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The method rests on the arefulﬁlledatankleandelbowlevels kamagra chewable 100 mg with mastercard,thedataarenot assumptions that the same afferents are responsible yet conclusive at knee level generic kamagra chewable 100mg with visa. At ankle level, mono- for the H reﬂex (or the peak of homonymous Ia exci- synaptic excitation due to stimulation of super- tation in the PSTH) and the short-latency inhibition ﬁcial peroneal afferents could have obscured the of the H reﬂex (or the PSTH) in the antagonist, and deep peroneal-induced inhibition in some studies. In contrast, in those Suppression of reciprocal Ia inhibition by activation subjects, in whom it is possible to evoke an H reﬂex of recurrent inhibitory pathways provides a unique in the tibialis anterior, reciprocal inhibition can be method of conﬁrming that the pathway is truly that demonstrated consistently at rest. This has been observed at in favour of ﬂexors is reminiscent of data in the cat. At elbow level, there is evidence for a profound and symmetrical reciprocal Ia inhibition between ﬂexors Critique of the tests to study reciprocal and extensors. Interneurones responsible for the disynaptic Resume´ ´ 237 inhibition between wrist muscles are activated by mechanism responsible for the absence of increased group I afferents from a variety of muscles, not reciprocal Ia inhibition during tonic contractions: it only the antagonist but also the target muscle and reducestheefﬁcacyoftheartiﬁcialconditioningvol- muscles operating at the elbow. This widespread leyindischargingIainterneurones,andpreventsthe convergence is consistent with mediation through central facilitation of Ia interneurones from mani- interneurones of non-reciprocal group I inhibition. Facilitation-occlusion curves for soleus, reﬂecting (iii) Origin and function: Increased peroneal- convergence of the two conditioning volleys onto induced reciprocal Ia inhibition may be due to common Ia interneurones, reveal facilitation of Ia a descending drive onto Ia interneurones and/or interneuronesonlywhentheperonealvolleyisweak. Inﬂexion–extensionmovements,the ticospinalvolleys,and(iii)stimulationofthevestibu- stretch-induced Ia discharge triggered in the antag- lar apparatus. This can produce two Motor tasks and physiological undesirable effects: a stretch reﬂex in the antagonis- implications tic soleus muscle, and inhibition of agonist tibialis anterior motoneurones through extensor-coupled Voluntary contraction of the Ia interneurones. The unwanted stretch reﬂex may antagonistic muscle be minimised by several mechanisms (addressed in A depression of the soleus H reﬂex precedes and Chapter 11), and the activation of extensor-coupled accompanies a voluntary ankle dorsiﬂexion, due to Ia interneurones can be prevented by the discharge changes in at least three mechanisms: reciprocal Ia of tibialis anterior-coupled Ia interneurones. Dur- inhibition, presynaptic inhibition of soleus Ia termi- ing the dynamic phase of rapid shortening (concen- nals, and longer-latency propriospinally mediated tric) contractions, spindle endings in the contract- inhibition. In this chapter, only the changes in recip- ing muscle will be unloaded and may be silenced, rocal Ia inhibition are considered. This ﬁnd- Reciprocal Ia inhibition directed to active motoneu- ing indicates that, during dorsiﬂexion, the natural rones is depressed during voluntary contractions Ia discharge decreases the efﬁcacy of the peroneal of the corresponding muscle, and the stronger the volley in activating Ia interneurones. Par- depression,whichoccursatthesynapsebetweenthe allel descending activation of active motoneurones Ia ﬁbre and the Ia interneurone, is the most likely and coupled Ia interneurones produces, through 238 Reciprocal Ia inhibition mutual inhibition of Ia interneurones, inhibition ﬂexors to dorsiﬂexors is probably enhanced during of the opposite Ia interneurones directed to the the stance phase. This provides a further exam- antagonistic motoneurones are kept inactive during ple of the depression of reciprocal Ia inhibition to appropriate phases of the walking cycle. This modu- motoneurones activated in a movement of ﬂexion- lationis,however,lessmarkedthanduringvoluntary extension in order to prevent their undesirable contractions at equivalent levels of EMG activity. Studies in patients and clinical implications Co-contractions During co-contractions of dorsi- and plantar ﬂex- Methodology ors of the ankle, reciprocal inhibition is depressed So far, changes in transmission in the pathway of with respect to rest, and always smaller than the sum reciprocal Ia inhibition have been investigated in of the effects evoked by isolated dorsi- and plantar patientsonlyatanklelevel,mainlyfromtheperoneal ﬂexion. Reciprocal the conditioning stimulus selectively to the deep Ia inhibition is maximally depressed even at low peroneal nerve, using conditioning stimuli that are co-contraction levels, indicating a decoupling of not above 1×MT. The pathway mediating reciprocal Ia inhibition is actively inhibited during such con- Spasticity tractions, through increased presynaptic inhibition Resting conditions on Ia terminals and increased recurrent inhibition. Functionally the decrease in reciprocal Ia inhibi- Different studies have reported quite variable ﬁnd- tion ensures unopposed activation of antagonistic ings. In patients with focal lesions (either cerebral or motoneurone pools during co-contractions. This reveals a coupling of Thus, corticospinal lesions reduce reciprocal Ia motoneurones and corresponding Ia interneurones inhibition of ankle extensors and release recipro- during automatic postural adjustments. Walking TheamountofreciprocalIainhibitionbetweenankle During voluntary dorsiﬂexion ﬂexors and extensors is modulated, with prominent inhibition from dorsiﬂexors to plantar ﬂexors dur- The normal increase in reciprocal Ia inhibition ingtheswingphase,whereasinhibitionfromplantar observed at the onset of the movement has not been References 239 found. Journal of Neurology, Neurosurgery an unwanted stretch reﬂex of the triceps surae in and Psychiatry, 40, 910–19. Synaptic connections to indi- Plasticity vidual tibialis anterior motoneurons in man. Journal of Neurology, Neurosurgery and Psychiatry, 41, 684– Regular peroneal stimulation has been shown to 9. Plastic changes occurring in Reciprocal inhibition between wrist ﬂexors and extensors the pathway of reciprocal Ia inhibition after training in man: a new set of interneurones? Journal of Physiology couldbeafactor intheapparentlyconﬂictingresults (London), 487, 221–35.
Metabotropic glutamate re- move from protein to protein within a dendritic ceptors cheap 100 mg kamagra chewable with mastercard, particularly the ones in the family of spine or presynaptic terminal to phosphorylate G protein–coupled receptors buy 100mg kamagra chewable amex, may also need to proteins and alter their function. Phosphatases, be activated for the generation of LTP in some which dephosphorylate proteins, also have an types of synapses. This cascade of induction and maintenance of LTP and in trig- events continues to be explored. It occurs at the par- of the apparently mandatory steps for signal allel fiber–Purkinje cell synapse and at the transduction occurs when calcium binds to climbing fiber synapse. Once releases glutamate onto metabotropic and this molecule autophosphorylates, it is no AMPA receptors. In many respects, LTD is a longer dependent on a continued rise in cal- reversal of the processes that lead to LTP, cium. A key molecular switch in cortical expe- although the total effects of the two can be rience-dependent plasticity,263 CaMKII phos- additive. In LTD, the AMPA and NMDA phorylates AMPA receptors at the postsynaptic receptor–mediated excitatory postsynaptic cur- membrane and increases the number of deliv- rent decreases along with a postsynaptic de- ered AMPA receptors. Finding drugs that act as memory Kleim and colleagues used cortical micros- molecules is a major pursuit of pharmaceutical timulation and morphologic techniques to re- companies. The region of M1 that repre- Growth of Dendritic Spines sents wrist and digit movements enlarged its representation as rats trained in a skilled reach- Motor learning induces genes that modify cell ing task for food pellets. This representational structures and functions, such as increasing the map expansion and synaptogenesis colocalized number of synaptic spines. Thus, an ing process, the induction of LTP increases the initial unmasking of latent synapses for the number of AMPA receptors in a postsynaptic neuronal assemblies representing the digits led dendritic spine. The postsynaptic membrane to an increase in the number of synapses enlarges, then splits into several spines. The number of synapses related to the initial activity-induced signal then in- Neurotrophins creases. A decrease in AMPA Neurotrophins are also important effectors of receptors and membrane material leads to a morphologic changes with activity-dependent decrease in the size of the postsynaptic mem- plasticity. Several of the neurotrophins, dis- brane, and finally to the loss of the dendritic cussed further in Chapter 2 (see Table 2–5), are spine. In the most studied model of LTP mem- influenced by the properties of dendrites. This mor- pression likely affects the molecular and cellular phologic mechanism also helps explain how the events that influence cortical plasticity, motor effects of an enriched environment and learn- learning, and memory, including greater synap- ing paradigms may increase synapse number tic efficacy and dendritic sprouting. For example, fluorescent-la- Chemical neurotransmission across synapses beled BDNF was shown in a set of experiments permits the computational flexibility and regu- to move antegrade down presynaptic axons in lation that contribute to synaptic plasticity. Other proteins For hippocampal learning, BDNF rapidly participate in bringing the vesicles that are modulates presynaptic transmission over sec- filled with neurotransmitters to the nerve ter- onds to minutes. In addition, the neurotrophin minal where the packets dock, fuse, and un- modulates postsynaptic hippocampal transmis- dergo endocytosis, then recycle. By activating postsynaptic that mediate neurotransmitter release are es- trkB receptors, BDNF depolarizes the postsy- sential for information processing and the goal naptic neuron, probably by opening sodium of learning and memory. Further studies LTP, secreted neurotrophins prolong the ef- may reveal genetic differences between people fects of presynaptic neurotransmitters and in, for example, their dopaminergic tone, which postsynaptic responsiveness. For example, may correlate with neuropsychiatric disorders when BDNF binds to its receptor on a presy- and differences in the ability to learn. The release of a neurotransmitter across the One of these cascades leads to the production synaptic cleft transduces a physiologic signal af- of synapsin, which tethers tiny vesicles of neu- ter the messenger binds to the postsynaptic re- rotransmitters such as glutamate and GABA ceptor. Table 1–4 lists the primary actions of and helps control their availability and re- neurotransmitters at a synapse. G protein–coupled receptors, which then acti- Given that most of the identified neu- vate a cascade of secondary messengers. Glial rotrophins are available for pharmacologic test- cells can also modulate synaptic transmission ing, they offer a potential means for enhancing by releasing or taking up most neurotransmit- synaptic efficacy during the relearning of skills ters. Neurotrophins and parallel networks for sensorimotor and cogni- drugs that mimic them, as well as other po- tive processes. Projections from the hypothala- neuropeptides, cytokines, and neurotransmit- mus may affect attention, mood, motivation, ters that act as neuromodulators rather than for learning, and vigilance. Four other neuromod- synapse-specific transmission, offer great ulators project widely, especially to the frontal promise.
Both leucovorin reg- administration all were variables to be studied to imens demonstrated signiﬁcant improvement in 134 TEXTBOOK OF CLINICAL TRIALS response rate and overall survival compared to were similar between the Mayo and RPMI 5-FU 5-FU alone buy kamagra chewable 100mg visa. As discussed previously discount 100 mg kamagra chewable free shipping, in the late of the two regimens did differ, but no clear win- 1990s and early 2000s, several randomised tri- ner was identiﬁed. Based largely on cost consid- als were conducted in both the US and Europe in erations, investigators from the Mayo Clinic and which infusion-based 5-FU regimens or regimens the North Central Cancer Treatment group chose that combine 5-FU with CPT-11 or oxaliplatin to pursue the Mayo regimen for future testing. In addition, the oral agent capecitabine setting naturally led to the evaluation of several has been approved as an alternative to IV 5-FU of these regimens in the adjuvant treatment of in advanced disease. In the advanced disease setting, the Mayo 5-FU a study that was suspended after accrual of + leucovorin regimen has been replaced as the 317 patients (based on the results of a large standard of care, indeed a welcome advance. Increased toxicity has clearly been was 74%, compared to 63% in the control group demonstrated for multiple drug combinations in the adjuvant setting,84 demonstrating the value of (p = 0. This result established the efﬁcacy of the Mayo 5-FU plus leucovorin regimen in waiting for the results from these deﬁnitive tri- the adjuvant setting. The regimens included the Mayo 5-FU plus leucovorin regimen for 6 months, 5-FU plus 1. Surg, Gynecol Obstet (1981) 153: leucovorin (the RPMI regimen) for 8 months, 690–2. In this study of 3759 patients, results Schlag P, Favre J-P, Dalesio O, Buyse M, GASTROINTESTINAL CANCERS 135 Duez N. Cuschieri A, Weeden S, Fielding J, Bancewicz J, in esophageal cancer: results of a study of the Craven J, Joypaul V, Sydes M, Fayers P. Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, cancer: long-term results of the MRC random- Gunderson L, Mortimer J, Estes N, Haller DG, ized surgical trial. Janunger KG, Hafstrom L, Nygren P, Gli- surgery alone for localized esophageal cancer. Preoperative therapy for dahl SA, Estes NC, Haller DG, Ajani JA, Gun- esophageal cancer: a randomized comparison of derson LL, Jessup JM, Martenson JA. J Clin diotherapy after surgery compared with surgery Oncol (1990) 8: 1352–61. New Engl J Med (2001) Mantion G, Elias D, Lozach P, Ollier J-C, Pavy 345: 725–30. Webb A, Cunningham D, Scarffe JH, Harper P, followed by surgery compared with surgery alone Norman A, Joffe JK, Hughes M, Mansi J, Find- in squamous-cell cancer of the esophagus. New lay M, Hill A, Oates J, Nicolson M, Hickish T, Engl J Med (1997) 337: 161–7. Randomized trial com- Hassel MB, Gedouin D, Boutin D, Campion JP, paring epirubicin, cisplatin, and ﬂuorouracil ver- Launois B. A randomized study of chemother- sus ﬂuorouracil, doxorubicin, and methotrexate apy, radiation therapy, and surgery versus surgery in advanced esophagogastric cancer. J Clin Oncol for localized squamous cell carcinoma of the (1997) 15: 261–7. Urba SG, Orringer MB, Turrisi A, Iannettoni M, Reitemeier RJ, Rubin J, Schutt AJ, Weiland LH, Forastiere A, Strawderman M. Randomized trial Childs DS, Holbrook MA, Lavin PT, Livs- of preoperative chemoradiation versus surgery tone E, Spiro H, Knowlton A, Kalser M, Bar- alone in patients with locoregional esophageal kin J, Lessner H, Mann-Kaplan R, Ramming K, carcinoma. Walsh TN, Noonan N, Hollywood D, Kelly A, Lokich J, Chaffey J, Corson JM, Zamcheck N, Keeling N, Hennessy TPJ. Therapy of locally unresectable pan- multimodal therapy and surgery for esophageal adenocarcinoma. New Engl J Med (1996) 335: creatic carcinoma: a randomized comparison of 462–7. Herskovic A, Martz K, Al-Sarraf M, Leich- ate dose radiation (4000 Rads +5−ﬂuorouracil), man L, Brindle J, Vaitkevicius V, Cooper J, and high dose radiation +5−ﬂuorouracil. Klaassen DJ, MacIntyre JM, Catton GE, Eng- radiotherapy alone in patients with cancer of the strom PF, Moertel CG. Minsky BD, Berkey B, Kelsen DK, Ginsberg R, a randomized comparison of 5-ﬂuorouracil alone Pisansky T, Martenson J, Komaki R, Okawara G, with radiation plus concurrent and maintenance Rosenthal, S.
This indicates that the pathway of Ib inhi- regard to the target motoneurones 100mg kamagra chewable fast delivery, like that of Ia bition can be suppressed during locomotion buy discount kamagra chewable 100 mg on-line, allow- terminals (cf. In any event, the ing activation of alternative excitatory pathways, not differential control of Ib pathways to active soleus open at rest. Evidence for a similar Ib excitation and inactive quadriceps motoneurones would have of homonymous and synergistic motoneurones has a focusing action, increasing motor contrast (see been sought in human subjects during walking. Ib pathways to extensors Ib inhibition to inactive motoneurones during Transmission in the pathway of Ib inhibition voluntary contractions of the antagonists from gastrocnemius medialis to soleus Gastrocnemius medialis-induced Ib inhibition of Transmission in this pathway has been compared at the soleus H reﬂex has been investigated at the rest, during a voluntary contraction of triceps surae onset of a brief phasic contraction of pretibial ﬂex- at 20% MVC and in the middle of the stance phase ors (Yanagawa, Shindo & Nakagawa, 1991). This increased all reduction of the inhibition was not more pro- inhibition appeared before the contraction-induced nounced than during voluntary contractions of tri- peripheral feedback reached the spinal cord, and ceps surae, a result similar to that reported by Faist was presumably due to descending facilitation of et al. However, in 4 of 15 subjects, in whom Ib interneurones, probably of corticospinal origin. This tion during walking, and this occurred at a latency ﬁndingwasattributedtoocclusionininterneurones, consistent with an oligosynaptic Ib excitatory path- and this implies that at least some Ib interneurones way. Overall, these effects are disappointingly mod- could be ﬁred by the descending command. A move- est compared to the reversal from Ib inhibition of ment due to contraction of the agonist (here, tibialis ankle extensors to Ib excitation observed consis- anterior) would produce a stretch-induced Ia dis- tently in the decerebrate cat (see p. However, the Ia due to (i) the different preparation (normal awake discharge also projects to interneurones mediating humans versus decerebrate cats), though a clear non-reciprocal group I inhibition of these motoneu- exampleofreﬂexreversalhasbeenobtainedinintact rones (pp. Thus, during voluntary contrac- humans in another paradigm (see below), (ii) the tion of a ﬂexor, facilitation of interneurones medi- weak strength of the conditioning stimulus, neces- ating non-reciprocal group I inhibition to extensors, sarytoavoidrecurrentinhibition,or(iii)thedifferent together with other mechanisms (cf. Different roles of the triceps surae in Changes in Ib inhibition during walking quadrupedal and bipedal locomotion An important ﬁnding concerning transmission in Ib In thecat,duringthestancephaseofwalking,thetri- pathways has been the demonstration of a switch ceps surae and quadriceps have the same functional 274 Ib pathways role (i. In contrast, in is group I in origin, since its threshold is below that humans, (i) the knee and ankle movements are out of group II afferents. It starts 4 ms after the expected of phase (Brandell, 1977), and (ii) the quadriceps time of arrival at motoneuronal level of the fastest contraction occurs in early stance when it supports Ia afferents in the conditioning volley. How- central delay of this inhibition is difﬁcult to establish ever the triceps surae contraction resists the passive precisely because: (i) Ib inhibition is depressed dur- ankle dorsiﬂexion produced by the resultant of the ing voluntary activation of the target motoneurones extrinsic forces (kinetic force, gravity), and progres- (see above), (ii) summation of the effects evoked sively increases during the stance phase. It has been by slower group I afferents is probably necessary suggested that the differential cutaneous suppres- to allow it to appear, and (iii) the suppression may sive control of Ib pathways to quadriceps and soleus be superimposed on a preceding small excitation. Suppression of Ib inhibition to quadriceps motoneurones by the cutaneous volley created by Changes in peroneal-induced effects the foot contacting the ground would bring a safety during walking margin to the quadriceps contraction. In contrast, it is important that soleus activity be overcome by dor- At the end of the swing phase of walking, the early siﬂexion forces if the body is to be brought forward suppression of peroneal group I inhibition is simi- and, together with other mechanisms, the absence lar to that observed during voluntary contractions at of cutaneous depression of Ib inhibition to soleus equivalent levels of EMG activity and is again pre- motoneurones would be expedient (see Chapter 11, ceded by a questionable Ia excitation (Fig. In striking contrast, in the beginning of the stance phase, the suppression is replaced by facilitation occurring at the same latency as the inhibition in Ib pathways to ﬂexors the swing phase (Fig. The facilitation, found Changes in Ib inhibition from pretibial ﬂexors to in most of the subjects, is of group I origin, since biceps femoris have been compared during human it is observed with stimuli below group II thresh- standing and walking (Marchand-Pauvert & Nielsen, old, and cannot be reproduced by cutaneous stim- 2002). The latency of the facilitation is compatible with an oligosynaptic group I effect. The observed reﬂex reversal presumably results from the opening of an Peroneal-induced changes in excitability of excitatory group I pathway in the early stance of biceps motoneurones during standing walking with a concomitant shut-down of heterony- At rest a group I volley to the deep peroneal nerve mous group I inhibition. During a tonic voluntary co-contraction In early stance there is a lengthening contraction of biceps and tibialis anterior while standing, a deep from pretibial ﬂexors and this results in a signiﬁcant Studies in patients 275 (a) Ib INs 24 (c) Tonic TA + Bi Bi Ib MN 0 Ia TA (d ) Swing phase 30 MN DPN 0 (e) 24 120 (b) Stance phase 100 80 0 0 4 8 12 0 40 80 ISI (ms) Latency after DPN stimulation (ms) Fig. Vertical dotted lines indicate the onset of the EMG suppression ((c), (d )) or facilitation (e). At this time of the gait cycle, implications the group I discharge facilitates biceps motoneu- rones. Quadriceps motoneurones would also be Ib inhibition facilitated by the group I–group II discharges (cf. Facilitation of the two antag- Methodology onistic muscles operating at knee level by afferent discharges from ankle dorsiﬂexors would contribute So far, changes in transmission in Ib inhibitory path- to the co-contraction, and help ensure maximal sta- ways in patients have been investigated only by bilityofthekneejointinearlystance(seeChapter11, assessing the inhibition of the soleus H reﬂex pro- p. This is, indeed, the best method because normal subjects, the inhibition could be obtained changes in Ib inhibition are not contaminated by with stimulus intensities as low as 0. However, it is necessary to keep the con- 1 × MT, it was quite weak (on average, reducing the ditioning stimulus below 1 × MT to avoid recur- test reﬂex to 93. In patients with rent inhibition, and few group I afferent ﬁbres will spinal cord lesions, the amount of inhibition of the be recruited by conditioning volleys of such weak soleus H reﬂex was not signiﬁcantly different from intensity.
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