Amer Aldouri MBChB MD MRCS FRCS

• (Hepatobiliary)
• Specialist registrar in surgery
• St James? University Hospital, Leeds, UK

Many workers are exposed to copper in agriculture cholesterol lowering diet foods to avoid buy atorlip-5 5 mg low cost, industries connected with copper production cholesterol elevated order atorlip-5 5mg mastercard, metal plating cholesterol levels charts buy 5mg atorlip-5 mastercard, and other industries lowering cholesterol with diet tips 5mg atorlip-5 with mastercard. Little information is available concerning the forms of copper to which workers are exposed definition low cholesterol diet atorlip-5 5 mg overnight delivery. People living near copper smelters and refineries and workers in these and other industries may be exposed to high levels of dust-borne copper by both inhalation and ingestion routes cholesterol percentile chart discount atorlip-5 5mg fast delivery. For example, ingestion of 300 mg of soils near copper smelters by children could result in the intake as high as 0. Industrial releases are only a fraction of the total environmental releases of copper and copper compounds. Other sources of copper release into the environment originate from domestic waste water, combustion processes, wood production, phosphate fertilizer production, and natural sources. Quantitative information on release of copper to specific environmental media is discussed below. A summary of copper concentrations in environmental media is provided in Table 6-3. Other natural sources of copper emitted into air (in terms of estimated ranges of worldwide emissions) are 6 6 forest fires (0. Based on these data, the mean total 6 non-crustal sources of copper emitted into the atmosphere is 1. Anthropogenic emission sources include nonferrous metal production, wood production, iron and steel production, waste incineration, industrial applications, coal combustion, nonferrous metal mining, oil and gasoline combustion, and phosphate fertilizer manufacture. Global atmospheric anthropogenic and 6 6 natural emissions of copper have been estimated to be 35x10 and 28x10 kg/year, respectively (Giusti et al. The estimates for the anthropogenic and natural emissions are based on the sum of copper emissions from various sources as shown in Tables 6-4 and 6-5, respectively. The sources of emissions and the estimated quantities of copper emitted in 10 kg/year are: primary copper smelters, 0. Daily stack emission rates have been reported for three coal-burning power plants on a kg/day/1, 000 megawatt basis (Quee Hee et al. Summary of Copper Concentrations in Environmental Media Environmental media Concentration Units Atmosphere Aerosol 0. Global Emissions of Copper from Natural Sources (x10 kg/year) Median Range Wind-borne particulates 8. Global Emissions of Copper from Anthropogenic Sources 6 (x10 kg/year) Median Range Coal combustion 5. Emission factors in grams of copper released to the atmosphere per ton of product have been estimated for various industries (Nriagu and Pacyna 1988). Missing from these emission estimates is fugitive dust arising from drilling, blasting, loading, and transporting operations associated with copper mining. The highest concentrations of copper in atmospheric particulate matter were obtained from mining activities, primary and secondary production, and industrial manufacturing (Table 6-6). The concentration of copper in air near the 3 3 3 plant decreased from 66 ng/m (fine particles) and 131 ng/m (coarse particles) to 22 ng/m (fine 3 particles) and 50 ng/m (coarse particles) during a period of inactivity at the plant, clearly demonstrating the contribution of plant emissions to copper levels in the surrounding area. The amount of copper and other pollutants in fugitive dust originating from copper production sites, such as from smelter bag houses, or waste sites, is of some concern. The deposition rate was then determined from the amount of copper in the moss bags accumulated over the summer of 1985 and compared with that for an agricultural control area. In a study of automobile exhaust emitted from light duty vehicles conducted in Denver, Colorado, it has been shown that this source of copper emission makes a small local contribution to copper in air. The amount of copper emitted in the exhaust from automobiles powered by regular gasoline has been measured to be 0. Copper released into the atmosphere will be in particulate matter in the elemental form or in the form of an oxide, sulfate, or carbonate. Combustion processes are reported to release copper into the atmosphere as the oxide, elemental copper, and adsorbed copper. Cupric oxide has been identified in emissions from steel manufacturing and in fly ash from oil-fired power plants and open hearth steel mills (Graedel 1978; Perwak et al. These copper 3 concentrations in air are generally above the annual atmospheric concentrations of 0. Copper is a natural constituent of soil and will be transported into streams and waterways in runoff either due to natural weathering or anthropogenic soil disturbances. Sixty-eight percent of releases of copper to water is estimated to derive from these processes. Copper sulfate use represents 13% of releases to water and urban runoff contributes 2% (Perwak et al. In the absence of specific industrial sources, runoff is the major factor contributing to elevated copper levels in river water (Nolte 1988). This mean concentration of copper in runoff water is higher than the geometric mean concentration of 4. Of the 71 priority pollutants analyzed, copper, along with lead and zinc, was the most frequently detected. Riverine input is estimated to be 10x10 kg/year as dissolved 6 copper and 1, 500x10 kg/year as copper bound to particulates. Domestic waste water is the major anthropogenic source of copper in waterways (Isaac et al. Louis showed discharges of copper into sewer systems from residential areas to be significant, with an average loading of 42 mg/person/day (Perwak et al. In a more comprehensive review, Jenkins and Russell (1994) reported a range of average copper loadings derived from residential and some small industrial contributions of 2. Concentrations of copper in influents to 239 waste water treatment plants (12, 351 observations) were 0. Inputs into the Narraganset Bay, Rhode Island, in decreasing order of importance, are sewage effluent, rivers, urban runoff, and atmospheric fallout (Mills and Quinn 1984; Santschi et al. Ninety percent of both dissolved and particulate copper was from the effluent of sewage treatment plants that discharged into the Providence River. The range of removal efficiencies reported for pilot and full scale plants suggests that removal depends strongly on plant operation or influent characteristics. Copper in storm water runoff originates from the sidings and roofs of buildings, various emissions from automobiles, and wet and dry depositional processes (Davis et al. Storm water runoff normally contributes approximately 2% to the total copper released to waterways. By contrast, those plants using only primary treatment had a 37% median removal efficiency. The mass loadings of copper into the estuary as a function of source are (in kg/day): municipal treatment systems, 103. Discharges to water from active mining and milling are small and most of the western operations do not release any water because water is a scarce resource and is recycled (Perwak et al. Runoff from abandoned mines is estimated to contribute 314 metric tons annually to surface water (Perwak et al. These discharges are primarily insoluble silicates and sulfides and readily settle out into stream, river, or lake beds. Releases from manufactured products containing copper may be substantial, but are difficult to predict. Corrosion of copper in plumbing or construction may result in direct discharges or runoff into waterways. Copper concentrations in waste water from a selected open pit and underground copper mine were 1. Drainage from mining operations and abandoned mines has been shown to have an effect on copper content in local surface waters (see Table 6-7) with concentrations as high as 69, 000 ppb being measured (Rosner 1998). These industries and their mean and maximum discharges in ppm are: inorganic chemicals manufacturing (<1. Emission factors in nanograms of copper released per L of water outflow have been estimated for various industries. Effluents from power plants that use copper alloys in the heat exchangers of their cooling systems discharge copper into receiving waters (Harrison and Bishop 1984). At the Diablo Canyon Nuclear Power Station, a very high start up discharge containing 7, 700 ppb of copper fell to 67 ppb after 24 hours (Harrison et al. Except for after start-up of the cooling system, most of the soluble copper (that which passes through a 0. During normal operation, <20% of the copper released was in the <1, 000 molecular weight fraction, which contains the more available copper species. Copper sulfate is added directly to lakes, reservoirs, and ponds for controlling algae. Concentrations of Copper in Water Sample type/ Concentration (ppb) source Location Range (mean) [median] Comments Reference Representative New Jersey [3. The reduction in dissolved copper during this period was accompanied by an increase in particulate copper. The copper in the settled particulates is in equilibrium with the water column, which greatly favors copper in a bound state. A potential source of copper release into waterways is leachate from municipal landfills. Copper concentrations in leachate obtained from waste sites have been found to vary widely. For example, copper concentrations in leachate from municipal landfills have been found to range from 0. Although copper was measured in these leachates, its origin may not be from copper contained within the waste site, but from the surrounding soils. Therefore, the emissions of copper from landfills into leachates should be made relative to the contribution of copper from surrounding soils, as determined from appropriately selected control samples. For example, estimated loading rates of copper into surface water from irrigation water runoff near the Stillwater National Wildlife Refuge ranged from 0. The highest loading rates were obtained during the middle period (August through mid-September) of the irrigation season. The copper in the runoff water was found to be predominantly bound to drift material in the water. The copper in tailings represents the portion of copper that could not be recovered from the ore and is generally in the form of insoluble sulfides or silicates (Perwak et al. Much of this waste is landfilled directly or is in the form of residues following incineration. Emission factors in milligrams of copper released per gram of solid waste have been estimated for various industries. Sludge from sewage treatment plants is a major source of copper released to land (Nriagu and Pacyna 1988). Agricultural products are believed to constitute 2% of the copper released to soil (Perwak et al. However, even though the largest releases of copper are to land, uptake of copper in human populations through ingestion of copper in soil are expected to be minimal in comparison to the primary route of exposure through the ingestion of drinking water (see Section 6. Because of analytical limitations, investigators do not often identify the form of a metal present in the environment. A change in the transport or partitioning of a metal may result from the transformation of the metal from one form to another. For example, complexation of a metal with small organic compounds may result in enhanced mobility, while formation of a less-soluble sulfide would decrease its mobility in water or soil. Adsorption may be the result of strong bonds being formed (transformation) as well as weak ones. Characterizing weak and strong adsorption is dependent on the analytical method that is used and care should be exercised when comparing results from different studies. Speciation, compound formation, and oxidation-reduction are examined in Section 6. It is removed by gravitational settling (bulk deposition), dry deposition (inertial impaction characterized by a deposition velocity), in-cloud scavenging (attachment of particles by droplets within clouds), and washout (collision and capture of particles by falling raindrops below clouds) (Schroeder et al. The removal rate and distance traveled from the source will depend on a number of factors, including source characteristics, particle size, turbulence, and wind velocity. The importance of wet to dry deposition generally increases with decreasing particle size.

A shift in tracheal position can occult malignancy (arthritis or hepatosplenomegaly) cholesterol test starvation buy atorlip-5 5 mg on-line. Tactile fremitus may change with the presence of consolidation or air Palafox M et al: Diagnostic value of tachypnea in pneumonia in the pleural space cholesterol in eggs myth generic atorlip-5 5 mg without prescription. In older patients cholesterol medication online order cheap atorlip-5 line, unilateral crackles restrictive lung diseases cholesterol in scrambled eggs effective 5 mg atorlip-5, measure disease severity cholesterol your body makes 5mg atorlip-5, define pre are the most valuable examination finding in pneumonia cholesterol risk ratio purchase atorlip-5 no prescription. They Percussion may identify tympanic or dull sounds that can help can help define the risks of anesthesia and surgery and assist in define an intrathoracic process. For this reason, serial determinations of lung function (from hypoxemia or hypercapnia), cyanosis, clubbing, and are often more informative than a single determination. Evidence of cor pulmonale (loud pulmonic cooperation is essential for almost all physiologic assessments. Lung functions in infants and toddlers are available at Type of Lung Disease specialized centers. Despite these limitations, tests of lung Obstructivea Restrictiveb function are valuable in the care of children. Examples of obstruc are affected by abnormalities of respiratory control, gas tive processes include asthma, chronic bronchitis, and cystic exchange, respiratory mechanics, and the circulation. It is used to monitor alveolar helpful in following the course of pulmonary disorders that ventilation and is most accurate in patients without signifi are difficult to control and require multiple medications (eg, cant lung disease, particularly those with a good match of asthma). These devices can also be used to give patients with ventilation and perfusion and without airway obstruction. This assess Beydon N et al: An official American Thoracic Society/European Respiratory Society statement: Pulmonary function testing in ment is accurate in children who weigh more than 2 kg and preschool children. Measurement during a often seen because young children commonly develop small systolic pulse allows estimation of arterial oxygen saturation as airway obstruction and asthma. Parenchymal changes may the machine corrects for the light absorbed at the tissue level cause increased interstitial markings, consolidation, air between pulses. The pulse oxime When pleural fluid is suspected, lateral decubitus radio ter has reduced reliability during conditions causing reduced graphs may be helpful in determining the extent and mobil arterial pulsation such as hypothermia, hypotension, or infu ity of the fluid. Carbon monoxide bound by expiratory radiographs may show focal air trapping and shift hemoglobin results in falsely high oxygen saturation readings. American Heart Association and American Academy nique is also important in detecting vascular rings and slings, of Pediatrics, 2006. Characteristic pat Spontaneously expectorated sputum is the easiest and most terns seen in interstitial lung disease (eg, ground-glass opaci convenient sample to culture though it is rarely available fication) or airway disease (eg, bronchiectasis) are often from patients younger than age 6 years. Ventilation-perfusion scans can provide secretions and is generally successful in children older than information about regional ventilation and perfusion and age 10 years. Oropharyngeal swabs are widely used as a can help detect vascular malformations and pulmonary surrogate for lower airway cultures in nonexpectorating emboli (rare in children). Pulmonary angiography is occa patients, particularly children with cystic fibrosis. Cultures sionally necessary to define the pulmonary vascular bed more from the lower respiratory tract can be obtained invasively precisely. Patients breathing spontane wheezing, suspected foreign body, pneumonia, atelectasis, ously can be treated by nasal cannula, head hood, or mask chronic cough, hemoptysis, placement of an endotracheal (including simple, rebreathing, nonrebreathing, or Venturi tube, and assessment of its patency. The general goal of oxygen therapy is to achieve an specific the indication, the higher the diagnostic yield. With conscious sedation and topical anesthetics, the lead to substantial changes in inspired oxygen concentration procedure can be done at the bedside. The instrument can be used as an obturator to intubate Although the head hood is an efficient device for delivery a patient with a difficult upper airway. Even at high Improvements in digital optics have greatly enhanced the flow rates, oxygen by nasal cannula rarely delivers inspired image quality. In addition, this approach the adequacy of oxygenation should be measured as the to the airway allows better assessment of the subglottic space arterial oxygen tension, or oxygen saturation can be deter for stenosis. Aspiration and hemor caused by crying or breath-holding during attempts at arte rhage can be suspected in the presence of lipid and rial puncture. Analysis of lavage fluid can also be completed for cell assessments are essential to ensure the safety and adequacy of counts, surfactant proteins, and inflammatory mediators. Transbronchial biopsy in children is limited to evaluation for infection and rejection in transplant patients due to Ralston M et al (editors): Pediatric Advanced Life Support Provider poor diagnostic yield in most conditions. American Heart Association and American Academy biopsy may have a role in diagnosing diffuse lung diseases of Pediatrics, 2006. The inhaled adrenergic agonists may be delivered by metered-dose inhaler, dry powder inhaler, or nebulizer. Inhaled bronchodilators are as effective as All parents or other caregivers should be counseled about injected agents for treating acute episodes of airway obstruc environmental hazards to the lung. These drugs can be safely hazards includes small objects that may be aspirated, allergens administered at home as long as both the physician and the that can precipitate respiratory symptoms in atopic children, family realize that a poor response may signify the need for and tobacco smoke. The harmful effects of smoking in the corticosteroids to help restore adrenergic responsiveness. Children from families where Anticholinergic agents may also acutely decrease airway the parents and others smoke have decreased lung growth as obstruction. Furthermore, they may yield a longer duration well as decreased pulmonary function in comparison with of bronchodilation than do many adrenergic agents. Exposure of children to patients may benefit from receiving both adrenergic and tobacco smoke also leads to an increased frequency of lower anticholinergic agents. In general, this class of drugs is most respiratory tract infections and an increased incidence of effective in the treatment of chronic bronchitis. Health Chronic use of inhaled medications is common in chil care providers must increase their efforts to educate patients dren with chronic lung diseases. Many airway clearance techniques exist, but the inspiratory and the expiratory phases) or variable (air only a few long-term studies have compared the various flow limited more in one phase of respiration than in the options. Variable obstruction is common in children because chest physiotherapy, autogenic drainage, positive expiratory their airways are more compliant and susceptible to dynamic pressure (Flutter or Acapella), intrapulmonary percussive ven compression. With variable extrathoracic airway obstruction tilation, or high-frequency chest compression. Often obstruction (eg, bronchomalacia), limitation is greater dur bronchodilators or mucolytic medications are given prior to or ing expiration, producing expiratory wheezing. Inhaled corticosteroids and mining the phase of respiration in which obstruction is inhaled antibiotics should be given after airway clearance greatest may be helpful in localizing the site of obstruction. Auscultation should define the pattern and timing of respiration, detect the presence of Patients with abnormalities of the extrathoracic airway may crackles and wheezing, and determine whether findings are present with snoring and other symptoms of obstructive localized or generalized. The course of the Routine tests include plain chest radiographs, a sweat illness may be acute (eg, infectious croup), recurrent (eg, test, and pulmonary function tests in older children. Other spasmodic croup), chronic (eg, subglottic stenosis), or pro diagnostic studies are dictated by the history and physical gressive (eg, laryngeal papillomatosis). Treatment should be directed toward the primary tors are difficult delivery, ductal ligation, and intubation. If noninvasive Laryngomalacia is a benign congenital disorder in which the studies are unable to establish the cause, direct laryngoscopy cartilaginous support for the supraglottic structures is under and bronchoscopy remain the procedures of choice to estab developed. Treatment should be directed at in infants and usually is seen in the first 6 weeks of life. Stridor relieving airway obstruction and correcting the underlying has been reported to be worse in the supine position, with condition if possible. Gastroesophageal reflux may also be associated with Intrathoracic airway obstruction usually causes expiratory laryngomalacia requiring treatment. The history should include the following: improves with age and resolves by age 2 years, but in some 1. The diagnosis is established by direct laryngoscopy, which shows inspiratory collapse of 2. Precipitating factors (eg, exercise, upper respiratory ill an omega-shaped epiglottis (with or without long, redundant nesses, allergens, or choking while eating) arytenoids). Presence and nature of cough obstruction associated with feeding difficulties, failure to 5. Production of sputum thrive, obstructive sleep apnea, respiratory insufficiency, or 6. Previous response to bronchodilators severe dyspnea, surgical epiglottoplasty may be necessary. The examiner should look for cyanosis Zoumalan R et al: Etiology of stridor in infants. These are the main entities in the differential diagnosis for patients presenting Other rare congenital lesions of the larynx (laryngeal atresia, with acute stridor, although spasmodic croup, angioneurotic laryngeal web, laryngocele and cyst of the larynx, subglottic edema, laryngeal or esophageal foreign body, and retropha hemangioma, and laryngeal cleft) are best evaluated by direct ryngeal abscess should be considered as well. Laryngeal atresia presents immediately after birth with severe respiratory distress and is usually fatal. Viral Croup Laryngeal web, representing fusion of the anterior portion of the true vocal cords, is associated with hoarseness, aphonia, Viral croup generally affects younger children in the fall and and stridor. Surgical correction may be necessary depending early winter months and is most often caused by parainfluenza on the degree of airway obstruction. Cysts are more superficial, whereas laryngo enza virus, rubeola virus, adenovirus, and Mycoplasma pneu celes communicate with the interior of the larynx. Although inflammation of the entire airway is usually generally fluid-filled, whereas laryngoceles may be air or present, edema formation in the subglottic space accounts for fluid-filled. Airway obstruction is usually prominent and the predominant signs of upper airway obstruction. Subglottic hemangiomas are seen in infancy with signs of Clinical Findings upper airway obstruction and can be associated with similar A. Although these lesions Usually a prodrome of upper respiratory tract symptoms is tend to regress spontaneously, airway obstruction may followed by a barking cough and stridor. Laryngeal cleft is a very rare condition resulting from Patients with mild disease may have stridor when agitated. Patients with this condi As obstruction worsens, stridor occurs at rest, accompanied tion may have stridor but always aspirate severely, resulting in in severe cases by retractions, air hunger, and cyanosis. Barium examination, the presence of cough and the absence of swallow is always positive for severe aspiration, but diagnosis drooling favor the diagnosis of viral croup over epiglottitis. Lateral neck radiographs in patients with classic presenta Vijayasekaran S et al: Open excision of subglottic hemangiomas to tions are not required but can be diagnostically supportive avoid tracheostomy. Mist therapy has historically been used but clinical studies do not demonstrate effectiveness. Both racemic epinephrine and Life-threatening condition can occur, requiring careful epinephrine hydrochloride are effective in alleviating symp patient assessment. Once controversial, the efficacy of glucocorticoids in croup is now more firmly established. The definitive diagnosis is and this agent may be as effective as dexamethasone; however, made by direct inspection of the epiglottis, a procedure that dexamethasone is still the most cost-effective steroid of choice. If symptoms resolve within 3 hours of glucocorticoids and nebulized epinephrine, patients can safely be discharged B. Obtaining radio if respiratory distress persists, patients require hospitaliza graphs, however, may delay important airway intervention. Intubation with an endotracheal tube of general anesthesia (but not muscle relaxants) to facilitate slightly smaller diameter than would ordinarily be used is intubation. If the appropriate intravenous antibiotics to cover H influenzae and patient fails extubation, tracheostomy may be required. It is not clear if this was present prior to the croup episode or if the croup episode Prognosis itself altered airway function. Prompt recognition and appropriate treatment usually results in rapid resolution of swelling and inflammation. Duman M et al: Nebulised L-epinephrine and steroid combination in the treatment of moderate to severe croup. Sparrow A et al: Prednisolone versus dexamethasone in croup: A randomised equivalence trial. Bacterial Tracheitis Bacterial tracheitis (pseudomembranous croup) is a severe life 2. As the manage With the introduction of the Haemophilus influenzae conju ment of severe viral croup has been improved with the use of gate vaccine the incidence of epiglottitis has dramatically dexamethasone and vaccination has decreased the incidence decreased and is now rare in countries with immunization of epiglottitis, tracheitis has now become the most common programs. If disease occurs it is likely to be associated with H pediatric airway emergency requiring admission to the pediat influenzae in unimmunized children or other organisms ric intensive care unit. This diagnosis must be high in the such as nontypeable H influenzae, Neisseria meningitides, or differential when a patient presents with severe upper airway Streptococcus species in immunized populations.

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The photomicrographs are representative of the early (neutrophilic) (left) and later (mononuclear) cellular infiltrates (right) of infarcted myocardium cholesterol medication kidney disease purchase atorlip-5 5mg otc. For sake of simplicity cholesterol molecule buy genuine atorlip-5 on line, edema is shown as an acute transient response cholesterol in fish and shrimp buy discount atorlip-5 5mg, although secondary waves of delayed edema and neutrophil infiltration can also occur cholesterol phospholipid ratio buy atorlip-5 5mg on line. Figure 2-9 Scanning electron micrograph of a moving leukocyte in culture showing a filopodium (upper left) and a trailing tail cholesterol test how many hours fasting cheap atorlip-5 5mg. Different classes of cell surface receptors of leukocytes recognize different stimuli lowering cholesterol what foods to eat buy 5 mg atorlip-5 mastercard. Note that during phagocytosis, granule contents may be released into extracellular tissues. B, Production of microbicidal reactive oxygen intermediates within phagocytic vesicles. Superoxide is then converted into hydrogen peroxide (H2 O2), mostly by spontaneous dismutation. Most of the H2 O2 is eventually broken down by catalase into H2 O and O2, and some is destroyed by the action of glutathione oxidase. In response to activating stimuli, the cytosolic protein components translocate to the plasma membrane or phagosomal membrane, where they assemble and form the functional enzyme complex (see. A similar enzyme system generates reactive nitrogen intermediates, notably nitric oxide, which also helps to kill microbes. The latter is a potent antimicrobial agent that destroys microbes by 2 2 [33] halogenation (in which the halide is bound covalently to cellular constituents) or by oxidation of proteins and lipids (lipid peroxidation). In addition, neutrophil granules contain many enzymes, such as elastase, that also contribute to microbial killing (discussed later in the chapter). After killing, acid hydrolases, which are normally stored in lysosomes, degrade the microbes within phagolysosomes. The pH of the phagolysosome drops to between 4 and 5 after phagocytosis, this being the optimal pH for the action of these enzymes. Release of Leukocyte Products and Leukocyte-Induced Tissue Injury During activation and phagocytosis, leukocytes release microbicidal and other products not only within the phagolysosome but also into the extracellular space. The most important of these substances in neutrophils and macrophages are lysosomal enzymes, present in the granules; reactive oxygen intermediates; and products of arachidonic acid metabolism, including prostaglandins and leukotrienes. These products are capable of causing endothelial injury and tissue damage and may thus amplify the effects of the initial injurious agent. Products of monocytes/macrophages and other leukocyte types have additional potentially harmful products, which are described in the discussion of chronic inflammation. Thus, if persistent and [36] unchecked, the leukocyte infiltrate itself becomes the offender, and leukocyte-dependent tissue injury underlies many acute and chronic human diseases (Table 2-2). This fact becomes evident in the discussion of specific disorders throughout this book. Regulated secretion of lysosomal proteins is a peculiarity of leukocytes and other hematopoietic cells. Release may occur if the phagocytic vacuole remains transiently open to the outside before complete closure of the phagolysosome (regurgitation during feeding). If cells are exposed to potentially ingestible materials, such as immune complexes deposited on immovable flat surfaces. Cytotoxic release occurs after phagocytosis of potentially membranolytic substances, such as urate crystals, which damage the membrane of the phagolysosome. In addition, there is some evidence that proteins in certain granules, particularly the specific (secondary) granules of [37] [38] neutrophils, may be directly secreted by exocytosis. After phagocytosis, neutrophils rapidly undergo apoptotic cell death and are ingested by macrophages. Defects in Leukocyte Function From the preceding discussion, it is obvious that leukocytes play a central role in host defense. Not surprisingly, therefore, defects in leukocyte function, both genetic and acquired, lead to increased vulnerability to infections (Table 2-3). One such disorder is Chediak-Higashi syndrome, an autosomal recessive condition 62 characterized by neutropenia (decreased numbers of neutrophils), defective degranulation, and delayed microbial killing. The neutrophils (and other leukocytes) have giant granules, which can [39] be readily seen in peripheral blood smears and which are thought to result from aberrant organelle fusion. In this syndrome, there is reduced transfer of lysosomal enzymes to phagocytic vacuoles in phagocytes (causing susceptibility to infections) and abnormalities in melanocytes (leading to albinism), cells of the nervous system (associated with nerve defects), and platelets (generating bleeding disorders). The gene associated with this disorder encodes a large cytosolic protein that is apparently involved in vesicular traffic but whose precise function is not yet known. The secretion of granule proteins by cytotoxic T cells is also affected, accounting for part of the immunodeficiency seen in the disorder. The importance of oxygen-dependent bactericidal mechanisms is shown by the existence of a group of congenital disorders with defects in bacterial killing called chronic granulomatous disease, which render patients susceptible to recurrent bacterial infection. The most common variants are an X-linked defect in one of the plasma membrane-bound [40] [41] components (gp91phox) and autosomal recessive defects in the genes encoding two of the cytoplasmic components (p47phox and p67phox). This is seen following therapies for cancer (radiation and chemotherapy) and when the marrow space is compromised by tumor metastases to bone. Although we have emphasized the role of leukocytes recruited from the circulation in the acute inflammatory response, cells resident in tissues also serve important functions in initiating acute inflammation. Mast cells react to physical trauma, breakdown products of complement, microbial products, and neuropeptides. Macrophages recognize microbial products and secrete most of the cytokines important in acute inflammation. These cells are stationed in tissues to rapidly recognize potentially injurious stimuli and initiate the host defense reaction. In part, inflammation declines simply because the mediators of inflammation have short half-lives, are degraded after their release, and are produced in quick bursts, only as long as the stimulus persists. In addition as [42] inflammation develops, the process also triggers a variety of stop signals that serve to actively terminate the reaction. Not surprisingly, there is great interest in defining the molecular basis 63 of the brakes on inflammation, since this knowledge could be used to design powerful anti-inflammatory drugs. Chemical Mediators of Inflammation Having described the events in acute inflammation, we can now turn to a discussion of the chemical mediators that are responsible for the events. Many mediators have been identified, and how they function in a coordinated manner is still not fully understood. Here we review general principles and highlight some of the major mediators (. Cell-derived mediators are normally sequestered in intracellular granules that need to be secreted. The major cellular sources are platelets, neutrophils, monocytes/ macrophages, and mast cells, but mesenchymal cells (endothelium, smooth muscle, fibroblasts) and most epithelia can also be induced to elaborate some of the mediators. These secondary mediators may be identical or similar to the initial mediators but may also have opposing activities. There is thus a system of checks and balances in the regulation of mediator actions. Figure 2-13 A flat spread of omentum showing mast cells around blood vessels and in the interstitial tissue. Stained with metachromatic stain to identify the mast cell granules (dark blue or purple). The steps in the activation and regulation of complement are described in Box 2-2. The Complement System in Health and Disease the activation of the complement cascade may be divided into early and late steps. In the early steps, three different pathways lead to the proteolytic cleavage of C3. In the late steps, all three pathways converge, and the major breakdown product of C3, C3b, activates a series of other complement components. The Early Steps of Complement Activation the pathways of early complement activation are the following (see Figure): the classical pathway is triggered by fixation of C1 to antibody (IgM or IgG) that has combined with antigen, and proteolysis of C2 and C4, and subsequent formation of a C4b2b complex that functions as a C3 convertase. In this pathway, the spontaneous cleavage of C3 that occurs normally is enhanced and stabilized by a complex of C3b and a breakdown product of Factor B called Bb; the C3bBb complex is a C3 convertase. In the lectin pathway, mannose-binding lectin, a plasma collectin, binds to carbohydrate-containing proteins on bacteria and viruses and directly activates C1; the remaining steps are as in the classical pathway. The C3 convertases break down C3 into C3b, which remains attached to the surface where complement is activated, and a smaller C3a fragment that diffuses away. The Late Steps of Complement Activation the C3b that is generated by any of the pathways binds to the C3 convertase and produces a C5 convertase, which cleaves C5. C5b remains attached to the complex and forms a substrate for the subsequent binding of the C6-C9 components. These receptors are seven-transmembrane G protein-coupled receptors that are expressed on platelets, endothelial and smooth muscle cells, and many other cell types. The prostaglandins are also involved in the pathogenesis of pain and fever in inflammation. It causes a marked increase in pain produced by intradermal injection of suboptimal concentrations of histamine and bradykinin and is involved in cytokine-induced fever during infections (described later). Leukotrienes are several orders of magnitude more potent than histamine in increasing vascular permeability and causing bronchospasm. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes. Cell-cell contact enhances transcellular metabolism, and blocking adhesion inhibits lipoxin 70 production. The principal actions of lipoxins are to inhibit leukocyte recruitment and the cellular components of inflammation. There is an inverse relationship between the amount of lipoxin and leukotrienes formed, suggesting that the lipoxins may be endogenous negative regulators of leukotriene action and may thus play a role in the resolution of inflammation. These mediators inhibit leukocyte recruitment and activation, in part by inhibiting the production of cytokines. Thus, the anti-inflammatory activity of aspirin is likely attributable to its ability to inhibit cyclooxygenases (see below) and, perhaps, to stimulate the production of resolvins. Figure 2-16 Generation of arachidonic acid metabolites and their roles in inflammation. The molecular targets of action of some anti-inflammatory drugs are indicated by a red X. Figure 2-20 Ultrastructure and contents of neutrophil granules, stained for peroxidase activity. Extracellular release of low levels of these potent mediators can increase the expression of chemokines. As mentioned earlier, the physiologic function of these reactive oxygen intermediates is to destroy phagocytosed microbes. At higher levels, release of 74 these potent mediators can be damaging to the host. Adherent neutrophils, when activated, not only produce their own toxic species, but also stimulate xanthine oxidation in endothelial cells themselves, thus elaborating more superoxide. This leads to unopposed protease activity, with increased destruction of extracellular matrix. Serum, tissue fluids, and host cells possess antioxidant mechanisms that protect against these potentially harmful oxygen-derived radicals. These antioxidants were discussed in Chapter 1; they include: (1) the copper-containing serum protein ceruloplasmin; (2) the iron-free fraction of serum, transferrin; (3) the enzyme superoxide dismutase, which is found or can be activated in a variety of cell types; (4) the enzyme catalase, which detoxifies H2 O2; and (5) glutathione peroxidase, another powerful H2 O2 detoxifier. Thus, the influence of oxygen-derived free radicals in any given inflammatory reaction depends on the balance between the production and the inactivation of these metabolites by cells and tissues. The small peptides, such [72] as substance P and neurokinin A, belong to a family of tachykinin neuropeptides produced in the central and peripheral nervous systems. Nerve fibers containing substance P are prominent in the lung and gastrointestinal tract. Sensory neurons appear to produce other pro-inflammatory molecules, which are thought to link the [74] sensing of dangerous stimuli to the development of protective host responses. Recent studies are providing clues about the mechanisms of inflammation in two frequently encountered pathologic conditions. In Chapter 1 we described the role of hypoxia in causing cell injury and necrosis. Although it has been known for many years that necrotic cells elicit inflammatory reactions that serve to eliminate these cells, the molecular basis of this reaction has been largely unknown. This proinflammatory action of uric acid is the basis of the disease gout, in which excessive amounts of uric acid are produced and crystals deposit in joints and other tissues. When Lewis discovered the role of histamine in 75 inflammation, one mediator was thought to be enough. Yet, from this menu of substances we can emphasize a few mediators that may be particularly relevant in vivo (Table 2-6). Vasodilation, an early event in inflammation, is caused by histamine, prostaglandins, and nitric oxide. Prostaglandins play an important role in vasodilation, pain, and fever, and in potentiating edema. Lysosomal products and oxygen-derived radicals are the most likely candidates responsible for the ensuing tissue destruction. Outcomes of Acute Inflammation the discussion of mediators completes the description of the basic, relatively uniform pattern of the inflammatory reaction encountered in most injuries. Although hemodynamic, permeability, and leukocyte changes have been described sequentially and may be initiated in this order, all these phenomena may be concurrent in the fully evolved reaction to injury. As might be expected, many variables may modify this basic process, including the nature and intensity of the injury, Figure 2-21 Outcomes of acute inflammation: resolution, healing by fibrosis, or chronic inflammation (see text).

A 30-year-old African-American of severe chronic alcohol abuse presents with woman presents with bilateral hilar low-grade fever cholesterol hdl ratio fasting buy 5mg atorlip-5, jaundice cholesterol test walmart atorlip-5 5mg sale, hepatomegaly test cholesterol jeun 5mg atorlip-5 with visa, lymphadenopathy and reticular densities leukocytosis ldl cholesterol diet chart order genuine atorlip-5 on-line, and markedly abnormal liver in both lung fields cholesterol levels on low carb diet buy atorlip-5 5 mg free shipping. The amorphous material is intractable cholesterol test by mail purchase atorlip-5, severe, itching, burning, pruritic an example of rash of the hands and lower extremities that (A) apocrine metaplasia. A 49-year-old man has a recent diagnosis His father, paternal uncle, and several of small cell carcinoma of the lung. A 45-year-old man presents with a form transfusions, he died during an emergency of bacterial infection in which the invad laparotomy that revealed a ruptured spleen ing microorganisms are opsonized prior and a slightly enlarged liver. A 5-year-old boy is seen because he continuous through the years, there have has recurrent hemarthroses and a large been episodic exacerbations of these symp painful hematoma involving the soft tissues toms, which have worsened during the of his right thigh. This scenario suggests which of (D) Presence of Hurthle cells the following disorders On admission to the hospital, his brain are skin was cold and clammy, his pulse was (A) amyloid-containing neuritic plaques rapid and thready, and his blood pressure within cerebral cortex, amygdala, and was 60 systolic and 40 diastolic. Chest radiograph (C) nodular mesangial accumulations of demonstrates pulmonary infiltrates indica basement membrane-like material and tive of pneumonia. Which of the following is hyaline arteriolosclerosis of afferent and the most likely pathogen causing pulmonary efferent arterioles. A 23-year-old woman consults an obste (D) Hepatitis D trician because she is hoping to become (E) Hepatitis E pregnant but is concerned about possible consequences of rubella infection. A 65-year-old man has anemia, spleno received all of her childhood immunizations, megaly, and extramedullary hematopoiesis. Bone marrow biopsy cian administers a rubella vaccination and reveals marked proliferation of fibrous advises her to return for an anti-rubella titer tissue (myelofibrosis) consistent with prior to becoming pregnant. A 27-year-old man who recently arrived 65-year-old man with long-standing in the United States from Central America profound anemia shows megaloblas is found to have hypochromic microcytic tic erythroid hyperplasia. Measurement of which sub Magnetic resonance imaging of the brain stance is the most appropriate procedure in reveals T2 hyperintensities characteristic this patient A pathologist examining a histologic system preparation from an autopsy finds a lesion (D) Associated with leukemia or lymphoma with abundant granulation tissue. This find (E) Caused by prions ing is most likely to be indicative of which of the following An additional likely finding is (D) Tuberculosis (A) history of thorium dioxide (Thorotrast) (E) Wound healing exposure. While being investigated for long-stand (C) Myocardium ing hypertension, a 55-year-old woman is (D) Renal papillae found to have the following serum labora (E) Splenic arterioles tory test values: normal creatinine, total protein, albumin, and globulin; increased 85. A 3-month-old, apparently female calcium and alkaline phosphatase; and infant is evaluated for ambiguous genitalia. These findings the clitoris appears large, and there are pal suggest the presence of pable masses in the inguinal region. Several close rela (E) Klinefelter syndrome tives have had vascular tumors of the eye and cysts of the liver, kidney, and pancreas. A 60-year-old woman presents with (C) Lipoxygenase pathway fever, chills, dysuria, hematuria, and pain. A 56-year-old man with a history of (E) Thrombin time stable angina was seen in the emergency room 1 hour following the onset of 88. A 20-year-old man is hospitalized with were determined too early in the course fever, shaking chills, and widespread cutane of the disease. The diagnosis is generalized hyperpigmentation involving exposed surfaces of the skin, lips, and buccal mucosa. Baltimore, Lippincott following is an important characteristic of Williams & Wilkins, 2012, figure 12-82A, p. Gastric acid secretion is findings include pleuritis, diffuse interstitial refractory to proton pump inhibitors. Laboratory stud antibody fluorescence ies reveal conjugated hyperbilirubinemia, (D) Positive blood cultures for Streptococcus positive urine tests for bilirubin, and total viridans absence of urobilinogen in the urine and (E) Serum antibodies reactive with glomer stools. The probable diagnosis is ular and pulmonary alveolar basement (A) adenocarcinoma of the pancreas. A 5-year-old child in a refugee camp in occlusion of the circumflex branch of the sub-Saharan Africa is seen by a volunteer left coronary artery. Biopsy of the mass suggests it is a calcifications in the mass, which of the pleomorphic adenoma, and he is scheduled following would be most likely A 2-year-old girl with a history of multiple joints, with joint stiffness on rising repeated pulmonary infections is found to in the morning, and early afternoon fatigue have elevated chloride in a sweat test. Joint involvement is sym additional expected finding is metric, with the proximal interphalangeal (A) hypercalcemia. A 65-year-old man presents with (C) Urate crystals and neutrophils in recurrent fever and painless cervical and synovial fluid supraclavicular lymphadenopathy. Chest radiograph demonstrates (C) Degree of differentiation of tumor cells a cavitary lesion in the apex of the left (D) Distribution and extent of disease lung. A 25-year-old woman is seen because of erythrocytes numbness and pain in her fingers and hands (D) Clumping of erythrocytes at on exposure to cold. A 60-year-old woman with uterine (A) Buerger disease (thromboangiitis bleeding is found to have endometrial obliterans) hyperplasia and an ovarian tumor. A diagnosis of acute hematogenous biopsy specimen and confirms the working osteomyelitis is made in a 5-year-old boy diagnostic impression of adenocarcinoma. Colposcopy and cervical biopsy the bladder is performed, and histologic lead to a diagnosis of carcinoma of the cer evaluation demonstrates the presence of vix. The most likely diagnosis is (C) delayed responsiveness of lymphocytes (A) acute appendicitis. A 60-year-old man presents with the ing factor in the pathogenesis of clear cell new onset of dyspnea, chest pain, cough, adenocarcinoma of the vagina In the past, he had worked (A) Excess estrogen stimulation in construction, installing insulation in (B) Herpes simplex virus infection buildings. A 65-year-old man presents with (A) Small cell carcinoma urinary hesitancy, frequency, urgency, (B) Squamous cell carcinoma sensation of incomplete bladder emptying, (C) Mesothelioma and straining to start the urinary stream. Which of the (D) May frequently progress to bony following is the most likely diagnosis A 50-year-old chronic alcoholic with (D) Subdural hematoma jaundice and ascites secondary to known (E) Subarachnoid hemorrhage cirrhosis becomes disoriented and confused. He sustained a head injury his disease is most closely related to the after falling from a ladder. He now has headache, (B) Increased hepatic lymph formation vomiting, and borderline state of conscious (C) Increased portal venous pressure ness. In preparation for a stem cell transplant the following is the most likely diagnosis She states that the headache and (C) Hepatocyte nausea started suddenly several hours ago. A 30-year-old woman presents with following is the most likely mechanism ptosis and severe generalized muscle weak causing these findings A 45-year-old man with a history of right-sided parasagittal mass compressing chronic obstructive pulmonary disease (but not invading) the brain parenchyma. An autopsy is performed on a 75-year (D) Rheumatoid arthritis old man, who for the past several years had (E) Felty syndrome had a pill-rolling tremor in his hand, slow ing of his movements, and muscle rigidity. A 60-year-old woman with a 10-year Autopsy findings reveal depigmentation history of severe rheumatoid arthritis pres of the substantia nigra and locus ceruleus. Histologic examination of the strates a spindled cell population on micros testicular mass tissue demonstrates mor copy. A 12-year-old boy presents with smoky Imaging reveals a large mass in the head of brown-colored urine, oliguria, azotemia, his pancreas. Immunostaining with cytokera (A) Renal amyloidosis tin 20 shows perinuclear dot-like positivity (B) Diabetic nephropathy and synaptophysin is also positive. The laboratory abnormalities (increased serum calcium, parathyroid hormone, and alkaline phosphatase and decreased serum phosphorus) are diagnostic of primary hyperparathyroidism, a well-known cause of hypercalcemia. Fatty change, formation of cell blebs or myelin figures, and swelling of the cell or of organelles are all reversible changes. Modern management requires administration of IgG anti-Rh antibodies to the mother at the birth of a first Rh-positive child in order to avoid maternal sensitization. The risk of malignant transformation in familial multiple polyposis approaches 100%. The incidence of colon cancer is also increased in Crohn disease, but to a lesser degree than in ulcerative colitis. Granulosa cell tumors and thecomas of the ovary characteristically produce estrogen. The clinical history is strongly suggestive of pyogenic meningitis, the most common form of meningitis in the newborn. The absence of both fetal kidneys leads to a decreased volume of amni otic fluid (oligohydramnios) because fetal urine is a major source of amniotic fluid. This leads to a group of secondary abnormalities, often including distorted facies and unilat eral pulmonary hypoplasia. Carcinoma of the urinary bladder, almost always transitional cell carci noma, is associated with industrial exposure to aniline dyes, such as naphthylamine, usually many years in the past. Multiple myeloma often presents with diffuse demineralization of bone, even though punched-out lesions are more characteristic. Findings in this scenario that distinguish multiple myeloma from other conditions also characterized by bony demin eralization include anemia, hypergammaglobulinemia, proteinuria, and normal (rather than increased) serum alkaline phosphatase. Henoch-Schonlein purpura is an IgA immune complex disease char acterized by involvement of small vessels (venules, capillaries, arterioles) with multiple lesions, all about the same age, and is a form of hypersensitivity or leukocytoclastic vas culitis. This combination often results in almost 100% saturation of iron-binding capacity. The scenario is typical of neuroblastoma, the most frequently occurring tumor in infants less than 1 year of age. Marked amplification of N-myc is characteris tic, and greater amplification is a negative prognostic indicator. A linear pattern of glomerular immunofluorescence for IgG is found in Goodpasture syndrome, which is caused by antibodies that react with both glomerular and alveolar basement membranes. Expected findings in this condition include increased serum and urine glucose and ketones. Hypochromic erythrocytes are typical of iron deficiency anemia, some cases of the anemia of chronic disease, and the thalassemias. Although evidence of acute coronary artery obstruction may be found, mor phologic myocardial changes and serum myocardial marker protein elevations are most often delayed for several hours. The most important factor in the pathogenesis of endometrial carcino ma appears to be prolonged estrogen stimulation, such as that associated with estrogen therapy or estrogen-secreting tumors. Other nondiabetic endocrine disorders associated with hyperglycemia include Cushing syndrome, either pituitary or adrenal, with hyperse cretion of corticotropin or cortisol; acromegaly, with hypersecretion of growth hormone; and hyperthyroidism, with hypersecretion of thyroxine. The principal manifestation of this condition, more common in boys, is projectile vomiting, most often occurring in the first 3 to 6 weeks of life. Although now rare in the United States, tertiary syphilis remains the most common cause of this abnormality in many parts of the world. The most frequent causes of mild anemia with hypochromia and microcytosis include iron deficiency anemia, the anemia of chronic disease, and b-thalassemia minor. It often presents in an advanced stage and has the poorest prognosis of the Hodgkin lymphoma variants. The clinical presentation is illustrative of acanthosis nigricans, a cutane ous lesion that may be associated not only with diabetes and other endocrinopathies, but also with visceral malignancy, such as carcinoma of the stomach, lung, breast, or uterus. Adult polycystic kidney is frequently associated with berry aneurysm of the circle of Willis, often in association with cysts in the liver or pancreas. The vignette describes an instance of traumatic fat necrosis, which must be distinguished from enzymatic fat necrosis. Both aflatoxin B1 ingestion and hepatitis B infection are risk factors for hepatocellular carcinoma. The location is most often central rather than peripheral, and there is a marked association with cigarette smoking. Severe diarrhea, fever, and toxicity following broad-spectrum antibiotic therapy is likely due to pseudomembranous colitis. This disorder is caused by overgrowth of Clostridium difficile, a commensal microorganism indigenous to the bowel, and is marked morphologically by superficial mucosal erosions with overlying necrotic, loosely adherent mucosal debris. The clostridia remain intraluminal, but secrete an enterotoxin that is responsible for the clinical and pathologic manifestations of the disorder. Pseudomonas aeruginosa is the most likely pathogen causing chronic pulmonary infection and pulmonary failure, and is the leading cause of death in patients with cystic fibrosis. Hepatitis C virus is the most frequent cause of what was formerly termed non-A, non-B hepatitis. Teardrop-shaped erythrocytes, as well as scattered nucleated red cells and granulocytic precursor cells, can be found in the peripheral blood smear. Patent ductus arteriosus and septal defects are the most frequent con genital cardiac abnormalities associated with congenital rubella infection; however, defects are not limited to the cardiovascular system, and congenital infection can also lead to deafness and mental retardation. In addition, congenital rubella infection, along with other congenital intrauterine infections, accounts for only a small proportion of cases of congenital heart disease, the majority being of unknown cause. The hallmark of the megaloblastic anemias is the finding of megalo blastic erythroid hyperplasia in the bone marrow; pernicious anemia is a megaloblastic anemia.

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