Jack S. Elder, MD

• Clinical Professor of Urology, Case School of Medicine,
• Cleveland, Ohio
• Chief, Department of Urology, Henry Ford
• Health System, and Associate Director, Vattikuti Urology
• Institute, Department of Urology,
• Children? Hospital of Michigan,
• Detroit, Michigan

Monodermal or highly specialized presently called as "monodermal teratoma and somatic-type tumors arising from a dermoid cyst calories and cholesterol in shrimp tricor 160 mg buy online. Age group: Usually detected in young women during the active reproductive years with a peak incidence in the third decade cholesterol test can you drink coffee best order tricor. Cut Section · Cyst contains yellow or gray how many cholesterol in eggs order 160 mg tricor free shipping, buttery or cheesy sebaceous material with variable amount of hair test je cholesterol tricor 160 mg order visa. It shows the greatest variety of tissue types from all three germ cell layers and teeth tend to be located at this site cholesterol ratio triglycerides hdl tricor 160 mg purchase. The cyst wall consists of skin (stratified squamous epithelium) with skin appendages (sebaceous glands, hair shafts, and other skin adnexal structures). Limbic encephalitis may develop as a rare paraneoplastic complication with teratomas containing mature neural tissue. Malignancy in Mature Cystic Teratomas One of the mature cellular elements may undergo malignant change in about 1% of the dermoids. They tend to occur in older women and include squamous cell carcinoma, thyroid carcinoma, melanoma, basal cell carcinoma, and carcinoid tumor. Solid Teratoma Rarely, mature (benign) teratoma can be solid with mature tissues derived from two or three germ layers. On gross examination, these tumors are difficult to differentiate from the malignant, immature teratomas. Cut Section · Predominantly solid and have lobulated and variegated appearance showing heterogeneous mixture of various tissues. Microscopy Varying amounts of immature tissues mixed with some mature tissues derived from the two or three germ layers. The immature elements include immature neuroepithelium (neuroepithelial rosettes and immature glia), cartilage, bone, muscle, and others. They may be functional (producing 5-hydroxytryptamine) and result in carcinoid syndrome. Strumal carcinoid: It is a combination of struma ovarii and carcinoid in the same ovary. Predisposing factors: Gonadal dysgenesis (including pseudohermaphroditism) is one of the risk factors. Molecular changes: n n Like seminomas, dysgerminomas express transcription factors, namely Oct3, Oct4, and Nanog. Gross · · · · · note on morphology of Usually unilateral (80­90%) Solid, firm, round to oval, encapsulated tumors. Tumor Cells Resemble primordial germ cells with following characteristics: · Cells: Individual tumor cells are monotonous (uniform). Stroma Similar to seminoma, the fibrous stroma is infiltrated with mature lymphocytes (most are of T-cell type) and occasional granulomas. Lymphatic spread: Through lymphatics, it spreads commonly to the contralateral ovary and retroperitoneal nodes. Dysgerminoma is treated surgically, and 5-year survival for patients with stage I is almost 100%. Origin: From differentiation of malignant germ cells along the extraembryonic yolk sac lineage. Tumor Marker · -fetoprotein and 1-antitrypsin in tumor cells by immunohistochemistry · -fetoprotein in the serum Prognosis: Aggressive and rapidly growing tumor. Nongestational Choriocarcinoma Choriocarcinoma in females may be: v Gestational: More common of placental origin. This is because after puberty the origin from an ovarian, ectopic pregnancy cannot be ruled out. Pure choriocarcinomas of ovary are extremely rare and most coexist with other germ cell tumors. Prognosis: In contrast to gestational, these nongestational types generally do not respond to chemotherapy and are fatal. Mixed germ cell tumors: They shows various combinations of dysgerminoma, teratoma, endodermal sinus tumor and choriocarcinoma. Immature teratoma: · Predominantly solid · Composed of immature embryonal or fetal tissue admixed with mature tissue. Monodermal teratomas and somatic-type tumors arising from a dermoid cyst: Rare type of teratoma composed entirely of one tissue type. Glomerulus-like structure composed of a central blood vessel enveloped by germ cells within a space lined by germ cells. Choriocarcinoma: Consists of cytotrophoblast and syncytiotrophoblast without any villi. Hormonal activity: Some of these cells normally secrete estrogens (granulosa and theca cells) or androgens (Leydig cells). The corresponding tumors may be either feminizing (granulosa-theca cell tumors) or masculinizing (Leydig cell tumors). Stromal Component Granulosa cell tumors contain a variable amount of fibromatous or thecomatous stroma. Reticulin stain: It shows reticulin fibers surrounding the nests of tumor cells, except in stromal regions. Typically they present with postmenopausal bleeding in older women and menorrhagia, metrorrhagia, or amenorrhea in younger patients. Behavior: All granulosa cell tumors are considered as low-grade malignant tumors because it may spread locally as well as metastasize. Biochemical markers: Inhibin is secreted by granulosa cells and elevated tissue and serum levels of which are useful for identifying granulosa tumor and monitoring treated patients. Tumors arising from ovarian stroma (pure stromal tumors) that are composed of: v Only fibroblasts are called fibromas and are hormonally inactive. Microscopy Consist of well-differentiated fibroblasts separated by scant collagenous connective tissue. Sex cord-stromal tumors: Produce hormones (estrogen or androgens) and most are benign (but potentially malignant). Meigs syndrome: (1) Ovarian fibroma, (2) Hydrothorax usually on right side and (3) Ascites. Source of Primary Tumor v From genital tumors: Most common metastatic tumors are derived from tumors of the uterus, fallopian tube, and contralateral ovary. Gross features, which point to metastatic carcinoma are: n Bilateral ovarian involvement. Metastatic tumors of ovary: Most common source of metastasis from genital tumors originate from uterus, fallopian tube, and contralateral ovary. Krukenberg tumor: Microscopy shows nests of mucin-producing, signet-ring cancer cells within a cellular stroma of the ovary. Gestational trophoblastic disease consists of tumors and tumor-like lesions characterized by proliferation of placental tissue (villous or trophoblastic). Definition: Hydatidiform mole is benign, non-neoplastic, gestational trophoblastic disease of placenta characterized histologically by cystic swelling of the chorionic villi, accompanied by variable trophoblastic proliferation. Androgenetic diploidy (diploid paternal-only genome) is the genetic cause in majority of cases. Significance: Hydatidiform mole is associated with an increased risk of invasive mole or choriocarcinoma. Age: Mostly present in the fourth or fifth month of pregnancy with vaginal bleeding. Currently, due to routine ultrasound examination during early pregnancy, moles are detected at earlier gestational ages. Ethnic background and obstetric history also influence the risk of developing hydatidiform mole. Depending on cytogenetic and histological features, benign, noninvasive moles are divided into two types: 1. Thus, the characteristic feature is complete absence of maternal chromosomes (empty ovum) and the genetic material is completely paternally derived (from sperm). Most commonly (~90%), complete moles develop from fertilization of an empty egg/ovum by one sperm. The genetic material/chromosomes of the sperm (23,X not 23,Y) undergoes duplication a phenomenon called androgenesis. Less commonly (~10%), complete moles are formed by the fertilization of an empty ovum by two sperm (dispermy). Microscopy of Partial Mole Histological differentiation of complete mole from partial molar is important. Invasive Mole Definition: It is defined as a hydatidiform mole, complete or partial that penetrates or even perforates the uterine wall. Choriocarcinoma Definition: Gestational choriocarcinoma is a rapidly invasive malignant neoplasm of trophoblastic cells which metastasizes widely. Appearance · Soft, fleshy, yellow-white tumor · Secondary changes: ­ Large pale areas of ischemic necrosis ­ ­ Extensive areas of hemorrhage Foci of cystic softening. Clinical Features Uterine choriocarcinoma usually manifests as irregular vaginal spotting of a bloody, brown fluid. Treatment of gestational choriocarcinoma: It consists of: v Evacuation of the contents of the uterus v Surgery v Chemotherapy: Results in nearly 100% remission and a high rate of cures. Placental Site Trophoblastic Tumor Placental site trophoblastic tumor is derived from the placental site or intermediate trophoblast. The morphological and functional features of intermediate trophoblast overlap with those of trophoblasts and syncytiotrophoblasts. Prognosis: It has an indolent clinical course, usually with a favorable outcome if the tumor is confined to the endomyometrium. These tumors are not as sensitive to chemotherapy when compared with other trophoblastic tumors. Definition: Ectopic pregnancy/gestation is the implantation of the fetus in any site other than a normal intrauterine location. Other sites: Ovary, abdominal cavity, and the intrauterine portion of the fallopian tube (cornual pregnancy). Other causes of peritubal scarring and adhesions, such as appendicitis, endometriosis, and previous surgery. With time trophoblastic cells and chorionic villi of the placenta invade the fallopian tube wall as they do in the uterus during normal pregnancy. Clinical Features the ectopic pregnancy presents as severe abdominal pain due to rupture of the tube leading to pelvic hemorrhage and constitutes a medical emergency. Complete hydatidiform mole: Whole placenta is neoplastic without any fetal parts and are diploid. Partial mole: Part of placenta is neoplastic, fetal parts present and triploid (karyotyping shows 69 chromosomes). Invasive mole: · Invades or perforates uterine wall · Shows villi with trophoblastic proliferation Gestational choriocarcinoma: Highly invasive malignant neoplasm of trophoblastic cells which metastasizes widely. Each lobule consists of a variable number of terminal ductules/acini embedded within specialized intralobular stroma and is connected to the intralobular terminal duct. This leads to a collecting (lactiferous or galactophorous) duct, which opens onto the surface of the nipple. A fusiform dilation is seen beneath the nipple between the collecting and the segmental duct, known as the lactiferous sinus. Classification: According to the subsequent risk of developing breast carcinoma, the benign epithelial lesions of breast can be divided into three groups: Nonproliferative Breast Changes (Fibrocystic Changes) Q. Write a short note on morphology of nonproliferative breast changes (fibrocystic disease of breast). Apocrine metaplasia: It is a common change, most often seen in dilated ducts and cystic structures. Calcification: It is less common and line the bottom of a rounded cyst and mammographers use the term "milk of calcium" to describe these calcifications. Chronic inflammation, fibrosis, hyalinization contribute to the firmness of the breast during palpation. Adenosis: It is defined as an increase in the number of acini (terminal ductule) per lobule. Flat epithelial atypia is probably the earliest recognizable precursor of low-grade breast cancers. Lactational adenoma: They develop as palpable masses in pregnant or lactating women. Proliferative Breast Disease without Atypia Characterized by proliferation of ductal epithelium and/or stroma without cytologic or architectural features of carcinoma in situ. Epithelial hyperplasia: Normal breast ducts and lobules are lined by two layers of cells: Inner (luminal) epithelial cells and outer myoepithelial cells. The number of acini per lobule is increased and at least double the number found in uninvolved lobules. On occasion, stromal fibrosis may produce a microscopic appearance mimicking invasive carcinoma. Complex sclerosing lesion: Its components include sclerosing adenosis, papillomas, and epithelial hyperplasia. Papillomas: It consists of multiple branching central fibrovascular cores lined by luminal and myoepithelial cells. Torsion on the stalk may produce infarction of the papilloma causing a bloody discharge. Most of the small duct papillomas present as small palpable masses, or detected as densities or calcifications on mammograms. Proliferative Breast Disease with Atypia this group includes atypical ductal hyperplasia and atypical lobular hyperplasia. Proliferative disease is associated with a mild increase in risk, while proliferative disease with atypia has a moderate risk of carcinoma.

Saliva Though saliva is 98% water cholesterol lowering fast foods discount tricor master card, there are a plethora of other components in it cholesterol levels u.k order tricor 160 mg otc. The functions of saliva are: Lubrication (essential for speech cholesterol medication morning or night buy tricor 160 mg on-line, mastication Buffering and clearance of acids (due to slightly Maintenance of tooth integrity (by influenc- Salivary gland structure the basic unit of a salivary gland consists of an acinus cholesterol levels 26 year old male buy 160 mg tricor amex, a secretory duct and a collecting duct cholesterol ratio of 2.5 purchase tricor overnight delivery. The acinus has a central lumen surrounded by pyramidal-shaped cells and myoepithelial cells. Acini are classified as serous (numerous cytoplasmic granules), mucous (clear cytoplasm) or mixed. The secretory ducts are composed of intercalated and striated ducts, which are intralobular. The collecting ducts are composed of two cell layers ­ the inner flat cells and the outer and swallowing) alkaline pH) ing mineralisation, demineralisation and remineralisation) Antibacterial activity Taste Digestion (salivary amylase initiates digestion of carbohydrates) [4] the salivary glands 201 Table 14. It is associated with diabetes, alcohol, obesity, liver disease, malnutrition (and eating disorders) and medications such as ramipril [5]. History Sialosis can present as a unilateral or bilateral swelling noticed by the patient. Past medical history should reveal any of the aforementioned conditions or medications. Examination An examination should reveal bilateral symmetric, non-tender parotid glands. The patient may only have noticed one side, but objective examination should reveal bilaterally, enlarged parotids. Acute salivary gland infections Acute infection of the salivary glands (acute sialadenitis) can be caused by a variety of viruses and bacteria. It most commonly affects the parotid gland, though it can affect any salivary gland [6]. Acute bacterial suppurative parotitis is caused most commonly by Staphylococcus aureus and mixed oral aerobes and/or anaerobes (see Table 14. It often occurs in the setting of debilitation, dehydration and poor oral hygiene. It can be associated with other serious complications such as sensorineural hearing loss, aseptic meningitis, orchitis and pancreatitis. Investigation Imaging studies can be used to differentiate between acute suppurative infection and frank abscess collection, and are useful to assess for inflammation or duct obstruction by a stone. Note that x-ray sialography, which requires the injection of contrast into the salivary duct, cannot be used during acute infection. It can detect stones in the duct or parenchyma, thereby differentiating between obstructive and non-obstructive sialadenitis. An abscess collection may be seen as a hypoechogenic area surrounded by an irregular echogenic rim within the gland parenchyma. It is, however, highly operator dependent and may be poorly tolerated during acute infection, which can be exquisitely tender. It can also identify calcifications, intraglandular masses and adjacent inflammatory stranding [7]. Microbiology When purulent discharge is present, it should be collected for gram stain and culture. This must be interpreted with caution due to likely contamination with oral flora. The duct openings of each gland must be inspected whilst manually massaging the gland to see if pus can be expressed. Management Treatment of suppurative parotitis includes hydration and intravenous antibiotics. Duration of therapy depends on the the salivary glands 203 Viral Paramyxovirus, parainfluenza, Coxsackie, influenza A, cytomegalovirus, Epstein­Barr, human immunodeficiency virus Bacterial Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae, Haemophilus influenzae, Peptostreptococcus, Bacteroides, Fusobacterium Mumps has an incubation period of 2­3 weeks followed by symptoms of low-grade fever, malaise and anorexia prior to signs of gland infection. In considering viral causes, a drug and immunisation history should also be taken. Recurrent infection may raise suspicion of sialolithiasis with obstruction of the duct leading to secondary infection of the gland. Acute suppurative sialadenitis is commonly seen in the hospital in patients who are unable to maintain oral hydration and hygiene independently. Past medical history is important, as it is more common in patients with diabetes and renal failure. Examination Acute suppurative sialadenitis is characterised by the sudden onset of a firm, erythematous swelling of the affected gland with exquisite local pain and tenderness. Fluctuance in the parotid may not be clinically evident until the abscess is quite advanced because of the overlying tense parotid fascia. Systemic features such as fevers, chills and marked toxicity are generally present. Since suppurative parotitis may potentially spread to deep fascial spaces of the head and neck and is potentially life-threatening, outpatient management with oral antibiotics is not advised. Surgical incision and drainage should be implemented if there is no clinical response after 48 hours of treatment with empiric intravenous antibiotics. Prognosis/follow-up/complications Progression of the infection may lead to massive swelling of the neck, respiratory obstruction, septicemia and osteomyelitis of the adjacent facial bone. In rare instances, recurrent infection of the parotid gland may occur, particularly in patients with comorbid conditions, such as diabetes mellitus. History Patients generally present with a history of recurrent pain and swelling of the affected salivary gland, typically post-prandial. Intraoral palpation should extend to the floor of the mouth and soft tissue of the tongue and cheek. All of the major salivary glands should be examined for masses, symmetry and the presence of discharge, and the neck should be palpated for lymphadenopathy. Anteroposterior, lateral and oblique intraoral occlusal views are used and calculi are radiopaque in 70% of cases [8]. A disadvantage of this scan is that no anatomical information about the ductal system or soft tissues is available. Sialography Sialography can be used to evaluate sialoliths as well as other obstructive entities and inflammatory and neoplastic disease. This investigation is contraindicated in patients with an iodine allergy or in acute sialadenitis [8]. Obstructive salivary gland disease and sialolithiasis Obstructive salivary gland disease is the most common non-neoplastic salivary gland disorder and may be caused by calculi, ductal stenosis, fibromucinous plugs, foreign bodies or anatomical variants of the ductal system. The submandibular gland is involved in 80%­90% of cases, followed by the parotid gland (95%­10%) and sublingual glands (<1%). Management the primary objective of salivary gland sialolithiasis treatment should be preservation of gland function, and minimisation of complication and discomfort for the patient. Conservative treatment Non-invasive conservative management with gentle gland massage, use of warm compresses, sialagogues and irrigation is the first-line approach. This includes removal via sialendoscopy, extracorporeal shockwave lithotripsy or open surgical removal. Sialendoscopy Stones up to 4 mm can be drawn out with sialendoscopy and basket retrieval if in a suitable position distal to the gland. A basket is passed behind the stone and activated to collect and retrieve the stone out of the duct [10]. Briefly, this approach involves using sialendoscopy to locate the stone and then guide an open dissection onto the stone to enable its removal without requiring excision of the gland [11]. Lithotripsy Moderately sized stones 5­8 mm in diameter can potentially be targeted with lithotripsy. Stone excision Stones that are visible or easily palpable superficially in the oral cavity may be excised transorally and the duct marsupialised. Gland excision For recalcitrant disease not amenable to or having failed all available alternative means described previously can be managed definitively with gland excision. Follow-up Following minimally invasive intervention or conservative management, patients should be encouraged to carry out gland massage several times a day combined with a sour diet and sialagogues to stimulate salivary flow. Recurrence of sialoliths is uncommon and is estimated to occur in 1%­10% of patients [9]. Benign salivary gland neoplasms Salivary gland neoplasms are uncommon and are generally benign. The proportion of tumours that are malignant rises progressively in submandibular glands, sublingual glands and minor salivary glands [13]. Pathology Pleomorphic adenoma Pleomorphic adenomas, also known as benign mixed tumours, are the most common salivary gland tumour. Pleomorphic adenomas can also originate in minor salivary glands, most commonly in the palate and then the upper lip. These tumours are unique among the subset of benign salivary tumours because their capsule has varying thickness or completeness with satellite nodules or pseudopodia being well described in the literature [15]. This is why when performing surgery to excise these tumours a surrounding cuff of tissue is mandated by some as essential to reduce the risk of recurrence. Pleomorphic adenoma can uncommonly recur and typically does so at the periphery of the lesion. Surgical excision remains the mainstay of management for recurrent disease and has an increased risk of facial nerve damage and risk of recurrence. Consider radiotherapy for elderly patients after first attempt at revision surgery, but for younger patients repeated surgical procedures can be considered. Histologically, it demonstrates papillae of eosinophilic epithelia projecting into cystic spaces with a lymphoid matrix [18]. It has an intact basement membrane, which differentiates it from pleomorphic adenoma. It can be difficult to distinguish from solid adenoid cystic carcinoma on biopsy [19]. Others Other rare benign salivary gland neoplasms include canalicular adenoma and myoepithelioma. History Benign tumours of the salivary glands usually present as a slow-growing, painless lump. Examination Benign tumours are usually well defined, non-tender and freely mobile. Deep lobe parotid tumours may extend into the parapharyngeal space and may result in a medialised tonsil on inspection of the oropharynx. It has a greater than 85% specificity for differentiating benign and malignant disease [20]. It must be borne in mind the risk of a false negative result and therefore not regarded as a definitive diagnosis alone. The most common diagnostic error is inadequate sample, so ultrasound guidance is often recommended to improve diagnostic yield. Advantages of imaging: be influenced by institutional factors such as availability and cost. Surgical management the surgical principles of management of benign salivary gland tumours have remained constant for many years. The key features for parotidectomy are: Complete excision with an adequate margin to Type of resection. Tips for identifying facial nerve branches distally during parotidectomy: Marginal mandibular: Below the lower border Accurate delineation of location/extent Relation to neurovascular structures Perineural spread Skull base invasion Intracranial extension ­ Ultrasound is inexpensive, non-invasive and free of complications. The choice of which imaging modality tends to of the mandible as it crosses superficial to facial vessels Buccal: Underneath the parotid-masseteric fascia, coursing parallel to the parotid duct Zygomatic: Half-way between lateral canthus and tragus Complications following parotidectomy Facial nerve palsy Facial nerve palsy following parotid surgery for benign disease is common. Temporary weakness occurs in up to half of patients, whilst permanent weakness is much lower and reported to be approximately <3% [21]. Permanent weakness is more likely in revision cases or where total parotidectomy is performed, and often can be predicted and the patient counselled appropriately with facial reanimation planned appropriately. The salivary glands 207 In the instance of facial nerve palsy, diligent eye care to avoid exposure keratitis is necessary. Sensory deficits Greater auricular nerve injury is common during this operation and in many instances it is not possible to save the posterior branch to the ear lobe. It is caused by aberrant cross-reinnervation between the postganglionic secretomotor parasympathetic fibres to the parotid and the postganglionic sympathetic fibres supplying the sweat glands of the skin. When the patient chews a sialogogue there is an appearance of dark blue spots along the face confirming gustatory sweating. Oral anticholinergics such as glycopyrrolate may be helpful for temporarily reducing salivary flow. Malignant salivary gland neoplasms Salivary gland malignancies make up only 3% of head and neck malignancies. They are diverse and heterogeneous in their histological appearance and behaviour. The most common primary salivary gland neoplasm is mucoepidermoid carcinoma, followed by adenoid cystic carcinoma. In Australia, the most common malignant parotid lesion is metastatic squamous cell carcinoma. Management is dependent on histological type and grade, and where lesions are resectable, surgery tends to be the mainstay, with or without adjuvant postoperative radiotherapy. Pathology Mucoepidermoid carcinoma Mucoepidermoid carcinoma is the most common salivary gland cancer, with the majority arising in major salivary glands. Grading is important and correlates strongly with clinical behaviour: Low-grade predominantly cystic with abundant superficial parotidectomy that resolves spontaneously) Antiperspirant over the skin Glycopyrrolate (1%) Injection of Botox A Tympanic neurectomy well-differentiated mucous cells, less aggressive with lower risk of cervical metastasis and recurrence High-grade more solid with squamoid and intermediate cells predominating [25] Adenoid cystic carcinoma Adenoid cystic carcinoma is notorious for its infiltrative growth and slowly progressive behaviour with a high rate of late recurrences and distant metastases, related to perineural invasion, and spread over a protracted course of many years. Patients with these Salivary fistulas/sialoceles Salivary fistula can occur in up to 14% of patients [24]. It manifests with clear fluid discharge from the wound or as a fluid collection under the skin flaps. Histologically there are three growth patterns: Tubular: Small tubules, sitting in a pink, hyalin- Recurrence occurs in one-third of patients and 10% metastasise locally or distantly.

The islet amyloid protein may be directly cytotoxic to islets causing -cell dysfunction cholesterol lowering by diet purchase tricor 160 mg otc. Pathogenesis of complications of diabetes is multifactorial and includes: v Hyperglycemia (glucotoxicity) is the main mediator v Insulin resistance (described already) v Obesity (described already) cholesterol medication pravastatin 160 mg tricor buy fast delivery. HbA1C should be maintained below 7% in diabetic patients and its measurement is helpful in knowing the glycemic control over the lifespan of a red cell (120 days) xzk cholesterol 160 mg tricor with mastercard. Common organs damaged are kidneys (end-stage renal disease) le cholesterol definition tricor 160 mg purchase on-line, eyes (adult-onset blindness) cholesterol found in shrimp order on line tricor, nerves, and blood vessels (gangrene of lower extremity). Effects of Hyperglycemia Harmful effects of persistent hyperglycemia on peripheral tissues can be brought out by three distinct metabolic pathways. Persistent hyperglycemia increases the intracellular glucose in these tissues excess intracellular glucose is metabolized by the enzyme aldose reductase to sorbitol (polyol) to fructose. The morphological changes include: · Reduced number and size of islets: It is seen in type 1 diabetes which is mild in type 2 diabetes. In advanced stages, the islets may be virtually obliterated and may show fibrosis. Blood Vessels · Hyaline arteriolosclerosis: It can be found in hypertension, elderly nondiabetics without hypertension and more severe degree in diabetics also. Classical classic triad of diabetes: It consists of polyuria, polydipsia, polyphagia, and in severe cases ketoacidosis, are due to metabolic derangements. Consequences of Insulin Deficiency Insulin is an anabolic hormone and its deficiency results in a catabolic state, which affects glucose metabolism, fat and protein metabolism. In the mitochondria of liver cells, fatty acyl coenzyme A molecules are oxidized to ketone bodies (acetoacetic acid and -hydroxybutyric acid). When the rate of production of ketone bodies exceeds the rate of utilization by peripheral tissues, it results in ketonemia and ketonuria. If the excretion of ketone bodies in the urinary is compromised by dehydration, it results in systemic metabolic ketoacidosis. Due to increase in obesity and sedentary lifestyle, it is now detected also in children and adolescents. Diabetic Macrovascular Disease the lesions of large- and medium-sized muscular arteries are the most common causes of mortality in long-standing diabetes. Myocardial infarction: It is due to atherosclerosis of the coronary arteries and is the most common cause of death in diabetics. Diabetics have greater risk of coronary artery disease and cardiovascular complications than nondiabetics. Gangrene of the lower extremities: It results from advanced vascular disease and is more common in diabetics. Microvascular Disease (Microangiopathy) It involves small vessels and is characterized by capillary dysfunction in target organs and is mainly observed in kidneys (nephropathy), retina (diabetic retinopathy) and peripheral nerves (neuropathy). The different stages in diabetic nephropathy are: n Microalbuminuria: It is the earliest manifestation of diabetic nephropathy in which the urine has low amounts of albumin (>30 mg/day, but <300 mg/day). Microalbuminuria is also a marker for increased cardiovascular morbidity and mortality in either type 1 or type 2 diabetics. Retinopathy is the most common and it develops in ~60-80% of diabetics, about 15­20 years after diagnosis. Retinopathy may in be seen in two forms: nonproliferative retinopathy and proliferative retinopathy. The retinal exudates can be "soft" (microinfarcts) or "hard" (deposits of plasma proteins and lipids). Vitreous v hemorrhages due to the rupture of newly formed capillaries and their subsequent organization can lead to retinal detachment. This develops due to insulin resistance, which causes increased production of atherogenic lipoproteins by liver and decreased uptake of circulating lipids in peripheral tissues. Increased Susceptibility to Infections Infections of the skin, tuberculosis, pneumonia, and pyelonephritis are common in diabetes. The increased susceptibility may be due to defective neutrophil functions (chemotaxis, adherence to the endothelium, phagocytosis, and microbicidal activity), and impaired cytokine production by macrophages. Hyperglycemia: It is the fundamental basis for the diagnosis of diabetes mellitus. In symptomatic cases: Diabetes can be confirmed by finding glucosuria and a random plasma glucose level above 200 mg/dL. The severity of clinical symptoms of polyuria, polyphagia and polydipsia depends on the degree of hyperglycemia. In asymptomatic cases: Most of these patients have persistently elevated fasting plasma glucose level. The American Diabetes Association (2016) has recommended definite diagnostic criteria for early diagnosis of diabetes mellitus (Box 24. Urine Examination Urine examination is economical and convenient test for the diagnosis of diabetes mellitus. Disadvantages: Apart from diabetes mellitus, glucosuria may be found in other conditions (refer Box 14. However, if both glucose and ketone bodies are present, diagnosis of diabetes is almost certain. Single Plasma Glucose Estimation Estimation of plasma glucose is absolutely necessary for diagnosis of diabetes mellitus. It is advisable that all individuals above 45 years of age must undergo screening fasting glucose test every 3-years, and relatively earlier if the person is overweight. This is because fasting plasma glucose identifies the abnormal glucose metabolism. Because carbohydrate-restricted diet reduces glucose tolerance, patient should be with normal physical activity. Postprandial Plasma Glucose Determination of plasma glucose level 2 hours after food has no standardized role in the diagnosis of diabetes mellitus. Glycosylated Hemoglobin (HbA1c) Blood glucose level in diabetics varies with the dietary intake of the previous day of estimating blood glucose. Long-term assessment (for the last 90­120 days) of degree of glycemic control is assessed by measurement of glycosylated hemoglobin (HbA1c). Advantages of HbA1c assay are (i) it has a direct relation between poor control and development of complications and (ii) it is also a good measure of prediction of microvascular complications. Glycosylated Plasma Proteins (Fructosamine) It may also be measured as an index of diabetic control. It measures glycation of all serum proteins and the major component being glycosylated albumin. Since albumin accounts for most of the protein in blood, the measurement of fructosamine, for practical purposes, measures glycated albumin. As albumin has a turnover of about 2 weeks, fructosamine reflects glycemia over the preceding 2­3 weeks (shorter period). It is useful in diabetic patients with anemia or hemoglobinopathy and in pregnancy (when hemoglobin turnover is changeable). Other Investigations these are sometimes performed in specific conditions in diabetics and for research purposes. This C-peptide is released into the circulation during conversion of proinsulin to insulin in equimolar quantities to insulin. This test is more sensitive than insulin assay because its levels are not affected by treatment with insulin. Islet autoantibodies: Markers of cell-mediated autoimmune destruction of islet cells can be used as a marker for type 1 diabetes mellitus. Bone is a specialized connective tissue which has structural, protective, metabolic and hematopoietic functions (produces blood cells). Metaphysis: It is the region which extends from the region of the growth plate to area where the diameter of the bone becomes significantly narrow (becomes funnel-shaped). Diaphysis (shaft): It is the zone which extends from base of one metaphysis to the base of the opposing metaphysis. Osteoclasts: these are mature multinucleated cells (on an average 6­12 nuclei) that are responsible for bone resorption (removal by absorption). Formation of Granulation Tissue It consists of proliferating capillaries and fibroblasts and are formed at the site of fractures. They activate osteoprogenitor cells in the periosteum, medullary cavity, and surrounding soft tissues. Osteoblasts derived from activated osteoprogenitor cells migrate into the granulation tissue and differentiate into osteoid synthesizing units. They deposit large quantities of osteoid collagen in a haphazard pattern producing woven bone (unmineralized bone is called osteoid). At this stage, callus is predominantly uncalcified and is called soft-tissue callus or procallus, which provides a type of temporary connection between the ends of the fractured bones. The callus depending on its site and appearance can be divided into external and internal callus. It bridges the fracture site outside the bone and continues to grow inwards toward the fracture site. In this region, the osteoprogenitor cells may also differentiate into chondroblasts, which form fibrocartilage and hyaline cartilage around the fracture site. This bridges the fracture in the region of medullary cavity but in contrast to external callus does not contain cartilage. The repair tissue attains maximal thickness at the end of the second or third week and consists of hyaline cartilage and woven bone. Reparative Phase Lamellar Bone Formation As the healing advances, the hyaline cartilage and woven bone of the original fracture callus are replaced by lamellar bone. Endochondral Ossification the replacement process is known as endochondral ossification with respect to the hyaline cartilage and bony substitution with respect to the woven bone. Bony Callus At this stage, the callus is mineralized (calcified) and is known as bony (osseous) callus. As the mineralization proceeds, the stiffness and strength of the callus increases. Remodeling Phase Several weeks after a callus has sealed the bone ends, the remodeling phase begins. As the callus is subjected to weight-bearing forces, the portions of bony callus that are not physically stressed by this weight are slowly resorbed by osteoclasts. Local factors Excessive movement of fractured bone during healing process Infection of the fractured site Severe local soft-tissue injury Wide separation of fracture ends Extensive necrosis of the fractured bone Poor or impaired blood supply. Pseudoarthrosis: In case of nonunion, too much movement along the fracture gap can cause cystic degeneration in the callus, creating a false joint or pseudoarthrosis. Remodeling Inflammatory phase · Fracture and inflammatory cells · Granulation tissue formation Callus: Granulation tissue containing (mineralized or unmineralized) bone or cartilage. Reparative phase · Callus formation · Lamellar bone deposition Fracture healing: Mineralized callus is called bony/osseous callus. Rate of newly synthesized osteoid mineralization is best estimated by: Tetracycline labeling. Any infection (bacteria, viruses, parasites, fungi) may cause osteomyelitis, but infections by certain pyogenic bacteria and mycobacteria are the most common. Portal of Entry of Organism Causative organisms may reach the bone through the bloodstream, directly or extend from a contiguous site. Minor injuries to the mucosa (vigorous chewing of hard foods, brushing of teeth), or minor infections of the skin, release these organisms into the blood causing temporary bacteremia reach the bone. In children (5­15 years) and drug addicts (infected needles), it develops in the long bones. Direct Implantation Organisms may enter into bone by penetrating wounds, open fractures, or surgical procedures (staphylococci, streptococci, anaerobic organisms). Spread from Adjacent (Contiguous) Site For example, infections of the feet may spread into the bone in diabetics. The sequence of events and morphological features in osteomyelitis are described together. Infection reaches metaphysis of long bone: Because in the metaphysis, capillaries form loop which slows the blood flow provides time for bacteria to penetrate blood vessel walls and establish infective foci within the marrow. Inflammatory reaction: Once in bone, the bacteria grow and induce an acute inflammatory reaction with exudates. Necrosis of bone: Exudate increases the pressure on the adjacent vessels and further decreases the blood supply produces bone necrosis. Bacterial infections and pus spreads into cortex and collect beneath the periosteum may lift the periosteum reduces the blood supply to the affected region results in segmental necrosis of the bone due to both suppuration and ischemia. Draining sinus: n the pus penetrates the periosteum and leads to a soft-tissue abscess may penetrate the skin form a draining sinus. Hole formed in the bone during the formation of a draining sinus is known as cloaca. Involucrum: After first week, chronic inflammatory cells become more numerous and the cytokines released stimulates osteoclastic bone resorption and deposition of reactive bone in the periphery. Reactive new bone forms a sheath around the necrotic (segment of devitalized infected bone) sequestrum. The morphologic features depend on the stage (acute, subacute, or chronic) and location of the infection. As the diseases become chronic, neutrophils admixed with chronic inflammatory cells (lymphocytes and plasma cells) are seen. Sclerosing osteomyelitis of Garré: It is characterized by extensive new bone formation, which obscures the underlying structure of the bone and typically develops in the jaw. Acute suppurative arthritis: Infection may spread through the articular surface into a joint producing suppurative arthritis may lead to destruction of the articular cartilage and permanent disability. Squamous cell carcinoma: It may arise from the epithelialized sinus tract, rarely sarcoma of bone may develop. Chronic osteomyelitis: It may develop due to delay in diagnosis, extensive bone necrosis, and inadequate therapy.

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Repeated atherosclerotic-induced ischemic attacks can result in dilated cardiomyopathy and heart failure (Chapter 52) cholesterol ratio scale discount tricor 160 mg with amex. An estimated 90% of cases of myocardial infarction (Chapter 64) cholesterol test recommendations 160 mg tricor purchase amex, 60% of strokes (Chapter 379) cholesterol estimation test tricor 160 mg buy on line, most cases of heart failure (Chapter 52) cholesterol medication during pregnancy purchase 160 mg tricor, and up to one third of all cases of dementia (Chapter 374) are due to atherosclerosis cholesterol medication trilipix buy discount tricor online. The inflammatory biomarker C-reactive protein does not cause atherosclerosis but reflects ongoing inflammation that may accelerate the atherosclerotic process. The atherosclerotic process typically is silent for months, years, and even decades, and it may never result in clinical manifestations. Platelet aggregates that form on these exposed surfaces are stabilized by a fibrin network. Tissue factor, expressed in the vascular smooth muscle cells and macrophages of the atherosclerotic plaque, is the primary cellular initiator of the blood coagulation cascade that leads to fibrin formation. Atherothrombi expand rapidly and can fill the lumen within minutes, thereby leading to ischemia and infarction. Matrix metalloproteinases and cysteine proteinases, which are produced by macrophages, are found at sites of plaque rupture and have been implicated in rupture, but their effects on the composition and size of lesions are complex. If this process fails, secondary necrosis ensues, thereby leading to reduced mechanical integrity and accumulation of prothrombotic material from dead cells. Inhibitors of platelet aggregation are widely used for secondary prevention of atherosclerotic cardiovascular disease. Aspirin inhibits formation of proaggregatory prostaglandins, whereas other inhibitors of platelet aggregation modulate expression of platelet adhesion molecules. In addition to medical therapies, interventional therapies have greatly impacted the health burden of atherosclerosis. These include coronary artery angioplasty and stenting, including drug eluting stents (Chapter 65). Cell therapy for heart disease: trial sequential analyses of two Cochrane reviews. Cholesterol efflux to high-density lipoprotein (Hdl) counteracts the tendency to foam cell formation. Molecules released from oxidatively modified ldl activate endothelial cells to express leukocyte adhesion molecules that promote binding of monocytes and t cells to the surface of the artery. Chemokines stimulate monocytes and t cells to migrate into the intima, where the monocytes differentiate into macrophages and cytokines promote vascular smooth muscle cell proliferation. Some macrophages are activated, thereby leading to release of pro-inflammatory cytokines, eicosanoids, radicals, and proteases. Boosting inflammation resolution in atherosclerosis: the next frontier for therapy. Increased passive stiffness promotes diastolic dysfunction despite improved Ca2+ handling during left ventricular concentric hypertrophy. Smooth, cardiac, and skeletal Answer: B Cardiac muscle is termed striated muscle, and it is anatomically and mechanistically similar to but distinct from skeletal muscle. Smooth muscle comprises the media of the arteries in the heart and is responsible for arterial contraction and tone. Which of the following functions is not a property of adult mammalian cardiac muscle Regeneration after injury Answer: E Adult cardiomyocytes are terminally differentiated, which means that they no longer can divide to form additional cells. They respond to stress by undergoing hypertrophy, a process in which individual cells enlarge, but the number of cells remains constant. The mechanism of cardiac muscle contraction involves shortening of the sarcomeres. Thick and thin filaments are present in cardiac, skeletal, and smooth muscle sarcomeres. Both pharmacomechanical and electromechanical processes can activate cardiac muscle. Answer: B Potassium channels are involved in repolarization of the cardiac action potential, but calcium is the ion that activates muscle contraction by binding to troponin C and allowing actin-myosin cross-bridging to occur, thereby shortening the sarcomere. The source of calcium is intracellular calcium release from the sarcoplasmic reticulum through the ryanodine receptor/ calcium release channel. Phase 0 of the action potential, when the cardiac muscle cell is depolarized, represents influx of which of the following ions Sodium Answer: E Opening of the sodium channel, which is the initial event in the action potential, allows sodium to rush into the cardiomyocyte and to depolarize the membrane potential. Depolarization of the cell membrane opens voltage-gated calcium channels; repolarization occurs when potassium channels are activated. Extrusion of calcium from the cell across the plasma membrane Answer: B the release of calcium from the sarcoplasmic reticulum through the ryanodine receptor/calcium release channel occurs when the channel opens, allowing calcium to flow out of the sarcoplasmic reticulum and down its concentration gradient (millimolar inside the sarcoplasmic reticulum and nanomolar in the cytoplasm). Coronary artery vascular smooth muscle proliferation Answer: C the antecedent history of exertional chest pain is consistent with narrowing of one or more coronary artery due to enlarging atherosclerotic plaques. Acute rupture of an atherosclerotic plaque can present as a myocardial infarction. It has also been described in hypercalcemia and brain injury, and it may connote risk of idiopathic ventricular fibrillation (see later). Voltage amplitude is measured on the vertical axis (typically 10 mm equaling 1 mV) and time on the horizontal axis. Multiple leads are typically recorded simultaneously from the top to the bottom of the page. A single lead (or multilead) rhythm strip is recorded below for the entire 10 seconds. Surface electrocardiography may be supplemented with intracardiac recordings, which are particularly helpful in the diagnosis and management of cardiac arrhythmias (Chapter 56). This electrical wave front spreads throughout the right and left atria; specialized conducting tracts called the Bachmann bundle speed the depolarizing wave front to the left atrium. Electrical atrial activation triggers atrial muscular contraction, thereby propelling blood through the tricuspid and mitral valves into the right and left ventricles. The bundle of His bifurcates into right and left bundle branches; the left bundle branch divides into the left anterior and left posterior fascicles. The bundle branches and their more distal ramifications of specialized conducting tissue are called the Purkinje system. From these specialized conducting tissues, the depolarizing wave front enters into and then moves through ventricular muscle. As in the atria, ventricular electrical activation begets muscular contraction, which pumps blood through the semilunar valves into the pulmonary and systemic circulations. After electrical activation, or depolarization, a period of electrical recovery, or repolarization, is necessary before repeated activation. At the cellular level, a complex orchestration of ion channels opening and closing determines the membrane potential throughout this process. The flow of ions into and out of the myocardial cells inscribes an action potential, which reflects depolarization and repolarization, as well as the spontaneous depolarization of pacemaker cells (Chapter 55). The P wave represents atrial muscular depolarization; in severe hyperkalemia, atrial electrical activation may be unaccompanied by atrial muscular activation, and no P wave is inscribed. Atrial muscle also requires repolarization before the next depolarizing wave front. Abnormalities in P wave amplitude, morphology, and axis may reflect atrial enlargement. Q, q, S, and s waves are negative excursions from the isoelectric baseline, whereas R and r waves are positive deflections. Sinoatrial nodal depolarization is not visible on the surface Ecg; the p wave corresponds to atrial muscular depolarization. These unipolar leads compare electrical potential between the chest electrode and a reference electrode called the Wilson central terminal. The Wilson central terminal combines the right arm, left arm, and left leg potentials through 5000- resistors. Initial ventricular activation involving the septum is directed from left to right; left ventricular depolarization, which dominates right ventricular depolarization because of the differential in myocardial mass, then moves apically and laterally. In lead V1, to the right of the sternum, the P wave is biphasic (reflecting right and then left atrial activation). Initial ventricular activation of the septum inscribes an r wave, whereas subsequent activation away from lead V1 records a dominant S wave. In lead V6, the P wave is positive, and initial ventricular septal depolarization inscribes a tiny "septal" q wave (usually 0. Right-sided chest leads should be recorded when right ventricular abnormalities are suspected. Mild right axis deviation beyond +90 degrees is a normal variant in children and adolescents. Because two lines pointing 180 degrees apart can be drawn perpendicular to any given line, examination of the other limb leads defines the direction in which the axis points. Clockwise rotation (transition zone at V4 or later) may portend a higher risk of future coronary events, and counterclockwise rotation (transition zone at V3 or earlier) a lower risk of events. Although a number of different lead systems are possible (and some are actually used in research settings), standard electrocardiography uses 12 vantage points. In reality, only three limb leads are actually used to generate recordings; the right leg lead serves as an electrical ground. The limb leads, called the frontal plane leads, generate bipolar and augmented unipolar lead recordings. In unipolar recordings, the lead of interest, the exploring electrode, is compared with a reference electrode. By convention, a positive deflection is recorded if the electrical wave front is moving toward the positive electrode in a bipolar pair or toward the exploring electrode in a unipolar lead. Note the small r wave and deep S wave in lead V1, the transition at around V3 or V4, and the "septal" q wave and large r wave in lead V6. Normal (Nl) = -30 to +90 degrees; left axis deviation (lad) = -30 to -90 degrees (moderate -30 to -45 degrees; marked -45 to -90 degrees); right axis deviation (rad) = +90 to +180 degrees (moderate +90 to +120 degrees; marked +120 to +180 degrees); extreme right axis deviation (Erad) = -90 to ±180 degrees. Note that the vectors for leads i, ii, and iii are in the same direction as in A, but now, like the augmented limb leads, these standard limb lead vectors have been moved so that they emanate from the center of the figure. The P wave is biphasic in lead V1 and then positive in the other precordial leads. Septal q waves, reflecting not lateral infarction but rather normal early septal depolarization, are present in leads V5 and V6. Electrocardiography in patients with coronary artery disease is reviewed in Chapters 62 to 64 and in patients with arrhythmias in Chapters 55 to 60. An isolated left bundle branch block in an otherwise healthy person is associated with a two-fold higher risk for development of a cardiovascular event or dying of a cardiovascular cause. As a result, this finding should trigger an evaluation for possible cardiac disease. By comparison, a complete right bundle branch block generally has not traditionally been associated with an increased risk, although one study suggested up to a 30% increased risk in cardiovascular mortality. St segments are downsloping, and t waves are discordant with the QrS complex in the right precordial leads. QrS duration is normal, and r wave progression across the precordial leads is delayed. St segments and t waves are discordant with the QrS complex throughout the precordium. Note the striking S wave amplitude in the right precordial leads and r wave amplitude in the left precordial leads. Over-reading by a physician, including comparison with previous tracings when available, remains mandatory. The differential diagnosis is broad (Table 48-4), and many patients will not have a clinically apparent underlying explanation. The absolute risk of sudden death in apparently healthy patients with the early repolarization pattern remains quite low, however. Whether the "early repolarization syndrome" is a distinct arrhythmic syndrome or a predisposing factor in patients with other arrhythmic substrate(s) is unclear. Bradycardia, variable p wave morphology, Mobitz i (Wenkebach) second degree aV block, and junctional escape beats all reflect hypervagotonia in this thin, 18-year-old athlete. Mild right axis deviation is present, not uncommon in adolescents and young adults. Note sinus p waves following junctional beats that are blocked; this is not abnormal physiology. The early repolarization pattern is seen frequently in athletes and may not necessarily imply significant risk in this setting. A1,11 For asymptomatic adults at intermediate or high risk, evidence is insufficient to make a recommendation. Recent years have seen an explosion in smartphone-based heart rate and electrocardiographic monitoring applications. The use of these apps to promote fitness seems selfevident, and physicians have begun to see "self diagnosis" of arrhythmias, both benign and more serious, using these technologies. Normal limits of the electrocardiogram derived from a large database of Brazilian primary care patients. The prognostic significance of right bundle branch block: a metaanalysis of prospective cohort studies. Early repolarization is associated with a significantly increased risk of ventricular arrhythmias and sudden cardiac death in patients with structural heart diseases. Canadian Cardiovascular Society/Canadian Heart Rhythm Society joint position statement on the cardiovascular screening of competitive athletes. Ultrasound is strongly attenuated by bone and air, so echocardiography relies on acoustic "windows," where ultrasound can penetrate to the heart while avoiding the ribs and lungs. With transthoracic imaging, the patient is positioned to bring the cardiac structures close to the chest wall, usually in a left lateral decubitus position, and the transducer is placed on the chest, with use of gel to provide acoustic coupling between the transducer and skin.

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