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Evidence of traction spur formation within the anterolateral band has also been found which further implicates its involvement with the development of impingement [21] blood pressure medication toprol buy cheap valsartan 80mg on-line. This finding may provide at least one possible explanation behind the development of traction-type spurs on the anterolateral acromion with advancing age blood pressure chart emt generic valsartan 40mg on line, potentially leading to extrinsic compression of the superior cuff tendons blood pressure eating purchase valsartan 80 mg online. However arteria labialis superior generic 40 mg valsartan otc, whether or not the thickness of the anterolateral band is a cause or effect of rotator cuff disease has not been elucidated blood pressure after exercise buy valsartan 40 mg lowest price. This failed fusion results in a defect known as an "os acromiale" and occurs in approximately 8 % of the population where 1/3 of these individuals are affected bilaterally [24] heart attack 101 generic 80 mg valsartan with amex. Os acromiale is a mobile accessory ossicle that, when unstable and pulled inferiorly by contraction of the deltoid with arm elevation, has been associated with the development of identifiable impingement lesions and pain at the top of the shoulder. In addition, surgical treatment strategies for os acromiale that involve increasing the volume of the subacromial space has not resulted in an improvement in clinical outcomes [26]. Further study is therefore needed to clarify the effects of os acromiale on normal rotator cuff tendons. Unfortunately, these authors did not report their findings at the time of surgery. As a result of this conflicting data, further study is needed to determine if acromial morphology, as described by Bigliani et al [30], is truly associated with the development of symptomatic subacromial impingement and rotator cuff tears. Although a common variant, this acromial morphology has not been associated with rotator cuff disease in the literature. A first line is drawn connecting the superior and inferior rims of the glenoid and extended superiorly such that the line completely crosses the acromion. A second line is drawn vertically that corresponds with the most lateral extent of the acromion. Theories exist that rationalize both increased and decreased acromial indices with rotator cuff disease; however, further study is needed to elucidate the precise role of the acromion in the development of rotator cuff disease. This acromial morphology may have some involvement in the development of subacromial impingement, although further study is needed to substantiate this claim (From Tucker and Snyder [41]; with permission). Excessive lateral extension of the acromion, which is best quantified through calculation of the acromial index. Some investigators report that decreased coverage of the humeral head by the acromion. Although the acromial index appears to play some role in the development of rotator cuff disease, additional studies are needed to fully elucidate the exact pathomechanisms behind this phenomenon. If this theoretical mechanism is factually correct, the supraspinatus tendon could then make contact with the acromion, possibly leading to the cascade of events commonly associated with rotator cuff disease. A similar mechanism may occur when considering glenoid anteversion and retroversion in which tearing of the subscapularis and infraspinatus is observed, respectively [52]. Although at least one study found that surgically decreasing the glenoid inclination angle may decrease the measured amount of superior humeral head translation with passive abduction [49], none of the more recent imaging studies have shown significant associations between any type or degree of glenoid version and the presence of rotator cuff lesions, regardless of location of the tear or the tendon involved [54, 55]. However, a well-designed prospective study would be needed to confirm these claims given the current lack of conclusive clinical data suggesting any association between either the acromial index or glenoid inclination and any shoulder pathology. They argue that degenerative changes and/or traumatic injuries weaken the contractile strength of supraspinatus muscle which predictably leads to superior humeral head migration and cuff impingement beneath the acromion with humeral elevation. Spurring of the anterolateral acromion and erosion of the greater tuberosity are then observed (due to repeated reciprocal contact) along with rotator cuff degeneration. The deterioration of tendon quality due to advanced age is often implicated as one of the primary causes of rotator cuff weakness, potentially resulting in proximal humeral head migration, subsequent bursal irritation and cuff tendinopathy. While the incidence and severity of rotator cuff disease has been found to increase with age on several occasions, Ogata and Uhthoff [59] found that acromial osteophytes were not always present in older patients. Further, those who did have acromial osteophytes actually had articular-sided partial-thickness rotator cuff tears (as opposed to bursal-sided tears). However, a more recent study identified the presence of anterolateral acromial spurs as an independent risk factor for the development of rotator cuff disease [33]. Further research is needed to identify and elucidate the roles of mechanical compression and intrinsic tendon degeneration on the progression of rotator cuff disease. Lohr and Uhthoff [12] identified an area along the edges of supraspinatus tears in which no vessels were present, suggesting that spontaneous healing of a torn rotator cuff tendon is probably not feasible without surgical intervention. They described a hypovascular zone on the surface of the supraspinatus tendon, confirming the findings that had been reported by others. This area of the insertional footprint, termed the "critical zone" by Moseley and Goldie [64] in 1963, may have an increased propensity to develop partial- or full-thickness rotator cuff tears as a result of poor tendon nutrition and a limited capacity for spontaneous healing. Therefore, consideration of all available information, including other clinical tests and historical features, is necessary to synthesize an accurate physical diagnosis in every patient. When the diagnosis is in question, it is often useful to inject a local anesthetic into the subacromial space before repeating each test. Arrows correspond to the region of avascularity and asterisks indicate the location of the supraspinatus footprint on the greater tuberosity. This technique is usually referred to as the Neer impingement test which should not be confused with the Neer impingement sign (described below). Stabilization of the scapula is essential to maximize the utility of the test since upward rotation of the scapula (and therefore the acromion) with forward elevation will decrease the likelihood of reproducing cuff impingement under the acromion. Several investigators have evaluated the clinical efficacy of the Neer impingement sign in its ability to accurately diagnose subacromial impingement (Table 4. Interestingly, although each study reported similar sensitivity values, their specificity values were divergent (95 % and 10 %, respectively). These results highlight the significant variability that may exist in the performance and interpretation of physical examination findings, specifically with regard to subacromial impingement syndrome. In that study, the overall calculated sensitivity of the Neer impingement sign was 72 % while its overall specificity was approximately 60 %. The examiner stabilizes the scapula with one hand and uses the other hand to passively forward-flex the humerus to a point of maximal elevation. The examiner then internally rotates the humerus which is thought to induce impingement between the greater tuberosity and the undersurface of the acromion. Pain with this maneuver is another possible indicator of subacromial impingement, especially when used in combination with the tests described above. Although this test is not very sensitive in isolation, it does boast a modest specificity as reported by Hegedus et al. In contrast to subacromial impingement which likely involves a multitude of intrinsic and extrinsic factors, most authors agree that many subscapularis tears associated with a narrowed coracohumeral interval. In this test, the patient attempts to abduct the humerus within the scapular plane against resistance provided by the examiner. Weakness or pain with this maneuver may indicate the presence of subacromial impingement, although other tests are needed to confirm this finding. In this image, both arms are tested simultaneously which may be more sensitive for the detection of more subtle pathology. Although primary subcoracoid impingement has been relatively understudied, it probably involves multiple intrinsic and extrinsic factors that lead to a narrowed coracohumeral interval. Malunited fractures of the glenoid neck, proximal humerus, glenoid or coracoid can impinge upon the subscapularis muscle, thus resulting in anterior shoulder pain [85]. Iatrogenic causes can include any type of anterior shoulder surgery, potentially causing the formation of subcoracoid adhesions and a functionally narrowed coracohumeral interval. Idiopathic causes may include ganglion cysts, congenitally malformed coracoid processes or subscapularis calcifications. Recently, several studies have described the various morphologic characteristics of the coracoid and their potential roles in the development 4. The doubleheaded red arrow lies perpendicular to the white line and travels to the most lateral tip of the coracoid process. The double-headed white arrow represents the distance between the lesser tuberosity and the most posterior aspect of the coracoid process. When the humerus is internally rotated, the coracoid induces a "roller wringer" effect on the subscapularis tendon which induces stretching and tearing of the tendon when the coracohumeral interval is narrowed [87]. Despite this evidence, the instigating factor involved in the development of anterosuperior cuff pathology in patients with a narrowed coracohumeral interval has yet to be completely elucidated. This pain may radiate distally along the brachium if the long head of the biceps tendon is involved. Although patients typically present with a full range of motion, they typically present with pain over the coracoid that is exacerbated by forward flexion, internal rotation, and cross-body adduction. Because this entity has not been studied extensively, it remains a diagnosis of exclusion when all other causes of anterior shoulder pain have been ruled out. Despite the lack of literature on the subject, it is important to remember that subcoracoid impingement may be the result of disordered scapular mechanics. Thus, it is critically important to evaluate the scapula in patients suspected of having subcoracoid impingement (physical evaluation of the scapula is discussed in Chap. In the setting of a normal scapular exam, the subcoracoid impingement test may be an important tool in the diagnosis of subcoracoid impingement. As the arm is adducted and internally rotated, the patient with subcoracoid impingement will complain of a dull anterior shoulder pain. Although this test has not been fully evaluated in the literature, we have found the test useful to identify patients with chronic lesions involving the subscapularis tendon. Because the subscapularis muscle makes a significant contribution to the bicipital sheath, testing for pathology of the long head of the biceps tendon is also indicated when subcoracoid impingement is suspected (physical examination of the long head of the biceps tendon is discussed in Chap. When resistance is felt, it is sometimes useful to gently force the humerus into a greater degree of adduction, especially in cases where the test is inconclusive. The test is positive for subcoracoid impingement when a dull anterior shoulder pain is elicited. The term "internal impingement" refers to a normal physiologic occurrence where the greater tuberosity makes contact with the posterosuperior glenoid labrum when the humerus is abducted and externally rotated. Although its primary function may involve the prevention of hyperexternal rotation and maintenance of stability, repeated episodes of this impingement (which often occurs with repeated overhead activities such as throwing) may lead to posterosuperior labral tears and posterosuperior rotator cuff tears which eventually become symptomatic. In essence, the posterosuperior labrum and rotator cuff become pinched between the greater tuberosity and the bony glenoid rim leading to posterior shoulder pain (due to pathology of the posterosuperior labrum and rotator cuff) especially when the humerus is abducted and externally rotated. Hyperabduction and external rotation may pinch the posterosuperior cuff between the greater tuberosity and the glenoid, possibly leading to articular-sided posterosuperior rotator cuff tears and tearing of the posterosuperior glenoid labrum. In acute injuries, patients will typically recall the specific events leading to their shoulder pain, weakness, and dysfunction. Although each type of impingement involves a chronic process, many patients are asymptomatic until the tear has reached sufficient size and/or has resulted in altered glenohumeral kinematics. As such, it is thought that previously asymptomatic rotator cuff lesions may progress to larger, full-thickness tears especially in patients with altered tendon biology [12, 101]. Without treatment, small tears with intact glenohumeral mechanics can progress to larger tears, leading to weakness and unbalanced force couples and, subsequently, increased shoulder pain and dysfunction [102, 103]. As discussed above, subacromial impingement involves a combination of intrinsic factors. As the cuff tear develops and increases in size, pain and weakness become the predominant features. Pain and weakness become worse as the tear extends to involve other tendons, such as those of the infraspinatus (posterosuperior tear) or subscapularis (anterosuperior tear). Left untreated, pain will often diminish and the patient will complain of weakness as the primary symptom [104]. Similar to subacromial impingement, the progression of small, structural lesions of the subscapularis can lead to large, full-thickness tears resulting in progressive pain, dysfunction and, in some cases, anterior instability [10]. Symptomatic internal impingement occurs as a result of repetitive hyperabduction and external rotation which leads to posterosuperior articularsided rotator cuff tears and labral lesions (see. These patients may also report a gradual decrease in throwing performance such as a decline in throwing accuracy and 94 4 Rotator Cuff Disorders velocity.
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Pemphigus vulgaris blood pressure numbers for seniors purchase valsartan 80mg otc, which is described in the clinical scenario arteria tapada en ingles buy 160 mg valsartan overnight delivery, often begins as oral lesions and subsequently appears cutaneously blood pressure 9870 discount valsartan 160mg with visa. The Nikolsky sign is positive (pressure at the edge of a blister causes extension of the bulla into adjacent normal skin) in pemphigus blood pressure medication helps acne cheap 160 mg valsartan with visa, while in bullous pemphigoid the Nikolsky sign is negative blood pressure pulse discount 160mg valsartan visa. For more details on junctional complexes zebrafish arrhythmia buy discount valsartan 160 mg on-line, see the table in the answer for question 83. Cytoplasmic microtubules (answer b) are found in the singlet form and undergo constant association and dissociation of tubulin at their plus ends and minus ends, respectively. Flagella (answer c) have the same "9+2" arrangement as cilia, but are limited to one per cell and in adult humans are found only in sperm. Stereocilia (answer e) are large, modified microvilli, found in the epididymis and on hair cells in the organ of Corti, therefore, they are not composed of microtubules. On physical examination it is noted that she has scoliosis, pectus excavatum, ectopia lentis, and myopia. Her musculoskeletal exam reveals long upper and lower extremities, including the fingers and toes, and an overall gangly, lanky appearance. She has very flexible fingers and a narrow face as well as a narrow mouth with overcrowded teeth. Which part of the cardiovascular system would often be adversly affected in this syndrome? Middle cerebral artery Basilar artery Aorta Lymphatic vessels Superior vena cava 87. The extracellular matrix and the cytoskeleton communicate across the cell membrane through which of the following? A pregnant 29-year-old woman diagnosed with type I diabetes 2 decades ago, taking Humulin three times per day, is referred to the ophthalmology clinic. Dilated indirect ophthalmoscopy coupled with biomicroscopy and fundus photography detect the presence of proliferative diabetic retinopathy with leaky retinal vessels indicative of increased vascular permeability, growth of new, fragile vessels on the retina and posterior surface of the vitreous and macular edema. Overexpression of fibronectin is a histological marker of diabetic microangiopathy. Which of the following is the primary function of fibronectin in the basement membrane? Elasticity Cell attachment and adhesion Binding to selectins Binding to cadherins Binding to actin filaments 89. A 36-year-old man is referred by his family medicine physician to the pulmonary clinic. He complains of shortness of breath following physical activity and a decreased capacity for exercise. He says that strenuous exercise including yard work is impossible without sitting down and resting every few minutes. He is not a smoker and as an office worker he is not exposed to dust, fumes or other irritants at work. In the synthesis of collagen, the hydroxylation of proline and lysine occurs in which of the following? Golgi apparatus Secretory vesicles Rough endoplasmic reticulum Smooth endoplasmic reticulum Lysosomes 91. The primary function of entactin (also known as nidogen) is to crosslink which of the following? Laminin to collagen Cells to the basal lamina Cells to the extracellular matrix Collagen Actin 93. A 14-year-old boy presents with thin, translucent skin, and a history of easy bruising. Rupture of the intestinal or aortic walls Hyperextensibility of the integument Hypermobility of synovial joints Increased degradation of proteoglycans in articular cartilages Imperfections in dentin formation (dentinogenesis imperfecta) 174 Anatomy, Histology, and Cell Biology 94. The tissue shown in the photomicrograph differs from white adipose tissue in which of the following ways? Export of fatty acids Role as a thermal insulator Use of fatty acids to produce heat Activation of the adenylate cyclase system Initiation of shivering 95. Diseases in which there is a loss of function mutation in integrin expression on lymphocytes would most likely result in: a. Leukopenia Leukocytosis Lymphadenopathy Lymphocyte apoptosis Increased numbers of plasma cells in the blood Connective Tissue 175 96. A 33-year-old homeless woman has been living in an abandoned building eating dried meat, bread from the trash cans outside a bakery. She presents at the free clinic with bleeding under the skin particularly around hair follicles with bruises on her arms and legs. She is irritable, clinically depressed, and fatigued with general muscle weakness. She is afebrile and a glucose finger stick is normal and urine dipstick shows no sugar, protein or ketones. Decreased degradation of collagen Stimulation of prolyl hydroxylase Formation of unstable collagen helices Excessive callus formation in healing fractures Organ fibrosis 97. Which of the following is a major contributor to the tensile strength of collagen? As an integrin In cell-cell adhesion As the insoluble scaffolding of the basal lamina As the filtration molecule in the basement membrane In adherence of epithelia to the basement membrane 176 Anatomy, Histology, and Cell Biology 99. A 40-year-old woman is referred to a dermatologist with more than 100 oval or round red-brown macules on her back. There are an excessive number of the metachromaticallystained cells labeled with the arrows and shown in the inset to the lower left in the photomicrograph below. A 46-year-old woman who has been a type I diabetic for 35 years visits your family medicine office. You prescribe Beclaperin gel, a prescription drug for the treatment of diabetic foot ulcers. His physical examination reveals slight right-sided muscular weakness and a pulse of 78/min, regular; blood pressure 140/82 mm Hg. X-ray examination of the spine showed two wedged thoracic vertebrae, T7 and T8; no osteolytic lesions are observed. The bone marrow shows an increase in the cells shown in the accompanying light micrograph. Collagen Heparin and histamine Histaminase IgA Myeloperoxidase Connective Tissue 179 102. She works as a software developer and lives with her 52-year-old husband and 12-year-old daughter. She is a nonsmoker; and drinks an occasional glass of wine when she and her husband go out to dinner. In this patient, during the period of weight gain which of the following responses would be most expected in the cells shown in the photomicrograph? Up-regulation of leptin-receptors Decreased synthesis of leptin Decreased release of leptin into the serum Increased secretion of neuropeptide Y Increased release of norepinephrine from nerve terminals in adipose tissue 180 Anatomy, Histology, and Cell Biology 103. A 65-year-old African-American man who has a history of both urinary tract infections and urinary stones presents at the urology clinic with hematuria. He has a dietary history high in saturated fats and has been exposed to second-hand smoke both at home (his wife smokes) and at work where many of his coworkers smoke. Decreased elasticity of lung tissue causes an increased tendency toward spontaneous pneumothorax, also known as a collapsed lung. The aorta is the most affected organ because of the extensive elastin in the wall, and dissecting aortic aneurysms are common in these patients. Marfan malformations include cardiovascular (valve problems as well as aortic aneurysm), skeletal (abnormal height and severe chest deformities), and ocular systems. The result is the dislocation of the lens because of loss of elasticity in the suspensory ligament. The receptor structure includes an intracytosolic portion that binds to the actin cytoskeleton through the attachment proteins talin or -actinin. Proteoglycans (answer a) are located on the extracellular surface of the plasma membrane and throughout the extracellular matrix. The cadherins (answer c) function as transmembrane glycoproteins involved in the formation of parts of the intercellular junctional complexes. Intermediate filaments and microtubules (answers d and e) are found intracellularly and constitute the cytoskeleton. It is important for modulation of cell migration in the adult and during development. Neural crest and other cells appear 181 182 Anatomy, Histology, and Cell Biology to be guided along fibronectin-coated pathways in the embryo. Fibronectin is found in three forms: a plasma form that is involved in blood clotting; a cell-surface form, which binds to the cell surface transiently; and a matrix form, which is fibrillar in arrangement. Cell-cell interactions involve both transient and more long-term, stable processes. Cell-cell adhesion is mediated by transmembrane proteins called cell adhesion molecules which include the calcium or magnesium-dependent selectins, integrins, and cadherins (answers c and d) and the non-calcium-dependent immunoglobulin (Ig) superfamily. The stable adhesion junction, known as the zonula adherens, links the cytoskeleton of adjacent cells through cadherins (transmembrane linker proteins) to actin filaments inside the cell [answer e (see feedback for question 199)]. Desmosine and isodesmosine are amino acids unique to elastin and responsible for the covalent binding of elastin fibers to each other. Microfibrils, composed of fibrillin, facilitate formation of the elastin molecules, but are not directly involved in cross-linking. Onethird of elastin is composed of the hydrophobic amino acid glycine, which is randomly distributed throughout the elastin molecule. The overall hydrophobicity of elastin molecules allows for their distensibility and facilitates their capacity to slide over one another. Hydroxyproline, which constitutes 10% of collagen, is often used to determine the collagen content of various tissues. Hydroxylation of proline stabilizes the triple helix through interchain hydrogen bonds, and hydroxylation of lysine is critical for the cross-linking stage of collagen assembly. Procollagen is subsequently transported in transfer vesicles to the Golgi for packaging into secretory vesicles. Outside of the cell, N-terminal and C-terminal specific procollagen peptidases cleave the nonhelical registration peptides, which results in the formation of tropocollagen. Tropocollagen spontaneously assembles in a staggered array to form collagen fibrils. Lysyl oxidase (answer a) is an extracellular enzyme responsible for the formation of covalent cross-links between tropocollagen molecules. Fibrils form collagen fibers under the influence of other extracellular matrix constituents, such as proteoglycans and glycoproteins. Collagenases (answer d) specifically cleave tropocollagen in the extracellular matrix. Integrins like laminin receptors (answer b) bind cells to the basal lamina; fibronectin receptors bind cells to the extracellular matrix (answer c). Laminin receptors in the cell membrane also organize the assembly of the basal lamina. Collagen (answer d) is cross-linked by covalent intramolecular and intermolecular cross-links that form primarily between the nonhelical segments at the ends of the collagen molecules. Lysyl oxidase is a key enzyme in the cross-linking process; it deaminates lysine and hydroxylysine to form aldehyde groups that react with each other to form the covalent bonds. Actin is cross-linked 184 Anatomy, Histology, and Cell Biology (answer e) into bundles by actin-binding proteins such as the bundling protein -actinin and the gel-forming protein (fimbrin). This results from a genetic mutation that alters the propeptide sequence in such a way that the molecular orientation and cross-linking are adversely affected. Both types of fat tissue (brown and white) are highly vascularized and function in protection from the cold. Brown fat specifically is involved in heat production, whereas white fat is a true thermal insulator. Brown fat is involved in nonshivering thermogenesis and generates heat (answer c), probably as a protective device for developing organs in the fetus and neonate. White adipose tissue is specialized for lipid storage and functions as a thermal insulator (answer b) and shock absorber. White adipose tissue is unilocular, and the cells have a single, large lipid droplet in the cytoplasm that provides the "signet-ring" appearance often described for fat cells. Brown adipose tissue has a multilocular appearance and is brown because of numerous mitochondria. In white adipocytes, the released fatty acids and glycerol are exported from the cells. Heat is transferred to the blood by the extensive capillary networks found in brown adipose tissue. Shivering (answer e) initiates the mobilization of lipid in white adipose tissue because shivering requires energy. E and P-selectins bind reversibly to glycoproteins on leukocytes causing them to roll along the endothelial surface. Adhesion of leukocytes results in arrest of leukocyte motion, allowing secreted proteases to disrupt endothelial tight junctions and the basement membrane, subsequently resulting in diapedesis. Lymphocyte apoptosis (answer d) is not regulated directly by integrins and plasma cells do not normally enter the blood (answer e). The leukocyte adhesion cascade involves several precise ordered steps: rolling, integrin activation and firm adhesion of the leukocytes, all necessary prerequisites to transendothelial migration.
An example of this is serum sickness (see Section 12-16) blood pressure medication on empty stomach buy 160 mg valsartan, which is caused by injection of large amounts of serum proteins blood pressure when pregnant 160mg valsartan. This is a transient disease pulse pressure calculator valsartan 80 mg without prescription, lasting only until the immune complexes have been cleared blood pressure chart guide discount 40mg valsartan overnight delivery. The second circumstance is seen in chronic infections such as bacterial endocarditis heart attack effects buy valsartan 160 mg fast delivery, where the immune response to bacteria lodged on a cardiac valve is incapable of clearing infection blood pressure medication causing low blood pressure discount valsartan 80mg on line. The persistent release of bacterial antigens from the valve infection in the presence of a strong antibacterial antibody response causes widespread immune-complex injury to small blood vessels in organs such as the kidney and the skin. This is an immune complex-mediated disease characterized by chronic IgG antibody production directed at ubiquitous self antigens present in all nucleated cells. The main antigens are three intracellular nucleoprotein particles the nucleosome, the spliceosome, and a small cytoplasmic ribonucleoprotein complex containing two proteins known as Ro and La (named after the first two letters of the surnames of the two patients in which autoantibodies against these proteins were discovered). In order for these autoantigens to participate in immune-complex formation, they must become extracellular. The consequent tissue damage releases more nucleoprotein complexes, which in turn form more immune complexes. Eventually, the inflammation induced in small blood vessel walls, especially in the kidney, can cause sufficient damage to kill the patient. Panel b, a similar section stained with fluorescent antiimmunoglobulin, reveals immunoglobulin deposits in the basement membrane. Panel c, by electron microscopy the immune complexes are seen as dense protein deposits between the glomerular basement membrane and the renal epithelial cells. Polymorphonuclear neutrophilic leukocytes are also present, attracted by the deposited immune complexes. The presence of an autoantibody by itself is not sufficient to cause autoimmune disease. For disease to occur, the autoantigen must be available for binding by the autoantibody. Two examples illustrate how the availability of autoantigens and the resulting expression of disease can be modulated by environmental cofactors. This pattern of disease expression was explained when it was discovered that pulmonary hemorrhage was found almost exclusively in those patients who smoked cigarettes. What differs between basement membrane in glomeruli, alveoli, and the cochlea is the availability of the antigen to antibodies. The major function of glomerular basement membrane is the filtration of plasma, and the endothelium lining glomerular capillaries is fenestrated to allow access of plasma to the basement membrane. Glomerular basement membrane is therefore immediately accessible to circulating autoantibodies. In the alveoli, in contrast, the basement membrane separates the alveolar epithelium from the capillary endothelium, whose cells are joined together by tight junctions. Injury to the endothelial lining of pulmonary capillaries is therefore necessary before antibodies can gain access to the basement membrane. Cigarette smoke stimulates an inflammatory response in the lungs, which damages alveolar capillaries and exposes the autoantigen to antibody. Finally, in the inner ear, the cochlear basement membrane seems to remain inaccessible to autoantibodies at all times. This disease, which is characterized by a severe necrotizing vasculitis, is strongly associated with the presence of autoantibodies to a granule proteinase of neutrophils. The autoantigen is proteinase-3, an abundant serine proteinase of neutrophil granules. If such an individual develops an infection, however, this frequently induces a severe flare-up of the vasculitis. IgG antibodies in the serum reactive with cytoplasmic granules are detected by addition of fluorescein-conjugated antibodies against IgG. It is thought that the reason for this is that resting neutrophils do not express proteinase-3 on the cell surface, and so in the absence of infection the antigen is inaccessible to anti-proteinase-3 autoantibodies. After infection, a variety of cytokines activate neutrophils, with translocation of proteinase-3 to the cell surface. Antiproteinase-3 antibodies can now bind neutrophils and stimulate degranulation and release of free radicals. In parallel, activation of vascular endothelial cells by the infection causes the expression of vascular adhesion molecules, such as E-selectin, which promote the binding of activated neutrophils to vessel walls with resultant injury. In this way, a variety of nonspecific infections can exacerbate an autoimmune disease. The pattern of inflammatory injury in autoimmunity can be modified by anatomical constraints. Another example of how the expression of autoimmune inflammation can be modified by anatomical factors is seen in membranous glomerulonephritis. In this disease, patients develop heavy proteinuria (the excretion of protein in the urine), which can cause life-threatening depletion of plasma protein levels. The proteinuria can be abolished by depletion of any of the proteins of the membrane-attack complex of complement but is unaltered by depletion of neutrophils. This shows that the antibodies deposited beneath the glomerular basement membrane in this disease cause tissue injury by activation of complement, but the glomerular basement membrane acts as a complete barrier to inflammatory leukocytes. In other autoimmune diseases, high levels of autoantibodies against intracellular antigens can be found in the absence of any evidence of antibody-induced inflammation. One such example is a rare myositis (inflammation of muscle) associated with pulmonary fibrosis. Addition of these autoantibodies to cell-free extracts in vitro stops translation and protein synthesis completely. There is, however, no evidence that these antibodies cause any injury in vivo, where it is unlikely that they can enter living cells. In this disease, the autoantibody is thought to be a marker of a particular pattern of tissue injury, and does not contribute to the immunopathology of the myositis. Other examples of autoantibodies that are useful diagnostic markers of the presence of disease, but that might play no part in causing organ injury, are antibodies against mitochondrial antigens associated with primary biliary cirrhosis and antibodies against smooth muscle antigens in chronic active hepatitis. The mechanism of autoimmune tissue damage can often be determined by adoptive transfer. To classify a disease as autoimmune, one must show that an adaptive immune response to a self antigen causes the observed pathology. Initially, the demonstration that antibodies against the affected tissue could be detected in the serum of patients suffering from various diseases was taken as evidence that the diseases had an autoimmune basis. However, such autoantibodies are also found when tissue damage is caused by trauma or infection, though these are typically of much lower affinity than those associated with autoimmune disease. This suggests that autoantibodies can result from, rather than be the cause of, tissue damage. Thus, one must show that the observed autoantibodies are pathogenic before classifying a disease as autoimmune. It is often possible to transfer disease to experimental animals through the transfer of autoantibodies, causing pathology similar to that seen in the patient from whom the antibodies were obtained. This does not always work, however, presumably because of species differences in autoantigen structure. This natural experiment is one of the best proofs that particular autoantibodies exert pathogenic effects. Serum from some patients with autoimmune disease can transfer the same disease to experimental animals. When the autoantigen is very similar in humans and mice or rats, the transfer of antibody from an affected human can cause the same symptoms in an experimental animal. Some autoimmune diseases that can be transferred across the placenta by pathogenic IgG autoantibodies. These diseases are caused mostly by autoantibodies to cell-surface or tissue-matrix molecules. This suggests that an important factor determining whether an autoantibody that crosses the placenta causes disease in the fetus or newborn baby is the accessibility of the antigen to the auto-antibody. Autoimmune congenital heart block is caused by fibrosis of the developing cardiac conducting tissue, leading to slowing of the heart rate (bradycardia), and there is evidence that this expresses abundant Ro antigen (see Section 13-9). Ro protein is a constituent of an intracellular small cytoplasmic ribonucleo-protein. It is not yet known whether it is expressed at the cell surface of cardiac conducting tissue to act as a target for autoimmune tissue injury. Antibody-mediated autoimmune diseases can appear in the infants of affected mothers as a consequence of transplacental antibody transfer. In pregnant women, IgG antibodies cross the placenta and accumulate in the fetus before birth (see. Babies born to mothers with IgG-mediated autoimmune disease therefore frequently show symptoms similar to those of the mother in the first few weeks of life. Fortunately, there is little lasting damage as the symptoms disappear along with the maternal antibody. Children of mothers making thyroid-stimulating antibody are born with hyperthyroidism, but this can be corrected by replacing the plasma with normal plasma (plasmapheresis), thus removing the maternal antibody. IgE is found mainly associated with mast cells just beneath epithelial surfaces (especially of the respiratory tract, gastro-intestinal tract, and skin). T cells specific for self antigens can cause direct tissue injury and have a role in sustained autoantibody responses. Affected tissues in patients with these diseases are heavily infiltrated with T lymphocytes and activated macrophages. It is much more difficult to demonstrate the existence of autoreactive T cells than it is to demonstrate the presence of autoantibodies. Second, it is difficult to identify the antigen recognized by a T cell; for example, autoantibodies can be used to stain self tissues to reveal the distribution of the autoantigen, whereas T cells cannot. Nevertheless, there is strong evidence for the involvement of autoreactive T cells in several autoimmune diseases. Recurrence of disease can be prevented by the immunosuppressive drug cyclosporin A (see Chapter 14), which inhibits T-cell activation. Progress towards identifying the targets of such autoreactive T cells and proving that these cells cause disease will be discussed in Section 13-15. This approach is particularly useful if the autoantibody causes disease in animals, from which large amounts of tissue can be obtained. Autoantibodies can also be used to examine the distribution of the target antigen in cells and tissues by immunohistology, often providing clues to the pathogenesis of the disease. For example, in myasthenia gravis the autoantibodies that cause disease bind mainly to the chain of the acetylcholine receptor and can be used to isolate the receptor from lysates of skeletal muscle cells. Thus, both autoreactive B cells and autoreactive T cells are required for this disease. Autoantibodies from the serum of myasthenia gravis patients immunoprecipitate the acetylcholine receptor from lysates of skeletal muscle cells (top panels). T cells specific for epitopes of the acetylcholine receptor are stimulated to proliferate and can thus be detected. Tissue damage in this disease is caused by immune complexes of autoantibodies directed against a variety of nucleoprotein antigens (see Section 13-9). These autoantibodies show a high degree of somatic hypermutation, which has all the hallmarks of being antigen-driven (see Section 4-9), and the B cells that produce them can be shown to have undergone extensive clonal expansion. Further evidence for this comes from the collective autoantibody specificities observed in individual patients. A B cell whose receptor binds a component of this particle will internalize and process the particle, present the peptide to these autoreactive T cells, and receive help from them. Such B-cell-T-cell interactions initiate the antibody response and promote clonal expansion and somatic hypermutation, thus accounting for the observed characteristics of the autoantibody response as well as the clustering of autoantibody specificities in individual patients. This allows the spreading of the autoimmune response to different components of multimolecular complexes, known as antigen spreading or determinant spreading. Autoreactive helper T cells of one specificity can drive the production of autoantibodies with several different specificities, in a phenomenon known as antigen spreading. This B cell can receive help from a T cell specific for one of the peptides derived from H1 (top panels). Thus, a single auto-reactive helper T cell can stimulate a diverse antibody response, but the antibodies will be restricted to those specific for the constituents of a single type of particle. B cells able to bind ribosomes, for example, do not present the H1 peptide and so will not be activated to produce anti-ribosomal antibodies in this patient (bottom panels). The target of T cell-mediated autoimmunity is difficult to identify owing to the nature of T-cell ligands. Although there is good evidence that T cells are involved in many autoimmune diseases, the T cells that cause particular diseases are hard to isolate, and their targets are difficult to identify. As many autoimmune diseases in animals are induced by immunization with self tissue, the nature of the autoantigen can be determined by fractionating an extract of the tissue and testing the fractions for their ability to induce disease. This disease resembles human multiple sclerosis, in which characteristic plaques of tissue injury are disseminated throughout the central nervous system. Plaques of active disease show infiltration of nervous tissue by lymphocytes, plasma cells, and macrophages, which cause destruction of the myelin sheaths that surround nerve cell axons in the brain and spinal cord. Activated T cells specific for myelin proteins have also been identified in patients with multiple sclerosis. Although it has not yet been proved that these cells cause the demyelination in multiple sclerosis, this finding suggests that animal models might provide clues to the identity of autoantigenic proteins in human disease. Engagement with this antigen triggers the T cells to release lymphokines that initiate local inflammation within the joint. This causes swelling, accumulation of polymorphonuclear leukocytes and macrophages, and damage to cartilage, leading to the destruction of the joint. Rheumatoid arthritis is a complex disease and also involves antibodies, often including an IgM anti-IgG autoantibody called rheumatoid factor. Some of the tissue damage in this disease is caused by the resultant IgM:IgG immune complexes.
The basal layer remains intact and attached to the basal lamina because the hemidesmosomes do not contain cadherins blood pressure natural safe valsartan 160 mg. Bullous pemphigoid is also a blistering disease prehypertension lower blood pressure cheap valsartan 40mg online, but the blistering occurs at the epidermal-dermal junction pulse pressure glaucoma effective 160mg valsartan. The stomach is a grinding organ with glands in the fundus and body that produce mucus (surface and neck cells) arrhythmia burlington ma generic valsartan 40 mg, pepsinogen (chief cells) blood pressure 6040 cheap valsartan 80mg line, and acid and intrinsic factor (parietal cells) heart attack heartburn valsartan 40 mg. Intrinsic factor binds to vitamin B12 and is required for uptake of that vitamin from the intestine. The parietal cell functions in a similar fashion to the osteoclast in using carbonic anhydrase to produce protons that are pumped into the intracellular canaliculi, which are lined by microvilli in the active parietal cell. In the inactive parietal cell, the proton pumps are sequestered in tubulovesicles in the cytosol. The small intestine is an absorptive organ with folds at several levels (plicae, villi, and microvilli) that increase surface area for more efficient absorption. The microvilli also contain specific enzymes for the breakdown of sugars (disaccharidases), lipids (lipases), and peptides (peptidases). The major digestive processes in the small intestine occur through the action of the pancreatic juice, which contains trypsinogen, chymotrypsinogen, procarboxypeptidases, amylase, lipase, and other enzymes. Lipids are broken down to triglycerides in the small intestinal lumen which are subsequently degraded to glycerol, fatty acids, and monoglycerides that are transported into the enterocyte. The chylomicra are exocytosed into the lacteals and travel to the cisterna chyli and through the thoracic duct to the venous system. Other digested materials travel through the hepatic portal vein to the liver where hepatocytes process the digested nutrients. Cell types in the small intestine include enterocytes (absorption), Paneth cells (production of lysozyme, defensins, and cryptidins), goblet cells (mucus), and enteroendocrine cells (secretion of peptide hormones). New cells are born in the crypt, move up the villus, die by apoptosis, and are sloughed off at the tip. The primary function of the colon, which appears histologically as crypts with prominent goblet cells and no villi, is water resorption. The major salivary glands (parotid, submandibular, and sublingual) are exocrine glands that secrete amylase and mucus, primarily regulated by the autonomic nervous system. The liver is also a dual-function gland whose exocrine product is bile, synthesized by hepatocytes, and transported by a duct system to the gallbladder for storage and concentration. The endocrine products include glucose and major blood proteins (albumin, fibrinogen, coagulation proteins). Alcohol detoxification is one of the major processes carried out in the hepatocyte. The bile canaliculus is defined as apical, the junctional complexes as lateral, and the blood surface with the space of Disse and hepatic sinusoids is considered basal. The sinusoids are lined by hepatic stellate cells, endothelial cells, and Kupffer cells. The hepatic stellate cells are affected following chronic alcohol toxicity and are converted into myofibroblasts during the onset of cirrhosis. Those cells synthesize large quantities of High-Yield Facts 31 collagen and are responsible for the fibrotic changes observed in cirrhosis. The Kupffer cells are the antigen-presenting cells of the liver and are derived from monocytes. Hepatocytes are arranged in interlocking cords and plates so there are several ways of analyzing the histological organization of the liver. The classic lobule emphasizes the endocrine function of the liver; the portal lobule emphasizes the exocrine function of the liver, and the liver acinus focuses on actual blood supply and regeneration. The neurohypophysis is derived from the floor of the diencephalon and consists of astrocyte-like glial cells (pituicytes) and expanded terminals of nerve fibers originating in the hypothalamus. The neurohypophysis contains the hormones vasopressin and oxytocin, which are synthesized primarily in the supraoptic and paraventricular nuclei respectively. The adrenal medulla, derived from the neural crest, synthesizes epinephrine and norepinephrine (see figure on the following page). Most of the blood that reaches the adrenal medulla has passed through the adrenal cortex and contains glucocorticoids that regulate the norepinephrine/epinephrine balance in the adrenal medulla through regulation of phenylethanolamine-Nmethyl-transferase. The fetal adrenal cortex functions to produce dehydroepiadrosterone, an androgen that is transported to the placenta where it serves as a precursor of estrogen. The gland is covered by a connective tissue capsule and divided into a cortex containing steroid-producing cells with prominent lipid droplets and a medulla containing chromaffin cells that secrete catecholamines and neuropeptides. Congenital virilizing adrenal hyperplasia results from the deficiency of an enzyme required for cortisol production. The thyroid gland is characterized by an extracellular hormone precursor (iodinated thyroglobulin) stored in its follicles. The follicular cells endocytose the storage product to form the thyroid hormones [triiodothyronine (T3) and thyroxine (T4)]. Scattered between the follicular cells are High-Yield Facts 33 "C" cells (parafollicular cells), which secrete calcitonin, a hormone that reduces blood calcium levels. Binding of antibodies to those molecules interferes with their uptake and function respectively. Infiltrating T cells and autoantibodies destroy the thyroid follicular cells resulting in hypothyroidism. The result is unregulated activation of the receptor and overproduction of thyroid hormones (hyperthyroidism). The pineal gland contains pinealocytes that secrete melatonin and is innervated by postganglionic sympathetic fibers. Endocrine cells of the pancreatic islets secrete primarily insulin and glucagon, hormones that regulate blood sugar by lowering and increasing gluocse respectively. Blood entering the islets bypasses the peripherally located glucagonsecreting cells to reach the more centrally-located insulin-producing beta cells. Blood leaving the beta cells contains insulin that influences glucagon secretion from the alpha cells. Blood leaving the islets travels to the surrounding exocrine pancreas and influences secretion from the acini. The beta cells are overworked and eventually lose their ability to secrete enough 34 Anatomy, Histology, and Cell Biology insulin in response to meals. Epithelial cells of the proximal tubule are specialized for absorption and ion transport. They remove most of the sodium and water from urine, as well as virtually all of the amino acids, proteins, and glucose. The cells of the distal tubule, under the influence of aldosterone, resorb sodium and acidify the urine. Transitional epithelium (allowing for stretch) is found lining the calyces, renal pelvis, ureters, and urinary bladder. Spermatogenesis involves the following lineage: spermatogonia (germ cells) (spermatocytogenesis) primary spermatocytes secondary spermatocytes (completion of meiosis) spermatids (spermiogenesis) mature sperm. The epididymis, like most of the male duct system, is lined by a pseudostratified epithelium characterized by modified microvilli (stereocilia). High-Yield Facts 35 the seminal vesicles produce fructose and other molecules that activate spermatozoa. The prostate is a fibromuscular organ that produces the enzymes responsible for the liquefaction of the ejaculate. Oocyte (germ cell) maturation involves several stages of follicular development (granulosa cells plus the oocyte): primordial follicle primary follicle secondary follicle mature, or Graafian, follicle. The theca interna synthesizes androgens, which are converted into estradiol by granulosa cells. After ovulation, these thecal cells form the theca lutein; the granulosa cells become the granulosa lutein, which produces progesterone (see figure below). During this phase, endometrial cells accumulate glycogen preliminary to the synthesis and secretion of glycoproteins. The vaginal epithelium is made up of stratified squamous cells and varies with maturity, phase of the menstrual cycle, pregnancy, and cancer (detected by vaginal Pap smear). During parturition, oxytocin secreted by the neurohypophysis stimulates the contraction of uterine smooth muscle. The breast (mammary gland) is a resting alveolar gland except during pregnancy, when the lactiferous ducts proliferate and milk production is initiated. Rhodopsin is a visual pigment found within lamellar disks of the outer segment of the rod cell. Rhodopsin consists of retinal and opsin; photons induce an isomeric change in retinal, leading to dissociation of the retinal/opsin complex. This signal is transmitted to interneurons within the retina and finally to ganglion cells. The fovea defines the center of the retina, and is the point of sharpest visual acuity. The fovea contains all cones and is directed toward whatever object you wish to see or read, for example, these PreTest words at this very moment. Production of lens fibers (elongated, protein-filled cells) continues throughout life without replacement. The aqueous humor, produced by processes of the ciliary body, flows between the lens and iris to the anterior chamber of the eye toward the iridocorneal angle, where it is drained into the canal of Schlemm. Blockage of the canal of Schlemm or associated structures leads to increased intraocular pressure and glaucoma. The external ear, largely formed from the first two branchial arches, funnels sound to the tympanic membrane. The middle ear is made up of the malleus, incus, and stapes formed from the first two arch cartilages. The internal ear consists of a membranous and a bony labyrinth filled with endolymph and perilymph, respectively. The saccule (ventral) and utricle (dorsal), parts of the membranous labyrinth, form from the otic vesicle (an ectodermal invagination). The cochlea contains three spaces, the scala vestibuli, scala media (cochlear duct, which extends from the saccule), and scala tympani. The semicircular canals (which extend from the utricle) contain the cristae ampulares, made up of cupulae with hair cells embedded in a gelatinous matrix that respond to changes in direction and rate of angular acceleration. The hair cells are located within the organ of Corti and respond to different frequencies. In the saccule and utricle, the maculae, along with stereocilia, kinocilia, and otoconia (crystals of protein and calcium carbonate), detect changes in position with reference to gravity. The major ascending pathways are the dorsal (posterior) columns and the anterolateral system. The dorsal funiculus divides into a medial fasciculus gracilis (sacral, lumbar, and lower thoracic inputs) and a lateral fasciculus cuneatus (upper thoracic and cervical inputs). The ventral spinocerebellar tract originates from spinal cord gray matter and enters the cerebellum via the superior cerebellar peduncle. Ascending secondary neurons make abundant reflex connections with autonomic and somatic pathways and terminate in the reticular formation and intralaminar thalamic nuclei. Special visceral efferents (associated with branchial archderived muscle) are located lateral and ventral to the general somatic efferents. Destruction of upper motor neurons (from higher centers) results in spastic paralysis: initally hyporeflexia and later hyperreflexia. However, some (such as the muscles of the upper face and the muscles of mastication and muscles of the larynx) are represented bilaterally. Lesions result in altered muscle tone (usually rigidity), paucity of movement, and the appearance of rhythmic tremors and writhing or jerky movements. The injury causes deltoid muscle paralysis and skin anesthesia over the lateral deltoid region. Midhumeral fracture may involve the deep brachial artery and the radial nerve as they wind about the posterior aspect of the humerus. Arterial injury produces ischemic contracture; nerve injury paralyzes the wrist extensors and extrinsic extensors of the hand ("wrist-drop"). Scaphoid fracture is the most common hand bone break because it transmits forces from the abducted hand directly to the radius. Because the blood supply enters distally, the proximal portion of the scaphoid is especially prone to avascular necrosis. Lunate dislocation is most common in falls on the out-stretched hand, compressing the median nerve within the carpal tunnel and producing carpal tunnel syndrome. Extension of the medial four digits at the metacarpophalangeal joints and interphalangeal joints is accomplished by the extensor digitorum in the forearm, innervated by the radial nerve.
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