Massage Therapy Attenuates Inflammatory Signaling After Excercise-induced Muscle Damage

Massage reduced signs of inflammation, and massaged muscles cells were betterable to make new mitochondria promoting faster recovery from exercise-inducedmuscle damage. Massage activates mechanosensory sensors. Massage activates the formation of additional mitochondria, presumably acceleratinghealing of the muscles. Massage reduced accumulation of inflammatory mediator nuclear factor kappa B(NFkB), and reduced the activity of immune cytokines interleukin-6 (IL-6) and tumornecrosis factor alpha (TNF-a), a sign of less cellular stress and inflammation. However, massage did not help clear lactic acid from tired muscles. FROM ABSTRACT Massage therapy is commonly used during physical rehabilitation of skeletal muscle toameliorate pain and promote recovery from injury. Although there is evidence thatmassage may relieve pain in injured muscle, how massage affects cellular functionremains unknown. To assess the effects of massage, we administered either massage therapy or notreatment to separate quadriceps of 11 young male participants after exercise inducedmuscle damage. Muscle biopsies were acquired from the quadriceps (vastus lateralis)at baseline, immediately after 10 min of massage treatment, and after a 2.5-hourperiod of recovery. We found that massage: * Activated the mechanotransduction signaling pathways * Increased mitochondrial biogenesis * Mitigated the rise in nuclear factor kB (NFkB) Moreover, despite having no effect on muscle metabolites (glycogen, lactate), massage attenuated the production of the inflammatory cytokines tumor necrosis factor – a (TNF-a) and interleukin-6 (IL-6), thereby mitigating cellular stress resultingfrom myofiber injury. In summary, when administered to skeletal muscle that has been acutely damagedthrough exercise, massage therapy appears to be clinically beneficial by reducinginflammation and promoting mitochondrial biogenesis. KEY POINTS FROM THIS STUDY: 1) Complementary and alternative medicine (CAM) is increasingly used as a costeffective adjunct to conventional medical care. Many CAM techniques, such asacupuncture, massage therapy, or chiropractic manipulations, are aimed at managingpain, relieving stress, and preventing injury. 2) The increasing use of massage therapy as an adjunct to conventional care formusculoskeletal injury recovery and the growing number of physician referrals for massage represent a shift toward nondrug-based therapies for personal health. 3) Given the spiraling cost of primary care and medications in the US, it is likelythat more patients will seek out this therapy as well as other nontraditional medicalalternatives to complement more conventional approaches to their healthcare. 4) Massage therapy is a well-known form of alternative medicine that consists ofphysical manipulation of muscle and connective tissue at a site of injury, inflexibility,or soreness to reduce pain and promote recovery. 5) Massage has been hypothesized to moderate inflammation, improve blood flow,and reduce tissue stiffness, resulting in a diminished sensation of pain. 6) The potential benefits of massage could be useful to a broad spectrum ofindividuals including the elderly, those suffering from musculoskeletal injuries, andpatients with chronic inflammatory conditions. 7) There are several reports that long-term massage therapy reduces chronic painand improves range of motion in clinical trials. 8) Muscle inflammation and pain are typically present when damage to themyofibrillar structure has occurred. 9) Muscle trauma initially results in inflammation with immune cell activation andcytokine release. 10) The inflammatory immune response is led by NFkB. Repression of NFkBactivation improves tissue repair and reduces immune cell infiltration into muscle. 11) A mechanical stimulus to a muscle will physically alter the cells membrane andthe extracellular matrix and transmit signals via proteins known as integrins.Integrins in turn activate and propagate mechanotransduction signals that modulateprotein synthesis, glucose uptake, and immune cell recruitment. 12) The mechanical stretch during massage activates mechanotransductionsignaling that increases muscle glucose uptake, protein synthesis and muscle growth. 13) Any physiological benefits due to massage would likely be initiated throughmechanical effects on skeletal muscle followed by changes to intracellular regulatorycascades. 14) Massage alters processes related to the cytoskeleton and to inflammation. 15) After activating cellular signaling pathways through mechanotransduction,massage attenuated the rise in several other signaling pathways indicative of muscleinflammation and cell stress regulated by NFkB. 16) Damage to skeletal muscle activates the inflammatory NFkB pathway, whichincreases prostaglandin synthesis [like PGE2] and inflammatory cytokine expression[IL-6, TNF-a]. These inflammatory cytokines impede muscle repair by increasingmuscle protein breakdown and suppressing myosin synthesis. 17) Also these inflammatory cytokines activate nociceptors, causing increasedsensitivity to pain (hyperalgesia). 18) Cyclooxygenase inhibitors blunt most of the hyperalgesia derived from local IL-6and TNF-a, indicating that prostaglandins are largely responsible for the sensitizationof muscle-associated nerves caused by inflammatory cytokines. 19) Similarly, pain and inflammation in human patients are often treated withanalgesic medications that block the local formation of prostaglandins, suggesting thatmassage may act in a similar fashion. 20) One class of analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), are some of the most commonly consumed drugs in the world. Massagemay provide similar benefits without side effects. Massage may be useful insituations where areas of low blood flow (the muscle tendon interface) restrict theaccess of circulating analgesics to a site of inflammation. 21) The positive effects of massage are a result of an attenuated production ofinflammatory cytokines, which may reduce pain by the same mechanism asconventional anti-inflammatory drugs such as NSAIDs. 22) These results elucidate the biological effects of massage in skeletal muscle andprovide evidence that manipulative therapies may be justifiable in medical practice. Massage Does The Following: * Activates the mechanotransduction signaling pathways * increases muscle glucose uptake, protein synthesis and muscle growth * Increases the biosynthesis of mitochondria; this increases the production of theATP energy required for protein synthesis and repair of injury. * Reduces the production of NFkB. * Reduces the production of inflammatory prostaglandins [PGE2]. * Reduces the production of inflammatory cytokines [TNF-a, IL-6]. * Reduces pain. * Accelerates healing, faster recovery.

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Maternal Metabolic Conditions and Risk for Autism and Other Neurodevelopmental Disorders

KEY POINTS FROM THIS ARTICLE: 1) This study looked at 1004 children: 517 with autism 172 with developmental delays 315 controls 2) Mothers with metabolic conditions (diabetes, obesity) increased theirchildrens risk of: * Autism by 61% * Developmental Delays by 135% 3) Conclusions: Maternal metabolic conditions are associated with neurodevelopmental problems in children. With obesity rising steadily, theseresults appear to raise serious public health concerns. 4) Several studies suggest that the pathogenesis of autism most likely begins inutero. 5) Obesity is linked to * Chronic inflammation * Type II diabetes * Hypertension 6) In the United States, in women of childbearing age: * 60% are overweight * 33% are obese * 16% have metabolic syndrome 7) After adjusting for covariates, mothers with diabetes were 2.3 times morelikely to have a child with Developmental Delays 8) The risk of having a child with Autism or Developmental Delays relative toTypical Development was significantly increased among obese women: * 67% for Autism * 108% for Developmental Delays 2 9) For women with any metabolic condition, the increase risk of: * Autism 61% * Developmental Delays 135% 10) In this study, diabetes, hypertension, and obesity were more commonamong mothers of children with Autism and Developmental Delays compared to controls. 11) Obesity is a significant Dental X-Rays and Risk of Meningioma risk factor for both hypertension and diabetes and is characterized by increasedinsulin resistance and chronic inflammation. 12) In a diabetic and possibly pre-diabetic pregnancy, poorly regulated maternalglucose can result in adverse fetal development. Prolonged fetal exposure toelevated glucose levels results in chronic fetal hyperinsulinemia, which in turntriggers the fetus to increase oxygen consumption and metabolism, inducingchronic intrauterine tissue hypoxia. 13) Mothers with metabolic conditions (diabetes, obesity) increase the risk of theirchildren having Autism and Developmental delays through these mechanisms: A)) Chronic hyperinsulinemia causes chronic intrauterine hypoxia: B)) Iron deficiency: Both fetal hypoxia and iron deficiency can profoundly affect neurodevelopment in humans, including alterations in myelination and cortical connectivity. Fetal iron deficiency is also linked to reduced recognition memory andbehavioral problems. C)) Increased maternal levels of the pro-inflammatory cytokine interleukin-6: Interleukin-6 will cross the placenta and disrupt normal fetal brain development. 14) Maternal obesity and diabetes may be associated with neurodevelopmentalproblems in children and therefore could have serious public health implications.

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Dental X-Rays and Risk of Meningioma Cancer

KEY POINTS FROM THIS STUDY: 1) Intracranial meningioma is the most frequently reported primary brain tumor in the United States, accounting for 33.8% of all primary brain and CNS tumors. 2) Ionizing radiation is consistently identified as a modifiable risk factor for intracranial meningioma. The most consistent environmental risk factor identified for meningioma is exposure to ionizing radiation (IR), with relative risks from 6-fold to 10-fold reported. 3) The objective of this study was to examine the association between dental x-rays the most common artificial source of ionizing radiation and the risk of intracranial meningioma. This is the largest case-control study to date examining the correlation between dental x-rays and the risk of meningioma. 4) The sample used in this analysis included 1433 patients who had intracranial meningiomas diagnosed at ages 20 to 79 years, and 1350 controls. 5) Over a lifetime, intracranial meningioma patients were more than twice as likely as controls to report having ever had bitewing dental x-rays. Significantly elevated risk was observed across all ages with the exception of individuals aged 50 years at the time of the bitewing x-rays. 6) Regardless of the age at which the x-rays were obtained, those who received bitewing x-rays on a yearly basis or with greater frequency had an elevated risk for intracranial meningioma: * ages 10 years: 40% increased risk * ages 10 to 19 years: 60% increased risk * ages 20 to 49 years: 90% increased risk * ages 40 years: 50% increased risk 2 7) An increased risk of meningioma also was associated with panorex films taken at a young age or on a yearly basis or with greater frequency, and individuals who reported receiving such films at ages 10 years had a 4.9 times increased risk of meningioma. [Exposing children younger than 10 years of age to panorex dental xrays appears to be a very bad idea]; [Exposing anyone to yearly panorex dental x-rays also appears to be a very bad idea] 8) Regardless of the age, more frequent receipt of bitewing films was associated with increased risk of intracranial meningioma. 9) A similar elevated risk for meningioma was observed for full-mouth series among individuals who received yearly or more frequent scans at a young age. 10) Significant increases in the risk of meningioma was associated with young age at receipt of screening as well as more frequent screening, and individuals who were aged 10 years at the time of screening had an almost 5-fold increase in risk (490%). 11) Our findings suggest that dental x-rays, particularly when obtained frequently and at a young age, may be associated with an increased risk of intracranial meningioma. 12) Our findings indicate a statistically significant increased risk with both bitewing and panoramic films. Risk estimates for full-mouth films, although not statistically significant, were consistently in the same direction as for the other 2 film types. 13) The findings presented here are important, because dental x-rays remain the most common artificial source of exposure to IR for individuals living in the United States. 14) The American Dental Association’s recent statement on the use of dental radiographs highlights the need for dentists to examine the risk/benefit ratio associated with the use of dental x-rays and confirms that there is little evidence to support the use of dental x-rays to search for occult disease in asymptomatic patients or to obtain routine dental studies from all patients at preset intervals.

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1 Statin Use and Musculoskeletal Pain Among Adults With and Without Arthritis

KEY POINTS FROM THIS STUDY 1) Statins are one of the most widely prescribed medications in the United States and globally. 2) In 2003-2004, it was estimated that 24 million US individuals took statins. 3) Musculoskeletal symptoms are common adverse effects of statins drugs, including muscle aches, pain, weakness, and cramps. 4) This study assessed 8228 subjects over 40 years of age, and 5170 had not been diagnosed with arthritis. 5) The cofounders adjusted for in this study included age, sex, race/ethnicity (non-Hispanic white, non-Hispanic black, Mexican-American, others), smoking status (never, former, current), self-reported health, coronary heart disease, diabetes, cancer, systolic blood pressure, BMI, total cholesterol, and ankle brachial index. 6) Among 5,170 participants without arthritis, the prevalence of musculoskeletal pain was significantly higher for statin users reporting pain, as follows: * Pain in any region was found in 23% among statin users compared with 18% among those not using statins. * Pain in the lower extremities was found in 12% among statin users compared with 8% among those not using statins. 7) After controlling for confounders, among those without arthritis, statin use was associated with a significantly higher prevalence of musculoskeletal pain, as follows: * Pain in any region was increased by 33%. * Pain in the lower back was increased by 47%. * Pain in the lower extremities was increased by 59%. 2 8) Compared with those without arthritis, those with arthritis showed approximately 2-fold the prevalence of reported musculoskeletal pain in all regions. 9) Statin use among those without arthritis remained significantly associated with a higher prevalence of musculoskeletal pain, particularly in the lower extremities and lower back, with a number needed to harm of 17 for musculoskeletal pain in any region. 10) Among those with arthritis, our data did not show higher prevalence of musculoskeletal pain among statin users. Arthritis commonly typifies a more prominent pain and could mask statin-associated pain, thus mitigating the association between statin-related pain and arthritis. 11) In this population-based study, statin use was associated with a higher prevalence of musculoskeletal pain, particularly in the lower extremities, among individuals without arthritis. CLINICAL SIGNIFICANCE FROM AUTHORS ‚óŹ Individuals without arthritis using statins were 33% more likely to report musculoskeletal pain overall. * 1 out of every 17 people taking statin drugs developed musculoskeletal pain syndromes (number needed to harm = 17). COMMENTS FROM DAN MURPHY On the positive side: This study could be good for our business. Millions of people take statin drugs, and statin drugs increase the incidence of all pain, but particularly low back and leg pain. On the negative side: If statin drugs are the primary cause of our patients pain syndromes, these drugs may reduce the effectiveness of traditional chiropractic spinal adjusting in the management of such pain syndromes. Consequently, it may be necessary to include adjunct strategies such as stopping statin drugs, alternatives to statin drugs, dietary changes (especially the elimination of refined carbohydrates), and supplementation with CoQ10. 3 1. Cannon CP, Steinberg BA, Murphy SA, Mega JL, Braunwald E. Meta-analysis of cardiovascular outcomes trials comparing intensive versus moderate statin therapy. J Am Coll Cardiol. 2006;48:438. 2. Cheung BMY, Lauder IJ, Lau CP, Kumana CR. Meta analysis of large randomized controlled trials to evaluate the impact of statins on cardiovascular outcomes. Br J Clin Pharmacol. 2004;57:640-651. 3. Fonarow GC, Watson KE. Effective strategies for long-term statin use. Am J Cardiol. 2003;92:27-34. 4. Maggon K. Best-selling human medicines 2002-2004. Drug Discov Today. 2005;10:739-742. 5. Mann D, Reynolds K, Smith D, Muntner P. Trends in statin use and low-density lipoprotein cholesterol levels among US adults: impact of the 2001 National Cholesterol Education Program Guidelines (September). Ann Pharmacother. 2008;42:1208-1215. Epub 2008 Jul 22. *6. McKenney JM, Davidson MH, Jacobson TA, Guyton JR. Final conclusions and recommendations of the National Lipid Association Statin Safety Assessment Task Force. Am J Cardiol. 2006;97(8A):89C-94C. 12. Bruckert E, Hayem G, Dejager S, Yau C, Begaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients the PRIMO study. Cardiovasc Drugs Ther. 2005;19:403-414. 13. Franc S, Dejager S, Bruckert E, Chauvenet M, Giral P, Turpin G. A comprehensive description of muscle symptoms associated with lipidlowering drugs. Cardiovasc Drugs Ther. 2003;17:459-465. 14. Hansen KE, Hildebrand JP, Ferguson EE, Stein JH. Outcomes in 45 patients with statin-associated myopathy. Arch Intern Med. 2005;165: 2671-2676. 15. Frieze DA. Musculoskeletal pain associated with corticosteroid therapy in cancer. Curr Pain Headache Rep. 2010;14:256-260. 16. Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine myopathy and neuropathy. N Engl J Med. 1987; 316:1562-1568. Buettner et al Statin Use and Musculoskeletal Pain 181 18. Silva M, Matthews ML, Jarvis C, et al. Meta-analysis of drug-induced adverse events associated with intensive-dose statin therapy. Clin Ther. 2007;29:253-260. 19. Silva MA, Swanson AC, Gandhi PJ, Tataronis GR. Statin-related adverse events: a meta-analysis. Clin Ther. 2006;28:26-35

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Effect of Aspirin on Vascular and Nonvascular Outcomes Meta-analysis of Randomized Controlled Trials

SRK Seshasai, S Wijersuiya, R Sivakumaran, S Nethercott, S Erqou, N Sattar, KK Ray [NNT = Numbers needed to treat: this is the number of persons who would have to take aspirin for 6 years in order to prevent 1 event]. [NNH = Numbers needed to harm: this is the number of persons taking aspirin for 6 years in order to cause harm to 1 person]. KEY POINTS FROM THIS STUDY: 1) The net benefit of aspirin in prevention of CVD and nonvascular events remains unclear. These authors assessed the impact (and safety) of aspirin on vascular and nonvascular outcomes in primary prevention. 2) The authors used 9 good-quality randomized placebo-controlled trials of aspirin for primary prevention of CVD that included 102,621 participants who were followed-up for 6 years, making approximately 700,000 person-years. 3) These authors compared rates of any statistically meaningful associations (CVD or nonfatal MI) with rates of bleeding. 4) Nontrivial bleeding was defined as fatal bleeding; cerebrovascular or retinal bleeding; bleeding from hollow viscus; bleeding requiring hospitalization and/or transfusion; or study-defined major bleeding regardless of source. 5) This meta-analysis is the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention. 6) During a follow-up of 6.0 years involving over 100,000 participants, aspirin treatment: A)) Reduced total CVD events by 10%, but with a NNT of 120 [120 people had to take aspirin for 6 years to prevent 1 CVD event]. The NNT to avoid 1 CVD event over 6 years was 120. B)) Reduced nonfatal MI by 20%, but with a NNT of 162 [162 people had to take aspirin for 6 years to prevent 1 nonfatal MI]. The NNT to avoid 1 nonfatal MI event over 6 years was 162. C)) There was no significant reduction in CVD death or cancer mortality, and there was increased risk of nontrivial bleeding events by 31% (NNH was 73). At least 1 nontrivial bleeding event was caused for every 73 persons treated with aspirin for approximately 6 years. 2 D)) There was a 70% excess risk of total bleeding events and a higher than 30% excess risk of nontrivial bleeding events in people receiving aspirin. E)) The NNT to avoid nonvascular death over 6 years was 292. F)) The NNT to avoid cancer death over 6 years was 247. 7) The net benefits due to aspirin treatment were offset by increased rates of nontrivial bleeding. 8) Aspirin benefits are considerably offset by an elevated risk of bleeding (NNT for nonfatal MI of 162 vs NNH for nontrivial bleed of 73). 9) The findings reported herein do not suggest a protective role for aspirin against cancer mortality in people at low-to-moderate risk for CVD events. 10) The principal cardiovascular effect of aspirin in primary prevention is on nonfatal MI with no real benefit with regard to fatal MI, stroke, or CVD death. 11) The results suggest an increased risk of nontrivial bleeding in individuals receiving daily (vs alternate day) aspirin treatment, with a particularly unfavorable risk to benefit ratio for individuals at lower baseline CVD risk. 12) Both patients and physicians should carefully consider the relative merits of daily aspirin treatment in primary prevention. 13) Our analysis also showed that aspirin was no better than placebo for reducing nonfatal MI events in trials published after 2000. 14) Aspirin may add little extra value to other CVD risk reduction strategies, especially in low-risk individuals. 15) Aspirin may be associated with net harm owing to increased potential for bleeding. 16) Based on our findings of a marginal benefit on nonfatal MI, a nonsignificant effect on cancer death, and a significantly increased risk of clinically relevant bleeding, it is perhaps timely to reappraise existing guidelines for aspirin use in primary prevention. 17) A reappraisal of current guidelines appears to be warranted, particularly in countries where a large number of otherwise healthy adults are prescribed aspirin, since a significant proportion of them may develop bleeding complications.

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