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Low significant correlation between the duration of motility and seminal plasma buffering capacity corresponds to semen pH in shirbot may be related to this problem erectile dysfunction at age 19 cheap extra super viagra 200 mg with amex. Fish evolution and systematics: study erectile dysfunction doctor omaha purchase extra super viagra 200 mg visa, where the highest motility was found in pH of 9 Evidence from spermatozoa erectile dysfunction blood pressure medication purchase extra super viagra. Czech Journal of Animal Science erectile dysfunction causes in early 20s discount generic extra super viagra uk, potential for sperm motility by bicarbonate and pH in 51 erectile dysfunction drugs viagra purchase extra super viagra with amex,: 220?226 drugs for erectile dysfunction pills purchase generic extra super viagra line. The Experimental Biology, 136: 13?22 testicular main duct and the spermatic duct in some Nikpei, M. Determination of semen quality of the rainbow factors affecting sperm quality in cultured fih. Corrlation between biochemical and plasma proteins prolong the viability of rainbow trout spermatological parameters in rainbow trout semen. Changes in 8486(92)90241-C blood and seminal plasma composition of the mature Verma, D. Comparative Biochemistry and of semen and ultrastructure of spermatozoa in six carp Physiology, 64: 325?329. External characteristics including, head width, comb height, chest width, keel length, and shank length increased with feeding level during rearing. Full fed males endured a short period of weight loss prior to production that resulted in a lower testis weight without negatively impacting the semen volume, concentration, or sperm motility. Many thanks to the Poultry Unit manager at the University of Alberta, Lyle Bouvier. I have a great respect for your technical abilities, as well as, your immutable commitment to supporting students. I would like to thank Giles Hines, Nigel Davidson, Shawn Rankin, Felicity Denis, Kim Thorsteinson, Rob Renema, and Doug Korver for their assistance in collecting data and providing animal care in Alberta. At the University of Georgia, I would like to thank David Perry, Ken Roberts, Chris McKenzie, and the entire staff at the Poultry Research Station for their support in the feed mill and technical assistance with machinery and facilities. To Doug Ard and Ben Martin, thank you for your assistance in the care, maintenance, and data collection in Georgia. I would like to thank Jason Richardson and Emily Bowling for their help with the project in Georgia. Bramwell for their guidance, assistance, instruction and time as committee members. The importance of the broiler breeder male for fertilizing eggs is rivaled only by his genetic influence on broiler breeder progeny (Fiser and Chambers, 1981). The number of fertile eggs produced for hatching dictates the ultimate profitability of the breeder flock. Rapid growth and a large appetite are desirable traits in broilers and turkeys being grown for meat yield. However, intense selection for growth, yield, and carcass characteristics have been paramount in the development of the modern broiler at the expense of the reproductive fitness of the parent stock (Harms, 1984; Reddy, 1994). Managing the reproduction efficiency of the hen and rooster is the basis of broiler breeder production. Underfeeding causes failure to attain peak egg numbers, while overfeeding is more commonly associated with a very rapid decline in egg numbers following a brief period of peak egg output (McDaniel et al. In domestic birds, they are located just anterior to the kidneys and 2 are attached to the dorsal body wall. Therefore, spermatogenesis proceeds at the o internal body temperature of 41 C in birds as opposed to the scrotal temperature of o 24-26 C in mammals (Nickel et al. In many species of birds, there is a bilateral asymmetry, with the left gonad larger than the right (Lake, 1957; Lofts and Murton, 1973). Whether the mechanisms that are responsible for testicular asymmetry are the same as those that cause the marked ovarian asymmetry, in birds, is unknown. The testes are soft, lacking the connective-tissue septa commonly found in mammals. Broiler breeder males, fed protein levels ranging from 9 to 18%, showed no difference in testes weight at 53 weeks (wk) of age (Wilson et al. The weights of the testes were more closely associated with body size than with the level of dietary protein (Fontana et al. Leydig cells are dispersed in the spaces between the seminiferous tubules, where they are associated with blood and lymph vessels (Munro, 1938ab; Lake, 1957). Sertoli cells located within the seminiferous tubules secrete inhibin, estrogens, and androgen binding protein. There is evidence that both Sertoli cells and the epithelial cells of the epididymis can reabsorb spermatozoa in order to eliminate unejaculated sperm (Tingari and Lake, 1972). Sperm development can be separated into three processes: spermatocytogenesis, spermiogenesis, and spermiation. The first stage of spermatogenesis occurs in the periphery of the seminiferous tubules lined with spermatogonia (Zlotnik, 1947). Spermatogonia are diploid dividing mitotically, to retain a constant population of stem cells for spermatogenesis, and to produce the spermatocytes (Zlotnik, 1947; Lake, 1956). Through a total of 10 stages, spermatogonia are transformed from primary spermatocytes into two secondary spermatocytes, four spermatids, and spermatozoa. At each stage of spermatogenesis, the cell is transported closer to the lumen of the tubule, where it is finally released as a complete spermatozoon. The final phase of sperm formation, spermiogenesis, consists of the elongation of the 4 spermatid nucleus to form the head and the shedding of most of the cytoplasm (Lake, 1956). Since each region of the seminiferous tubule contains spermatozoa in a different stage of differentiation, the production of spermatozoa by the testes is continuous, although spermatogenesis by each section of the seminiferous tubule is phasic (Zlotnik, 1947; Aire et al. Tightly opposed to each testis is a small structure that has often been termed an epididymis or ductus epididymis (Lake, 1957; Johnson, 1986). The epididymal region consists of efferent tubules carrying sperm from the testis to a single epididymal duct, which is apparent on the epididymal surface (Lake, 1957). This duct is short (about 2-4cm) and is quite unlike the mammalian structure of the same name. Leading from each epididymis is a coiled tube, the vas deferens, which traverses posterior, is attached to the dorsal body wall, and terminates at a small phallus in the cloaca (Nickel et al. Just before its termination, the vas deferens become somewhat enlarged and serves as a storage site for spermatozoa, as does the entire duct (Lake, 1957; Lake, 1981). Each vas deferens terminates in small papilla and ejects the semen into the cloaca (Nickel et al. At the time of sexual excitation several small folds in the ventral cloaca become engorged with 5 lymphatic fluid and protrude, forming a trough-like structure to direct the flow of semen (Nishiyama, 1950; Nishiyama, 1955). The physiological role that the various juxtesticular structures play in maturation of spermatozoa is relatively unstudied in birds. The mammalian epididymis is clearly a site of great importance in sperm maturation, (Lake, 1957; Glover and Nicander, 1971; de Reviers, 1972). Structural differentiation of spermatozoa is thought to be complete before it leaves the rete tubules (Tingari, 1973). Early studies indicate that sperm, taken from the testis or epididymis of the cock, were capable of producing fertility at a very low level because sperm motility is obtained in the vas deferens (Munro, 1938a). Estimates of total transit time from the testes to the terminal region of the vasa deferentia range from 1 to 4 d (Munro, 1938a). The composition of semen is quite variable (Esponda and Bedford, 1985), the sperm cells being mixed with secretory fluids from the engorged phallic apparatus and with digestive and urinary tract wastes. The 6 contributions of these factors are not easily controlled and consequently considerable variation in semen composition has been reported. Seminal plasma consists of protein, fructose, sorbitol, citric acid, inositol, glyceryl phosphoryl choline, ergothioneine, sodium, potassium, calcium, magnesium, and chloride as reviewed by Lake (1971). Semen that is viscous and white has a high spermatozoa concentration, while semen that has a watery appearance is low in spermatozoa concentration (Parker et al. Removal of the pituitary (hypophysectomy) in the cock causes a rapid atrophy of the testes (Hill and Parks, 1934). Follicle stimulating hormone stimulated growth, differentiation and spermatogenic activity of the seminiferous tubules. Luteinizing hormone affects steroidogenic activity of the Leydig cells (Brown et al. Follicle stimulating hormone acts on Sertoli cells (Tcholakian and Steinberger, 1980). In the male, androgen production coincides with the development of spermatogenesis and testicular growth (Etches, 1996). Luteinizing hormone acts on Leydig cells to promote their development and the production of androgens such as testosterone (Nicholls and Graham, 1972). The principal steroids secreted by Leydig cells include testosterone and androstenedione, a precursor of testosterone. There is a marked increase in the secretion of androgen in the male chick at about 30 d post-hatch (Breneman and Mason, 1951). However, plasma levels of testosterone are several times lower than those found in the testicular vein (Ottinger and Brinkley, 1979). In broiler breeder males, Hocking and Bernard (2000) found plasma concentrations of testosterone peaked at less than 4 ng/mL at 30 wk of age and averaged 2. In caged broiler breeder males, plasma testosterone increased from 16 to 30 wk (Renden et al. In young broiler breeders, excessive natural mating activity occurred during high plasma concentrations of testosterone (Duncan et al. Androgens are also responsible for the full expression of the characteristic voice of the rooster, although capons and masculinized females will make feeble attempts to imitate the intact male (Etches, 1996). In both sexes, the development of the comb coincides with increased plasma concentration of androgens (Etches, 1996). Mashaly and Glick (1979) suggested that dihydrotestosterone might be of greater importance in stimulating comb growth than testosterone. Exogenous gonadal hormones may cause some precocious development of certain behavior patterns, particularly agonistic and sexual behavior patterns (Guhl, 1958). Testosterone is the major hormone found to affect mating behavior in males of different avian species (Mashaly and Glick, 1979). Testosterone injected into chicks 10 results in precocious male sexual behavior, such as mounting, treading, and crowing (reviewed in Appleby et al. More recently, inhibin B, produced in the Sertoli cells, has been associated with the negative feedback of the hypothalamus and pituitary (reviewed in Mather et al. Adipose tissue sends a message concerning fuel supply to the hypothalamus by secreting concentrations of leptin that reflect energy storage (reviewed in Heiman et al. Leptin functions as a tropic factor for the reproductive system (reviewed in Prolo et al. Studies in men and women clearly indicate that circulating leptin values are positively correlated with quantity of body fat (reviewed in Caro et al. In a review by Hossner (1998), leptin was not considered the primary puberty-inducing factor, but leptin can induce maturation when metabolic resources are adequate. Leptin appears to be controlled by feedback mechanisms within the male reproductive system. In boys, testosterone had a negative effect on leptin concentration, but not girls (Wabitsch et 12 al. Although homozygous obese male mice that were food restricted were also infertile, leptin treatment of these mice restored fertility and normalized testes weight and histology (Mounzih et al. In animal and human studies, weight gain significantly increases circulating leptin concentrations (Considine and Caro, 1997; Hebebrand et al. Caloric restriction, of homozygous obese mice, does not restore fertility, which suggests that obesity per se is not the cause of infertility in leptin deficiency, and that leptin is directly related to the modifications of reproductive capacity (Chehab et al. In animal and human studies, weight loss results in decreased leptin levels (Considine and Caro, 1997; Hebebrand et al. Corticosterone acts on the brain to influence behavior by changes in perception (Appleby et al. In mammals, elevated corticosteroids counter the negative feedback of reproductive steroids by enhancing or maintaining excitatory amino acid receptors, in the brain. These receptors drive the hypothalamo-pituitary-gonadal axis (Brann and Mahesh, 1997). There is also evidence that high plasma concentrations of corticosterone can differentially inhibit behavioral components of reproduction. Both short term feed deprivation and long-term energy restriction cause increased corticosterone secretion in laying chickens (Nir et al. Possible increases in corticosterone, with mating, territorial, and nesting pressures, may require either a facilitating role for corticosterone in reproduction or an uncoupling of changes in circulating corticosterone for various reproductive parameters, in order for the reproductive phase to survive (Carsia and Harvey, 2000). Estimations of sperm quality, but not sperm concentration, were highly correlated with the fertilizing ability of individual male chickens (Wishart and Palmer, 1986). Males with the largest testes from 16 to 44 wk of age produced the greatest quantity of semen (de Reviers and Williams, 1984). In general, large males have large testes and therefore broiler breeder males usually produce more semen than Leghorn males (de Reviers and Williams, 1984). In contrast, Brown and McCartney (1983) found that groups of broiler breeder males at 54 wk of age with the largest testes did not produce the largest amounts of semen. The number of Sertoli cells present in the testes is proportional to testicular size and therefore daily sperm production is also correlated with testicular size (Parker et al. However, neither the amount of semen obtained nor the weight of the testes appeared to have any effect on fertility 15 and hatchability of eggs (Brown and McCartney, 1983). Once the testes reach the minimum critical size (7 g), additional size increases have little effect on semen concentration. Only males with testes weighing less than 9 g at the time of necropsy yield semen irregularly throughout production (Fontana et al. Avian semen quality is often defined by four characteristics: semen volume and concentration, sperm viability (% of live spermatozoa), and sperm motility (movement) (McDaniel et al. Semen volume, concentration and sperm motility measurements are highly positively correlated with one another (McDaniel and Craig, 1959). However, Brown and McCartney (1983) found that neither the volume of semen obtained nor the weight of the testes appeared to have any effect on fertility and hatchability of eggs.

Effect of intensive blood pressure lowering on left ventricular hypertrophy in patients with diabetes mellitus: Action to Control Cardiovascular Risk in Diabetes Blood Pressure Trial erectile dysfunction over 80 buy discount extra super viagra 200 mg line. Effect of intensive versus standard blood pressure treatment according to baseline prediabetes status: a post hoc analysis of a randomized trial erectile dysfunction biking purchase genuine extra super viagra. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials erectile dysfunction tucson discount extra super viagra 200 mg with visa. Comparative efficacy and safety of blood pressure-lowering agents in adults with diabetes and kidney disease: a network meta-analysis erectile dysfunction treatment success rate discount 200mg extra super viagra amex. Diabetes erectile dysfunction diabetes permanent buy extra super viagra american express, other risk factors impotence lab tests order extra super viagra us, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients. Lifestyle modification, with an emphasis on improving insulin sensitivity by means of dietary modification, weight reduction, and exercise, is the foundation of treatment of the metabolic syndrome. The optimal antihypertensive drug therapy for patients with hypertension in the setting of the metabolic syndrome has not been clearly defined (1). Use of traditional beta blockers may lead to dyslipidemia or deterioration of glucose tolerance, and ability to lose weight (2). Anti-hypertensive drug treatment of patients with and the metabolic syndrome and obesity: a review of evidence, meta-analysis, post hoc and guidelines publications. Association between the metabolic syndrome and chronic kidney disease in Chinese adults. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Dose-dependent arterial destiffening and inward remodeling after olmesartan in hypertensives with metabolic syndrome. Prevention of atrial fibrillation with renin-angiotensin system inhibitors on essential hypertensive patients: a meta-analysis of randomized controlled trials. Electrophysiologic and electroanatomic changes in the human atrium associated with age. Atrial fibrillation: hypertension as a causative agent, risk factor for complications, and potential therapeutic target. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity. Valvular Heart Disease Recommendations for Treatment of Hypertension in Patients With Valvular Heart Disease References that support recommendations are summarized in Online Data Supplements 49 and 50. There is no evidence that antihypertensive medications will produce an inordinate degree of hypotension in patients with aortic stenosis. In patients with moderate or severe aortic stenosis, consultation or co-management with a cardiologist is preferred for hypertension management. Beta blockers may result in increased diastolic filling period because of bradycardia, potentially causing increased aortic insufficiency. Hypertension in aortic stenosis: implications for left ventricular structure and cardiovascular events. Nifedipine in asymptomatic patients with severe aortic regurgitation and normal left ventricular function. Synopsis Thoracic aortic aneurysms are generally asymptomatic until a person presents with a sudden catastrophic event, such as an aortic dissection or rupture, which is rapidly fatal in the majority of patients (3, 4). The rationale for antihypertensive therapy is based largely on animal and observational studies associating hypertension with aortic dissection (5, 6). A study in 20 humans with hypertension suggested that hypertension is associated with significant changes in the mechanical properties of the aortic wall, with more strain-induced stiffening in hypertension than in normotension, which may reflect destruction of elastin and predisposition to aortic dissection in the presence of hypertension (9). Recommendations for treatment of acute aortic dissection are provided in Section 11. In patients with chronic aortic dissection, observational studies suggest lower risk for operative repair with beta-blocker therapy (1). Chronic beta-blocker therapy improves outcome and reduces treatment costs in chronic type B aortic dissection. Simple risk models to predict surgical mortality in acute type A aortic dissection: the International Registry of Acute Aortic Dissection score. Acute type A aortic dissection in the elderly: clinical characteristics, management, and outcomes in the current era. First-line beta-blockers versus other antihypertensive medications for chronic type B aortic dissection. Altered dependence of aortic pulse wave velocity on transmural pressure in hypertension revealing structural change in the aortic wall. Prognostic impact of blood pressure variability on aortic dissection patients after endovascular therapy. Special Patient Groups Special attention is needed for specific patient subgroups. Race and Ethnicity In the United States, at any decade of life, blacks have a higher prevalence of hypertension than that of Hispanic Americans, whites, Native Americans, and other subgroups defined by race and ethnicity (see Section 3. Hypertension control rates are lower for blacks, Hispanic Americans, and Asian Americans than for whites (1). Morbidity and mortality attributed to hypertension are also more common in blacks and Hispanic Americans than in Whites. In 2014, age adjusted hypertension-attributable mortality rates per 1,000 persons for non-Hispanic white, non-Hispanic black, and Hispanic-American men and women were 19. However, Hispanics in the United States are a heterogeneous subgroup, and rates of both hypertension and its consequences vary according to whether their ancestry is from the Caribbean, Mexico, Central or South America, or Europe (6-8). Thus, pooling of data for Hispanics may not accurately reflect risk in a given patient. Blood pressure control in Hispanics in the antihypertensive and lipid-lowering treatment to prevent heart attack trial. Epidemiology and management of hypertension in the Hispanic population: a review of the available literature. Prevalence of hypertension, awareness, treatment, and control in the Hispanic Community Health Study/Study of Latinos. Status of cardiovascular disease and stroke in Hispanics/Latinos in the United States: a science advisory from the American Heart Association. Apolipoprotein L1 gene variants associate with hypertension attributed nephropathy and the rate of kidney function decline in African Americans. Apolipoprotein L1 gene variants associate with prevalent kidney but not prevalent cardiovascular disease in the Systolic Blood Pressure Intervention Trial. However, the adoption of lifestyle recommendations is often challenging in ethnic minority patients because of poor social support, limited access to exercise opportunities and healthy foods, and financial considerations. The greater prevalence of lower socioeconomic status may impede access to basic living necessities (8), including medical care and medications. Consideration must also be given to learning styles and preference, personal beliefs, values, and culture (9, 10). For optimum endpoint protection, the thiazide chlorthalidone should be administered at a dose of 12. Racial and ethnic differences should not be the basis for excluding any class of antihypertensive agent in combination therapy. For blacks who do not achieve control with 3 drugs, see resistant hypertension (see Section 11. Management of high blood pressure in blacks: an update of the International Society on Hypertension in Blacks consensus statement. A comparison of the efficacy and safety of a beta-blocker, a calcium channel blocker, and a converting enzyme inhibitor in hypertensive blacks. Regional and racial differences in response to antihypertensive medication use in a randomized controlled trial of men with hypertension in the United States. Department of Veterans Affairs Cooperative Study Group on Antihypertensive Agents. High prevalence of persistent cough with angiotensin converting enzyme inhibitors in Chinese. The effects of blood pressure reduction and of different blood pressure-lowering regimens on major cardiovascular events according to baseline blood pressure: meta-analysis of randomized trials. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level meta-analysis. Sex-Related Issues the prevalence of hypertension is lower in women than in men until about the fifth decade but is higher later in life (1). Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men. However, in prespecified analyses, there was no evidence of an interaction between sex and treatment effect. However, these sex-related differences might have been due to chance because of the large number of statistical comparisons that were performed. The Heart Attack Trial and Hypertension Care Computing Project reported that beta blockers were associated with reduced mortality in men but not in women, but this finding was likely due to the low event rates in women (3). Women were more likely to experience hypokalemia and hyponatremia and less likely to experience gout with diuretics (7). Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension. Pregnancy Recommendations for Treatment of Hypertension in Pregnancy References that support recommendations are summarized in Online Data Supplement 53. The goal of antihypertensive treatment during pregnancy includes prevention of severe hypertension and the possibility of prolonging gestation to allow the fetus more time to mature before delivery. There are 3 Cochrane database reviews of treatment for mild-to-moderate hypertension during pregnancy (10-12). An earlier review confined to assessing the effect of beta blockers found them generally safe and effective but of no benefit for newborn outcomes, either in placebo-controlled studies or when compared with other antihypertensive agents. There was a suggestion that beta-blocker therapy might be associated with small for gestational age and neonatal bradycardia (12). A review of treatment for pregnancy-associated severe hypertension found insufficient evidence to recommend specific agents; rather, clinician experience was recommended in this setting (14). Preeclampsia is a potentially dangerous condition for the pregnant woman and fetus, occurring in 3. Preeclampsia is associated with an increased risk of preterm delivery, intrauterine growth restriction, placental abruption, and perinatal mortality and is twice as likely to occur in the first pregnancy. It is beyond the scope of the present guideline to address the management of hypertension during pregnancy in detail. Several international guidelines provide guidance on management of hypertension during pregnancy (2, 3, 17). The American College of Obstetricians and Gynecologists has issued a task force report that includes recommendations for prevention (aspirin in selected cases) and treatment (magnesium for severe hypertension) of hypertension in pregnancy (2). A report detailing treatment of hypertensive emergencies during pregnancy and postpartum has also been released (2, 17, 18). Among the agents recommended, no specific agent is first choice because there are no data supporting one over another. Therapeutic classes are not recommended because potential toxicity differs among agents within classes. Adverse effects in the first trimester of pregnancy may be secondary to hypertension or the medication (4, 5). Adverse events in the later trimesters have been suggested by observational data and meta-analyses (6). Cardiovascular disease risk factors after early-onset preeclampsia, late-onset preeclampsia, and pregnancy-induced hypertension. Tight control of mild-moderate pre-existing or non-proteinuric gestational hypertension. Outcomes of 83 fetuses exposed to angiotensin receptor blockers during the second or third trimesters: a literature review. Older Persons Recommendations for Treatment of Hypertension in Older Persons References that support recommendations are summarized in Online Data Supplement 54. Synopsis Because of its extremely high prevalence in older adults, hypertension is not only a leading cause of preventable morbidity and mortality but, perhaps more importantly, is under-recognized as a major contributor to premature disability and institutionalization (2-5). Thus, isolated systolic hypertension is the predominant form of hypertension in older persons (7, 8). Older persons need to be carefully monitored for orthostatic hypotension during treatment. Initiation of antihypertensive therapy with 2 agents should be undertaken cautiously in older persons, and they need to be monitored carefully for orthostatic hypotension and history of falls. Older persons may present with neurogenic orthostatic hypotension associated with supine hypertension. For management of this problem, the reader is referred to the recommendations of a 2017 consensus panel (18). Self-reported causes of physical disability in older people: the Cardiovascular Health Study. Hospital diagnoses, Medicare charges, and nursing home admissions in the year when older persons become severely disabled. Prevalence and trends of isolated systolic hypertension among untreated adults in the United States. Comparison of active treatment and placebo in older Chinese patients with isolated systolic hypertension. Antihypertensive medications and serious fall injuries in a nationally representative sample of older adults. Hypertension, orthostatic hypotension, and the risk of falls in a community dwelling elderly population: the maintenance of balance, independent living, intellect, and zest in the elderly of Boston study.

They should be given information on the history of the programme impotence problems discount extra super viagra online visa, the rationale for its existence erectile dysfunction psychological buy 200 mg extra super viagra free shipping, programme benefits to individual newborns erectile dysfunction protocol discount order 200mg extra super viagra mastercard, families and society erectile dysfunction quizlet purchase genuine extra super viagra online, the financial strategies involved and future plans for the programme erectile dysfunction drugs staxyn order generic extra super viagra from india. The availability of information and education allows advocates to be informed and to provide information to others why alcohol causes erectile dysfunction purchase extra super viagra pills in toronto. It is the education and understanding of a few key individuals that can often determine the acceptance or rejection of newborn screening as a routine medical activity in local hospitals. In addition to the usually strategy of providing talks at professional meetings, workshops and seminars, the programme in the Philippines has found increased advocacy through organizations such as the national nursing society, the National Academy of Science and Technology, and local medical societies. Training and awareness seminars not only provide educational opportunities, they strengthen the advocacy of those who get involved. Ideally, newborn screening may be added to an existing health newborns in distant/ programme such as maternal and child health, where it can take difficult locations. It is likely that other government infrastructures can be utilized to provide assistance to the programme as it is being developed. For example, the Ministry of Health often oversees government hospitals and has a system of health clinics and nurses in place. This infrastructure has the potential for rapidly providing a mechanism for spreading newborn screening opportunities throughout the country, including remote areas. Without access to such an infrastructure, a newborn screening system that is in the initial stages of formation is destined to take a longer time to develop, as a similar system will have to be reinvented. There may be other government programmes that can provide assistance to newborn screening if their purpose is to improve public health service and systems of care. For example, birth or near-birth immunization programmes may provide a mechanism for collecting and transporting newborn screening specimens by using immunization programme personnel already in place as specimen collectors. Similarly, the transport networks used for immunization supplies might be available for the transport of specimens for the screening of newborns. In some settings, educational activities for existing child health programmes might be modified slightly to include educational components on newborn screening. Health records systems already in place might be simply modified to include newborn screening in individual health records, without the need to develop a new and parallel system. Government transport systems may already exist for other purposes and these could serve as mechanisms for the transport of specimens for newborn screening. It is important to take advantage of any available government networks and personnel that can be utilized for screening activities rather than trying to provide similar, and often duplicative, systems. Government can include legislative bodies (the programme national or federal assembly, congress, senate, or parliament), sustainability. The roles played by the government and governmental organizations in promoting, establishing and sustaining newborn screening systems are essential to the survival of these systems. In ensuring this right, parties are to take appropriate measures to ?diminish infant and child mortality? [Art. A large number of countries have ratified or are in the process of ratifying, this convention. The screening of newborns, in this regard, is a major step forward in primary health care for all children: this is a compelling argument that can serve to persuade the government policy makers of the need and benefits of newborn screening. Properly developed and administered health policies include assignment of responsibilities for health programme implementation and administration at all levels of operation. Health programmes that result from government policies ultimately lead to plans of action that develop organizational structures for the programme at all levels, including implementation at the local level. In addition to developing a financial strategy for administering the system, health plans usually define roles and responsibilities of each part of the organization and outline the steps necessary for programme implementation. It is important to note that even in China, with over 20 million newborns annually, a national mandate now exists encouraging the gradual development of a newborn screening programme to improve the health outcome of newborns as part of the law governing the health of mothers and their children. In Uruguay, there was a presidential proclamation that declared that all newborns should undergo newborn screening. In the Philippines, there is a Department of Health administrative order calling for the nationwide implementation of newborn screening and a national law was recently enacted requiring health care workers to make newborn screening available to all newborns. Non-governmental organizations can also have an impact at Non-governmental various levels on policy making for newborn screening. For example, it support is also helpful has been suggested that newborn screening as a service to patients in sustaining programme interests. At the hospital level, the hospital administrator and/or the medical director can issue directives that directly affect the implementation of newborn screening in that hospital. Since most developing programmes encompass a large number of hospitals that do not belong to the government, it is important to identify a contact person at each birthing facility who can assume responsibility for the organization and implementation of the programme within that facility. In this way, the programme can obtain multidimensional input into its policy making decisions. Formal recognition and institutionalization must be implemented of the newborn screening programme within the public health system is as a system in a way that will lead to its one of the most important steps in implementing and sustaining sustainability. To accomplish this, it is likely that public?private partnerships will be necessary if maximum programme efficiency is to be obtained. Where government support is available, integrating newborn screening into existing public health and other public service programmes can facilitate implementation. As an example of the utilization of existing government programmes, it is often possible to build on other programmes to create networks for collecting and transporting specimens, recalling potentially positive patients for confirmatory testing, ensuring proper management of detected disorders, and monitoring patient outcome. Academic centres may be helpful in providing expertise for the preparation of training and educational materials, and for managing and treating patients that have been identified with a disorder through screening. Prompt recall is Prompt recall of patients with a suspected disorder which has critical. Health clinics that belong to the government and are public, in tandem with outreach programmes, provide a means of patient contact that can be particularly useful in both rural and urban settings. In the urban environment, government clinics and hospitals are usually available to the majority of the population and they should be utilized as part of the follow-up system. In rural areas, public health nurses, local clinics, and an informal health network usually provide the necessary follow-up. Integration with child Building on the synergies of other government health health programmes programmes for infants and children can sometimes provide a unique should be considered. For example, programmes that include actions such as vaccinations that begin at or near birth are often well established and reach most newborn populations in developing countries. Adding newborn screening to vaccination programme activities has successfully aided programme implementation and outreach in at least one developing country. Utilizing immunization staff and networks already in place for vaccine delivery allowed for full newborn screening coverage within a very short time. While this model may not work in every setting, it offers an opportunity to reach babies born in remote areas where an established ?near birth? immunization is already effectively established and sustained. Subspecialists should In order to succeed, it is important that subspecialty care. Subspecialty care may be available at, or in conjunction with, government hospitals or medical centres or in the private sector. In cases where a subspecialty provider is desired but not available, it may be necessary to rely on a physician who has had experience with such cases in his(her) training, or who has a special interest in the condition of concern. Subspecialty care and availability can be a challenge in a developing country, but it is an integral part of the newborn screening system and must be a continuing consideration. Likewise, pharmaceuticals used for treatment may be difficult to obtain in a developing country and it may be necessary to cultivate relationships with suppliers outside the country in order to implement and sustain the treatments necessary to take advantage of the screening system. Education at all levels Education about newborn screening and the medical implications is essential. For education within a developing programme, it is prudent to obtain training videotapes and literature from developed programmes these can serve for developing local educational materials. Once developed, it is a simple matter to update materials periodically for sustainability. Eventually it may be possible to include newborn screening as a part of the education curriculum in formal training programmes for health care workers and physicians, including medical schools. Logistics are a major concern in most developing programmes Programme logistics and agencies: in this regard, organizations that handle transport and cannot be overlooked. For example, it may be possible to develop special shipping arrangements with courier, bus and postal services. Likewise, special telephone, telefax, or other telecommunication arrangements and fees may facilitate result reporting. In instances where immediate (emergency) testing follow-up is needed, government police may be able to assist and several examples of such assistance exist. Public?private partnerships have played a valuable role in Public?private establishing and sustaining successful newborn screening programmes partnerships may be around the world. Concerned businesses have sponsored important important to overall programme success. Often, private businesses have paid expenses for experts from developed programmes to assist developing ones. Contributions from private companies have supported scientific visits of staff from developing programmes as they seek to transfer knowledge from more developed programmes. In many cases, private laboratories have also played an important role in confirming screening test results and providing diagnostic testing to assist with diagnoses. It has been demonstrated repeatedly that laboratory testing for screening purposes that is centralized and processes a high volume of specimens is more efficient than hospital testing that processes a smaller volume of specimens and that it provides higher quality results for patients. However, private laboratories or hospital laboratories sometimes anticipate that low volume testing can improve their profitability and thus, they attempt to establish low volume newborn screening laboratories. Such laboratories have the potential for fragmenting the screening system by generally providing lower quality service at higher costs, and not contributing to the national data collection effort to evaluate the screening process. Confirmatory testing the availability of quality confirmatory testing is often assumed must be of high by the managers of the screening programme and little thought is given quality. Consideration should be given to ensuring quality systems for confirmation facilities. For example, in thyroid screening, laboratories and nuclear medicine facilities that provide confirmatory testing. In cases where appropriate confirmatory testing is not readily available, the programme should develop a listing of available service providers in other locations and assist in obtaining any needed testing services. However, in some cases, national or local government budgets do not include funding for the screening of newborns and the programme is left to obtain funds through other means. Many developing programmes find that a fee is necessary when the programme is starting up in order to defray the expenses of testing. Sound budgeting While some may view a newborn screening fee as unnecessary or too must support all programme expensive, the fee charged is usually significantly less than the cost of components most other pre-natal activities. Relative to other health care costs, newborn screening is considered inexpensive in most settings. In order to encourage screening, a plan should be developed to encourage prospective parents to save for it. Altruistic organizations or local governments may also participate in programme financing in order to lower or eliminate costs. Alternatively, it may be of benefit to educate prospective grandparents on the value of screening, and they may in turn assist in paying or contributing to the payment of any fee that may be required. Ideally, no one should be refused screening because of their inability to pay, but this idealistic goal usually can be reached only after the programme is established and costs can be supplemented with some sort of government or insurance assistance. It is important for the newborn screening programme to develop local financing models and advocate for their use. Financing should A comprehensive listing of all system expenses should be cover all aspects of maintained and used for budgetary planning. System funding may include supplemental payment for some of the costs relating to treatment if local circumstances permit this. Two primary fee collection mechanisms exist: (1) direct bill to the birthing facility following testing and (2) billing for collection cards that are purchased prior to screening. The former requires that the programme pay for itself pending payment after testing, while the latter can be established in such a way as to have the collection kits paid for in advance of testing. When fees for newborn screening are collected from the sale of laboratory collection kits, care must be taken to make the fee comprehensive so that non-laboratory costs are also covered. In all cases, sound accounting principles should be followed in establishing the fee. Any monies generated from newborn screening fees should first be used to pay for programme expenses before they are used for any other purposes. This practice detracts from programme improvement and should be avoided if at all possible. Because adequate funding is essential for a programme for the screening of newborns, a great deal of effort must usually be expended in developing necessary costing data and financial planning. Additionally, in cases where fees are necessary, a sound billing and collection system must be developed and implemented. Some programmes have found that billing hospitals for testing after it is completed, without an efficient collection system, results in postponed payments that eventually cause the programme to encounter financial difficulties. Strong leadership is ministry should critical and usually falls initially to the person or persons who have ultimately assume national coordination advocated most strongly for the programme. Most developed screening programmes have a newborn screening advisory committee of some type, not only for advice, but also for professional assistance and advocacy. Aside from technical expertise, the advisory committee might also include individuals who can adequately represent professional and community groups interested in or impacted by newborn screening. Whilst initially, it may be advisable to work with a small ?core? group of organizers in order to define the infrastructure needs and programme development approaches, it is usually prudent to invite local physicians knowledgeable in treatment of the conditions included in screening programme. They can play a key role in developing programme guidance and gaining acceptance and cooperation of other community physicians. It may also be useful to include representatives from public health, parent advocates, obstetricians, and others who might have a role in the screening process, such as insurers and hospital administrators.

It is not known whether hephaestin works independently of ferroportin 1 erectile dysfunction treatment in pune order extra super viagra 200 mg with mastercard, or if the two proteins interact to cause the oxidation (Miret et al impotence cream purchase extra super viagra cheap online, 2003) erectile dysfunction protocol pdf generic extra super viagra 200 mg line. Ceruloplasmin erectile dysfunction yoga purchase extra super viagra mastercard, which is found in plasma erectile dysfunction doctors orange county buy extra super viagra with amex, is also a ferroxidase and may be involved in the oxidation of ferrous iron to ferric iron during binding to transferrin erectile dysfunction devices diabetes purchase cheap extra super viagra online. This means there is a time lag of 1?2 days between changes in systemic iron need and in the corresponding mucosal setting for iron uptake and transfer. This has implications for interpreting data from absorption studies and their relevance to practice and for understanding the potential toxicity of acute exposure to iron (see paragraphs 7. However, a large intake of dietary iron, in excess of that required to meet systemic needs, can itself induce the enterocytes autonomously to develop a ?mucosal block? (Granick, 1946) through ferritin induction which prevents excessive absorption by reducing the intestinal transfer of iron for several days (Frazer et al, 2003), even in the presence of systemic iron defciency. Transgenic mouse models have shown that hepcidin is the principaldown regulator of iron absorption in the small intestine,iron transport across the placenta, and iron release from macrophages and hepatocytes (Nicolas et al, 2002). In vitro studies in macrophage cells have shown that hepcidin exerts its effects by directly binding to and degrading the iron exporter molecule, ferroportin, on the cellular membrane; as a consequence, iron is prevented from leaving the cell (Nemeth et al, 2004). The released hepcidin, through its effect on ferroportin, then prevents the transfer of iron from the enterocyte to plasma transferrin. The iron that is not transferred is sequestered within the enterocytes and is eventually lost in the gut lumen when the enterocytes are shed and lost in the faeces. Similarly, during infammation or when the systemic iron content is adequate, hepcidin blocks the release of iron from macrophages. However, when systemic iron requirements are increased or iron stores are low, or both, hepcidin production is decreased, allowing intestinal iron transfer and the release of iron from depots in the macrophages. In addition, hepcidin production is reduced by systemic hypoxia, which also stimulates the production of erythropoietin which, in turn, stimulates the production of red blood cells (erythropoiesis). The coincident depression of hepcidin therefore ensures a supply of iron needed for the synthesis of haemoglobin as part of the erythro poietic response. These are characterised by increased iron absorption leading to excessive systemic iron accumulation and overload. This leads to either iron accumulation in phagocytic cells or in hepatic parenchymal cells and, unlike the other forms of genetic haemochromatosis, there is autosomal dominant inheritance. Transferrin comprises a core carrier glycoprotein, apotransferrin, which can bind one or two atoms of ferric iron to form holotransferrin, which is usually called transferrin. This is an effcient carrier system; however, non transferrin-bound iron has been detected in the plasma of patients with iron overload conditions (Grootveld et al, 1989). The apotransferrin and the TfR return to the cell surface and the apotransferrin is recycled into the plasma. Hepatocytes take up iron from transferrin by the receptor-mediated endocytosis described previously (see paragraph 2. Iron is released from the hepatocytes in times of increased need subject to regulation by hepcidin. Ferritin is the major intracellular storage protein found in all cells with the highest concentrations in the liver, spleen and bone marrow. Each molecule can theoret ically store up to 4500 atoms of ferric iron but, in practice, it is typically less than 2000 atoms. The protein shell surrounding the iron core is penetrated by six channels through which ferrous iron enters to interact with a ferroxidase at the centre of the molecule (Harrison and Arosio, 1996). They are lower in children than in adults; from puberty to middle age, mean concentrations are higher in men than in women (Worwood, 1982). Good correlations have been found between serum ferritin concentrations and storage iron mobilised by quantitative phlebotomy, stainable iron in bone marrow biopsies, and the concentration of both non-haem iron and ferritin in the bone marrow. This suggests a close relationship between the total amount of storage iron and serum ferritin concentration in normal individuals (Walters, 1973). Phlebotomy studies have demonstrated that a serum ferritin concentration of 1 ?g/L is equivalent to approximately 8 mg stored iron. Haemosiderin iron is found in lysosomes and cytosol and, as it is less soluble than ferritin iron, it is less easily mobilised. Both haem and non-haem iron absorption show an inverse relationship to serum ferritin concentrations which refect iron reserves (Lynch et al, 1989) (see section 4): absorption of dietary iron increases as ferritin depots decrease. If absorption is not adequate, tissue iron stores are slowly depleted and the amount available for recycling and redistribution to tissues is decreased; this results in less iron bound to circulating transferrin (reduction in ?transferrin saturation?). As a result, the delivery of iron to functional sites decreases and iron dependent functions, such as erythropoiesis, become impaired, leading to a decrease in haemoglobin concentration and the development of anaemia (see paragraphs 6. At a cellular level, ferritin synthesis is inhibited and transferrin receptor synthesis is increased in an effort to enhance cellular iron uptake. Concentrations of other iron-containing proteins such as myoglobin, cytochromes and iron-sulphur proteins are decreased (Dallman et al, 1982). It results in excessive absorption of dietary iron, causing high levels of iron to accumulate in the body. This can cause organ damage, leading to clinical manifestations including diabetes, arthritis and cirrhosis of the liver (Bothwell and MacPhail, 1998). The clinical penetrance of homozygosity for C282Y is very variable; the majority of people with this genotype never become ill as a result of iron overload (Beutler et al, 2002; Asberg et al, 2002; McCune et al, 2006). The H63D variant is more widespread in the general population worldwide and has a less defned role in predisposing towards iron loading. Although it has been suggested that heterozygotes may also have poorer control of iron absorption (Lynch et al, 1989), two studies reported no differences in iron absorption between heterozygotes and wild-type controls (Hunt and Zeng, 2004; Roe et al, 2005). The condition is associated with a propensity to accumulate iron by a different mechanism to those found in the haemochromatoses. In contrast to the haemochromatoses, the excess iron is in both the hepatocytes and Kupffer cells, and both heterozygotes and homozygotes appear to be affected (Andrews, 1999). Hepcidin is directly responsible for regulating both iron release from intestinal epithelial cells and from macrophages through binding to the iron export protein, ferroportin 1. In all three types, this results in enhanced iron transfer from the small intestine and enhanced release of iron from phagocytes breaking down senescent red cells. The consequence is an increase in systemic iron load which is manifested by elevated plasma iron and ferritin concentrations and increased iron in liver parenchymal cells. Consequently, 22 iron release from intestinal epithelial cells and macrophages is increased (as in types 1, 2 and 3) which leads to iron accumulation in hepatic parenchymal cells (Brissot et al, 2008). Aceruloplasminemia, a rare autosomal recessive disorder of iron metabolism, is caused by mutations in the gene encoding ceruloplasmin; six mutations have been characterised. It results in iron accumulation in the parenchymal cells (as seen in hereditary haemochromatosis) but the predominant clinical features are neurological and retinal degeneration accompanied by iron deposition in the brain (Gitlin, 1998). This paradoxical situation, of red cell and systemic functional iron defciency accompanied by increased systemic and macrophage iron deposits, can become sustained with chronic infammatory conditions and is known as the anaemia of chronic disease. Hepcidin, the key regulator of iron absorption and of its release from macrophages and hepatocytes, is part of this response and its production is increased as part of the acute phase reaction (Nemeth et al, 2003). Increased amounts of hepcidin may contribute to the development of the anaemia of infammation by reducing iron absorption and preventing the release of iron from macrophages. This condition is observed frequently in clinical practice and 23 chronic disease and is likely to be a signifcant confounder in population studies. Such transient disturbances of iron metabolism in response to intercurrent infections need to be considered when interpreting the standard markers of iron metabolism (see section 4). In developing countries, poverty, malnutrition and infection are associated with the acute phase response and a correspondingly high prevalence of the anaemia of chronic disease. Although information is usually inadequate to calculate precisely and accurately the range of requirements for a nutrient in a group of individuals, it has been assumed to be normally distributed. These considerations are relevant to iron and it is important to recognise that, as a result, reference values are usually translated conservatively from the data. The values therefore represent thresholds of concern rather than diagnostic thresholds for clinical and public health problems. Requirements for dietary iron are then estimated using an average fgure for the absorption and functional systemic use (i. In the case of iron, this can be problematic, as these estimates are based on short term studies that are usually carried out in iron replete individuals. Iron absorption will be down regulated in these individuals and might therefore not accurately refect the potential bioavailability of iron from 23 Institute of Medicine. Other uncertainties such as the paucity of data for some population groups, diffculties in comparing long and short term studies, problems measuring menstrual blood loss, as well as variability in individuals, limit the confdence with which requirements can be defned. Basal iron losses among normal healthy individuals were assumed to have a coeffcient of variation of 15%. For infants, children and adolescents, iron required for expanding red cell mass and growing body tissues was added to basal losses. In women of reproductive age, menstrual losses (average of 20 mg/28 day cycle25) were added to basal losses. The effects of menstruation on iron requirements are considered in more detail in paragraphs 3. Although they are derived from similar sets of data, the differences in the reference values between committees are primarily due to differences in assumptions regarding the effciency of iron absorption and utilisation in different population groups. Dietary advice for the general population regarding maximising iron absorption includes consuming iron-rich foods at the same time as foods or drinks high in vitamin C, such as fruit or fruit juice (which have been shown to enhance iron absorption), and not consuming foods containing iron with tea, coffee, or foods or drinks containing calcium (which have been shown to inhibit iron absorption). The effect of inhibitors and enhancers of iron absorption from the diet are considered in section 5. During the last third of pregnancy, the fetus accumulates about 2 mg of iron daily and the mature term neonate contains 150?250 mg of iron. Much of the remainder is in the reticuloen dothelial and hepatic tissue iron depots. After delivery, when the neonate starts breathing, it adapts to the higher ambient concentration of oxygen and the better oxygenation of its tissues by reducing its number of red cells and the level of haemoglobin by about 30%, and by changing the type of 27 haemoglobin to the adult form. At birth, haemoglobin concentration of neonates is about 160?180 g/L; by 2 months of age, this has decreased and stabilises at 90?110 g/L. The iron released from the degraded haemoglobin is retained as ferritin in the reticuloendothelial system and is subsequently redistributed peripherally for tissue synthesis. This is a major source of iron during early infancy; for example, in a term infant, a fall in haemoglobin of 60 g/L would recycle up to 60 mg of iron. This is then available to support lean tissue synthesis, which requires about 35 mg of iron per kg. The concomitant changes in iron deposition in ferritin are refected by an initial increase in serum ferritin concentrations which may reach 400 ?g/L at 1 month of age, followed by a decline, as iron is used in synthesis of new tissue, to about 30 ?g/L at 6 months of age (Siimes et al, 1974). These postnatal changes in haemoglobin synthesis and iron stores occur irrespective of gestational age. A randomised controlled trial in Mexico (Chaparro et al, 2006) reported that, at 6 months of age, infants (n=358) with delayed clamping (2 minutes after delivery) had similar haemoglobin values to infants who had their cords clamped around 10 seconds after delivery, but their systemic iron depots, refected by serum ferritin concentrations, were signifcantly higher (p<0. Although this effect on haemoglobin was not evident at 6 months (2 trials), serum ferritin concentrations were signifcantly higher at 3 months (mean difference, 17. However, signif cantly fewer infants in the early cord clamping group received phototherapy for jaundice compared with those in the late cord clamping group (relative risk: 0. The authors of the review concluded that long term follow-up studies were needed to confrm the long term benefts of late cord clamping. The iron requirements for preterm and low birth weight infants need special consideration and are not within the remit of this report. Iron defciency in the mother has no or little effect on the iron content of breast milk, and iron supplementation during lactation does not increase the iron content of breast milk (Zavaleta et al, 1995). This means that an infant receiving 800 ml/day of breast milk (assuming an iron content of 0. This implies that infants have no need for exogenous iron in the frst six months of life irrespective of whether they are breast fed or fed breast milk substitute. A trial in Honduras (n=139) reported that mean haemoglobin and plasma ferritin concentrations were signifcantly lower at six months in infants who had been exclusively breast fed compared to those who had been introduced to complementary foods at four months (Dewey et al, 1998). However, birth weight was the factor most strongly associated with haemoglobin and ferritin concentrations: infants with birth weights <2500 g were at greater risk of low haemoglobin (<103 g/L) and low plasma ferritin (<12 ?g/L) concentrations compared to infants with birth weights >3000 g, but values were within reference ranges. However, a study in Italy (Pisacane et al, 1995) of infants with birth weight >2500 g (n=30) reported that mean haemoglobin concentrations were signifcantly higher in infants aged 12 months who had been exclusively breast fed (i. There was no difference in mean serum ferritin concentration between the two groups. The principal ligand is phosphate, which binds iron as independent phosphate groups or in a much larger pool of phosphorylated protein complexes in the casein proteins. However, in usual circumstances, the bioavailability of iron from human breast milk is likely to be less than its potential availability because mucosal uptake and transfer of iron in infants is down regulated (see paragraph 3. Several studies have reported that consumption of cows? milk, especially in the frst six months of life (Sullivan, 1993; Robson, 1993) but also in the second six months (Michaelsen et al, 1995; Zlotkin, 1993), is associated with lower haemoglobin and ferritin concentrations. After 6 months of age, dietary requirements for iron are increased as iron stores diminish and the amount of iron provided from breast milk is no longer suffcient, even with up regulation of intestinal absorptive mechanisms, to meet the increasing demands for growth and blood volume expansion. No correlation was found between iron absorption and plasma ferritin concentration at both 6 and 9 months. Consequently, reference values are inclined to be conservative and cautious, assuming, for example, an estimated 10% absorption of iron from breast milk. Compared with boys, these changes are less for girls due to their lower growth velocity and differences in body composition. Whereas lean tissue, as a percentage of body mass, 30 increases during puberty in boys, there is actually a small decrease in girls (Molgaard et al, 1998). The peripheral use of iron due to increased growth rate means that serum ferritin concentrations may fall to levels at or below the usual reference range. This phenomenon does not necessarily indicate iron defciency per se but refects the use of endogenous iron depots and the probable preferential distribution of recently absorbed iron to functional sites rather than to ferritin depots. However, the growth spurt precedes menarche and as a consequence the decline in serum ferritin concentrations in pubertal girls also precedes menarche. Although menstrual blood losses are initially small, the menstrual blood loss of adolescent girls aged 15 years, is only marginally lower than in older women and it is generally assumed that adolescent menstrual losses are at the same level as those for adults (Hallberg and Rossander-Hulten, 1991). A number of studies have observed an association between serum ferritin concentration and length of the menstrual period (Galan et al, 1985; Soustre et al, 1986; Milman et al, 1993). Harvey et al (2005) reported a strong inverse correlation between menstrual blood loss and serum ferritin concentration with higher menstrual iron losses resulting in lower serum ferritin concentrations (p<0. Menstrual losses are affected by method of contraception, being signifcantly increased with intrauterine devices (Milsom et al, 1995) and reduced with oral contraceptives (Larsson et al, 1992).

These absorbance features are largely clearly seen against the background of common surfaces and textiles erectile dysfunction treatment alprostadil buy generic extra super viagra pills. This project has produced proof-of-concept development of a prototype camera requiring minimal operator technical knowledge that is capable of rapid and selective identification of blood stains in ambient lighting without the use of enhancement reagents erectile dysfunction xanax order extra super viagra discount. Imaging is achieved by chopping the source and digitally processing each pixel by a lock-in amplifier approach to produce an output that shows visual contrast between stain/no-stain regions erectile dysfunction differential diagnosis purchase extra super viagra 200mg with mastercard. We show this method is useful for visualizing thin coatings on fabrics that are invisible to the eye impotence homeopathy treatment buy extra super viagra in united states online. We also take advantage of a ?like-detects-like? chemical filtering approach to chemical selectivity for the purpose of chemical identification using a broadband thermal detector erectile dysfunction treatment south florida purchase generic extra super viagra pills. There are many factors involved in optimizing discrimination by using optical filtering aids erectile dysfunction causes and remedies buy extra super viagra discount, including, but not limited to , the detector response, optical throughput of the system, optical properties of the samples, and optical properties of the materials for sensitizing films/filters. There are nearly infinite possible setups for the system, which means it is neither cost nor time-efficient to physically test each one. In lieu of this, we developed approaches to simulate the camera output, per pixel, given specific conditions. Beginning with measured spectra of calibration samples or standards, a figure of merit (in our case, the discrimination between stained and non-stained regions) was employed to predict performance for large numbers of combinations of chemical films as filters. This approach has produced acceptably high signal-to-noise ratios and enabled visualization of blood well below 100? We have also demonstrated that this method can be used to discriminate between a blood stain and four common interferents to other blood detection methods: bleach, rust, cherry soda, and coffee. These results indicate that this system could be useful for crime scene investigations by focusing non-destructive attention on areas more likely to be suitable for further confirmatory analysis. Concurrent with research in instrument development, we have conducted fundamental studies to advance the scientific basis, and our understanding of, infrared imaging for crime scene visualization. Knowledge and understanding of the nature of diffuse reflectance on surfaces coated with chemical stains may have further implications for the interpretation and uses of the infrared reflectance of many types of coated materials. Ultimately, the fundamental relationships observed could lead to the design of an improved system for the measurement of surface coatings of forensic relevance. Specific research conducted includes a study of coating effects on the infrared reflectance spectra of fabrics, evaluation of blood discrimination on textile fabrics, determination of achievable detection limits for blood on fabrics, examination of the effects on spectra of blood induced by fabric orientation and coating uniformity, estimation of the age of blood stains 3-9 months old by infrared spectroscopy, and a theoretical investigation of the fundamental Kubelka-Munk model of diffuse reflectance and an extension of that model to three dimensions. The sections of the main body of the technical report document the accomplishments, methodology, and results of our project. The appendix to this technical report contains papers that have been accepted or submitted for publication and other manuscripts that are in revision prior to submission for publication. However, these items may not be arranged in an orderly manner; more often, a crime scene is chaotic. The initial task of a forensic investigator is to recognize items that might have evidentiary value and to collect samples for further study. Latent stains, those invisible to the naked eye, may result if only trace amounts of blood are present, or if an attempt has been made to modify or clean a surface. Even patent stains, those visible to the naked eye, can still be difficult to detect if a lack of contrast exists between the stain and the background surface. If nothing is observed, but there is reason to believe blood might be present, a presumptive test such as luminol or another enhancement chemical (such as amido black, fluorescein, leuco 1-5 crystal violet, phenolphthalein, leucomalachite green, and benzidine) is often used. A major issue is that the crime scene can be contaminated thoroughly by such treatment. An approach to visualization of blood at crime scenes that is rapid, non-invasive, and not adversely affected by potential interferents would be ideal. Literature citations and review Crime scene investigators often employ high intensity light sources to highlight stains for further visual inspection. However, this step can be insufficient for detection if only trace amounts of blood are present, if the bloodstained area has been cleaned, and/or if a strong contrast does not exist between the blood and a dark surface. If nothing is observed, but there is reason to believe blood might be present, chemical enhancement reagents. A presumptive test is a test, which is used to screen for the presence of a substance, typically performed when there is doubt as to whether an object at a crime scene should be processed and collected. Plasma consists of soluble proteins, the two most prevalent being albumin (70%) and immunoglobulin G (10%). The heme moiety is usually the part of the hemoglobin that interacts with a chemical enhancement reagent for detection of blood. For example, the phenolphthalein and leucomalachite green tests are based on an oxidation-reduction reaction with heme, causing conversion of the colorless reagents to colored by-products after oxidation. The luminol test is based on the peroxidase activity of the heme moiety, with a positive result indicated by chemiluminescence over the first minute or two after exposure of blood to luminol. The chemiluminescence, including splatter patterns, can then be photographed for documentation. In many cases, luminol is used for dual purposes, both to visualize patterns 1-4,6-10 and as a presumptive test for blood. Although crime scene investigators at the South this document is a research report submitted to the U. Specificity can also be an issue if the chemical employed also reacts with other protein-based biological fluids. While many of the false positive reactions can be identified during the presumptive testing procedure, problems can arise if the examiner does not exactly follow the prescribed procedure within the allotted time frame and/or has not conducted extensive testing on known standards so as to have a full understanding of a positive reaction process due to blood. Furthermore, false negatives can occur with these tests, causing blood samples to be left at the scene. This is usually the result of a strong reducing agent being present that interferes with the oxidation-reduction reaction, preventing or delaying color formation. Due to the possibility of false positives and false negatives with presumptive testing, confirmatory testing is ultimately required in the laboratory to prove the presence or absence of a substance. Confirmatory methods for blood include microcrystalline tests such as the Takayama or Teichman tests in which chemical reagents are added to blood causing the formation of 1,2,8 distinctive hemoglobin derivative crystals. Although presumptive tests for blood can be easy to perform and are effective with both fresh and aged bloodstains, drawbacks exist. While luminol is more sensitive than the phenolphthalein 7 9 and leucomalachite green presumptive tests, the reaction must be observed in the dark. This makes subsequent manipulation by examiners difficult and may limit its use at outdoor crime 1,6 scenes. The reaction typically only lasts a few seconds; additional treatment may be needed to 7,8 maintain a positive reaction for long-exposure photography to document the stain. Using water-based reagents on non-absorbent surfaces can also cause bloodstain splatters to smear and may 1,8 obliterate patterns. Further, like the phenolphthalein and leucomalachite green presumptive 1,2 tests, luminol is not very specific for blood. It can give false reactions with any biological material with heme or heme-like structures. Interference can also occur with peroxidases (found in pulps of certain root vegetables), copper metal, some metal salts, some enamel and spray 1,5,14-17 paints, furniture polish, certain disinfectants, and hypochlorite-based cleaning agents. Finally, health concerns exist for crime scene investigators with the use of any of the chemical reagents required 1,2 for stain enhancement and/or presumptive testing. These drawbacks have also fostered 18 research efforts with alternative chemical detection strategies. Methods to replace the enhancement reagents and presumptive tests for blood are sought 19 20 continuously. Typically, an ultraviolet light sources is employed to 23 detect bloodstains by the reflected light, or by the emitted fluorescence. Polilight, an adaptable light source for blood detection based on a strong narrow absorption band near 415 nm. This device was reported to be able to detect biological fluids on different 24-26 fabric types even though it performed poorly at distinguishing between the types of fluid. Statement of hypothesis or rationale for the research the unique infrared spectral signature of blood proteins (Figure 1) has been used for detecting 28 stains on fabrics and surfaces. Absorbances within these regions are strong enough that sub-micrometer-thick films, invisible to the eye, give rise to 29 measurable spectral effects. Imaging is achieved by chopping the source and digitally processing each pixel by a lock-in amplifier approach to produce an output that shows visual contrast between stain/no stain regions. The response of the detector was optimized by a combinatorial simulation-driven design process to select chemical filters that maximize the discrimination between blood and unstained surfaces. The eventual goal of further development might be a camera system, operated by a laptop and requiring minimal operator technical knowledge. These efforts have included a study of coating effects on the infrared reflectance spectra of fabrics, evaluation of blood discrimination on textile fabrics, determination of achievable detection limits for blood on fabrics, examination of the effects on spectra of blood induced by fabric orientation and coating uniformity, estimation of the age of blood stains up to 9 months by infrared spectroscopy, and a theoretical investigation of the fundamental Kubelka Munk model of diffuse reflectance and an extension of that model to three dimensions. This research has to date created five publications in print and one patent award. Another three preliminary patents have been filed, and at least two additional research papers are being edited for publication. Light reflected from the scene is employed to achieve imaging by chopping the source, and digitally processing each pixel by a lock-in amplifier approach in real time, to produce an output that is proportional to contrast between stain/no-stain regions. While further development and validation is necessary for realization of the ultimate forensic goals, the present research has opened novel and intriguing imaging applications for diffuse reflectance in the mid-infrared region spectrum for forensic applications. The chopper was based on a modified fan bearing with a geared motor drive; the standard was used to synchronize data analysis. By controlling the uniformity of coating and orientation of calibration samples, reproducible blood-doped standard calibration samples at varying dilution levels have provided an estimate of the achievable detection limit for blood using a benchtop mid-infrared diffuse-reflectance this document is a research report submitted to the U. Figure 3(left) shows 95% confidence ellipsoids in principal component space for 20 spectra from neat nylon fabric versus nylon doped with 25? At this level of dilution, spectra of blood stained fabric are clearly distinguished from spectra of neat 37,38 samples, and this distinction continues down to the lowest dilutions tested. Other experiments show the effect of a chemical coating (blood) on the infrared reflectance spectra of fabrics is nonlinear, with low concentrations of doping producing a spectrum of greater intensity than might be expected, while high concentrations tend to reach a plateau in response. This effect is partly a consequence of the blood flowing into crevices between and around fibers, and thus roughening the fiber surface in a non-uniform manner. Estimates of the detection limits of blood on nylon, acrylic, cotton, and polyester fabric are at ca. The spectra on which these estimates are based were taken on a benchtop diffuse reflectance instrument, rather than our more selective camera system, where we have seen signal-to-noise ratios for blood approaching 1000:1. However, their sensitivity to mid-infrared light makes them ideal for viewing biological stains on surfaces and fabrics from a distance of a few feet using a diffuse reflectance approach. The letters ?X?, ?V?, ?L? and ?C? were deposited using diluted blood, where the dilution factors are 10, 25, 50 and 100 times. The letter ?I? was made with neat blood, while the letters ?X?, ?V?, ?L? and ?C? were made using blood of 10-, 25-, 50 and 100-fold dilutions. We required a means of determining the best filter or filter set to achieve this purpose. We have the capability of creating a wide range of possible filtering elements, and for each filter element we have the capability of producing them in various optical thicknesses. At a minimum, hundreds of thousands of different filter selections are possible, and it is impractical to measure them each experimentally for optimal performance. In such cases, simulation of the instrument performance can provide a computer system with a means of testing 35 large numbers of elements to arrive at optimized designs in relatively short order. The simulation is based on Equation 1 below, which provides the estimated signal when sample i is viewed through a filter element j. We then developed Matlab programs to calculate the expected camera response for a given setup. The results of simulation were validated using experimental results using the modeled setup. This validated simulation is now available to find the optimal set of filters to distinguish a given analyte on a known substrate (eg. The design is optimal in the sense that the best filter is 39 chosen by linear discriminant analysis to be the most discriminating. The spectra of possible filtering elements is determined by estimating the spectral absorption coefficients of the filtering materials, and then simulating the filters at a range of filter thicknesses. The computer routine is then used to simulate each measurement of the neat and stained fabrics when viewed through the chemical filters. For example, we observed that images required time to stabilize once the modulated infrared light source was turned on, as illustrated in Figure 5: Figure 5. The gold standard shows sharp on/off transitions, while the fabric data show heating and cooling effects throughout the measurement. The reflectance standard showed no gradual increase in signal, while the reflectance of the fabric samples increased approximately exponentially. Further, the modulation of signal from the fabric samples did not follow the square-wave pattern of the source with fidelity. During the ?on? portion of the cycle, blackbody radiation from the sample increased as it warmed, with cooling during the ?off? part o of the cycle. This thermal modulation was determined to be about 1/3 C, but its phase is shifted approximately 90 degrees from the excitation. Although small compared to the reflectance, the reflectance portion of the signal follows the source faithfully and can be cancelled out, leaving an image of the thermal properties of the sample as shown in Figure 6. The origin of this contrast is not chemical, but physical due to the larger amount of solids in the blood stain that affect the thermal properties of the fabric. The wood grain of the plywood on which the fabric is mounted can be seen in these images. Most of the work we have performed to date involves diffuse reflectance, in which light penetrates into the near-surface areas of fabrics and other materials. However, we also worked to understand the behavior of materials when the substrate has a very high absorbance, limiting the penetration depth of light so that only the topmost surface reflection, called the Fresnel diffuse 37-38 reflectance or the specular reflectance, of the fabric can be observed.

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