There are two di¤erent time scales corresponding to the two following functions: activity (milliseconds) and synaptic modulation (seconds) 200mg cialis extra dosage with amex. For each of them discount cialis extra dosage 60 mg fast delivery, the structural hierarchy is given in terms of neurons (axon hillocks) 200mg cialis extra dosage for sale, synapses buy discount cialis extra dosage 40mg online, and channels (figure 7. Functional interactions are for activity, the membrane po- tential c that propagates from one neuron at r0 to another at r and for synaptic mod- ulation, the postsynaptic potential F at s, or equivalently, synaptic e‰cacy m. Let the density of neurons at r be rðrÞ and the density connectivity between the neurons at r0 and the synapses at s0 be p 0 0. For synapses at s in neurons at r, the density connec- r s tivity prs is determined by the connectivity in the postsynaptic neuron between spines and soma where the membrane potential is measured. A similar hierarchical structure in the synapses in which the channels are distributed leads to a similar field equation for the functional interaction at this level, say g, given the anatomy of the system. Operators are determined by the explicit analytical relationship between input and output: Pðr0Þ applies to c; that is, it transforms the action potential c into the postsynaptic potential f using the synaptic e‰cacy s in the activity time scale. The structure of the field equation is such that these operators correspond to an input- output block model, that is, a nonlinear transfer function. PCðrÞ applied to post- synaptic potentials f, and then integrated over all the pathways gives rise to the membrane potential at r. The neural field equations derived using the S-propagator formalism for the c-field at ðr; tÞ in the time scale fTg, and with the unknown factor Kðs0; s; dÞ (in case of linearity for the propagators P) for the f-field equation at ðs; tÞ in the time scale ftg, are given by Eq. Each of these equations corresponds to a level of functional organization. These two levels of functional organization are coupled by a relationship, for example: Et A ½ti; ti þ Dt: sðtÞ¼sðtiÞ¼mðtiÞ or hsðtÞiDtðtiÞ¼mðtiÞ; ð7:8Þ where Dt is the time unit defined experimentally and hsðtÞi denotes the average value of sðtÞ taken over this time interval. Application of the Formalism The Cerebellum and the Coordination of Movement Clinical studies have established that the coordination of movement depends on specific circuits in the cerebellar cortex and on highly organized interactions among several nuclei in the brain (Thompson, 1986, 1990). Over the past few years, the adaptive control of movement has been extensively investigated through mathemati- cal studies of artificial as well as biological neural networks (Barto et al. Much e¤ort has gone into determining the mechanisms of pattern learn- ing and recall; in other words, toward defining the conditions of stability in dynamic systems. Mathematical Modeling of Neuromimetic Circuits 143 The cerebellar cortex is a network of networks. An element of the cerebellar cor- tex, called the Purkinje unit, consists of five types of cell: the Purkinje cell, which has the largest number of dendrites; the granular cells; the Golgi cell; and the basket and stellar cells. The geometry of the cortex allows us to define (approximately) a Pur- kinje unit. Consider a granular cell (gc) belonging to the unit containing the nearest Purkinje cell it is in contact with. Then (gc) may be considered to belong to a specific unit labeled k if the following conditions are satisfied: (gc) synapses with at least one Purkinje cell of unit k, the distance between (gc) and the Purkinje cells is the smallest distance between (gc) and any Purkinje cell it is in contact with outside the unit, and (gc) synapses with at least one Golgi cell of unit k. The basket and stellar cells included in the unit are those that are in contact with the Purkinje cell of unit k. This unit may be divided into two subsystems, the granular cell subsystem (GCS), that is, the neural network composed of granular cells (figure 7. The Purkinje unit, which is the repeating unit of the cerebellar cortex, is thus the basic element of a hierarchical network. We know that the function of the cerebellar cortex is the learning and recall of spatiotemporal patterns (Thompson, 1994). Therefore, a satisfactory transformation of the cerebellum would Y F X1... The nonlinear transformation is F, and for signals before transformation, lower-case letters are used (e. Inputs are the outputs Xi of the granule cell subsys- tem (on the right). Berger require that the output of the system remain within physiological limits and that the modifiable synaptic weights be asymptotically stable to ensure the learning process. The conditions necessary for the stability of the observed function call for adequate values of geometric and physiological parameters, that is, the number of cells in- volved, the value of the synaptic weighting, and so on. These conditions thus con- tribute to the determination of the Purkinje unit.
Repetitive from altered spinothalamic and spinocerebel- practice under a variety of conditions may in- lar inputs to primary motor cortex purchase 60mg cialis extra dosage free shipping. The spino- duce many of the neurochemical buy generic cialis extra dosage 40 mg, trophic generic cialis extra dosage 200mg visa, and cerebellar pathway runs along the outer rim of morphologic changes in the spinal cord that spinal cord white matter buy cialis extra dosage 200 mg otc, so it may be partially underpin proposed neural repair strategies. These experiments are OF REPAIR TO CLINICAL TRIALS often given a breathless sound byte by the me- dia, which raises expectations about an immi- The number of failed phase 2 and phase 3 hu- nent cure for paralysis. Clinicians often express rodent models of injury,320–324 as of the year the misconception that basic research with an- 2002, at least 65 randomized clinical trials in imals is easier to carry out, more scientifically stroke, 25 in cerebral trauma, and 8 in SCI have rigorous, and permits the measurement of not led to better outcomes for patients. Only more clearcut outcomes than any possible de- one or two acute interventions for each type of sign for a clinical trial in patients. Investigators ventional studies in animal models have sys- and pharmaceutical companies have tried to tematic flaws that may mislead clinicians about find ways to explain the failures to translate ro- the potential for efficacy in human trials? Overview of Animal Models of Neural Repair for Spinal Cord Injury MODELS Rodents Standard drop weight contusion Focal demyelination Focal compression Root avulsion Hemisection—dorsal or lateral cord Transgenic mouse gene manipulation Tract ablation Nonhuman primates Tract ablation Root avulsion MEASURED OUTCOMES Gross tissue preservation Histology Label and count new axons, growth cones, boutons Morris water maze Label and count new neurons Activity meter Behaviors (often videotaped evaluations) Robotic device measures—kinematics, torques Forepaw use—feeding, locomotion, climbing Sensation—tail flick analgesia Hindlimb use—BBB scale for qualitative locomotion; footprint placement; grid, beam or ladder walk BBB, open-field Basso, Beattie, Bresnahan score. Also, microstimulation of the motor cortex that represents the paw and 1. In animal re- distal arm reveals a much smaller representa- search, vendors provide healthy, highly inbred tion for the wrist in Fischer rats than in Long- rats and mice. Intensive training of paw reaching and strain, same age, weight, and gender. The CNS of a gle gene mutation permits the study of a spe- neonate may still be developing, allowing for cific phenotype, such as absence of an in- far greater opportunity for morphologic adap- hibitory molecule in the matrix of the cord or tations than may evolve in an adult. In human excessive production of a particular neu- trials, the study population has great variabil- rotrophin. Different inbred murine strains re- ity in genes, age, sex, medication taken, and spond quite differently to ischemia or trauma premorbid health. Such heterogeneity in hu- and most mice respond differently than most mans may not be overcome by simply using rats in terms of injury and regenerative cas- large sample sizes and some obvious inclusion cades. Indeed, large sample sizes will not be cannot assume that a human subject will have practical for trials of neural repair strategies. Even in rats, significant interspecies and in- Laboratory rodents are kept in separate trastrain variablity may foil the results of stud- cages in most instances, so they do not injure ies carried out in different laboratories. Although the rodents animals depend largely upon rules that evolved came from the same strain, different vendors from interactions with natural environments. Indeed, although highly in- than others to develop a glial scar after the bred transgenic mice are wonderful tools for same SCI that produces a large barrier to ax- the study of the effects of specific genes, envi- onal regeneration in another species. Differ- ronmental conditions have led to a reversal of ences in injury-induced T-cell responses and in those gene effects. The biologic effects of an in- Biologic Adaptations and Neural Repair 131 tervention and its behavioral outcomes have, produce a uniform lesion with particular fea- for example, been repeatedly confounded by tures that represent a partial equivalent to hu- differences in caloric intake, whether sponta- man damage, the model may not serve a study neous or secondary to the experimental of repair. Some injury models originally aimed to search for repair mechanisms may yield results evaluate NMDA receptor-mediated neuronal in rats that are not clearly relevant to people. Most hu- For example, I discussed trials in which run- man lesions from stroke or TBI do not even ning in an enriched environment increased involve the hippocampus, unless global hypo- production of a variety of neurotrophins, as perfusion or hypoxia develop. The AMPA recep- ural environments evolved to find food and tors of oligodendrocytes mediate cytotoxic in- shelter by scurrying about as they vigilently at- jury, not NMDA receptors. Aimless tions across tissues help account for the failure exercise, such as jogging on a treadmill or wan- of human clinical trials of interventions for dering in a shopping mall, may be much less NMDA receptor-mediated injury. Differences of an inducement for the stimulation of BDNF in receptor types within regions of the brain and other growth factors, genes that promote and spinal cord and further changes brought plasticity, memory molecules, or neurons in pa- on by injury will also have to be reckoned with tients with neurologic diseases. If such stimu- in the translation of models to human neural lation is part and parcel to human learning, as repair. Among other queries, the reader of an it seems, learning paradigms will need to be experiment carried out with animals or cell cul- designed for rehabilitation that stimulate genes tures must always wonder how similar the re- and cells.
The therapeutic ratio for a drug relates key there is to translate from the effect scale the positive effect to the negative effect buy 100 mg cialis extra dosage with mastercard. Also assume cialis extra dosage 200mg otc, for the time being cheap 200 mg cialis extra dosage otc, ple doses order cialis extra dosage 100mg overnight delivery, and when two treatments (drug plus that the dose–response curves for positive and inhaler) are to be compared, at least one of negative effects are parallel. Then a therapeutic them can in general be varied on some kind of ratio for this drug of 2 means that twice as dose scale. Thus we can define prove that dose a of a treatment A is therapeuti- the therapeutic ratio for drug A as TR(A)= cally equivalent to a treatment B (dose need not ED50(side-effect)/ED50(effect). If we have two be specified), we can study doses a/2 and 2a of A drugs, we can define the relative therapeutic (not dose a! By assuming a lin- index of A to B as TR= T R(A)/T R(B),which ear dose–response relationship (versus log-dose) is equivalent to the ratio ρ(effect)/ρ(side-effect), for A, we can estimate the dose of A that has the where ρ is the relative dose potency for the same effect as treatment B. Now, if the 90% confidence limit for the relative therapeutic index, but also confidence RESPIRATORY 395 intervals to the estimate, by assessing the relative means together with straight line approximations dose potencies. Moreover, we can define the to the dose–response curves for each variable. From it only requires that the dose–response curves these straight lines we can estimate the relative for efficacy are parallel and the dose–response dose potency, as discussed earlier, for each curves for the side-effect are parallel. We can variable separately: estimate the therapeutic index by combining effects from two studies – one on efficacy and 95% Confidence one on side-effect, but better still is to obtain all Variable ρ limits the information in one study. The first problem to solve is the precise FEV 147 65, 534 1 definition of outcome variables, both positive and S-potassium 60 41, 91 negative. It is therefore Thus we see that in terms of efficacy, the long- important that the precise objective is spelt out acting drug A is almost 150 times more efficient and the outcome variables related to this. A is 60 times more potent, so from this data we see that the relative therapeutic index is estimated Example: Estimating the Relative Therapeutic to be 146. To obtain confidence Index limits is somewhat involved since we need to take In order to assess the relative usefulness of a into account the covariation of the two variables. The study was of crossover design with single- The conclusion from this is, that in terms of the dose administrations and serial measurement of variables of this analysis treatment A is estimated both variables taken. Of course, this result index we need many patients, relatively speaking, is not better than data. We crossover study was designed with the following can repeat the analysis by only incorporating the single dose treatments: placebo, 6 µg, 24 µg doses 24 and 72 µgofA and 1800 µgofB for and 72 µgofdrugA and 200 µg and 1800 µg serum potassium. Each treatment period consisted of a single dose administration which was OTHER ISSUES followed for 4 hours and from each experimental sequence the maximal FEV1 value and the PHASE IV minimal S-potassium value was extracted for statistical analysis. We with competitor products in order to demonstrate see (period and baseline adjusted) treatment the advantages of the new product. This has been 396 TEXTBOOK OF CLINICAL TRIALS 124 100 98 120 96 94 116 92 112 90 88 108 86 104 84 100 101 102 103 100 101 102 103 Dose Dose Figure 22. Adjusted mean values for each treatment and outcome variable discussed in previous chapters and will not be devices, consultations with physicians, emer- repeated here. In addition to that, special safety gency room visits and hospitalisations. Indirect costs, defined as lost productivity, call for large-scale studies in order to study some include time off work or school, either patient rare event. Indirect costs may account for up to 50% of PHARMACO-ECONOMICS the cost of asthma. There of managing controlled asthma, whereas emer- should thus be room for a significant cost gency room and hospital costs can be assumed reduction by improving disease control. Assuming this to The costs can, basically, be divided into be about 75% of the total cost, the major part three categories (usually only the first, although of the costs of asthma appear to be a result of sometimes also the second category is measured): inadequately controlled disease. Direct costs, defined as health care resources can be done by patient education39 and prophy- consumed, include costs associated with drugs, lactic therapy. As an example of the latter, it RESPIRATORY 397 has been demonstrated that the introduction of support in answering the question on whether high-dose inhaled steroids in patients with severe the additional effectiveness (or quality of life or asthma reduced the number of days of hospital- asthma control) can justify the extra costs. This is so because tic therapy, like inhaled steroids, might decrease the outcome of a new treatment will depend on these costs. Some of these cases are probably due to clinical trials it is thus important to measure these bad compliance with treatment regimens.
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