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It has been estimated that 20% of all adult opsoclonus cases are of paraneoplastic origin discount sildenafil 25 mg with amex green tea causes erectile dysfunction. Anti- immunomodulatory measures may need to be tried neuronal antibodies in patients with Opsoclonus that is not related to neoplastic sequentially before a treatment response is neuroblastoma and paraneoplastic opsoclonus- achieved safe 50mg sildenafil erectile dysfunction due to old age. Pediatr Neurol 1998;18: Corticosteroids are commonly applied in this progressive encephalopathy 432-434 purchase sildenafil with a visa erectile dysfunction in the military. In view of the delayed motor and cognitive neuroblastoma and opsoclonus-myoclonus- high rate of spontaneous improvement and development. Immunoabsorption, and other Opsoclonus-myoclonus syndrome: gabapentin as a immune therapies do not show consistent new therapeutic proposal. Opsoclonus-myoclonus-ataxia syndrome in may show resolution of opsoclonus after neuroblastoma: clinical outcome and anti-neuronal Unfortunately, no well-designed treatment trials successful tumor removal, and rare patients exist to guide the clinician. Hemorrhage at the disc margin occurs in Optic neuritis refers to inflammation of the less than 6% of patients. Optic neuritis The optic disc may become pale weeks after the may be acute, chronic, or subclinical. Many patients Acute optic neuritis can usually be distinguished from should raise suspicion of, but is not pathognomonic notice color desaturation and difficulty seeing in dim other conditions on clinical grounds. Ninety percent of patients have mild to suggestive with compressive optic neuropathy from moderate pain in or around the eye, usually worse intracranial tumors, anterior ischemic optic with eye movement. Patients presenting with bilateral Blood Work anterior optic neuritis should be evaluated for The following tests should be considered: Incidence papilledema. Pattern reversal stimulus Corticosteroids have longbeen the cornerstone of theraph;for optic neurit(s mean visual acuity 12 months after the onset is presentation yields more reproducible results, 20/15. Fewer than 10% have visual acuity less than despite conflicting studies of effectiveness. Contraindications In patients with a suspected infectious etiology, corticosteroids should --be withheld until appropriate antibiotic therapy is Management instituted. Walsh N/A potassium, and glucose levels should be and Hoyts clinical neuroophthalmology, 5th ed. While controlled studies are lacking, some Baltimore: Williams & Wilkins, 1998:599-647, be avoided. Ingestion of ice-cold liquids or the use consider treating steroid recalcitrant visual loss with Optic Neuritis Study Group. The five-year risk of suggested to maximize visual function with multiple sclerosis after optic neuritis; experience refractive techniques and to exclude potentially of the Optic Neuritis Treatment Trial. N/A --____Seizures, pseudoseizures Loss of heart rate Age Porphyria increment indicates severe autonomic failure. Non-neurogenic orthostatic Heart rate variation to deep breathing and Cardiac impairment (mygcardial infarction, bradycardia/tachycardia ratio during Vatsalva Sex myocarditis) maneuver is typically reduced. Riley-Day syndrome in Ashkenazi Jews on loss Thermoregulatory sweat test-body is covered by chromosome 9 (q31)]. Cardiol Clin 1997;15: Side effects: 50% hypokalemia, 50% Diabetic neuropathy-increased risk for 177-194. Schedule activities for the Pathophysiologic basis for vasodepressor syncope [ ProAmatine (Midodrine): starting dose 5 mg afternoon since the symptoms are typically worse review]. Clinical and laboratory indices that enhance scalp pruritus; urinary retention; supine High sodium and 2-2. A patient may A specific area of the nervous system is targeted in Toxic neuropathies (vitamin B6 overdose, harbor a paraneoplastic nervous system disease each of these syndromes. Serum and Vertigo urine immunoelectrophoresis, fasting glucose, serum B12 level, and urine heavy metals may also be appropriate. Although Neuroimaging is important to rule out alternative Admission may be required for hydration and patients may die from progression of their causes. After several months, brainstem, cerebral, and Medications cerebellar atrophy is often noted. There are reports of spontaneous remission or other tests deemed appropriate by the or improvement with treatment of the underlying oncologist. The disease progresses rapidly over a Myoclonic encephalopathy of childhood (the may showevidepce of muscle denervatlon. A clinical analysis of 55 anti-Yo secondary complications like aspiration neuroblastomaddo remit with corticosteroid antibody-positive patients. Physical therapy may assist with gait and Interestingly, prolonged survivals even without Author(s): Julie E. The initial symptoms Sex develop insidiously over months to N/A Males are slightly more frequently affected than years. This procedure can be performed Palilalia (repetition of the first syllable) " p bilaterally with few long-term side effects. The most common side effects and orthostatic hypotension increase controversial as a first-line agent due to from these medications are the result of the dramatically as the patient ages. There is arl absolute common to all the dopaminergic agents and pergolide (Permax, 0. Due to of C/L) has not shown any evidence of hepatic complicated combinations of all of the above. Anew combination pill incorporating the disease progresses, most patients require is rarely, if ever, used. D most patients require at failed to show any statistically significant evidence 2nd ed. Dysphagia with resultant aspiration pneumonia as prolonged use greater than 5 to 10 years is and falling are two common causes of morbidity and Professional Communications, 1999. Subclinical or silent courses surgery) confirms pituitary apoplexy, Additionally, may occur. In case of subacute or silent symptoms, retrospective analysis of pituitary ambulant (conservative) management can be Usually recovery following a critical clinical course apoplexy. Discharge Pituitary apoplexy: endocrine, surgical and surgery have been done in time. Incidence, clinical course outpatient management prognosis is generally favorable. Symptoms of Information and management of the Medications pituitary apoplexy rapidly reversed with follow-up examinations listed above. Neurosurgery Contraindications No specific contraindications unless specific hypersensitivity reactions are present. Visual recovery after blindness from Avoid sudden withdrawal of any of these pituitary apoplexy. In medial cord Incidence/Prevalence postradiation lesions, muscles innervated by the ulnar nerve and This is an uncommon disorder occurring at Hereditary neuropathies: hereditary those muscles that receive C8 and T1 via the approximately 1.
While this notion may appear simplistic generic sildenafil 50 mg visa erectile dysfunction drug approved to treat bph symptoms, there are now a number of studies pursuing this general concept that environmental changes can alter patterns of gene methylation purchase 100mg sildenafil visa erectile dysfunction drugs kamagra. Although early models of lineage commitment proposed distinct terminally differentiated Th subsets buy sildenafil on line erectile dysfunction caverject injection, more recent evidence argues against this more static view . Now there is a growing body of data in support of epigenetic regulation of cellular plasticity of Th cells . While Foxp3 is essential for the maintenance of suppressive function in Treg cells, it has been shown that depletion of Foxp3 expression results in acquisition of effector functions by these cells with concomitant loss of regulatory properties [73,74]. These obser- vations have led to the speculation that Th-effector functions in Treg cells are continuously maintained in a dormant state by an active Foxp3-mediated mechanism. This shows that Treg population represents a differentiated cell lineage committed to a specic function but retains develop- mental plasticity that may be mediated through epigenetic mechanisms. Challenging traditional models of epigenetic control of T-cell lineage commitment, Wei et al. It is speculated that bivalent epigenetic marks in master regulators of the Th differentiation maintain these tran- scription factors at a poised state for expression in non-expressing cell lineages and under appropriate conditions they can be induced leading to an alternate cell fate [76,77]. This shows that epigenetic mechanisms play a dual role in Th differentiation: ensure a committed state of Th-cell response upon activation while conferring cellular plasticity. Preliminary results from an animal model provide some evidence that this is possible. Non-pathogenic microbial strains (Acinetobacter lwof) isolated from farming environments can induce epigenetic effects when administered to pregnant animals and protect the offspring from experimental postnatal asthma . Notably, these effects were abolished by inhibition of histone acetylation following garcinol treatment. This is an area for future research with clear implications on therapeutic as well as preventive strategies for allergic diseases. While the postnatal microbial exposure has the most obvious implications for the developing immune system, there is emerging evidence that effects of microbial exposure may begin much earlier with maternal microbial exposure showing potential to modulate fetal immune Epigenetics in Human Disease function. Both human and animal studies clearly demonstrate that in utero exposure to both pathogenic and non-pathogenic microbial products can prevent allergic outcomes in the offspring, independent of postnatal exposure [85e88]. These ndings together, are highly suggestive of microbial exposure during pregnancy can modify fetal immune responses through epigenetic mechanisms [81e83]. Of immediate relevance here, this dietary pattern in pregnancy appears to provide less tolerogenic conditions during early immune development promoting allergic outcomes in the offspring . Indeed, diet and nutrition in pregnancy have been a dominant basis for notions of the developmental origins of many diseases . The rst evidence that maternal dietary changes in pregnancy can alter immune function and allergic outcomes through epigenetic modications came from animal studies. A diet rich in methyl donors (folate) fed to pregnant mice induced allergic airway disease and a Th2 phenotype to in the offspring (F1 generation) . This folate-rich maternal diet induced methylation changes in 82-gene loci in the offspring, resulting in increased airway hyperresponsiveness, airway eosinophilia, and production of inammatory cytokines. This trait was then inherited to the subsequent F2 generation, demonstrating the transgenerational effects of environmental 376 modication. While some human studies reported that folic acid supplementation during pregnancy is associated with an increased risk of asthma and respiratory infections in infants , a recent Dutch study revealed no association between maternal folic acid supplementation and allergic outcomes in neonates . However, until this is fully explored in human studies and the mechanistic pathways are clearly delineated, it is not appropriate to change the current practice of folate fortication to prevent neural tube defects. The role of vitamin D as an immune-modulatory substance is currently under much debate. Epidemiological associations between vitamin D levels and allergic diseases remain incon- clusive. Vitamin D intake during pregnancy has been associated with either increased risk  or decreased risk [99,100] of allergic disease in infants. However, at this stage it is not clear whether it is related to epigenetic modu- lation. It can be postulated that through these effects antioxidants can favor the development of Th1 cells while suppressing the Th2 development. The effect of dietary antioxidants during pregnancy on fetal immune development is limited . Evidence that oxidative stressors can modify the disease risk through epigenetic mechanisms suggests a role for these pathways . Puried compounds isolated from garlic and broccoli have been reported to have epigenetic effects . Based on the immune modulatory property of these extracts, these common dietary components may be an addi- tional source of epigenome modiers in allergy risk and warrant further study. There is mounting evidence that epigenetic modications induced by tobacco smoke are associated with the development of these chronic diseases . Exposure to cigarette smoke in pregnancy has many adverse effects on the fetus, including effects on lung function and asthma risk [112,113]. Smoking in the last trimester has been associated with early onset of airway hyperreactivity (likely asthma) by the age of 1 year . Moreover, both maternal and grandmaternal smoking during pregnancy are associated with increased risk of childhood asthma, suggesting a persistent heritable effect . In addition, the study revealed that smoking affects epigenetic marks in gene specic manner. Using a CpG loci screen, eight genes were found differentially methylated in exposed children as opposed to unexposed children. The effect of tobacco smoke exposure on methylation of specic genes could possibly be due to de novo methylation in specic gene promoters, perhaps by incomplete erasure during methylation reprogramming that occurs in the embryo after fertilization . These agents cause exacerbation of asthma symptoms in affected individuals but a causative link to asthma has not been well dened. In addition to its carcinogenic properties , it has been found not only to impair functions of airway cells and smooth muscle cells but also diminish responsiveness to standard therapy given to asthmatics . Furthermore, the exposure level was highly correlated with increased risk of asthma symptoms in the offspring before age 5 years. The direct relevance of this 378 nding to asthma pathogenesis has not been dened but epidemiological studies have revealed the alterations in fatty acid composition in the diet  and cord blood  are associated with the increased risk of asthma. Of most concern, some of these products have been measured in breast milk, cord blood, and placental tissue [138e140] emphasizing the possible adverse outcome in early development and subsequent disease pathogenesis in offspring. At higher levels these products can have immunosuppressive effects in humans , whereas at low levels some appear to selectively inhibit type 1 immune responses , leading to speculation that this could possibly favor allergic (type 2) immune responses. More evidence for epigenetic alterations induced by exposure to organic pollutants comes from rodent studies . This may inuence long-term epigenetic programming and disease susceptibility throughout the life course. The levels of many pollutants are declining in some regions as a result of restrictions imposed on the use of pesticides and other toxic chemicals, and this is reected in declining levels measured in adipose tissue . Nevertheless, the effects of these factors should not be ignored, as epigenetic effects may potentially reect exposure of subsequent several genera- tions and this relationship may be obscured in cross-sectional epidemiological studies. This may affect the cytokine milieu at the fetoematernal interface and could be a mechanistic link of attenuated Th1 responses commonly observed in infants born to atopic mothers .
Changes to water levels may involve a cyclical fluctuation buy sildenafil overnight erectile dysfunction japan, a seasonal recession cheap generic sildenafil uk impotence grounds for divorce states, or a combination of these methods safe 25mg sildenafil erectile dysfunction louisville ky. Shoreline drainage, removing and burning driftwood, and controlling growth of shoreline vegetation 72 should all be a part of this action so water level fluctuation will not cause an increased breeding area for another pest species. Aquatic vegetation protects mosquito larvae and pupae protection from wave action and natural enemies and, in some cases, may seriously interfere with larvicidal applications on the water surface. If such vegetation is a serious problem, its elimination becomes an essential part of mosquito abatement. Either chemical or mechanical removal may be the proper procedure, depending on the type of vegetation, size of area, and how the water is used. Give consideration to soil erosion and effects of any vegetation management techniques on fish and wildlife. To manage mosquitoes in these areas, alter the salt content of water in the marsh, or use dikes and tide gates designed to control flooding. Planners need a thorough knowledge of the species and habits of the mosquitoes present to effectively conduct this type of management. Salt content in the water may seriously affect or limit the breeding of some species. Opening channels to let sea water enter breeding areas, or excluding sea water to reduce salt content may measurably reduce mosquito breeding. Use tide gates to prevent salt water from leaking in natural water courses or ditches. Surface feeding fish are sometimes used as a supplementary control measure against mosquito larvae. Use pumps to drain water when the area to be drained is at or below the water level of an adjacent body of water. Several standing pools may be drained into one, and the water pumped from this pool to the selected outfall. Fill and grade shallow pools to prevent mosquitoes from breeding in such places as beneath buildings, on improved grounds, or beside roadways. Cracks and low areas are likely to form as the fill settles, and will afford breeding places when flooded; pest managers can effectively treat these areas with mosquito larvicides. Adequate ditching should remove water so ground surfaces become dry and ditch levels return to normal within 4-7 days (depending on climate and species) after the ditch is filled by heavy rainfall or irrigation. In designing drainage systems, care is needed to prevent creating mosquito breeding areas in new locations. Larvicides and adulticides are the most important temporary mosquito abatement methods. Pest managers should use such temporary measures to give immediate relief from mosquitoes and when more permanent measures are lacking or in planning. Temporary methods are often much less costly than permanent measures and, in some instances, may be used at less expense than permanent systems, provided they do not adversely effect people or the environment. Also, it is often vital to take such temporary methods to rapidly reduce disease vectors during an arthropod-borne disease epidemic or during short-term operations an endemic disease area. To temporarily manage mosquito breeding, treat water surfaces with insecticides, or eliminate small water accumulations in temporary containers. All such water-holding containers must be treated for effective management to be achieved. Solutions, emulsions, suspensions, dusts or granules may be applied with ground-operated equipment. Solicit the help of all people in the area to eliminate temporary water containers. Adequately screening occupied structures is also essential where mosquitoes occur. Use space sprays to manage mosquitoes indoors where immediate reduction is needed. These sprays have little or no residual effect and must be reapplied whenever new mosquitoes enter the area. Where frequent reentry is a problem, or where disease-bearing species are present, apply residuals to all surfaces where mosquitoes are likely to rest (unless otherwise prohibited, such as in a food service area or hospital). Screens with apertures equivalent to 18 x 16 mesh are essential to keep disease-bearing and pest mosquitoes, flies, and other insects from entering buildings. Such repetitive treatments are usually very expensive and pose some risk to people or the environment; avoid them except in the most unusual conditions. Exterior residual sprays have a limited value in protecting single residences or small camps. Mosquitoes are generally the most important arthropods managed in contingency operations because of the number, types and distribution of diseases they transmit. These actions are essential to effectively combat such mosquito-borne diseases: (1) Individual protective measures. For additional protection, they should wear the uniform properly with sleeves down and buttoned and pants tucked into the boots. In areas where malaria is endemic, preventive drug treatments (chemoprophylaxis) should be started before deployment and rigidly enforced as long as people are in the area and for a prescribed period of time after leaving the area as directed by the command surgeon or preventive medicine officer. The main unit effort should focus on training people in protective measures and then strictly enforcing them, especially the regular use of malaria chemoprophylaxis as directed by the command surgeon or preventive medicine officer. Since Air Force and Navy units normally operate from established bases, their units normally receive direct unit support from the preventive medicine or pest management engineering units described in Army and Marine Corps units operate more diversely and as a result must have an increased pest management capability in each unit. Unit field sanitation teams give this support before deployment, using 2-gallon pesticide sprayers and selected premixed pesticides, such as those normally included in self-help programs on fixed installations. Pest management support beyond this level is given by preventive medicine or engineering units. Area protective measures are those carried out by preventive medicine or engineering units with specially trained technicians using special equipment and controlled or restricted-use pesticides. These are the only military units with the equipment and training needed to conduct a large scale pest management operation. You should be aware of the life cycle of mosquitoes so you can take steps to avoid rearing mosquito larvae in water containers on your property. Water gardens or small fountains should be treated with larvicides or contain mosquito eating fish to prevent emerging adult mosquitoes. Maintenance of screen doors and windows will prevent adult mosquitoes from entering homes. Remember, any container that will hold water for 5 to 7 days is a potential breeding site for mosquito larvae. If it is not possible to drain areas, then treating them with larvicides if they are supporting larvae is an alternative. Many mosquito larvicides on the market are very host specific and only disrupt the larval stage of mosquitoes and do not harm non target species.
It is hoped that continued study and monitor- and long-term problems with bowel and bladder incon- ing of these factors will result in a healthier population tinence order sildenafil on line erectile dysfunction 47 years old. Current indications for episiotomy include shoul- Suggested Reading der dystocia (impaction of the babys shoulder against Blumenthal buy sildenafil 25 mg with mastercard erectile dysfunction korean ginseng, D order 50mg sildenafil with visa erectile dysfunction doctors in el paso tx. Introduction to environ- the maternal symphysis pubis), breech delivery, and mental health (2nd ed. These are all circumstances in health: How to conceptualise, operationalise and measure them? Episiotomy and laceration (cut or tear) repair are generally performed using a continuous length of Suggested Resources absorbable synthetic suture. Infection is generally treated by remov- vehicle for advancing womens rights beyond those ing the sutures and prescription of oral antibiotics. A already achieved with the passage of the 19th hematoma may be evacuated by removing the sutures Amendment, which had given women the right to vote. This may require women of equal treatment in the eyes of the law and in surgery at a later date. There was a split with some womens groups which feared that the labor laws that Suggested Reading had been enacted to protect women would be jeopar- Baxley, E. Episiotomy for vaginal birth strong women leaders on the left were openly suspi- (Cochrane review). Preventing fessional women at the expense of wage-earning perineal trauma during childbirth: A systematic review. This while not identical to its earlier incarnation, neverthe- change of support reflected the changing political and less adhered to the same basic premise: that sex should economic atmosphere within the country. However, with the Unfortunately, the inability to carefully lay out a definite introduction of the Civil Rights Act of 1964, new and strategy to promote the proposed amendment helps more powerful forms of protection supplanted the explain why it ultimately failed to be ratified in the older protective laws. On the 75th anniversary of the 1848 Womans woman to support herself and two children. This Schlafly led intense opposition based on the same fears appears to be increasingly true. The countrys recogni- that had once been generated to oppose womens suf- tion of this diversity and its recognition of the consid- frage. Many vacy rights would be overturned, women would be sent other nations are also having similar experiences of into combat, and abortion rights and homosexual mar- increasing diversity among people and a movement riages would be upheld. Intense opposition on these away from earlier tendencies to devalue cultural differ- grounds from various conservative religious and politi- ences and to keep cultural and ethnic groups segre- cal organizations effectively brought the Amendments gated. Ultimately it, too, failed to approve the proposed taining similar values and characteristics within a given amendment. However, increasing diversity of it being adopted in two of the remaining fourteen may also lead to a blending of ethnic differences, thus states was remote at best. First, ethnicity is defined should provide a lesson to any future incarnation of and related to other concepts. Finally, some of cerns relating to womens status as full and equal the difficulties in the measurement of ethnicity and citizens. Bloomington: Indiana race generally refers to biological factors that are the University Press. Chicago: University of that provide a basis for perceiving, believing, commu- Chicago Press. New York: Oxford University cise definitions of ethnicity or race or culture, and it is Press. The extensive list of that many people do not distinctly fall into one of the possible central characteristics that may be used to others. Note that among that list, Hispanic is omitted define an ethnic group hints at the complexity of the because it is now recognized that Hispanic is a sepa- concept itself and the varied ways in which it is used. Federal Office of primarily because none of those latter groups represent Management and Budget, which announced this system a majority. The Mexico, no traditionally labeled group represents a Department of Health and Human Services and the U. Those who use it, often The absurdity of this ethnocentric usage and meaning to meet federal standards, are encouraged by govern- of ethnicity as commonly applied in the United States mental guidelines to consider making such ethnicity thus becomes apparent. This too suggests that the sociopolit- common set of characteristics would be considered an ical systems that have evolved this scheme also recog- ethnic group, irrespective of its numbers relative to other nize that ethnicity is more complex than what the groups, including so-called whites. Thus, although ethnicity is usually characteristics or behaviors are reported to vary as a measured by simple broad self-labels, it is actually function of membership in an ethnic group. Below we based upon a complex concept that reflects many will discuss some of the many problems with the ana- dimensions. A central goal for these objectives was to help showed a much lower decline in suicide rate (2%) than reduce disparities in health care among various ethnic other groups, probably because their rate was already groups in the United States and to encourage significant the lowest by far. The disparity ratio actually increased improvement in the health indicators for the population over the period for motor vehicle crash (2. Examination of important indicators of health status in the United trends for the period 19901998 showed that most of States. The disparity ratio among groups actually sure of health status among groups and nations world- increased slightly from 2. The per- occurred over the decade of the 1990s, and for some centages of women with no prenatal care during their groups on some measures, notable increases were first trimester of pregnancy in 1998 showed marked revealed, particularly for American Indians/Alaskan declines of 2435% compared to 1990. The sure a concept, much debate has focused on the appro- ratio of rates between highest and lowest groups (the priateness of using self-reported ethnicity or race as a disparity ratio) was 2. A con- Percentages of decline across ethnic groups were sensus among researchers is not apparent, but ethnicity roughly similar with two major exceptions: (a) the rate (and gender) continue to be used as if they are poten- of suicide for American Indians/Alaskan Natives actually tial causes in a wide range of health outcomes. But reli- argue that ethnicity and race are simply sociopolitical gious preference would still be a substitute variable concepts that have little, if any, basis in scientific real- since many Hispanics may express a Catholic religious ity. Knowledge about gious doctrine or prior experiences with birth control or such factors might contribute to more effective diagno- the lack of experience with birth control methods. Still others argue that even if Measures of these might well show much better ability group genetic differences do matter, cultural and social to predict birth control use than simply having the sta- differences between ethnic groups contribute greatly to tus of Hispanic ethnicity. Commonly, nic groups may be predictors of average health status, that means measuring past behaviors or current atti- it is much more important to examine differences tudes or beliefs fairly directly rather than simply assess- within the ethnic group than to examine the differences ing ethnic group status. Additional problems with using mixed ethnicity or individuals who are not aware ethnicity to explain or predict health are substantial. Two major of great diversity within ethnic groups is compounded problems are apparent with this thinking. First, as pre- by researchers who homogenize so-called minority viously discussed, there is considerable variation among groups by comparing the responses of all minority eth- individuals within an ethnic group on almost all char- nic groups to whites, as if all members of all minority acteristics. Second, ethnicity usually serves as a substi- ethnic groups share something in common. Researchers often attempt to associated with the outcome is easier to defend scien- control for such differences using statistics, but seri- tifically. For example, if a researcher were studying use ous problems exist for interpreting such analyses that of birth control and determined that those who identi- equate groups using various covariates. Simply put, fied themselves as Hispanic were significantly less real differences in groups cannot be meaningfully elim- likely to use birth control pills, it would be scientifically inated using abstract mathematical corrections. A variable that might be closer to the outcome Recommendations for the application of several (here, use of a specific birth control method) might be guidelines for using ethnicity in research have been religious preference because Hispanics predominantly made by many authors: (a) make clear the assumptions 256 Exercise that are the basis for the use and assessment of ethnicity Suggested Reading in a particular context; (b) test specific hypotheses Alvidrez, J.