Dennis F. Zagrodnik II MD, FACS
Kaplowitz P: Precocious puberty: Update on secular trends doctor for erectile dysfunction order levitra jelly 20 mg with mastercard, definitions erectile dysfunction foods to eat purchase genuine levitra jelly on-line, diagnosis erectile dysfunction treatment calgary levitra jelly 20 mg online, and treatment erectile dysfunction vacuum pumps reviews best order for levitra jelly. Examination the adult adrenal cortex has a regional distribution of while the child is in the squatting position or in a warm bath terminal steroid production. No treatment for retractile testes is necessary, and losa is the predominant source of aldosterone. A fetal zone, or provisional cortex, that predominates during fetal development proA. Surgical Treatment duces glucocorticoids, mineralocorticoids, androgens, and the current recommendation for treatment of cryptorchiestrogens. The pattern of serum cortisol concentration Gynecomastia is a common, self-limited condition that may follows this pattern with a lag of a few hours. Glucocorticoids are critical for gene expression in a many Gynecomastia may sometimes occur as part of Klinefelter cell types. In excess, glucocorticoids are both catabolic and syndrome, or it may occur in boys who are taking drugs such antianabolic; that is, they promote the release of amino acids as antidepressants or marijuana. Therapy, either medical from muscle and increase gluconeogenesis while decreasing (antiestrogens or aromatase inhibitors) or surgical, should incorporation of amino acids into muscle protein. Diffuse tansecretion is the volume-and sodium-sensitive renin-angiotenning with increased pigmentation over pressure points, scars, sin-aldosterone system. Elevations of serum potassium also and mucous membranes may be present in primary adrenal directly influence aldosterone release from the cortex. Androgen (dehydroepiandrosterone and androstenedione) production by the zona reticularis is insignificant before puberty. Laboratory Findings tion increases and may be an important factor in the dynam1. The adrenal gland is a major adrenal insufficiency, serum sodium and bicarbonate levels, source of androgen in the pubertal and adult female. In central adrenal insufficiency, the leading causes of adrenal insufficiency are hereditary serum sodium levels may be mildly decreased as a result of enzyme defects (congenital adrenal hyperplasia), autoimimpaired water excretion. Eosinophilia and moderate lymmune destruction of the glands (Addison disease), central phopenia occur in both forms of insufficiency. A temporary salt-losing disorder resulting from partial mineralocorticoid deficiency or renal underred. Verification of an intact axis or precipitate an adrenal crisis in patients with adrenal insuffilocalization of the site of impairment is possible with careful ciency. In the neonatal period, Clinical Findings adrenal insufficiency may be clinically indistinguishable from respiratory distress, intracranial hemorrhage, or sepsis. Corticosteroids in Patients with Adrenocortical venously, is given over the first hour and repeated if necesInsufficiency Who Undergo Surgery sary to reestablish vascular volume. However, adequate cortiCourse & Prognosis sol replacement is critical because pressor agents may be the course of acute adrenal insufficiency is rapid, and death ineffective in adrenal insufficiency. Patients who have received long-term treatment nephrine in the treatment or prophylaxis of fulminant infecwith adrenocorticosteroids may exhibit adrenal collapse if tions remains controversial. Pharmacologic the generalized Shwartzman reaction in fatal cases of menindoses of glucocorticoids during these episodes may be gococcemia. In all forms of acute adrenal insuffiif there is possible adrenal insufficiency, particularly if there ciency, the patient should be observed carefully once the is hypotension and circulatory collapse. Maintenance Therapy Patients with chronic adrenocortical insufficiency who Following initial stabilization, the most effective substitution receive adequate therapy can lead normal lives. The latter finding has allowed more precise heterozygote detection and prenatal diagnosis. Nonclassic presentations of 21-hydroxylase deficiency Increased pigmentation, especially of the scrotum, labia have been reported with increasing frequency. In its severe form, excess adrenal androgen producare characteristic of 21-hydroxylase deficiency. An asymptotion starting in the first trimester of fetal development causes matic form has also been identified in which individuals have virilization of the female fetus and life-threatening hypovonone of the phenotypic features of the disorder, but have lemic, hyponatremic shock (adrenal crisis) in the newborn. The nonclassic form appears to include 11-hydroxylase, 3fi-ol dehydrogenase, 20,22-desmobe less severe than the classic form. Clinical and laboratory findings in adrenal enzyme defects resulting in congenital adrenal hyperplasia. These children usually receive mineralocorticoid as well as glucocorticoid treatment. Signs of adrenal been accomplished, as evidenced by normalization of serum insufficiency (salt loss) may occur in the first days of life but 17-hydroxyprogesterone, patients are placed on maintemore typically appear in the first or second week. Various serum and urine androgens deficiency, growth rate and skeletal maturation are accelerhave been used to monitor therapy, including 17-hydroxyated and patients appear muscular. Pubic hair appears early progesterone, androstenedione, and urinary pregnanetriol. Excessive pigmentation may normal menses are a sensitive index of the adequacy of develop. In this circumstance, enlargement of the penis and gen secretion is critical to avoid virilization of the fetus, increased pigmentation may be noted during the first few particularly a female fetus. The testes are not enlarged except in the given orally once a day or in two divided doses. Periodic rare male in whom aberrant adrenal cells (adrenal rests) are monitoring of blood pressure and plasma renin is recompresent in the testes, producing unilateral or asymmetrical mended to adjust dosing. In the rare isolated defect of 17,20desmolase activity, ambiguous genitalia may be present B.
The more resemblance there is between an individual and its descendants erectile dysfunction pills in south africa cheap levitra jelly express, the more likely it is that beneficial traits possessed by the individual will be present in its descendants erectile dysfunction causes heart buy cheap levitra jelly 20mg on line. If an individual could choose its own erectile dysfunction reviews order levitra jelly without prescription, most advantageous zyprexa impotence buy cheap levitra jelly 20 mg on line, method of reproduction, it would opt for cloning. Failing cloning, an individual would want to mate with another individual that was as nearly identical to itself as possible. Such a procedure would tend to minimize the extent of differences between itself and its descendants. Genetic Diversity and Evolution However, as Darwin tells us, evolution is driven by variation. In another limit case we could consider what would happen if the entire population of some species consisted of identical clones, genetic duplicates, of a single individual. Natural selection (or selective breeding) would not work in this population because there are no genetically transmittable differences between individuals for natural selection (or human breeders) to select. Although these individuals might be as fit as the members of some other population, and although their species as a whole might be competitive with other species, they would be unable to evolve further in the manner available to other, normal species that did possess individual variation. More genetic diversity causes more variation and therefore aids 114 the Evolution of Aging evolution. From an evolution standpoint, an individual should mate with another individual that is as different as possible from itself. Therefore, there is a conflict and apparently a necessary compromise between the needs of the evolution process itself and individual advantage. Darwin could well imagine that variation was caused by some non-changing fundamental property of life. The idea that the evolution process itself varies and can be affected by evolved characteristics leads directly to evolvability theory (to be described). If an animal had an inherited behavior pattern that caused it to prefer mating with close relatives, that behavior would favor individual advantage. If it had a behavior that led it to seek mates that were less related, that behavior would favor evolution at the expense of individual advantage. The second case is individually adverse for another reason: Presumably, close relatives are physically closer and therefore easier to find. An animal mating with a close relative is therefore less likely to die before finding a mate. Most of the more complex animals actually do have complicated mating behaviors that generally appear to avoid mating between close relatives. The above discussions disclose weaknesses in the individual fitness concept that will be discussed further in sections to follow. Genomic Design, Evolutionary Rigidity, Pleiotropy, and Group Selection Everybody recognizes that the phenotypic future of an organism is largely dictated by its current design. The potential path followed by future evolution of an organism is largely constrained by its past. However, it is now increasingly recognized that the genome of an organism also has a particular design and that this design also incrementally evolves and additionally constrains the path of future evolution. Darwin imagined that mutations happen and natural selection selects among the mutations, a simple and elegant idea formulated prior to any understanding of inheritance mechanisms. However, as shown in below and described in Chapter 5 intervening genetics discoveries have revealed that many different processes are involved in genome evolution and that these processes operate over dramatically different time scales. Suppose an anteater needs a longer snout and tongue because ants are building deeper nests. If this change can be accomplished by merely recombining alleles that already exist in the local population, we all agree that the change can be accomplished in a very short time (by evolutionary standards). This is the sort of change that could be accomplished by selective breeding and could occur in a few generations. Even if snout length is one of the parameters that happen to be affected by the variable fraction of genetic data, the range of achievable phenotypic change might be very limited. Further, selectively breeding for longer snouts would likely introduce changes to other phenotypic parameters, all of which are nominally adverse. This limitation, which would also apply to natural selection, is an example of linkage between phenotypic design parameters caused by genomic design. If the change required specific complementary changes to many different genes, a yet longer time scale would be involved. If the change could not be accomplished without the creation of an entirely new gene, a yet longer time regime would be invoked. For various theoretical reasons, the creation of a functionally different gene is an extremely difficult event, even relative to those already mentioned and yet it is obvious that, at some point in the evolution of complex organisms, new genes would be required. The conservation of genes and the time scale involved here is thought to be longer than typical species life (time since the species diverged). This is the basis of the gene-centered evolutionary mechanics theories such as the selfish gene theory described below. Therefore, we can read down the rigidity chart in order of genomic design aspects that are increasingly more fundamental, therefore more conserved, and more rigid or increasingly difficult to change. Near the bottom are aspects that have been nearly completely conserved during the evolutionary life of the Earth. The rigidity of linkages depends on the degree of difficulty involved in removing them. Robustness and plasticity are other terms used to describe the difficulty and therefore evolutionary time required to accomplish a specific change or resistance to specific changes. Pleiotropy refers to the fact that a single gene typically controls multiple phenotypic properties. A single change to a single gene would typically alter more than one phenotypic property, thus displaying one specific type of genomic linkage. Williams (1957) suggested pleiotropic linkage between aging and some unspecified individually beneficial qualities as the reason why aging would not have been selected out despite its individually adverse nature. One of the problems with this idea is that according to the underlying value-of-life concept, a longer lifespan has always been individually beneficial, at least since the development of sexually reproducing organisms. Nature would therefore have had a very long time (~3 billion years) to overcome the pleiotropic linkage. Complementary changes to many genes might well be able to accomplish the beneficial phenotypic function without the side-effects. Therefore pleiotropy would appear to operate over a time frame shorter than typical species life. Such linkages did not prevent the anteater from obtaining a longer snout or prevent different mammals from evolving grossly different phenotypic designs. Pleiotropy represents a degree of rigidity that is short-term relative to a typical mammal species life time. Therefore pleiotropy does not appear to be a valid reason for explaining why an individually adverse design characteristic (aging) would not have selected out over a very much longer time. If a pleiotropic linkage between a group-benefiting but individually adverse design characteristic. In this concept, pleiotropy need not be perfectly rigid thus overcoming the difficulty mentioned above. According to this concept, antagonistic pleiotropy works better for aging as a group-benefiting but individually adverse design characteristic than 117 the Evolution of Aging it does for a characteristic. Pleiotropy is only one of the aspects of genomic design that plausibly impact evolutionary mechanics theory. Buy levitra jelly 20mg mastercard. ED Treatments: Relaxation Breathing for Erectile Dysfunction.
Many of the activities involved in maintenance erectile dysfunction treatment definition order levitra jelly toronto, such as cell division and replacement erectile dysfunction treatment options-pumps order 20 mg levitra jelly amex, would appear to largely duplicate those involved in the original growth and development erectile dysfunction treatment in dubai order levitra jelly pills in toronto. Therefore erectile dysfunction due to old age discount levitra jelly american express, it is reasonable to believe that a relatively small number of genes are exclusively associated with the maintenance function, such as genes that control initiation of cell division only in a maintenance context. The idea that mutations could occur that would cause adverse effects has been verified by substantial work that has been done in an effort to understand human genetic diseases (see Genetics). Many human diseases have been traced to errors that have occurred in genetic code. Symptoms of some genetic diseases are even age-related and tend to increase with age. There are problems with the idea that such mutations cause aging as put forth in the mutation accumulation theory: the mutation accumulation theory only works if the fitness effect of aging is effectively zero. This would also apply to any other trait that had the same or less beneficial effect. Aging in mammals affects strength, speed, agility, and other factors that affect fitness even in relatively young animals. It therefore does not appear plausible that aging has a negligible effect on fitness. Such minor differences due to aging could plausibly be expected to appear at very young ages. These issues led to the subsequent development of the antagonistic pleiotropy theory described in the next section. Death in these species appears to be controlled by the reproductive function or controlled by whatever triggers reproduction as opposed to calendar age. Aging in mammals, as a gradual, diffuse, and multi-tissue degradation loosely tied to sexual maturity, could plausibly result from random mutations variably degrading a family of beneficial maintenance characteristics. However, this scenario does not appear to work for bamboo and salmon, which exhibit what appears to be programmed death tied directly to reproduction and clearly not associated with a generalized maintenance function. How could suicidal behavior result from the random mutation degradation of a beneficial characteristicfi The basic problem is that mutation accumulation is too simple a mechanism to explain the detail in the observed aging processes of different species. As we will see in later sections of this book, the traditional model of non-aging species also grossly understates the negative fitness effects of aging in actual animals. According to Medawar and his test tube model, an older immortal mature animal would be functionally identical to its younger mature self. The difference between younger and older animals is that the populations of older animals would be smaller and that the smaller populations would have less effect on the evolution process. Some gerontologists think of Medawar as a major prophet, essentially the father of modern gerontology. Indeed the more recent programmed aging theories are based on the idea that the evolutionary value of survival and reproduction declines with age. Pleiotropy is defined as a situation in which a single allele or form of a gene (see Genetics) may affect more than one trait. In human genetic diseases, a defect in a single gene typically can affect a number of traits and have simultaneous diverse symptoms such as nerve and vision problems, bone deficiencies, and skin changes. In general, a single gene can be activated in more than one tissue and therefore a defect in a gene can affect more than one tissue. A gene resulting from natural selection could have a rather catastrophic negative effect on an older animal if the negative effect was balanced by an even relatively minor beneficial effect on younger animals. Williams predicted that species with younger age of sexual maturity and more vigorous reproduction traits would tend to have shorter lifespans. Hopes that only a relatively small number of factors causing aging would be eventually found and successfully treated as suggested by the mutation accumulation theory were therefore, according to Williams, misplaced. Over the years many theories were developed suggesting that aging was rigidly linked to some beneficial property. Aging could be a rigidlylinked site-effect of [insert your own favorite beneficial property here]. The antagonistic pleiotropy theory (along with other rigid-linkage theories) has a number of difficulties. Evolution would therefore presumably be trying to find ways of accomplishing the beneficial effects without the adverse (aging) side effects. One 52 the Evolution of Aging obvious answer is that there is no way to accomplish the presumably essential beneficial effect without the side effect, (a conclusion that is very pessimistic regarding successful treatment of aging and age-related diseases). This conclusion requires that we believe that the pleiotropic relationships are indefinitely rigid, that is, that they have withstood the force of evolution for at least the time that sexually reproducing organisms have existed on Earth. This is because Williams offers no suggestion to the effect that the value of extended life would be less in the more primitive organisms that constitute ancestors of mammals. Evolution would have been trying to overcome the pleiotropic linkage in these ancestors and in their ancestors for billions of years. Had it been successful, mammals would have inherited the advantage without the disadvantage. Other aspects of genetics science provide extensive arguments contravening his conclusion that pleiotropy causes indefinitely rigid linkage between individually adverse and individually beneficial design characteristics (to be discussed). It turns out that pleiotropy is only one of several genetic characteristics that lead to linkage. Further, even considering only mammals, random rigid linkages do not appear to have prevented different mammal species from evolving grossly different designs that adapt them to their individual circumstances. Another difficulty with the antagonistic pleiotropy theory is the very great variation in observed aging characteristics between otherwise similar animals such as similar birds and fish. If aging is a side effect of genes that have a beneficial effect in youth, then why would the adverse side effects of such presumably similar genes be so differentfi
Transfusions are indicated to improve oxygen-carryrate identification of older persons with sickle cell trait depends ing capacity during acute severe exacerbations of anemia erectile dysfunction laser treatment buy discount levitra jelly 20 mg on-line, as on hemoglobin electrophoresis erectile dysfunction quick natural remedies 20 mg levitra jelly free shipping, which typically shows about occurs during episodes of splenic sequestration or aplastic 60% hemoglobin A and about 40% hemoglobin S viagra causes erectile dysfunction cheap 20 mg levitra jelly fast delivery. Red cell transfusions are not indicated for the treator hemolysis is present erectile dysfunction hand pump purchase levitra jelly 20 mg on-line, and the physical examination is normal. Exposure to environmental hypoxia (altitude > 3100 m Transfusions may also be used prior to high-risk procedures [10,000 ft] above sea level) may precipitate splenic infarcsuch as surgery with general anesthesia and arteriograms tion. However, most persons with sickle cell trait who choose with ionic contrast materials. Some patients who develop to visit such altitudes for skiing, hiking, or climbing do so severe vaso-occlusive complications may benefit from chronic without difficulty. The most common indication for transnuria, and about 4% experience painless hematuria, usually fusion is stroke. Without transfusions, children with stroke microscopic but occasionally macroscopic. This risk of recurrent neurologic events is reduced progress to significant renal dysfunction. Daily administratraining found a higher risk of sudden unexplained death tion of oral hydroxyurea increases levels of fetal hemoglobin, following strenuous exertion in recruits with sickle cell trait decreases hemolysis, and reduces by 50% episodes of pain in than in those with normal hemoglobin. The hematoconcerns about exercise and exertion for persons with the logic effects and short-term toxicity of hydroxyurea in chiltrait. However, considerable evidence suggests that exercise dren are similar to those in adults. Thus hydroxyurea is being is generally safe and that athletic performance is not used increasingly for selected children and adolescents who adversely affected by sickle cell trait. Hemoglobin C Disorders Academy of Pediatrics, Section on Hematology/Oncology and Committee on Genetics: Health supervision for children with Hemoglobin C is detected by neonatal screening. Glucose metabolism via the hexose microcytic hemolytic anemia and may develop splenomegaly. Congenital deficiencies of many glycolytic pathway enzymes have been associated with hemolytic anemias. Hemoglobin E Disorders possibility of a red cell enzyme defect should be considered during the evaluation of a patient with a congenital Hemoglobin E is the second most common hemoglobin hemolytic anemia in the following instances: when the pevariant worldwide, with a gene frequency greater than 10% ripheral blood smear does not show red cell morphology in some areas of Thailand and Cambodia. In Southeast Asia, typical of membrane or hemoglobin defects (eg, spherocytes, an estimated 30 million people have hemoglobin E trait. The diagnosis is conPersons homozygous for hemoglobin E are also asymptofirmed by finding a low level of the deficient enzyme. Compound heterozygotes for hemoglobin E and fi0-thalassemia are normal at birth and, 1. Unlike homozygotes, they subsequently develop mild to severe microcytic hypochromic anemia. In some cases, the anemia becomes severe African, Mediterranean, or Asian ancestry. In certain areas of the United States, hemoglobin E/fi0-thalassemia has Neonatal hyperbilirubinemia. Other Hemoglobinopathies Hundreds of other human globin-chain variants have been General Considerations described. The disorder has Xhemoglobinopathies, are generally asymptomatic and usually linked recessive inheritance and occurs with high frequency have no anemia or hemolysis. The principal significance of among persons of African, Mediterranean, and Asian most hemoglobin variants is the potential for disease in ancestry. In most instances, the deficiency is due to for fi-thalassemia or sickle hemoglobin. Glycolysis also produces the 2,3sons of African ancestry usually is less severe than in other diphosphoglycerate levels needed to modulate the oxygen ethnic groups. Most episodes of hemolysis are Acetanilide Niridazole self-limiting, but red cell transfusions may be lifesaving when Doxorubicin Nitrofurantoin signs and symptoms indicate cardiovascular compromise. Furazolidone Phenazopyridine Methylene blue Primaquine Nalidixic acid Sulfamethoxazole 2. Pyruvate Kinase Deficiency Reproduced, with permission, from Beutler E: Glucose-6-phosphate dehydroPyruvate kinase deficiency is an autosomal recessive disorder genase deficiency. ApproxiClinical Findings mately one third of those affected present in the neonatal A. Symptoms and Signs period with jaundice and hemolysis that require phototherapy or exchange transfusion. In older children, rubinemia and require phototherapy or exchange transfusion the hemolysis may require red cell transfusions or be mild to prevent kernicterus. Jaundice and neonatal hyperbilirubinemia in infants of Mediterranean or splenomegaly frequently occur in the more severe cases. Hemolytic episodes blood smear, but these findings may be absent prior to are often triggered by infection or by the ingestion of oxidant splenectomy. The diagnosis depends on the demonstration drugs such as antimalarial compounds and sulfonamide antiof low levels of pyruvate kinase activity in red cells. Ingestion of fava beans may trigger Treatment of pyruvate kinase depends on the severity of hemolysis in children of Mediterranean or Asian ancestry but the hemolysis. Blood transfusions may be required for signifusually not in children of African ancestry. Although ysis are associated with pallor, jaundice, hemoglobinuria, and the procedure does not cure the disorder, it ameliorates the sometimes cardiovascular compromise. Characteristically, the reticulocyte count increases and echinocytes become more prevalent B. Laboratory Findings after splenectomy, despite the decreased hemolysis and the hemoglobin concentration, reticulocyte count, and peincreased hemoglobin level. Autoimmune Hemolytic Anemia mon, and the reticulocyte count increases within a few days. Kernicterus is a risk for infants with significant neonatal Reticulocytosis and spherocytosis. In almost all cases, the direct and indirect proliferative syndrome; or, rarely, malignancies. Symptoms and Signs ficity or an Rh-like specificity constitute warm autoimmune the disease usually has an acute onset manifested by weakhemolytic anemia with extravascular destruction by the ness, pallor, dark urine, and fatigue. Some cases have complement alone on red blood cells, optimal reactivity in a more chronic, insidious onset. The anemia is normochromic and normocytic and may vary Paroxysmal cold hemoglobinuria usually has a different from mild to severe (hemoglobin concentration < 5 g/dL). The laboratory evaluation is identical to cold autoimthe reticulocyte count and index are usually increased but mune hemolytic anemia except for antigen specificity (P) occasionally are normal or low. Other laboratory data consistent with hemolysis are present, such as increased indirect and total bilirubin, lactic dehydrogenase, aspartate aminotransferase, and urinary urobilinoDifferential Diagnosis gen. Intravascular hemolysis is indicated by hemoglobinemia Autoimmune hemolytic anemia must be differentiated from or hemoglobinuria. Examination of bone marrow shows other forms of congenital or acquired hemolytic anemias. The presence Serologic studies are helpful in defining pathophysiology, of other cytopenias and antibodies to platelets or neutrophils planning therapeutic strategies, and assessing prognosis suggests Evans syndrome. In general, children with warm autoimmune hemocollapse, requiring emergency management. The complicalytic anemia are at greater risk for more severe and chronic tions of an underlying disease, such as disseminated lupus disease with higher morbidity and mortality rates. Patients with cold autoimmune hemolytic anemia or Treatment paroxysmal cold hemoglobinuria are more likely to have Medical management of the underlying disease is important acute, self-limited disease (< 3 months). Defining the clinical syndrome prohemoglobinuria is almost always associated with infection vides a useful guide to treatment. In Zecca M: Rituximab for the treatment of refractory autoimmune severe cases unresponsive to more conventional therapy, hemolytic anemia in children. |
