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Some prac- Twenty-year follow-up of a randomized trial tical improvements in the continual reassessment comparing total mastectomy cheap cytotec 100 mcg overnight delivery symptoms vitamin d deficiency, lumpectomy discount cytotec 100 mcg mastercard medications to treat anxiety, and method for phase I studies. Stat Med (1995) 14: lumpectomy plus irradiation for the treatment of 1149–61. Effects of adjuvant tamoxifen and strategies for phase I trials with delayed patient of cytotoxic therapy on mortality in early breast outcome. First, childhood cancer is com- ated epithelial tissues, like the aerodigestive tract paratively rare. According to statistics released or breast or prostate, do not occur in children. Stated another way, the average cancer seen, the host differences related to age annual age-adjusted incidence rate for all child- necessitate that paediatric studies of anti-cancer hood cancers is 150 per million persons, aged drug dosage, efficacy and safety are needed. This is under 2% of the total cancers Recognising that children are not just small adults diagnosed in the USA. Despite the rarity and and that special considerations apply, the FDA notwithstanding the spectacular success in treat- has issued regulations mandating the testing of ment of paediatric cancer, compared to inci- new drugs in paediatric patients. Only accidents and firearms kill more chil- long-term consequences of therapy for children dren than cancer. Further, the distribution of can- are also potentially much greater than in adults, cer diagnoses in children is very different from as the therapy can interfere with normal growth that in adults. There are a number of major and development, leaving them exposed for Textbook of Clinical Trials. Green  2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 102 TEXTBOOK OF CLINICAL TRIALS decades at risk for serious sequelae, major Table 7. Children diagnosed with cancer generally also Leukaemia have less of a problem with competing mortality a Infant ALL :50 risks, when compared to adult cancer. B-Cell (SIg+)ALLa:45 In fact, in some situations, such as randomised ANLLa: 300 Phase III trials of new regimens compared to already effective front-line treatments, nation- Lymphoma wide multi-institutional trials are a necessity. Accrual duration in childhood trials may be con- Brain Tumours siderably longer than a corresponding adult trial. Astrocytoma: 140 However, since clinical practice closely approx- Medulloblastoma: 140 Glioma: 70 imates that of the ongoing study, it is rare that Ependymoma: 35 progress from an external source ever renders the study question obsolete. For example, this would occur if the impact of A is highly dependent Embryonal upon whether B is given or not. Hepatoblastoma: 65 Germ Cell Tumours: 25 Based on previous trials and internal registry data of the major national paediatric coopera- aALL = Acute Lymphoblastic Leukaemia AML = Acute Non-Lymphoblastic Leukaemia tive oncology groups, Table 7. COG was formed in Canadian hospital with a childhood paediatric 2000 by the merger of the Pediatric Oncol- haematology/oncology division belongs to COG. A special section dealing with the patients to member institutions of COG and par- ethical aspects and unique considerations affect- ticipation in clinical trials. The final section is devoted to a nosed from 1989–91, and compared observed look into the future. According to this survey, 92% of children aged less than 15 years in the US Statistically and clinically significant improve- received their care at a CCG or POG institu- ments have been achieved in all major forms tion, thereby providing at least a mechanism of childhood cancers through conduct of well- approximating population-based studies. How- organised single institution and cooperative group ever, the ratio (O/E) for 15–19 year olds was clinical trials which have resulted in sequen- only 0. Most probably on urinary screening for elevated levels of the inclusion benefit related to participation in catecholamines, a notable exception. In the following section, examples are tices and procedures, on-study review of radio- cited where translational research has affected therapy port films, and close monitoring for toxi- the design of paediatric cancer trials. It is beyond the scope of this chapter to review the • Adjuvant chemotherapy improves survival from 20% to 70% in non-metastatic osteosarcoma of treatment advances achieved through clinical trials the extremity. Paediatric investigators at Success in treatment of the most common Stanford, beginning in 1970, first pioneered com- form of paediatric malignancy, acute lymphoblas- bined modality treatment for children with HD tic leukaemia (ALL), has been most gratifying. Advances have been all high-grade, diffuse malignancies, differing achieved by many single institutions and coopera- markedly from the distribution of histologic types tive groups treating childhood leukaemias, includ- typically seen among older adults.

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Fusimotor drive Co-contractionsmayinvolvegreaterfusimotordrive Presynaptic inhibition of Ia terminals to the contracting muscles than occurs during iso- lated contractions producing equivalent EMG (see Presynaptic inhibition on Ia terminals on FCR p purchase cytotec 100mcg line symptoms 0f food poisoning. The increased drive would be required to motoneurones is decreased to a similar extent dur- maintain an effective Ia feedback despite increased ing separate wrist flexion or extension and during presynaptic inhibition on Ia terminals (see above) generic cytotec 200 mcg with amex treatment yeast in urine, co-contraction of wrist muscles, whether associated and would be in line with the fusimotor activa- with tonic wrist abduction or a power grip (R. Conversely, during power grip the effects of the interposed reciprocal inhibition. Because only 2% of the cor- Spinal mechanisms ticospinal (but 15% of the rubrospinal) cells have During co-contraction reciprocal inhibition monosynaptic excitatory projections on both antag- between antagonistic ankle muscles is depressed onistic wrist flexors and extensors (Fetz et al. Increases in recur- be mediated through common driving of cortico- rent inhibition and presynaptic inhibition on Ia motoneuronalcellswhichthemselvesinnervateonly terminals (see above) contribute to an active inhi- one set of synergists, or through an oligosynaptic bition. However, the relationship between these pathway with diverging projections on antagonis- mechanisms and the strength of the contraction tic motoneurones. The propriospinal system would is different: reciprocal Ia inhibition is maximally be a good candidate since, apart from propriospinal depressed even at low co-contraction levels, but neurones that project to both motoneurones and recurrent inhibition and presynaptic inhibition Ia inhibitory interneurones, others project only to on Ia terminals increase with the strength of co- motoneurones and are assumed to subserve the co- contraction. Moreover, there are no projections contraction of antagonists (Alstermark et al. This implies that motor cortex have provided evidence for differen- other mechanisms contribute to the decoupling tial cortical control of flexion–extension movements of motoneurones and interneurones mediating and co-contractions (Nielsen et al. Joint stiffness measured during voluntary contrac- (i) Some cortical cells are active during co- tion as the stretch-induced torque increment, i. Strong output to be modulated in parallel in wrist flexors co-contraction results in greater stiffness of the limb and extensors during co-contractions. Thus, in a co- about the joint than with activity of any of the two contraction intended to produce a power or preci- antagonistic muscle groups separately. This holds sion grip in a given wrist position, Renshaw cell dis- true at all joints investigated: elbow, interphalangeal charge produced by the dominating contraction of joints of the fingers, thumb, and ankle (Feldman, either muscle (extensors or flexors) can automati- 1980; Akazawa, Milner & Stein, 1983;Carter, Crago & cally adjust the contraction of the antagonist. Ithasbeenshown (ii) The absence of projections from Renshaw at ankle level that the increased stiffness during co- cells to inhibitory interneurones mediating non- contraction occurs too early after application of the reciprocal group I inhibition between wrist flexors external load to be mediated through a reflex mech- and extensors enables a parallel increase in the out- anism (Nielsen et al. This is not of the greater stiffness during co-contraction with possible at hinge joints (see above). Control of the stretch reflex at hinge joints Stretch reflex Because co-contraction of the different muscles operating at the ankle will stabilise the joint in dif- The findings that increased recurrent inhibition is ficult tasks (see above), there may be no need for not required and that presynaptic inhibition is not additional stiffness through an active stretch reflex. Under these conditions, itated (or at least unsuppressed) recurrent inhibi- several non-exclusive mechanisms might prevent tion (see above), will prevent oscillations and clonus the stretch reflex braking into oscillations. Control of the excitation at ball joints (ii) Tactile cutaneous receptors provide critical information for the control of grip force according to Renshaw cells the physical properties (weight, slipperiness, shape A different control of the motor output is likely and mass distribution) of the manipulated object. Unlike the quadrupedal increased during tonic co-contractions, this does digitigrade stance of the cat, humans balance on not imply that the strong corticospinal facilitation their skeleton as an inverted pendulum (see below). The control of body sway during quiet stance (iv) Similarly, the fact that recurrent inhibition and of responses to destabilising perturbations to may be suppressed during strong co-contraction at stance may involve different mechanisms and are wrist level does not mean that the flexible control therefore treated separately. Normal quiet standing Because the centre of gravity is maintained over Conclusions arelatively small base of support, human stand- The main cause of the greater joint stiffness dur- ing posture is inherently unstable. Body instabil- ing co-contraction is simply that more muscles are ity, therefore, has a high potential energy, leading to then active, not an increase in stretch reflex activ- the priority of equilibrium control during almost all ity. The decoupling of motoneurones and group I motor tasks including quiet standing. This trasts with the linkage seen during simple flexion- posture requires a background triceps surae activity, extension movements, and allows the simultaneous which is, however, not continuous, and little mus- activation of antagonistic motoneurone pools to be cular activity is needed to maintain balance (Bon- relatively unhindered by reciprocal inhibition. The main body sway occurs in the decoupling results from different drives for the two sagittalplane,wheretherearequasi-randomsponta- types of movements from higher centres. In addi- neous alternating movements of the centre of mass, tion, the different organisation of the connections which happen mostly at the ankle joint (e. Ithasthereforebecomecommontoregardthe increased recurrent inhibition and presynaptic inhi- body as an inverted pendulum pivoted at the ankle bition of Ia terminals. Smallersway movements also occur in the frontal plane, mostly at hip level, where they are stabilised by hip abductor– Maintenance of bipedal stance adductor activity (Deniskina & Levik, 2001).

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Is the model of injury and repair in ro- had been used and how applicable the partic- dents similar enough to what happens to peo- ular model of injury and repair will be to the ple? Scooping out cortex in an ablation model majority of clinical injuries and of mechanisms for stroke may produce the same amount of tis- of restitution or substitution buy cytotec 100 mcg visa medications via g-tube. Is the brain and spinal cord of a rat or cade of molecules and gene expression that fol- mouse simply a thimble-sized version of the hu- low injury will differ between ablation and man brain? The surface area of the brain of a ischemia purchase 100mcg cytotec visa symptoms before period, as described in Experimental Case mouse is 1/1000th that of the human brain. The milieu for mechanisms of re- Studies of axonal regeneration in rats and mice pair will differ as well with the type of lesion consider an extension of axons for a few mil- induced. A cortical infarct will not elicit the limeters to a centimeter as exuberant growth. Axons in human brain to moderate cortical injury that resolves in sev- or spinal cord may have to grow from several eral days. A human injury may include contu- centimeters to over a meter to reach targets. These differences in pathology and the Signaling molecules that fashioned the CNS persistence of injury-induced cascades in hu- during embryogenesis and development never mans make interventions for neuroprotection had to manage such long distance tours. Very different fective dose-response curve for biologic inter- mechanisms and outcomes may unfold in hu- ventions in man? A repair intervention in mice mans over time as molecular cascades interact. Since humans will need to produce complex behav- the injury model was originally developed to iors such as goal-directed walking and manip- 132 Neuroscientific Foundations for Rehabilitation pair intervention in the rat or mouse and the timing of the same intervention in patients? Medications may have con- founding effects on an intervention for repair. The need for immunosuppressants after a transplant of cells may have adverse effects on regenerative capacity. In addition, animals do not take drugs for hypertension, diabetes, pain, seizures, and other ailments. How will adjunct drugs and associated diseases affect the human equivalent of an animal intervention, especially over the weeks and months needed for some types of repair? Adjuncts may alter the ab- sorption or metabolism or bioavailability of the experimental intervention. Also, an interven- tion in a rodent model is derived from dose- response curves for serious toxicity such as death. Human trials almost invari- man brain compared to a whole brain and spinal cord from ably use doses of drugs that are far lower than a rat and the even smaller CNS of a mouse. The differ- what worked in the animal, to avoid lesser tox- ences in size carry over to the magnitudes of difference in icities such as confusion, agitation, somno- the distance a regenerating axon or migrating neuronal precursor would have to travel to reach a target location. Inverted U-shaped dose- As another comparison, human neocortex is approximately response curves are not uncommon, in which 100 times larger than that of the commonly studied squir- low doses and high doses fail to work and in- rel monkey. A dose that is most likely resentation for the forearm 12 mm2 in the monkey com- pared to approximately 1100 mm2 in humans. If the drug intervention developed in an an- imal model must pass the human blood-brain ulation of objects. The number of fibroblasts barrier, will penetration in humans be enough that secrete a neurotrophin or the number of to give the same effect as in the rodent? Neu- implanted stem cells that must migrate and rotrophins that worked in rodents had no ap- reintegrate will very likely be far greater for tri- parent effect when given subcutaneously to treat als with human subjects. The delivery tive simplicity of structures that mediate the of cells and substances into the region of inter- modest cognitive functions of rodents makes est poses far more invasive and injurious poten- any anatomical reconstruction for a simple- tial to humans than to rodents. Better delivery minded behavior in the rodent of unclear ap- vehicles will be needed for patients. What were the measures of efficacy in ro- executive function impairments. Is the timing of an intervention after in- relevant to outcomes in patients? In the rodent, rather pair intervention for patients may start in a bed limited behaviors are tested; physiologic, his- of injury-induced molecules and tattered ar- tologic, and molecular measures take prece- chitecture that differs from the state of affairs dence. Given that most rodents use such specific surrogate markers for behav- show quite a bit of improvement within hours ioral outcomes. For many injury of stepping from the BBB scale after SCI may models, the Morris water maze serves as the appear impressive statistically, but would this primary motor and spatial memory outcomes change in function be relevant to bipeds after test.

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