Muhammad A. Munir, MD

• Director
• Department of Inventional Pain Management
• Southwest Ohio Pain Institute
• West Chester, Ohio

One study of Danish patients exposed to Thorotrast found that the risk for bile duct and gallbladder cancers was increased 14-fold and that for liver cancers more than 100-fold (Andersson and Storm erectile dysfunction water pump cheap super avana 160mg fast delivery, 1992) best erectile dysfunction pills 2012 cheap super avana 160 mg mastercard. Furan is the only chemical known to cause cholangiocarcinomas experimentally in rats (Hickling et al erectile dysfunction causes n treatment buy super avana 160mg with amex. The molecular pathogenesis of hepatocellular carcinoma is complex and poorly understood erectile dysfunction when cheating 160 mg super avana mastercard. The malignant transformation of hepatocytes occurs as a result of increased cell turnover due to chronic liver injury erectile dysfunction at the age of 18 super avana 160mg on-line, persistent inflammation erectile dysfunction doctors naples fl buy generic super avana online, regeneration, and cirrhosis (Wands and Moradpour, 2006). An overall imbalance between stimulation of proliferation and inhibition of apoptosis in the liver leads to the survival and expansion of these preneoplastic cells (Fabregat et al. This concept is supported by the observation that 30% of hepatocellular carcinomas show mutations in the tumor suppressor gene p53; the mutation rate is up to 70% in areas with high aflatoxin exposure (Wands and Moradpour, 2006). The functional inactivation of p53 by mutations prevents the induction of apoptosis. Because most chemotherapeutic agents require p53 to induce apoptosis in these cancer cells, hepatocellular carcinomas are mostly resistant to conventional chemotherapy (Bruix et al. It was shown that telomere dysfunction and chromosomal instability in combination with p53 mutations are critical for the progression from neoplasms to malignant carcinomas (Farazi et al. Because telomere dysfunction (shortening) limits the capacity of cancer cells to proliferate, the activity of the telomere-synthesizing enzyme telomerase is activated in advanced hepatocellular carcinomas (Satyanarayana et al. Many of these pathways may offer novel therapeutic targets to prevent or eliminate hepatocellular carcinoma (Aravalli et al. Location and specialized processes for uptake and biliary secretion produce higher exposure levels in the liver than in other tissues of the body, and strikingly high levels within certain types of liver cells. Then, the abundant capacity for bioactivation reactions influences the rate of exposure to proximate toxicants. Subsequent events in the pathogenesis appear to be critically influenced by responses of sinusoidal cells and the immune system. Discussion of the evidence for the contributions of these factors to the hepatotoxicity of representative compounds requires commentary about mechanistic events. In vitro systems using tissue slices, the isolated perfused liver, primary isolated cultured liver cells, and cell fractions allow observations at various levels of complexity without the confounding influences of other systems. Some hepatoma cell lines with maintained drug metabolizing enzyme expression can be useful to study mechanisms of drug hepatotoxicity (Guguen-Guillouzo et al. Models using cocultures or chemicals that inactivate a given cell type can document the contributions and interactions between cell types. Whole animal models are essential for assessment of the progression of injury and responses to chronic insult and the confirmation of in vitro results. Use of chemicals that induce, inhibit, deplete, or inactivate gene products can define roles of specific processes, although potential influences of nonspecific actions can confound interpretations. Application of molecular biology techniques for gene transfection or repression attenuates some of these interpretive problems. Gene knockout animals are extremely useful models to study complex aspects of hepatotoxicity. However, it is critical that the relevance of in vivo systems for the human pathophysiology is being established. In addition, compensatory responses due to the loss of a specific gene always need to be considered when using gene knockout animals (Ni et al. Uptake and Concentration Hepatic "first pass" uptake of ingested chemicals is facilitated by the location of the liver downstream of the portal blood flow from the gastrointestinal tract. Lipophilic compounds, particularly drugs and environmental pollutants, readily diffuse in to hepatocytes because the fenestrated epithelium of the sinusoid enables close contact between circulating molecules and hepatocytes. Other toxins are rapidly extracted from blood because they are substrates for transporters located on the sinusoidal membrane of hepatocytes (Hagenbuch and Gui, 2008; Roth et al. Phalloidin and microcystin are illustrative examples of hepatotoxins that target the liver as a consequence of extensive uptake in to hepatocytes by sinusoidal transporters (Frimmer, 1987; Runnegar et al. Ingestion of the mushroom Amanita phalloides is a common cause of severe, acute hepatotoxicity in continental Europe and North America. Microcystin has produced numerous outbreaks of hepatotoxicity in sheep and cattle that drank pond water containing the blue-green alga Microcystis aeruginosa. An episode of microcystin contamination of the water source used by a hemodialysis center in Brazil led to acute liver injury in 81% of the 124 exposed patients and the subsequent death of 50 of these patients (Jochimsen et al. Microcystin contamination was verified by analysis of samples from the water-holding tank at the dialysis center and from the livers of patients who died. This episode indicates the vulnerability of the liver to toxicants regardless of the route of administration. Because of its dual blood supply from both the portal vein and the hepatic artery, the liver is presented with appreciable amounts of all toxicants in the systemic circulation. Subsequent studies found that cotreatment with substrates (eg, cyclosporin A, rifampicin) known to prevent the in vivo hepatotoxicity of phalloidin or microcystin would also inhibit their uptake in to hepatocytes by sinusoidal transporters for bile acids and other organic anions (Ziegler and Frimmer, 1984; Runnegar et al. Accumulation within liver cells by processes that facilitate uptake and storage is a determining factor in the hepatotoxicity of vitamin A and several metals. Vitamin A hepatotoxicity initially affects stellate cells, which actively extract and store this vitamin. Early responses to high-dose vitamin A therapy are stellate cell engorgement, activation, increase in number, and protrusion in to the sinusoid (Geubel et al. Hepatocytes contribute to the homeostasis of iron by extracting this essential metal from the sinusoid by a receptor-mediated process and maintaining a reserve of iron within the storage protein ferritin. Acute Fe toxicity is most commonly observed in young children who accidentally ingest iron tablets (Chang and Rangan, 2011). The cytotoxicity of free iron is attributed to its function as an electron donor for the Fenton reaction, where hydrogen peroxide is reductively cleaved to the highly reactive hydroxyl radical, an initiator of lipid peroxidation. Accumulation of excess iron beyond the capacity for its safe storage in ferritin is initially evident in the zone 1 hepatocytes, which are closest to the blood entering the sinusoid. Thus, the zone 1 pattern of hepatocyte damage after iron poisoning is attributable to location for (1) the preferential uptake of iron and (2) the higher oxygen concentrations that facilitate the injurious process of lipid peroxidation (Table 13-3). Chronic hepatic accumulation of excess iron in cases of hemochromatosis is associated with a spectrum of hepatic disease including a greater than 200-fold increased risk for liver cancer (Ramm and Ruddell, 2005). Therefore, hepatocytes contain high levels of phase I enzymes, which have the capacity to generate reactive electrophilic metabolites. In contrast, if the amount of the reactive metabolite exceeds the capacity of the hepatocyte to detoxify it, covalent binding to cellular macromolecules will occur and potentially result in cell injury (Park et al. However, an overdose can cause severe liver injury and even liver failure in experimental animals and in humans (Lee, 2004). Acetaminophen-induced mitochondrial oxidant stress and its influence on cellular signaling. In addition, excess N-acetyl cysteine is degraded and supports the mitochondrial energy metabolism (Sai to et al. This finding may apply to the potential interaction with other drugs and dietary chemicals. In addition to these intracellular signaling mechanisms leading to cell death, additional events may expand the area of necrosis. The release of calpains, which are Ca2+-activated proteases, during necrosis can promote further cell injury in neighboring cells (Mehendale and Limaye, 2005). First, necrotic cell death is in most cases not caused by a single catastrophic event but can be the result of a cellular stress, which is initiated by metabolic activation and triggers sophisticated signaling mechanisms culminating in cell death. Second, the multitude of events following the initial stress offers many opportunities for therapeutic interventions at later time points. Because these events are not occurring in all cells to the same degree and at the same time, delayed interventions may not completely prevent cell damage but limit the area of necrosis enough to prevent liver failure. This targeted toxicity is due to the fact that >90% of a dose of ethanol is metabolized in the liver. The formation of excess reducing equivalents and acetate stimulates fatty acid synthesis and is a major factor in the development of alcohol-induced steatosis. The increased levels of acetaldehyde present in individuals that carry this polymorphism is thought to cause the "flushing" syndrome after ethanol exposure. This may be the reason for the overall reduced incidence of alcoholism in Asia compared to Europe and North America (Chen et al. In this reaction, ethanol functions as an electron donor for the reduction of hydrogen peroxide to water. Thus, the capacity of this pathway is limited due to the low levels of hydrogen peroxide. It is estimated that <2% of an ethanol dose is metabolized through this pathway (Stewart and Day, 2006). The mechanisms of alcohol-induced liver disease are complex and still incompletely understood. In addition to the enhanced synthesis and reduced consumption of fatty acids, ethanol exposure inhibits the transfer of triglycerides from liver to adipose tissue. These effects of ethanol and its metabolites can be compounded in the presence of a high-fat diet. Although steatosis alone does generally not develop in to more severe liver disease, it has been hypothesized that it plays a critical role in the advancement of the disease process (Day and James, 1998a, b). Steatosis is considered the "first hit," which requires a "second hit" to progress to severe alcoholic liver disease (Day and James, 1998a, b). However, more recent data support the concept of lipotoxicity as a critical determinant of disease progression (Neuschwander-Tetri, 2010). This intracellular oxidant stress in hepatocytes can ultimately induce mitochondrial dysfunction and cell death of hepatocytes, but also activate stellate cells and promote fibrosis (Dey and Cederbaum, 2006). In addition to the intracellular events, alcohol exposure causes an inflammatory response, which contributes to the oxidant stress (Arteel, 2003; 654 Hines and Wheeler, 2004). Inhibition of the proteasome pathway, a wellrecognized feature of chronic alcohol exposure, can enhance chemokine formation in hepatocytes and promote inflammatory liver injury (McClain et al. Additional proinflammatory mediators and immune responses can be triggered by protein adducts of acetaldehyde and malondialdehyde (Freeman et al. Another defense mechanism that is activated during alcoholic liver disease is autophagy, which can remove damaged cell organelles and modified proteins (Ding et al. In addition to the intracellular events, Kupffer cell activation can contribute to liver injury (elSisi et al. The preferential occurrence of allyl alcohol injury in zone 1 hepatocytes (Table 13-3) is caused by the predominant uptake of allyl alcohol in the periportal region and the oxygen dependence of the toxicity (Badr et al. Although protein binding of the reactive metabolite acrolein and subsequent adduct formation appears to be the main cause of liver cell death (Kaminskas et al. Loss of hepatocytes due to hepatectomy or cell injury triggers proliferation of all mature liver cells. This process is capable of restoring the original liver mass (Michalopoulos and DeFrances, 1997; Faus to , 2000). However, if hepatocyte replication is blocked, hepatic stem cells or oval cells may proliferate to replace the lost parenchyma (Michalopoulos and DeFrances, 1997; Faus to , 2000). Hepatocytes are normally quiescent, that is, they are in G0 phase of the cell cycle. For details on the intracellular signal mechanisms of hepatocyte regeneration, the reader is referred to excellent reviews on this subject (Trautwein, 2006; Michalopoulos, 2007). Inhibition of mitosis with colchicine prevented tissue repair and aggravated liver injury after thioacetamide (Mangipudy et al. In contrast, stimulation of repair by exposure to a moderate dose of a hepatotoxicant strongly attenuates tissue damage of a subsequent high dose of the same chemical (autoprotection) or a different hepatotoxin (heteroprotection) (Mehendale, 2005). In addition to the dose of the hepatotoxicant, other factors such as age, nutritional status, and disease state may influence tissue repair (Mehendale, 2005). Of particular interest is the potential increased susceptibility of diabetic animals to hepatotoxicants. However, it remains to be evaluated if the reduced susceptibility is caused by the chemical streptozotocin rather than diabetes. This may have been caused by the increased oxidant stress in these steatotic livers (Kon et al. However, under certain circumstances, these inflammatory cells can aggravate the existing injury by release of directly cytotoxic mediators or by formation of proand anti-inflammatory mediators. Kupffer cells and neutrophils are potent phagocytes, which have a vital function in host defense and removal of cell debris. Upon activation, Kupffer cells generate mainly hydrogen peroxide, which can diffuse in to neighboring liver cells and create an intracellular oxidant stress leading to cellular stress and injury (Bilzer et al. Kupffer cells can be activated by bacterial products, opsonized particles, and activated complement factors to cause oxidant stress and cell injury (Bilzer et al. Despite the capacity to directly cause cell damage, a prominent function of Kupffer cells is to generate inflammatory mediators (Decker, 1990). These mediators may aggravate injury by recruiting cytotoxic neutrophils in to the liver (Bajt et al. However, Kupffer cells can also generate anti-inflammatory mediators such as prostaglandin E2 and interleukin-10 (Decker, 1990), which downregulate formation of proinflammatory cytokines and attenuate toxin-induced liver injury (Bourdi et al. Thus, Kupffer cells can promote or inhibit an injury process and assist in removal of cell debris and apoptotic bodies. In addition, newly recruited mononuclear cells (macrophages) can function in a similar way as Kupffer cells in liver. Although there is a capacity for additional damage by these cells, in general, the recruitment of macrophages in to the damaged liver and even the formation of proinflammatory mediators are important signals for inducing regeneration and repair of the damaged tissue (Holt et al. Neutrophils are activated and accumulate in the liver vasculature in response to extensive cell injury or bacterial infection.

The oxygen saturation (SaO2) tells us the relative percentage of the maximum possible sites that can be bound erectile dysfunction protocol book scam cheap 160mg super avana amex. Note that anaemia will not reduce SaO2; lower haemoglobin means there are fewer available sites but the relative percentage of possible sites that are saturated stays the same erectile dysfunction related to prostate order 160mg super avana amex. The relationship between the partial pressure of oxygen and percentage saturation of haemoglobin is represented by the oxygen dissociation curve zantac causes erectile dysfunction cheap 160mg super avana with mastercard. Any impairment is particularly noticeable during exercise incidence of erectile dysfunction with age super avana 160 mg on line, when pulmonary flow increases and blood spends an even shorter time in the capillaries icd 9 code of erectile dysfunction purchase genuine super avana line, exposed to alveolar oxygen doctor for erectile dysfunction in hyderabad purchase super avana online from canada. Impaired diffusion is, however, a much less common cause of hypoxaemia than ventilation:perfusion mismatching. PaO2 tells us the pressure of the oxygen molecules dissolved in plasma, not those bound to haemoglobin. SaO2 tells us how many of the possible haemoglobin binding sites are occupied by oxygen. To calculate the amount of oxygen you would also need to know haemoglobin levels and how much oxygen is dissolved. Oxygen content (CaO2) is the only value that actually tells us how much oxygen is in the blood and, unlike PaO2 or SaO2, it is given in units which denote quantity (mL O2/dL). Oxygen transport Once oxygen has diffused in to the capillaries it must be transported to the body tissues. The actual mechanical change to ventilation is carried out by the respiratory muscles: these are known as the effectors of the control system. Body temperature regulation Body temperature is achieved mainly by insensible heat loss. Metabolism the lungs have a huge vascular supply and thus a large number of endothelial cells. Hormones such as noradrenaline (norepinephrine), prostaglandins and 5-hydroxytryptamine are taken up by these cells and destroyed. Excretion Carbon dioxide and some drugs (notably those administered through the lungs. In acute disease it is important to test for blood pH and bicarbonate levels, and these are included in the standard arterial blood gas results. It can be considered in two parts: that lying outside the thorax (upper tract) and that within the thorax (lower tract). These will be considered in turn, detailing both macroscopic and microscopic structure. Sensation to the area is provided mainly by the maxillary branch of the trigeminal nerve. Lymphatic vessels drain in to the submandibular node, then in to deep cervical nodes. Pharynx the pharynx extends from the base of the skull to the inferior border of the cricoid cartilage, where it is continuous anteriorly with the trachea and posteriorly with the oesophagus. It is described as being divided in to three parts: the nasopharynx, oropharynx and the laryngopharynx, which open anteriorly in to the nose, the mouth and the larynx, respectively. The nasopharynx is situated above the soft palate and opens anteriorly in to the nasal cavities at the choanae (posterior nares). During swallowing, the nasopharynx is cut off from the oropharynx by the soft palate. The nasopharynx contains the opening of the eustachian canal (pharyngotympanic or auditory tube) and the adenoids, which lie beneath the epithelium of its posterior wall. Macroscopic structure Upper respiratory tract Nose and nasopharynx the nose is the part of the respiratory tract superior to the hard palate. It consists of the external nose and the nasal cavities, which are separated in to right and left by the nasal septum. The main functions of these structures are olfaction (not detailed) and breathing. The paranasal air sinuses (frontal, sphenoid, ethmoid and maxillary) drain in to these meatuses via small ostia, or openings. Musculature, neurovascular supply and lymphatic drainage the tube of the pharynx is enveloped by the superior, middle and inferior constrictor muscles, respectively. These receive arterial blood supply from the external carotid through the superior thyroid, ascending pharyngeal, facial and lingual arteries. Venous drainage is by a plexus of veins on the outer surface of the pharynx to the internal jugular vein. Nasal neurovascular supply and lymphatic drainage the terminal branches of the internal and external carotid arteries provide the rich blood supply for the internal nose. The sphenopalatine artery (from the maxillary artery) and the anterior ethmoidal artery (from the ophthalmic) are the two most important branches. Nasopharynx Tongue Oropharynx Oropharynx Hyoid bone Epiglottis Larynx Laryngopharynx Oesophagus Trachea Larynx the larynx is continuous with the trachea at its inferior end. At its superior end, it is attached to the U-shaped hyoid bone and lies below the epiglottis of the tongue. This cartilaginous skeleton comprises the epiglottis, thyroid, arytenoid and cricoid cartilages. The vocal folds close, the epiglottis is pushed 10 the respiratory tract 2 A Epiglottis Hyoid bone B Hyoid bone Thyrohyoid membrane Epiglottis Thyroid notch Laminae of thyroid Thyroid cartilage Cricothyroid ligament Cricoid cartilage Cricotracheal membrane Trachea Tracheal cartilages Superior cornu Thyroid cartilage (left half) Arytenoid cartilage Cricoid cartilage Articular surface for inferior cornu of thyroid cartilage. One external muscle, the cricothyroid, and numerous internal muscles attach to the thyroid membrane and cartilage. The internal muscles may change the shape of the larynx: they protect the lungs by a sphincter action and adjust the vocal folds in phonation. Important relations of the trachea within the neck are: 1 the thyroid gland, which straddles the trachea, with its two lobes positioned laterally, and its isthmus anterior to the trachea with the inferior thyroid veins. Blood and nerve supply and lymphatic drainage the blood supply of the larynx is from the superior and inferior laryngeal arteries, which are accompanied by the superior and recurrent laryngeal branches of the vagus nerve (cranial nerve X). The internal branch of the superior laryngeal nerve supplies the mucosa of the larynx above the vocal cords, and the external branch supplies the cricothyroid muscle. The recurrent laryngeal nerve supplies the mucosa below the vocal cords and all the intrinsic muscles apart from the cricothyroid. Lymph vessels above the vocal cords drain in to the upper deep cervical lymph nodes; below the vocal cords, lymphatic vessels drain in to the lower cervical lymph nodes. Lower respiratory tract the lower respiratory tract is that contained within the thorax, a cone-shaped cavity defined superiorly by the first rib and inferiorly by the diaphragm. Trachea the trachea is a cartilaginous and membranous tube of about 10 cm in length. It extends from the larynx to its 11 Organization of the respiratory tract Thoracic inlet Clavicle 1st rib Subcostal muscle Neurovascular bundle Manubrium sterni Body of sternum Xiphoid process Costal cartilages Costal groove Thoracic outlet Thoracic vertebra Vein Artery Nerve External intercostal muscle Internal intercostal muscle Costal cartilages. Pleurae and pleural cavities the pleurae consist of a continuous serous membrane, which covers the external surface of the lung (parietal pleura) and is then reflected to cover the inner surface of the thoracic cavity (visceral pleura). The visceral and parietal pleurae are so closely apposed that only a thin film of fluid is contained within the pleural cavity. This allows the pleurae to slip over each other during breathing, thus reducing friction. Normally, no cavity is actually present, although in pathological states this potential space may expand. Each rib makes an acute angle with the spine and articulates with the body and transverse process of its equivalent thoracic vertebra, and with the body of the vertebra above. The upper seven ribs (true ribs) also articulate anteriorly through their costal cartilages with the sternum. The eighth, ninth and 10th ribs (false ribs) articulate with the costal cartilages of the next rib above. The 11th and 12th ribs (floating ribs) are smaller and their tips are covered with a cap of cartilage. Lying obliquely between adjacent ribs are the internal and external intercostal muscles. Deep to the intercostal muscles and under cover of the costal groove lies a neurovascular bundle of vein, artery and nerve. Trachea Rib Hilum of lung Pleural cavity Visceral pleura Parietal pleura Diaphragm Mediastinum the mediastinum is situated in the midline and lies between the two lungs. At the root of the lung (the hilum) in the mediastinum, the pleurae become continuous and form a double layer known as the pulmonary ligament. The parietal pleura has a blood supply from intercostal arteries and branches of the internal thoracic artery. Venous and lymph drainage follow a return course similar to that of the arterial supply. Nerve supply is from the phrenic nerve; thus, if the pleura becomes inflamed this may cause ipsilateral shouldertip pain. Conversely, the visceral pleura receives its blood supply from the bronchial arteries. Venous drainage is through the bronchial veins to the azygous and hemiazygous veins. Lymph vessels drain through the superficial plexus over the surface of the lung to bronchopulmonary nodes at the hilum. The visceral pleura has an autonomic nerve supply and therefore has no pain sensation. The lobar bronchi divide again to give segmental bronchi, which supply air to regions of lung known as bronchopulmonary segments. This is important because it means that a segment of diseased lung can be removed surgically. Microscopic structure Here differing tissue and cell types are discussed, moving from the nose down to the alveoli. Upper respiratory tract Nose and nasopharynx the upper one-third of the nasal cavity is the olfactory area and is covered in yellowish olfactory epithelium. A Apex of right lung B Apex of left lung Oblique fissure Upper lobe Left pulmonary artery Left main bronchus Lymph nodes Lower lobe Cardiac notch Middle lobe Pulmonary veins Horizontal fissure Lower lobe Upper lobe Pulmonary ligament. The nasal sinuses and the nasopharynx (lower twothirds of the nasal cavity) comprise the respiratory area, which is adapted to its main functions of filtering, warming and humidifying inspired air. With the exception of a few areas, this pattern of epithelium lines the whole of the respiratory tract down to the terminal bronchioles. Throughout these cells are numerous mucus-secreting goblet cells with microvilli on their luminal surface. Coordinated beating of the cilia propels mucus and entrapped particles to the pharynx, where it is swallowed, an important defence against infection. Below the level of the vestibular fold (with the exception of the vocal folds, which are lined with keratinized stratified squamous epithelium), the larynx and trachea are covered with respiratory epithelium. Trachea the respiratory epithelium of the trachea is tall and sits on a thick basement membrane separating it from the lamina propria, which is loose and highly vascular, with a fibromuscular band of elastic tissue. Under the lamina propria lies a loose submucosa containing numerous glands that secrete mucinous and serous fluid. The C-shaped cartilage found within the trachea is hyaline in type and merges with the submucosa. Oropharynx and laryngopharynx the oropharynyx and laryngopharynx have dual function as parts of both the respiratory and alimentary tracts. Bronchi the respiratory epithelium of the bronchi is shorter than the epithelium of the trachea and contains fewer 14 the respiratory tract 2 A Midclavicular line Apex of lung Microvilli Cilia 2 4 Horizontal fissure 6 8 10 12 Mucus-secreting goblet cell. The lamina propria is denser, with more elastic fibres and it is separated from the submucosa by a discontinuous layer of smooth muscle. The cartilage of the bronchi forms discontinuous flat plates and there are no C-shaped rings. The lamina propria of the tertiary bronchi is thin and elastic, being completely encompassed by smooth muscle. Submucosal glands are sparse and the submucosa merges with surrounding adventitia. Bronchioles the epithelium here is ciliated cuboidal but contains some Clara cells, which are non-ciliated and secrete proteinaceous fluid. Bronchioles contain no cartilage, meaning these airways must be kept open by radial traction and there are no glands in the submucosa. Adjusting the tone of the smooth-muscle layer alters airway diameter, enabling resistance to air flow to be effectively controlled. Goblet cells are absent but there are a few alveoli in the walls; thus, the respiratory bronchiole is a site for gaseous exchange. Alveolar ducts Alveolar ducts consist of rings of smooth muscle, collagen and elastic fibres. They open in to two or three alveolar sacs, which in turn open in to several alveoli. Because alveoli are so numerous, they provide the majority of lung volume and surface area. A Epithelium Lamina propria B Mucus Visceral pleura Smooth muscle Cartilage Blood vessels Gland Goblet cell. Branch of pulmonary artery Bronchiole Terminal bronchiole Respiratory bronchiole Arteriole Branch of pulmonary vein Alveolar duct Alveoli Connective tissue Capillary beds majority of alveoli open in to the alveolar sacs. Communication between adjacent alveoli is possible through perforations in the alveolar wall, called pores of Kohn. Type I pneumocytes To aid gaseous diffusion, type I pneumocytes are very thin; they contain flattened nuclei and few mitochondria.

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It usually occurs after recurrent acute sinusitis and is common in patients who are heavy smokers and work in dusty environments erectile dysfunction groups in mi buy super avana 160 mg with visa. It is characterized by sinusitis erectile dysfunction young living order super avana 160 mg with visa, bronchiectasis constipation causes erectile dysfunction discount super avana 160mg otc, otitis media erectile dysfunction treatment over the counter purchase super avana 160mg line, dextrocardia and infertility erectile dysfunction protocol download pdf purchase super avana mastercard. Neoplasms of the nasopharynx Nasopharyngeal carcinoma is the most common neoplasm to affect the nasopharynx erectile dysfunction treatment atlanta ga purchase super avana 160mg. Clinical features Clinical features are similar to those of acute sinusitis but are typically less severe. There is marked geographical variation in incidence; in parts of China the incidence is as high as 25 per 100 000, compared to an incidence of 2 per 100 000 in western Europe. Pathology Nasopharyngeal carcinomas are predominatly squamous cell carcinomas in origin. Surgical resection can be used in those tumours that fail to regress following radiotherapy. There is, as expexted, a seasonal variation in laryngitis, with peaks in viral laryngitis in autumn and spring (rhinovirus) and in winter (influenza). The incidence of bacterial laryngitis has reduced significantly since the introduction of the Haemophilus influenzae type B (Hib) vaccine. N3a N3b Metastasis M0 M1 No distant metastases Distant metastases Aetiology are poorly differentiated, low-grade tumours are well differentiated). They can also be classified in terms of whether they are keratinizing or non-keratinizing. Keratinizing tumours are associated with local invasion of adjacent structures and a poor prognosis. Investigation and management Laryngitis is a clinical diagnosis based on accurate history and examination findings. Management is usually supportive with analgesia, and viral infections are self-limiting. In croup, there is an acute inflammatory oedema and infiltration by neutrophil polymorphs. Drug treatment, if required, includes steroids (oral dexamethasone), oxygen and nebulized adrenaline (epinephrine). Closer examination revealed that Lucy had a hoarse voice and a cough that sounded like a bark. She had moderate-to-severe croup and was treated with 100% oxygen, nebulized adrenaline (epinephrine) and budesonide as well as having oral dexamethasone. Laryngotracheobronchitis (croup) vs acute epiglottitis Laryngotracheobronchitis (croup) is an extremely common condition in paediatrics, particularly during the winter months, and is caused by a viral infection. In clinical practice it is vitally important to make the distinction between children presenting with croup and those presenting with acute epiglottitis, which is a medical emergency. The incidence of epiglottitis has dramatically fallen due to the introduction of the Hib vaccine. Pathology In epiglottitis, there is necrosis of epithelium and formation of an extensive fibrous membrane on the trachea and main bronchi. As with other serious Haemophilus influenzae infections, prophylactic treatment with rifampicin is offered to the close contacts. Age range Onset Cough Temperature Stridor Drooling Voice Able to drink Active Mortality Reactive nodules Reactive nodules are common, small, inflammatory polyps usually measuring less than 10 mm in diameter. Pathology Keratosis develops at the junction of the anterior and middle thirds of the vocal cord on each side. Investigations and treatment Investigations include endoscopy, followed by histological confirmation. Aetiology the disease is caused by infection of the epithelial cells with human papillomavirus types 6 and 11, and can be acquired at birth from maternal genital warts. Squamous cell carcinoma Squamous cell carcinoma is the commonest malignant tumour of the larynx, affecting men and women in the ratio of 5:1. Predisposing factors include alcohol and tobacco smoking (the condition is very rare in non-smokers). Clinical features Clinical features include hoarseness of the voice and an abnormal cry. A B Subglottic (20%) Tongue Vocal cord Epiglottis Glottic Hyoid bone Epiglottis (70%) Supraglottic neoplastic growth Glottic neoplastic growth Subglottic neoplastic growth Trachea Subglottic (10%) False cord. Further reading Birmingham Research Unit of the Royal College of General Practitioners, 2006. As a consequence of this cycle, sleep is unrefreshing and daytime sleepiness is common, particularly during monotonous situations such as motorway driving. Each arousal also causes a transient rise in blood pressure, which may lead to sustained hypertension, pulmonary hypertension and cor pulmonale, ischaemic heart disease and stroke. Conversely, in central sleep apnoea, the airway remains patent but there is no efferent output from the respiratory centres in the brain. This cycle can be repeated many times during the night and leads to a disruptive sleep pattern. Central sleep apnoea is rarer than obstructive sleep apnoea but is more common in patients with congestive heart failure and patients with neurological diseases. It can also be seen in people with no abnormalities, such as those who live at high altitude. It is very common in those who are overweight and obese, affecting up to 70% of these individuals. Pathogenesis Obstructive sleep apnoea results from occlusion of the upper airway and is common in overweight, middle-aged men. In inspiration upper-airway pressure becomes negative, but airway patency is maintained by upper-airway muscle. During sleep these muscles relax, causing narrowing of the upper airways, even in normal subjects. However, if the airway is already narrowed, for example by the weight of adipose tissue in obese patients or a small jaw (micrognathia), the airway collapses and obstructive sleep apnoea results. In addition to the above, the patient may appear obese and have a wide neck or small jaw. Investigations Patients can have the severity of their suspected sleep apnoea assessed using the Epworth Sleepiness Scale 137 Sleep disorders. Sleep apnoea can be detected by reduced air flow and a delayed desaturation following the apnoea. Conversely, in central sleep apnoea there is neither thoracic nor abdominal movement because the respiratory centre in the brain has stopped instructing the respiratory muscles to move. Obstructive sleep apnoea Apnoea Central sleep apnoea Apnoea Nasal air flow Nasal air flow Abdominal movement Abdominal movement Thoracic movement O2 saturation Paradoxical breathing Thoracic movement O2 saturation No respiratory effort (see epworthsleepinessscale. Between 10 and 15 indicates likely mild-to-moderate disease, and medical advice should be sought. Patients are subsequently referred to a sleep or respiratory specialist for overnight sleep study, polysomnography. Patients also often complain that the machine is noisy and cumbersome, thus affecting their relationship with their partner. However, this has to be balanced against the increased health risks associated with sleep apnoea, as well as the noise from snoring! Treatment Some patients can be managed conservatively and are advised to lose weight and avoid alcohol and sedatives as these relax the upper-airway dilating muscles. Some success has been obtained with medications which have a stimulator effect on the respiratory system, such as theophylline. This method is therefore only suitable if patients can protect their own airway, but has the advantage of reducing the risks of a hospital-acquired infection. On a personal level, the constant snoring can put a big strain on the relationship between a patient and his or her partner. Furthermore, it can have more widespread consequences for 138 Narcolepsy patients who drive, as daytime somnolence significantly increases the risk of falling asleep at the wheel, a dangerous consequence for both the patient and anyone else on the road. It is important to tell patients that they must inform the Driver and Vehicle Licensing Agency of their diagnosis. As most patients are overweight or obese, they are already at increased risk of heart disease, diabetes and associated complications. However, even taking that in to account, these patients are at increased risk for developing hypertension, heart disease and stroke. This is because the constant surges of adrenaline and increases of blood pressure as the body tries to wake the patient and stimulate breathing cause a proinflammatory response. In fact, as patients often have the two conditions, it can be very difficult to distinguish them. Diagnosis is through a combination of clinical findings (obese patient, cyanosis) and arterial blood gas results, which reveal the characteristic hypoxia and hypercapnia pattern. Treatment, as with obstructive sleep apnoea, initially involves conservative measures such as weight loss. Associated conditions Obesity hypoventilation is a disorder of breathing commonly associated with obstructive sleep apnoea, characterized by chronic hypoxia and hypercapnia, in the absence of lung disease. The exact underlying mechanisms are not known, but it is thought to be a combination of a lack of stimulation from the brainstem combined with a large volume of excess weight compressing the chest and upper airways. Occupational asthma is increasing; currently over 200 materials encountered at the workplace are implicated. Prevalence of asthma in the Western world is rising, particularly in children; up to 20% have symptoms at some time in their childhood. Extrinsic asthma is more common in boys than girls, whilst women tend to more affected by intrinsic disease. Extrinsic asthma this is classical asthma with onset in childhood, commonly with a previous history of atopy such as food allergy or eczema. Intrinsic asthma this subtype tends to be of adult onset, is more progressive and is less responsive to therapy. They are associated with human lung mast cells and include histamine, neutral proteases and chemotactic factors for eosinophils. Some of these mediators are derived from the membrane phospholipids and are associated with the metabolism of arachidonic acid. The production of inflammatory cytokines and chemokines is important in the activation and recruitment of inflammatory cells, ultimately leading to a so-called late response (see below). Airway remodelling may cause a fixed airway obstruction which may not be reversible with anti-inflammatory agents or bronchodilators. This is much more difficult to reverse than the immediate reaction and there is an increase in the level of airway hyperreactivity. The biphasic nature of asthma attacks is the basis behind patients being admitted for observation for approximately 24 hours after a moderate or severe attack. For example, nocturnal coughing is a common presenting symptom, especially in children. It is important to try and discern the exact timing of symptoms, as this can be crucial not only in diagnosing the asthma but also in identifying the underlying trigger. Worsening of symptoms at work (with reduction when on holiday or at home) can be very useful in those with occupational asthma. Other features to look out for in the history include a personal or family history of atopy. Children have often been previously diagnosed with milk allergy and/or eczema as a toddler and then will present with symptoms of asthma once they start school. Clinical features vary according to the severity of asthma (classified from mild to severe and either intermittent or persistent).

Exertional dyspnea is the most frequent presenting symptom erectile dysfunction remedies natural quality super avana 160 mg, followed by fatigue erectile dysfunction urban dictionary discount 160mg super avana visa, weakness crestor causes erectile dysfunction order super avana 160 mg on-line, and complaints of general exertion intolerance erectile dysfunction at 25 cheap super avana uk. Syncope erectile dysfunction treatment natural way cheap super avana 160 mg with mastercard, owing to atrial and ventricular arrhythmias erectile dysfunction statistics india purchase super avana master card, occurs in one-third of patients. There is no discomfort at rest, but normal physical activity causes increased dyspnea, fatigue, chest pain, or presycope. There is no discomfort at rest, but less than ordinary activity causes increased dyspnea, fatigue, chest pain, or presyncope. Dyspnea and/or fatigue may be present at rest, and symptoms are increased by almost any physical activity. Thus, syncope and chest pain occur late in the course of the disease and are indicative of more severe limitations in cardiac output. These symptoms are ominous and, in 7% of patients, may presage ventricular dysrhythmias and sudden death. Other symptoms include orthopnea and paroxysmal nocturnal dyspnea which suggest elevated pulmonary venous pressure and pulmonary congestion due to suboptimally treated left-sided heart disease. Other auscultatory findings of a tricuspid regurgitant murmur, right ventricular S3, marked distention of the jugular veins, palpable left parasternal lift, hepatomegaly, and ascites signify right ventricular dysfunction and advanced disease. Findings of peripheral edema, however, are not synonymous with cor pulmonale and may, instead, reflect the presence of secondary hyperaldosteronism in patients with functional renal insufficiency induced by high renal vein pressures, hypercapnic acidosis and/or hypoxemia. Signs of right ventricular failure include right ventricular S3 gallop, marked distention of the jugular veins, pulsatile hepatomegaly, peripheral edema and ascites. Hypotension, diminished pulse pressure and cool extremities, are particularly ominous signs that signal significantly reduced cardiac output and peripheral vasoconstriction. Radiographic findings of pulmonary venous congestion (associated with pulmonary venous hypertension) or lung hyperinflation (associated with chronic obstructive pulmonary disease) may also be gleaned from the chest radiograph and offer clues to the underlying diagnosis. The presence of left atrial enlargement, even in the absence of left ventricular dysfunction, should raise the possibility of left-sided heart disease that may contribute to observed pulmonary pressure elevations. In addition, intracardiac and intrapulmonary shunts may be assessed echocardiographically using bubble-contrast techniques. Thus, extrapulmonary causes of pulmonary hypertension including mitral valve disease, left ventricular dysfunction, and intracardiac shunt may be elucidated using this technique. The presence and/or severity of congential or acquired leftto-right shunt may be confirmed. Vasodilator testing is performed with inhaled nitric oxide, intravenous epoprostenol, or intravenous adenosine during the initial right heart catherization. Antinuclear antibodies may be positive at low titers in the absence of underlying collagen vascular disease. In the absence of parenchymal disease, the restrictive lung defect associated with pulmonary hypertension is usually mild. Loss of normal distensibility of all lung tissues including the pulmonary vasculature and lung compression by the enlarged right heart may contribute to reduced lung volumes in some patients. Cardiopulmonary exercise testing and the recent development of the manometer-tipped catheters that permit continuous pulmonary artery pressure measurements may provide a more accurate assessment of the hemodynamic derangements in response to exercise and the impact of different treatment modalities on these changes. Patchy, nonsegmental diffuse defects may also be seen in patients with venoocclusive disease. This diagnostic tool has emerged over the past decade as an important component in evaluation of the patient with suspected pulmonary embolism. Standard results yield right and left apical posterior and the right and left oblique views of the lungs. Partial studies with vessel injection based on V/Q findings are acceptable and help to minimize the amount of contrast material given during the procedure. Angiographic evidence of acute thrombi includes intravascular filling defects on two or more projections. Less consistent and nonspecific observations on angiography include vascular cutoffs, hypovascularity and vascular pruning. Rounded cutoffs of segmental vessels and irregular intimal surfaces also indicate chronicity. Five angiographic patterns associated with organized thromboembolic material during thromboendarectectomy have been identified: pouch defects; pulmonary artery webs or bands; intimal irregularities; abrupt narrowing of the major pulmonary arteries; and, obstruction of lobar or segmental vessels at their origin, with complete absence of blood flow to the pulmonary segments that are normally perfused by those vessels. Oxygen therapy is utilized to treat and/or prevent hypoxemia, which may cause vasoconstriction and worsening of pulmonary hypertension. The benefits of supplemental oxygen therapy in improving the quality of life and decreasing morbidity among patients with chronic respiratory insufficiency are well established. Patients may be normoxemic at rest but suffer severe desaturations with exercise or sleep. Shunt-induced hypoxemia due to a secondary opening of a patent foremen ovale may be profound and usually refractory to increased inspired oxygen. Continuous oxygen therapy may be necessary to attenuate symptoms in patients with severe right heart failure and resting hypoxemia. Digitalis is occasionally indicated for patients with right ventricular failure and atrial dysrhythimias. Serum electrolytes and indices of renal function should be closely monitored with both drugs. Hyperemesis, anorexia, and diarrhea are frequent problems in the cancer patient, and thus diuretics should be administered judiciously to avoid severe volume depletion. However, levels of activity that trigger angina, presycope, or syncope should be avoided. High altitudes (elevations above 1500 m) may promote hypoxicinduced pulmonary vasoconstriction and aggravate the disease. Travel by commercial airlines is generally considered safe, although supplemental oxy- gen may be indicated in selected patients. Other amphetamine-related drugs, including nasal decongestant medications and drugs with adrenergic properties should be avoided, if possible. Only patients who demonstrate a positive response to vasodilator challenge should be considered for calcium channel blocker therapy. Close monitoring is recommended to determine both the efficacy and safety of therapy. The most frequently used short-acting vasodilators include nifedipine, diltiazem, and amlodipine. Calcium channel blockers with negative inotropic effects, such as verapamil should be avoided. Many of these medications have already received regulatory approval or are under regulatory review (Table 21-4). Significant improvements in exercise capacity, hemodynamics, quality of life, and survival have been shown following epoprostenol therapy. It has also been shown to improve the 6 minute walk distance, functional class, and hemodynamics, along with decreasing the risk of clinical worsening. Adverse effects related to this route of administration include erythema and local pain. Iloprost is given via an inhaled route which means that more of the medication is delivered directly to the lungs, with fewer systemic side effects. Because of the relatively short half-life (20 to 25 minutes), this agent must be dosed 6 to 9 times per day. The hemodynamic effects are also short-lived, lasting only 30 to 90 minutes of inhalation. Beraprost is absorbed rapidly in fasting conditions with a peak concentration after 30 minutes and elimination half-life of 35 to 40 minutes after oral administration. Bosentan is one of two endothelin antagonists that is approved for use in the United States. In addition, bosentan is shown to be teratogenic in animal studies and may decrease the efficacy of oral contraceptives. Headaches, mild anemia, fluid retention, testicular atrophy, and possibly male infertility include other possible side effects of the drug. Similar to bosentan, monthly liver function tests, a monthly pregnancy test in women of child-berating potential, and periodic hemoglobin measurements are required with ambrisentan therapy. Nasal congestion and lower extremity edema has been described following ambrisentan therapy, which tends to be more frequent and severe in patients over 65 years of age. Sildenafil and tadalafil are both selective for the pulmonary circulation, but only sildenfil has demonstrated improvement in arterial oxygenation. The route of administration, side-effect profile, patient preference, functional status, and clinical judgment all help determine the best therapy. Combination therapy using agents with different molecular targets may act synergistically and is advocated in patients who fail to show improvement or deteriorate with monotherapy. The goal of combination therapy should be to maximize efficacy, while minimizing toxicity. Interventional and surgical therapeutic options should be considered in patients with progressive functional decline and right ventricular dysfunction despite medical therapy. These hemodynamic effects are seen clinically as resolution of syncopal and precyncopal episodes, decreased systemic venous congestion, and improved exercise tolerance. In the goaloriented strategy, parameters considered prognostically relevant are identified and therapy is escalated until these goals are met or significant toxicities occur. Sleep architecture changes with age and may be disrupted by sleep disorders, medications, alcohol, underlying medical illness and/or sleep deprivation. In normal individuals, sleep deprivation has been reported to depress ventilatory responses to hypercapnia and hypoxia. Optimization of sleep disorders may thus play a significant role in the successful treatment of a broad range of clinical diseases, including infection, cardiac disorders, and cancer. One of the major categories of sleep-related breathing disorders is sleep apnea, which may be regarded as obstructive or central. Both disorders are diagnosed by polysomography and are characterized by repetitive cessation of breathing during sleep. Often this event provokes sleep arousals, which may be associated with normal breathing and restoration of normal gas exchange. These periods of hypoxia trigger a sympathetic response, resulting in oscillation of systemic and pulmonary pressures, heart rate, and cardiac function. In abnormal states, recurrent episodes of apneas and hypopneas during sleep result in exaggerated stimulation of vascular sympathetic activity and the release of circulating catecholamines, resulting in increased peripheral vascular resistance. Changes in intrathoracic pressures upon termination of the apneic episode causes increased cardiac output, which, in the presence of a constricted peripheral vascular bed, results in acute surges in nocturnal blood pressure. It is thought that the nocturnal increases in sympathetic vascular tone remain elevated in normoxemic conditions during the day, leading to daytime hypertension. Sleep apnea severity correlates with the degree of impairment of the left ventricular ejection fraction. These bradyarrhythmias tend to be atropine-responsive and may occur in the absence of any primary disease within the cardiac conducting system. Tachyarrhythmias also occur and their prevalence and severity are increased in patients with underlying cardiac disease. Endothelial damage and vascular remodeling caused by hypoxemia and apneic episodes are thought to promote the development sustained elevations in pulmonary artery pressures over time. The mechanism of stroke in these patients is unclear but likely relates to increased prevalence of hypertension and atherosclerosis in these patients. Sleep disturbances and associated symptoms of daytime hypersomnolence and fatigue are ubiquitous problems in cancer patients which may present before, during or after cancer therapy. Most of these studies have focused on the influence of sleep disorders and cardiac dysfunction in normal individuals. Sleep disorders are a ubiquitous problem among chronically ill patients, including patients with cancer. The impact of disordered sleep on cardiac dysfunction in this patient population remains unknown. Interestingly, many of these markers are also increased in cardiovascular disease. A role for these drugs in reducing the risk of cardiovascular disease has not been confirmed. Altered Heart-Lung Interactions Associated With Cancer Therapy Pneumotoxicity Caused by Chemotherapeutic Agents the lungs are particularly susceptible to injury from a variety of standard chemotherapeutic agents as well as a growing list of immunobiologic and molecular targeted therapies. The role of synergism from other drugs, radiation, or oxygen is well described but poorly understood. Newer patterns of lung involvement from complex multi-drug and multimodality regiments are still being described. Patients typically present with dry cough, dyspnea, hypoxia, and fever, regardless of the inciting drug. Acute and hyperacute reactions have been reported following exposure to some drugs, such as paclitaxel or methotrexate while delayed reactions, occurring months to years after drug administration, have been described following busulfan, bleomycin, cyclophosphamide, and gemcitabine administration. Furthermore, results from laboratory evaluation and respiratory function are not sufficient to exclude competing diagnoses. The adverse cardiopulmonary reactions triggered by some of these agents may be severe and rapidly fatal. Therefore, the clinician must maintain a high index of suspicion and must be familiar with the welldescribed pulmonary toxicities triggered by classic chemotherapeutic agents as well as emerging toxicities associated with newer chemotherapeutic agents. Pulmonary hypertension, triggered by drug-induced thromboembolic phenomena or endothelial injury, is also well described. Alternatively, pulmonary decompensation induced by chemotherapy-related myocarditis and heart failure is also reported following administration of some cancer agents, including the newer molecular targeted therapies.