By M. Rhobar. Samuel Merritt College.
Enzyme Reaction Uridine-cytidine kinase Uridine ATP S UMP ADP Cytidine ATP S CMP ADP Deoxythymidine kinase deoxythymidine ATP S dTMP ADP Deoxycytidine kinase Deoxycytidine ATP S dCMP ADP 756 SECTION SEVEN / NITROGEN METABOLISM – Free Bases Nucleoside O O C Uracil Ribose 1-phosphate Uridine CH2 or or CH Cytosine Cytidine + – Pi H3N COO Aspartate Deoxyribose 1-phosphate H2N Thymine Thymidine C O Pi O P Carbamoyl Fig buy seroquel 200 mg with visa. Salvage reactions for pyrimidine phosphate nucleoside production seroquel 50 mg with visa. Thymine phosphory- lase uses deoxyribose 1-phosphate as a –O O substrate cheap 200mg seroquel with amex, such that ribothymidine is rarely C formed buy seroquel 200mg low price. Conversion of carbamoyl phosphate and aspartate to UMP. The defective enzymes in hereditary orotic aciduria are indicated ( ). CHAPTER 41 / PURINE AND PYRIMIDINE METABOLISM 757 C. Regulation of De Novo Pyrimidine Synthesis O Base P O P O The regulated step of pyrimidine synthesis in humans is carbamoyl phosphate syn- thetase II. The enzyme is inhibited by UTP and activated by PRPP (see Fig. Thus, as pyrimidines decrease in concentration (as indicated by UTP levels), CPS- NDP HO OH II is activated and pyrimidines are synthesized. As cells approach S-phase, CPS-II becomes more sensitive to PRPP acti- SH NADP+ thioredoxin vation and less sensitive to UTP inhibition. At the end of S-phase, the inhibition by SH UTP is more pronounced, and the activation by PRPP is reduced. These changes in thioredoxin ribonucleotide the allosteric properties of CPS-II are related to its phosphorylation state. Phospho- reductase reductase rylation of the enzyme at a specific site by a MAP kinase leads to a more easily acti- S vated enzyme. Phosphorylation at a second site by the cAMP-dependent protein NADPH thioredoxin S kinase leads to a more easily inhibited enzyme. THE PRODUCTION OF DEOXYRIBONUCLEOTIDES H For DNA synthesis to occur, the ribose moiety must be reduced to deoxyribose (Fig. This reduction occurs at the dinucleotide level and is catalyzed by ribonu- dNDP HO H cleotide reductase, which requires the protein thioredoxin. Reduction of ribose to deoxyri- side diphosphates can be phosphorylated to the triphosphate level and used as pre- bose. Reduction occurs at the nucleoside cursors for DNA synthesis (see Figs. A ribonucleoside diphos- The regulation of ribonucleotide reductase is quite complex. The enzyme con- phate (NDP) is converted to a deoxyribonucle- tains two allosteric sites, one controlling the activity of the enzyme and the other oside diphosphate (dNDP). Thioredoxin is oxi- controlling the substrate specificity of the enzyme. ATP bound to the activity site dized to a disulfide, which must be reduced for activates the enzyme; dATP bound to this site inhibits the enzyme. Substrate speci- the reaction to continue producing dNDP. ATP bound to the substrate site activates the reduction of N a nitrogenous base. The dUDP is not used for DNA synthesis; rather, it is used to produce dTMP (see below). Once dTMP is pro- duced, it is phosphorylated to dTTP, which then binds to the substrate site and induces the reduction of GDP. As dGTP accumulates, it replaces dTTP in the sub- strate site and allows ADP to be reduced to dADP. This leads to the accumulation of dATP, which will inhibit the overall activity of the enzyme. These allosteric changes are summarized in Table 41. When ornithine transcarbamoylase dUDP can be dephosphorylated to form dUMP, or, alternatively, dCMP can be is deficient (urea cycle disorder), deaminated to form dUMP.
The temporal dynamics of the circuits relative to the behaviors they are thought to mediate is critically important buy seroquel 50 mg without a prescription. Recordings are made from 500 ms before to 500 ms after movement onset over multiple trials generic 50mg seroquel free shipping. Changes in neuronal activity in the normal condition begin approximately 200 ms before movement onset and reach a new baseline or steady state approximately 300 ms after movement onset buy cheap seroquel 50mg on-line. Information can traverse the basal ganglia-thalamic-motor cortex within 6 cheap 50 mg seroquel with mastercard. It is possible for information to have traversed the circuits 63–78 times during the course of a 500-ms-long behavior. Thus, the sequential nature of the one-dimensional ‘‘push-pull’’ dynamics of the current model cannot begin to account for such a complex reentrant system. Rather, the function or dysfunction associated with disorders of the basal ganglia must be reconceptualized into a distributed and parallel system of re-entrant oscillating circuits. The basic units of function and therefore the subject of analyses are no longer the individual structures of the cortex, basal ganglia, and thalamus but rather the basal ganglia-thalamic-cortical circuit as a whole. Evidence in support of a parallel and distributed system within the time frame of behavior is seen in recordings of MC and Pt neuronal activity during the course of a wrist flexion and extension task (29). Utilizing a method that relates changes in neuronal activity to behavioral events (30), it was possible to determine which behavioral event was best related to the change in neuronal activities. Thus, neurons in MC and Pt were identified that were preferentially related to the appearance of the go signal or movement onset. Neurons responding to the go signal typically became active before those related to movement onset (Fig. However, go signal– related neurons in the Pt became active at nearly the same time as those in the MC. Similarly movement onset–related Pt neurons became active at the same time as movement onset–related neurons in MC. EPISTEMOLOGY OF CURRENT MODELS OF PHYSIOLOGY AND PATHOPHYSIOLOGY Scientists and philosophers repeatedly warn that attention to how some- thing is known often is as important as what is known. Numerous aphorisms have been coined for such warnings, such as ‘‘we see what we are prepared to see’’ or ‘‘when all you have is a hammer, everything becomes a nail. What follows is such a discussion of our current conceptual approaches to systems neurophysiology that may help to understand why specific questions have been asked rather than others and the origins of the assumptions that underlie those questions. This effort will be very important in creating the new theories of basal ganglia physiology and pathophysiol- ogy. FIGURE 13 The time of onset of neuronal activity of go-signal– and movement onset–related neurons in motor cortex and putamen demonstrating nearly virtually simultaneous onset of activity change. Reasoning by Anatomy The proposition is offered that in conceptual approaches to systems neurophysiology are the results of anatomical studies to the greatest degree followed by clinical observations of disease states. The actual incremental increases in our understanding offered by direct recordings of neuronal activities during the course of behavior have contributed relatively little in comparison. Indeed, there have been circumstances where recordings of neuronal activity would appear contradictory to the inferences drawn from the anatomy (11,26). These contradictory findings have received scant attention. This is not to discount the importance of anatomical understanding or research. In fact, anatomical data provide a critical reality check because any theory of systems neurophysiology cannot contradict validated anatomical fact. However, the anatomy can only provide information in the widest sense in that its limits are only the maximum possibilities and the physiological realities are likely to be only a subset of the anatomical possibilities (31). Further, as the complexities of anatomical organization and interconnections increase, it will become increasingly difficult to predict function from the structure. This is particularly true if, as is likely, the interactions are highly nonlinear. Any new model would require as its basis the same anatomical facts that underlie the current anatomical model. However, as will be seen, there may be emergent properties of the new dynamical models that are not intuitive from the current anatomical model and, therefore, represent such a quantitative change as to be qualitatively different. Hierarchical Processing The macro-neuron approach leads to structures that are then linked with a very specific directional aspect, for example, the cortex projects to Pt, which in turn projects to GPi, which projects to the VL thalamus.
Sometimes individuals can tolerate more extension on one day and less on the next discount seroquel 50mg with visa. If the spasticity is weaker or the children are less than 10 years old seroquel 100mg generic, a low-temperature plastic orthotic that is molded to the flexor surface of the elbow with straps around the olecranon is simpler and much cheaper to construct order seroquel 200 mg free shipping. Usually order seroquel 300 mg line, these or- thotics are fabricated by an occupational therapist, and they can also be easily modified with a low-temperature heat gun if more or less flexion is re- quired. There has been a recent commercial promotion to use elastic hinges at the elbow, which have continuous passive stretch on the elbow. No ob- jective data exist to support this concept, and the standard teaching is that spastic and elastic do not mix. This saying comes from the usual finding that a constant elastic stretch on a spastic muscle usually continues to initiate the spasticity. A fixed stretch will allow the muscle to slowly relax and stop con- tracting. However, this dogma is not well substantiated by objective testing. Pronation contractures are very common in the forearm of children with spasticity. There are no orthotics that can effectively control a spastic fore- arm pronation deformity, although trying circumferential wraps are usually not uncomfortable for the child with a mild deformity (Figure 6. Hand and Wrist Orthoses Wrist and finger flexion combined with thumb abduction and flexion are very common deformities in children with CP. Wrist extension orthoses are used mainly after surgical reconstruction to protect the tendon transfers for some additional months after cast immobilization has been discontinued. Usually, these orthotics are volar splints, which maintain the wrist in 20° to 30° of wrist extension and are worn full time (Figure 6. These wrist splints seldom provide a functional benefit to children and are usually poorly tol- erated for long-term use. In children or adolescents with hemiplegia, there is a major cosmetic concern about the appearance of the limb. The orthotic provides no functional gain and is very apparent; therefore, it is usually cos- metically rejected. Most children with good cognitive function object to wearing a wrist orthosis for more than a short postoperative period. A dor- sal wrist extension splint is sometimes better tolerated; however, there is no 184 Cerebral Palsy Management Figure 6. Using a soft foam material with A Velcro closures, a circumferential wrap can be designed to provide some supination (A) stretch along with wrist dorsiflexion and thumb abduction (B). Many children with strong pronation spasticity do not tolerate these wraps. B apparent improvement in function over the volar splint. The benefit of the dorsal splint is that it covers less of the palm and volar surface of the wrist and should therefore make more sensory feedback available to children dur- ing functional use. The disadvantage of the dorsal splint is that the force in the palm to extend the wrist is applied over a much smaller surface area, and if high force is required because of strong spasticity, the skin will often be- come irritated or develop breakdown. Resting Splints Resting hand splints, in which the wrist and fingers are all maximally ex- tended to the comfort level of individual children, are good splints to help stretch the forearm muscles during the adolescent growth period. This splint may be made with a dorsal or volar forearm component (see Figure 6. The dorsal forearm component is easier to stabilize on the arm; however, it is often harder for caretakers to apply. The opposite is true if a volar forearm component is used. The resting hand splint can incorporate thumb abduc- Figure 6.
Severe Foot Deformities Severe foot deformities in adolescence can cause pressure and skin breakdown over bony prominences cheap seroquel 300 mg with visa. Typically discount seroquel 300mg overnight delivery, these deformities are either severe varus or severe valgus foot deformities cheap 100 mg seroquel fast delivery. The use of soft moccasin shoes and suspend- ing the feet should be the primary treatment buy 50mg seroquel with mastercard. The feet can be suspended by building an enclosed suspension-type footrest that looks like a padded open box, which prevents the lower extremities from swinging freely and swinging off to the side but does not put any pressure on the soles of the feet. Seating During Transportation Safe seating of individuals with disabilities has only attracted attention since the 1980s. Most young children, up to age 2 years, can be transported in standard children’s car seats; then when they are too large and no longer fit, adaptive seats are required. Generally, these seats are of a similar design to regular infant car seats but are much larger (Figure 6. There are several companies that advertise that the standard wheelchair seat can be removed, placed on the automobile seat, and used for seating during vehicular mobility. From a practical perspective of the care- takers, this option does not work because these seats cannot be placed into the car with these children in the seats. These seating systems tend to be large and difficult to handle in and of themselves. Use of this system means that children have to be taken out of the wheelchair, the wheelchair has to be dis- assembled, and the seat has to be secured to the car seat, then the children have to be placed into the car seat again. The problem is that there is no place to put the children while the wheelchair is being disassembled except to lay them on the ground. Because of these difficulties, a separate car seat is re- quired when children need this level of seating support for safe travel. For children over 20 kg in weight who have adequate trunk and head control, seating in a regular car seat is fine. The other option is to transport these chil- dren in wheelchairs; however, this requires a specially adapted van. The car seats for children with disabilities are very similar to those sold for children without disabilities, except the spe- cial needs car seats are designed for much larger children. Special Wheelchair Vans and Lifts As children become adult sized, especially if they are fully dependent for lift transfers, routine transportation in an automobile becomes very difficult. It is easier to use a van that is equipped with a wheelchair lift or ramp. The wheelchair lift is the best solution but also is the most expensive, and this lift is not considered a medical device by medical insurance companies in the United States. Therefore, it is often difficult for families to afford to purchase a van and have a wheelchair lift installed. Also, when individuals are trans- ported sitting in a wheelchair, approved tie-down systems and wheelchair frames that are approved for tie-down have to be used. These approved sys- tems currently include most standard wheelchairs except for many strollers, which are typically not approved for tie-down or transportation of individ- uals in a vehicle. Special Seating and Positioning There are many different chairs manufactured to provide special seating for children with disabilities. Although there may be some functional advantage to using seats with barrel shapes in which children straddle the seat,29 these special seats have relatively limited use. These special barrel or saddle seats are probably most beneficial if used in a school or therapy environment, where they can be shared by many children. Another problem that many par- ents have with all the different special seats is the limited space in the home. Before long, parents begin to feel that their house looks like a storeroom filled with medical equipment. A correctly adapted wheelchair can fill all these children’s seating needs, although having other places where they can sit in the home has aesthetic value and may provide them with differ- ent levels of stimulation. The amount of additional seating should be deter- mined by the needs of the individual child and the living environment of the family.
Alternately seroquel 50 mg line, many disorders of intermedullary metabolism have acute insults during toxic events before the diagnosis has been made 50mg seroquel overnight delivery. With proper management buy cheap seroquel 50mg line, these disorders become static and mimic similar children with CP order 100 mg seroquel. These metabolic disorders often require very specific management pro- tocols during surgery. An example of such a condition is glutaric aciduria type 1, which presents with infants who are normal. When an infant expe- riences a stress, such as a childhood illness with a high fever, an acidosis de- velops that causes damage to the brain, especially the putamen and caudate areas. This insult leaves the child with a wide range of spastic and movement disorders, often with significant dystonia. However, these children must be prevented from becoming acidotic during operative procedures by infusing high levels of glucose, usually using a 10% dextrose solution as the intravenous fluid. A wide variety of infections leave children with permanent neurologic deficits. Most of these deficits are static and therefore definitely fall into the CP diagnosis group. Prenatal and neonatal viral infections are the most com- mon infectious cause of CP. Cytomegalovirus (CMV) leaves 90% of children with mental retardation and deafness, but only 50% develop CP or motor defects. Children who develop congenital rubella infections very commonly will have mental retardation; however, only 15% develop CP. In utero vari- cella zoster infection causes high rates of CP. This same high rate is seen in lymphacytic choriomeningitis, which is a rodent-borne arenavirus. All these conditions cause neurologic insults that are static and should be treated as CP. Infections with human immunodeficiency virus (HIV) may cause neuro- logic sequelae; however, this is a progressive encephalopathy and these chil- dren should be treated anticipating a very short life expectancy. The most common parasite is Toxoplasma gondii, which is an intracellular parasite whose most common host is the household cat. With aggressive medical treatment, the infection can be eradicated, and approximately 30% of chil- dren are left with CP and mental retardation. Neonatal bacterial meningitis may be caused by many organisms and may be very severe, with as many as 30% to 50% of survivors having CP. Temporary neurologic deficits are caused by many toxic agents, with al- cohol being the most commonly encountered. Alcohol almost never causes a static neurologic deficit. Also, children with prolonged anoxic events, such as near drowning, near hanging, or near asphyxia, can make remarkable re- coveries. However, when these children do not recover completely, they are usually left with extremely severe neurologic deficits and are among the most neurologically disabled individuals in our practice. These children tend to be relatively healthy and, in spite of severe neurologic deficits, tend to grow and thrive physically with good nursing care. One child in our practice has been ventilator dependent for 10 years from an anoxic event at age 9 months. As noted in the beginning of this chapter, knowing the exact etiology is not always important to care for children’s motor disabilities; however, it is important to understand whether these lesions are static or not. Also, par- ents may be more relaxed if physicians have some understanding of the spe- cific etiology, if known, of their children’s problems. Etiology, Epidemiology, Pathology, and Diagnosis 39 Epidemiology Because of the wide variety of causes of CP, the exact numbers from differ- ent studies do not completely agree. However, there is remarkable similarity in the prevalence across the world, from Sweden in the 1980s with a preva- lence of 2. A report from England, which is representative of many studies, shows that there has not been much change in prevalence over the past 40 years. However, the patterns of CP have shifted more toward diplegia and spastic quadriplegia and away from hemiplegia and athetosis.