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fibromyalgia는 나를 지금의 의료인으로 만들어준 주제다.
환자들은 나의 의료상식으로는 이해할 수 없는 지속적인 통증을 호소했는데 그중 하나가 바로 fibromyalgia이다. 몇년을 이놈과 씨름하다가 나의 통증에 대한 지식과 직관, 통찰은 깊어갔다. 그리고 포기와 재이해, 재치료도전을 반복했다.
통증이 인간에게 주는 피해를 알게해주었고,
만성통증에 대한 개념을 이해하게 해주었고,
뇌과학을 이해하게 해주었고,
심리학, 상담심리학의 길로 이끌어주었다.
그리고 이제 그 지독한 놈의 치료법제시의 문턱에 와 있다.
fibromyalgia의 병리
- muscle spasm, tp, myositis, muscle fibrosis, 반사성 근수축, multiple pain, sensitization, 인간영혼의 파괴(마음의 상처, 우울증, 자포자기, 뇌의 흥분, pain conditioning등)
- 직관에 의한 해답은 met(등장성 원심성 수축)와 pnf, 최적화된 움직임의 재교육 그리고 근육의 재생이다.
골격근의 재생
- 골격근에 있는 핵은 분열할 수 없느나 조직은 광범위하게 재생된다. 재생되는 세포의 근원은 위성세포(satellite cell)로 생각된다. 위성세포는 방추형의 세포로 성숙한 각각의 근섬유를 둘러싸고 있는 기저판에 위치한다. 이와 같이 위성세포는 근섬유표면에 밀착되어 있기 때문에 전자현미경하에서만 관찰가능한 세포다. 이들은 근육분할 후 계속 남아있는 활성이 없는 근모세포로 간주된다. 쉬고 있는 정상위성세포는 손상 또는 어떤 자극이 있을때 활성을 갖게 되어 증식하고, 서로 융합되어 새로운 골격근 섬유를 형성한다. 이러한 위성세포의 활동은 근육비대와 연관이 되어 있다. 운동 후 위성세포들은 원래 존재해 있던 근섬유와 융합하여 근육의 부피를 증가시키게 된다. 이러한 골격근의 재생능력은 심한 근육손상이나 근육변성후라 할지라도 극도 제한되어 있다.
fibromyalgia의 MET적 치료방법
- 등장성 원심성 수축
너무도 오랫동안 고민해오던 문제다.
당장 시행해봐야겠다. 당연히 자가치료방법도 가르치고 sol상태가 gel상태로 바뀌는데는 반감기 300일에서 500일 소요.....
이론적으로 1년만 꾸준히 하면 근육의 반절은 정상으로 돌아온다는 말이다.
Panic bird.....
근섬유통과 발통점
- mps와 fibromyalgia는 같은 질환인가? 이 분야에 선구적 연구자인 Baldry에 의하면 두상태의 증상은 유사하거나 거의 동일하다고 하였다.
같은점
# 추운날씨에 영향을 받는다.
# 교감신경계 활동을 증가시키고, 레이노이드 현상과 같은 증상을 동반한다.
# 긴장성 두통과 이상감각이 주 증상으로 나타난다.
# 진통제에 반응하지 않는다.
차이점
# fibromyalgia는 주로 여자에게서 발생
# fibromyalgia는 전신적인 증상
# mps의 30%환자에게서 근육에 팽팽한 고무밴드와 같은 느낌이 있고, fibromyalgia는 60% 이상
# fibromyalgia환자가 근지구력이 더 약한다. 더 빨리 피로
# fibromyalgia는 수면장애가 주증상이고, mps에서는 가끔 있는 증상이다.
# fibromyalgia는 아침에 뻣뻣함이 있다.
# fibromyalgia는 피로가 주증이다. mps는 통증이 주증
# fibromyalgia는 과민성 장증후군, 월경곤란증, 관절이 붓는 느낌 등이 흔하다.
# fibromyalgia는 삼환계 항우울제가 수면장애, 기타 증상에 도움을 준다.
# fibromyalgia는 도수교정치료, 침술 등에 효과를 보이기 까지 많은 시간이 필요하다.
BRIEF REVIEW
Medicine & Science in Sports & Exercise. 15(3):187-198, 1983.CARLSON, BRUCE M. and; FAULKNER, JOHN A.
Abstract:
Regeneration is a unique adaptation of skeletal muscle that occurs in response to injury. Following direct trauma or disease, regeneration results in restoration, to some degree, of the original structure and function of the muscle. Our purpose is to summarize the main features of the regeneration of skeletal muscle fibers and entire muscles with an emphasis on aspects of regeneration that may be important to the understanding and treatment of sports injuries. The regeneration of skeletal muscle is compared structurally and functionally with its embryonic development. The free muscle graft is used as a model to illustrate the integration of regenerating muscle with the rest of the body. Finally, the breakdown and regeneration of skeletal muscle fibers are discussed in relation to local anesthetics, sports injuries, and disease.
Satellite cells, the primary stem cells of adult skeletal muscle
1. Muscle injury can result in a significant loss of function that can impact on quality of life. In this review we describe how muscles can be injured by external factors such as: contusion, laceration, or crush; by internal factors such as muscle strains during sudden and severe falls; or during the performance of some actions during sports. In addition, we describe the injury to a muscle that occurs when its blood supply is interrupted – an occurrence common in clinical settings. An overview of muscle regeneration is presented as well as a discussion of some of the potential complications that can compromise successful muscle repair and lead to impaired function and permanent disability.
2. Improving muscle regeneration is important for hastening muscle repair and restoring muscle function and this review describes ways in which this can be achieved. We describe recent advances in tissue engineering that offer considerable promise for treating muscle damage, but highlight the fact that these techniques require rigorous evaluation before they can become mainstream clinical treatments.
3. Growth promoting agents are purported to increase the size of existing and newly regenerating muscle fibres and therefore could be employed to improve muscle function if administered at appropriate times during the repair process. This review provides an update on the efficacy of some growth promoting agents, including anabolic steroids, insulin-like growth factor-I (IGF-I) and β2-adrenoceptor agonists (β2-agonists), to improve muscle function after injury. Although these approaches have clinical merit, a better understanding of the androgenic, IGF-I, and β-adrenergic signalling pathways in skeletal muscle is important if we are to devise safe and effective therapies to enhance muscle regeneration and function after injury.
Skeletal muscles can be injured by external factors such as: contusion, laceration, or crush1-3 from road trauma, workplace accidents, or collisions on the sports field; or by internal factors such as strains, e.g. a hamstrings muscle tear when running or kicking;4-6 or during surgery involving muscle laceration or during reconstructive or transplantation surgery, when muscles are excised by surgeons and transferred from one part of the body to another to provide supporting structures and help restore some level of function.7,8 These transplantation procedures involve an unavoidable disruption (or interruption) to the muscle’s normal blood supply (called ‘ischaemia’). Subsequent return of the blood supply (reperfusion) is problematic in that a severe secondary injury can ensue mediated by production of damaging free radicals when blood flow is restored.9-12 The same process occurs after revascularization of an amputated limb, compartment syndromes associated with vascular injury and following excessive tourniquet application.13 Muscle injuries such as crush, ischaemia-reperfusion, and contraction-mediated damage involve injury to the muscle’s support structures (including blood and nerve supply), such that functional repair is compromised.14,15 All of these events can severely impair muscle structure and function, mobility and quality of life. Skeletal muscle injury is a significant health issue that costs billions in health care every year in most developed nations.
The cellular and molecular mechanisms of muscle regeneration after injury and degeneration have been described extensively.16-20 Unfortunately, all evidence indicates that once muscles are damaged, the muscle repair/regeneration process is not always complete and can often be slow or complicated by fibrotic infiltration and scarring. Incomplete and slow repair can result in disability or handicap. Thus, developing therapeutic approaches to enhance the regeneration process and hasten restoration of muscle function is critical for improving the long-term physical outcome of patients and athletes suffering muscle injuries and for preventing or minimising functional disability after surgery.5,21
Muscle injury and repair involves a complex balance between local muscle fibre repair, regeneration, and scar-tissue formation.22 A variety of methods have been examined for the purpose of hastening muscle regenerative processes in order to restore muscle function, by either enhancing muscle fibre growth and regeneration and/or promoting vascularity and nerve repair. Anti-inflammatory medications, corticosteroids, surgical methods, and exercise protocols have been studied.21,22 Current research efforts are exploring closer interactions between developmental biology and tissue engineering in order to enhance existing tissue or develop new tissues to replace those that are damaged irreparably.23,24 Regenerative medicine and tissue engineering provide novel therapeutic approaches to restore muscle structure and function to damaged skeletal muscles after injury or disease.25-28 These approaches include the use of stem cells (including skeletal muscle-derived stem cells), bioinductive factors, and bioscaffolds to facilitate release of cells or biological growth factors to repair and/or regenerate skeletal muscle.28-31 While offering considerable promise for the treatment of muscle damage, realistically it will take many years before these emerging techniques are perfected and become mainstream clinical treatments.
To evaluate the current status of all the different approaches for treating muscle injury is beyond the scope of this brief review. Instead, we have focussed attention on therapies that have purported anabolic or growth promoting effects on skeletal muscle. The basic rationale is that growth promoting agents can hasten muscle regeneration by increasing the size of existing and newly regenerating muscle fibres and thereby improving muscle function. Muscle growth promoting agents include (but are not limited to) growth hormone, testosterone-derived or testosterone-like hormones such as anabolic steroids, insulin-like growth factor-I (IGF-I), and β2-adrenoceptor agonists (β2-agonists). We will provide a brief overview of the current state of knowledge regarding the efficacy of some of these growth promoting agents (anabolic steroids, IGF-I and β-agonists) to improve muscle function after injury.
Androgenic-anabolic steroids (AAS) are synthetic derivatives of the male hormone testosterone capable of exerting strong effects on the human body that can benefit athletic performance.32 Testosterone replacement therapy has been effectively used to counteract loss of lean body mass in hypogonadal men,33,34 in older men with normal or low serum testosterone,35,36 and HIV-infected men with low serum testosterone.37 Similarly, muscle growth has been achieved in eugonadal states after supraphysiological administration to young, healthy men,38,39 and HIV-infected men with normal testosterone levels.40 Although some studies have demonstrated enhanced muscle strength following testosterone administration,41 others have reported no effect of androgen therapy on muscle function despite increases in muscle size.42 Although anabolic steroids have been used for the treatment of HIV- related wasting and other wasting conditions for many years, many questions remain unanswered, including those regarding appropriate and safe doses for long-term administration and the associated potential risks or side effects.43,44
There have been numerous studies that have investigated the effects of anabolic steroids on skeletal muscles that are simultaneously responding to other stimuli such as functional overload,45 hindlimb suspension in rats46 or heavy resistance training in humans.47 However, few studies have examined the effect of anabolic steroids on skeletal muscle regeneration per se. One of the most important investigative techniques used in studying this process is to follow the muscle fibre degeneration and subsequent spontaneous fibre regeneration after an intramuscular injection of a myotoxin, such as snake venoms (e.g. notexin or cardiotoxin) or local anaesthetics such as bupivacaine hydrochloride.48 Ferry and colleagues49 examined whether treating rats with nandrolone deconoate improved regeneration of fast-twitch extensor digitorum longus (EDL) and slow-twitch soleus muscles after myotoxic injury caused by direct intramuscular injection of notexin. Nandrolone increased the mass of regenerating soleus muscles and decreased the relative amount of fast myosin heavy chain protein, but anabolic steroid treatment had no effect on regenerating EDL muscles.49 In a follow-up study, the authors found that anabolic steroid treatment had no significant effect on the functional properties of regenerating EDL or soleus muscles at 21 days post notexin injury.50 Beiner and colleagues51 examined whether nandrolone deconoate could enhance the function of regenerating rat skeletal muscles following contusion injury. They found that at 7 days post-injury anabolic steroid treatment had no beneficial effect on the force producing capacity of gastrocnemius muscles in situ but by 14 days post-injury muscles from treated rats had improved twitch (but not tetanic) forces. Although interesting, this does not represent a definitive improvement in muscle strength since in vivo, all muscle actions result from graded tetanic (not twitch) contractions. However, the authors concluded that anabolic steroids could help the functional recovery of injured muscles and therefore “may have an ethical clinical application to aid healing in severe muscle contusion injury, and their use in the treatment of muscle injuries warrants further research”.51
In a recent preliminary study, tibialis anterior (TA) muscles from castrated male mice were injured by intramuscular injection of the myotoxic agent, bupivacaine, and then treated with nandrolone decanoate to determine whether muscle regeneration could be enhanced.52 Anabolic steroid treatment increased the incidence of small diameter fibres (as a proportion of the total number of fibres) at 14 days post-bupivacaine injury by 65% compared with injured muscles from untreated mice. At 28 days post-injury, there was no effect of treatment on the number of these smaller diameter fibres, but the incidence of large fibres (as a proportion of the total number of fibres) was two-fold greater in muscles from treated compared with untreated mice. It should be noted that the variable size of the regenerating muscle fibres could also indicate that bupivacaine injured some fibres but spared others. We have previously shown that the extent of muscle fibre injury in mice following an intramuscular injection of bupivacaine is significantly less than that after an intramuscular injection of a more powerful myotoxin such as notexin.48 Regardless, the study showed that anabolic steroid treatment could improve myofibre growth during the later stages of muscle regeneration.52
Another preliminary study examined the effect of two doses of nandrolone deconoate on regeneration and satellite cells in mouse skeletal muscles following an intramuscular injection of venom from the jararacucu snake (Bothrops jararacussu) of South America.53 At 6 mg/kg, the anabolic steroid increased the number of myotubes after 3 and 7 days post venom injection and the number of muscle fibres with normal morphology after 21 days. Muscle satellite cell proliferation at 7 and 21 days was also increased in mice that received this dose. However, regeneration was not improved in the injured muscles of mice treated with nandrolone deconoate at a lower dose of 2 mg/kg. Thus, the higher dose (6 mg/kg) of the anabolic steroid was required in mice in order to produce a beneficial effect on muscle regeneration after severe myotoxic damage.53
Another important issue is whether anabolic steroids may have clinical application in treating the symptoms of skeletal muscle diseases especially where muscle repair mechanisms are defective and recurring episodes of fibre injury and inefficient and incomplete regeneration are a critical aspect of the pathophysiology, such as in Duchenne muscular dystrophy (DMD). In a study on dystrophic mdx mice, an animal model of DMD that also exhibits ongoing injury and regeneration in the limb muscles throughout the lifespan, treatment with anabolic steroids did not have a beneficial effect.54 In fact, anabolic steroid treatment aggravated the dystrophic pathology in the EDL and soleus muscles, as evidenced from elevated creatine kinase activity and a doubling of the number of centrally nucleated muscle fibres (an index of accumulated injury and repair). Interestingly, the size of some fibre populations actually decreased in mdx mice after anabolic steroid treatment.54
Regardless of the initial cause of muscle injury, effective fibre regeneration is dependent on the timed induction of myogenic regulatory factors and growth factors, including IGF-I.3,20,55 IGF-I activates both myoblast proliferation and subsequently differentiation, crucial processes for successful muscle repair and regeneration.56 The importance of IGF-I in muscle regeneration has been demonstrated in transgenic mice, where muscle-specific overexpression of IGF-I maintained regenerative capacity in aged mice57 and reduced the skeletal muscle pathology in dystrophic mdx mice.58,59 Exogenous administration of recombinant human IGF-I (rhIGF-I) increased the rate of functional recovery after myotoxic injury60 and improved the dystrophic pathology in mdx mice.61-63 Clearly, administration of IGF-I and other growth factors has the potential to accelerate healing processes and other tissues after trauma, but their use in sports medicine is restricted because of the potential for abuse as performance-enhancing agents.64
Although rhIGF-I administration and transgenic IGF-I overexpression have beneficial effects on skeletal muscle, their mechanism of action differs considerably. Transgenic IGF-I overexpression in mice produced muscle hypertrophy58 whereas rhIGF-I administration to mice did not.61-63 We have speculated that these differential effects may be attributed to different interactions with IGF-binding proteins (IGFBPs) following systemic delivery of IGF-I to mice compared with muscle-specific overexpression of IGF-I in transgenic mice. Although the effects of rhIGF-I administration and IGF-I overexpression on skeletal muscle regeneration have been well characterised, the role of IGFBPs in skeletal muscle regeneration remains poorly understood. Recently, we examined whether inhibiting IGF-I interactions with IGFBPs influenced muscle regeneration after myotoxic injury using the aptamer NBI-31772 which binds all six IGFBPs with high affinity and releases “free” endogenous IGF-I. Continual release of NBI-31772 into the circulation of mice via a mini-osmotic pump increased the rate of functional recovery in mouse tibialis anterior muscles after notexin-mediated damage.65 These results support the notion that abrogating IGFBP interactions with systemic IGF-I has therapeutic potential for enhancing muscle repair after muscle injury.
Although β2-adrenoceptor agonists (β2-agonists) are traditionally prescribed for alleviating bronchospasm in the treatment of asthma because of their bronchodilatory effects on smooth muscle, some β2-agonists actually have potent anabolic effects on skeletal muscle especially when administered systemically and at higher doses.66-68 These muscle hypertrophic effects of β2-agonists combined with their known lipolytic actions, have proved desirable for those working in the livestock industry trying to improve meat quality and yield.69,70 Not surprisingly, β2-agonists have also been used and abused by many athletes involved in competitive bodybuilding, strength- and power-related sports, and sports such as wrestling where athletes need to “make weight” in order to compete in specific weight classes.71,72 However, because of their anabolic effects on skeletal muscle, β2-agonists have significant clinical potential particularly for muscle wasting disorders including the muscular dystrophies.72
Skeletal muscle contains a significant proportion of β-adrenoceptors, mostly of the β2-subtype, with approximately 7-10% β1-adrenoceptors present and a sparse population of α-adrenoceptors, usually in higher proportions in slow-twitch muscles.69,70,73,74 Slow-twitch muscles have also been shown to have a greater density of β-adrenoceptors than fast-twitch muscles.70 Since β-adrenoceptors exist in the heart as well as skeletal muscle, any approach involving the systemic administration of exogenous β-agonists must take into account potential effects on tissues other than skeletal muscle, particularly the heart. Synthetic β2-agonists promote skeletal muscle hypertrophy via activation of cAMP dependent mechanisms that increase protein synthesis and inhibit protein degradation pathways.72,75 Recently, PI3K-Akt signalling, which is known to be implicated in skeletal muscle hypertrophy, has also been linked to β2-adrenergic receptor signalling.76
We and others have also shown that systemic administration of β-agonists can promote regeneration of injured skeletal muscles, specifically to hasten the functional recovery of rat muscles after myotoxic injury with bupivacaine77 or notexin.48,78 Daily fenoterol administration to rats (1.4 mg/kg/day, i.p.) enhanced the force output of injured/regenerating rat EDL muscles by 19% at 14 days post injury, which was associated with increases in protein content and muscle fibre size.77 Daily clenbuterol treatment to rats (2 mg/kg/day, by oral gavage) increased protein content in regenerating soleus muscles and caused significant transitions from slow to fast fibres.78 More recently, we have studied aspects of β-adrenoceptor signalling during early regeneration of rat EDL and soleus skeletal muscles after bupivacaine injury and found that despite β-agonist (fenoterol) treatment decreasing β-adrenoceptor density in regenerating rat EDL and soleus muscles, the cAMP response to β-adrenoceptor stimulation, relative to healthy (uninjured) muscles, remained elevated.79
The potential for β-agonists to improve the size and strength of muscles of human patients affected by neuromuscular diseases where muscle regenerative mechanisms are defective, has received relatively limited attention. Preliminary trials using the β2-agonist, albuterol, to treat young boys with facioscapulohumeral dystrophy, found that year-long administration at doses of 16 and 32 mg/day had only limited beneficial effects on strength, and was associated with some adverse cardiovascular related events such as palpitations and in some cases, muscle tremor.80 Fowler and colleagues81 administered albuterol at a lower dose of 8 mg/day for 28 weeks to boys with DMD or BMD and found modest increases in strength with no side effects. Albuterol was well tolerated, but elicited only modest improvements in muscle mass and strength. It is our contention that one of the factors currently limiting the application of β2-agonists for DMD and related disorders is that albuterol is simply not a powerful enough anabolic agent to counteract the severe muscle wasting and to stimulate muscle regenerative mechanisms sufficiently. We have shown unequivocally that newer generation β2-agonists, such as formoterol, have powerful skeletal muscle anabolic effects (in mice and rats) even when administered in micromolar doses.67,82 Most importantly formoterol is more selective for the β2-adrenoceptor and its effects on the heart (comprising predominantly β1-adrenoceptors) are much less than those of older generation β2-agonists like albuterol or clenbuterol. Blocking stimulation of the β1-adenoceptors is possible with highly selective β1-adrenoceptor antagonists (such as CGP 20712A65) and the importance of blocking β1-adrenoceptors in heart failure to abrogate cardiotoxic β1-adrenoceptor-mediated effects is well known.83,84
It is clear that better understanding the androgenic, IGF-I, and β-adrenergic signalling pathways in skeletal muscle is important for devising and optimising safe therapies to enhance muscle regeneration and function following different types of muscle injury. Although many aspects of these signalling cascades have been described in detail elsewhere,72,75 the complementary interactions between them especially in relation to the activation of pathways induced by anabolic agents specifically for enhancing muscle functional recovery after injury has not been described widely (see Figure 1). The extracellular and intracellular mechanisms of action of the three classes of anabolic agents discussed in this review: anabolic steroids, IGF-I and related therapeutics, and β2-adrenoceptor agonists; exhibit significant “cross-talk” and converge on pathways responsible for protein synthesis. Extracellular cross-talk between these signals includes increased IGF-I levels and the modulation of IGFBPs due to β2 agonist administration,85 and increased levels of IGF-I as a consequence of anabolic steroid administration.86,87 Intracellular cross-talk between these signals is extensive and includes activation of PI3K by the β/γ subunits of G-protein complex following andrenoceptor stimulation72,75 and activation of PI3K and p70S6K by IGF-I and following AR stimulation.88,89 Details regarding these signalling pathways and their interactions are incomplete and further delineation of novel signalling molecules will yield new therapeutic targets for enhancing skeletal muscle regeneration after injury (Figure 1).
Figure 1. Signalling cascades induced by anabolic agents that result in enhanced functional recovery after skeletal muscle injury. The extracellular and intracellular mechanisms of action of anabolic steroids, IGF-I related therapeutics and β2-adrenoceptor agonists, exhibit significant “cross-talk” and converge on protein synthetic pathways. Extracellular cross-talk between these signals includes increased IGF-I levels and modulation of IGFBPs (either increased or decreased levels of specific IGFBPs) following β2 agonist administration,85 and increased levels of IGF-I due to anabolic steroid administration.86,87 Intracellular cross-talk between these signals is extensive and includes activation of PI3K by the β/γ subunits of G-protein complex following andrenoceptor stimulation (for review see Lynch & Ryall (2008)72 and Lynch et al. (2007)75) and activation of PI3K and p70S6K by IGF-I and in response to AR stimulation.88,89 These signalling pathways have not been characterised completely and further delineation of novel signaling molecules will yield new therapeutic targets for enhancing muscle regeneration. [α: alpha subunit of G-protein complex; β/γ: β and γ subunits of G-protein complex; AR: androgen receptor; B2-AR: β2-adrenoceptor; CRE: 3′-5′-cyclic adenosine monophosphate (cAMP) response element; CREB: cAMP response element-binding protein; IGF-I: insulin-like growth factor-I; IGFBPs: insulin-like growth factor binding proteins; IGF-IR: insulin-like growth factor-I receptor; IRS ½: insulin receptor substrate 1/2; PI3K: phosphoinositide-3 kinase; p70S6K: 70 kDa ribosomal protein S6 kinase; PKA: protein kinase A].
For anabolic therapies, concerns regarding potential pharmaceutical toxicity and safety issues are often only related to high doses, so low-dose, short-term treatment strategies are likely to have less toxic effects and their clinical merit is worthy of testing. To this end, extensive preclinical and clinical studies are needed to determine the optimum doses and treatment regimens that will elicit significant improvements in muscle fibre size and strength without causing deleterious side effects such as cardiovascular complications or perhaps the formation of tumours if growth factors are administered systemically. Alternatively, intramuscular delivery and the use of emerging tissue engineering technologies that facilitate the timed and controlled release of growth factors, anabolic and/or antifibrotic agents, could help minimise potential side effects while exerting beneficial effects on regenerating muscle fibres to hasten restoration of muscle function after injury.
Supported by research grant funding from the Australian Research Council Discovery-Project funding scheme (DP0665071, DP0772781), the National Health and Medical Research Council of Australia (350439, 454561, 509313), the Muscular Dystrophy Association (USA, 3595, 4167), and Pfizer Inc. (USA).
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