Duncan G. de Souza, MD, FRCPC

• Assistant Professor
• Anesthesiology
• University of Virginia
• Charlottesville, Virginia

They found that variation in allelic frequency was greatest between small isolated villages in the upper valley but decreased between larger villages and towns farther down the valley antibiotics for acne inversa discount 100mg doxycycline fast delivery. This result is exactly what we expect with genetic drift: there should be more genetic drift and thus more variation among villages when population size is small infection examples generic doxycycline 200 mg on line. Methods Buri examined the frequencies of two alleles (bw75 and bw) that affect Drosophila eye color in 107 replicate small populations over 19 generations virus movie purchase 100mg doxycycline overnight delivery. Several factors determine the equivalent number of breeding adults antibiotic joint pain cause buy doxycycline 200 mg amex, including the sex ratio antibiotics japan over counter purchase 100mg doxycycline, variation between individuals in reproductive success infection white blood cell count cheap doxycycline 100 mg fast delivery, fluctuations in population size, the age structure of the population, and whether mating is random. The amount of change in allelic frequency due to genetic drift is inversely related to the effective population size (the equivalent number of breeding adults in a population). Allele g for fat production increases in a small population because birds with more body fat have higher survivorship in a harsh winter. Random mutation increases the frequency of allele A in one population but not in another. Allele m is lost when a virus kills all but a few individuals and just by chance none of the survivors possess allele m. For ecological and demographic studies, population size is usually defined as the number of individuals in a group. The evolution of a gene pool depends, however, only on those individuals who contribute genes to the next generation. Population geneticists usually define population size as Causes of genetic drift All genetic drift arises from sampling error, but there are several different ways in which sampling error can arise. First, a population may be reduced in size for a number of generations because of limitations in space, food, or some other critical resource. A second way that sampling error can arise is through the founder effect, which is due to the establishment of a population by a small number of individuals; the population of bighorn sheep at the National Bison Range, discussed in the introduction to this chapter, underwent a founder effect. Although a population may increase and become quite large, the genes carried by all its members are derived from the few genes originally present in the founders (assuming no migration or mutation). Chance events affecting which genes were present in the founders will have an important influence on the makeup of the entire population. A third way in which genetic drift arises is through a genetic bottleneck, which develops when a population undergoes a drastic reduction in population size. Before 1800, thousands of elephant seals were found along the California coast, but the population was devastated by hunting between 1820 and 1880. By 1884, as few as 20 seals survived on a remote beach of Isla de Guadelupe west of Baja, California. Restrictions on hunting enacted by the United States and Mexico allowed the seals to recover, and there are now more Population Genetics 709 25. All seals in the population today are genetically similar, because they have genes that were carried by the few survivors of the population bottleneck. The effects of genetic drift Genetic drift has several important effects on the genetic composition of a population. Because drift is random, allelic frequency is just as likely to increase as it is to decrease and will wander with the passage of time (hence the name genetic drift). Through random change, an allele may eventually reach a frequency of either 1 or 0, at which point all individuals in the population are homozygous for one allele. Other alleles are lost (reach a frequency of 0) and can be restored only by migration from another population or by mutation. Today, these seals have low levels of genetic variation; a study of 24 protein-encoding genes found no individual or population differences in these genes. The southern elephant seals also were hunted, but their population size never dropped below 1000; therefore, unlike the northern elephant seals, they did not experience a genetic bottleneck. Given enough time, all small populations will become fixed for one allele or the other. Which allele becomes fixed is random and is determined by the initial frequency of the allele. A third effect of genetic drift is that different populations diverge genetically with time. Eventually, all the populations reach fixation; some will become fixed for one allele, and others will become fixed for the alternative allele. The three results of genetic drift (allelic frequency change, loss of variation within populations, and genetic divergence between populations) take place simultaneously, and all result from sampling error. The first two results take place within populations, whereas the third takes place between populations. Genetic drift causes a change in allelic frequencies within a population, a loss of genetic variation through the fixation of alleles, and genetic divergence between populations. Shown here is a computer simulation of changes in the frequency of allele A2 (q) in five different populations due to random genetic drift. Natural Selection A final process that brings about changes in allelic frequencies is natural selection, the differential reproduction of genotypes (see p. Suppose the average number of viable offspring produced by three genotypes is Genotypes: Mean number of offspring produced: A1A1 10 A1A2 5 A2A2 2 To calculate fitness for each genotype, we take the mean number of offspring produced by a genotype and divide it by the mean number of offspring produced by the most prolific genotype: Fitness(W): A1 A1 10 W11 = = 1. The hairs of their fur stay erect even when wet, and thick layers of blubber provide insulation, which protects against subzero temperatures. If the adaptive traits have a genetic basis, they are inherited by the offspring and appear with greater frequency in the next generation. A trait that provides a reproductive advantage thereby increases with the passage of time, enabling populations to become better suited to their environments-to become better adapted. Natural selection is unique among evolutionary forces in that it promotes adaptation (Figure 25. The fitness of genotype A1A1 is designated W11, that of A1A2 is W12, and that of A2A2 is W22. A related variable is the selection coefficient (s), which is the relative intensity of selection against a genotype. We usually speak of selection for a particular genotype, but keep in mind that, when selection is for one genotype, selection is automatically against at least one other genotype. The selection coefficient is equal to 1 - W; so the selection coefficients for the preceding three genotypes are A1A1 A1A2 A2A2 Selection coefficient (1 - W): s11 = 0 s12 = 0. It is measured as fitness, which is the reproductive success of a genotype compared with other genotypes in a population. Fitness and the selection coefficient the effect of natural selection on the gene pool of a population depends on the fitness values of the genotypes in the population. Here, the term relative is critical: fitness is the reproductive success of one genotype compared with the reproductive successes of other genotypes in the population. A1A2 2pq W12 2pqW12 2 pqW12 w A2A2 q2 W22 q2W22 q 2W22 w p2 W11 p W11 p 2W11 w 2 Population Genetics 711 Table 25. We can predict the effect of natural selection on allelic frequencies by using a general selection model, which is outlined in Table 25. Use of this model requires knowledge of both the initial allelic frequencies and the fitness values of the genotypes. It assumes that mating is random and that the only force acting on a population is natural selection. The general selection model can be used to calculate the allelic frequencies after any type of selection. It is also possible to work out formulas for determining the change in allelic frequency when selection is against recessive, dominant, and codominant traits, as well as traits in which the heterozygote has highest fitness (Table 25. Female fruit flies with different Adh genotypes produce the following numbers of offspring when alcohol is present: Mean number of offspring 120 60 30 Genotype AdhF/AdhF AdhF/AdhS AdhS/AdhS a. Fitness is the relative reproductive output of a genotype and is calculated by dividing the mean number of offspring produced by that genotype by the mean number of offspring produced by the most prolific genotype. To calculate the frequency of the AdhF allele after selection, we can apply the table method. In the first row of the table above, we record the initial genotypic frequencies before selection has acted. If mating has been random (an assumption of the model), the genotypes will have the Hardy­Weinberg equilibrium frequencies of p2, 2pq, and q2. In the second row of the table above, we put the fitness values of the corresponding genotypes. The proportion of the population represented by each genotype after selection is obtained by multiplying the initial genotypic frequency times its fitness (third row of Table 25. The mean fitness (w) of the population is the sum of the proportionate contributions of the three genotypes: w = p2W11 + 2pqW12 + q2W22 = 0. The mean fitness w is the average fitness of all individuals in the population and allows the frequencies of the genotypes after selection to be obtained. The frequency of a genotype after selection will be equal to its proportionate contribution divided by the mean fitness of the population (p2W11/w for genotype A1A1, 2pqW12/w for genotype A1A2, and q2W22/w for genotype A2A2) as shown in the fourth line of Table 25. For more practice with the selection model, try Problem 33 at the end of the chapter. The results of selection the results of selection depend on the relative fitnesses of the genotypes. If we have three genotypes (A1A1, A1A2, and A2A2) with fitnesses W11, W12, and W22, we can identify six different types of natural selection (Table 25. In type 1 selection, a dominant allele A1 confers a fitness advantage; in this case, the fitnesses of genotypes A1A1 and A1A2 are equal and higher than the fitness of A2A2 (W11 = W12 > W22). Because both the heterozygote and the A1A1 homozygote have copies of the A1 allele and produce more offspring than the A2A2 homozygote does, the frequency of the A1 allele will increase with time, and the frequency of the A2 allele will decrease. This form of selection, in which one allele or trait is favored over another, is termed directional selection. Type 3 and type 4 selection also are directional selection but, in these cases, there is incomplete dominance and the heterozygote has a fitness that is intermediate between the two homozygotes (W11 > W12 > W22 for type 3; W11 < W12 < W22 for type 4). When A1A1 has the highest fitness (type 3), the A1 allele increases and the A2 allele decreases with the passage of time. When A2A2 has the highest fitness (type 4), the A2 allele increases and the A1 allele decreases with time. Eventually, directional selection leads to fixation of the favored allele and elimination of the other allele, as long as no other evolutionary forces act on the population. To see the effects of natural selection on allelic and genotypic frequencies, view the Mini-Tutorial Two types of selection (types 5 and 6) are special situations that lead to equilibrium, where there is no further change in allelic frequency. Here, the heterozygote has higher fitness than the fitnesses of the two homozygotes (W11 < W12 > W22). With overdominance, both alleles are favored in the heterozygote, and neither allele is eliminated from the population. Initially, the allelic frequencies may change because one homozygote has higher fitness than the other; the direction of change will depend on the relative fitness values of the two homozygotes. The allelic frequencies change with overdominant selection until a stable equilibrium is reached, at which point there is no further change. The ^ allelic frequency at equilibrium (q) depends on the relative fitnesses (usually expressed as selection coefficients) of the two homozygotes: ^ q = f (A 2) = s11 s11 + s22 (25. Directional selection favors one allele over another and eventually leads to fixation of the favored allele. Overdominance leads to a stable equilibrium with maintenance of both alleles in the population. Underdominance produces an unstable equilibrium because the heterozygote has lower fitness than those of the two homozygotes. Change in the allelic frequency of a recessive allele due to natural selection the rate at which selection changes allelic frequencies depends on the allelic frequency itself. The frequency of the A2 allele will decrease with time (because the A2A2 homozygote produces no offspring), and the rate of decrease will be proportional to the frequency of the recessive allele. When the frequency of the allele is high, the change in each generation is relatively large but, as the frequency of the allele drops, a higher proportion of the alleles are in the heterozygous genotypes, where they are immune to the action of natural selection (the heterozygotes have the same phenotype as the favored homozygote). Thus, selection against a rare recessive allele is very inefficient and its removal from the population is slow. The relation between the frequency of a recessive allele and its rate of change under natural selection has an important implication. Some people believe that the medical where s11 represents the selection coefficient of the A1A1 homozygote and s22 represents the selection coefficient of the A2A2 homozygote. The last type of selection (type 6) is underdominance, in which the heterozygote has lower fitness than both homozygotes (W11 > W12 < W22). Underdominance leads to an unstable equilibrium; here, allelic frequencies will not change as long as they are at equilibrium but, if they are disturbed from the equilibrium point by some other evolutionary force, they will move away from equilibrium until one allele eventually becomes fixed. This mistaken belief was the basis of eugenic laws that were passed in the early part of the twentieth century prohibiting the marriage of persons with certain genetic conditions and allowing the involuntary sterilization of others. However, most copies of rare recessive alleles are present in heterozygotes, and selection against the homozygotes will have little effect on the frequency of a recessive allele. Thus, whether the homozygotes for a recessive trait reproduce or not has little effect on the frequency of the disorder. Mutation and natural selection Recurrent mutation and natural selection act as opposing forces on detrimental alleles; mutation increases their frequency and natural selection decreases their frequency. Eventually, these two forces reach an equilibrium, in which the number of alleles added by mutation is balanced by the number of alleles removed by selection. Their short- and long-term effects on allelic frequencies are summarized in Table 25. In some cases, these changes continue until one allele is eliminated and the other becomes fixed in the population. Genetic drift and directional selection will eventually result in fixation, provided these forces are the only ones acting on a population. With the other evolutionary forces, allelic frequencies change until an equilibrium point is reached, and then there is no additional change in allelic frequency. Mutation, migration, and some forms of natural selection can lead to stable equilibria (see Table 25. The different evolutionary forces affect both genetic variation within populations and genetic divergence between populations.

In the intact heart antimicrobial mold cleaner discount doxycycline 200mg on-line, preload is best characterized by the end-diastolic volume or pressure pcr antibiotic resistance buy cheap doxycycline 200 mg line, which are indirect indicators of end-diastolic fiber length (see Chapter 40) antibiotics after root canal doxycycline 100 mg without prescription. The performance of the normal ventricle is highly preload dependent antibiotic resistance conference generic doxycycline 200 mg otc, but the failing heart operates at high preloads and on the flat part of the ventricular function curve (see vanquish 100 antimicrobial discount 100mg doxycycline free shipping. Thus antimicrobial workout clothes order 200 mg doxycycline with mastercard, unlike the normal ventricle, a modest decrease in preload will have little effect on left ventricular filling pressures, whereas an increase in preload will not improve systolic function but will further worsen pulmonary congestion. Thus, preload reduction by diuresis or by reducing venous return with venodilating agents will generally have a beneficial clinical effect in heart failure. Left ventricular afterload is frequently equated with arterial pressure or systemic vascular resistance, but a more accurate measurement of afterload is systolic wall stress, defined as [(pressure Ч the radius of the left ventricle)] divided by [(2 Ч the thickness of the left ventricle)] (see Chapter 40). Thus, at any given arterial pressure, afterload is increased in a dilated thin ventricle and lower with a smaller or thicker ventricle. Increased afterload has an effect quite similar to that of depressed contractility, so afterload reduction can improve cardiac performance. Increasing heart rate enhances the inotropic state by upregulating cytosolic calcium concentrations. Second, heart rate is an important determinant of cardiac output and is the primary mechanism by which cardiac output is matched to demand in situations such as exercise. Because stroke volume is relatively fixed in the failing heart, heart rate becomes the major determinant of cardiac output. However, chronic tachycardia impairs ventricular performance, and cardiac function often improves with control of tachyarrhythmias such as atrial fibrillation. Optimal cardiac performance depends on a well-coordinated sequence of contraction. Patients with heart failure frequently have intraventricular conduction abnormalities, which result in dysynchronous contractions, such that the septum and parts of the anterior wall begin contracting only after systole has ended in other regions. In the normal heart, myocardial blood flow is closely coupled to oxygen requirements and it is not ordinarily considered a determinant of cardiac performance. However, myocardial ischemia is associated with a rapid decline in contractile function that may persist long beyond the episode (myocardial stunning). Chronically inadequate blood flow may lead to a reduction in contractility, which serves to re-establish the balance between oxygen delivery and demands (hibernation). Low arterial diastolic pressures may interfere with the autoregulatory reserve of the coronary circulation, which is limited at diastolic pressures below 60 mm Hg. Endothelial dysfunction, which is common in heart failure patients, may also limit blood flow. At the same time, tachycardia, increased afterload, and substantial left ventricular hypertrophy increase myocardial oxygen requirements. Thus, inadequate myocardial blood flow plays an important role in the pathogenesis of cardiac dysfunction, sometimes even in patients without obstructive coronary disease. The initial manifestations of hemodynamic dysfunction are a reduction in stroke volume and a rise in ventricular filling pressures, perhaps in the basal state but more consistently under conditions of increased systemic demand for blood flow. These changes have downstream effects on cardiovascular reflexes and systemic organ perfusion and function, which in turn stimulate a variety of interdependent compensatory responses involving the cardiovascular system, neurohormonal systems, and alterations in renal physiology. It is this constellation of responses that lead to the characteristic pathophysiology of the heart failure syndrome. Recognition of the role of neurohormonal activation in heart failure has grown with the increasing understanding of its pathophysiology and with evidence that blockade of some of these responses can have a profound effect on the natural history of the disease (Table 47-3). The number of hormonal systems known to be activated in heart failure continues to grow. Initial activation of the sympathetic nervous system probably results from reduced pulse pressures, which stimulate arterial baroreceptors, and renal hypoperfusion. Evidence for its activation comes from elevated levels of circulating norepinephrine, direct sympathetic nerve recordings showing increased activity, and increased norepinephrine release by several organs, including the 210 Figure 47-1 Pathophysiology of heart failure, illustrated by Venn diagram. As cardiac function deteriorates, responsitivity to norepinephrine diminishes, as evidenced by baroreceptor desensitization and down-regulation of cardiac adrenergic receptors and signal transduction. The adaptive role of norepinephrine is to stimulate heart rate and myocardial contractility and to produce vasoconstriction. All of these actions serve to reverse the depression of cardiac output and blood pressure. However, elevated levels of plasma norepinephrine are associated with worse prognosis, although it is unclear whether this is a cause-and-effect relationship. There is also convincing, albeit circumstantial, evidence that norepinephrine has adverse effects on the myocardium. In this regard, beta-adrenoceptor blockade, which for many years has been considered dangerous in heart failure because it deprives the heart of important compensatory stimulation, consistently improves left ventricular function and prognosis as well. Elements of the renin-angiotensin-aldosterone system are activated relatively early in heart failure. The presumptive mechanisms of induction include renal hypoperfusion, beta-adrenergic system stimulation, and hyponatremia. Aldosterone causes sodium retention, which serves to restore normal cardiac output by enhancing intravascular volume. Excessive vasoconstriction can depress left ventricular function, and sodium retention worsens the already elevated ventricular filling pressures. Levels of several natriuretic peptides are consistently elevated in heart failure, and they may counterbalance the vasoconstricting and sodium retaining actions of the renin-angiotensin-aldosterone and sympathetic nervous systems. It does, however, appear that responses to these natriuretic hormones are down-regulated, so that they do not have the same diuretic effects in chronic heart failure that they manifest in normal individuals. Endothelin and arginine vasopressin are elevated in many heart failure patients, and interference with their actions may promote vasodilation and diuresis. Arginine vasopressin induces vasoconstriction through a vascular (V-1) receptor and reduces free water clearance through a renal tubular (V-2) receptor. The endothelins cause prolonged vasoconstriction, reductions in glomerular filtration, mesangial hypertrophy, bronchoconstriction, and pulmonary arteriolar constriction. Circulating levels of a number of proinflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6, are elevated in patients with relatively severe heart failure and may be involved in the syndrome of cardiac cachexia. In most patients with chronic heart failure, the kidneys are anatomically and structurally normal. Reduced blood pressure, diminished stroke volume, and reduced renal perfusion pressure and flow are sensed as reduced blood volume by the high-pressure baroreceptors and the juxtaglomerular apparatus that maintain cardiovascular homeostasis. In chronic heart failure, these receptors become desensitized, generating reduced afferent responses. Thirst and fluid intake may be increased as a result of activation of the cerebral thirst center. Thus, although heart failure is usually associated with a normal or even increased blood volume, it is paradoxically characterized by activation of the same homeostatic responses as those to hemorrhage and shock; the result is abnormal retention of sodium and water. In advanced heart failure, usually characterized by low cardiac output and/or hypotension (or with co-existing renal vascular disease), the glomerular filtration rate may become so severely reduced that sodium and fluid retention becomes refractory to diuretic therapy. After an initial insult precipitates heart failure, progressive alterations occur in myocardial structure and function owing to continuing damage by the underlying process as well as responses to hemodynamic stresses and neurohormonal activation. The left ventricle progressively dilates and changes from the normal ellipsoid shape to a more spherical geometry. This "remodeling" is accompanied by changes in the cardiac interstitium, leading to altered orientation of the myofibrils and progressive fibrosis. A more subacute presentation is of progressive dyspnea associated with systemic fluid retention over a period of days to a few weeks. Other such insults include the acute development of valvular regurgitation from ruptured chordae tendineae, bacterial endocarditis, or aortic dissection or of rapidly progressive myocarditis or toxic damage. Rapid diagnosis by non-invasive testing, early cardiac catheterization, and, in some cases, endomyocardial biopsy is critical. Treatment is cause specific and may include early coronary revascularization, valve repair or replacement, or supportive care (inotropic support, intra-aortic balloon pumping, ventricular assist devices). If not reversed, cardiac transplantation (see Chapter 71) may be the best option for appropriate candidates. In adults, the great majority of patients with heart failure have abnormalities of the left ventricle as the underlying cause. Nonetheless, the clinical presentation may be variable, sometimes suggesting predominantly or even exclusively right ventricular dysfunction. The manifestations of left ventricular dysfunction are related to elevated filling (diastolic) pressures, which are transmitted backward to the left atrium and pulmonary veins, or inadequate cardiac output. The former results in dyspnea, sometimes at rest but usually with activity, and, when severe, pulmonary edema, classically associated with rales and possibly pleural effusions. The cardiac output may be insufficient to support peripheral organ function, causing exertional muscle fatigue, impaired renal function and salt excretion, or even depressed mentation. Right-sided heart failure results from either chronic right ventricular pressure overload. However, it is important to emphasize that the most common cause of right ventricular pressure overload is left-sided heart dysfunction resulting in pulmonary hypertension. When the symptoms and signs of left-sided heart failure are absent or difficult to elicit, the physician may inappropriately seek a primarily right-sided pathology. The primary manifestations of right-sided failure are related to chronically elevated right atrial and systemic venous pressures: jugular venous distention, peripheral edema, ascites, hepatic and bowel edema, and varied gastrointestinal complaints. Myocardial mechanisms that lead to the syndrome of heart failure can be differentiated into conditions that depress left ventricular systolic function and those that occur despite preserved contractility. Although arbitrary, a left ventricular ejection fraction threshold of 45 to 50% is often employed for this distinction. Until the recent widespread use of non-invasive assessments of left ventricular function, heart failure with preserved systolic function was considered unusual in the absence of valvular abnormalities or other specific and uncommon causes. However, it is now recognized that 20 to 40% of heart failure patients have normal ejection fractions. In the ongoing Cardiovascular Health Study, a population-based study of more than 5000 patients age 65 and older, more than 70% of patients developing heart failure had normal or only mildly impaired systolic function. Indeed, it is likely that the large majority of elderly heart failure patients have primarily diastolic dysfunction as the cause. Although there are many potential causes of heart failure with preserved systolic function, most patients have current hypertension or a history of treated hypertension; the resulting left ventricular hypertrophy and increased fibrosis are probably responsible for increased chamber stiffness. Ischemic heart disease may also contribute to heart failure with preserved systolic function, probably by virtue of subendocardial fibrosis or as a result of acute, intermittent ischemic dysfunction. Age itself is a critical predisposing factor because it causes loss of myocytes (apoptosis), increased fibrosis with shifts to more rigid forms of collagen, and loss of vascular compliance. The mortality rates of patients with preserved systolic function are lower than those with low ejection fractions but remain higher than the general population, even in comparison with similarly older aged individuals. However, hospitalization and rehospitalization rates for these patients are comparable to those with reduced ejection fractions, and there are few data on treatment to guide physicians in the management of these patients. Although heart failure patients with preserved systolic function are often considered to have diastolic dysfunction, there are many other explanations for this presentation, some of which are reversible or warrant specific therapy (Table 47-4). Ejection fraction measurements may be inaccurate, particularly when their technical quality is suboptimal. Regurgitant valve diseases may lead to a dissociation between the ejection fraction and underlying myocardial dysfunction, because in this setting the afterload may be very low. There are also a number of conditions in which left ventricular function is transiently impaired but subsequently measured ejection fractions may be normal; intermittent ischemia, presenting as episodic heart failure ("flash pulmonary edema") is the most important, because revascularization may be indicated. Severe hypertension with subsequent treatment and transient arrhythmias may also have temporary effects on ejection fraction. Some patients with alcoholic cardiomyopathy may exhibit very rapid recovery in ejection fraction when they cease drinking. The remaining patients most likely have diastolic dysfunction as the underlying disorder. Unfortunately, the non-invasive measurement of diastolic function remains problematic. The most common test used, Doppler echocardiography, is neither sensitive nor specific for diastolic dysfunction. Particularly in the elderly, Doppler mitral valve filling patterns show impaired early diastolic filling in the majority of subjects, whether or not they have evidence of heart failure. Thus, diastolic dysfunction is basically a diagnosis of exclusion based on accompanying conditions and circumstantial evidence. Many patients with chronic heart failure maintain a stable course and then abruptly present with acutely or subacutely worsening symptoms. Although this decompensation may reflect unrecognized gradual progression of the underlying disorder, a number of precipitating events must be considered and, if present, addressed (Table 47-5). An important focus is on changes in medications (by patient or physician), diet, or activity. Superimposed new or altered cardiovascular conditions, such as arrhythmias, ischemic events, hypertension, or valvular abnormalities, should be considered. Systemic processes such as fever, infection, or anemia may also cause cardiac decompensation. The symptoms generally reflect, but may be dissociated from, the hemodynamic derangements of elevated left- and right-sided pressures and impaired cardiac output or cardiac output reserve. Dyspnea, or perceived shortness of breath, is the most common symptom of patients with heart failure. The most important is pulmonary congestion with increased interstitial or intra-alveolar fluid, which activates juxtacapillary J receptors, which in turn stimulate a rapid and shallow pattern of breathing. Increased lung stiffness may enhance the work of breathing, leading to a perception of dyspnea. Central regulation of respiration may be disturbed in more severe heart failure, resulting in disordered sleep patterns and sleep apnea. Hypoxia, which is uncommon in heart failure patients unless there is accompanying pulmonary disease, suggests the presence of pulmonary edema. It should also be noted that dyspnea is a common symptom of patients with pulmonary disease, obesity, and anemia and in sedentary individuals. Orthopnea is dyspnea that is positional, occurring in the recumbent or semirecumbent position.

A new slow-release formulation has been developed antibiotic kidney stones order 200 mg doxycycline otc, avoiding many of the side effects and dosing frequency required of earlier preparations antibiotic unasyn discount 200mg doxycycline with visa. A calcium-binding resin bacteria 4 conditions discount 100 mg doxycycline with visa, sodium cellulose phosphate infection japanese horror 100 mg doxycycline sale, reduces calcium absorption when taken with meals 10th antimicrobial workshop generic doxycycline 200mg. This approach has not demonstrated a high success rate antibiotic used to treat cellulitis doxycycline 100 mg on-line, possibly due to reflex hyperoxaluria. Because citrate lowers calcium oxalate supersaturation by binding calcium and, to some extent, by reducing calcium excretion, correcting hypocitraturia should reduce the recurrence of nephrolithiasis. Uncontrolled studies suggest an efficacy of approximately 88% over a 2-year period (see Table 114-5). Citrate therapy may be very useful for patients who demonstrate hypocitraturia as a result of thiazide diuretic therapy. Furthermore, in patients with inflammatory bowel disease or renal tubular acidosis, citrate therapy seems a very rational replacement for the losses of alkali. Because of the volume expansion effects, sodium bicarbonate or sodium citrate does not have the required actions of potassium citrate to lower urinary calcium and improve calcium balance. A simple dietary excess of oxalate from foods may increase urinary oxalate, and a low-calcium diet may further increase excretion. Treating this mild form of dietary hyperoxaluria associated with calcium oxalate stones consists of altering the diet to avoid foods that contain high concentrations of oxalate. However, no carefully controlled trials have proven the efficacy of this approach. Hyperoxaluria observed in patients with inflammatory bowel disorders and intestinal bypass is usually associated with hypocitraturia. Patients exhibiting hypocalciuria should be treated with a low-fat diet in addition to calcium supplements. Cholestyramine, a non-resorbable resin that binds fatty acids, bile acids, and oxalate (4 to 16 g/day in four divided doses with meals), oral citrate supplements, and high fluid intake are the mainstays of therapy. Magnesium replacement may be important to increase urinary citrate excretion in response to exogenous potassium alkali. Type I primary hyperoxaluria occasionally responds to pyridoxine supplement (2 to 200 mg/day). High urinary volume and supplemental citrate, thiazide diuretics, and possibly oral phosphate supplements can also be used. After renal transplantation, a special protocol is required to avoid accelerated renal oxalosis. Liver transplantation restores the missing enzymes, and many patients with hyperoxaluria have been treated in this manner. Because an excess of purine in the diet causes hyperuricosuria, normal levels of dietary purine should prevent stones. However, careful studies documenting a response to low purine diets are not available. Compelling evidence that hyperuricosuria contributes to the formation of calcium oxalate stones comes from a prospective double-blind trial that demonstrated a reduction in stone formation with allopurinol compared with placebo (see Table 114-5). Acidic urine is a common finding in patients with uric acid stones, and many of these patients also have gout. However, avoidance of temporary periods of acidification sufficient to nucleate uric acid or uric acid and calcium oxalate is difficult. Because of the general tolerance and safety of allopurinol, which is very effective in reducing urinary uric acid excretion rates, it is the mainstay of therapy. Struvite, or magnesium ammonium phosphate, crystals are produced when the urinary tract is colonized by bacteria, producing high concentrations of ammonia. Patients who produce only struvite stones generally present with large stones that cause bleeding, obstruction, and infection without stone passage. These patients rarely have idiopathic hypercalciuria and often have reduced renal function. Patients who pass struvite stones have a higher frequency of idiopathic hypercalciuria because the stone is usually a calcium stone that became secondarily infected, resulting in the struvite. Contralateral spread of struvite stones due to urinary tract infection is frequent. Prolonged use of antibiotics in patients with struvite stones amounts to treatment of an infected foreign body. Once patients are free of stones, they benefit from antibiotics directed against the predominant urinary organism, although no controlled studies support this reasonable approach. Acetohydroxamic acid has limited use because of patient intolerance of side effects. Approximately 2% of patients attending renal stone clinics exhibit a hereditary defect of amino acid transport 627 leading to excessive amounts of cystine in the urine. Cystine is the disulfide of cysteine, which is soluble in the urine to the level of only 20 to 48 mg/dL (1 to 2 mM/L). The rate of cystine excretion in patients with cystinuria ranges from 480 to 3600 mg/day (2 to 15 mM/day) so that high fluid intake can prevent stones in only some patients. Both combine with cysteine to form a soluble salt that reduces, through competition, the formation of cystine. The ability of these treatments to reduce stone frequency is not quantitatively known, although they are effective. However, they exhibit a high rate of intolerance due to severe side effects, which require careful surveillance. Very good review by an established leader in nephrolithiasis, on the pathogenesis of hypercalciuria, low bone mineral density in nephrolithiasis, and treatment options. Individual renal cysts, which derive from segments of the renal tubule and glomerular capsule, are composed of a single layer of tubular epithelium encapsulating a fluid-filled cavity. Solitary cysts visible to the naked eye are the most common structural abnormalities observed in the kidneys. Generalized cystic diseases are typified by cysts scattered throughout the cortex and the medulla of one or both kidneys. Polycystic is a term reserved for conditions in which innumerable cysts are diffusely scattered throughout the renal cortex and medulla. In medullary cystic diseases the lesions occur primarily in the medulla and papilla. In an affected individual, each renal tubule cell carries a single copy of a mutated gene, which in itself is not sufficient to cause cysts to form. This process occurs within a relatively few solitary renal tubule cells and leads to increased epithelial proliferation. This sustained proliferation causes enlargement of the tubule, which is eventually recognized as a "microcyst. In these solitary sacs of liquid, cyst growth continues as a consequence of the steady cellular proliferation and the secretion of NaCl and water under the influence of growth factors, hormones, and intracellular cyclic adenosine monophosphate. The expanding cysts remodel the tubular basement membranes and other interstitial structures, similar to invading benign cellular tumors, and in approximately 50% of patients this cyst-interstitium interaction leads to profound tubulointerstitial fibrosis that ultimately compromises renal function. Although cysts develop in fewer than 1% of the renal tubules and glomerular capsules, polycystic kidneys are strikingly enlarged. The cysts are scattered diffusely throughout the kidneys and vary in size from a few millimeters to several centimeters in diameter. The cysts are lined by epithelium that in most cases appears relatively undifferentiated with respect to the tubule site of origin. In the early stage of development the cysts are filled with a urine-like fluid, but in more advanced cases the fluid may be blood tinged or dark amber and relatively thick because of bleeding or the shedding and accumulation of tubule epithelial cells within the cyst cavity. Renal insufficiency occurs relatively late in this disorder and is not usually an initial feature. No distinguishing laboratory features of the disease are noted other than mild degrees of proteinuria and the appearance of urinary lipid bodies in approximately 60% of individuals with moderately advanced disease. Gene linkage studies can be done with a high degree of certainty, but this test requires at least two affected and willing family members and is only performed in a relatively few centers. Medullary cystic diseases typically affect children, and when encountered in adults, the kidneys are not enlarged and the cysts are limited to the medulla. By contrast, the remainder progress to end-stage renal failure at highly variable rates. Stringent restriction of dietary protein in patients with advanced disease is of little benefit, although moderate limitation of protein (0. Uncontrolled hypertension has been shown to be associated with a more rapid rate of functional decline than in patients without hypertension. Although a controlled study has not yet been done to show that treatment of hypertension is beneficial to the kidneys over the long term, it is strongly recommended that the hypertension be treated sufficiently to keep the blood pressure within the range of normal for age and gender. Control of blood pressure is also indicated to prevent secondary effects on the entire cardiovascular system. Salt restriction and long-acting diuretics in conjunction with angiotensin inhibitors and calcium blocking agents have been found to control the hypertension in most cases. Once the cysts become infected, eradication of the infection can be 629 difficult. For uncomplicated lower urinary tract infections, generally accepted treatment programs can be initiated, with a clear urine sediment and a negative urine culture used as satisfactory therapeutic end points. On the other hand, parenchymal infection as revealed by urinary pus casts, fever, leukocytosis, and a kidney(s) tender to palpation is best treated with bactericidal antibiotics specifically targeted to the organism cultured from the blood or urine. Treatment should be continued until the renal pain has subsided completely and the urine has been cleared of pus cells. If oral antibiotic therapy fails to reverse the train of symptoms, parenteral administration of an antibiotic that penetrates cysts is indicated, including ciprofloxacin, chloramphenicol, or trimethoprim-sulfamethoxazole. Gross hematuria is usually due to a ruptured cyst, and the bleeding ordinarily subsides in a day or two with bed rest and hydration. Renal calculi composed of urate or calcium oxalate are relatively common and are treated by conventional measures, including lithotripsy. Renal adenocarcinoma, although no more common than in the population at large, can be difficult to diagnose. Cranial aneurysms occur with sufficient frequency to warrant consideration in all patients. In the absence of a family history of aneurysm and no symptoms or signs of intracranial disease, no diagnostic radiographic tests are currently recommended. Chronic renal failure is treated with hemodialysis or peritoneal dialysis and renal transplantation. It is common practice to defer diagnostic testing in children at risk until they reach the age of majority, which in most states is 18 years, unless a family history of aneurysm is present or the child has hypertension or other signs of renal disease. The status of renal function can be monitored by repeated measurement of the serum creatinine concentration. Although no specific treatment is at hand to slow or prevent the development and progressive enlargement of polycystic kidneys, adherence to diets limited in protein and salt, control of hypertension with pharmacologic agents, and avoidance of nephrotoxic drugs appear to be lengthening the functional duration of kidneys destined for failure. Aspiration of fluid by surgical or laparoscopic decompression of hundreds of cysts within the kidneys has not proved to slow progression, although renal discomfort is usually improved by these procedures. The diagnosis is occasionally made in utero during routine fetal ultrasound monitoring. Neither parent is aware that they carry a copy of the mutant gene until they have had an affected child. Each subsequent child has a 1 in 4 chance of inheriting the disease and a 50-50 chance of being a gene carrier. Occasionally, the massive kidneys must be removed in infants because of their effect of compromising respiration. Approximately half of affected children will live to adulthood with moderately enlarged cystic kidneys. These patients usually exhibit hepatic fibrosis, often severe enough to cause portal hypertension and hypersplenism. Supportive care is given with attention to the treatment of hypertension and urinary tract infections. Renal and hepatic transplantation has been performed when these organs fail to function adequately. Both autosomal dominant and recessive forms (chromosome 2q13) of medullary cystic disease have been described. The kidneys are moderately small and exhibit medullary cysts and severe tubulointerstitial inflammation and fibrosis. A history of polyuria and polydipsia, pallor, lethargy, and growth retardation is frequently obtained. The disease may progress to the end stage before the age of 20 years, but abnormalities have been described in the seventh decade of life. Diagnosis is difficult, but in some cases the medullary cysts can be seen well enough by sonography to be definitive. Open renal biopsy may be needed to establish a definite diagnosis in patients without clear-cut medullary cysts. Medullary sponge kidney is encountered most frequently in the course of a work-up for nephrolithiasis. It has been described in association with parathyroid adenoma and hyperparathyroidism. The collecting ducts demonstrate ectatic segments in which calcium deposits may collect. The kidneys exhibit a spongy quality on cut section, which accounts for the name used to describe this condition. The disease is usually noticed in the fourth or fifth decade of life, when it may be associated with microscopic hematuria or nephrolithiasis. The disease seldom progresses to end-stage renal failure, and only then as a consequence of infectious or surgical complications related to nephrolithiasis.

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The effects of vitamin C virus zombie movies doxycycline 100 mg free shipping, vitamin B6 antibiotics libido purchase 200 mg doxycycline mastercard, vitamin B12 antibiotics for acne and rosacea discount 200 mg doxycycline visa, folic acid antibiotic zosyn cheap doxycycline 100mg without prescription, riboflavin infection worse than mrsa doxycycline 100 mg overnight delivery, and thiamin on the breast milk and maternal status of well-nourished women at 6 months postpartum antibiotic that starts with l discount 200mg doxycycline visa. Relation of riboflavin nutriture in healthy elderly to intake of calcium and vitamin supplements: evidence against riboflavin supplementation. Riboflavin status in Gambian pregnant and lactating women and its implications for recommended Dietary Allowances. Effect of supplementing low protein diets with the limiting amino acids on the excretion of N1-methylnicotinamide and its pyridones in rat. Biochemical markers for assessment of niacin status in young men: urinary and blood levels of niacin metabolites. Excretion of tryptophan metabolites as affected by pregnancy, contraceptive steroids, and steroid hormones. Relationship between body store of vitamin B6 and plasma pyridoxal-P clearance: metabolic balance studies in Humans. Electroencephalographic changes and periodontal status during short-term vitamin B6 depletion of young, nonpregnant women. Pyridoxal-5-phosphate determination in Human plasma by high performance liquid chromatography: How appropriate are cutoff values for vitamin B6 deficiency? The influence of protein intake on vitamin B6 metabolism differs in young and elderly Humans. Urinary 4-pyridoxic acid, plasma pyridoxal phosphate, and erythrocyte aminotransferase levels in oral contraceptive users receiving controlled intakes of vitamin B6. Changes in vitamin B6 status indicators of women fed a constant protein diet with varying levels of vitamin B-6. Maternal and foetal plasma levels of pyridoxal phosphate at term: adequacy of vitamin B6 supplementation during pregnancy. Studies in Human lactation: milk composition and daily secretion rates of macronutrients in the first year of lactation. Pantothenic acid nutritional status in the elderly-institutionalized and noninstitutionalized. Increased urinary excretion of 3-hydroxyisovaleric acid and decreased urinary excretion of biotin are sensitive early indicators of decreased status in experimental biotin deficiency. As a result of this trend, it is fast becoming an epidemic in some countries of the world with the number of people affected expected to double in the next decade due to increase in ageing population, thereby adding to the already existing burden for healthcare providers, especially in poorly developed countries. This review is based on a search of Medline, the Cochrane Database of Systemic Reviews, and citation lists of relevant publications. Subject heading and key words used include type 2 diabetes mellitus, prevalence, current diagnosis, and current treatment. No cure has yet been found for the disease; however, treatment modalities include lifestyle modifications, treatment of obesity, oral hypoglycemic agents, and insulin sensitizers like metformin, a biguanide that reduces insulin resistance, is still the recommended first line medication especially for obese patients. Other effective medications include nonsulfonylurea secretagogues, thiazolidinediones, alpha glucosidase inhibitors, and insulin. Inhaled insulin was licensed for use in 2006 but has been withdrawn from the market because of low patronage. Olokoba Division of Gastroenterology, Department of Medicine, University of Ilorin Teaching Hospital, Ilorin, Nigeria. Studies examining data trends within Africa point to evidence of a dramatic increase in prevalence in both rural and urban setting, and affecting both gender equally. Obateru Department of Medicine, Irrua Specialist Teaching Hospital, Irrua, Nigeria. Olokoba Department of Ophthalmology, University of Ilorin Teaching Hospital, Ilorin, Nigeria. These are physical inactivity, sedentary lifestyle, cigarette smoking and generous consumption of alcohol. Given inadequate levels of insulin and increased insulin resistance, hyperglycemia results. Although the predominant theory used to explain this link is the portal/visceral hypothesis giving a key role in elevated non-esterified fatty acid concentrations, two new emerging theories are the ectopic fat storage syndrome (deposition of triglycerides in muscle, liver and pancreatic cells). However, practicing physicians frequently employ other measures in addition to those recommended. In July 2009, the International Expert Committee Oman Medical Specialty Board Oman Medical Journal (2012) Vol. This committee suggested that the use of the term pre-diabetes may be phased out but identified the range of HbA1c levels 6. Preprandial administration allows flexibility in case a meal is missed without increased risk of hypoglycemia. These agents are most effective for postprandial hyperglycemia and should be avoided in patients with significant renal impairment. Their use is usually limited due to high rates of side-effects such as diarrhoea and flatulence. In addition, emerging evidence suggests incretin-based therapies Oman Medical Journal (2012) Vol. They are effective as monotherapy in patients inadequately controlled with diet and exercise and as add-on therapy in combination with metformin, thiazolidinediones, and insulin. Augmentation therapy with basal insulin is useful if some beta cell function remains. Rescue therapy using replacement is necessary in cases of glucose toxicity which should mimic the normal release of insulin by the beta cells of the pancreas. The long acting forms are less likely to cause hypoglycemia compared to the short acting forms. Insulin analogues Insulin therapy was limited in its ability to mimic normal physiologic insulin secretion. Currently, two rapid-acting insulin analogues, insulin lispro and insulin aspart, and one long-acting insulin analogue, insulin glargine, are available. Studies have however shown that inhaled insulin is as effective as, but not better than short acting insulin. Insulin-releasing glucokinase activators and pancreaticG-protein-coupled fatty-acid-receptor agonists, glucagon-receptor antagonists, and metabolic inhibitors of hepatic glucose output are being assessed for the purpose of development of new drug therapy for type 2 diabetic patients. Novel drugs are being developed, yet no cure is available in sight for the disease, despite new insight into the pathophysiology of the disease. The worldwide epidemiology of type 2 diabetes mellitus: present and future perspectives. Diabetes in sub-saharan Africa: kenya, mali, mozambique, Nigeria, South Africa and zambia. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Global prevalence of diabetes: estimate for the year 2000 and projections for 2030. The global burden of chronic diseases: overcoming impediments to prevention and control. Expert committee recommendations regarding the prevention, assessment and treatment of childhood and adolescent overweight and obesity: Summary report. Association of urinary bisphenol A concentration with medical disorders and laboratory abnormalities in adults. Effect of obesity and insulin resistance on resting and glucose-induced thermogenesis in man. Antagonist: diabetes and insulin resistance­philosophy, science, and the multiplier hypothesis. Pathophysiology of type 2 diabetes and the role of incretin hormones and beta-cell dysfunction. Active smoking and the risk of type 2 diabetes: a systematic review and meta-analysis. A cross sectional pooled analysis of 900,000 individuals in the Asia cohort consortium 2011. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacyglycerol storage in rodents skeletal muscle. Drug interactions of clinical importance with antihyperglycaemic agents: an update. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Kawamori R, Tajima N, Iwamoto Y, Kashiwagi A, Shimamoto K, Kaku K; Voglibose Ph-3 Study Group. Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in Japanese individuals with impaired glucose tolerance. Insulin therapy for type 2 diabetes: rescue, augmentation, and replacement of beta-cell function. Prandial inhaled insulin plus basal insulin glargine versus twice daily biaspart insulin for type 2 diabetes: a multicentre randomised trial. The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus: a systematic review and economic evaluation. Increased risk of a second neoplasm in childhood cancer survivors treated with somatropin - in particular meningiomas in patients treated with radiation to the head for their first neoplasm (5. Doses of concurrent antihyperglycemic drugs in diabetics may require adjustment (5. Patients treated with glucocorticoid replacement for previously diagnosed hypoadrenalism may require an increase in their maintenance doses (7. Norditropin (somatropin) injection is indicated for the treatment of pediatric patients with short stature associated with Noonan syndrome. Norditropin (somatropin) injection is indicated for the treatment of pediatric patients with short stature associated with Turner syndrome. Treatment with Norditropin for short stature should be discontinued when the epiphyses are fused. Pediatric Patients with Short Stature Associated with Noonan Syndrome Not all patients with Noonan syndrome have short stature; some will achieve a normal adult height without treatment. Pediatric Patients with Short Stature Associated with Turner Syndrome A dosage of up to 0. Recent literature has recommended initial treatment with larger doses of somatropin. Non-weight based - based on published consensus guidelines, a starting dose of approximately 0. This dose can be increased gradually every 1 to 2 months by increments of approximately 0. Maintenance dosages vary considerably from person to person, and between male and female patients. A lower starting dose and smaller dose increments should be considered for older patients, who are more prone to the adverse effects of somatropin than younger individuals. In addition, obese individuals are more likely to manifest adverse effects when treated with a weight-based regimen. In order to reach the defined treatment goal, estrogen-replete women may need higher doses than men. Parenteral drug products should always be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. There have been reports of sudden death when somatropin was used in such patients [see Warnings and Precautions (5. Norditropin is not indicated for the treatment of pediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should not be used in patients with any evidence of progression or recurrence of an underlying intracranial tumor [see Warnings and Precautions (5. Systemic hypersensitivity reactions have been reported with postmarketing use of somatropin products [see Warnings and Precautions (5. Two placebo-controlled clinical trials in non-growth hormone deficient adult patients (n=522) with these conditions in intensive care units revealed a significant increase in mortality (42% vs. The safety of continuing somatropin treatment in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation with somatropin in patients experiencing acute critical illnesses should be weighed against the potential risk. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnea before initiation of treatment with somatropin. If, during treatment with somatropin, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnea, treatment should be interrupted. All patients with Prader-Willi syndrome treated with somatropin should also have effective weight control and be monitored for signs of respiratory infection, which should be diagnosed as early as possible and treated aggressively [see Contraindications (4)]. Intracranial tumors, in particular meningiomas, were the most common of these second neoplasms. Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated, these patients should be carefully monitored for development of neoplasms. Monitor patients on somatropin therapy carefully for increased growth, or potential malignant changes, of preexisting nevi. As a result, previously undiagnosed impaired glucose tolerance and overt diabetes mellitus may be unmasked during somatropin treatment.

The relative actions of these key regulatory centers and their respective hormones are influenced by a myriad of genetic antibiotics for uti in horses cheap 200mg doxycycline amex, environmental and developmental factors virus test purchase doxycycline 100 mg without a prescription. In addition treatment for dogs with fits buy doxycycline 100mg overnight delivery, special attention will be given to the proposed mechanisms through which abnormal cortisol release patterns antibiotic treatment for acne cheap doxycycline 200 mg with amex, particularly hypocortisolism infection control nurse certification doxycycline 200 mg without prescription, arise antibiotics for acne or pimples discount 100mg doxycycline fast delivery. The metabolic and clinical consequences of abnormal cortisol states, accurate diagnostic methods and appropriate treatment modalities will also be reviewed. The Stress Response System A vast amount of research has been conducted to understand the intricate cascade of events that occur once the brain detects a disruption in homeostasis* (a stressor) and the hormonal responses driven by these systems. Like the stress response in general, cortisol is intended to shunt cellular processes away from long-term metabolic processes and toward those that function primarily on immediate survival and homeostasis. Thus, the negative feedback loop of cortisol on its own secretion is designed to limit long-term exposure of tissues to these short-term catabolic and immunosuppressive actions. Innate qualities such as age, gender (female preponderance) and hereditary predisposition, coupled with personality characteristics (i. The result is a paradoxical rise in cortisol levels in the evening hours and initial phases of sleep. A vicious cycle ensues whereby nocturnal hypercortisolism causes sleep fragmentation, raising cortisol levels even further. The hypoxemia induced by recurrent obstruction to airflow causes pulsatile release of cortisol and sleep fragmentation. Cortisol secretion helps maintain these levels by stimulating gluconeogenesis and causing peripheral and adipose insulin resistance. While these effects are intended to allow for short-term "fight or flight" benefits, they can lead to disastrous consequences if maintained for more than acute episodes. Individuals who regularly consume high glycemic foods and/or are insulin resistant will often induce a hypoglycemic "crash" after a meal, triggering the cortisol response. He was able to show that irrespective of the diverse stressors he placed upon the animals, a similar physiological response ensued. Chronic exposure to a stressor leads to a recurring set of physiological outcomes (hypertrophy of the adrenal gland, atrophy of the lymphatic organs, and ulcers in the stomach). While numerous advances in our understanding of the stress response have been published in the past 50 years, the simple observation that the same stress response mechanisms are elicited by virtually all stressors has remained unchanged. There are many events that alter homeostasis, at least as determined by the hypothalamus. Sources of acute stress are usually fairly obvious, but it is vital for the clinician to help patients identify their unique source(s) of chronic stress when treating any chronic health condition. However, the consequence of protecting the immune system by blunting cortisol production is not without consequence on other pathophysiological systems (see hypocortisolism section). Only three to five percent of the total plasma cortisol is unbound (free) and able to passively diffuse into cells. Cortisol enters the acinar cells lining the saliva glands via passive diffusion, and is not affected by the saliva flow rate. This passive transport prevents proteins or protein-bound molecules from entering the saliva. This means that the cortisol measured in the saliva is the active "free" fraction. When serum levels are measured, free cortisol must be measured in the milieu of large amounts of "bound" cortisol (inactivated); and the available literature clearly suggests that saliva cortisol is more closely correlated with the free cortisol fraction in serum compared to total serum cortisol. Cortisol is highest in the morning; levels drop gradually until about noon and stay steady throughout the afternoon, then drop again in the late evening before midnight. It is important for each clinician to become well-acquainted with the "normal" ranges used in the laboratories they are using. Pattern 1 represents one potential hypercortisol curve where the secretion of cortisol does not shut down throughout the day. This may be due to an ongoing acute stressor or a resistance to cortisol feedback by the hypothalamus and pituitary. There might be a slight diurnal nature to the curve, but the overall production of cortisol is so low that it is of little consequence. Pattern 2 represents one of a number of odd diurnal patterns that may cause disturbance in sleep patterns (this person probably has trouble getting to sleep at night or finds sleep less than restful) or depression. One study found that when diurnal salivary cortisol of individuals with major depression were compared with controls, evening cortisol levels were significantly increased. It is also critical to ensure that the test is taken on a day that the patient predicts will be as typical (stress-wise) as possible to avoid measuring anomalies caused by sudden or anticipated physical or emotional stress. Figure 2 25 22 Normal Diurnal Range 40 35 30 nM Cortisol 35 Loss of Circadian Rhythm 31 28 20 nM Cortisol 30 15 10 5 4 4 12 7 6 3 1 25 19 20 15 10 5 0 3 16 10 1 10 1 -5 0 Morning 7­9 a. The overall actions of glucocorticoids are immunosuppressive, particularly on cellular immunity. Impaired cytokine production and function, loss of tissues important in immune cell production (lymphoid, thymic and splenic tissue), and impaired leukocyte trafficking contribute to increased susceptibility to infection and neoplasm. Since these hormones antagonize the effects of cortisol, their absence further potentiates the actions of the now-unopposed catabolic corticosteroids, further impairing growth, repair and reproductive functions. Cortisol increases insulin levels; and the coelevation of these two hormones, as well as a reduction in the levels of androgens, promotes visceral adipose deposition. Fat deposition is further promoted by increased and prolonged levels of the enzyme lipoprotein lipase. Hypocortisolism Hypocortisolism describes any condition in which paradoxically low cortisol, flattened daytime production patterns and blunted cortisol release to stressors are observed. Evidence suggests that hypocortisolism may be a common, yet underappreciated, consequence of exposure to severe acute stress and chronic intermittent stress. Studies have confirmed states of hypocortisolism in patients chronically exposed to stressful environments, those with unpredictable schedules and in those with traumatic early life experiences. Intrinsic dysfunction of the adrenal glands secondary to chronic stress has not been reliably demonstrated. One model suggests that under the influence of chronic stress, the initial adaptive hypercortisolism response transforms over time into a self-preserving hypocortisolism state in order to protect the metabolic machinery, and most importantly, the brain. Inadequate glucocorticoid signaling, decreased levels of bioavailable cortisol, and failure of cortisol action at the level of the receptor have all been proposed. Left unchecked, levels of pro-inflammatory cytokines increase fueling what has been termed the "sickness response. Since cortisol is profoundly influential in maintaining homeostasis within the immune system, a decrease in baseline levels or a suboptimal stress induced rise in its levels may lead to maladaptive immune system dysfunction. Cortisol selectively suppresses cellular immunity thereby preventing tissue damage from excessive inflammation. The lack of cortisol suppression on sympathetic tone and catecholamine levels potentiate this process by further increasing the levels of pro-inflammatory cytokines. Patients may complain of low-grade fever, easy fatigability, myalgias, weight loss and muscular weakness. Abdominal pain, nausea and vomiting, postural hypotension and hypoglycemia may also be seen. Many of these are also the symptoms seen in critically ill, glucocorticoid-deficient patients. Taking control of known stressors Stress analysis (via questionnaire) and management tools are an obvious start for those whose lifestyle includes avoidable stress. Moderate, non-competitive exercise can be a valuable stress reducer that provides numerous other health benefits. If anger, fear, anxiety and depression are typical responses to unavoidable situations, adrenal stress is sure to follow. Glycemic control the interrelationship between stress and glycemic dysregulation is perhaps one of the most overlooked contributors to metabolic abnormalities. When we think of stress, we often think of major life events-those often found on a life-stress inventory (divorce, death of spouse, major health concern). While these episodic stressors have negative consequences, the most common stressors are ones that often go unrecognized, operating chronically at low levels, resulting in profound negative clinical outcomes. This should come as no surprise, since one of the main functions of cortisol is related to eight 2010 glucose regulation during stress. The glycemic impact of the diet is vitally important to maintain appropriate insulin and cortisol levels. Chronic glycemic dysregulation results in chronic high cortisol levels, placing the individual in an ongoing catabolic state. So while they may be helpful in the controlled environment of a clinical trial or for making general diet recommendations, what is needed is a number that helps an individual know the true glycemic impact of the meal they will consume. Soluble fibers and fermentable fibers (carbohydrates that can be fermented into short-chain fatty acids by gut micro-flora) seem to have an especially profound effect, not only on the glycemic response of the initial meal consumed, but on subsequent meals consumed. Researchers at Lund University in Sweden have recently published data showing that a single breakfast meal consisting of high amounts of soluble and fermentable fibers will decrease the glycemic impact of the subsequent lunch and dinner meals. Willett) · Reduce glycemic impact by reducing refined carbohydrates, soft drinks and other sweetened beverages, and increase the use of whole grains. This meal sets the foundation for glycemic control for the entire day and helps ensure the normal transition from high morning cortisol production. Fasting serum tests (especially fasting serum glucose) are ineffective ways to discover insulin sensitivity impairments in at-risk populations. Impaired glucose tolerance often begins years before changes in fasting glucose levels will suggest a problem. Use of oral glucose tolerance tests or other post-prandial tests will identify at-risk patients earlier and allow lifestyle approaches to have the greatest impact. In fact, getting baseline insulin sensitivity for all patients where there is a family history of diabetes, obesity or heart disease would be advisable. All of these measurements are routinely available through numerous laboratories at reasonable (and often reimbursable) rates. All stressors, regardless of origin, will result in episodic or chronic elevations in cortisol. Over the past few decades, sleep time (primarily less sleep before midnight) and regularity (weekday vs. Patients (as well as those with whom they sleep) should be questioned about sleeping patterns, duration and symptoms of sleep apnea. Maintaining regular patterns of sleep for at least seven hours per night should be recommended. Most studies show weight loss will maximize six months into a program, then subjects begin to creep back to their starting weight. Even so, these individuals still have improved metabolic parameters over those who never lost the weight in the first place. It should be emphasized to patients that even small decreases in their weight or increases in their physical activity can have tremendous benefits. Vitamins and Minerals the synthesis and secretion of cortisol is dependent on adequate supplies of various vitamins. Vitamin C, needed for steroid biosynthesis, is depleted from the adrenal cortex upon high cortisol secretion. Pantothenic acid and folic acid are vital to maintain steroid secretion from the adrenal cortex. The effects of pantothenic acid deficiency have been specifically linked to decreased adrenal function in both animals and humans. Aldosterone (a mineralocorticoid), made by the adrenal cortex, has a profound effect on the regulation of minerals. Under stress, calcium may be depleted in adrenal tissues, as it is required for the secretion of both hormones. Serum levels of potassium, zinc, iron and copper are reduced under cortisol secretion. Pregnenolone is a precursor to all of the adrenal corticosteroids (See Figure 1) and is considered by some clinicians to be helpful in both hypercortisolism as well as hypocortisolism. Physiological (rather than pharmacological) doses of 25­50 mg oral (5­10 mg/day, sublingual) of pregnenolone is also popular among some physicians and are currently available as dietary supplements in the U. The evaluation of these studies is made difficult by the wide-range of patients included, outcomes studies and doses used. Glycyrrhizin, one of the major components of licorice root, has a structure similar to corticosteroids. These compounds have been shown to block 11-hydroxysteroid dehydrogenase, the enzyme responsible for the conversion of cortisol to the inactive cortisone. Chronic high levels of licorice have been known to raise blood pressure by causing increased cortisol binding to the mineralocorticoid receptors in the kidneys, increasing water retention and blood volume. When taken in smaller targeted doses, licorice root extracts can be used to maintain cortisol levels. Therapeutic use of licorice root extract should be reserved for patients determined to have hypocortisolism. Severe hypocortisolism may require three or four separate doses throughout the day. Based on the in vivo and clinical evidence, a suggested acceptable daily intake of 0. Individuals with hypertension (especially salt-sensitive hypertensives), should be monitored for waterretention when given licorice root extract. Glandular Using animal glands and organs as supplemental ingredients may be new to some, but the concept is ancient. Dietary use of organ meat for therapeutic functions has been going on in many cultures for centuries. In fact in 1896, at least three pharmaceutical companies (Chaix and Raimy, Paris; Oppenheimer Son and Co.