By M. Karmok. Louisiana State University at Shreveport. 2018.

    PFK-1 is an allosteric Fructose–2 proven aricept 5 mg,6–bisP enzyme that has a total of six binding sites: two are for substrates (Mg-ATP and fruc- tose-6-P) and four are allosteric regulatory sites (see Fig generic aricept 10mg with mastercard. The allosteric regula- v tory sites occupy a physically different domain on the enzyme than the catalytic site generic aricept 5 mg otc. Vmax When an allosteric effector binds, it changes the conformation at the active site and may activate or inhibit the enzyme (see also Chapter 9). The allosteric sites for PFK-1 include an inhibitory site for MgATP, an inhibitory site for citrate and other anions, an allosteric activation site for AMP, and an allosteric activation site for fructose 2,6-bis- phosphate (fructose-2,6-bisP) and other bisphosphates. Several different tissue-specific 2 4 6 8 10 isoforms of PFK-1 are affected in different ways by the concentration of these sub- ATP (mM) strates and allosteric effectors, but all contain these four allosteric sites. ALLOSTERIC REGULATION OF PFK-1 BY AMP AND ATP ATP and fructose-2,6-bisP. ATP ATP binds to two different sites on the enzyme, the substrate binding site and an increases the rate of the reaction at low con- allosteric inhibitory site. Under physiologic conditions in the cell, the ATP concen- centrations, but allosterically inhibits the tration is usually high enough to saturate the substrate binding site and inhibit the enzyme at high concentrations. This effect of ATP is opposed by AMP, which binds to a separate allosteric activator site (Figure 22. For most of the PFK-1 isoenzymes, the binding of AMP increases the affinity of the enzyme for fructose 6-P (e. Thus, increases in AMP con- centration can greatly increase the rate of the enzyme (see Fig. REGULATION OF PFK-1 BY FRUCTOSE 2,6-BISPHOSPHATE Fructose-2,6-bisP is also an allosteric activator of PFK-1 that opposes the ATP inhi- bition. Its effect on the rate of activity of PFK-1 is qualitatively similar to that of AMP, but it has a separate binding site. Fructose-2,6-bisP is NOT an intermediate Otto Shape has started high-intensity exercise that will increase the production of lactate in his exercising skeletal muscles. In skeletal muscles, the amount of aerobic versus anaerobic glycolysis that occurs varies with intensity of the exercise, with dura- tion of the exercise, with the type of skeletal muscle fiber involved, and with the level of training. Human skeletal muscles are usually combinations of type I fibers (called fast glycolytic fibers, or white muscle fibers) and type IIb fibers (called slow oxidative fibers, or red muscle fibers). The designation of fast or slow refers to their rate of shortening, which is determined by the isoenzyme of myosin ATPase present. Compared with glycolytic fibers, oxidative fibers have a higher content of mitochondria and myoglobin, which gives them a red color. The gastrocnemius, a muscle in the leg used for running, has a high content of type IIb fibers. However, these fibers will still produce lactate during sprints when the ATP demand exceeds their oxidative capacity. The enzyme is therefore named phosphofructokinase-2 tory features match the role of gly- (PFK-2); it is a bifunctional enzyme with two separate domains, a kinase domain colysis in different tissues. At the kinase domain, fructose-6-P is phosphorylated to types of PFK-1 isoenzyme subunits exist: M fructose-2,6-bisP and at the phosphatase domain, fructose-2,6-bisP is hydrolyzed (muscle), L (liver), and C. PFK-2 is regulated through changes in the ratio of activity of show variable expression in different tis- sues, with some tissues having more than the two domains. For example, in skeletal muscles, high concentrations of fructose- one type. For example, mature human mus- 6-P activate the kinase and inhibit the phosphatase, thereby increasing the concen- cle expresses only the M subunit, the liver tration of fructose-2,6-bisP and activating glycolysis. The liver isoenzyme contains a phosphorylation site near the amino units. The C subunit is present in highest lev- terminal that decreases the activity of the kinase and increases the phosphatase els in platelets, placenta, kidney, and activity. This site is phosphorylated by the cAMP-dependent protein kinase (protein fibroblasts but is relatively common to most kinase A) and is responsible for decreased levels of liver fructose-2,6-bisP during tissues.

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    Parameter Full gait analysis Routine clinical evaluation Global Motor Function GMFM may use only standing dimension buy aricept 5mg. Record what general functions 5 mg aricept with amex, such as single leg and Balance (GMFM) standing cheap aricept 5mg on-line, 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. Fair Patient is able to initiate muscle contractions upon command, but is unable to completely isolate the contraction through the entire available passive range of motion. Poor Patient is unable to isolate individual muscle contractions secondary to synergistic patterns, increased tone, and/or decreased activation. Muscle Strength Grading Score Description 1 Contraction visible in the muscle but no visible movement of the joint. Independent community ambulation, uses no assistive device or wheelchair 2. Ambulation with assistive device such as walker or crutches, uses a wheelchair less than 50% of the time for community mobility 3. Household ambulation, uses a wheelchair more than 50% of the time for community mobility 4. Exercise ambulation, uses a wheelchair 100% of the time for community mobility 5. Primary wheelchair user in home and the community, does weightbearing transfers in and out of wheelchair 6. Good Patient is able to isolate individual muscle contraction through entire available passive range of motion upon command. Fair Patient is able to initiate muscle contraction upon command, but is unable to completely isolate contraction through entire passive range of motion. Poor Patient is unable to isolate individual muscle contraction secondary to synergistic patterns, increased tone, and/or decreased or absent activation. Gait 275 Muscle Strength Strength of each major muscle or muscle group in the lower extremity is tested with a 0 to 5 rating scale (see Table 7. Testing the muscle strength in children with spasticity can be difficult. We use the standard term of re- sistance until children cannot sustain the load. The strength levels of mov- ing against gravity may be difficult to determine with spasticity present, as co-contraction severely limits motion, not in the technical sense of muscle weakness, but because the agonist cannot overpower the co-contraction of the antagonist. It is best to stay with a narrow definition of strength assign- ment, but make comments if the strength is strongly affected by spasticity or co-contraction. Strength testing depends on voluntary motion of children who can give their full effort. If the children’s behavior or severe mental retarda- tion preclude this level of cooperation, strength testing cannot be completed. When strength testing children weighing 15 kg compared with adolescents weighing 80 kg, a subjective assessment of their appropriate strength has to be made by the examiner.

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    One recent report of monozygotic PD twins noted that the twins without PD had smoked more (p ¼ 0 generic 10mg aricept with amex. Lewy body inclusions and marked substantia nigra pigmented neuron loss is the hallmark of PD (6 5mg aricept with visa,40 cheap 5 mg aricept with mastercard,134), and presence of LB observed incidentally at autopsy has been regarded as an indication of preclinical PD (40,134). In one autopsy series of 220 brains, incidental LB inclusions had no relation to ever smoking or current smoking (41), nor was there any association between presence of LB and the pack-years of smoking (41). The risk of LB inclusion correlated with the age of the patient (41). If smoking was protective against PD, one would expect that smokers would have a lower frequency of incidental LB. Smoking benefit to PD risk would also be evident in age of onset and rate of progression. Smokers, in fact, have a younger (113,133) onset age, and the progression is not influenced by continued smoking (119). In summary, the literature on smoking and risk of PD remains controversial. In spite of several epidemiological studies suggesting a protective effect, as noted above, several critical pieces of evidence do not support this hypothesis. The reported negative association notwithstanding, it is likely that smoking is a marker of the underlying personality trait (119,120). Studies of the association between PD and the consumption of alcohol have also produced controversial results (120). Lower frequency of PD has been reported in coffee drinkers (117,120). A recent report on diet in twins, on the other hand, indicates that chocolate consumption increases the risk of PD (135). In Western cultures where coffee and alcohol use is common, the incidence of PD is higher than in cultures that do not utilize these substances (77,79). The evidence for coffee, alcohol, or other foods having a protective effect on PD remains weak. Comorbid Psychiatric Disorders Depression Prior to the onset of motor symptoms, depression is more common in PD than in the matched control subjects (114,136–141). Between 30 and 90% of PD patients (142) have been reported to have depression. Depression is frequently unrecognized by patients and caregivers. The available evidence indicates that depression in PD has an endogenous basis in addition to being in reaction to the severity of physical disability (143–146). Dementia and Parkinsonism The reported frequency of dementia in PS ranges from 2% (147) to 81% (148), although most were minimally affected in this study. Some cognitive impairment has been reported even in mild early parkinsonian patients (149,150) and is more likely in depressed patients (146). The reported frequency of dementia varies depending on the patient population and the intensity of the search. Several other studies have reported that approximately one third of PS patients at any given time have dementia (147,152–154). Late age of PD onset is associated with increased dementia risk. Dementia was more common in those with onset after age 60 years than the earlier onset (25% vs. Dementia evolves at a higher rate in PD than in the matched population. In a community- based study, nondemented PD patients (156) were compared with the age-, sex-, and educational level–matched general population.

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    The primary plantar flexors at the ankle are the soleus generic 10 mg aricept otc, which is the largest muscle generic 5 mg aricept overnight delivery, and the gastrocnemius discount 10mg aricept with amex, which has approximately two thirds the cross-sectional size of the soleus. The gastrocnemius is primarily a fast-twitch aerobic type 1 muscle, whereas the soleus is predominated with slow-twitch type 2 fibers. The ankle is the primary power output for normal walking. Stance phase of the ankle is best broken into ankle rockers. First rocker is from foot contact to foot flat and is controlled by an eccentric contraction of the tibialis anterior. Second rocker is the time in which the foot is flat on the ground and the tibia is rolling forward on the fixed foot, a motion that is mainly controlled by an eccentric gastrocsoleus contraction. Third rocker occurs from heel rise until toe-off and is controlled by a concentric contraction of the gastrocsoleus. During this ankle rocker period, the normal period of gait defined in the context of the whole gait cycle also oc- curs. The ankle motion, ankle moments, and power curves also demonstrate the ankle rocker phases. Gait 295 contraction in the gait cycle between the gastrocnemius and soleus is very similar,1 and for practical clinical conditions, especially in children with CP, they can be considered to be contracting at the same time. The secondary plantar flexors are the tibialis posterior, the flexor digitorum longus, the flexor hallicus longus, and the peroneus longus and brevis. All these muscles are predominantly active during terminal stance phase and preswing. The only muscle with consistent activity during weight acceptance is the tibialis posterior. All together, these muscles only generate approximately 10% of the force of the soleus. The main function of these muscles is to stabilize the foot segment. Foot Segment The foot segment is a very complex structure that depends heavily on muscle force to maintain its function as a stable ground contact segment. The func- tion of the subtalar joint is to allow the foot to be stable when the ground sur- face is uneven. The subtalar joint has very complex motions that are discussed in full in Chapter 11. The motion through the subtalar joint is linked to mid- foot motion, especially the calcaneocuboid joint and the talonavicular joints. The importance of these joints for normal gait is to provide stability to the foot. This stability is controlled by muscles, with the tibialis anterior and the peroneus longus working in opposing directions, and the peroneus brevis and the tibialis posterior working in opposing directions. These muscles are primarily responsible for providing mediolateral stability. The long toe flex- ors and extensors can significantly increase the length of the foot segment by stiffening the toes so they also become a stable part of the foot segment. Knee The knee joint connects the thigh and shank segments, and its primary role is allowing the limb to shorten and lengthen. This function greatly improves the efficiency of gait. If the limb is given no ability to change its length, the vertical movement of the center of gravity would be approximately 9. This decreased vertical oscillation represents an energy savings of approximately 50%. The primary knee flexors are the hamstring group including semimembranosus, semitendinosus, biceps femoris, and gracilis.

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