A double-blind randomized controlled trial of the effects of eicosapentaenoic acid supplementation on muscle inflammation and physical function in patients undergoing colorectal cancer resection.

BACKGROUND: Resection of colorectal cancer (CRC) initiates inflammation, mediated at least partly by NFĸB (nuclear factor kappa-light-chain-enhancer of activated B-cells), leading to muscle catabolism and reduced physical performance. Eicosapentaenoic acid (EPA) has been shown to modulate NFĸB, but evidence for its benefit around the time of surgery is limited. OBJECTIVE: To assess the effect of EPA supplementation on muscle inflammation and physical function around the time of major surgery. DESIGN: In a double-blind randomized control trial, 61 patients (age: 68.3 ± 0.95 y; 42 male) scheduled for CRC resection, received 3 g per day of EPA (n = 32) or placebo (n = 29) for 5-days before and 21-days after operation. Lean muscle mass (LMM) (via dual energy X-ray absorptiometry (DXA)), anaerobic threshold (AT) (via cardiopulmonary exercise testing (CPET)) and hand-grip strength (HG) were assessed before and 4-weeks after surgery, with muscle biopsies (m. vastus lateralis) obtained for the assessment of NF-ĸB protein expression. RESULTS: There were no differences in muscle NFĸB between EPA and placebo groups (mean difference (MD) -0.002; 95% confidence interval (CI) -0.19 to 0.19); p = 0.98). There was no difference in LMM (MD 704.77 g; 95% CI -1045.6 g-2455.13 g; p = 0.42) or AT (MD 1.11 mls/kg/min; 95% CI -0.52 mls/kg/min to 2.74 mls/kg/min; p = 0.18) between the groups. Similarly, there was no difference between the groups in HG at follow up (MD 0.1; 95% CI -1.88 to 2.08; p = 0.81). Results were similar when missing data was imputed. CONCLUSION: EPA supplementation confers no benefit in terms of inflammatory status, as judged by NFĸB, or preservation of LMM, aerobic capacity or physical function following major colorectal surgery. CLINICAL TRIALS REFERENCE: NCT01320319.

Myopathy in a 61-year-old Hispanic man.

A 61-year-old Hispanic man presented to a county hospital for subacute progressive weakness, heliotrope rash and dysphagia. There was initial suspicion for dermatomyositis (DM) given the history; however, the physical exam was not consistent. An MRI followed by a muscle biopsy revealed necrotising autoimmune myositis and anti-3-hydroxy-3-methylglutary-coenzyme A-reductase antibody titers returned positive; the patient was diagnosed with necrotising autoimmune myositis. He was treated with corticosteroids and intravenous immunoglobulin, which resulted in improvement in his weakness and functional status. This case represents a unique instance in which a cardinal feature of DM, the heliotrope rash, prompted an erroneous initial diagnosis. It highlights the necessity of developing abroad differential diagnosis and subsequent thorough investigation into patients presenting with suspected idiopathic immune-mediated myopathies.

Instrument-assisted soft tissue mobilization: effects on the properties of human plantar flexors.

The effect of instrument-assisted soft tissue mobilization (ISTM) on passive properties and inflammation in human skeletal muscle has not been evaluated. Passive properties of muscle, inflammatory myokines and subjective reporting of functional ability were used to identify the effects of ISTM on the plantar flexors. 11 healthy men were measured for passive musculotendinous stiffness (MTS), passive range of motion (PROM), passive resistive torque (PASTQ) and maximum voluntary contraction peak torque (MVCPT) for plantar flexor muscles of the lower leg. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) were measured from muscle biopsies from the gastrocnemius, and subjective measurements of functional ability were taken using the perception of functional ability questionnaire (PFAQ). MTS, PROM, PRT and MVCPT were measured in the treatment leg (TL) and control leg (CL) before, immediately after, 24 h, 48 h and 72 h following IASTM. Biopsies for IL-6 and TNF-α and PFAQ responses were collected before as well as 24 h, 48 h and 72 h after IASTM. There were no significant differences in MTS, PROM, PASTQ, MVCPT, IL-6 and TNF-α between the TL or CL. A significant decrease in the perception of function and a significant increase in pain for the TL were found following IASTM.

Investigating the mechanisms of massage efficacy: the role of mechanical immunomodulation.

Massage has the potential to attenuate the inflammatory process, facilitate early recovery, and provide pain relief from muscular injuries. In this hypothesis-driven paper, we integrate the concept of mechanotransduction with the application of massage to explore beneficial mechanisms. By altering signaling pathways involved with the inflammatory process, massage may decrease secondary injury, nerve sensitization, and collateral sprouting, resulting in increased recovery from damage and reduction or prevention of pain. Our goal is to provide a framework that describes our current understanding of the mechanisms whereby massage therapy activates potentially beneficial immunomodulatory pathways.

Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis.

Arthrogenic alphaviruses, such as Ross River virus (RRV), chikungunya, Sindbis, mayaro and o'nyong-nyong viruses circulate endemically worldwide, frequently causing outbreaks of polyarthritis. The exact mechanisms of how alphaviruses induce polyarthritis remain ill defined, although macrophages are known to play a key role. Macrophage migration inhibitory factor (MIF) is an important cytokine involved in rheumatoid arthritis pathogenesis. Here, we characterize the role of MIF in alphavirus-induced arthritides using a mouse model of RRV-induced arthritis, which has many characteristics of RRV disease in humans. RRV-infected WT mice developed severe disease associated with up-regulated MIF expression in serum and tissues, which corresponded to severe inflammation and tissue damage. MIF-deficient (MIF(-/-)) mice developed mild disease accompanied by a reduction in inflammatory infiltrates and muscle destruction in the tissues, despite having viral titers similar to WT mice. In addition, reconstitution of MIF into MIF(-/-) mice exacerbated RRV disease and treatment of mice with MIF antagonist ameliorated disease in WT mice. Collectively, these findings suggest that MIF plays a critical role in determining the clinical severity of alphavirus-induced musculoskeletal disease and may provide a target for the development of antiviral pharmaceuticals. The prospect being that early treatment with MIF-blocking pharmaceuticals may curtail the debilitating arthritis associated with alphaviral infections.

Transcutaneous electrical nerve stimulation (TENS) reduces chronic hyperalgesia induced by muscle inflammation.

Transcutaneous electrical nerve stimulation (TENS) reduces pain through central mechanisms involving spinal cord and brainstem sites. Since TENS acts through central mechanisms, we hypothesized that TENS will reduce chronic bilateral hyperalgesia produced by unilateral inflammation when applied either ipsilateral or contralateral to the site of muscle inflammation. Sprague-Dawley rats were injected with carrageenan in the left gastrocnemius muscle belly. Mechanical withdrawal threshold was tested bilaterally before and 2 weeks after carrageenan injection. After testing withdrawal thresholds at 2 weeks, rats received TENS treatment either ipsilateral or contralateral to the site of inflammation. In each of these groups, rats were randomized to control (no TENS), low frequency (4 Hz), or high frequency (100 Hz) TENS treatment. TENS was applied for 20 min at sensory intensity under light halothane anesthesia. Mechanical withdrawal thresholds were re-assessed after TENS or 'no TENS' treatment. Unilateral injection of carrageenan to the gastrocnemius muscle significantly reduced the mechanical withdrawal threshold (mechanical hyperalgesia) bilaterally 2 weeks later. Either low or high frequency TENS applied to the gastrocnemius muscle ipsilateral to the site of inflammation significantly reversed mechanical hyperalgesia, both ipsilateral and contralateral to the site of inflammation. Low or high frequency TENS applied to the gastrocnemius muscle contralateral to the site of inflammation also significantly reduced mechanical hyperalgesia, both ipsilateral and contralateral to the site of inflammation. Since ipsilateral or contralateral TENS treatments were effective in reducing chronic bilateral hyperalgesia in this animal model, we suggest that TENS act through modulating descending influences from supraspinal sites such as rostral ventromedial medulla (RVM).

The effect of creatine supplementation upon inflammatory and muscle soreness markers after a 30km race.

We have evaluated the effect of a creatine supplementation protocol upon inflammatory and muscle soreness markers: creatine kinase (CK), lactate dehydrogenase (LDH), prostaglandin E2) (PGE2) and tumor necrosis factor-alpha (TNF-alpha) after running 30km. Runners with previously experience in running marathons, with their personal best between 2.5-3h were supplemented for 5 days prior to the 30km race with 4 doses of 5g of creatine and 15g of maltodextrine per day while the control group received the same amount of maltodextrine. Pre-race blood samples were collected immediately before running the 30km, and 24h after the end of the test (the post-race samples). After the test, athletes from the control group presented an increase in plasma CK (4.4-fold), LDH (43%), PGE2 6.6-fold) and TNF-alpha (2.34-fold) concentrations, indicating a high level of cell injury and inflammation. Creatine supplementation attenuated the changes observed for CK (by 19%), PGE2 and TNF-alpha (by 60.9% and 33.7%, respectively, p<0.05) and abolished the increase in LDH plasma concentration observed after running 30km, The athletes did not present any side effects such as cramping, dehydration or diarrhea, neither during the period of supplementation, nor during the 30km race. All the athletes finished the race in a time equivalent to their personal best +/- 5.8%. These results indicate that creatine supplementation reduced cell damage and inflammation after an exhaustive intense race.

Prolonged vitamin C supplementation and recovery from eccentric exercise.

We have previously shown that vitamin C supplementation affects recovery from an unaccustomed bout of demanding exercise, with the most pronounced effect being that on plasma interleukin-6 concentration. However, because of the proposed role of interleukin-6 in the regulation of metabolism, it was unclear whether this represented a reduced response to muscle damage or some form of interaction with the metabolic demands of the activity. Therefore, the aim of the present study was to investigate the effect of the same form of supplementation on a bout of exercise that initiated similar muscle damage but had a low metabolic cost. Fourteen male subjects were allocated to either a placebo (P) or a vitamin C (VC) group. The VC group consumed 200 mg of ascorbic acid twice a day for 14 days prior to a bout of exercise and for the 3 days after exercise. The P group consumed identical capsules that contained 200 mg lactose. Subjects performed 30 min of downhill running at a gradient of -18% and recovery was monitored for up to 3 days after exercise. Plasma VC concentrations in the VC group increased following supplementation. Nevertheless, downhill running provoked a similar increase in circulating markers of muscle damage (creatine kinase activity and myoglobin concentration) and muscle soreness in P and VC groups. Similarly, although downhill running increased plasma interleukin-6, there was no effect from VC supplementation. These results suggest that vitamin C supplementation does not affect interleukin-6 concentrations following eccentric exercise that has a low metabolic component.

Influence of nonsteroidal anti-inflammatory drug treatment duration and time of onset on recovery from exercise-induced muscle damage in rats.

OBJECTIVE: To determine if duration and time of onset of treatment with diclofenac sodium influence force recovery after exercise-induced muscle damage in rats. DESIGN: Randomized placebo-controlled trial. SETTING: Animal laboratory. ANIMALS: A total of 217 female adult Wistar rats. INTERVENTION: Rats were submitted to a protocol consisting of 450 eccentric contractions of the ankle dorsiflexors. Treatment by gavage with diclofenac sodium (1 mg/kg, twice daily) was started at different times pre- and postprotocol or for various treatment durations. MAIN OUTCOME MEASURES: In vitro contractile properties. RESULTS: When treatment was initiated shortly postprotocol, force recovery was roughly proportional to treatment duration during the first 3 days but not at 7 and 28 days postprotocol. A 7-day treatment was no more effective than 1- or 2-day treatments when force was measured at 7 and 28 days; however, such prolonged treatment had no deleterious effect on muscle force at either time. A single-dose prophylactic treatment was as effective as a 2-day treatment initiated soon after the protocol when force was assessed 2 days postprotocol; on the other end, a treatment delayed for 3 days had no effect when force was measured at 7 days. CONCLUSIONS: Treatment with diclofenac sodium extending past the acute inflammatory phase was no more effective than short and timely treatment in this model of skeletal muscle damage.

The effects of fish oil and isoflavones on delayed onset muscle soreness.

INTRODUCTION/PURPOSE: Fish oils (FO) have been shown to modulate the inflammatory response through alteration of the eicosanoid pathway. Isoflavones (ISO) appear to reduce the inflammatory pathway through their role as a tyrosine kinase inhibitor. Delayed onset muscle soreness (DOMS) develops after intense exercise and has been associated with an inflammatory response. Therefore, we hypothesized that physical parameters associated with DOMS could be decreased via the modulation of the inflammatory response by supplementing subjects with either FO or ISO. METHODS: 22 subjects were recruited and randomly assigned to one of three treatment groups: FO (1.8 g of omega-3 fatty acids x d(-1)), ISO (120 mg soy isolate x d(-1)), or placebo (PL) (Western fat blend and/or wheat flour). All treatment groups received 100-IU vitamin E x d(-1) to minimize lipid peroxidation of more highly unsaturated fatty acids. Subjects were supplemented 30 d before the exercise and during the week of testing and were instructed to refrain from unusual exercise. DOMS was induced by 50 maximal isokinetic eccentric elbow flexion contractions. Strength parameters, pain, arm circumference, and relaxed arm angle (RANG) were measured at 48, 72, and 168 h post exercise. Cortisol, creatine kinase (CK), interleukin-6 (IL-6), tumor necrosis factor (TNFalpha), malondialdehyde (MDA), and serum iron were measured before supplementation, after supplementation, and post exercise. RESULTS: Significant decreases were observed in RANG and strength 48 h postexercise among all groups, and there were significant increases in pain and arm circumference. There were no significant changes among all groups from baseline at 168 h (7 d) post exercise. There were no significant treatment effects between groups for the physical parameters or for cortisol, CK, IL-6, TNFalpha, MDA, or serum iron. CONCLUSION: These data indicate FO or ISO, at the doses supplemented, were not effective in ameliorating DOMS with the above-cited protocol.

Idiopathic inflammatory myopathy: management and prognosis.

We are entering an exciting era in our understanding and management of the connective tissue diseases and, in particular, inflammatory myopathy. There is an established array of immunosuppressive regimens available to clinicians; rehabilitative and physical therapeutic interventions are evolving to provide many nonpharmacologic options to complement current therapy. Our ability to quantify [table: see text] the disease burden, using newly developed tools to distinguish myositis disease activity from disease damage, will allow us to measure with greater sensitivity the effects of treatment interventions. These measures, together with the development of international consensus regarding the standardization of many clinical trial design parameters, will enhance our capacity to conduct well-designed, prospective, multicenter studies of established and newly developed therapies. The explosion of immunopathogenetic information, in conjunction with novel biologic agents (Table 4), will afford investigators a treatment menu with multiple therapeutic options. The continuing challenge for the practitioner is the development of a logical, well-studied, multifaceted, and multidisciplinary holistic approach that optimizes the risk: benefit ratio for each individual patient and uses a rational combination of immunomodulatory agents in conjunction with ancillary measures.

Massage and ultrasound as therapeutic modalities in exercise-induced muscle damage.

Although both massage and ultrasound treatment are used in clinical settings to enhance muscle functional recovery following exercise-induced muscle damage, there is a paucity of experimental evidence for their efficacy. Theoretically both massage and ultrasound could affect some physiological factors associated with enhancement of postexercise muscle recovery. However, the actual physiological mechanisms by which massage or ultrasound could influence postexercise muscle damage and repair are unknown. Most experimental evidence suggests that massage has little influence on muscle blood flow, clearance of "noxious" substances, recovery of postexercise muscle strength, or delayed soreness sensation. However, more data is needed before conclusions can be drawn as to the ability of massage to influence postexercise inflammatory response or various other physiological changes that characterize exercise-induced muscle damage and repair. There is even less information on the ability of ultrasound to influence physiological or functional factors associated with postexercise muscle damage. The few experiments that have been done tend to be contradictory and have yet to consider the range of ultrasound treatment parameters for therapeutic effectiveness in treating postexercise damage and influencing repair processes. Much more research is needed to determine whether either treatment modality can have any therapeutic effect on exercise-induced muscle damage and recovery of postexercise muscle function.

Myositis-induced functional reorganisation of the rat dorsal horn: effects of spinal superfusion with antagonists to neurokinin and glutamate receptors.

The study aimed at identifying some of the receptors for neurotransmitters/neuromodulators that are involved in the myositis-induced neuroplastic changes in spinal neurones. In anaesthetised rats, an experimental myositis was induced in the gastrocnemius-soleus muscle and the activity of single dorsal horn neurones recorded in the segment L3, just rostral to the main input region from that muscle. During the development of the myositis, the segment L3 was continuously superfused with antagonists to neurokinin receptors (GR 82.334, Spantide II), NMDA receptors (MK-801, AP 5) or AMPA/kainate receptors (CNQX). Each of the antagonists reduced the myositis-induced increase in excitability, but acted on different aspects of the hyperexcitability. GR 82.334 was most effective in preventing the expansion of the neurone population that responded to A-fibre input from the inflamed muscle, which was the main myositis effect in the present study. None of the antagonists influenced the background activity of the neurones. The results show that in the myositis-induced hyperexcitability of dorsal horn neurones all of the above receptors are involved. Excitability by peripheral input and background activity of the neurones are probably controlled by different mechanisms.

The effects of athletic massage on delayed onset muscle soreness, creatine kinase, and neutrophil count: a preliminary report.

It was hypothesized that athletic massage administered 2 hours after eccentric exercise would disrupt an initial crucial event in acute inflammation, the accumulation of neutrophils. This would result in a diminished inflammatory response and a concomitant reduction in delayed onset muscle soreness (DOMS) and serum creatine kinase (CK). Untrained males were randomly assigned to a massage (N = 7) or control (N = 7) group. All performed five sets of isokinetic eccentric exercise of the elbow flexors and extensors. Two hours after exercise, massage subjects received a 30-minute athletic massage; control subjects rested. Delayed onset muscle soreness and CK were assessed before exercise and at 8, 24, 48, 72, 96, and 120 hours after exercise. Circulating neutrophils were assessed before and immediately after exercise, and at 30-minute intervals for 8 hours; cortisol was assessed before and immediately after exercise, and at 30-minute intervals for 8 hours; cortisol was assessed at similar times. A trend analysis revealed a significant (p < 0.05) treatment by time interaction effect for 1) DOMS, with the massage group reporting reduced levels; 2) CK, with the massage group displaying reduced levels; 3) neutrophils, with the massage group displaying a prolonged elevation; and 4) cortisol, with the massage group showing a diminished diurnal reduction. The results of this study suggest that sports massage will reduce DOMS and CK when administered 2 hours after the termination of eccentric exercise. This may be due to a reduced emigration of neutrophils and/or higher levels of serum cortisol.

Attenuation of contraction-induced skeletal muscle injury by bromelain.

The proteolytic enzyme, bromelain, reportedly has therapeutic effects in the treatment of inflammation and soft tissue injuries. We tested the hypothesis that bromelain attenuates skeletal muscle injury induced by lengthening contractions. The left extensor digitorum longus (EDL) muscle of anesthetized hamsters was injured using a motorized foot pedal which repeatedly flexed/extended the foot through a range of 125 degrees. The EDL muscle was electrically stimulated for 400 ms during plantarflexion. Animals were assigned randomly to either a 0-d group (evaluated 3-h post-injury) or to untreated (UT) or bromelain-treated (T) groups, evaluated 3, 7, or 14 d post-injury. Following injury, T received 5 mg.kg-1 b.w. of bromelain, twice daily. Maximum isometric tetanic force (Po) was measured in vitro, then muscles were fixed, sectioned, and examined for evidence of fiber damage. The Po of injured muscles from T were higher than Po of injured muscles from UT at 3 (18.7 +/- 0.4 vs 16.5 +/- N.cm-2 and 14 d (20.5 +/- 0.6 vs 18.2 +/- 0.6 N.cm-2) (P less than 0.05), but not 7 d (19.5 +/-0.7 vs 17.7 +/- 0.8 N.cm-2). The Po of UT injured muscles were significantly lower than Po of contralateral control muscles at all time periods. Po of injured muscles from T were lower than Po from control muscles at 3 and 7 d (P less than 0.05), but not 14 d. The number of intact fibers of 3-d UT injured muscles was lower than the number of intact fibers in control muscles (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Discharge behaviour of feline gamma-motoneurones following induction of an artificial myositis.

The study was undertaken to test the widely held hypothesis that a painful lesion of the skeleto-motor system leads to an increase in the neuromuscular component of muscle tone by activating gamma-motoneurones in the affected region. In chloralose-anaesthetized cats, artificial myositis was induced in the lateral gastrocnemius-soleus (LGS) muscle and several hours later the impulse activity was recorded from single gamma-motoaxons supplying the medial gastrocnemius (MG) muscle. Under the conditions of the study, the majority of the fusimotor neurones had a resting activity and could be readily excited by natural stimuli. In contrast to the assumptions of the working hypothesis, the gamma-motoneurones in the myositis animals were not activated but showed a strong inhibition; both resting activity and excitability by electrical and natural stimuli were decreased. Additional recordings from fusimotor neurones of a flexor muscle (tibialis anterior, TA) demonstrated that in the preparation used, the behaviour of the flexor gamma-motoneurones was different from extensor ones in that the former usually had no resting activity and did not respond to natural stimuli. The only discernible effect of a myositis of the LGS muscle on the TA gamma-motoneurones was a decrease in their electrical reflex threshold. The results of the study do not support the assumption that a painful muscle lesion is followed by an activation of the gamma-loop that leads to an increase in muscle tone. Instead, the data may offer an explanation for the weakness and--in chronic cases--the reflex atrophy of lesioned muscles.

Muscle breakdown and repair in polymyositis: a case study.

Muscle breakdown and repair were measured by metabolic balance techniques in a patient with polymyositis who was being treated with prednisolone and azathioprine. Changes in body muscle mass that had been estimated from nitrogen and phosphorus balances correlated with antropometric assessments of thigh muscle mass and quadriceps strength. Decline in muscle strength was associated with a net rate of muscle breakdown of 148 g/day. Recovery was associated with a net rate of muscle repair of up to 100 g/day. Early reduction in corticosteroid treatment appeared to enhance the rate of repair. Changes in the isometric contraction force of the quadriceps muscle (but not in clinical symptoms, plasma creatine kinase [CK] or erythrocyte sedimentation rate [ESR] were found to reliably indicate whether the muscle was in a state of breakdown or repair. Treatment of the individual patient may be quantitatively monitored by metabolic balance studies or, more simply, by measurement of muscle strength.