By C. Campa. University of Indianapolis.
The first enzyme of this pathway buy cheap vantin 100 mg online treatment for dogs cracked pads, glucose 6-phosphate dehydrogenase buy generic vantin 100 mg online infection zombie movie, oxidizes the alde- hyde at C1 and reduces NADP to NADPH. The gluconolactone that is formed is rap- idly hydrolyzed to 6-phosphogluconate, a sugar acid with a carboxylic acid group at C1. The next oxidation step releases this carboxyl group as CO2, with the electrons being transferred to NADP. This reaction is mechanistically very similar to the one catalyzed by isocitrate dehydrogenase in the TCA cycle. Thus, two moles of NADPH per mole of glucose 6-phosphate are formed from this portion of the pathway. NADPH, rather than NADH, is generally used in the cell for pathways that require the input of electrons for reductive reactions because the ratio of NADPH/NADP is much greater than the NADH/NAD ratio. The NADH generated from fuel oxidation is rap- idly oxidized back to NAD by NADH dehydrogenase in the electron transport chain, so the level of NADH is very low in the cell. NADPH can be generated from a number of reactions in the liver and other tissues, but not the red blood cell. For example, in tissues with mitochondria, an energy-requiring transhydrogenase located near the complexes of the electron transport chain can transfer reduc- ing equivalents from NADH to NADP to generate NADPH. NADPH, however, cannot be directly oxidized by the electron transport chain, and the ratio of NADPH to NADP in cells is greater than one. The reduction potential of NADPH therefore can contribute to the energy needed for biosynthetic processes and provide a constant source of reducing power for detoxification reactions. CHAPTER 29 / PATHWAYS OF SUGAR METABOLISM: PENTOSE PHOSPHATE PATHWAY, FRUCTOSE, AND GALACTOSE METABOLISM 533 2. RIBOSE 5-PHOSPHATE FROM THE OXIDATIVE ARM OF H O THE PATHWAY C To generate ribose 5-phosphate from the oxidative pathway, the ribulose 5-phos- H phate formed from the action of the two oxidative steps is isomerized to produce HO ribose 5-phosphate (a ketose-to-aldose conversion, similar to fructose 6-phos- phate being isomerized to glucose 6-phosphate; see section III. The H C OH ribose 5-phosphate can then enter the pathway for nucleotide synthesis, if needed, H or can be converted to glycolytic intermediates, as described below for the nonox- CH OPO2– 2 3 idative phase of the pentose phosphate pathway. The pathway through which the Glucose 6–phosphate ribose 5-phosphate travels is determined by the needs of the cell at the time of its synthesis. The Nonoxidative Phase of the Pentose dehydrogenase NADPH + H+ Phosphate Pathway The nonoxidative reactions of this pathway are reversible reactions that allow inter- O mediates of glycolysis (specifically glyceraldehyde-3-P and fructose-6-P) to be C converted to five-carbon sugars (such as ribose-5-P), and vice versa. The needs of H the cell will determine in which direction this pathway proceeds. If the cell has pro- O HO duced ribose-5-P, but does not need to synthesize nucleotides, then the ribose-5-P will be converted to glycolytic intermediates. If the cell still requires NADPH, the H C OH ribose-5-P will be converted back into glucose-6-P using nonoxidative reactions H C (see below). And finally, if the cell already has a high level of NADPH, but needs 2– CH2OPO3 to produce nucleotides, the oxidative reactions of the pentose phosphate pathway will be inhibited, and the glycolytic intermediates fructose-6-P and glyceraldehyde- 6–Phosphoglucono– δ–lactone 3-P will be used to produce the five carbon sugars using exclusively the nonoxida- tive phase of the pentose phosphate pathway. THE CONVERSION OF RIBOSE 5-PHOSPHATE TO H+ GLYCOLYTIC INTERMEDIATES The nonoxidative portion of the pentose phosphate pathway consists of a series O O– of rearrangement and transfer reactions that first convert ribulose 5-phosphate to C ribose 5-phosphate and xylulose 5-phosphate, and then the ribose 5-phosphate H and xyulose 5-phosphate are converted to intermediates of the glycolytic path- HO way. The enzymes involved are an epimerase, an isomerase, transketolase, and transaldolase. H C OH The epimerase and isomerase convert ribulose 5-phosphate to two other 5-carbon H C OH sugars (Fig. The isomerase converts ribulose 5-phosphate to ribose 5-phos- CH OPO2– 2 3 phate. The epimerase changes the stereochemical position of one hydroxyl group (at 6–Phosphogluconate carbon 3), converting ribulose 5-phosphate to xylulose 5-phosphate. Transketolase transfers 2-carbon fragments of keto sugars (sugars with a keto NADP+ group at C2) to other sugars. Transketolase picks up a 2-carbon fragment from xylu- 6–phosphogluconate + dehydrogenase NADPH + H lose 5-phosphate by cleaving the carbon–carbon bond between the keto group and CO2 the adjacent carbon, thereby releasing glyceraldehyde 3-phosphate (Fig. The 2-carbon fragment is covalently bound to thiamine pyrophosphate, which transfers CH2OH C Xyulose 5-phosphate has recently been identified as an activator of protein phos- H phatase 2A (PP2A).
Although there are multiple causes of the initiation of planovalgus buy cheap vantin 200mg online antibiotik jerawat, the development of the deformity occurs over a long time frame 200 mg vantin with visa treatment for dogs ear mites, which is important in the treatment planning and interpretation of the outcome of the treatment. Natural History Children with diplegia usually start standing and cruising around 2 years of age. This standing is predominantly on the toes with an equinovarus foot po- sition. For many of these children, the foot is clearly in hindfoot valgus with a decrease in the medial longitudinal arch when they stand foot flat. Another group of children stand early with severe planovalgus feet, and even when they stand on the toes, they are still in valgus in the hindfoot. From 2 to 6 years of age, there can be a dramatic change in these foot positions, with some of the severe planovalgus feet completely correcting (Case 11. This tendency for improvement of planovalgus feet in young children has been previously noted,23 but the natural history of planovalgus feet has not been studied. In general, by 7 years of age, the planovalgus position will be as good as spon- taneous correction can provide. This spontaneous correction probably is due to improving motor control, which starts to make a positive impact in con- trolling foot position because it occurs most in relatively high-functioning ambulatory children with diplegia. In middle childhood, the planovalgus foot position tends to be stable with little change. By adolescent growth, al- most all children with some degree of planovalgus have some progression of the deformity, and this is the time when the foot usually becomes painful. In general, the pain comes from high pressure over the medial bony prominence, which is the talar head and navicular tuberosity. Often, the increased dis- comfort is associated with rapid weight gain and increased crouching. Pathologic Deformity in Ambulators Although it is important to understand the etiology and natural history of planovalgus feet, the treatment also depends on understanding the poorly defined pathologic anatomy. The anatomy of the subtalar joint is complex but well described in many anatomy texts. This anatomical description is based on the acetabulum pedis concept, which defines the talus as the ball structure articulating a cup structure made up of the calcaneus inferiorly and the navicular anteriorly that functions as an acetabulum113,114(Figure 11. In this anatomical concept, the foot articulates through the subtalar joint as a relatively rigid structure. The articulation of the talonavicular joint, middle facet, and anterior facet of the calcaneus makes a very elliptical acetabulum. Continuing to the posterior talus though, the posterior facet has an articulation that is out of the plane, with a condyle on the calcaneus that articulates with a plateau on the talus 744 Cerebral Palsy Management Case 11. He had just started independent ambu- lation, and his parents’ primary concern was related to his severe flat feet. On physical examination the ankle dorsiflexion was to 20° with knee flexion and with knee extension. There was more spasticity on the left, but otherwise there was not much difference between right and left. The feet were clearly in severe planovalgus (Fig- ure C11. He was placed in articulated AFOs to pro- vide support for the feet. Over the next several years, the feet spontaneously improved, but by age 5 years, he had developed significant in-toeing and equinus on the left side. During this development, the tone and movement limita- tions on the right almost disappeared, and he developed a clear hemiplegic pattern. There was complete resolution of the planovalgus on the left with a mild residual on the right (Figure C11. At this time, he had a left-side- only femoral derotation osteotomy, rectus transfer to the sartorius, and lengthening of the hamstrings and gastroc- nemius. One year after this surgery his right foot remained completely normal and the left foot had a mild planoval- gus (Figure C11. This case shows the difficulty in predicting the outcome of feet in young children. The se- vere early planovalgus of the left foot completely resolved without any direct treatment, and the right foot made substantial improvements.
D5 and the rat D1b are species homologs because they map to the same chromosomal locus (26) order 100 mg vantin with mastercard virus blocker. D5 and D1b have a 10-fold higher afﬁnity for dopamine generic vantin 200mg overnight delivery antibiotic for dogs, suggesting that D5 receptors are activated at neurotransmitter concentrations that are subthreshold for the D1 receptor (21). The D2-like receptors bind butyrophenones and benzamides with high afﬁnity and bind benzazepines with low afﬁnity (10,15,16). The pharmacological distinction of dopamine receptor subtypes holds tremendous potential for treatment of nervous system dysfunction. Dopamine receptors are the primary targets for the pharmacological treatment of PD, schizophrenia, and several other nervous system disorders. Presently used drugs have signiﬁcant limitations that are in part due to their nonselective binding to many receptor subtypes. For example, drug-related side effects, including dyskinesias and delirium, are frequent and important problems in parkinsonian patients receiving levodopa or dopamine agonist therapy. These adverse effects result from stimulation of dopamine receptors in motor and cognitive circuits, respectively (21). Conversely, treatment of schizophrenia with dopaminergic antagonists, although intended to Copyright 2003 by Marcel Dekker, Inc. Clearly, drugs aimed at molecular subtypes of dopamine receptors offer the potential for speciﬁc therapeutic interventions for motor and psychiatric disorders of the nervous system. Although there are agonists and antagonists that are highly selective and that can discriminate between D1-like and D2-like receptor subfamilies, there are few agents that are highly selective for the individual receptor subtypes (Table 1). Some progress has been made in the development of antagonists for the D2 receptor family. For the D1/D5 receptor subtypes, there are currently no compounds that exhibit high selectivity. Thus, the high overall sequence homology between dopamine receptors of the same subfamily have made it difﬁcult to develop speciﬁc ligands that do not interact with related receptors. The high afﬁnity of the ‘‘atypical’’ neuroleptic, clozapine, for D4 receptors and the low level of D4 receptor expression in the striatum and high levels in the cerebral cortex and certain limbic brain areas led to the suggestion that the antipsychotic properties of the neuroleptics may be mediated through blockade of D4 receptors, whereas the side effects may be mediated through blockade of D2 receptors (15,60). This hypothesis was strengthened by the low incidence of extrapyramidal side effects for clozapine. However, clozapine at therapeutic doses also blocks many other types of receptors in addition to D4 receptors making it difﬁcult to draw deﬁnitive conclusions. For example, clozapine binds to muscarinic acetylcholine receptors and is 20- to 50-fold more potent at these sites than at D2 receptors (for review, see Ref. By determining fractional occupancies of receptors bound by therapeutic drug levels, it has been demonstrated that the dominant factor for deciding if a particular antipsychotic drug will elicit parkinsonism is whether it binds more tightly or more loosely than dopamine at the D2 receptor subtype. Thus, for those antipsychotic drugs that elicit little or no parkinsonism, it appears that the high endogenous dopamine in the human striatum must outcompete the more loosely bound neuroleptic at the striatal D2 receptor subtype. Dopamine less readily displaces the more hydrophobic radioligands of the haloperidol type, providing an additional correlate between the magnitude of in vivo competition with endogenous agonists and parkinsonism. The separation of antipsychotic drugs into ‘‘loose’’ and ‘‘tight’’ binding to D2 receptors is consistent with the observation that catalepsy induced by olanzapine and loxapine (more loosely bound than Copyright 2003 by Marcel Dekker, Inc. T Properti es ofD opam i ne R eceptorS ubtypes D l e l e R eceptorsubtype A i no aci ds C h rom osom e q p q p p þ S econd esseng er cA P cA P cA P ch annel cA P K ch annel a ch annel ch annel C a m R S tri atu i ppocam pus K i dney S tri atu ucleus A ccu bens erebralcortex S electi v e ag oni sts S S rom ocri pti ne PA T — B utaclam ol Pram i pexole Perg oli de Perg oli de R opi ni role R opi ni role PD S electi v e antag oni sts S S S pi perone S pi perone S pi perone R aclopri de R aclopri de lozapi ne S ulpi ri de S ulpi ri de N afodotri de S ata from R efs. Taken together, these observations suggest that D2 blockade may be necessary for achieving antipsychotic action. This suggestion is in keeping with the observation that many patients will suddenly relapse when stopping clozapine, perhaps due to a sudden pulse of endogenous dopamine arising from emotional or physical activity which displaces the loosely bound neuroleptic from the receptor. Clinical dosing schedules can be adjusted to obtain sufﬁcient but low occupancies of D2 receptors in order to minimize the development of parkinsonism. The psychosis caused by levodopa or bromocriptine can be readily treated by low doses of either clozapine or remoxipride (62), since there is very little endogenous dopamine to compete with the antagonist. Further studies are needed to determine whether newer antipsychotic drugs with low afﬁnity for D2 receptors and with low risk for parkinsonism will cause less tardive dyskinesia.
Little literature addresses the incidence and prevalence of dementia due to depression in PD and whether dementia in patients with comorbid depression improves with treatment and resolution of depressive symptomatology (89) cheap 200mg vantin with amex bacterial cell wall. Etiological inferences about an individual PD patient’s dementia vantin 200 mg amex antibiotic neomycin, when the dementia is accompanied by marked depression, should probably be deferred until such time as the depression has been adequately treated and neuropsychological revaluation has been performed. Recent attention has also been drawn to the need to distinguish depression from apathy in PD (90). Apathy may occur in as many as 45% of patients with PD and, like depression, may be associated with executive deﬁcits (91). Anxiety Anxiety disorders are seen in approximately 40% of patients with PD (92). Despite their frequent occurrence and contribution to morbidity and caregiver burden (10), anxiety symptoms in PD have received relatively little attention, perhaps because they overlap with symptoms of depression and medication effects and are thus difﬁcult to measure (93). The relationship between anxiety and cognition in PD has received virtually no attention. Self-reported trait anxiety was negatively related to performance on a neuropsychological screening battery, accounting for approximately 70% of the variance. The authors posit that anxiety may partly explain the association between depression and cognition in PD, although replication of their ﬁndings and additional large-scale studies are needed. EFFECT OF PHARMACOLOGICAL AND SURGICAL TREATMENTS ON COGNITIVE FUNCTIONS IN PARKINSON’S DISEASE Modern treatment algorithms for patients with PD consist of both pharmacological and surgical intervention strategies (95). Neuropsycholo- gical evaluation can facilitate objective measurement of cognitive, neuro- behavioral, emotional, and quality-of-life outcomes associated with treatment as well as aid in determinations regarding treatment (96). Pharmacological Treatments Anticholinergics and Cholinesterase Inhibitors Anticholinergic medications used to treat motor symptoms in PD potentially produce adverse effects on memory, executive functions, as well as global cognitive abilities. In placebo-controlled studies, Bedard and colleagues found anticholinergics to induce executive deﬁcits in PD but not in control participants (97,98). Although anticholinergic-induced memory decrements are observable even in patients without preexisting cognitive impairments (99), Saint-Cyr (100) found that confusional states are more likely to be induced by anticholinergics in patients with preexisting cognitive impairment. Thus, anticholinergics should be avoided in elderly patients who are susceptible to developing confusional states (101). Cholinesterase inhibitors were initially used sparingly and rarely in PDD and LBD. There is increasing recognition that cholinesterase inhibitors such as rivastigmine may improve not only cognition, but also neuropsychiatric symptoms in both conditions, and that these agents are well tolerated by patients with PD (102,103). Levodopa and Dopamine Agonists Findings concerning the impact of levodopa on cognitive functions are inconsistent, with studies showing improvement, decrements, and an Copyright 2003 by Marcel Dekker, Inc. Despite these inconsistent ﬁndings, evidence is accumulating that levodopa has short-term effects on certain aspects of memory and executive functions, perhaps as mediated by disease stage. For example, Kulisevsky and colleagues (105) reported short-term improve- ments in learning and memory, visuoperception, and certain executive functions associated with dopamine-replacement therapies but stated that these cognitive improvements were not maintained over time. That levodopa affects only certain components of cognitive functions is consistent with the ﬁndings of Fournet and colleagues (107), who reported poorer performance only on working memory tasks in patients with PD after withdrawal from levodopa, and of Lange et al. Levodopa’s rather selective effects on working memory and certain executive functions may be related to its mediation of dorsolateral frontal cortex blood ﬂow in response to executive task activation (109). Selegiline Selegiline, a selective monoamine oxidase-B inhibitor, has been hypothe- sized to exert a neuroprotective effect in PD by way of reducing physiological stress associated with MAO-B oxidation of dopamine. Along with improvement in motor functions, several small, uncontrolled studies have found selegiline to be associated with improved global cognitive functioning, P300 latencies, and/or memory in patients with PD (110–113). In contrast, selegiline was reported not to signiﬁcantly impact cognition in a large sample of untreated patients with early PD (114). Surgical Interventions Ablative Surgeries Ablative surgical interventions for treatment of PD involve stereotactic procedures in which lesions are placed in the globus pallidus, thalamus, or subthalamic nucleus to reduce motor symptoms. Cognitive and emotional outcomes after ablative procedures for PD in the 1950s and 1960s are sparsely documented. Wilkinson and Troster¨ (115) pointed out that outcomes in early and more recent studies are difﬁcult to compare for a Copyright 2003 by Marcel Dekker, Inc. In general, however, modern studies reveal that ablative procedures such as pallidotomy, thalamotomy, and subthalamotomy (especially unilateral) are relatively safe from a cognitive perspective. With regard to unilateral pallidotomy, declines in verbal ﬂuency performance have been reported in approximately 75% of outcome studies that included a measure of verbal ﬂuency (48,116–118). Postoperative decrements on measures of attention, memory, and executive functions (typically mild and transient) have been reported occasionally, and signiﬁcant cognitive complications even more rarely (for review, see Refs. Preexisting cognitive impairment, advanced age, and dominant hemisphere surgery have been proposed as increasing the risk for postoperative cognitive decline.
There does not seem to be a place for this ap- proach in the leg discount 100mg vantin visa antibiotics kellymom, because walking by nature requires both limbs and is an enforced-use function discount vantin 100 mg without prescription treatment for dogs with food poisoning. This approach to enforced-use therapy in children with cerebral palsy is new, and many questions need to be answered before specific recommendations for routine use can be formulated. No data cur- rently exists to determine at what age child this works best, what level of physical disability responds best or worst, how long the benefit lasts, if there is a role for repeating the immobilization of the unaffected arm, or how long the arm should be immobilized. Based on current knowledge, enforced-use therapy looks like a useful treatment intervention, and many of the questions will likely be answered over the next several years to allow much better def- inition of the specific protocol and outcome expectations. A Current Physical Therapy Approach Current pediatric physical therapists are moving toward an intellectual con- struct of being a coach or teacher of a child’s motor system instead of a molder of the brain as the child develops. This modern approach more of- ten uses the understanding of dynamic motor control to structure tasks and change motor patterns. This new approach requires a broader view of the child and has to include an understanding of how he or she is functioning in the home, family, and school environment. This approach also places the therapist in a much better position to bridge the gap between the educational and medical systems. Another important focus required in this role as teacher or coach is a realistic assessment of the child’s ability. For example, teachers have to routinely make realistic assessments concerning the functional abil- ity of a child to learn specific material. Normal children have a widely vari- able ability to learn a level of mathematics at each age level, and teachers have to be aware of the level of the individual child. Some children in fourth grade may still be struggling to learn addition, while others are ready to learn geometry, but none would be ready to do calculus. In a community popula- tion of children, many will never be able to develop enough math skills to learn advanced calculus. Using this same analogy, the physical therapist needs to have a good ability to understand what the possibilities are for each individual child, while at the same time continuing to motivate the child to improve his motor skills. Understanding the child’s functional possibilities means the therapist can avoid frustrating them with unreasonable demands and help their parents understand reasonable functional goals for the child. The strategy for physical therapy is very dependent on age and functional ability. Added to the age appropriateness, the therapy plan should have specific objective, quantifiable short-term goals. Such goals include improv- ing how long the child can stand on one leg, learning to jump, using a walker independently, or improving a specific amount on a global measure such as the Gross Motor Function Measure (GMFM). These specific short-term goals can help the therapist, child, and parents judge progress. Also, this type of goal setting is an important part in the reimbursement of therapy services 160 Cerebral Palsy Management from insurance companies. Another part of the treatment plan includes teach- ing the family how to handle the child, teaching the child and family an ex- ercise program, assessing the general function of the family in the home environment, and helping the family understand the long-term expectations of the child. A difficult aspect of the therapist’s treatment plan is integrating the child’s other medical treatments with fragmented medical care. The time constraint, which does not give the therapist time to attend medical ap- pointments, leaves many therapists to gather this information from parents. Obtaining medical notes from physician visits can be another mechanism for the therapist to stay informed. The treatment program at this age, which is carried out by either a physical or occupational therapist, usu- ally includes a combination of stimulation through handling the children, sensory stimulation through positional changes, and getting the children into correct seating. Many of the techniques used in infant stimulation ap- proaches are combinations of NDT, sensory motor, and sensory integration approaches. Therapy frequency at this age may be two or three times a week; however, care should be taken not to place too high a burden on new par- ents with many medical visits. We have seen one very frustrated mother who was scheduled to see 21 medical practitioners for an 18-month-old child who had been discharged from an intensive care unit (Table 5. This num- ber is far too much of a burden, and the therapists are in a good position to sense this and help parents decide what is reasonable. This is especially help- ful when there are frequent team-generated treatment plans saying, for ex- ample, that a child should have four physical therapy treatment sessions in a week; however, due to the therapists’ schedules, he will be scheduled to see three different therapists in 1 week. This is the worst kind of fragmented care, and it is very frustrating to parents.
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