-secreting tumors (aka gastinomas) of pancreas. There is hyperplasia and hypertrophy of the fundic region. There is a high acid secretion that is independent of food ingestion. Complications include: fulminant (sudden) stomach ulceration, diarrhea (gastrin causes inhibition of water and electrolyte absorption in the intestine), steatorrhea (inability to absorb fat due to inactivation of pancreatic lipase by the low pH) and hypokalemia (lower than normal level of K+ in the blood). H+ secretion continues regardless of [H+] of stomach since pancreatic gastirn is not regulated by negative feedback.

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4. Gastic Reflux (Barret's Esophagus)

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4. Due to extensivegastroesophageal reflux. Symptoms include heartburn, indigestion, or gas; burning sensation below and behind the breastbone (sternum); treat with antacids and acid-blocking drugs. Barrett's esophagus is due to a change in the epithelium of esophagus (stratified squamous to simple columnar) - this change is not accompanied by new symptoms. These pts are at a high risk for esophageal adenocarcinomas (30-125X's higher); usually found late and therefore not curable.

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5. Gluten enteropathy

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5. Results form the destructive effects of certain glutens (rye, wheat) on intestinal villi. Reduces the surface area that is available for absorption. Treat: eliminate wheat and rye products from the diet.

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6. Inflammatory Bowel Disease

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6. This includes: Ulcerative Colitis and Crohn's disease; clinically characterized by diarrhea, pain and periodic relapses. Ulcerative colitis can affect the mucosa of the LARGE intestine, Crohn's disease affects ANY segment of the intestinal tract, small & large. Chrohn's diseases is a chronic inflammatory process, with immune system cells (lymphocytes, neutrophils and macrophages) producing cytokines damaging intestinal mucosa, progressing into submucosa and muscularix externa; there is a presence of granulomas. Will also see lymphocyte aggregates. Complications include: occlusion of the intestinal lumen by fibrosis, formation of fistulas and intestinal performation.

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7. Hirschsprung's disease

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7. (AKA Congenital Megacolon): cause by a mutation in 1-4 genes that prevent the migration and differentiation of NEURAL CREST CELLS into neurons of ENTERIC nervous system. (AKA Aganglionosis) therefore an aganglionic segment is permanently contracted the therefore does not allow entry of contents and therefore it results in abnormal form of constipation. Seen shortly after birth when the infant abdomen becomes distended and little meconium is eliminated. Biopsy of mucosa and submucose confirms diagnosis --> thick and irregular nerve bundles and a lack of ganglion cells. Treatment: surgical removal of affected region of colon and reattachment of the rest.

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8. Colorectal carcinoma

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8. 2nd highest cause of cancer death in the US. Usually affects 55 or older. Usually arises from adenomatous polyps, may be asymptomatic for years; rectal bleeding frequently present. Probably diet related (high fat, refined carbs, and low fiber) Treatment: surgery with or without chemo and radiation therapy.

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9. Diverticulosis/Diverticulitis

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9. Diverticulosis is a herniation of the muscle wall of the colon, the mucosa and/or submucosal layers protrude through a weak site in the muscle wall. Diverticulitis is the inflammation at the site of diverticulosis. Symptoms: abdominal pain, tenderness in left lower side of abdomen; cramping, nausea, vomiting, fever, chills, chang in bowel habits; complications include bleeding, infections, perforations, blockage of colon. Dominant theory of cause is a consumption of low-fiber diet. Treatment: increase fiber in diet.

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10. Appendicitis

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10. Inflammation of the appendix due to a blockage or previous infection. Symptoms: abdominal pain that originates in the navel and shifts to the lower right abdomen. Pain will increase ove 12-18 hours becoming sever. Complications: rupture of appendix that leads to an abscess and or peritonitis. treatment: surgical removal

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1. Salivary Gland Tumors

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1. See box 16.4 80% of tumors are benign, most originate in the parotid. Most are pleomorphic adenomas, and are characterized by ductal and myoepithelial cells intermingled with areas resembling ground substance of connective tissues. These connective-like tissues are produced by myoepithelial cells. (ground substance and collagen) most common treatment is surgical removal. Complications of surgical treatment include facial nerve dysfunction and Frey's syndrome (aka gustatory sweating).

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2. Sjogren (show-grins)

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2. Major symptoms are xerostomia and dry, gritty eyes; component of systemic disease, 2nd most common autoimmund disease, female dominant. Diagnosis involves inner lip biopsy. Positive if there are aggregates of 50 lymphocytes adjacent to mucous acini. Lymphocytes eventually replace the acini.

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3. Acute pancreatitis

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3. an inflammatory condition of the exocrine pancrease that results from injury to acinar cells. Acincar cell injury and duct obstruction are the major initiators. Some causes: 1. secretion against obstruction (gallstone). 2. inappropriate activation of proenzymes, 3. AIDS, 4. ethanol. Most common causes are alcohol abuse and bile duct obstruction.

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4. Cystic Fibrosis

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4. CF - 80% of CF patients have visible secretory abnormalities of the pancreas; CF causes mucous inspissation in ducts and 2ndary atrophy of exocrine glands, atrophy of glands are due to blocking the duct lumens.

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5. Centrilobular Necrosis

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5. Hepatocytes in Zone 3 undergo ischemic necrosis, in for example, congestive heart failure when they do not receive proper oxygen. No changes of cells occur in Zones 1 and 2. Noticable are multiple round vacuoles in Zone 3, which indicates extensive lipid accumulation. See box 18.1 Side note from box: "Centrilobular necrosis, as a result of hypoxia, is referred to as cardiac cirrhosis.

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6. Alcoholic hepatitis

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6. a) swollen (balloon cells) hepatocytes in the cetrilobular region, b) Mallory bodies in hepatocytes, c) neutrophils present, d) collagen deposisted (fibrosis) around central vein; e) some hepatocytes become fat cells.

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7. Cirrhosis

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7. death of hepatocytes leads to replacement by CT, which leads to scarring or increased production of collagen destroying normal architecture. (no more classic lobule arrangement)

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8. Cholecystitis

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8. gallstone impacted in cystic duct leading to: a) thickened muscular layer due to trying to overcome pressure, b) impaired breakdown of fat, c) high pressure in gall bladder rearranges mucosa.

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9. Role of hepatic stellate cells (Ito) in portal hypertension

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9. hepatic stellate lose storage function and now lay down matrix and affect sinusoids (These cells are of mesenchymal origin and are primary storage sites for Vitamin A. They are involved in storage and release of retinoids (forms of vit A), production collagen and ECM, and regulation of blood flow in the sinusoid.) In pathologic conditions, these hepatic stellate cells lose their lipid storage capability and change into collagen/ECM producing cells. The deposition of extra collagen (I & III) and ECM increases, leading to increasing fibrosis, typical of cirrhosis. Stellate cells also convert to myofibroblasts, constrict the sinusoids, and further increase vascular resistance. This increase in resistance to the flow of portal venous blood in the hepatic sinusioids leads to portal hypertension.

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10. alpha-1 Anti-Trypsin (AAT) deficiency

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10. AAT is produced in the liver and one of its functions is to protect the lung form neutrophil elastase activity (review 10 in 10 lung). 50% of pts will develop liver cirrhosis. The ATT accumulates in the liver in PAS postitive globules. Treatment for AAT deficiency is pooled AAT given intravenously and liver and lung transplantation.