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His-Purkinje System and Ventricular Muscle The most common are dizziness or light-headedness cheap malegra fxt 140 mg mastercard, Propafenone slows conduction and inhibits auto- metallic taste generic malegra fxt 140mg with visa, nausea cheap malegra fxt 140 mg overnight delivery, and vomiting; the most serious matic foci purchase 140mg malegra fxt visa. Electrocardiographic Changes Contraindications Propafenone causes dose-dependent increases in the Propafenone is contraindicated in the presence of se- PR and QRS intervals purchase malegra fxt 140 mg on-line. Other contraindications include by an increase in right atrial, pulmonary arterial, and severe bradycardia, hypotension, obstructive pulmo- pulmonary artery wedge pressures in addition to an in- nary disease, and hepatic and renal failure. Because of crease in vascular resistance and a decrease in the car- its weak -blocking action, propafenone may cause pos- diac index. This problem is great- may be observed in patients with preexisting left ven- est in patients who are slow metabolizers. In the absence of cardiac abnor- malities, propafenone has no significant effects on car- diac function. SA, sinoatrial; D, decrease in conduction velocity; I, increase in conduction velocity; –, no significant effect with clinically relevant doses;,mini- mal effect. Bear in mind the com- Atrium plete spectrum of cardiovascular effects of these agents Propranolol has local anesthetic properties and ex- when prescribing their use. For example, while patients erts actions similar to those of quinidine on the atrial with a normally functioning cardiovascular system may membrane action potential. Membrane responsiveness tolerate adrenergic blockade of the heart, patients with and action potential amplitude are reduced, and ex- compensated heart failure, who depend on adrenergic citability is decreased; conduction velocity is reduced. A-V Node Propranolol The depressant effects of propranolol on the A-V node are more pronounced than are the direct depres- Propranolol (Inderal) is the prototype -blocker (see sant effects of quinidine. It decreases the effects of sympathetic dual actions of -blockade and direct myocardial de- stimulation by competitive binding to -adrenoceptors. Propranolol administration results in a de- crease in A-V conduction velocity and an increase in Electrophysiological Actions the A-V nodal refractory period. The second is associated with its direct myo- His-Purkinje System and Ventricular Muscle cardial effects (membrane stabilization). The latter ac- Propranolol decreases Purkinje fiber membrane re- tion, especially at high clinically employed doses, may sponsiveness and reduces action potential amplitude. These which enhanced -receptor stimulation does not play a changes result in a decrease in His-Purkinje conduction significant role in the genesis of the rhythm disturbance. However, these electrophysiological alter- ations are observed at propranolol concentrations in Sinoatrial Node excess of those normally used in therapy. The most Propranolol slows the spontaneous firing rate of striking electrophysiological property of propranolol nodal cells by decreasing the slope of phase 4 depolar- at usual therapeutic concentrations is a depression of ization. Blockade of -receptors Individual Antiarrhythmic prolongs systolic ejection periods at rest and during ex- Drugs ercise. However, these alterations are Drugs Therapeutic Uses offset by factors that tend to reduce oxygen consump- tion, such as decreased heart rate and decreased force Acebutolol Ventricular arrhythmias, ventricular ectopy of contraction. The decrease in oxygen demand pro- Adenosine Supraventricular tachycardia duced by a decrease in heart rate and a decrease in Wolff-Parkinson-White syndrome force of contraction is usually greater than the increase Amiodarone Hemodynamically unstable ventricular in oxygen demand that results from increased heart size tachycardia and increased ejection time. The net result is that oxy- Ventricular fibrillation Bretylium Ventricular arrhythmias after cardiac gen demand is decreased. In se- Procainamide Atrial tachycardia, ventricular lected cases of sinus tachycardia caused by anxiety, tachycardia Premature ventricular contractions pheochromocytoma, or thyrotoxicosis, -blockade will Propafenone Atrial fibrillation, ventricular reduce the spontaneous heart rate. Patients with Postoperative ventricular arrhythmias Wolff-Parkinson-White syndrome supraventricular extrasystoles and intermittent parox- Quinidine Atrial arrhythmias, ventricular ysms of atrial fibrillation may benefit from -receptor tachycardia blockade with propranolol. Sotalol Ventricular arrhythmias, ventricular The arrhythmias associated with halothane or cyclo- fibrillation propane anesthesia have been attributed to the interac- Tocainide Premature ventricular contractions Ventricular tachycardia tion of the anesthetic with catecholamines, and they Verapamil Paroxysmal supraventricular tachycardia have been suppressed by IV administration of 1 to 3 mg Atrial fibrillation propranolol. An increase in circulating catecholamines also has been observed in patients with acute myo- cardial infarction and has been correlated with the de- velopment of arrhythmias. Electrocardiographic Changes Clinically, tachyarrhythmias associated with digitalis excess (including supraventricular and ventricular ex- Propranolol prolongs the PR interval but does not trasystoles) and ventricular tachycardia have been sup- change the QRS interval. Although propranolol is highly effective in the treatment of digitalis-induced arrhyth- Hemodynamic Effects mias, phenytoin and lidocaine are preferred. The blockade of cardiac -adrenoceptors prevents or Long-term treatment with -adrenoceptor blocking reduces the usual positive inotropic and chronotropic agents is clearly associated with an increased rate of 184 III DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM TABLE 16. However, the effect of -adrenoceptor blockade on the A-V node will decrease the ventricular response to the atrial tachyarrhythmia. Atrial flutter/tachycardia -Adrenoceptor blockers will reduce the ventricular rate by inhibition of transmission through the A-V node as a result of inhibition of adrenergic influences. Ventricular arrhythmias Premature ventricular complexes Effective in mitral valve prolapse, hypertrophic cardiomyopathy, digitalis-related ectopic activity, and ventricular complexes associated with exercise or induced by ischemia. Ventricular tachycardia Most effective against arrhythmias associated with digitalis toxicity and exercise, particularly if the latter is related to ischemia.

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A positive antibody test means that the donor may be infected with the HIV virus; a confirmatory Western blot is necessary order malegra fxt 140 mg with amex. Because there is a delay of 22 d between HIV exposure and the development of the HIV antibody trusted malegra fxt 140mg, a potential risk of HIV transmission exists even with blood from a donor who is HIV-negative malegra fxt 140mg generic. CMV Incidence in donors is very high (approaches 100% in many series) buy cheap malegra fxt 140 mg on line, but clinically represents a major risk mostly for immunocompromised recipients and neonates cheap malegra fxt 140 mg mastercard. Leukocyte filters can reduce the risk of transmission if procedures are strictly followed. The vast majority of patients admitted to the hospital can be given one of these hospital diets without any specific supplementation or modification. Most hos- 11 pitals have diet manuals available for reference, and registered dietitians are usually on staff for nutritional consultation. A physician order for diet instruction by a clinical dietitian is recommended for all patients being discharged with a therapeutic or modified diet. NUTRITIONAL ASSESSMENT Nutritional screening should be incorporated into the history and physical evaluation of all patients. Identifying patients at nutrition risk is crucial because malnutrition is prevalent among hospitalized patients and has been associated with adverse clinical outcomes. Situa- tions that predispose a patient to malnutrition include recent and continuing nausea, vomit- ing, diarrhea, inability to feed oneself, inadequate food intake (cancer-related, others), decreased nutrient absorption or utilization, and increased nutrient losses and nutritional re- quirements. If needed, detailed nutritional assessment may be needed for some patients and is discussed in the following section. Although many patients are admitted to the hospital in a nutritionally depleted state, some patients become malnourished during their hospital stay. According to guidelines from the American Society for Parenteral and Enteral Nutrition, “patients should be considered malnourished or at risk of developing malnutrition if they have inadequate nutrient intake for 7 days or more or if they have a weight loss of 10% or more of their preillness body weight. Anthropometric evaluations include comparisons of actual body weight to ideal and usual body weight. Other anthropometric measurements, such as MAMC and TCF, have much 205 Copyright 2002 The McGraw-Hill Companies, Inc. Absolute lymphocyte count is sometimes used as a marker of visceral proteins and im- munocompetence. Visceral protein markers, such as prealbumin and transferrin, may be helpful in evaluating nutritional insult as well as catabolic stress. Although the most com- monly quoted laboratory parameter of nutritional status is albumin, the albumin concentration often reflects hydration status and metabolic response to injury (ie, the acute phase response) more than the nutritional state of the patient, especially in patients with intravascular volume deficits. Preal- bumin is superior as an indicator of malnutrition only because of its shorter half-life. Use of these serum proteins as indicators of malnutrition is subject to the same limitation, however, because they are all affected by catabolic stress. Patients can generally be classified as mildly, moderately, or severely nutritionally depleted based on these parameters. Caloric needs can be determined by one of two means: the Harris–Benedict BEE and the “rule of thumb” method. Total energy requirements = BEE ×Activity factor × Stress factor Use the following correction factors: Activity Level Correction Factor Bedridden 1. T h u s i s m o r e s e n s i t i v e i n d i c a t o r 1 0 – 1 5 m g / d L M i l d d e p l e t i o n o f a c u t e c h a n g e i n n u t r i t i o n a l s t a t u s t h a n i s 5 – 1 0 m g / d L M o d e r a t e d e p l e t i o n a l b u m i n o r T F N < 5 m g / d L S e v e r e d e p l e t i o n N o t r o u t i n e l y a v a i l a b l e L e v e l s a r e q u i c k l y d e p l e t e d a f t e r t r a u m a o r a c u t e i n f e c t i o n. A l s o d e c r e a s e d i n r e s p o n s e t o c i r r h o s i s, h e p a t i t i s, a n d d i a l y s i s, a n d t h e r e - f o r e, s h o u l d b e i n t e r p r e t e d w i t h c a u t i o n A b s o l u t e l y m p h o c y t e c o u n t 1 4 0 0 – 2 0 0 0 M i l d d e p l e t i o n M a y n o t b e v a l i d i n c a n c e r p a t i e n t s. DETERMINING THE ROUTE OF NUTRITIONAL SUPPORT Once nutritional support is indicated, the route for administration is chosen. Enteral supple- mentation by mouth or tube and parenteral nutrition are the main routes for providing nutri- tional support. Enteral Supplementation and Tube Feeding 11 Enteral nutrition encompasses both supplementation by mouth and feeding by tube into the GI tract. In addition, patients who have a functioning GI tract but for whom oral nutrition intake is contraindicated should be consid- ered for tube feedings. If the GI tract is functioning and can be used safely, tube feedings should be ordered in- stead of parenteral nutrition when nutrition support is necessary because it • Is more easily absorbed physiologically • Is associated with fewer complications than TPN • Maintains the gut barrier to infection • Maintains the integrity of the GI tract • Is more cost-effective than TPN • Contraindications to tube feeding can be found in Table 11–3. Parenteral Nutrition Parenteral nutrition usually offers no advantage to the patient with a functioning GI tract. Some patients, because of their disease states, cannot be fed enterally and require par- enteral feedings.

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If both parents carry a copy of the at these ages are often associated with future death dur- mutated gene buy malegra fxt 140mg on-line, there is a 25% likelihood that their child ing a symptomatic episode cheap malegra fxt 140 mg fast delivery, recurrent seizures throughout will be homozygous for MCAD deficiency quality malegra fxt 140 mg. Genetically discount 140 mg malegra fxt mastercard, life buy malegra fxt 140 mg low cost, the development of cerebral palsy, and/or the devel- the probability that an affected person will have a sibling opment of speech disabilities. In population studies of known MCAD deficient individuals, it has been observed Diagnosis that an average of 32% of these individuals have at least one sibling either known to be affected with MCAD defi- The Departments of Health in Massachusetts and ciency or to have died with a misdiagnosis of SIDS. Additionally, Neo Gen Screening offers Signs and symptoms voluntary newborn screening at birthing centers through- There is no classic set of symptoms that characterize out the Northeastern United States. The severity of symptoms observed in Iowa also began a pilot program to screen all newborns in 718 GALE ENCYCLOPEDIA OF GENETIC DISORDERS MCAD deficiency (Gale Group) that state. It is expected that MCAD deficiency screening Treatment and management will become mandatory statewide in Iowa sometime in Because individuals affected with MCAD deficiency 2001. The most mutation in the MCAD gene by the difference in molec- common precipitators of MCAD deficiency symptoms ular weight in this gene versus the molecular weight of are stress caused by fasting or by infection. This DNA is then reproduced als often cannot meet these increased metabolic multiple times by the polymerase chain reaction (PCR demands. Once enough sample has been made, the The main treatments for MCAD deficiency are sample is labeled with a fluorescent chemical that binds designed to control or avoid precipitating factors. Persons specifically to the region of chromosome 1 that contains affected with MCAD deficiency should never fast for the MCAD gene. How this fluorescent chemical binds to more than 10 to 12 hours and they should strictly adhere the MCAD gene region containing the G985A mutation to a low-fat diet. Blood sugar monitoring should be allows the identification of homozygous G985A, het- undertaken to control episodes of hypoglycemia. During erozygous G985A, and normal (no G985A mutations) acute episodes, it is usually necessary to administer glu- MCAD genes (FRET analysis). This Prenatal testing for MCAD deficiency is also avail- vitamin is responsible for transporting long chain fatty able using a test similar to the PCR/FRET blood test. Elevated this case, however, the DNA to be studied is extracted levels of L-carnitine ensure that these individuals break- from the amniotic fluid rather than from blood. Another down long chain fatty acids in preference to medium prenatal test involves studying the ability of cultured chain fatty acids, which helps prevent acute symptomatic amniotic cells to breakdown added octanoate, an 8-car- episodes of MCAD deficiency. Because MCAD deficiency is generally treatable if it is recognized prior to the onset of symptoms, most par- Some individuals affected with MCAD deficiency ents of a potentially affected child choose to wait until present symptoms for the first time when they receive the birth to have their children tested. It is impor- GALE ENCYCLOPEDIA OF GENETIC DISORDERS 719 tant that any person suspected to be affected with MCAD deficiency receive treatment for hypoglycemia in con- IMcCune-Albright syndrome nection with the administration of this vaccine. Chicken Definition pox and middle ear infections (otitis media) have also been shown to initiate symptoms of MCAD deficiency. A disorder characterized by abnormalities in bone development, skin pigmentation, and endocrine gland Prognosis function. MCAD deficiency has a mortality rate of 20–25% Description during the first episode of symptoms. If an affected indi- vidual survives this first attack, the prognosis is excellent The McCune-Albright syndrome is an uncommon for this individual to have a normal quality of life as long disorder in which a mutation distributed across various as appropriate medical treatment is sought and followed. The most notable features are abnormal bone Resources development, pigmented skin spots, and endocrine gland PERIODICALS dysfunction. The defect is a octanoylcarnitine and other acylcarnitines in newborn mutation in the GNAS1 gene, which is associated with a blood spots by tandem mass spectrometry. The mutation first occurs in a single cell ORGANIZATIONS during the early stages of formation of the embryo. Of course, WEBSITES this figure probably underestimates the true prevalence of Matern, D. The pelvis and femur, or thigh bone, are the most commonly involved areas of the skele- Pituitary gland—A small gland at the base of the ton. Bony abnormalities in the skull can cause blindness brain responsible for releasing many hormones, or deafness. The majority of patients with McCune- including luteinizing hormone (LH) and follicl- Albright syndrome have many of these lesions, hence the stimulating hormone (FSH). In addition to these fibrous lesions, some patients develop osteosarcoma, which is a malignant tumor of the certain bones and tissues, especially in the face and bone. Some people with acromegaly grow to very originate from the fibrous lesions within the bone. If too much prolactin is Pigmented skin spots produced, then breast tissue will secrete milk inappropri- ately, both in boys and girls.

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Therefore generic malegra fxt 140 mg without prescription, if the internal model is represented via a population code order malegra fxt 140 mg mastercard, then generalization is described by the shape of the tuning curves of the elements of computation discount 140mg malegra fxt overnight delivery. From the experiment in which we observed generalization in one arm from one workspace to another workspace cheap 140mg malegra fxt otc,17 we can now conclude that the tuning functions could not have had “preferred positions” of the hand discount malegra fxt 140 mg free shipping, in the sense that this implies sharply tuned activity functions around that position. If they did, then experiencing force at one hand position could not be generalized to another hand position far away. To describe mathematically how discharge varies with arm position and velocity, we note that cell activity in Copyright © 2005 CRC Press LLC M1 is modulated globally and often linearly as a function of limb position,29 and cells have PDs of movement that often change as a function of the shoulder angle. The position-dependent term is a linear function that encodes joint angles, q = (θshoulder, θelbow), while the velocity-dependent term encodes joint velocities. As a result, both the PD of the tuning and the depth of modulation vary with the starting position of the reach. The gradient vector k reflects sensitivities for the shoulder and elbow displacement, and b is a constant. The velocity-dependent term is a Gaussian that encodes joint velocity q˙ centered on the preferred velocity q˙i. The multiplicative nature of this encoding is one of the requirements of basis functions. For example, in addition to M1, linear modulation of discharge with respect to limb position has been observed in the spinocerebellar tract31 and the somatosensory cortex. Consider a situation in which the internal model is constructed as a linear combination of these nonlinear bases. With training at a given arm configuration, the preferred force vector of some of these bases will change. The change will occur in those bases that happen to be most active at this arm configuration. The way that these active bases change their static discharge with arm position dictates how far in position space the learning will generalize. Next, note that because the bases encode joint velocity and not hand velocity, the PD of movement (which is represented in Cartesian coordinates) will rotate for some of the cells as the shoulder joint changes position. The way that the elements change their PDs with arm position dictates the coordinate system of the generalization. Let us first examine how adaptation with these elements results in generalization in terms of the spatial displacement of the hand. At the left and right targets a curl field was present (clockwise at left, counterclockwise at right). Subjects were divided into four groups based on the distance between the left and right targets: d = 1, d = 6, d = 14, and d = 24 cm. Typical movements for single subjects in the d = 1 and d = 24 cm groups are shown (field trials are dashed, catch trials are dotted). The 24-cm group could learn the task: they had clear after-effects and movements in the field improved. Note the increased interference in the center target for the 1 cm group as field trials start. The gain k dictates how close two workspaces have to be (in position space) before learning of conflicting fields becomes impossible. When the gain is high, output of the bases changes greatly as a function of hand position. This results in poor generalization between neighboring positions of the hand, making it possible to learn two different patterns of force at two different hand positions. The firing rate of one basis function is plotted for eight directions of movement during movement time, and at the hold time at the start and end of the movement. Firing rate is also plotted for another basis for movements that start from nine different start positions. Because of multiplicative interaction of position sensitivity with directional tuning, depth of modulation varies with start position. This is the ratio of standard deviations (SD) for the center movements 420–504 versus 1–84. The bases appear to account for the generalization pattern of our subjects over this small displace- ment of the hand. The bases produced similar patterns of generalization as our subjects over this large displacement. At its limit, output changes not at all as a function of hand position and there is effectively no coding of hand position. In this situation, forces generalize globally in hand position space and it is not possible to learn two different forces for the same spatial direction of movement in two different spatial locations.

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