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Give oil preparations deeply into a large muscle mass generic aleve 500mg amex pain treatment for burns, preferably gluteal muscles aleve 500 mg with amex myofascial pain treatment center watertown ma. With estradiol skin patches cheap aleve 250 mg overnight delivery tailbone pain treatment yoga, apply to clean dry skin of the To facilitate effective absorption and adherence to the skin and abdomen, buttocks, upper inner thigh, or upper arm. Avoid avoid skin irritation breasts, waistline areas, and areas exposed to sunlight. Observe for therapeutic effects Therapeutic effects vary, depending on the reason for use. With estrogens: (1) When given for menopausal symptoms, observe for decrease in hot flashes and vaginal problems. With progestins: (1) When given for menstrual disorders, such as abnor- mal uterine bleeding, amenorrhea, dysmenorrhea, pre- menstrual discomfort, and endometriosis, observe for relief of symptoms. With estrogens: (1) Menstrual disorders—breakthrough bleeding, dysmen- Estrogen drugs may alter hormonal balance. When high doses of estrogens are used as post- coital contraceptives, nausea and vomiting may be severe enough to require administration of antiemetic drugs. Thromboembolic disorders thrombosis, and coronary thrombosis; edema and weight are most likely to occur in women older than 35 y who take oral con- gain traceptives and smoke cigarettes, postmenopausal women taking long-term estrogen and progestin therapy, and men or women who receive large doses of estrogens for cancer treatment. Women with an intact uterus should also be given a pro- gestin, which opposes the effects of estrogen on the endometrium. Most studies indicate little risk; a few indicate some risk, espe- cially with high doses for prolonged periods (ie, 10 y or longer). However, estrogens do stimulate growth in breast cancers that have estrogen receptors. With progestins: (1) Menstrual disorders—breakthrough bleeding Irregular vaginal bleeding is a common adverse effect that decreases during the ﬁrst year of use. This is a major reason that some women do not want to take progestin-only contraceptives. Combined estrogen and progestin oral contraceptives: (1) Gastrointestinal effects—nausea, others Nausea can be minimized by taking the drugs with food or at bedtime. However, for women older than 35 y who smoke, there is an increased risk of myocardial infarction and other cardiovascu- lar disorders even with low-dose pills. This is attributed to increased concentration of cholesterol in bile acids, which leads to decreased solubility and increased precipitation of stones. Drugs that decrease effects of estrogens, progestins, and oral contraceptives: (1) Anticonvulsants—carbamazepine, oxcarbazepine, phe- Decrease effects by inducing enzymes that accelerate metabolism nytoin, topiramate of estrogens and progestins. Rifampin induces drug-metabolizing en- mycin, clarithromycin, dirithromycin), metronidazole, zymes that accelerate drug inactivation. Other antimicrobials act penicillin V, rifampin, sulfonamides, tetracyclines, mainly by disrupting the normal bacterial flora of the gastroin- trimethoprim testinal tract and decreasing enterohepatic recirculation of estro- gens. This action may decrease effectiveness of contraceptives (b) Antifungals—fluconazole, itraconazole, ketoco- or cause breakthrough bleeding. To prevent pregnancy from oc- nazole curring during antimicrobial therapy, a larger dose of oral con- (c) Antivirals—efavirenz, ritonavir, lopinavir/ritonavir traceptive or an additional or alternative form of birth control is combination probably advisable. Prepare a teaching plan for perimenopausal or post- Nursing Notes: Apply Your Knowledge menopausal woman about nonpharmacologic measures to manage menopausal symptoms and prevent osteoporosis. Answer: Factors such as the number of doses omitted and the time of the month such omission occurred may affect whether skipped doses could alter therapeutic drug levels. If Jane remem- SELECTED REFERENCES bers a skipped dose within hours, instruct her just to take the pill Barbieri, R. Teach Jane to take her birth control pills at the same time Drug facts and comparisons. Louis: Facts and each day, in association with a daily task or ritual (eg, after Comparisons. Answer: the nurse has provided adequate patient teaching con- Marcus, E. Philadelphia: garding the drug–drug interaction between ampicillin and oral Lippincott Williams & Wilkins. Structure and function of the female reproductive the effectiveness of the oral contraceptives and could result in an system. Philadelphia: Lippincott Williams & protection during the month she is taking the antibiotic. Postmenopausal Review and Application Exercises hormone replacement therapy. What are the reproductive and nonreproductive functions Letter 44(1122), 8. What are the adverse effects of hormonal contraceptives, agement, 7th ed. Risks and beneﬁts of estrogen plus progestin in healthy postmenopausal women: 5. Discuss uses and effects of exogenous andro- of the dietary supplements androstenedione gens and anabolic steroids. Describe potential consequences of abusing androgens and anabolic steroids. Critical Thinking Scenario You are a nurse working in a rural high school. The wrestling coach asks you to talk with his wrestling team about anabolic steroids. Confusion regarding the difference between anabolic steroids and corticosteroids. Strategies that might be effective in limiting the use of anabolic steroids among young athletes. The main functions of testosterone are related to the development of male sexual characteristics, reproduc- Androgens are male sex hormones secreted by the testes in tion, and metabolism (Box 29–1). Like the female sex hormones, the naturally occurring to plasma albumin or to sex hormone–binding globulin and male sex hormones are steroids synthesized from cholesterol. The the sex organs and adrenal glands can produce cholesterol or bound testosterone is either transferred to the tissues or bro- remove it from the blood. Cholesterol then undergoes a series ken down into inactive products that are excreted. Much of of conversions to progesterone, androgenic prehormones, and the testosterone that transfers to tissues undergoes intracellu- testosterone. The androgens produced by the ovaries have lar conversion to dihydrotestosterone, especially in the ex- little androgenic activity and are used mainly as precursor ternal genitalia of the male fetus and the prostate gland in the substances for the production of naturally occurring estrogens. The dihydrotestosterone combines with receptor the adrenal glands produce several androgens, including proteins in the cytosol; the steroid–receptor combination then migrates to the cell nucleus where it induces transcription androstenedione and dehydroepiandrosterone (DHEA). Androstenedione and DHEA are weak androgens with little Almost all testosterone effects result from the increased for- masculinizing effect that are mainly converted to estrogens.

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There are two classes of with- withdrawal reﬂexes drawal reﬂexes in the lower limbs: early reﬂexes occurring with a latency less than 120 ms generic 250mg aleve with mastercard pain burns treatment, and Early withdrawal reﬂexes are organised on a func- long-latency responses buy aleve line ankle pain treatment running. Afferent pathway (i) Trunk skin reﬂexes are regarded as nociceptive Small diameter purchase discount aleve on-line pain treatment center west plains mo, slowly conducting (17–28 m s−1) reﬂexes, even though they may be elicited by stimuli A ﬁbres convey the afferent input for withdrawal of innocuous quality, such as touch, though this may reﬂexes and pain sensation. However, there is some be because of the convergence of tactile and noxious evidence that A ﬁbres can contribute to both afferents on common interneurones. Stimulation of the ball of the toe evokes a general ﬂexion reﬂex of the lower limb, Central pathways of early withdrawal including toe 1 dorsiﬂexion. A stimulus to the hollow responses of the foot and the surrounding areas produces the Because of the slow conduction velocity of A normal plantar reﬂex, i. This facilitation- ment at joints proximal to the stimulus represents suppression is due to a spinal mechanism, possibly the classical ﬂexion reﬂex, while extensor muscles post-activation facilitation and depression of trans- areactivatedbystimulitotheoverlyingandadjacent mission at the synapses of the cutaneous afferents skin. The depression of RIII responses period in hand muscles is appropriate for protecting by tactile afferents is maximal at ISIs of 100–300 ms the hand, opening and withdrawing it when there is and lasts for several hundred milliseconds. Late withdrawal responses Changes in withdrawal reﬂexes during These reﬂex responses occur at latencies above motor tasks 120 ms after distal stimulation of the lower limb. In patients with complete spinal transection, These are poorly documented. Several features of these late reﬂexes are given stimulus are not invariant, and may be altered reminiscent of the late FRA responses disclosed by a change in posture or an appropriate voluntary in the acute spinal cat treated with DOPA: (i) contraction. The functional signiﬁcance of this sup- Lateresponsesobservedinnormalsubjectsdonot pression would be to prevent the reﬂexes from inter- have the characteristics of late FRA reﬂexes, because fering with the supporting action of the lower limb. In addition, it has been shown that respecttorestduringtonicvoluntarycontractionsof these late withdrawal responses can adapt to a new soleus or tibialis anterior. Cutaneomuscular reﬂexes evoked by non-noxious stimuli Interactions between different inputs in withdrawal reﬂex pathways the different responses (i) Repeated painful cutaneous volleys facilitate (i) the RII reﬂex evoked in the short head of the withdrawal reﬂexes at short ISIs (below 3 s) and biceps femoris by low-intensity stimuli to the sural Resume´ ´ 443 nerve is the most consistent example of a cutaneo- for the conduction time of the test reﬂex discharge muscular reﬂex recordable at rest. In grounds, transmission through spinal pathways is theupperlimb,withvolleysappliedtotheﬁngers,the probable for: (i) the RII reﬂex of the biceps femoris; typical pattern is a triphasic response with a modest (ii) the early cutaneomuscular responses, whether early excitation (E1) at a latency of ∼30–35 ms, fol- E1 in the upper limb or early inhibition in the tibialis lowedbyaninhibition(I1)andbyalargelong-latency anterior and soleus; (iii) the short latency inhibition excitation (E2). Such responses have been recorded and following facilitation of the FCR H reﬂex after in many distal, hand and forearm, muscles. Temporal summation lower limb, cutaneomuscular reﬂexes have a much is required to cause the RII reﬂex to appear at rest, less stereotyped pattern. Excitation at spinal latency and this makes uncertain speculations about the (E1) is rarely seen (extensor digitorum brevis, pero- number of interneurones intercalated between the neus longus), and inhibition appears in both the cutaneous terminals and motoneurones. When soleus and tibialis anterior after stimulation of the thecutaneomuscularresponsecanbeobtainedwith sural nerve. These early responses are followed by a a single shock, a more precise estimate of the central long-latency excitation in all muscles. This may be as short as 1–2 ms in (iii) Monosynaptic reﬂex modulation: In the lower some cases, implying an oligosynaptic pathway. Given Afferent conduction the delay of transmission through the loop, any effect on motoneurones resulting from a change GiventhelowthresholdoftheRIIreﬂex(5mA),there in the drive would only occur at long latencies. Accordingly, stimuli evoking has been observed only with afferents from the skin these responses generally require an intensity of ﬁeld that would have come into contact with an 2–2. This would cies earlier than 45–50 ms in the upper limb and 70– explain why sural stimulation produces profound 80 ms in the lower limb are probably spinal. For the suppression of the on-going EMG in tibialis anter- modulation of the monosynaptic reﬂex, allowance ior and soleus but not of the soleus H reﬂex. As a result, unconditioned tib- supraspinal pathway relies on several arguments. The skewed distribution of supraspinal centre with reﬂex activation of the mus- cutaneous inputs within the tibialis anterior cles in a rostrocaudal sequence. The diffuse pattern of excitation evidence for a transcortical origin of the I1 and E2 of distal muscles, the ﬁnding that it is increased components. It has been shown that cutaneous vol- an excitatory response appears at spinal latency in leys facilitate, at the appropriate latency, the MEP tibialis anterior when stance is unstable. During the and the peak of cortical excitation in the PSTHs, swingphaseofgait,excitatoryresponsesarerevealed when the cortical stimulation is magnetic, but not in ﬂexor muscles. However, there is increas- ing evidence that they are mainly transcortically mediated. Projections of cutaneous afferents to different types of motoneurones Studies in patients and clinical Cutaneous afferents from the index ﬁnger can shift implications the weighting of synaptic input associated with a voluntary contraction to favour the recruitment of Complete spinal transection the more powerful fast-twitch motor units in the ﬁrst dorsal interosseous. Similarly, sural nerve stim- During spinal shock, withdrawal reﬂexes are abol- uli below pain threshold produce inhibition in the ished. Finally, some 2– the grasp reﬂex observed in patients with frontal 6 months after the initial injury when the lesion lobe lesions is due to the summation of two local is chronic, early responses are suppressed and re- reﬂexes: an early cutaneous reﬂex followed by a placed by long-latency responses. In patients with stretch reﬂex of ﬁnger ﬂexors, the latter ineffective a chronic spinal cord injury, withdrawal responses in the absence of the former. The RII reﬂex evoked have an invariant pattern of ﬂexion, regardless of the in wrist and elbow ﬂexors by cutaneous afferents stimulus location on the foot or leg. With mechanical stimuli, the patho- periods are abnormally brief or virtually absent; logicalresponseinvolvestherecruitmentofextensor and (iv) habituation is less evident than normal. The pathophysiology of the Babin- Transcortical inhibitory responses (I1) in intrinsic ski response involves the suppression of the nor- muscles of the hand are suppressed with respect to mal segmental reﬂex plantar ﬂexion and disinhibi- normal subjects. Accordingly, the upward response of toe 1 will be accompanied by activation of other muscles of the Abbruzzese, G. Task- dependent effects evoked by foot muscle afferents on leg ﬂexor synergy. Electroencephalography and ski sign may be due to a pressure palsy of the pero- Clinical Neurophysiology, 101, 339–48. London:Perg- (iii) Alterations of lower limb withdrawal reﬂexes amon Press. Muscleand involved, decreased threshold, delay or suppression Nerve, 22, 1520–30. Reﬂexresponses of early reﬂex components, and dishabituation of in active muscles elicited by stimulation of low threshold reﬂex activity. JournalofNeurophysiology, (iv) Flexor spasms are due to an overly vigorous 67, 1375–84. Du phenomene´ ` des orteils et sa valeur talinputs,andhavethesameclinicalandphysiologi- semiologique. In Handbook of Physiology, 446 Cutaneomuscular and withdrawal reﬂexes sectionI,TheNervousSystem,vol. Federation Proceed- Evidencesuggestingthatatranscorticalreﬂexpathwaycon- ings, 41, 2907–18. Evidence for transcortical reﬂex path- the evolution of function in the nervous system. An investigation upon the plantar reﬂex, with changesintheresponsestolow-thresholdcutaneousaffer- reference to the signiﬁcance of its variations under patho- ent volleys in the human lower limb. Journal of Physiology logical conditions, including an enquiry into the aetiology (London), 432, 445–58.

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Sample size requirements Estimation of failure probabilities in the presence and length of study for testing interaction in a of competing risks: new representations of old 2 × k factorial design when time-to-failure is the estimators order generic aleve from india pain treatment topics. Estima- tistical methods for the analysis and presentation tion of survival distributions of treatment policies of the results of bone marrow transplants aleve 500mg visa marianjoy integrative pain treatment center. Part I: in two-stage randomization designs in clinical tri- unadjusted analysis best purchase aleve pain treatment center of tempe. Contr Clin Trials (2000) 21: proportion of immunes in censored samples: a 167–89. SONDAK 1Fred Hutchinson Cancer Research Centre, Seattle, WA 98109 1024, USA 2University of Michigan Comprehensive Cancer Centre, Ann Arbor, MI 48109 0932, USA INTRODUCTION and death from melanoma. Clinically localised melanomas are grouped into three prognostic Randomised Phase III clinical trials are the categories based on the thickness of the pri- gold standard for medical decision making, mary tumour as measured by the pathologist particularly in terms of adjuvant therapies where using a micrometer built into the microscope eye- a modest incremental beneﬁt is sought. The attempt to reconcile at times conﬂicting clinical presence of ulceration of the primary tumour interpretations. The prognosis of localised cutaneous melanoma the prognostic signiﬁcance of the presence of is based on several well-deﬁned factors. Patho- nodal metastasis far outweighs the signiﬁcance of logic analysis of the primary tumour can predict tumour thickness: a thin or intermediate-thickness the likelihood of regional and distant metastasis melanoma with nodal metastases generally has Textbook of Clinical Trials. Green  2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 150 TEXTBOOK OF CLINICAL TRIALS a worse prognosis than a thick melanoma with from reactive nodes, but is still not able to identify negative nodes. Once nodal metastasis has been microscopic foci of melanoma in normal nodes. Ade- staging is used in the majority of patients with quate wide excision of the primary tumour site higher-risk lesions. For any patient with clinically (generally taking a margin of 1 to 2 cm of nor- evident nodal involvement, a complete therapeu- mal skin around the visible edge of the melanoma tic lymph node dissection is associated with cure or biopsy scar) is highly efﬁcacious in controlling in about 20% to 40% of patients. Ret- rospective reviews suggested a survival advan- Physical examination is the mainstay of clini- tage for elective node dissection compared to cal staging of the regional nodes. Any palpa- clinical staging with subsequent therapeutic node dissection at the time of nodal recurrence. Unfortunately, both the speciﬁcity and sensitivity of physical examina- strated beneﬁt is not the same as the demonstra- tion for detecting melanoma nodal metastases are tion of no beneﬁt, elective dissection of clinically low. In muscular or obese patients, even rela- normal nodes is not considered standard practice tively large lymph node metastases can be missed for cutaneous melanoma at the present time. Lymph nodes may be is clear, however, that elective node dissection enlarged after a biopsy procedure due to reactive results in durable regional disease control in the hyperplasia without containing metastasis. Most vast majority of patients, and failures within the importantly, metastatic involvement of normal- dissected nodal basin are quite uncommon. SURGICAL STAGING BY SENTINEL LYMPH Radiologic studies–computed tomography (CT) NODE BIOPSY and positron emission tomography (PET)–are also available to clinically stage the regional nodes. Currently there are no predictive showed conclusively that the pathologic status of methods to distinguish one group of patients the sentinel node accurately determines whether from another, therefore it is necessary to treat melanoma cells have metastasised to that spe- all patients in hopes of gaining an incremental ciﬁc lymph node basin. Hence, in addition to of sentinel node biopsy is a detailed histologic the overall level of efﬁcacy, clinicians evaluate examination of the sentinel lymph nodes. Gen- toxicity, convenience, cost-effectiveness and the erally, this examination is more thorough than prospects of post-relapse salvage therapy when is practical to perform on the larger number deciding whether to employ adjuvant therapy. This more detailed pathologic analysis, com- accurately only in randomised trials. In published multivariate anal- trials involving the same basic interferon regimen yses, histologic status of the sentinel nodes is have not only failed to put this controversy to the most powerful predictor of disease-speciﬁc rest, but have in fact enhanced it. Importantly, patients with positive sentinel nodes go on to E1684 elective complete lymph node dissection. Among Eastern Cooperative Oncology Group (ECOG) patients with negative sentinel nodes, only 4% trial E1684, with 280 eligible patients with thick or fewer ultimately experience a clinically evi- primary (≥4. Thus, sentinel who were randomly assigned after surgery to node biopsy matches the excellent regional con- observation or post-operative adjuvant treat- trol achieved by elective node dissection while ment with IFN-α2b for one year, demonstrated subjecting fewer patients to the morbidity of the statistically-signiﬁcant improvements in relapse- complete node dissection procedure. IFN-α2b therapy increased ADJUVANT THERAPY FOR MELANOMA the median relapse-free survival by 9 months (1. Although many patients are cured by 5-year overall survival rate (46% for IFN-α2b surgery, some beneﬁt from adjuvant treatment patients versus 37% for observation patients). Moreover, par- observation after complete resection of all known ticularly for adjuvant therapy trials, the accep- disease. The eligibility criteria were restricted to trials demonstrating a statistically the same as for E1684, except for the fact that signiﬁcant beneﬁt in overall survival. From this elective node dissection was not required for perspective, there seems to be an obvious discrep- patients entered onto E1690 with thick primary ancy among the two observation-controlled trials: melanomas and clinically negative nodes. Results E1684 demonstrated seemingly striking beneﬁts of this trial conﬁrmed the relapse-free survival from the high-dose interferon regimen in both advantage seen in E1684 but with no survival relapse-free and overall survival, whereas E1690 advantage observed. However, the impor- E1694 tance of relapse-free survival may be worth closer examination in the current setting. In light of the discordant survival results in Statistically it is commonly known that, com- E1684 and E1690, the initial results of another pared to overall survival, disease relapse is a less Intergroup trial, E1694, have received intense objective endpoint because it depends on the def- scrutiny. This trial compared one year of high- inition of relapse as well as the frequency and dose interferon not to an observation control method of detection. Deﬁning relapse is less of as in the two earlier studies, but rather to two an issue in the adjuvant setting since patients years of a ganglioside vaccine called GMK. In a well-conducted clinical trial the For the ﬁrst time, staging of the lymph nodes interval and method of disease assessment are by sentinel node biopsy was performed in a speciﬁed in the protocol and generally complied signiﬁcant fraction of patients. Gangliosides are with by trialists, thereby rendering relapse-free carbohydrate antigens found on the surface of survival a more reliable endpoint than in other melanoma cells, as well as normal cells of neural situations. From the purely clinical viewpoint, crest origin and tumour cells of other types. A patients have made clear that they are willing pilot randomised trial suggested a relapse-free to accept even toxic adjuvant therapies that pro- survival beneﬁt in patients who were treated vide improvements in relapse-free survival, even with puriﬁed ganglioside GM2 (the speciﬁc if they do not result in any prolongation of over- ganglioside in the GMK vaccine) plus BCG all survival. This observation has been directly compared to those treated with BCG alone. In addition, relapse-free survival often overall survival, and mandated that the study represents a truer reﬂection of the biologic activ- results be disclosed early. While there is some evidence of differential post-relapse treatment received, concluding that the lack of interferon survival beneﬁt observed RECONCILING THE STUDY RESULTS BASED in E1690 is due to these differences is not ON CLINICAL CONSIDERATIONS justiﬁed. Making this conclusion presupposes Two of the three randomised Phase III trials of survival efﬁcacy from these salvage therapies, high-dose interferon, E1684 and E1690, demon- which cannot be substantiated with currently strate a relapse-free survival advantage. In addition, comparing outcomes trial, E1694, also shows a relapse-free survival by post-relapse treatment groups provides little beneﬁt but with GMK vaccine and not obser- useful information because patients were not vation as the control treatment. The implication randomised to salvage treatment strategies upon of this design difference is discussed in detail relapse. Nevertheless, many consider there is uni- unknown patient selection factors cannot be formity of evidence that high-dose interferon has accounted for by analysis techniques and their biologic activity in at least delaying relapse after impact can easily remain even after adjusting surgical therapy. Therefore, although the lack of proven alternatives, is enough for available data appear compatible with the notion many patients to choose interferon therapy in the that initial observation after surgery followed by absence of consensus regarding the overall sur- high-dose interferon in case of resectable relapse vival beneﬁt. The original trial, E1684, was conclusion is that salvage treatment difference unlikely to have been affected by crossover for is a possible confounding factor that limits the two reasons.

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Further studies subjects order aleve online from canada treatment for residual shingles pain, it may not excite only the primary spindle isolating Ib afferents during a voluntary contrac- ending purchase generic aleve canada pain treatment lupus. Nevertheless cheap aleve american express pain management utica ny, response of the primary ending switches off during the data in Figs. Responses during voluntary Cutaneous mechanoreceptors movements will not be accurately predictable, par- Most cutaneous mechanoreceptors respond to ticularlyifthevibratorisnotservo-controlledsothat vibration. Ribot-Ciscar, Vedel & Roll, 1989), and there is a constant force of application to the mov- it is probable that Rufﬁni endings in joints do so as ing tendon (Cordo et al. Motor tasks and physiological Contracting muscles implications In contractingmuscles,fusimotordrivecanenhance the spindle response to vibration (Burke et al. First, the application of the vibra- Remote contractions may be of limited functional tor to the tendon is not exactly the same as in the signiﬁcance, but the mechanisms responsible for relaxed state, secondly, the spread of the vibration the widespread reﬂex enhancement accompanying wave to the muscle belly is altered when the mus- such contractions have long been a matter of dis- cle contracts and the tendon stiffens, and thirdly, the pute, and the manoeuvre is important in the clin- contraction may not be associated with a sufﬁcient ical examination. It was previously thought that per- increase in drive to offset these effects. Indeed, if formance of the Jendrassik manoeuvre potentiated thecontractionisareﬂexcontractiontothevibration tendonjerksinuninvolvednon-contractingmuscles (tonic vibration reﬂex, TVR), unloading is the rule, in duetowidespreadactivationofdynamic motoneu- human subjects (Burke et al. Similarly, the reﬂex potentiation accompany- (Clark, Matthews & Muir, 1981). These problems are ing other alerting stimuli, such as a warning cue, has even greater if overt movement occurs at the joint, been attributed to the same mechanism. However, because movement can displace the vibrator and attractive as it may be, this hypothesis is seriously because the responses of different endings are not ﬂawed for a number of reasons. For (i) It is based on the belief that the H reﬂex is not example, the response of primary endings is maxi- potentiated to the same extent by the reinforcement malduringthestretchingphaseofpassiveoscillating manoeuvre. The effects of alternating passive movements on the spindle response to vibration. The response increases more gradually through subharmonics during the stretching phase to 1:2. With shortening, the response gradually decreases again through subharmonics. If a mechanism was responsible Increased spindle discharge for the reﬂex reinforcement, one would expect the during contraction effects on spindle activity to be large, not small, not restricted to a few afferents, and one would expect Evidence for activation of γ motoneurones all studies to have no difﬁculty demonstrating this When movement is prevented so that contractions same ﬁnding. Panel (b ) plots the size sure block experiments suggest that this increase in of the muscle afferent volley from soleus against the spindle discharge is mediated, at least in part, by the intensity of tendon percussion. The round symbols activation of motoneurones (Burke, Hagbarth & represent data when the subject was at rest and the Skuse,1979). Theunloadingreﬂexprovidesevidence triangles when the subject performed the Jendrassik that muscle afferent feedback (presumably mainly manoeuvre. There is no difference in the relation- of spindle origin) contributes to the maintenance ships. However, the manoeuvres were effective re- of motor ﬁring during a tonic isometric contrac- inforcing manoeuvres because a tendon jerk tion. When a muscle is pulling against a ﬁxed resis- occurred (ﬁlled symbols) with weaker percussion tancethatsuddenlygivesway,asilentperiodappears and a lesser afferent volley. Panel (c ) plots, for the in the EMG of the contracting muscle at a latency same data, the size of the reﬂex response against the appropriate for the withdrawal of Ia afferent support intensity of the afferent volley. Jendrassikmanoeuvre(triangles),thereﬂexresponse Thus, overall the fusimotor-driven inﬂow from pri- was obtained at lower threshold than at rest (circles) maryandsecondaryendingsduringavoluntarycon- and was larger for any given size of afferent volley. Decreased presynaptic inhibition of Ia terminals has been suggested (Zehr & Stein, 1999), but, if any- Spindle acceleration after the onset of EMG thing,presynapticinhibitionofIaterminalstosoleus motoneurones is slightly increased at the onset of With brisk phasic contractions, the increase in spin- abrisk ECR contraction (Meunier & Morin, 1989; dle discharge follows the appearance of EMG in the Chapter8,p. Teethclenchinghasbeenreported contracting muscle by up to 50 ms (Vallbo, 1971), to enhance the H reﬂexes of both soleus and tibialis evidence that is inconsistent with the follow-up anterior (as might be expected for a reinforcement length servo hypothesis (Merton, 1951, 1953; see manoeuvre) but also to decrease peroneal-induced Matthews, 1972). Attempts to produce consistent reciprocalIainhibitionofthesoleusHreﬂex(Takada spindle activation in advance of EMG by, e. However, reciprocal Ia viding a warning cue, by using biofeedback train- inhibition is only one of a number of circuits that ing or in learning paradigms, have been unsuc- could be involved in the reﬂex potentiation due to a cessful (Burke, McKeon, Skuse & Westerman, 1980; remote muscle contraction. Gandevia & Burke, 1985;Al-Falahe & Vallbo, 1988; 134 Muscle spindles and fusimotor drive (b) (a) (c) Fig. Effects of the Jendrassik manoeuvre on muscle afferent discharge and the size of the tendon jerk. During the Jendrassik manoeuvre, there is a descending excitatory inﬂuence that enhances reﬂex transmission to motoneurones (MN), but not (or minimally) to MNs. Taps that failed to produce a tendon jerk are shown as open symbols alongside the appropriate afferent volley size. Dashed lines are linear regression lines for the taps that produced reﬂex EMG. The data obtained during reinforcement manoeuvres (ﬁlled triangles) differ signiﬁcantly (P < 0. Motor tasks – physiological implications 135 Al-Falahe, Nagaoka & Vallbo, 1990a,b;Vallbo & is shortening against a load, the discharge pattern Al-Falahe, 1990). Spindles in nearby inactive synergists may be amplitudeandvelocitybecausethefusimotoreffects unloaded (Vallbo, 1973, 1974;Burke et al. The discharge of muscle of movement (Bergenheim, Ribot-Ciscar & Roll, spindle endings in the contracting muscle declines 2000;Roll, Bergenheim & Ribot-Ciscar, 2000). Co- during long-lasting contractions by about one-third contractions may involve greater fusimotor drive to over 60 s, even when the presence of increasing EMG the contracting muscles than occurs during isolated activityindicatessomefatigue-MACROS-. During platform, there is little or no EMG activity in the unloaded phasic shortening contractions, it is likely pretibial muscles, there is a poorly sustained spin- that muscle spindle endings in the contracting mus- dle afferent activity, and manoeuvres that increase clewillbesilenced,andanyperceptualorreﬂexcues the reliance on the proprioceptive feedback do not will come from other receptors, particularly spin- signiﬁcantly alter the fusimotor drive in the absence dles in the antagonist (see Ribot-Ciscar & Roll, 1998). However, when the receptor- Spindle endings in the contracting muscle may dis- bearing muscles are activated tonically or phasically charge, but this occurs after the appearance of the to maintain balance their contraction is accompan- ﬁrst EMG potentials and before the limb has actually ied by an increase in fusimotor drive sufﬁcient to commenced moving. Static fusimotor motoneurones the discharge of both primary and secondary spin- Possible role of the fusimotor system dle endings increases during voluntary contractions during normal movement (Figs. Further evidence indicating a of debate, and it is likely that its importance in the s action consists of an increase in static sensitivity, moment-to-moment control of movement differs in a decrease in the dynamic response of primary end- the cat and man – in part because of the species dif- ings to stretch (though this could be due to a change ferences discussed earlier (see pp. The view in the damping effect of the stiffness of muscle and that some movements can be initiated by ﬁrst acti- tendon), and a loss of the pause in discharge that vating efferents is now rejected for both species, primaryendingsundergofollowingpassiveshorten- but the extent to which the fusimotor system pro- ing (Vallbo, 1973, 1974;Vallbo et al. In addi- vides a necessary support to voluntary contractions tion, there is an increase in the variability of spindle has not been clariﬁed. Microneurography has been discharge, and the appearance of a negative serial used for ∼35 years, but in this time we have learnt a correlation between successive interspike intervals lot about what the fusimotor system does not do and (Burke, Skuse & Stuart, 1979), something that is a relatively little about its essential contribution to the feature of s drive (see Matthews & Stein, 1969; control of human movement. Role of afferent feedback Dynamic fusimotor motoneurones Is movement possible without afferent feedback? There is some evidence that d drive is increased in addition to s (Kakuda & Nagaoka, 1998). How- Movement is possible without any afferent feed- ever, the study compared the dynamic responses to back from the contracting muscle.