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INTRODUCTION AND HISTORY Parkinson’s disease (PD) purchase 20mg vasodilan amex, like other neurodegenerative disorders vasodilan 20mg amex, is clinically heterogeneous (1) buy 20 mg vasodilan with mastercard. Age of onset, the relative prominence of certain signs and symptoms, course and rate of progression, and the responsiveness to therapy are variable but still assist in differentiating it from atypical forms of parkinsonism (2). Mainly described by its cardinal motor manifestations (bradykinesia/akinesia, rigidity, resting tremor, and postural instability), progression is inevitable, as there is a continuous loss of nigrostriatal dopaminergic neurons in the substantia nigra pars compacta (SNpc) (3). Before 1918, treatment was primarily supportive (4). However, the encephalitis epidemic of 1917–1926 and the emergence of the postencepha- litic form of parkinsonism led to a more aggressive pursuit of effective therapies. The pursuit initially focused on the development of an effective vaccine, and then necessarily toward symptomatic therapy (5,6). As we cannot, at this time, halt the progression of PD, symptomatic relief remains Copyright 2003 by Marcel Dekker, Inc. While this is at times inadequate, the available symptomatic therapies for PD are far more effective than those available for any other neurodegenerative disease (3). A number of natural remedies have been tried to treat the symptoms of PD over the last century and a half. Charcot, in the latter half of the nineteenth century, described the use of potato plant extracts, such as Bulgarian belladonna and atropine, to treat PD. These were initially received with great promise, but fell short of expectations. In the decade following the emergence of postencephalitic parkinsonism, many studies were published comparing the various plant extracts, evaluating the effectiveness of certain agents for specific symptoms; for example, stramonium was felt to be effective for rigidity and hyoscine for tremor (4). By the early 1950s, synthetic drugs became available to treat the symptoms of PD. Trihexyphenidyl hydrochloride, a synthetic anticholiner- gic, was highly touted for its effectiveness for relieving rigidity, tremor, akinesia, and oculogyric crisis. It was heralded as more effective than the plant extracts and better tolerated than other early synthetic preparations (4,7,8). While still used today, its limitations in treating all the symptoms of PD were recognized even then. Levodopa (LD) has become the cornerstone of symptomatic therapy. It is a metabolic precursor of the neurotransmitter dopamine (see below). Guggenhiem, in 1913, isolated LD from the broad bean plant (10). Its use in PD only emerged after the important works of various researchers in the late 1950s and early 1960s that demonstrated that dopamine depletion was characteristic of PD. Carrlson in 1957 and 1958 (11,12) demonstrated in animal models that the akinetic effects of reserpine (an agent known to deplete dopamine) could be reversed by LD. In addition, Carrlson reported that the striatum was a site of dopamine concentration (11,12). Hornykiewicz in 1960 showed that the striatum of parkinsonian brains were depleted of dopamine and 2 years later that intravenous doses of LD (50 mg) had anti-parkinsonian effects (13). However, studies in the early and mid-1960s showed variable results, and, in fact, treatment with LD was almost abandoned. It was the seminal work of Cotzias, who examined the role of high-dose oral LD in modifying parkinsonism, that dramatically changed the landscape of PD treatment (14,15). Food and Drug Administration (FDA) for use in PD in 1970, 60 years after its discovery and more than 10 years after the realization that dopamine depletion was the key abnormality in PD (16). In 1973, the combined use of a peripheral aromatic amino acid decarboxylase inhibitor (AADI) with LD was reported. Its use resulted in a decrease in peripheral metabolism of LD to dopamine and fewer peripheral side effects such as hypotension and nausea Copyright 2003 by Marcel Dekker, Inc. Controlled-release formulations were tested in the 1980s to treat fluctuations (see below), and one was approved in the United States in 1991 (3).

The latter include anticipation quality vasodilan 20mg, planning purchase 20 mg vasodilan with amex, initiation cheap 20 mg vasodilan otc, and the monitoring of goal-directed behaviors. The biochemical basis for these deficits is thought to be, at least in part, due to denervation of the dopaminergic and noradrenergic inputs to the frontal lobes. Other factors include basal ganglia dysfunction, which can independently impair selected aspects of attention and mental flexibility. Iatrogenic factors that can affect cognition in PD include the use of dopaminomimetic therapy to treat motor symptoms. This drug effect is complex and variable, with levodopa being unable to compensate for all the cognitive deficits observed in PD (7). It depends on the duration of illness, the severity of motor signs, the presence of dementia, sleep disturbances, and possibly depression. For instance, in the early stages of PD, levodopa treatment can improve executive functions normally regulated by the prefrontal cortex. However, this improvement is incomplete and task specific. As the disease advances, patients with a stable clinical response to levodopa fail to exhibit a notable improvement in vigilance and executive function, and patients who exhibit motor fluctuations tend to exhibit transient deterioration in these functions (8). Finally, the effect of these drugs in patients with PD and dementia is likely to be more notable and complex. Other negative iatrogenic influences on cognitive function in PD include the use of drugs like anticholinergics and amantadine, often used to treat tremor and dyskinesias, and psychotropics used to treat sleep disturbances and affective symptoms. These drugs can negatively affect different aspects of memory and attention, particularly in already demented patients. Like these drug effects, many intercurrent medical illnesses and Copyright 2003 by Marcel Dekker, Inc. DEMENTIA: THE PD/AD/LBD OVERLAP SYNDROMES Dementia occurs in approximately 20–30% of PD patients. It represents a major risk factor for the development of many behavioral disturbances, including psychotic symptoms. Dementia appears to be associated with the combined effect of age and the severity of extrapyramidal symptoms (9). Pathologically, up to 40% of autopsy cases with a primary diagnosis of PD have comorbid findings consistent with senile dementia of the Alzheimer’s type (SDAT) (10,11). Conversely, up to 30–40% of patients with SDAT have comorbid parkinsonian features and harbor Lewy body pathology that extends beyond the dopamine neurons in the brainstem to involve the frontal cortex, hippocampus, amygdala, and basal forebrain (12). These defects conspire with aminergic deficits to increase disability and the incidence of psychotropic-induced side effects. They also contribute to the progression of parkinsonian motor symptoms by narrowing the therapeutic window of all antiparkinsonian agents. Lewy body dementia (LBD) is an increasingly recognized syndrome in which dementia is accompanied by spontaneous parkinsonian features, depressive features, and apathy (5,13). Unlike SDAT, this form of dementia exhibits significant fluctuations in arousal ranging from ‘‘narcoleptic-like’’ sleep attacks to delirium in advanced cases. Sleep is often disrupted by sleep fragmentation due to rapid eye movement (REM)–related behavioral disorders. Patients have spontaneous features of PD and are extremely sensitive to drug-induced parkinsonism. Although parkinsonism associated with LBD can be indistinguishable from idiopathic PD, several clinical features tend to help differentiate the two. The course of LBD is more rapid than that of idiopathic PD (5–7 vs. Compared to SDAT patients, LBD patients have spontaneous and drug-induced visual hallucinations early in the course of the illness and frequently exhibit fixed delusions.

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This energy is used for carrying out diverse functions such as moving generic 20 mg vasodilan fast delivery, think- Fuels: ing discount vasodilan 20mg fast delivery, and reproducing effective vasodilan 20 mg. Thus, a number of our metabolic pathways are fuel oxidative Carbohydrate Vitamins pathways that convert fuels into energy that can be used for biosynthetic and Fat Minerals Protein H2O mechanical work. But what is the source of energy when we are not eating— between meals, and while we sleep? How does the hunger striker in the morning Xenobiotics headlines survive so long? We have other metabolic pathways that are fuel storage Digestion pathways. The fuels that we store can be molibized during periods when we are not absorption, eating or when we need increased energy for exercise. For example we have dietary requirements for some amino acids, but we can synthesize other amino acids from our fuels and a dietary nitrogen precursor. The Biosynthetic Fuel storage compounds required in our diet for biosynthetic pathways include certain amino pathways pathways acids, vitamins, and essential fatty acids. Detoxification pathways and waste disposal pathways are metabolic pathways Body Fuel components stores devoted to removing toxins that can be present in our diets or in the air we breathe, introduced into our bodies as drugs, or generated internally from the metabolism of O2 Detoxification dietary components. Dietary components that have no value to the body, and must and waste Fuel be disposed of, are called xenobiotics. The synthesis of proteins from amino acids is an example of an ana- H O 2 bolic pathway. Catabolic pathways are those pathways that break down larger mol- Waste ecules into smaller components. Fuel oxidative pathways are examples of catabolic products pathways. In the human, the need for different cells to carry out different functions has Fig. General metabolic routes for dietary components in the body. The types of Path- resulted in cell and tissue specialization in metabolism. However, adipose tissue is lacking many of the pathways that synthesize required compounds from dietary precursors. To enable our cells to cooperate in meeting our metabolic needs during changing con- ditions of diet, sleep, activity, and health, we need transport pathways into the blood and between tissues and intercellular signaling pathways. One means of communi- cation is for hormones to carry signals to tissues about our dietary state. For exam- ple, a message that we have just had a meal, carried by the hormone insulin, signals adipose tissue to store fat. We will describe the fuels in our diet, the compounds produced by their digestion, and the basic patterns of fuel metabolism in the tissues of our bodies. We will describe how these patterns change when we eat, when we fast for a short time, and when we starve for prolonged periods. Patients with medical problems that involve an inability to deal normally with fuels will be introduced. These patients will appear repeatedly throughout the book and will be joined by other patients as we delve deeper into biochemistry. We obtain our fuel primarily from carbohydrates, fats, and Essential Nutrients proteins in our diet. As we eat, our foodstuffs are digested and absorbed. The Fuels products of digestion circulate in the blood, enter various tissues, and are eventu- Carbohydrates Fats ally taken up by cells and oxidized to produce energy. To completely convert our Proteins fuels to carbon dioxide (CO2) and water (H2O), molecular oxygen (O2) is Required Components required.

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Most of these are probably DDH hips whose range of motion is substantially diminished because of spasticity cheap 20mg vasodilan overnight delivery. At this age buy discount vasodilan 20mg, if children have a fixed hip dislocation generic vasodilan 20mg visa, it should be treated as a DDH with open reduction and femoral shortening. Almost all children who have spastic hip disease at this age, even if the hip is almost dislocated, do not have a fixed dislocation and can be treated with muscle lengthening alone. However, a principle to remember in this gray zone is that these dislocated hips will never get easier to treat or be less of a problem for children by just waiting. Between the ages of 1 and 2 years, if children present with a subluxated hip and spasticity, it should always be considered spastic hip disease and treated with muscle lengthening unless there was a previously verified DDH. Established Developmental Dislocation For established dislocated DDH hips in older children with CP, the treatment philosophy that is in line with the DDH treatment for that specific age should be used rather than the spastic hip disease indications (Case 10. An oc- casional dilemma may present when new patients are being seen for the first time and there are no previous hip radiographs. If these children are 8 years of age or older and have a dislocated hip with very severe acetabular defi- ciency, it may still be difficult to determine whether this is a missed DDH or a spastic hip disease. The principles outlined previously for the treatment of spastic hip disease do not work for DDH because the hip dislocation oc- curred much earlier and there is generally much less acetabulum present to reconstruct. It may be very difficult to tell the difference between DDH and spastic hip disease when the spastic hip dislocation occurs between the ages of 2 and 3 years and the children are seen at age 10 years. In this scenario, the spastic hip dislocation may mimic the DDH more closely. However, this condition should seldom happen because it would indicate children who really have not been receiving appropriate medical care. No child with spasticity should ever present with a dislocated hip at age 6, 7, or 8 years without having previous radiographs to verify when that hip dislocation oc- curred. Children should also seldom present at this age with a dislocated hip. It is much less common to have children with CP present with a dislocated hip than normal children with DDH because the ease of determining a spas- tic hip dislocation is much more clear, as it is always empirically obvious that these children have CP. Hip 635 Slipped Capital Femoral Epiphysis Slipped capital femoral epiphysis has never been reported in a spastic hip and we have never seen a slipped epiphysis in a spastic hip. We have seen one child who developed a slipped capital femoral epiphysis on the normal side. This boy had hemiplegia, was severely obese, and started complaining of pain on his normal side. The presence of coxa valga is probably protective of the slipped capital femoral epiphysis in the spastic hip, although even hips that have had a varus osteotomy have not had a slipped epiphysis. Perthes Disease in Children with Spasticity Perthes disease also has not been reported in children with spastic hips and we have seen only one case. Use of orthotics is extremely difficult in these children, but otherwise the hips should be treated as they would be in normal children with Perthes disease. Hip Dislocation in Children with Down Syndrome and Cerebral Palsy Children with Down syndrome often develop hip dislocation secondary to muscle laxity and hypotonia from the Down syndrome. The problems re- lated to dislocation of hips in normal Down syndrome children are a major problem but are not addressed here. When Down syndrome is combined with CP, there are additional problems in treating the hip dislocation due to the spasticity. For nonambulatory children with Down syndrome who have CP and present with a dislocated hip that is asymptomatic, it is best to leave the hip alone (Case 10. The combination of soft-tissue laxity present in children with Down syndrome and spasticity makes reducing and maintain- ing these hips very unpredictable. We have followed several children with this scenario until age 21 years and none have developed hip pain and all have maintained relatively good range of motion of the hip. There is no other published report of outcome in children with this combination. For children who are being followed with the combination of Down syn- drome and CP and do develop a hip subluxation or dislocation, treatment should be considered.

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Extraoc- ular muscles would also have more of these fibers than type I quality vasodilan 20 mg. Smooth Muscle Cells Smooth muscle cells are found in the digestive system buy vasodilan 20mg with visa, blood vessels discount vasodilan 20mg amex, bladder, air- ways, and uterus. The cells have a spindle shape with a central nucleus (see Fig. The designation of smooth refers to the fact that these cells, which contain a single nucleus, display no striations under the microscope. The contraction of smooth muscle is controlled involuntarily (the cells contract and relax without any conscious attempt to have them do so; examples of smooth muscle activity include moving food Table 47. Properties of Muscle Fiber Types Type I Fibers Type II Fibers Type IIa Type IIb • Slow-twitch (slow speed • Intermediate-twitch (fast • Fast-twitch (fast speed of of contraction) speed of contraction) contraction) • Slow-oxidative (low glyco- • Fast-oxidative glycolytic • Fast-glycolytic (high glyco- gen content) fibers (intermediate gen content) glycogen levels) • High myoglobin content • Intermediate fiber • Low myoglobin content (appear red) diameter (appear white) • Small fiber diameter • High myoglobin content • Low mitochondrial (appear red) content • Increased concentration • Increased oxidative • Limited aerobic of capillaries surrounding capacity on training metabolism muscle (greater oxygen • Intermediate resistance to • Large fiber diameter delivery) fatigue • High capacity for aerobic • More sensitive to fatigue metabolism as compared with other fiber types • High resistance to fatigue • Least efficient use of energy, primarily glycolytic • Used for prolonged, • Used for sprinting and aerobic exercise resistance tasks CHAPTER 47 / METABOLISM OF MUSCLE AT REST AND DURING EXERCISE 865 along the digestive tract, altering the diameter of the blood vessels, and expelling urine A reduced flow of oxygen-rich from the bladder). In contrast to skeletal muscle, these cells have the ability to main- blood to the heart muscle may lead tain tension for extended periods, and do so efficiently, with a low use of energy. The amount of ATP that can be gen- erated by glycolysis alone is not sufficient to C. Cardiac Muscle Cells meet the energy requirements of the con- The cardiac cells are similar to skeletal muscle in that they are striated (contain fibers), tracting heart. The multicellular contacts allow the cells to act as a common unit and to con- tract and relax synchronously. Cardiac muscle cells are designed for endurance and consistency. They depend on aerobic metabolism for their energy needs because they contain many mitochondria and very little glycogen. These cells thus generate only a small amount of their energy from glycolysis using glucose derived from glycogen. NEURONAL SIGNALS TO MUSCLE For an extensive review of how muscle contracts or a detailed view of the signaling to allow muscle contraction, consult a medical physiology book. The ryanodine receptors are cal- The nerve–muscle cell junction is called the neuromuscular junction (Fig. This binding stim- coplasmic reticulum of muscle cells. One ulates the opening of sodium channels on the sarcolemma. The massive influx of type of receptor can be activated by a depo- larization signal (depolarization-induced cal- sodium ions results in the generation of an action potential in the sarcolemma at the cium release). Another receptor type is acti- edges of the motor end plate of the neuromuscular junction. The action potential vated by calcium ions (calcium-induced sweeps across the surface of the muscle fiber and down the transverse tubules to the calcium release). The proteins received their sarcoplasmic reticulum, where it initiates the release of calcium from its lumen, via name because they bind ryanodine, a toxin the ryanodine receptor (Fig. The calcium ion binds to troponin, resulting in a obtained from the stem and roots of the conformational change in the troponin–tropomyosin complexes such that they move plant Ryania speciosa. Ryanodine inhibits away from the myosin-binding sites on the actin. When the binding site becomes sarcoplasmic reticulum calcium release, and available, the myosin head attaches to the myosin-binding site on the actin. It was first used ing is followed by a conformational change (pivoting) in the myosin head, which commercially in insecticides. After the pivoting, ATP binds the myosin head, which detaches from the actin and is available to bind another myosin-binding site on the Schwann cell Synaptic Axon vesicles terminal Synaptic cleft Acetylcholine Sarcolemma Voltage-gated Acetylcholine Na+ channels receptor Muscle cell Fig. When appropriately stimulated, the synaptic vesi- cles, containing acetylcholine, fuse with the axonal membrane and release acetylcholine into the synaptic cleft. The acetylcholine binds to its receptors on the muscle cells, which will ini- tiate signaling for muscle contraction. Events leading to sarcoplasmic reticulum calcium release in skeletal muscle.

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