By L. Torn. Massachusetts College of Pharmacy and Health Sciences.

The aim of this chapter is ies of drug metabolism and bio-availability of recombinant gonadotrophins in infertile women buy zoloft 100 mg with visa. An overview Most phase I trials are either directly or indi- of different types of trials is provided and refer- rectly supported by the pharmaceutical industry ence will be made to specific challenges generic zoloft 50 mg online, includ- and involve relatively small numbers of subjects order zoloft 50 mg with mastercard. Examples involving multiple investigations such as blood Textbook of Clinical Trials purchase 25mg zoloft. Green  2004 John Wiley & Sons buy zoloft 100mg online, Ltd ISBN: 0-471-98787-5 338 TEXTBOOK OF CLINICAL TRIALS Table 21. Taxonomy of clinical trials current standard management for the same con- dition in a large trial involving a substantial Phased trials Phase I number of patients. This is also the design used Phase II Phase III for non-pharmacological interventions, which are Phase IV increasing in number. The majority of the tri- als referred to in this chapter are phase III tri- Conduct Pragmatic Explanatory als. This is the point of evaluation following which interventions are introduced into clini- Design Parallel group cal practice. Crossover Factorial Patient preference PHASE IV CLINICAL TRIALS Cluster randomisation Even after a treatment finds general acceptance, Randomisation True Quasi-randomisation unanswered questions about its safety and long- term effectiveness continue to be addressed in the context of phase IV trials. The long-term counts, biochemistry, endocrine profile and liver implications of new methods of treatment of and kidney function tests. Medium- medicine can sometimes be challenging as a large term data have been presented in a number of publications. PRAGMATIC AND EXPLANATORY TRIALS PHASE II CLINICAL TRIALS In terms of design, clinical trials are often described as either explanatory or pragmatic. These are also fairly small-scale investigations Explanatory trials measure efficacy–the benefit a into the efficacy and safety of a drug and require treatment produces under ideal conditions. Sometimes matic trials measure effectiveness–the benefit the they can be employed as a screening process treatment produces in routine clinical practice. They may also be used drugs used to treat menorrhagia or those used to determine the most appropriate dose and to undertake medical termination of pregnancy. Examples The aim is to assess the outcome of a new drug of these types of trials include those involving under controlled conditions using a homogeneous the use of misoprostol for medical termination group of patients. In contrast, a pragmatic trial aims to mirror the normal variations between patients that occur PHASE III CLINICAL TRIALS in real life. For example, a pragmatic trial of After a drug has been shown to be reasonably medical versus surgical treatment for menorrha- effective it is essential to compare it with the gia will include all women with a subjective GYNAECOLOGY AND INFERTILITY 339 complaint of heavy menstrual loss. As domised to drug treatment, who find the interven- this type of trial is most easily understood by tion unacceptable and elect for surgery, do not researchers as well as patients, examples abound. Furthermore, the treatment trials will be dictated by the minimum significant offered to patients in the surgery arm may not difference in outcome between any two arms. A similar attitude would apply number of women required to show a clinically to a pragmatic trial of physiotherapy for prolapse significant difference in pregnancy rates between or counselling for premenstrual syndrome, where IUI and IVF is smaller than that necessary to identical interventions cannot be guaranteed by show a difference between IUI and stimulated different physiotherapists or counsellors. IUI, and will ultimately be the one chosen for There are other differences between the two this trial. Blinding is more likely to be used in an explanatory trial such as one comparing CROSSOVER oral metformin with placebo in women with polycystic ovarian syndrome. Pragmatic trials Crossover trials have the advantage of using may also be blinded, but this is often not feasible women as their own controls, thus reducing (for example, in surgical versus medical trials), the sample size required. There is also less of a exposed to either the control or the intervention compulsion to use placebos, as the objective is arm first, followed by the other. Clinician and patient this design is more suited for medical treatments biases caused by the absence of blinding may of chronic conditions as opposed to surgical not necessarily be detrimental to the trial, but trials or infertility trials. In the first group the could actually be seen to be part of the response practicalities of the situation render such a design to treatment. In the second, a definite outcome such as one comparing oral clomiphene citrate such as pregnancy has the natural effect of (a drug treatment) versus expectant management preventing women from completing later phases of the trial. From a practical the treatment as well as the associated placebo point of view, only data from the first phase effect as this best reflects the likely clinical of the crossover trial may be valid. TRIAL DESIGN SIMPLE PARALLEL GROUP FACTORIAL This is the simplest and commonest trial design Factorial designs are often efficient as they can involving a comparison between two groups, address two questions within the context of a 340 TEXTBOOK OF CLINICAL TRIALS Women with unexplained infertility Randomisation A B Expectant management Clomiphene C D Intra-uterine insemination Clomiphene + intra-uterine (IUI) insemination (IUI) Figure 21. Women with unexplained infertility is not targeted at individual patients, but at can be randomised to receive either expectant groups of patients. This can happen where the management (no treatment), insemination alone, intervention is an information package for the clomiphene alone or clomiphene and insemina- management of menorrhagia in primary care9 tion treatment as shown in Figure 21. In been expected to manage both study (information this case, the effect of IUI alone can be assessed leaflet, clinical guidelines) and control patients.

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The question to ask is whether the paragraph generic zoloft 50 mg fast delivery, and the piece as a whole generic 25mg zoloft otc, would work better if it were turned around? You may be giving the reader plenty of informa- tion purchase 50 mg zoloft fast delivery, but without a framework on which that information can be digested buy zoloft 50 mg without a prescription. There are two main remedies: (1) agree that the unmarked paragraphs are redundant generic zoloft 100 mg free shipping, so cut them out, or (2) write a new key sentence for the start of each paragraph so that the reader can understand why the information is there. This is another sign of overload: if all sentences are of the same weight, then you are in danger of writing a shopping list. A bullet point list implies that all points are of equal importance, yet the yellow marker test has shown that they are not. The remedy is simple: rank in strict order of impor- tance or consider two or more lists. The yellow marker test is particularly valuable when preparing balanced feedback for a colleague: if you feel that a piece of writing is not working, it will usually tell you why. Once you have written what you have set out to write, you can hope to have a little more of it. Szpalski (Editors) The Aging Spine With 53 Figures and 40 Tables IV Prof. Robert Gunzburg Institute Centenary Clinic for Evaluative Research Harmoniestraat 68 in Orthopaedic Surgery 2018 Antwerp University of Bern Belgium Stauffacherstr. Marek Szpalski Iris South Teaching Hospitals 142 Rue Marconi 1190 Brussels Belgium ISBN 3-540-24408-5 Springer Berlin Heidelberg NewYork Also published as Volume 12, Supplement 2, October 2003 of the European Spine Journal ISSN 0940-6719 Library of Congress Control Number: 2005920460 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broad- casting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Product liability: The publishers cannot guarantee the accuracy of any information about the application of operative techniques and medications contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover design: e STUDIO CALAMAR, Pau/Girona Typesetting: ROTABENE, Rothenburg o. Printing and bookbinding: Mercedes-Druck, Berlin Printed on acid-free paper 24/3150/PF 5 4 3 2 1 0 V Dieter Grob Foreword It is the merit of the Bone and Joint in view of the generally reduced Decade to draw our attention with health situation of the involved pa- increased intensity to the problem of tients. The important role of the the changes related to aging of our biphosphonates in the treatment, and musculoskeletal system and the asso- perhaps even more so in the preven- ciated socioeconomic implications. I congratu- starts with accurate diagnostic proce- late the editors of the present supple- dures. The profound knowledge and ment of the European Spine Journal sophisticated diagnostic techniques in picking up this interesting topic of the complex pathoanatomical and engaging opinion leaders to con- changes in the spine including the tribute their knowledge in this sup- involvement of the neural structures plement. The various contributions (contribution by Dvorak) often go cover some of the important prob- beyond the capacity of a spine sur- lems, which are included in the vast geon. Teamwork and adequate com- specter of aging spine: osteoporosis, munication is mandatory. Reduced general health issue of the natural history of the ag- status, life expectancy with or with- ing spine, pointing out that this pro- out cancer that occurs more frequent- cess is a progressive change ending ly in elderly persons, and expecta- up in a collapse of the system, a fact tions of the patient and social envi- that has implications for treatment ronment are nonsurgical factors to strategy and disease management. Grob (✉) plexity of the construction and the ity are problems to overcome during Spine Unit, Schulthess Clinic, variety of responses that the spine is surgery. Therefore, who explained and described in the con- carries the ultimate risk of financial else remains than politicians? If not at pre- be their rote to establish rules fair research on these techniques does sent, we as treating physicians will enough to guarantee basic medical not reveal a single comparative study be confronted in the near future with treatment. Where does be based on facts and figures for de- ground knowledge for decision mak- the money come from to treat this in- cision making. It is here that the med- ing in view of the giant number of creasing section of population? Do ical professional world must come osteoporotic fractures that occur we have to decide for selection of into action. The literature ating carefully existing and new ly in most countries these items have search by Lippuner demonstrates the treatment modalities to provide a not yet become reality, but in a fu- relatively high standard of evaluation reasonable base for decision making.

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Systems that access terior occipital cortex (at 120 ms) cheap zoloft 50 mg on-line, marched for- verbs are elsewhere buy 100 mg zoloft fast delivery, close to the neural enti- ward and lateralized to the left hemisphere (at ties that support concepts of movement and re- 180 ms) buy zoloft 50mg on line, spread to posteroventral and lateral lationships in time and space discount zoloft 25mg with amex. For example discount zoloft 50 mg with visa, the temporal areas (at 220 ms), progressively in- bilateral posterior temporoparietal region volved the anterior temporal lobe (at approxi- called MT, which is activated by the percep- mately 300 ms) and the ventral prefrontal cor- tion of motion, is also engaged when subjects tex (at approximately 450 ms), and then faded name an action, such as the word stirring after 500 ms. Within these distributed systems, paral- tary tasks offer valuable information regarding lel and interlocking streams of corticocortical processing, but may not reflect the neural ar- projections build up the levels of complexity of chitecture of ordinary discourse. Posterior re- the temporal lobe language region tend to re- gions included mostly bilateral perisylvian tem- spond to only one aspect of language, such as poral cortex and inferior portions of the angu- either when a subject listens to a word or lar gyrus, along with extrasylvian lateral occipital, speaks that word. This wide swath of anatomical sub- to have a narrow behavioral repertoire. They strate for discourse suggests early stages for may respond solely to one word from a list, only forming concepts and accessing the lexicon and second syllables, or only particular linguistic 64 Neuroscientific Foundations for Rehabilitation characteristics of language. This narrow band many points of entry into these cascades may of behavioral response seems to apply to most be available for a neuropharmacology of reha- individual neurons within the cognitive associ- bilitation. Electrical signals carry- ments or aphasia subtypes and affect the de- ing information among the nodes of networks gree of eventual recovery. The plas- solving, practice, reward, and optimizing sen- ticity associated with gains in patients who are sory inputs relevant to a motor task may be es- aphasic, appreciated using functional neu- sential for successful adaptation of molecules, roimaging, is discussed in Chapter 3. Functional neuroimaging studies provide a sense of which cortical networks are special SUMMARY contributors to movement and cognition under various conditions. By understanding the task- The anatomic and functional structure of as- related conditions that modulate brain regions, semblies of neurons, their axonal projections, rehabilitationists may be able to design physi- and their synapses are increasingly informing cal, cognitive, pharmacologic, and biologic re- us about mechanisms of movement and cogni- pair interventions that enhance the engage- tion. To understand the basis for the symptoms ment of the nodes in a network. The potential plas- cord by top-down commands and bottom-up ticity of residual assemblies and networks is sensory inputs. Retraining paradigms, pharmaco- experience and perceptual goals organize vol- logic interventions, and the biological inter- untary movements and skills learning. The as- ventions discussed in Chapter 2 offer exciting semblies that participate in the performance of new options to lessen the impairments and dis- a task are highly distributed and project infor- abilities of patients. Goal-oriented be- gument gains after a CNS or PNS injury rest haviors, along with paradigms that optimize im- upon basic scientific knowledge of structure plicit and explicit learning, induce plasticity and and function. REFERENCES Many signaling pathways contribute to the storage of sensorimotor and cognitive informa- 1. An organizing principle for cerebral Plasticity in Sensorimotor and Cognitive Networks 65 function: The unit module and the distributed sys- 23. The Neuro- sistent features in the forelimb reperesentation of sciences Fourth Study Program. How somatotopic is the porary Management of Motor Control Problems: motor cortex hand area? The coordination and regulation of in primary motor cortex of adult squirrel monkeys. In: Edelman G, Gall W, Cowan cortex lesion on step-tracking movements of the W, eds. Neural basis of motor con- tion of corticospinal projections from the frontal trol and its cognitive implications. Trends Cogn Sci lobe: Motor areas on the lateral surface of the hemi- 1998; 2:97–102. Beisteiner R, Windischberger C, Lanzenberger R, through adaptive combination of motor primitives. Information process- centers for finger movements in human primary mo- ing with population codes. Limits of reorganization in cortical cir- vation in voluntary arm movements: a model. NeuroImage 2001; 13: between hand motion and population vectors from 968–974. Muscle and move- cortical encoding of serial order in a context-recall ment representations in the primary motor cortex.

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Zeigher RS generic 25mg zoloft mastercard, Heller S buy zoloft 100 mg mastercard, Mellon MH buy generic zoloft 25 mg online, Forsythe AB buy zoloft 100mg cheap, dermatological literature buy zoloft 25mg with amex. Ashcroft DM, Li Wan Po A, Williams HC, Grif- development of atopy in early infancy: a ran- fiths CEM. J Allerg Clin Immunol (1989) 84: come in psoriasis: a critical appraisal of their qual- 72–89. J Invest Dermatol (1996) 106: of the impact of leg ulcers on quality of life: 183–6. Krueger GG, Feldman SR, Camisa C, Duvic M, J Am Acad Dermatol (1994) 31: 49–53. Moffatt CJ, Franks PJ, Oldroyd M, Bosanquet N, for patients with psoriasis and their clinicians: Brown P, Greenhalgh RM, McCollum CN. Matthews JNS, Altman DG, Campbell MJ, Roys- pean Dermato-Epidemiology Network. Analysis of serial measurements in medical ized clinical trials for psoriasis 1977–2000: the research. A double-blind, randomized, multi- Crossover and self-controlled designs in clinical center trial. Kessels AG, Cardynaals RL, Borger RL, Go MJ, value of simple wound measurements. Lindholm C, Bjellerup M, Christensen OB, Zed- with alopecia androgenetica. Reliability testing of the opment of an Acne Quality of Life scale: reli- dermatology index of disease severity (DIDS). The mark T, van de Kerkhof PC, Larko O, Nieboer C, Nottingham Eczema Severity Score: preliminary Roed-Petersen J, Strand A, Tikjob G. Quality of life measures in psoriasis: PSY IA TR Y Textbook of Clinical Trials. In terms of either defini- vomiting and purging for mentally ill patients tion it would appear that psychiatry has a long were common, as were more whimsical forms history; Pythagoreans, for example, employed of treatment such as whirling or spinning a a form of music therapy with emotionally ill madman round on a pivot. These treatments were patients,1 and Aretaeus (AD 50–130) observed in addition to the continued use of manacles and mentally ill patients and did careful follow-up chains for restraint. As a result, he established that what these treatments also had in common was manic and depressive states often occur in the that they were mostly ineffective. For example, on 18 July 1646 enlightened approach to the mentally ill had been the Court of Governors of Bethlem Hospital Textbook of Clinical Trials. A scene of any blows or ill language to any of the mad human degradation. One positive change from some institutes housing the insane began to earlier times, however, was that now some offer kindness, attention to health, cleanliness clinicians began to take the first small steps to and comfort. Empiricism was, at last, about to the dangers of idleness, and the need for patients play a role in psychiatric practice. Such an approach was now considered to be PSYCHIATRIC TREATMENT AND ITS more likely to restore reason than harshness EVALUATION: THE EARLY TWENTIETH or severity. CENTURY But although there was an increasing desire for caring to replace constraint in dealing with 3 In the 1920s Dr Henry A. Cotton proposed a the- the mentally disturbed, drugs such as corium, ory relating focal infection to mental disorders, in digitalis, antimony and chloral were still used particular the functional psychoses. According to to quieten patients, replacing physical fetters Dr Cotton: with pharmacological ones. And despite the best efforts of the advocates of the moral treatment The so called functional psychoses we believe approach, asylums housing the insane often today to be due to a combination of many remained depressing and degrading places until factors, but the most constant one is the intra- well into the twentieth century, as is illustrated cerebral, bio-chemical cellular disturbance arising by the following account of a visit by a newly from circulating toxins originating in chronic appointed psychiatrist in 1953 to the chronic foci of infection, situated anywhere in the body, ward of a mental hospital in Cambridge in the associated probably with secondary disturbance United Kingdom: of the endocrin system. Instead of considering the psychosis as a disease entity, it should be considered as a symptom, and often a terminal I was taken in by someone who had a key to unlock symptom of a long continued masked infection, the the door and lock it behind you. This led into a big Dr Cotton identified infection of the teeth and bare room, overcrowded with people, with scrubbed tonsils as the most important foci to be consid- floors, bare wooden tables, benches screwed to the ered, but the stomach and in female patients, the floor, people milling around in shapeless clothing. At the back of the infected tissue, all infected teeth and tonsils cer- ward were the padded cells, in which would be tainly and for many patients, colectomies.

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The test stimulus (SM) is supramaximal for Recurrent collaterals have been found for axons of motoraxonsandproducesanantidromicmotorvol- motoneurones innervating proximal muscles but ley in all motor axons generic zoloft 25mg line. The H1 conditioning reflex not for axons of motoneurones of distal muscles zoloft 25 mg on line. They are inhibited by cutaneous ronesthatdischargeinH willbeaffectedbythepost- and group II afferents and by corticospinal vol- spike AHP because these motoneurones discharged leys buy generic zoloft 25 mg. There is a striking overlap between the dis- in the H1 conditioning reflex generic zoloft 50mg on-line. At conditioning- tribution of heteronymous Renshaw inhibition and test intervals ≥10 ms cheap 50mg zoloft, Ib inhibition evoked by the Resume´ ´ 189 conditioning volley cannot contaminate recurrent and probably when plateau potentials develop in inhibition. Evidence for recurrent inhibition Comparison with a reference H reflex At low conditioning reflex amplitudes H remains The amplitude of the H test reflex also depends equal to H1, but further increases in H1 result in on any changes in motoneurone excitability in the aprogressive decrease in H , which is related to tested situation. The excitability of the motoneu- the size of the conditioning reflex discharge. This rone pool should be monitored using a control H strongly suggests that, in addition to the AHP, the reflex (reference H) of the same size as H in the con- reflex depression is caused by recurrent inhibition trolsituation. Becauseofchangesinmembranecon- set up by the larger conditioning reflex discharge. Thus, there will have been evidence for a change in recurrent inhibition when there is greater change in the H test reflex than in the reference Pharmacological validation Hreflex: greater facilitation of H reflects decreased Intravenous injection of a cholinergic agonist (L- recurrent inhibition, and greater inhibition of H acetylcarnitine, L-Ac), that does not alter the size increased recurrent inhibition. This provides independent evidence for a Renshaw origin of the Conclusions suppression. Although it appears complex, the paired H reflex technique is the only method available to assess homonymous recurrent inhibition under physiolog- Two conditions must be met to use the paired H ical and pathological conditions. However, it would reflex technique be prudent to interpret changes in the size of the H ThesizeoftheH1conditioningreflexdischargemust test reflex with care, taking into account whether the be identical in the situations that are compared, AHPmighthavebeendifferentinthecontrolandtest and the H1 conditioning discharge must be within conditions. Methods to investigate heteronymous recurrent inhibition Possible changes in the post-spike AHP Underlying principle The depression of the test reflex after the H1 dis- A conditioning motor discharge, whether a reflex charge also depends on the AHP of the motoneu- or an antidromic motor volley, is used to activate rones discharging in H1. Suppression of H will Renshaw cells, and the resulting recurrent inhibi- therefore provide an accurate measure of recurrent tion is assessed in a heteronymous muscle by one inhibition, only if the AHP does not change. How- of the methods exploring the excitability of the ever, the AHP can vary under certain conditions: motoneurones: PSTHs of single units, H reflex, and activation of descending monoaminergic pathways, modulation of the on-going EMG or the MEP. In addition the depression Lower limb is commonly preceded by a peak of monosynap- Recurrent connections are much more widely dis- tic Ia excitation. When the conditioning discharge is tributed than in the cat hindlimb with, in particu- a monosynaptic reflex, there are cogent arguments lar, transjoint connections between quadriceps and against a significant contribution of other pathways all muscles operating at the ankle, and from tri- to the suppression. There is a striking overlap electrical stimuli above 1 × MT, its Renshaw origin between the distributions of heteronymous recur- may be more questionable, because the condi- rent inhibition and of heteronymous monosynaptic tioning afferent volley is more complex. However, some Ia connections are not the findings may be validated by the administra- matched by equivalent recurrent connections and, tion of L-Ac, which increases the long-lasting inhi- conversely, some recurrent connections have no Ia bition produced by the antidromic volley above equivalent. Upper limb Limitations Heteronymous transjoint connections are much Ia EPSPs elicited by the conditioning volley can con- more restricted in the upper than in the lower limb taminate recurrent inhibition, and the test response and do not exist from proximal to distal muscles. Ia inhibitory interneurones Ia inhibitory interneurones are inhibited by the Conclusion recurrent pathway at elbow and ankle levels. Recur- rent inhibition of reciprocal inhibition does not In clinical studies, the modulation of the on-going exist at wrist level. Organisation and pattern of connections Homonymous projections to motoneurones TMS suppresses homonymous and heteronymous recurrent inhibition There is evidence for homonymous recurrent inhi- bition affecting the motor nuclei of all proximal This is an effect that occurs only a few milliseconds muscles so far tested. The absence of recurrent later than the cortical excitation of motoneurones. Resume´ ´ 191 Motor tasks and physiological soleus-coupled Renshaw cells, which is likely to be implications of supraspinal origin. Recurrent inhibition of motoneurones of a Recurrent inhibition during co-contraction muscle involved in a selective contraction of antagonistic muscles InthepairedHreflextechnique,changesinrecurrent Voluntary contractions of antagonists inhibition can be inferred from differential changes During voluntary co-contractions of soleus and the in the H test reflex and in a reference H reflex of the pretibial flexors, whether strong tonic or towards same size at rest. This contrasts (i) Inhibition of H while reference H is facilitated with the greater facilitation of H than of reference has been observed during weak tonic soleus con- H observed during voluntary plantar flexion at an tractions and at the beginning of ramp contractions. Both the That a similar result may be observed prior to the amount of inhibition during strong co-contractions rampcontraction,i. The During active stance, homonymous recurrent inhi- greater facilitation of H may result from a reduc- bition is increased with respect to that when stand- tion of recurrent inhibition or of the AHP. This increase in recurrent inhibi- merappearsmorelikely,becauseasimilarresultwas tion is probably descending, possibly vestibular in obtained with heteronymous recurrent inhibition to origin, and is probably required because the activ- active motoneurones, i. The reduction of recurrent inhibition was shown not to be due to an occlusive mechanism between nat- Heteronymous recurrent inhibition opposing ural motor and conditioning reflex discharges run- matched Ia excitation ningthroughthesamerecurrentpathway.

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