By L. Grobock. Tennessee Temple University.

Further studies confirmed the presence of decreased mineralization (decreased calcification) of the skeleton (called osteopenia if mild and osteoporosis if more severe) and high methionine and homocysteine but low cystine levels in the blood buy discount sildenafil 100 mg on line erectile dysfunction in young. All of this information order sildenafil 100 mg free shipping erectile dysfunction treatment by homeopathy, plus the increased length of the long bones of Homer’s extremities and a slight curvature of his spine (scoliosis), caused his physician to suspect that Homer might have an inborn error of metabolism. THE ROLE OF COFACTORS IN AMINO ACID METABOLISM Amino acid metabolism requires the participation of three important cofactors. Pyridoxal phosphate is the quintessential coenzyme of amino acid metabolism (see Chapter 38). All amino acid reactions requiring pyridoxal phosphate occur with the amino group of the amino acid covalently bound to the aldehyde carbon of the coen- zyme (Fig. The pyridoxal phosphate then pulls electrons away from the bonds around the -carbon. The result is transamination, deamination, decarboxylation, -elimination, racemization, and -elimination, depending on which enzyme and amino acid are involved. The coenzyme FH4 is required in certain amino acid pathways to either accept or donate a one-carbon group. Chapter 40 describes the reactions of FH4 in much more detail. Pyridoxal phosphate covalently attached to an amino acid substrate. The arrows indicate which bonds are broken for the various types of reactions in which pyridoxal phos- phate is involved. The X and Y represent leaving groups that may be present on the amino acid (such as the hydroxyl group on serine or threonine). The coenzyme BH4 is required for ring hydroxylations. The reactions involve molecular oxygen, and one atom of oxygen is incorporated into the product. BH4 is important for the synthesis of tyrosine and neurotransmitters (see Chapter 48). AMINO ACIDS DERIVED FROM INTERMEDIATES OF GLYCOLYSIS Four amino acids are synthesized from intermediates of glycolysis: serine, glycine, cysteine, and alanine. Serine, which produces glycine and cysteine, is synthesized from 3-phosphoglycerate, and alanine is formed by transamination of pyruvate, the product of glycolysis (Fig. When these amino acids are degraded, their car- bon atoms are converted to pyruvate or to intermediates of the glycolytic/gluco- neogenic pathway and, therefore, can produce glucose or be oxidized to CO2. Serine In the biosynthesis of serine from glucose, 3-phosphoglycerate is first oxidized to a 2-keto compound (3-phosphohydroxypyruvate), which is then transaminated to form phosphoserine (Fig. Phosphoserine phosphatase removes the phosphate, forming serine. The major sites of serine synthesis are the liver and kidney. Serine can be used by many tissues and is generally degraded by transamination to hydroxypyruvate followed by reduction and phosphorylation to form 2-phospho- glycerate, an intermediate of gycolysis that forms PEP and, subsequently, pyruvate. Glucose Glycine Serine also can undergo -elimination of its hydroxyl group, catalyzed by serine dehydratase, to form pyruvate. Regulatory mechanisms maintain serine levels in the body. When serine levels fall, 3-Phosphoglycerate Serine serine synthesis is increased by induction of 3-phosphoglycerate dehydrogenase and by release of the feedback inhibition of phosphoserine phosphatase (caused by higher lev- els of serine). When serine levels rise, synthesis of serine decreases because synthesis 2-Phosphoglycerate Cysteine of the dehydrogenase is repressed and the phosphatase is inhibited (see Fig. Glycine Pyruvate SO4 Glycine can be synthesized from serine and, to a minor extent, threonine. The major route from serine is by a reversible reaction that involves FH4 and pyridoxal phos- Alanine phate (Fig. Tetrahydrofolate is a coenzyme that transfers one-carbon groups Fig. Amino acids derived from interme- at different levels of oxidation. It is derived from the vitamin folate and is discussed diates of glycolysis.

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Does the child wear orthotics and for how much time If the orthotics are being worn but are ineffective discount 25mg sildenafil with visa erectile dysfunction prevalence, other treatment is indicated buy 25mg sildenafil visa erectile dysfunction zinc deficiency. Some adolescents refuse orthotic wear because of cosmetic concerns and this has to be considered. A good idea of the child’s function at home and in the community is important to consider. Does the child use an assistive device in the community A good idea of the child’s function at home and in the community is important to or school? This, again, is a part of understanding the function of the child, and a child using a wheelchair as primary ambulation is hard to change to ambulation. The family will not be happy with any treatment outcome if their concerns are not addressed. What are the child’s concerns if he or she is mature Also, addressing the child’s concerns, especially if he or she is an adolescent, is enough to have an opinion? These concerns are often different from the parents’ concerns. What have been the previous musculoskeletal surgeries Future treatment has to consider prior treatment. A specific set of parameters that also relate to motor development should be monitored (Table 7. For a more in-depth gait analysis, the use of the Gross Motor Function Measure (GMFM) is recommended. The whole GMFM measure can be used, but we prefer to use only the fourth dimension, which is the standing dimension of the GMFM that focuses on standing and transitional movements. These movements are of most interest to orthopaedists, espe- cially in children who are being evaluated for gait problems. This measure gives a numerical score and is useful as a general measure of children’s bal- ance, motor control, and motor planning. Other more specific tests of balance or motor planning are available, but currently these are mainly used for research purposes and not for standard diagnostic clinical evaluations. Motor Control Individual muscle motor control is tested on routine evaluation by noting in general terms if children can make steps on command, move the foot on command, and stand on one leg with the hand held. For more detailed gait analysis, an assessment of each major muscle group in the lower extremities should be made. For example, a child is asked to extend the knee, and if knee extension is performed as an isolated movement, it is rated as good. If the knee can be extended, but only associated with joint motion, such as hip extension or plantar flexion with the knee extension, it is rated as fair. If no voluntary focal movement of the specific joint occurs, it is rated as poor mo- tor control (Table 7. Children with cognitive limitations that are so severe that they do not understand the concept cannot be rated. Parameter Full gait analysis Routine clinical evaluation Global Motor Function GMFM may use only standing dimension. Record what general functions, such as single leg and Balance (GMFM) standing, hopping, or running, a child can do. Muscle strength Do manual muscle testing of the major muscles of the Record general comments of good to poor strength. Passive joint range of Do goniometer measurements of all major joint motions Record ROM of hip abduction, rotation, popliteal angle, motion in lower extremity. Record ROM of hip abduction, knee extension, ankle dorsiflexion with knee extended rotation, popliteal angle, knee extension, ankle and knee flexed at each outpatient clinic visit. Motor control Record active motor control of major lower extremity Make a general comment of motor control, such as good motions. Motor Control Grading Score Description Good Patient can isolate individual muscle contractions through the entire available passive range of motion upon command.

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Community-based prevalence studies (5–7) reveal that the proportion of PD patients with dementia ranges from 30 to 40% discount 75mg sildenafil overnight delivery erectile dysfunction 5k. The incidence of dementia in a community-based cohort of PD patients was found to be 95 25mg sildenafil fast delivery erectile dysfunction causes tiredness. Most studies have shown that older age at onset of PD, longer duration of PD, and greater severity of motor symptoms are positive predictors of the development of dementia. Pathology The pathological findings in demented PD patients have been quite varied and inconsistent. This variability is due in part to selection bias (clinically unusual cases are more likely to come to autopsy) and in part to varying histopathological techniques used to study these brains. A consistent feature of the older pathological studies of PD dementia is a significant loss of neurons in the nucleus basalis of Meynert associated with extensive reductions of choline acetyltransferase in cortical regions (9,10). These findings suggest that the dementia of PD is in part related to the same cholinergic defect that is seen in Alzheimer’s disease. Further supporting a Copyright 2003 by Marcel Dekker, Inc. However, the plaque and tangle counts did not correlate precisely with the presence or absence of dementia or with the degree of depopulation of the nucleus basalis. More recent pathological studies have focused on the association of cortical Lewy bodies with dementia in PD. The advent of ubiquitin immunohistochemistry led to the recognition that the number of cortical Lewy bodies correlated positively with the degree of cognitive impairment (13). The discovery of the alpha-synuclein gene mutation in an Italian PD kindred (14) led rapidly to the development of alpha-synuclein immunohis- tochemistry, which even more reliably identifies both cortical and brainstem Lewy bodies. Recent studies have now shown that cortical Lewy bodies positive for alpha-synuclein are the most sensitive and specific markers for dementia in PD, with amyloid plaques and neurofibrillary tangles being present only inconsistently (15,16). One group has calculated that cortical Lewy bodies (as identified with alpha-synuclein immunostaining) are 91% sensitive and 90% specific for dementia in PD (15). They used the Mayo Health Sciences Research Database to identify all patients seen between 1976 and 1997 who had definite PD (defined as two of three cardinal features and a levodopa response) and who later (after at least 4 years from onset of PD) developed dementia. Thirteen such patients had brain autopsy material available; one patient was found to have progressive supranuclear palsy, and the other 12 had findings consistent with diffuse or transitional Lewy body disease. Of great importance, the histories of these patients revealed that while most had a favorable response to levodopa early in the clinical course, the benefit from this drug was later lost as the dementia became severe later in life. The authors have demonstrated that for the most common scenario of PD dementia in which dementia develops late in the clinical course and is associated with a relative diminution of the levodopa response, the pathological substrate is widespread cortical Lewy bodies. Clinical Presentation In light of the presence of both Lewy body and Alzheimer pathology in the brains of demented PD patients, some authors have suggested that PD and AD are not really different diseases but merely extremes of a spectrum of neurodegeneration (18). They raised the intriguing possibility that those Copyright 2003 by Marcel Dekker, Inc. Regardless of whether this view is correct, it is clear that the timing of symptom onset and severity of dementia and parkinsonism factor heavily into the clinical diagnosis assigned during life. At the risk of oversimplifying the situation, patients presenting early with dementia who later develop mild to moderate parkinsonism are usually diagnosed with AD (after other identifiable causes of senile dementia are excluded) while the converse presentation (early prominent levodopa-responsive parkinsonism with later onset of dementia) fits with a clinical diagnosis of Parkinson’s disease. Diffuse Lewy body disease (DLB) is diagnosed when dementia and parkinsonism develop together with fluctuating cognitive status and formed visual hallucinations (19). Classically, the dementia of PD has been described as a ‘‘subcortical’’ dementia in which psychomotor retardation, memory abnormalities, cognitive impairment, and mood disturbances are considered cardinal features (20). A number of studies comparing patients with PD dementia to those with AD matched for dementia severity have suggested important differences in the clinical features of the dementia in these two conditions. They also reported that demented PD patients were more impaired on executive tasks than AD patients. Others have been less impressed with these differences and have suggested that the dementia of PD has substantial ‘‘cortical’’ features in common with AD (23). A major problem with such comparative studies is the inherent difficulty in matching the groups for dementia severity. If scores on neuropsychometric testing are used to match the groups, then obviously no differences in the test results will be found. Similarly, it is difficult to match the groups on disability because the motor defects seen in PD patients contribute to disability, making it difficult to tease out the contribution of the dementia per se to the overall disability of the patient.

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