Sara L. Best, MD

• Associate Professor Department of Urology
• University of Wisconsin School of Medicine and Public Health Madison, Wisconsin

The pathobiology of the failing heart results in maladaptive regulation of multiple neurohormonal pathways that reduce intrinsic cardiac contractility and cause prototypical ventricular remodeling (Chapter 47) xanax medications for anxiety cheap lumigan 3ml with visa. Alterations in cardiac extracellular matrix and replacement fibrosis increase the connective tissue content and further impair systolic and diastolic function (Chapter 47) medications given for uti buy lumigan 3ml amex. Adrenergic nervous system activation plays a pivotal role in the development and progression of left ventricular dysfunction medicine 8 - love shadow cheap 3ml lumigan with amex. Reduced pulse pressure activates arterial baroreceptors and stimulates sympathetic nervous system activity symptoms 2 days before period purchase line lumigan, elevated levels of circulating norepinephrine medicine to stop vomiting cheap lumigan 3 ml without prescription, and increased release of norepinephrine by several organs medicine images buy generic lumigan 3ml line, including the heart. Exposure of cardiac myocytes to chronically elevated levels of norepinephrine reduces the density of their -adrenergic receptors, downregulates signaling pathways, and is directly toxic. The renin-angiotensin-aldosterone system, which is also activated relatively early in heart failure, causes vasoconstriction and sodium retention. The presumptive mechanisms of induction include renal hypoperfusion, -adrenergic system stimulation, and hyponatremia. Adrenergic and renin-angiotensin-aldosterone system activation stimulate the failing heart and support the circulation in the short-term. Over time, however, the prolonged activation of these systems causes maladaptive remodeling and further ventricular dysfunction. Further, the sympathetic nervous system and renin-angiotensin-aldosterone system are co-regulated, such that increased activity of each pathway stimulates a simultaneous increase in the other. The extent of natriuretic pathway activation is a marker of the severity of heart failure and is associated with adverse outcomes, including the risk for hospitalization and death. Arginine vasopressin induces vasoconstriction through a vascular (V1) receptor and reduces free water clearance through a renal tubular (V2) receptor. Endothelin causes prolonged vasoconstriction, reductions in glomerular filtration, and pulmonary arteriolar constriction. Cardiorenal interactions highlight the integral role of kidney dysfunction in the worsening of heart failure, with both organs contributing to the retention of sodium and water. In most patients with chronic heart failure, the kidneys are anatomically and structurally normal, but passive venous congestion and reduced renal perfusion lead to worsening renal function and a vicious cycle of progressive dysfunction of both organ systems. Renal failure may limit the ability to use inhibitors of the renin-angiotensin-aldosterone system to treat heart failure. Abnormal calcium cycling reduces the calcium content in the cardiac sarcoplasmic reticulum owing to diastolic leak through altered ryanodine receptors. The reduced calcium content of the sarcoplasmic reticulum alters the contraction interactions between cardiac myosin and actin myofilaments. In some patients, the tachycardic response to heart failure may itself contribute to worsening heart failure. These forms of heart failure may be reversible, depending on the relative contribution of the tachycardia to the underlying myocardial dysfunction. Genetic mutations are increasingly identified as important mediators of the cardiac structural and functional abnormalities linked to symptomatic heart failure (see E-Table 54-1). The majority of familial cardiomyopathies (Chapter 54), most of which are inherited in an autosomal dominant fashion, are related to defects in cytoskeletal or nuclear proteins. Inherited cardiomyopathies are also associated with muscular dystrophies, infiltrative diseases such as hemochromatosis, and mitochondrial disorders. Processes that interfere with myocardial energy metabolism, such as ischemia, compromise myocardial relaxation. Elevated filling pressures raise the pulmonary capillary wedge pressure and contribute to the sensation of dyspnea. Diastolic dysfunction may remain asymptomatic for years, but increasing age, renal dysfunction, hypertension, and progressive left ventricular dysfunction are associated with the development of symptomatic heart failure. The resting hemodynamic profile in heart failure with preserved ejection fraction is frequently normal, but physiologic perturbations such as tachycardia or exercise result in exaggerated increases in filling pressures. Abnormalities in ventricular relaxation and myocardial stiffness limit ventricular filling, so patients may have a narrow window for optimal fluid volume. Modest volume overload can substantially exacerbate symptoms of dyspnea, and diuresis may precipitate symptomatic hypotension owing to ventricular underfilling. Although isolated diastolic dysfunction can occur, the majority of patients with ventricular dysfunction have both systolic and diastolic components. As a result, it is preferable to characterize patients as having heart failure with a preserved ejection fraction or heart failure with a reduced ejection fraction rather than as having systolic or diastolic heart failure. High-output heart failure is seen in severe anemia and hyperthyroidism (Chapter 213). It is also seen in patients with vasodilative states such as obesity (Chapter 207), late-stage liver disease (Chapter 145), arteriovenous shunts, hypoxic-hypercapnic lung disease, and myeloproliferative/myelofibrotic disorders with extramedullary hematopoiesis (Chapter 157). In contrast, the diagnosis may be missed or delayed in patients who experience a more insidious course with vague symptoms, such as fatigue and exercise intolerance. The use of biomarkers such as natriuretic peptides has significantly improved diagnostic accuracy in recent years. In principle, diastolic dysfunction in heart failure with a preserved ejection fraction can result from increased ventricular stiffness due to hypertrophy and interstitial fibrosis as well as from abnormal ventricular relaxation due to dysfunctional calcium cycling. Although there are many potential causes of heart failure with preserved ejection fraction, most patients have current or prior hypertension; the resulting left ventricular hypertrophy and fibrosis are responsible for increased chamber stiffness. Ischemic heart disease also may contribute to heart failure with a preserved ejection fraction by virtue of subendocardial fibrosis or as a result of intermittent ischemic dysfunction. Age itself is a crucial predisposing factor because it causes loss of myocytes (apoptosis), increased fibrosis with shifts to more rigid forms of collagen, and loss of vascular compliance. It is the most common reason that patients seek care for heart failure, both during the chronic state and with acutely decompensated heart failure. The relief of dyspnea is a primary treatment goal because of its effect on quality of life and its association with worse in-hospital and postdischarge outcomes. Orthopnea results from the increase in venous return from the extremities and splanchnic circulation to the central circulation with changes in posture. The increase in ventricular preload raises pulmonary venous and pulmonary capillary hydrostatic pressures. Orthopnea is clinically characterized by the number of pillows a patient requires to sleep comfortably without shortness of breath. Patients with orthopnea may report an inability to sleep in a bed and instead may sleep sitting upright. Orthopnea is a specific symptom of heart failure, and it correlates well with the severity of pulmonary congestion. The mechanism of bendopnea is poorly defined but appears to be related to increases in left ventricular filling pressures during bending in patients with a baseline elevation in pulmonary capillary wedge pressure. There appears to be an association between bendopnea and baseline mismatch of left- and right-sided filling pressures. The clinical spectrum of this symptom and its relationship to outcomes are not well understood, but recent data suggest that this symptom may be more common than has previously been recognized. A 12-lead electrocardiogram should be obtained for all patients presenting with heart failure. Echocardiography should be performed during the initial evaluation of patients with heart failure to assess ventricular function and valve function. Measurement of natriuretic peptides is recommended for the following indications: To support the diagnosis of heart failure in ambulatory patients with dyspnea as well as in those with possible acute heart failure, especially in the setting of an uncertain diagnosis. The initial evaluation of patients presenting with heart failure should include a complete blood count, urinalysis and renal function, serum electrolytes, glucose and lipid profile, liver function tests, and thyroid-stimulating hormone. Hemodynamic monitoring is recommended to guide therapy in patients who have respiratory distress or clinical evidence of impaired perfusion in whom the adequacy or excess of intracardiac filling pressures cannot be determined from clinical assessment. Chest Pain Chest pain (Chapter 45) may be mediated by myocardial ischemia related to underlying coronary artery disease or increased wall stress that is proportional to the degree of left ventricular dilation. Left ventricular hypertrophy may cause chest pain from a mismatch between oxygen supply and oxygen demand. Patients with amyloid heart disease can have chest pain owing to transient ischemia caused by deposition of amyloid protein in the medial layer of myocardial arterioles. Cardiac Cachexia As heart failure progresses, patients may develop constitutional symptoms, including nausea, vomiting, anorexia, abdominal pain, and muscle wasting. Patients with significant hepatic congestion may develop right upper quadrant abdominal pain and jaundice that can be difficult to distinguish clinically from gallbladder disease or other abdominal conditions (Chapter 146). In patients with advanced cardiogenic shock (Chapter 99), severe abdominal pain can be a particularly ominous sign of abdominal ischemia (Chapter 134). Cognitive Dysfunction and Mood Disorders Paroxysmal nocturnal dyspnea is acute, severe shortness of breath that awakens the patient from sleep. Paroxysmal nocturnal dyspnea usually occurs about 1 hour after the patient lies in a recumbent position and subsides with sitting or standing. Paroxysmal nocturnal dyspnea results from increased venous return and the mobilization of interstitial fluid from the splanchnic circulation and lower extremities, with accumulation of alveolar edema. Paroxysmal nocturnal dyspnea is relatively uncommon but almost always represents severe heart failure, and it appears to be associated with increased mortality. Cognitive dysfunction (Chapter 374) is common, particularly in elderly heart failure patients. Confusion can be a manifestation of worsening heart failure related to relative hypotension or precipitated by medications used to treat heart failure such as a -blocker. Although intrinsic brain function itself is not affected in most patients with heart failure, cerebral hypoperfusion in advanced heart failure can cause memory impairment, limited attention span, and altered mentation. Depressive symptoms (Chapter 369) occur in up to 25% of patients with heart failure. Depressive symptoms can be detected by simple questions such as the Patient Health Questionnaire depression module (see Chapter 21), which has an 80% predictive value for depression and is associated with worse outcomes in heart failure patients. Sleep Disorders Fatigue Fatigue occurs in more than 90% of patients with heart failure. Although nonspecific and difficult to quantify, it can be an occult and troublesome manifestation of heart failure. Sleep-disordered breathing is observed in upward of 70% of heart failure patients and is associated with increased morbidity and mortality. Patterns of sleepdisordered breathing include obstructive sleep apnea and central sleep apnea/ Cheyne-Stokes respiration (Chapter 80). Patients may have both types, and the relative proportion of each type varies with the severity of heart failure and its treatment. Nocturnal rostral fluid movement from the lower extremities of heart failure patients may worsen obstructive sleep apnea. Central sleep apnea is due in part to the instability of the ventilatory control systems in heart failure. Symptoms of sleep-disordered breathing (Chapter 377) include hypersomnolence, choking or gasping during sleep, recurrent awakenings, unrefreshing sleep, daytime fatigue, and impaired concentration or memory. The symptoms may be difficult to distinguish from other symptoms of heart failure, including unrefreshing sleep due to orthopnea and paroxysmal nocturnal dyspnea. Preliminary data suggest that diagnosis and treatment of sleep-disordered breathing with positive-pressure ventilation can improve quality of life in some patients with heart failure, but it does not reduce mortality. A1 the use of adaptive servo-ventilation increases mortality and should be avoided in this patient population. These findings are more common in patients with acute pulmonary edema due to sudden decompensation from an inciting event. Fluid may also accumulate in the pleural space related to the increased transudation of fluid and impaired lymphatic drainage in the setting of elevated systemic venous pressures (Chapter 92). The clinician should listen and percuss for the possible presence of pleural effusions (Chapter 92), which tend to lateralize to the right side owing to the greater surface area of the lungs and the position of the diaphragm. The cardiac examination is the cornerstone of the evaluation of the patient with heart failure. Visual inspection and palpation may reveal a right ventricular heave, suggestive of right ventricular dysfunction and underlying pulmonary hypertension. The location, size, and duration of the point of maximal impulse against the chest wall may provide details related to the degree of left ventricular dilation; the impulse is typically laterally displaced in the setting of left ventricular enlargement and may be sustained in the setting of left ventricular hypertrophy. Auscultation of the heart sounds provides important information related to the underlying rhythm and frequency of ectopic beats. Auscultation of a loud P2 or the ability to hear a P2 beyond the pulmonic listening area suggests pulmonary hypertension. The presence (or worsening) of valvular disorders (Chapter 66) can be characterized for their potential contribution to cardiac dysfunction. An S4 gallop is common in patients who have ischemic heart disease and hypertension, and it is more likely indicative of diastolic dysfunction. Pericardial effusions (Chapter 68) may also occasionally occur in the setting of heart failure, particularly in inflammatory cardiomyopathies. Cardiac Examination Physical Examination A carefully performed physical examination is critical to make an accurate diagnosis, to assess comorbid conditions, and to estimate prognosis. Patients with severe symptoms may be pale or diaphoretic and unable to speak in complete sentences. In extreme circumstances, they may be unable to lie recumbent in bed because of severe dyspnea. The heart rate may be elevated (>100 beats per minute), and premature ventricular beats or atrial arrhythmias are common. Approximately 30% of heart failure patients have atrial fibrillation (Chapter 58). Pulsus alternans (alternating amplitude of successive beats) is an uncommon sign but is virtually diagnostic for advanced heart failure. Blood pressure is most commonly normal or high, but it may be low (systolic blood pressure <90 mm Hg) in advanced lowoutput heart failure. Blood pressure has historically been identified as an important prognostic marker.

The main concern for these patients is pharyngocutaneous fistula (a salivary leak from the pharyngeal anastomosis) medications for factor 8 cheap lumigan 3 ml without prescription. Neck dissection carries additional specific risks to the internal jugular vein xanax medications for anxiety buy lumigan 3ml without prescription, accessory nerve symptoms of depression buy generic lumigan 3 ml, hypoglossal nerve medicine 666 order lumigan 3 ml, marginal mandibular nerve treatment quinsy discount 3 ml lumigan visa, vagus nerve and thoracic duct (leading to chyle leak) medicine 524 buy lumigan 3ml low price. Once the laser has transected through the tumour to reveal normal unaffected tissue at the deep margin, the surgeon completes the resection at that depth and the tumour is excised in anterior and posterior halves. The tumour is orientated and marked for the histopathologist before being formalin fixed. This means that the affected tissue has been subject to chronic local irritation (or may be a local manifestation of a systemic disease) and is at an increased risk of cancerous transformation [15,16]. The risk factors for developing this are not as clearly defined as in head and neck cancer, but are thought to include tobacco use, alcohol, vocal abuse and perhaps laryngopharyngeal reflux [15]. Management There are different grading systems in use for categorisation, management and prognostication Table 11. Patients diagnosed with laryngeal dysplasia should be managed by clinicians routinely involved with managing patients with head and neck cancer or by designated laryngologists. This risk is higher in those with severe dysplasia (up to 30%) compared to mild dysplasia [4,21]. The role of laryngopharyngeal reflux is unclear, but there is some limited evidence that the incidence of reflux is high in patients with premalignant disease [22]. Follow-up these patients require long-term follow-up akin to patients who have been treated for laryngeal cancer to observe any potential transformation. Patients should be educated as to the symptoms of malignancy (see earlier) so as to encourage early presentation of any tumour. History Hoarseness is typically constant and of particular distress to women, as it tends to result in a deeper voice. Management Conservative measures include smoking cessation, anti-reflux medication, and speech and language therapy. Improvement of voice is unlikely without cessation of exposure to tobacco smoke, despite speech therapy input. Vocal cord polyps Aetiology the aetiology of polyps arising from the vocal cords is not well understood. Mucous secreting glands are rarely seen at the glottis, and histological findings tend to show epithelial hyperplasia, oedema, vessel proliferation and hyperkeratosis. History the hoarseness is often preceded by an acute episode of vocal trauma (shouting, singing, etc. Management Surgery to excise the polyp, either with cold steel microdissection or transoral laser resection, is required to improve the dysphonia, alongside attention to the aforementioned clinical factors that may be considered contributory. Voice therapy to prevent any triggers may be of use and can be commenced preoperatively and continued afterwards. Vocal cord nodules Aetiology Nodules of the vocal cords are benign mucosal lesions that typically occur bilaterally at the midpoint of the membranous vocal cord (the posterior third of the vocal cord is the vocal process of the arytenoid cartilage). This site represents the maximal amplitude of the mucosal wave and is therefore subject to maximal phono-traumatic force [25]. Disproportionately high mechanical shear on the free edge of the vocal cord damages the superficial layer of the lamina propria and results in micro-vascular changes and subsequent epithelial hyperplasia and hyalinisation. A social and occupational history is essential to elucidate the voice misuse factors. Paediatric laryngeal papillomatosis can cause florid lesions to develop and can prove to be fatal due to airway obstruction if not managed expediently. However, monitoring and recording of disease site and status is recommended using photography, especially to assess disease activity over time. Laryngeal granulomas Aetiology Laryngeal granulomas are benign, chronic, inflammatory lesions arising in the posterior cartilaginous third of the vocal fold (the vocal process) [27]. These lesions are usually thought to arise as a result of trauma or irritation of the posterior glottis. This includes reflux of gastric contents into the laryngopharynx; trauma from endotracheal intubation is also considered an aetiological factor. History these can present with hoarseness, pain, cough or a globus-type sensation. Symptoms of reflux may be present, and a history of recent intubation is important to elicit. Laryngeal granulomas are unilateral, pale swelling often with overlying ulceration. Investigation A biopsy is often required due to the variable appearance to exclude cancer. Management Where the diagnosis is suspected but biopsy has been undertaken, intra-granuloma injection of steroid can be administered. These include the lower oesophageal sphincter, oesophageal peristalsis, saliva, gravity, and the upper oesophageal sphincter. History the most common symptoms are: Disease may be lifelong and recurrence is expected. Surgery tends to be conservative, in terms of always opting to preserve laryngeal structures and attempting to minimise scarring. Disease activity tends to regress spontaneously over a number of years but is highly variable. The same disease in adults tends to be less florid and presents a much-reduced risk to airway patency. Bevacizumab (a monoclonal antibody) has been described in small case series as an effective treatment [31]. Hoarseness (variable, worse in the morning) Excessive throat clearing Coughing Globus pharyngeus Belafsky et al. However, there is not a strong correlation between clinical findings and response of symptoms to antireflux treatment. Hoarseness Throat clearing Excess mucus/postnasal drip Difficulty swallowing fluids, solids or tablets Coughing after eating/lying down Breathing difficulties or choking episodes Cough Sensation of lump in throat Burning, heartburn, chest pain, indigestion or acid coming up (reflux) Total: 0 = no problem 5 = severe problem Table 11. Subglottic oedema Ventricular obliteration 0 = absent 2 = present 0 = absent 2 = partial 4 = complete 0 = absent 2 = arytenoid 4 = diffuse 0 = absent 1 = mild 2 = moderate 3 = severe 4 = polypoid 0 = absent 1 = mild 2 = moderate 3 = severe 4 = obstructive 0 = absent 1 = mild 2 = moderate 3 = severe 4 = obstructive 0 = absent 2 = present 0 = absent 2 = present Management A clear explanation of the underlying cause is required. Lifestyle changes include: Weight loss Smoking cessation Dietary changes (avoiding trigger foods or eat Alcohol avoidance Erythema Vocal fold oedema ing late at night) Laryngeal oedema Posterior commissure hypertrophy Medical management involves regular alginates with or without proton pump inhibitors. In those with strong clinical diagnosis of acid ref lux, H2-receptor antagonist can be added. It is generally regarded as a plaque present on a mucous membrane which cannot be rubbed/scraped off. This is a relatively low risk, and the relationship of clinical risk factors to this risk is not clear. Where there is low clinical concern and no histological evidence of dysplasia, patients can likely be discharged with education on seeking rereferral in the advent of recurrent/deteriorating symptoms. Smoking, alcohol drinking and cancer risk for various sites of the larynx and hypopharynx. Synchronous cancers in patients with head and neck cancer: Risks in the era of human papillomavirus-associated oropharyngeal cancer. It is often used incorrectly to imply a diagnosis, such as dysplasia, but this can only be confirmed histologically. At the point of histological diagnosis, the term leukoplakia should no longer be used. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. Outcomes of elective total laryngectomy for laryngopharyngeal dysfunction in disease-free head and neck cancer survivors. Experience in endoscopic laser surgery of malignant tumours of the upper aero-digestive tract. Criteria for grading in the Ljubljana classification of epithelial hyperplastic laryngeal lesions. A study by members of the Working Group on Epithelial Hyperplastic Laryngeal Lesions of the European Society of Pathology. The risk and interval to malignancy of patients with laryngeal dysplasia; a systematic review of case series and meta-analysis. Laryngeal precancer: A review of the literature, commentary, and comparison with oral leukoplakia. Laryngeal dysplasia, demographics, and treatment: A singleinstitution, 20-year review. Characterization of laryngopharyngeal reflux in patients with premalignant or early carcinomas of the larynx. Consensus statement by otorhinolaryngologists and pathologists on the diagnosis and management of laryngeal dysplasia. The prevalence and factors associate with vocal nodules in general population: Cross-sectional epidemiological study. High-dose sublesional bevacizumab (avastin) for pediatric recurrent respiratory papillomatosis. During speech, this is partially obscured by the soft palate, which then completely occludes the space during normal swallowing, due to the action of the muscles surrounding the torus, which then act to open the Eustachian tube for middle ear pressure equalisation. Hence, the logic behind swallowing repeatedly on the descent of a flight to raise the pressure in the middle ear to that of the surrounding environment. Lymphatic drainage Lymph fluid drains in a medial and lateral direction from the nasopharynx. Drainage medially is to the central retropharyngeal lymph nodes (the echelon lymph node) and laterally to the lateral retropharyngeal, and through the superior constrictor to the deep cervical and the posterior triangle lymph nodes (see Box 12. Innervation the dorsum sellae of the sphenoid separates the nasopharynx from the sphenoid sinus, which in turn is medial to the cavernous sinuses, home to the internal carotid arteries and the ophthalmic and maxillary nerves, V1 and V2. Boundary Anterior Anatomy Posterior choanae (divided by a strip of bone made up of the perpendicular plate of the ethmoid superiorly and the vomer inferiorly). The basal aspect of the sphenoid, the dorsum sellae joins the clivus of the basal aspect of the occiput in a postero-inferior graduation. The torus tubarius (formed by the cartilaginous Eustachian tube), anterior to the torus opens the Eustachian tube. Inferior to the torus, an anterior fold contains the salpingopalatine muscle and posteriorly a fold contains the salpingopharyngeus muscle. This is thought to be partly related to genetic factors and partly to the dietary predilection for salted fish [2,3]. This is located in posterolateral pharyngeal recess posterosuperior to the torus tubarius. This allows space for a tumour to grow to considerable size before it is symptomatic. Due to this, often patients will present with a neck mass as their primary complaint. Given the proximity to the skull base, sphenoid sinus and parapharynx, tumours are often locally advanced at presentation as well. Surgery is hence reserved for recurrence or residual disease and is associated with significant postoperative morbidity. Intensity modulation has improved the morbidity associated with primary radiation therapy [9]. Numerous surgical approaches to the nasopharynx have been described (see Table 12. It is a challenging area to gain optimal access to and the approach will be dictated by tumour size and extension, patient fitness for surgery, and habitus as well as surgeon experience. These include lateral rhinotomy, midfacial degloving, the Caldwell-Luc approach, transpalatal, Le Fort I and the infratemporal fossa approach. Those with intraorbital or intracranial extension Examination Flexible nasoendoscopy is key to evaluating the nasopharynx. Otoscopy may reveal an effusion, and neck examination is essential for assessment of potential nodal disease. An open medial maxillectomy can be used for tumours not extending into the lateral infratemporal fossa and is approached by a midfacial degloving. The sequence of bony cuts is: 1 Osteotomy below inferior orbital rim 2 Osteotomy antrum to vestibule 3 Osteotomy across frontal process of maxilla 4 Osteotomy along floor of nose 5 Osteotomy through lacrimal bone 6 Osteotomy vertically through posterior end of medial antrum A Le Fort I procedure is an alternative whereby the palate is downfractured following a horizontal osteotomy above the maxillary dental roots after pre-plating of the maxilla. This should be avoided in adolescents due to the impact on subsequent midfacial growth. Tumour size Smaller Surgical approaches Endoscopic transnasal Transpalatal Transantral Lateral rhinotomy Midfacial degloving Maxillary swing Le Fort I osteotomy Infratemporal fossa approach (Fisch type C) Transmaxillary, transpalatal Transmandibular, transpalatal Craniofacial approach Larger zygoma in the preauricular area and extends behind the hairline. Anteriorly, a fat pad on the muscle protects the superior branch of the facial nerve. From the posterior margin of the muscle, incise the muscle 1 cm below the superior temporal line down to deep fascia in order to mobilise the muscle inferiorly. Remove the zygomatic arch after pre-plating in order to facilitate reconstruction on completion of tumour dissection.

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In about 5% of cases 911 treatment for hair discount lumigan 3 ml with amex, Wilms tumor arises in three congenital syndromes at an early age and often bilaterally medications ms treatment buy generic lumigan line. Nephrogenic rests (small foci of persistent primitive blastemal cells medicine 018 buy lumigan 3 ml fast delivery, which are precursor lesions of Wilms tumors) are seen in the renal parenchyma adjacent to bilateral Wilms tumors medicine escitalopram generic 3 ml lumigan fast delivery. Blastemal component: It consists of small symptoms 4 months pregnant lumigan 3 ml free shipping, round to oval blue cells with scanty cytoplasm medications ok during pregnancy buy generic lumigan 3ml. Immature stromal (mesenchymal) component: It consists of undifferentiated fibroblast-like spindle cells or myxoid tissue. Immature epithelial component: Epithelial cells show differentiation in the form of small abortive (embryonic) tubules or immature glomeruli. Classically, the tumor shows triphasic (all three cell types) combination, although the percentage of each component varies. Occasionally, they contain only two elements (biphasic) or even only one (monophasic). Clinical Features Most children present with an abdominal mass, when large it may extend across the midline and down into the pelvis. Others: Hematuria, pain in the abdomen, intestinal obstruction, and pulmonary metastases are other patterns of presentation. Prognosis Clinical parameter: Children younger than 2 years of age have a better prognosis. Histological parameter: n Invasion of the renal capsule is associated with poor prognosis. Most of the epithelial tumors of the bladder are composed of urothelial (transitional) cell type and are known as urothelial (transitional) tumors. Many of urothelial tumors are multifocal and are most commonly seen in the bladder. But they may develop at any site where there is urothelium, from the renal pelvis to the distal urethra. Noninvasive papillary tumors: They show a range of atypical changes in the urothelial cells, and are graded according to their biological behavior. Epidemiology More common in developed than in developing countries, and in urban than in rural dwellers. Risk Factors of Urothelial Carcinoma Cigarette smoking: It is the most important risk factor and risk depends on the amount of smoking and smoking habits. Industrial exposure to arylamines: the aromatic amines (naphthylamine) and azo dyes that were widely used in the past in the aniline dye and rubber industries are associated with bladder carcinoma. More than three-fourth of the cancers are squamous cell type, and remaining urothelial type. Cyclophosphamide: It produces hemorrhagic cystitis, and increases the risk of carcinoma of the bladder. Radiation: Previous exposure of the bladder to irradiation (for other pelvic malignancies). Genetic Alterations in Urothelial Carcinoma Chromosome 9 monosomy or deletions: It frequently occurs in superficial papillary tumors and rarely in noninvasive flat tumors. General morphological features of urothelial tumors are: Site: Most urothelial tumors arise from the lateral or posterior walls at the bladder base. Size varies from small (less than 1 cm in diameter) to large masses (up to 5 cm in diameter). Microscopy Noninvasive Urothelial Lesions Urothelial papilloma It is uncommon (<4% of noninvasive bladder neoplasms) and consists of two histological forms: Classical exophytic papilloma and inverted papilloma. They have a central core of loose fibrovascular tissue covered by urothelium that is microscopically have normal appearance and thickness. Inverted papillomas these are rare and appear as nodular lesion in the mucosa of the urinary bladder, usually in the trigone area. They consists of invagination of inter-anastomosing cords of normal transitional epithelium, down into the lamina propria. The lining urothelium is thicker and/or more cellular than seen in normal urothelium and in papilloma. The nuclei may be slightly enlarged and more crowded relative to normal urothelial nuclei. The chromatin is uniformly even, without the scattered hyperchromatic nuclei seen in low-grade papillary carcinoma. Noninvasive Papillary Urothelial Carcinoma Definition: Papillary urothelial carcinoma is a papillary urothelial neoplasm with some cytological and architectural disorder seen at low to intermediate magnification. The lining urothelium consists of cytologically malignant cells is of variable thickness. Gross: On cystoscopy, it appears as areas of erythema (may be focal, multifocal, or diffuse) and may be difficult to identify. Cytological features Cells: Appearance of individual tumour cells may be quite variable. Nuclei: Large pleomorphic and hyperchromatic nuclei with one or more irregular nucleoli. Infiltrating Urothelial Carcinoma It is common malignant neoplasm of the urinary bladder. Definition: Infiltrating urothelial carcinoma is characterized by divergent differentiation of lining urothelial cells and invasion beyond the basement membrane. Microscopy: Remarkable for its diversity of morphological manifestations and can present with a wide range of architectural patterns. In larger nests, the tumour cells may show stratified architecture, with the nuclei lined up perpendicular to the basement membrane and with some maturation towards the centre recapitulating the structure of urothelium. This can produce a squamoid appearance, which should be distinguished from true squamous differentiation. Since significant outcome differences have been found between low- and high-grade invasive tumors, it is necessary to identify the grade of tumor. Tumors with the more infiltrative cords and single cell patterns have worse prognosis. Clinical Course of Bladder Cancer Painless hematuria: Sometimes, it may be the only clinical feature. Complications: When the tumor obstructs the ureteral orifice, it may lead to pyelonephritis or hydronephrosis. Recurrences: Urothelial tumors, irrespective of their grade may recur, usually at different sites than the original tumor. Prognosis: It depends on the histologic grade and the stage at the time of diagnosis. Laboratory diagnosis: Cytologic examinations of urine for malignant cells and biopsy of the tumor. Various components of normal urine with their reference value is presented in Table 20. Mother also complained that he passes dark brown (red or cola) colored (smoky) urine and the urine output was reduced (oliguria). On enquiry, mother informed that about 2 weeks back the child had upper respiratory tract infection. Describe the light microscopy, immunofluorescence and electron microscopic findings. Two weeks back the child had upper respiratory tract infection, favors poststreptococcal disease. Describe the light microscopy, immunofluorescence and electron microscopic findings (refer page 665). Case 2 History: A 6-year-old child was brought to the hospital for the complaint of increased puffiness around his eyes and he has become less active over the past 10 days. Examination: On physical examination, the boy had facial puffiness which is more prominent around his eyes and also had swelling of both ankles. Describe the light microscopic, electron immunofluorescence findings in this condition. Steroid-responsive proteinuria in a child is feature nephrotic syndrome due to minimal change disease and is the most common cause for nephrotic syndrome in children. The subsequent fall in plasma oncotic pressure leads to redistribution of extracellular fluid to the interstitial compartment, producing edema. Nephrotic syndrome should be distinguished from nephritic syndrome (characterized by hematuria, uraemia and a degree of renal failure). However, on electron microscopy, shows effacement of podocyte foot processes (fusion of podocyte foot processes) in the glomerulus and is the only pathologic finding found on electron microscopy. Case 3 History: A 57-year-old female admitted to the hospital with a history of increasing back pain and fevers for the last 3 days. There is no history of burning micturition or colicky abdominal pain or chronic ingestion of analgesics. On palpation, there is tenderness over the left loin without any tenderness on anterior abdomen. Diabetic and immunocompromised patients are predisposed to urinary tract infection. The symptoms of increasing back pain and fevers without burning micturition suggests an upper tract rather than lower urinary tract infection. Urine for culture and sensitivity will help in identify the causative organism and sensitivity of the organism to the antibiotics. Case 4 History: A 29-year-old female complains of fever and burning sensation when passing urine for the last 3 days. She also complains that she voids urine more often than usual without any sense of urgency and suffering from severe lower back pain that started 1 day back. She has never had this problem in the past and she is not taking any regular medications. There is no history of vaginal discharge or urinary incontinence except an episode of cystitis 3 months ago. Abdominal examination shows suprapubic tenderness and marked tenderness in both loins. Acute pyelonephritis is much more common in females than males and occurs due to ascending bacterial infection from lower to upper urinary tract. For other causative organisms include other enteric gram-negative bacteria such as Proteus, Klebsiella, Enterobacter and Pseudomonas species. Case 5 History: A 65-year-old male complaints of vague history of generalized weakness anorexia, bony pains and impotence for the past few months. He informs that he had hypertension for the past 20 years which was poorly controlled. Examination: Physical examination reveals conjunctival pallor and his blood pressure is 180/100 mm of Hg. The renal ultrasound shows small kidneys bilaterally, which suggests that this condition is long-standing. It develops due to progressive impairment of renal function with a decrease in the number of functioning nephrons. The symptoms of generalized weakness anorexia, bony pains and impotence are the consequences of complications of chronic kidney disease. It is indicative of severe renal damage (chronic kidney disease) with disturbance of both the concentrating and diluting abilities of the kidney. Penile Intraepithelial Neoplasia Definition: Penile intraepithelial neoplasia (PelN) is a histological alteration of the penile squamous epithelium characterized by dysplastic changes with an intact basement membrane. It was also termed as squamous cell carcinoma in situ, erythroplasia of Oueyrat and Bowen disease. These immature cells are small, monotonous and are basophilic with round to oval nuclei; inconspicuous nucleoli; and scant cytoplasm. There is prominent cellular pleomorphism, koilocytosis (characterized by multinucleation, nuclei with irregular contours, perinuclear halo, and dyskeratosis), and mitoses. They have a spiking surface with koilocytic changes, whereas the lower half of the epithelium is mainly consisting of small basaloid cells. When the atypia involves the full-thickness of the epithelium, it constitutes carcinoma in situ. In contrast to Bowen disease, it occurs at a younger age and the lesions are multiple (rather than solitary) reddish-brown papular lesions. It is usually associated with lichen sclerosus and other chronic inflammatory conditions. Papillary lesions: They appear similar to condylomata acuminata and usually produce a cauliflower-like fungating mass. Flat lesions: They appear as areas of epithelial thickening accompanied by fissuring of the mucosal surface. Microscopic features are similar to squamous cell carcinoma in other regions of the body (refer page 868). Spread and Metastases v Local spread: It can occur from one epithelial compartment to the other and from superficial to deep anatomical levels. Since carcinomas of penis are often associated with secondary infection, it commonly produces enlargement of inguinal nodes. Lymph node metastases are usually not common in exophytic tumors whereas it is common in deeply invasive tumors. Penis: Squamous cell carcinoma occurs on the glans or inner surface of the prepuce. Verrucous carcinoma: Exophytic well-differentiated variant of squamous cell carcinoma which has low malignant potential.

An epidemiologic survey of the general adult population in the United States demonstrated 12-month and lifetime prevalences of alcohol use disorder of approximately 13 medications side effects prescription drugs lumigan 3 ml generic. Alcohol use disorder was generally more prevalent in men treatment tmj buy discount lumigan 3ml, whites and Native Americans treatment yeast infection men purchase genuine lumigan on line, and younger individuals medications on a plane buy cheap lumigan 3 ml. Severe alcohol use disorder was more prevalent in individuals with the lowest income level treatment 2011 order lumigan online pills. In addition symptoms upper respiratory infection purchase on line lumigan, individuals with alcohol use disorder were more likely to experience comorbid substance use disorder related to other substances, and psychiatric comorbidity, especially depression, bipolar disorder, antisocial disorder, and borderline personality disorder. One study found that first marriage to a spouse with no lifetime alcohol use disorder is associated with a substantial reduction in risk for alcohol use disorder. Overall, although these and other data identify patient characteristics associated with alcohol use disorders, it should be emphasized that it is prevalent throughout all sociodemographic groups, and all individuals should be screened carefully. The "skid row" stereotype of the alcohol-dependent patient is much more the exception than the rule. The prevalence of alcohol use disorders is higher in most health care settings than it is in the general population because alcohol problems often result in treatment-seeking behaviors. The prevalence of problem drinking in general outpatient and inpatient medical settings has been estimated between 15 and 40%. These data strongly support the need for physicians to screen all patients for alcohol use disorders. Alcohol is absorbed rapidly into the blood stream from the stomach and intestinal tract. Because women have lower levels of gastric alcohol dehydrogenase, the enzyme primarily responsible for metabolizing alcohol, they experience higher blood alcohol concentrations than do men who consume similar amounts of ethanol per kilogram of body weight. The absorption of alcohol can be affected by other factors, including the presence of food in the stomach and the rate of alcohol consumption. A genetic variation in a significant proportion of the Asian population alters the structure of an aldehyde dehydrogenase isoenzyme, resulting in the development of an alcohol flush reaction, which includes facial flushing, hot sensations, tachycardia, and hypotension. Glycinuric and serotoninergic receptors also are thought to be involved in the interaction between alcohol and the brain. The phenomena of reinforcement and cellular adaptation are thought, at least in part, to influence alcohol-dependent behaviors. Alcohol is known to be reinforcing because withdrawal from ethanol and ingestion of ethanol itself are known to promote further alcohol consumption. After chronic exposure to alcohol, some brain neurons seem to adapt to this exposure by adjusting their response to normal stimuli. This adaptation is thought to be responsible for the phenomenon of tolerance, whereby increasing amounts of alcohol are needed over time to achieve desired effects. Although much has been learned about the variety of effects alcohol can have on various brain receptors, no single receptor site has been identified. A number of neuropsychological disorders are seen in association with chronic ethanol use, including impaired short-term memory, cognitive dysfunction, and perceptual difficulties. Direct liver toxicity may be among the most important consequences of acute and chronic alcohol use (Chapter 143). A variety of histologic abnormalities ranging from inflammation to scarring and cirrhosis have been described. Alcohol also has substantial negative effects on the heart and cardiovascular system. Direct toxicity to myocardial cells frequently results in heart failure (Chapter 52), and chronic heavy alcohol consumption is considered to be a major contributor to hypertension (Chapter 70). Other organ systems that experience significant direct toxicity from alcohol include the gastrointestinal tract (esophagus, stomach), immune system (bone marrow, immune cell function), and endocrine system (pancreas, gonads). The acute effects seen most commonly are alcohol intoxication and alcohol withdrawal. The clinical manifestations of alcohol intoxication are related directly to the blood level of alcohol. The symptoms of mild alcohol intoxication in nontolerant individuals typically occur at blood alcohol levels of 20 to 100 mg/dL and include euphoria, mild muscle incoordination, and mild cognitive impairment. At higher blood alcohol levels (100 to 200 mg/dL), more substantial neurologic dysfunction occurs, including more severe mental impairment, ataxia, and prolonged reaction time. Individuals with blood alcohol levels in these ranges can be obviously intoxicated, with slurred speech and lack of coordination. These effects progress as the blood alcohol level rises to higher levels, to the point at which stupor, coma, and death can occur at levels equal to or greater than 300 to 400 mg/dL, especially in individuals who are not tolerant to the effects of alcohol. The usual cause of death in individuals with very high blood levels of alcohol is respiratory depression and hypotension. Alcohol withdrawal can occur when individuals decrease their alcohol use or stop using alcohol altogether. Many individuals experience alcohol withdrawal without seeking medical attention, whereas others require hospitalization for severe illness. This state is thought to be the result of adaptive neurologic mechanisms being unrestrained by alcohol, with an ensuing release of a variety of neurohumoral substances, including norepinephrine. The clinical manifestations of alcohol withdrawal include hyperactivity resulting in tachycardia and diaphoresis. More severe alcohol withdrawal can result in nausea and vomiting, which can exacerbate metabolic disturbances. Perceptual abnormalities, including visual and auditory hallucinations and psychomotor agitation, are common manifestations of more moderate to severe alcohol withdrawal. Grand mal seizures commonly occur during alcohol withdrawal, although they do not generally require treatment beyond the acute withdrawal phase. Tremor is typically among the earliest symptoms and can occur within 8 hours of the last drink. Symptoms of tremulousness and motor hyperactivity typically peak within 24 to 48 hours. Although mild tremor typically involves the hands, more severe tremors can involve the entire body and greatly impair a variety of basic motor functions. Perceptual abnormalities typically begin within 24 to 36 hours after the last drink and resolve within a few days. When withdrawal seizures occur, they are typically generalized tonic-clonic seizures and most often occur within 12 to 24 hours after reduction of alcohol intake. The most severe manifestation of the alcohol withdrawal syndrome is delirium tremens. This symptom complex includes disorientation, confusion, hallucination, diaphoresis, fever, and tachycardia. Delirium tremens typically begins after 2 to 4 days of abstinence, and the most severe form can result in death. Chronic Effects Acute manifestations, including intoxication and withdrawal, are generally stereotypical in their appearance and time course, but chronic manifestations tend to be more varied. Many patients with alcohol dependence may be without evidence of any chronic medical manifestations for many years. As time goes on, however, the likelihood that one or more of these manifestations will occur increases considerably. All major organ systems can be affected, but the primary organ systems involved are the nervous system, cardiovascular system, liver, gastrointestinal system, pancreas, hematopoietic system, and endocrine system (Table 30-2). Patients who drink are at risk for a variety of malignant neoplasms, such as head and neck, esophageal, colorectal, breast, and liver cancers (see individual chapters on those cancers). Excessive alcohol use often causes significant psychiatric and social morbidity that can be more common and more severe than the direct medical effects, especially earlier in the course of problem drinking. Alcohol Withdrawal Syndrome Nervous System In addition to the acute neurologic manifestations of intoxication and withdrawal, alcohol has major chronic neurologic effects. About 10 million Americans have identifiable nervous system impairment from chronic alcohol use. Individual predisposition to these disorders is highly variable and is related to genetics, environment, sociodemographic features, and gender; the relative contribution of these factors is unclear. Patients may present with mild to moderate short-term or long-term memory problems or may have severe dementia resembling Alzheimer disease (Chapter 374). The degree to which the direct toxic effect of alcohol is responsible for these problems or the impact of alcohol-related nutritional deficiencies is uncertain (Chapter 388). Individuals who have recurrent acute pancreatitis may develop chronic pancreatitis, which typically presents with chronic abdominal pain, malabsorption, weight loss, and malnutrition. Alcohol also causes a polyneuropathy that can present with paresthesias, numbness, weakness, and chronic pain (Chapters 388 and 392). As with the central nervous system, peripheral nervous system effects are thought to be caused by a combination of the direct toxicity of alcohol and nutritional deficiencies. A small proportion (<1%) of patients with alcohol dependence may develop midline cerebellar degeneration, which presents as an unsteady gait. Hematopoietic System Cardiovascular System the most common cardiovascular complications of chronic alcohol consumption are cardiomyopathy, hypertension, and supraventricular arrhythmias. In fact, an epidemiologic study demonstrated that excessive alcohol use increased the risk of heart failure, myocardial infarction, and atrial fibrillation to a similar degree as other established "traditional" risk factors. It is the most common cause of nonischemic cardiomyopathy in Western countries, accounting for about 45% of cases. Like other causes, alcoholic cardiomyopathy also responds to conventional treatments of heart failure (Chapter 53). Abstinence from alcohol can result in significant improvement in cardiomyopathy in some patients. Increasing levels of alcohol consumption also are associated with increasing levels of systolic and diastolic hypertension (Chapter 70). The most common arrhythmias associated with chronic alcohol use include atrial fibrillation and supraventricular tachycardia; these are seen commonly in the setting of acute intoxication and withdrawal (Chapter 58). Alcoholic cardiomyopathy also is associated with arrhythmias, in particular, ventricular arrhythmias (Chapter 59). The association between high levels of alcohol intake and increased cardiovascular mortality may be lessened in the presence of high physical activity. Factors that predispose to early liver disease include the quantity and duration of alcohol exposure, female gender, and malnutrition. The range of clinical manifestations includes acute fatty liver, alcoholic hepatitis, and cirrhosis (Chapter 143). Fatty liver associated with alcohol ingestion can be asymptomatic or associated with nonspecific abdominal discomfort; it generally improves with abstinence from alcohol. Alcoholic hepatitis can present as an asymptomatic condition identified through abnormalities in liver enzymes or as an acute episode with abdominal pain, nausea, vomiting, and fever. Patients with alcoholic hepatitis have particularly high levels of aspartate aminotransferase in the blood and elevated levels of -glutamyltransferase. Alcoholic hepatitis typically improves with abstinence from alcohol along with supportive care. Alcohol-related cirrhosis is a major cause of death in the United States (Chapter 145). Although patients are often asymptomatic, patients with more advanced cirrhosis may present with a variety of symptoms and signs, including jaundice, ascites, and coagulopathy which can benefit from management approaches tailored to this patient population. Cirrhosis also is associated with gastrointestinal bleeding from esophageal varices (Chapter 129). Although there is some controversy about the use of liver transplantation to treat patients with alcoholic cirrhosis, many believe that patients in established recovery are good candidates for liver transplantation (Chapter 145). The anemia that commonly is seen in patients with chronic alcohol problems can be multifactorial. Studies of selected inpatients with alcohol dependence showed the prevalence of anemia to range from about 10 to 60%. Gastrointestinal blood loss due to Mallory-Weiss tears (Chapter 126), alcoholic gastritis (Chapter 123), or esophageal varices (Chapters 126 and 144) may be a key factor, and many patients develop subsequent iron deficiency. Dietary folate deficiency can be associated with megaloblastic anemias (Chapter 155). Alcohol also has a direct toxic effect on the bone marrow, which can lead to sideroblastic anemia that resolves after abstinence. Alcohol can suppress megakaryocyte production and cause thrombocytopenia, which may manifest as ecchymoses or bleeding (Chapter 163); the thrombocytopenia is particularly sensitive to abstinence, with platelet counts usually rebounding or returning to normal within 5 to 7 days after cessation of alcohol intake. Alcohol-related immune dysfunction, as evidenced by decreased production and function of white blood cells and derangement in humoral and cell-mediated immunity, partly explains why alcohol-dependent individuals are at higher risk for infectious diseases, such as pneumonia and tuberculosis. Malignant Neoplasms Liver Alcohol intake has been associated with numerous cancers,7 including cancer of the upper digestive, respiratory, and liver malignant neoplasms. The amount of alcohol exposure that increases cancer risk may vary widely and may not correlate with what might be considered to be "safe" levels of alcohol consumption. Concerning specific cancers, alcohol use is associated with squamous cell carcinomas of the esophagus (Chapter 183) and of the head and neck (Chapter 181). Either heavy alcohol use or smoking individually increases the rate of oropharyngeal cancer by about six or seven times that of the general population, whereas the rate for people with both risk factors is about 40 times that of the general population. Patients with alcohol-induced liver disease who also have a history of hepatitis B or C are at particularly increased risk for hepatocellular carcinoma (Chapter 186). Chronic alcohol use also has been associated with malignant neoplasms of the breast (Chapter 188), prostate (Chapter 191), pancreas (Chapter 185), cervix (Chapter 189), lung (Chapter 182), and colon (Chapter 184). Women who have more than one or two alcoholic drinks per day may increase their breast cancer risk 1. Hormonal mechanisms and direct carcinogenic effects of alcohol have been postulated as causes of this association. The association of cervical cancer with alcohol dependence may be due to alcohol-associated high-risk sexual behaviors that are thought to increase the risk for cervical cancer. Other Medical Issues Gastrointestinal Disease Chronic alcohol use is associated with a variety of esophageal problems, including esophageal varices, Mallory-Weiss tears, and squamous cell carcinoma of the esophagus (Chapter 183). The risk for squamous cell carcinoma is increased further in patients who smoke tobacco and drink alcohol (Chapter 183). Patients with these problems can present with difficulty swallowing, chest pain, gastrointestinal blood loss, and weight loss. Acute alcoholic gastritis typically presents with abdominal discomfort, nausea, and vomiting (Chapter 123).