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By T. Kan. Allen University.

Host variability aects the relative success of dierent parasite epitopes and the distribution of antigenic variants buy discount advair diskus 100 mcg line asthma definition religion. By contrast order advair diskus asthmatic bronchitis contagious person to person, limited genetic variability occurs in the germline genes that encode the antibody and T cell binding regions cheapest generic advair diskus uk asthma symptoms chart. Instead purchase advair diskus online now asthmatic bronchitis cure, vari- able antibody and T cell binding sites arise by somatic recombination. Somatic mechanisms to generate variation may buer the need for hosts to vary genetically. This variation leads to dierences in the thresholds that trigger immunity and in the intensity of particular immune eectors deployed against parasitic attack. Quantitative dierences in immune regulation can aect the intensity of selection on antigenic variants and the im- munodominance of host responses against dierent variants. Immu- nodominance, in turn, denes the selective pressures that shape the distribution of antigenic variants. Afewmajorpolymorphisms have been found in the promoters of cytokines, molecules that regulate key aspects of the immune system. Dierent promoter genotypes correlate with better or worse success in combating certain pathogens. Regulatory polymorphisms may be main- tained by trade-os, in which a more intense immune response clears parasites more eectively but also causes more collateral tissue damage to the host. Major regulatory polymorphisms have dierent alleles at high fre- quencies, each allele with a signicantly dierent eect on immune re- sponse. Each individual probably carries several minor regula- tory variants, causing signicant quantitative genetic variability between hosts in the regulation of the immune response. Strong challenge by a particular para- site could lead to selection favoring or disfavoring specic patterns of proteolysis. The intensity of direct selection on germline polymorphisms may be rather weak because specic recognition of antigens depends primarily on somatic mechanisms to create variability. However, the germline alleles do set the initial conditions on which somatic processes build, so it is certainly possible that germline polymorphisms inuence individual tendencies to react to particular antigens. Dierences between species do not directly inuence antigenic variation in parasites unless the parasites infect dierent species. Hill (1998) reviews cases in which variations in the hosts vitamin D and other cellular receptors are associated with susceptibility to various diseases. It is not clearwhetherminor variants of cellular receptors occur suciently frequently to favor matching variation of parasites for attachment to those receptors. Linkage studies of mice have begun to map locations of genes that in- uence quantitative variability in components of immunity (Puel et al. Many studies of humans report nucleotide poly- morphisms in promoters of cytokinesandother immune regulatory loci (Daser et al. Some human polymorphisms are associated with dierential response to particular diseases (Hill 1998; Foster et al. Various transcription factors and steroid hormones interact with the promoter region of this gene to produce synergistic combinations of positive and negative stim- ulifor transcription (Terry et al. These promoter polymorphisms inuenced expression level in a nonadditive way a single nucleotide change may have been associated with higher or lower levels of expres- sion depending on other variable sites in the haplotype. The three single nucleotide polymorphisms are separated by 25 and 398 nucleotides. I consider afewpossibilities in the remainder of this section and in the following sections. Thus, positive interactions and linkage between promoters and coding regions seem unlikely in this case. Alternatively, polymorphisms that aect phenotype are often main- tained by a balance between the rate at which deleterious mutation adds variability and the rate at which selection can remove deleterious mu- tants. Mutation-selection balance probably explains a signicant por- tion of the total quantitative geneticvariability observed in populations (Barton and Turelli 1987). Mutation-selection balance usually matches a high-frequency allele maintained by selection against a distribution of low-frequency mutant variants. Natural selection culls those lower-tness variants, but mu- tation maintains a constant ow of new variants. Mutation-selection balance proba- bly does explain the two rare trinucleotide haplotypes at frequencies of less than 1% observed by Terry et al. En- hanced exibility could occur in heterozygotes by increasing the range of inputs that control the response kinetics of the cytokine. However, by this scenario of heterozygote advantage, many individuals would carry lower-tness homozygote genotypes. Giv- en the three haplotype frequencies listed above, the expected frequency of homozygotes would be the sum of the squared haplotype frequencies, or 45%. The frequency of heterozygotes would be increased by a larger num- ber of promoterhaplotypes. Butsuchdiversity would mean thatany individual carried two randomly chosen haplotype patterns of regula- tory control among the possible haplotypes. It is dicult to image how complementarity between diverse regulatory haplotypes would occur. Variable transcription rates were associated with nucleotide polymorphisms in the promoters of these alleles. Thus, variable regulatory genotypes can inuence important aspectsofthehosts immune responses. Tissue-specic expres- sion or intermediate expression does not require heterozygosity with the associated cost of frequent, disadvantaged homozygotes. Continuous divergence of promoters as a function of phylogenetic distance suggests drifting changes constrained by the balance between mutational input and selection to maintain functional integrity. There may also be a tendency for compensatory nucleotide changes, in which one slightly deleterious substitution is compensated by a second substi- tution at a dierent site (Hartl and Taubes 1996; Burch and Chao 1999). For example, functionally synergistic associ- ations may exist between nucleotides in promoter and structural regions that cannot be explained by common phylogeny. On the positive side, a more intense immune response may clear infections more rapidly. On the negative side, immune eectors can often be harshmedicine, causing collateral damage to host tissues. Promoter polymorphisms may be maintained by the balance between eective clearance and tissue damage. Increasedexpression of this cytokine plays an important role in stimulating the inammatory immune response against the wide- spread gastric pathogen Helicobacter pylori (Jung et al. In this case, down-regulation of an immune eector, the macrophages, appears to reduce viral spread. Initial screening would naturally turn up major polymorphisms rather than rare variants, which would be harder to de- tect. The balance of mutation and selection almost certainly creates quan- titative variability in every aspect of immune regulation. Each individual likely has several rare mutants spread across dierent regulatory steps, causing variable quantitative genetic proles for the thresholds to trig- ger responses and the intensities of responses. The balance of mutation and selection sets the amount of quantita- tive variability in each regulatory component. The inux of quantitative variability depends on how mutations translate into quantitative eects on regulation. The culling of variation depends on the intensity of nat- ural selection acting on the particular regulatory step. Steps that aect tness relatively weakly will accumulate relatively more variation, un- til a balance of mutation and selection occurs. The major polymorphisms likely arise by processes in addition to mutation-selection balance. In those cases, various trade-os between immune control of parasites and collateral damage probably balance the tnesses of dierent variants. Or more rarely, the damage may arise from reducing the proliferation of immune cells that normally con- trol pathogens but also can be the target of parasitic attack. Regulatory variability may sometimes alter immunodominance be- cause cytokines modulate positive and negative stimulation of T and Bcell clones. In their study, normal levels of interferon- were associated with about a 5-fold ratio of immunodominant to subdominant T cell clones for two Listeria monocytogenes epitopes. Thus, variations in immune regulation may inu- ence patterns of antigenic variation. The B35 allele occurs in higher frequency in The Gambia, a region with en- demic malaria, than in parts of the world with less severe mortality from malaria. For example, one epitope variant may be common in one location and another variant common in another lo- cation. It would also be interesting to compare parasites that attack only a single host species with those that attack multiple vertebrate species. I also listed several hypotheses to explain those polymorphisms: linkage with synergistic coding regions, mutation-selection balance, and heterozygote advan- tage. These explanations lack empirical support, and the case of het- erozygote advantage may also have logical aws. Ireviewedtwo cases in which the costs and benets of a more potent regulatory stimulus may favor polymorphism. Against other pathogens that do not replicate in macrophages, reduced macrophage proliferation may favor the patho- gen against the immune system. Mathematical analysis could establish the necessary conditions to maintain polymorphism for controls of the immune response by trade- os between high and low expression. Such models would clarify the kinds of experiments needed to understand these polymorphisms. First, dierent patterns of immune regulation may aect immunodominance (Badovinac et al.

Electron transport-linked ubiquinone-dependent recycling of al pha-tocopherol inhibits autooxidation of mitochondrial membranes cheap advair diskus online mastercard asthma symptoms hay fever. Healthy aging: regulation of the metabolome by cel lular redox modulation and prooxidant signaling systems: the essential roles of su peroxide anion and hydrogen peroxide purchase genuine advair diskus online asthma symptoms and quality of life. Effects of coen zyme Q(10) administration on its tissue concentrations buy 250 mcg advair diskus with visa asthmatic bronchitis icd 10, mitochondrial oxidant gener ation 500mcg advair diskus for sale asthma treatment vitamins, and oxidative stress in the rat. Coen zyme Q10 attenuates diastolic dysfunction, cardiomyocyte hypertrophy and cardiac fibrosis in the db/db mouse model of type 2 diabetes. Osteopontin defi ciency protects against aldosterone-induced inflammation, oxidative stress, and in terstitial fibrosis in the kidney. Nutritional compounds influence tis sue factor expression and inflammation of chronic kidney disease patients in vitro. Docosahexaenoic acid enhan ces the antioxidant response of human fibroblasts by upregulating gamma-glutamyl- cysteinyl ligase and glutathione reductase. Antioxidative and anti-inflammatory actions of docosahexaenoic acid and eicosapentaenoic acid in renal epithelial cells and macrophages. Short- time infusion of fish oil-based lipid emulsions, approved for parenteral nutrition, re duces monocyte proinflammatory cytokine generation and adhesive interaction with endothelium in humans. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemo taxis in neutrophils. Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. The effects of dietary fish oil on inflam mation, fibrosis and oxidative stress associated with obstructive renal injury in rats. The use of ome ga-3 poly-unsaturated fatty acids in heart failure: a preferential role in patients with diabetes. Effects of omega-3 polyunsaturated fatty-acid supplementation on redox status in chronic re nal failure patients with dyslipidemia. In sights into the inhibition of platelet activation by omega-3 polyunsaturated fatty acids: Beyond aspirin and clopidogrel. Effects of purified eicosapentaenoic and docosahexaenoic acids on glycemic control, blood pressure, and serum lipids in type 2 diabetic patients with treated hypertension. Eicosapentaenoic acid improves imbalance between vasodilator and vasoconstrictor actions of endo thelium-derived factors in mesenteric arteries from rats at chronic stage of type 2 dia betes. Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4. Role of xanthine oxidase inhibitor as free radical scavenger: a novel mechanism of action of allopuri nol and oxypurinol in myocardial salvage. Effect of allopurinol in chronic kidney disease progression and cardiovascular risk. Effect of treatment of hyperuricemia with allopurinol on blood pressure, creatinine clearence, and pro teinuria in patients with normal renal functions. The effects of lower ing uric acid levels using allopurinol on markers of metabolic syndrome in end-stage renal disease patients: a pilot study. Relationship between serum carnitine, acylcarnitines, and renal function in pa tients with chronic renal disease. Practice recommendations for the use of L-carni tine in dialysis-related carnitine disorder. L-carni tine supplementation decreases the left ventricular mass in patients undergoing he modialysis. Effects of L- carnitine supplementation on cardiac morbidity in hemodialyzed patients. Propion yl-L-carnitine therapy: effects on endothelin-1 and homocysteine levels in patients with peripheral arterial disease and end-stage renal disease. Accumulation of circulating ad vanced oxidation protein products is an independent risk factor for ischemic heart disease in maintenance hemodialysis patients. Ure mia, atherothrombosis and malnutrition: the role of L-arginine-nitric oxide pathway. Abnormalities in L-arginine trans port and nitric oxide biosynthesis in chronic renal and heart failure. Activation of L-arginine transport in undialysed chronic renal failure and continuous ambulato ry peritoneal dialysis patients. Enhanced nitric oxide synthesis in uremia: implications for platelet dysfunction and dialysis hypotension. Evidence that renal arginine transport is impaired in spontaneously hypertensive rats. Potential ergogenic effects of L-arginine against oxida tive and inflammatory stress induced by acute exercise in aging rats. Mod ulation of apoptosis and improved redox metabolism with the use of a new antioxi dant formula. Long-term dietary antioxidant cocktail supplementation effectively reduces renal inflammation in diabetic mice. Effect of long-term treatment with antioxidants (vitamin C, vitamin E, coenzyme Q10 and selenium) on arterial compliance, humoral factors and inflammatory markers in patients with multiple cardiovascular risk factors. Introduction Calcific Aortic Stenosis is the most common cause of aortic valve disease in developed coun tries. Aortic valve replacement is the number one indication for sur gical valve replacement in the United States and in Europe. The natural history of severe symptomatic aortic stenosis is associated with 50% mortality within 5 years [2]. Bicuspid aortic valve disease is the most common congenital heart abnormality and it is the most common phenotype of calcific aortic stenosis. Understanding the cellular mechanisms of tricuspid versus bicuspid aortic valve lesions will provide further understanding the mechanisms of this disease. Previously, the Wnt/Lrp5 signaling pathway has been identified as a signaling mechanism for cardiovascu lar calcification [5, 16, 17]. The corollaries necessary to define a tissue stem cell niche: 1) physical architecture of the endothelial cells signaling to the adjacent subendothelial cells: the valve interstitial cell along the valve fibrosa. Re cently, the mechanisms of oxidative stress have been identified in the development of calcif ic aortic valve disease. This chapter will outline the factors important in the role of calcific aortic valve disease. The role of lipids in vascular and valvular disease The role of lipids in vascular atherosclerosis has been defined in the literature for years. The acti vation of these cellular processes is regulated by a number of pathways. Integrins pro vide an important role in the regulation of cellular adhesion in atherosclerosis [26]. In this inflammato ry environment, growth factors and cytokines are secreted to induce vascular smooth cell proliferation and recruitment of macrophage cells [32-37] which are important in the de velopment of the atherosclerotic plaque lesion. Patients who have the diagnosis of familial hyper cholesterolemia develop aggressive peripheral vascular disease, coronary artery disease, as well as aortic valve lesions which calcify with age [10, 42]. Rajamannan et al, have shown that the development of atherosclerosis occurs in the aortic valve in a patient with Familial Hypercholesterolemia with the Low density lipoprotein receptor mutation [10]. The athero sclerosis develops along the aortic surface of the aortic valve and in the lumen of the left cir cumflex artery [10]. This provides the first index case of atherosclerotic aortic valve disease in this patient population. Studies have confirmed in experimental hypercholesterolemia that both atherosclerosis and osteoblast markers are present in the aortic valves [4, 6, 13]. This background provides the foundation for studying valve calcification in an experimental atherosclerotic in vivo model. Aortic valve calcification The presence of calcification in the aortic valve is responsible for valve stenosis. Severe aort ic stenosis can result in symptomatic chest pain, as well as syncope and congestive heart fail ure in patients with severe aortic valve stenosis. However, the pathologic lesion of calcified aortic valves dem onstrate indicate the presence of complex calcification in these tissues. Furthermore, there are a growing number of descriptive studies delineating the presence of bone formation in the aortic valve [15, 43, 44]. These studies define the biochemical and histo logical characterization of these valve lesions. We and others, have also shown that specific bone cell phenotypes are present in calcifying valve specimens in human specimens [16, 50]. These data provide the evidence that the aortic valve calcification follows the spectrum of bone formation in calcifying tissues. The role of Lrp5/beta-catenin activation in cardiovascular calcification and osteoblast bone formation: Connection with the bone axis Bone and cartilage are major tissues in the vertebrate skeletal system, which is primarily composed of three cell types: osteoblasts, chrondrocytes, and osteoclasts. In the developing embryo, osteoblast and chrondrocytes, both differentiate from common mesenchymal pro genitors in situ, where as osteoclasts are of hematopoietic origin and brought in later by in vading blood vessels. Osteoblast differentiation and maturation lead to bone formation controlled by two distinct mechanisms: intramembranous and endochondral ossification, both starting from mesenchymal condensations. The transcription factor Cbfa1 [51] has all the attributes of a master gene differ entiation factor for the osteoblast lineage and bone matrix gene expression. During embryonic development, Cbfa1 expression precedes osteoblast differentiation and is restrict ed to mesenchymal cells destined to become osteoblast.

Second buy advair diskus 100 mcg cheap asthmatic bronchitis joint, shared antigenicity over long phylogenetic distances may be caused by convergent selection buy cheap advair diskus 100 mcg on line asthma 504 plan template. Supposeasmall set of alternative struc- tures for a parasite epitope retain similar function purchase advair diskus 100mcg visa asthma treatment by fish. Phylogenetic pattern will reveal short-term changes and occasional long-term similarity purchase advair diskus toronto asthma definition and causes. The genetic variants of the V3 loop may fall into relatively few conformational, antigenic types. The range of types may be constrainedbystabilizingselection, caus- ing short-termphylogenetic uctuations between types but occasional convergence to past types within phylogenetic lines of descent. Third, distinct antigenicity between phylogenetically close isolates implies very rapid diversifying selection. They tested the eighty-eight pairwise reactions between serum antibodies and viral isolates. The data showed viral escape mutants emerging at intervals of about fteen months, each escape followed approximately eight months later by new antibody responses that matched the escape variants. Diversifying selection within hosts favors es- cape variants that avoid antibodies or T cells. Convergent selection causes recurrence of previous antigenic types in response to diversifying selection and the stabilizing constraints that limit the range of alternative forms. They sequenced the V3 loop of the viral envelope from eighty-nineisolatescollected over a seven- year period. The isolates evolved over time through a series of replace- ments, with dierent sequences dominating in frequency at dierent times. The same sequence of 6 amino acids at the tip of the V3 loop evolved convergently in the two lineages. In summary, phylogeny provides thehistoricalcontext in which to interpret immunological patterns. Hypotheses about natural selection can be tested by mapping the sequence of immunological changes onto the lineal history of descent. Relations between antigenicity and phylogeny suggest hypotheses about how natural selection shapes anti- genic variation. Antigenicity groups isolates according to current host species, whereas phylogeny groups isolates according to the his- tory of transfers between species. This could oc- cur by adaptation of viral surfaces to host receptors associated with at- tachment. Such hypotheses, suggested by statistical pat- terns of association between phylogeny and antigenicity, must be tested by molecular studies. Most antigenic and phylogenetic data were collected for reasons other than analyzing rela- tions between antigenic and phylogenetic classications. Little thought has been given to the sampling schemes that maximize information about evolutionary process. Ideal studies require analysis of the inter- actions between evolutionary process, methods of measurement, and statistical inference. To detect relatively slow antigenic change, one should probably sam- ple over relatively long phylogenetic distances. The average divergence of genomes over long distances sets a standard against which one can detect reduced antigenic change at sites constrained by stabilizing se- lection. By contrast, diversifying selection accelerates change by favoring anti- genic types that dier from the currently prevalent forms. To detect rel- atively rapid change, one should probably sample over relatively short phylogenetic distances. This sets a low level of background change against which rapid, diversifying change can be detected. The degree of match or discord between antigenic and phylogenetic classications may depend on the demographic consequences of selection. If selection on a few closely linked epitopes determines the success or failure of a parasite lineage, then phylogeny may follow antigenicity. By contrast, selection may strongly inuence patterns of antigenic change without absolutely determining success or failure of lineages. Mathematical models would clarify the various relations that may arise between antigenic and phylogenetic classications. Those rela- tions depend on the time scales of dierentiation, the epitopes used for antigenic classication, and the antibodies used to discriminate between variant epitopes. Experimental Evolution: Foot-and-Mouth 12 Disease Virus Experimental evolution manipulates the environment of a population and observes the resulting pattern of evolutionary change. For ex- ample, one could manipulate immune selection by exposing parasites to dierent regimes of monoclonal antibodies. The parasites evolutionary response reveals the adaptive potential and the constraints that shape patterns of antigenic variation. I also use this virus as a case study to show how dierent methods combine to provide a deeper understanding of antigenic variation. These approaches include structural analysis of the virion, functional analysis of epitopes with regard to binding cellular re- ceptors, sequence analysis of natural isolates, and experimental analysis of evolving populations. This allows one to analyze how particular amino acid substitutions aect shape, charge, and interaction with antibodies. Structural infor- mation also aids functional analysis of substitutions with regard to bind- ing cellular receptors or aecting other components of viral tness. Most of these escape mutants were generated by application of monoclonal antibodies in controlled experimental studies. Several laboratory escape mutants occur in an exposed loop on the surface of the virion, which is also the site of a key antigenic region identied by sequencing natural isolates. This antigenic loop mediates binding to cellular receptors, an essential step for viralentryintohost cells. The pattern of antibody escape mutantsidentiesvarying and unvarying amino acid sites. The third section continues discussion of binding to host cells and tro- pism for dierent host receptors. Consequently, escape mutants in that conserved region arise readily, demonstrating that the conserved sites play an important role in recognition by anti- bodies. This highlights the dual selective pressures by antibodies and receptor binding that may shape key antigenic sites. The fourth section describes an experimental approach to analyze the tness consequences of amino acid substitutions. Molecular stud- ies can measure changes in binding anity for antibodies and cellular receptors associated with changes in amino acid shape and charge. But substitutions ultimately spread or fail based on their consequences for the dynamics of growth and transmission. I describe one study in which pigs were injected with a wild-type virus and various antibody escape mutants. The rela- tive success of parental and mutant viruses provides clues about how particular amino acid substitutions may inuence evolutionary dynam- ics. General discussions and examples of experimental evolution can be found in Rose (1991), Bennett and Lenski (1999), Landweber (1999), Crill et al. Phylogenetic distance between serotypes correlates reasonably well with antigenic distance measured by cross-reactivity to polyclonal antisera in other words, phylogeny roughly matches serology at a broad scale of sequence divergence (Mateu 1995). By contrast, small-scale phylogenetic divergence does not correspond to patterns of antigenicity. One or a few amino acid substitutions within a serotype can greatly alter antibody recognition (Mateu et al. The loops connecting the chains tend to be exposed on the protein surface, sometimes protruding from the protein core. The three proteins dier in the location and exposure of various loops, as indicateding. Redrawn from Haydon and Woolhouse (1998) based on original work in Harrison (1989, with permission from Nature, www. This loop has about 20 amino acids that contribute to several overlapping epitopes. The three dier- ent proteins group into a structural unit as shown in the lower left. On the capsid, the boldly lined pentagon contains ve structural units arrayed in ve- fold rotational symmetry about the pentagonal center. Each pentagonal vertex denes the intersection of six structural units aligned in threefold rotational symmetry. The wiggly lines labeled on one unit of the capsid show the location of structural loops that occur on the capsid surface (see g. Theblackcircle at the lower right shows the approximate relative size of an antibody-binding region (Fab), illustrating the potential coverage of capsid protein loops that may be involved in immune recognition. Redrawn from Mateu (1995, with permission from Elsevier Sci- ence) based on original work in Harrison (1989, with permission from Nature, www. Discontin- uous epitopes occur when amino acid residues from widely separated sequence locations come together conformationally to form a binding surface for antibodies. Two antigenic sites of serotypes A, O, and C have discontinuous epitopes that have received widespread attention (Mateu et al. The rst discontinuous site occurs near the capsid s threefold axes of symmetry at the vertices of the pentagonal structural units (g. The high specicity of antibodies means that the sequence and conformational dierences between serotypes change the detailed antigenic properties of particular regions. Studies focused on natu- ral selection of particular amino acid residues must account for back- ground dierences of sequence and conformation among test strains.

Usually one eye is considerably more affected than the other order advair diskus no prescription asthma treatment options, although both eyes can be affected simultaneously buy cheapest advair diskus and advair diskus asthma symptoms leg pain. Because the degener- ative process is limited to the macula cheap 500mcg advair diskus mastercard asthma symptoms heartburn,the periph- eral eld remains unaffected and the patient can walk around quite normally 250mcg advair diskus for sale asthma 4 year old boy. Difculty in recog- nising faces or in seeing bus numbers is also a common complaint. The wet form occurs more commonly in Caucasians and about one-third of the patients give a family history of similar prob- lems. Drusen can have varying degrees of hyperpig- Unfortunately, the word drusen has been used mentation. Most eyes with drusen maintain rather loosely in ophthalmology to refer to two good vision, but a signicant number will or three types of swelling seen in the fundus. There is usually a moderate ring to the multiple shiny excrescences seen on loss of vision. This is because there is no a senile change are also known as colloid leakage of uid or bleeding into the retina or bodies and perhaps this term is preferable. The growth of these new vessels seems to be important because they invade the breaks in Bruch s membrane. A sudden loss of central vision might be experienced as the result of such an episode. Subsequently, healing of the leaking vascular complex results in scar tissue formation, which further destroys the central vision permanently. Practical measures can be taken in the man- The various types of glaucoma have also been agement of these patients to alleviate their considered already, and the reader would realise handicap. Telescopic lenses might be needed for that glaucoma is simply the manifestation of a reading or watching television and full consid- group of diseases, each of which has a different eration should be given to the question of blind prognosis and treatment. It is important to explain the nature open-angle, glaucoma is the important kind in of the condition and prognosis to the patient. The physician and optometrist can play of total blindness and help the patient come to a vital part in the screening of this disease by terms with the problem. In most cases, one eye becoming familiar with the nature of glauco- is involved rst, the other following suit within matous cupping of the optic disc. The vision, as measured on the population over the age of 55 years is the Snellen chart, progressively deteriorates to thought to suffer from chronic simple glaucoma less than 6/60, but the peripheral eld remains and the gure could rise to as high as 30% in unaffected so the patient is able to nd his or those over 75 years. The treatment Cataract is preventative of further visual loss rather than curative. Chronic simple glaucoma is best This common condition in the elderly eye has managed in an eye unit on a long-term basis. By already been considered, but it is important that this means, the visual elds and intraocular every physician can identify and assess the pressure can be accurately monitored and the density of a cataract in relation to the patient s treatment adjusted as required. The physician must realise the potential the care of glaucoma patients is being shared of cataract surgery in the restoration of vision. The contraindica- Deformities of the Eyelids tions for cataract surgery are few and even in extreme old age the patient can benet. Surgery Both entropion and ectropion are common in might be delayed if the patient has only one eye the elderly and a complaint of soreness and or if there is some other pathology in the eye, irritation in the eyes as well as watering should which is likely to affect the prognosis. The need always prompt a careful inspection of the for someone to assist the patient in the instil- conguration of the eyelids. Entropion is lation of eye drops and the domestic chores revealed by pressing the nger down on the during the postoperative period might require lower lid so that the inverted lid becomes some attention but is not a contraindication. Sometimes About one-third of the population aged over 70 entropion can be intermittent and not present at years suffers from a cataract, but the quoted the time of examination,but usually under these gures vary according to the diagnostic criteria. Ectropion is nearly always an ophthalmoscope, and the pupil reacts quickly, obvious deformity because of the easy visibility then he or she is likely to do well after surgery. These lid deformities can recur sometimes and require further lid surgery, but careful surgery in the rst instance should largely prevent this. Temporal Arteritis This condition, also known as giant cell arter- itis, seen only in the elderly, can rapidly cause total blindness unless it is treated in time. The disease is more common than was originally supposed but it is rare under the age of 50 years. Histologically, the inammatory changes are characterised by the presence of foreign body disease is suspected, a biopsy is essential and giant cells and the thickening of the vessel wall this should be done without delay. Treatment is at the expense of the inner layers so that the can be commenced immediately, sometimes total breadth of the vessel might not be altered. However, it is advisable that In early disease, the inammatory changes tend the lag between starting treatment and biopsy to be segmental so that a single biopsy of a small is as short as possible (preferably less than segment of the temporal artery does not always two weeks). Often there is low-grade if necessary for several months (on average fever and there can be aches and pains in the 18 months). The blur- patients are liable to become blind unless ade- ring of vision is caused by ischaemia of the optic quate treatment is administered and in some nerve head or occasionally central retinal artery instances, extraocular muscle palsies causing occlusion. The diagnosis rests largely on nding diplopia and ptosis can confuse the diagnosis. Polymyalgia rheumatica is a syn- drome consisting of muscle pain and stiffness Patients who complain of visual symptoms after affecting mainly the proximal muscles without a stroke quite often have an associated homony- cranial symptoms. Once the to conrm this in a patient with poor vision and The Ageing Eye 155 normal fundi following a hemiplegic episode. The picture can be further complicated and seeing areas is well dened and can cut by true dyslexia and the patient might admit to through the point of xation. Fortunately, the being able to see the paper and yet be unable to central 2 or 3 of the visual eld are often make any sense of it. When there is so-called macular spar- pected if other higher functions, such as speech, ing, the visual acuity as measured by the Snellen have been affected by the stroke. Patients tend to complain tures of a homonymous hemianopic defect in of difculty in reading if the right homonymous the visual eld is the patient s complete lack of eld is affected rather than the left, and insight into the problem, so that even a doctor although they might be able to read individual might fail to notice it in himself. It is unusual for words, they have great difculty in following a homonymous hemianopia to show any signs the line of print. Thus, a patient with a right of recovery, but once the patients understand hemiplegia and a right homonymous hemi- the nature of the handicap they can learn to anopia might have normal fundi and visual adapt to it to a surprising degree. The foveal light reex, that is the spot How the Normal Features of reected light from the fovea, is absent or ill- Differ from Those in an Adult dened until the infant is four to six months old. By six months the movement of the eyes should At birth the eye is large, reaching adult size at be well co-ordinated, and referral to an ophthal- about the age of two years. The Stycar test globular and thus compensates for this by its can be used for three- to four-year olds or greater converging power. None the less, more sometimes younger children and a similar level than three-quarters of children aged under four of visual acuity is seen as soon as the child is years are slightly hypermetropic. Myopia is uncommon in infancy but tends to appear between the ages of six and nine How to Examine a Child s Eye years and gradually increases over subsequent years. The rate of increase of myopia is maximal The general examination of the eye has been during the growing years and this can often be considered already, but in the case of the child, a cause of parental concern. The iris of the newborn infant has a slate-grey Before the age of three or four years,it might not colour because of the absence of stromal pig- be possible to obtain an accurate measure of the mentation. The normal adult colouration does visual acuity, but certain other methods that not develop fully until after the rst year. The pupil reacts to light at birth but the reaction can rolling ball test measures the ability of the child be sluggish and it might not dilate effectively in to follow the movement of a series of white response to mydriatic drops. Another test to look grey and the optic disc somewhat pale, makes use of optokinetic nystagmus, which can deceiving the uninitiated into thinking that it is be induced by making the child face moving 157 158 Common Eye Diseases and their Management vertical stripes on a rotating drum. A casualty the stripes is then reduced until no movement situation, which occurs from time to time, is of the eyes is observed. In practice, a careful when a child is brought in distressed with a sus- examination of the child s ability to x a light, pected corneal foreign body or perhaps a per- and especially the speed of xation, is helpful. Here, it is simplest to wrap the The behaviour of the child can also be a helpful patient in a blanket so as to restrain both arms guide, for example the response to a smile or and legs and then examine the cornea by the recognition of a face. Particular impaired vision in infancy is overlooked or care must be taken when examining an eye interpreted as a psychiatric problem, but such with a suspected perforating injury in view of an error can usually be avoided by careful the risk of causing prolapse of the contents of ophthalmological examination. Any ophthalmological examination the pupils is an essential part of any visual demands placing one s head close to that of the assessment. One of the difculties in examining patient and this can alarm a child unless it is children is that they are rarely still for more than done sufciently slowly and with tact. It is some- a few seconds at a time, and any attempts at times helpful to make the child listen to a small restraint usually make matters worse. Before noise made with the tongue or ophthalmoscope starting the examination, it is useful to gain the to ensure at least temporary stillness. In fact, it is Screening of Children s Eyes sometimes better to ignore the anxious child deliberately during the rst few minutes of the In an ideal world, all children s eyes would be interview. Once the young patient has summed examined at birth by a specialist and again at six you up, hopefully in a favourable light, then a months to exclude congenital abnormalities and gentle approach in a quiet room is essential for amblyopia. Most children are also this has been done the pupils and anterior part screened routinely in school at the age of six of the eye can be examined, rst with a hand years, and any with suspected poor vision are lens but if possible with the slit-lamp micro- referred for more detailed examination. Fundus examination and measurement further examination is often conducted at the age of any refractive error demand dilatation of of nine or ten years and again in the early teens. The commonest defect to be found is refractive Cyclopentolate 1% or tropicamide 1% are both error,that is simply a need for glasses without any used in drop form for this purpose. The ophthalmological screening ophthalmoscope is a useful tool when examin- is usually performed by a health visitor in the ing the neonatal fundus, the wide eld of view preschool years and a school nurse for older chil- being an advantage in these circumstances. Screening tends to include measurement of the infant is asleep in the mother s arms, this visual acuity alone but checking any available can be benecial because it is a simple matter family history of eye problems would be helpful.

When the heart pumps blood cheap advair diskus 500 mcg amex asthma 9 year old, the blood shoots through the body at a fairly rapid speed purchase advair diskus without a prescription asthma treatment albuterol. The muscular contractions of the heart produce a certain amount of pressure which produces this pumping action throughout the body discount advair diskus 100mcg amex asthma united states. Here are some of the things which produce high blood pressure: Hardening of the arteries (arteriosclerosis) is a primary cause order advair diskus 250 mcg on-line asthma symptoms 3 days. They come to look like old water pipes, with congealed stuff sticking to the walls. Unfortunately, there is no pain as the hardening and clogging of arteries (which produce hypertension) progresses. So people keep living and eating the way they should not until one day the crisis comes. Here are some of the problems which, over a period of time, can occur in the heart: 1 - Arrhythmia. This is caused by problems in the cells in the heart which send out electrical signals to do the pumping sequences. An electrical error occurs, which sends some beat signals to the heart muscle (causing it to twitch) instead of carrying out its normal blood pumping action. Sometimes this is congenital; other times it is caused by rheumatic fever or endocarditis (infection of the heart muscle). Here are some of them: 1 - Cardiomegaly (cardiac hypertrophy) occurs when the heart can no longer function normally; it works so hard that it enlarges. Because fresh blood is no longer reaching the brain, the person falls unconscious. Sugar increases triglyceride levels, platelet adhesiveness, uric acid levels, and blood pressure. Over 3000 units a day add to the plaque development and hardening of atherosclerosis. Carotene (pro- vitamin A) in the diet, from orange and yellow vegetables and fruits, will not cause this problem. Here is still more information: To properly understand the information given in this article, be sure to read the other articles in this section, especially those listed at the end of this one, and in the next (dealing with circulatory problems). The best way to begin the day is to check your pulse when you wake up in the morning. But if your resting heart rate is above 80, that is not so good, and indicates that hypertension may be in progress of occurring. An estimated 25% of those who have heart attacks experienced no previous symptoms. Flaxseed oil contains Omega-3 fatty acids, which reduce risk of coronary heart and cardiovascular disease. More blood pools in the legs, and not so much tries to crowd in through the narrowed arteries into the heart. Sodium is a problem which must be dealt with, since it can increase the likelihood of heart disease. Prevention living right and eating right ahead of time is the best key to success. Obtain essential fatty acids; the best is cold-pressed flaxseed oil or wheat germ oil; also take selenium, vitamin E, 5-10 alfalfa tablets daily. Reduce vitamin D intake from all sources (meat, fish, dairy products, and the sun). Heating the oil changes it from the cis form to the trans form (also called a trans-fat), which is abnormal and can cause heart diseases, just as animal fats do. Physicians even use it to estimate how likely it is that you will have a heart attack. They carry cholesterol from the blood to the liver so it can be converted into bile and eliminated from the body. Very important, it also helps prevent recycling of bile from the bowel back to the liver. Taking 1-2 grams a day can produce a 30% reduction in cholesterol levels which are 400 or above. Because of its antioxidant function, it also prevents fatty acids from becoming toxic. It is not the "cure" for coronary atherosclerosis and severe angina, as suggested. The disease is systemic, and heavily influenced by nutritional, and other, factors. They are only emergency repair jobs which do not remove the cause which, unless properly corrected, will only return. But all who shall inherit these blessings must be partakers of the self-denial and self-sacrifice of Christ. The World Health Organization recognizes that cardiomyopathy is a selenium deficiency disease. It is typical that $1 per month in selenium supplement would prevent this disease and the need for a $250,000 procedure that carries a 20% mortality rate. Veterinarians have eliminated this disease [cardiomyopathy] in animals with selenium injections and oral supplementation of diets. Arteriosclerosis is hardening of the walls of the arteries; atherosclerosis is the hardening of plaque on the walls, which causes the walls to harden. The main difference between the two is that arteriosclerosis is primarily the hardened walls themselves (which the plaque especially produced). Whereas atherosclerosis is the thickening of that plaque in the arteries, so that the space for the blood to flow through keeps narrowing. In arteriosclerosis, these deposits are primarily composed of calcium; in atherosclerosis, the deposits consist of fatty substances, primarily cholesterol (a blood protein). The problem is that a clot of this plaque breaks loose, flows through the arteries, and gets stuck in a narrower artery. If this occurs in the heart muscle, angina and a heart attack may result; if in the brain, a stroke occurs. To complicate the matter further, not only can arteriosclerosis and atherosclerosis cause high blood pressure, but high blood pressure intensifies them both. Pain in the legs (usually in the calf, but sometimes in the feet or elsewhere in the legs), which increase when walking but stops as soon as one rests, is intermittent claudication (which see). There is a home test you can do to help determine if this is beginning to occur: Test the pulse in your legs and foot. There are three places where this can be done: Apply light pressure on the top of the foot, the inner hollow of the ankle, and in the hollow behind the knee. It has been shown to increase serum cholesterol levels, leading to atherosclerosis. Even 20% or more above ideal weight carries a significantly increased risk of atherosclerosis. Assume 100 pounds for the first five feet; add to this five pounds for each inch over that, for women; add seven pounds per inch over that, for men. It may inhibit production of new blood vessels needed to increase blood circulation. Best: Only eat plain fruit and plain bread for supper, and do this several hours before bedtime. High blood pressure can be a killer; low blood pressure is generally just something to live with. A researcher who investigated the strange death of Pope John Paul I (who had low blood pressure and few other physical problems) asked 30 physicians and specialists whether low blood pressure would shorten life. For this reason, you will find that medical guides say relatively little about hypotension. In some instances, low blood pressure is due to an impoverished diet, the existence of some chronic wasting disease, or some other condition that needs treatment on its own account. They will openly rejoice in all He has done and tell others how He can answer their needs also. Overweight, a ruddy complexion, and apparently robust health may be the only outward manifestations in a man 50 or 60, who may have systolic pressure as high as 200 or more. Hypertension is called the "silent killer" because it so often reveals few symptoms. A blood pressure gauge (sphygmomanometer) registers two readings: The first and higher one is the systolic; the second and lower one is the diastolic. The diastolic pressure occurs just before the heart beats, and is less important for determining blood pressure. But the systolic pressure reveals the pressure built up as the heart pumps blood out of the heart into the aorta (and thence through the arteries). High systolic pressure indicates that the cell walls are hardened and/or plaques are forming in the arteries, which are narrowing the passageways. Average normal systolic blood pressure in an adult varies between 120 and 150 millimeters of mercury, and tends to increase with age. The arteries of older people tend to harden and thicken with age, and this produces the higher readings in later life. Normal blood pressure readings for adults vary from 110/70 to 140/90 while readings of 140/90 to 160/90 or 160/95 indicate borderline hypertension. Tobacco is another cause of hypertension, as is the taking of oral contraceptives. Hypertension can result in coronary artery disease, enlargement of the heart, or strokes. Sudden attacks of convulsions in pregnant women (eclampsia), and other kidney diseases of pregnancy, usually cause high blood pressure. Women have hypertension less often than men until menopause is over; then, soon after, they have it as often. Include oat bran; it appears to be the very best type for the purposes you have in mind.

Wickham s striae or oral lesions favour the Individual lesions may last for many months and the diagnosis of lichen planus discount 500mcg advair diskus with amex asthma definition australia. As lesions resolve generic advair diskus 250mcg overnight delivery asthma definition medical, they become darker cheap advair diskus asthma questions and answers, atter and leave discrete brown or grey macules advair diskus 500 mcg mastercard asthma definition 5 s. The ulcerat- ive form of lichen planus in the mouth may lead to Treatment can be difcult. Systemic steroid probably caused by the coexisting hepatitis infections courses work too, but are recommended only in special mentioned above. Hyperkeratosis Prominent granular layer Basal cell degeneration Sawtooth dermo- epidermal junction Colloid bodies Band-like upper dermal lymphocytic infiltrate Fig. A defect in vitamin A metabolism was once Differential diagnosis suggested but has been disproved. Psoriasis is the disorder closest in appearance to pity- riasis rubra pilaris, but lacks its slightly orange tinge. The thickening of the palms and soles, the follicular Presentation erythema in islands of uninvolved skin, and follicular The familial type develops gradually in childhood and plugging within the plaques, especially over the knuck- persists throughout life. Later, red or pink areas grow quickly Investigations and merge, so that patients with pityriasis rubra pilaris are often erythrodermic. Small islands of skin A biopsy may help to distinguish psoriasis from may be spared from this general erythema, but pityriasis rubra pilaris; but, even so, the two disorders even here the follicles may be red and plugged with share many histological features. Similarly, the generalized plaques, although otherwise rather like psoriasis, may also Treatment show follicular plugging. The disorder responds slowly to systemic retinoids such as acitretin (in adults, 25 50 mg/day for 6 8 months; Course p. Oral methotrexate in low doses, once a week The palms and soles become thick, smooth and yellow. Systemic steroids are have gone, the skin may retain a rough scaly texture not indicated. Parapsoriasis and premycotic eruption Complications There are usually no complications. However, wide- Parapsoriasis is a contentious term, which many would spread erythroderma causes the patients to tolerate like to drop. Complications Patients with suspected premycotic/prelymphomatous eruptions should be followed up carefully, even though the development of cutaneous T-cell lymphoma may not occur for years. Differential diagnosis rather than grossly, and which persist despite anti- psoriasis treatment. It is worth trying to distinguish a This includes psoriasis, tinea and nummular (discoid) benign type of parapsoriasis from a premycotic type, eczema. Several biopsies should be taken if a premycotic erup- tion is suspected, if possible from thick or atrophic untreated areas. These may suggest an early cutaneous Cause T-cell lymphoma, with bizarre mononuclear cells both The cause is otherwise unknown. Perhaps the most important The use of these probes and of immunophenotyping Table 6. Psoriasis Treatment Pityriasis rubra pilaris Ichthyosiform erythroderma Treatment is controversial. Less aggressive treatments Pemphigus erythematosus are used for the benign type of parapsoriasis. The numerous small circular scaly macules and papules of the chronic type are easy to confuse with guttate psoriasis (p. However, their scaling is distinctive in that single silver-grey scales surmount the the histology is helpful but often it is non-specic. The acute type is characterized Erythroderma is the term used when the skin is red by papules that become necrotic and leave scars like with little or no scaling, while the term exfoliative those of chickenpox. Temperature regula- Other papulosquamous diseases tion is impaired and heat loss through the skin usually makes the patient feel cold and shiver. Sometimes the whole skin becomes red and scaly (see Journal of the American Academy of Dermatology Fig. The word eczema comes from the Greek for boiling aa reference to the tiny vesicles (bubbles) that are of these may be in action at the same time (Fig. To complicate matters further, the one of several possible types of skin inammation. This approach is now used by most dermatologists, although many stick to the term eczema when talking to patients for whom dermatitis may carry industrial and compensation Contact factors overtones, which can stir up unnecessary legal battles. In this book contact eczema is the same as contact der- matitis; seborrhoeic eczema the same as seborrhoeic Allergens Irritants dermatitis, etc. Classication of eczema Epidermis This is a messy legacy from a time when little was known about the subject. Crusting One time-honoured subdivision of eczema is into exogenous (or contact) and endogenous (or constitu- tional) types. Chronic lichenification when a contact eczema is superimposed on a gravita- tional one. Even atopic eczema, the type most widely accepted as endogenous, is greatly inuenced by Fig. In the acute stage, likely to be common to all subtypes and to involve oedema in the epidermis (spongiosis) progresses to the similar inammatory mediators (prostaglandins, formation of intraepidermal vesicles, which may co- leukotrienes and cytokines; p. The chronic stages sometimes activated by superantigens from Staphylo- of eczema show less spongiosis and vesication but coccus aureus, predominate in the inammatory more thickening of the prickle cell layer (acanthosis) inltrate. One current view is that epidermal cytokines and horny layers (hyperkeratosis and parakeratosis). Clinical appearance The different types of eczema have their own distin- guishing marks, and these will be dealt with later; most share certain general features, which it is con- venient to consider here. The absence of a sharp mar- gin is a particularly important feature that separates eczema from most papulosquamous eruptions. Chronic eczema Chronic eczema may show all of the above changes but in general is: less vesicular and exudative; more scaly, pigmented and thickened; more likely to show lichenication (Fig. Heavy bacterial colonization is common in all types of eczema but overt infection is most troublesome in the seborrhoeic, nummular and atopic types. Local sup- Differential diagnosis erimposed allergic reactions to medicaments can pro- voke dissemination, especially in gravitational eczema. First, eczema has to be All severe forms of eczema have a huge effect on separated from other skin conditions that look like it. Could be eczema but consider other erythemato- squamous eruptions Sharply marginated, strong Yes Likely to be psoriasis Can be confused with seborrhoeic eczema and colour, very scaly? Yes Could be lichen Also consider lichenoid drug eruptions Shiny at topped papules? Look at scales, cleared with potassium hydroxide, under a microscope or send scrapings to mycology laboratory. Check for contact with animals and for thickened toe nails No Localized to palms and soles? Once the diagnosis of eczema becomes light of the history and the clinical picture. A visit to solid, look for clinical pointers towards an external the home or workplace may help with this. This determines both the need for investiga- Photopatch testing is more specialized and facilities tions and the best line of treatment. A chemical is applied eruption will follow one of the well-known patterns to the skin for 24 h and then the site is irradiated with of eczema, such as the way atopic eczema picks out a suberythema dose of ultraviolet irradiation; the the skin behind the knees, and a diagnosis can then be patches are inspected for an eczematous reaction 48 h made readily enough. A contact element is likely if: Other types of eczema there is obvious contact with known irritants or allergens; The only indication for patch testing here is when the eruption clears when the patient goes on holiday, an added contact allergic element is suspected. This or at the weekends; is most common in gravitational eczema; neomycin, the eczema is asymmetrical, or has a linear or recti- framycetin, lanolin or preservative allergy can per- linear conguration; or petuate the condition and even trigger dissemination. Patients with atopic dermatitis often have multiple Investigations type I reactions to foods, danders, pollens, dusts and moulds. Some nd the measurement of serum total Each pattern of eczema needs a different line of immunoglobulin E (IgE), and of IgE antibodies specic inquiry. If the patient is allergic to the If the eczema is worsening despite treatment, or if allergen, eczema will develop at the site of contact there is much crusting, heavy bacterial colonization after 48 96 h. Opinions vary about the value of value in any type of eczema, but testing with suitably cultures for bacteria and candida, but antibiotic diluted allergens is essential in suspected allergic con- treatment may be helpful. With improvement, the frequency of the dressings can be cut down and a moisturiser can be substituted for the Acute weeping eczema corticosteroid. Parents can be taught the technique This does best with rest and liquid applications. Non- by a trained nurse, who must follow up treatment steroidal preparations are helpful and the techniques closely. Parents easily learn how to modify the tech- used will vary with the facilities available and the site nique to suit the needs of their own child. Vioform, bacitracin, fusidic acid, mupirocin a non-stick dressing or cotton gloves. However, traditional rem- Chronic eczema edies such as exposure and frequent applications of calamine lotion, and the use of half-strength magenta This responds best to steroids in an ointment base, but paint for the exures are also effective. Details of wet wrap tech- Even in adults one should be reluctant to prescribe niques are given below. This is a labour-intensive, but highly effective tech- nique, of value in the treatment of troublesome atopic eczema in children. After a bath, a corticosteroid is applied to the skin and then covered with two layers of tubular dressingathe inner layer already soaked in warm water, the outer layer being applied dry.