jeffrey dach md's Open Salon Blog

Low Testosterone Video on You Tube by Dr Jeffrey Dach MD

Fri, 20 Jan 2012 10:01:43 -0500

Dr Dach explains the Low Testosterone condition, diagnosis and treatment
in this You Tube Video.

Low Testosterone in males may cause symptoms of fatigue, and depression and is associated with increased mortality and responds well to testosterone supplementation. Total Testosterone declines with age, while SHBG increased resulting in greater decrease in Free Tesosterone.
Major symptoms of low testosterone: Fatigue, Low libido, absent interest in sex, Effect on body composition , loss of mucsle mass, increase of visceral fat (bad fat)

Originally taped Dec 16, 2011 on radio show Staying Healthy with Dr Dach, Jeffrey Dach MD WWNN AM147O Boca Raton Florida

next video is part two of a four part series
....................................................................................................

For All Four Parts:

part one http://youtube.com/watch?v=TYQL190w3UQ

part two http://youtube.com/watch?v=YLBMOwIwo5w

part three http://youtube.com/watch?v=VrJRHLj38mg

part four http://youtube.com/watch?v=bho83jvbfOc

Articles with related interest:

Symptoms of Low Testosterone
http://www.drdach.com/Symptoms_Low_Testosterone.html

Low Testosterone Diagnosis and Treatment by Jeffrey Dach MD
http://www.drdach.com/wst_page15.html

Low Testosterone Could Be Killing You
http://www.drdach.com/Low_Testosterone_Killing.html

Low Testosterone From Pain Pills by Jeffrey Dach MD
http://jeffreydach.com/2010/02/26/low-testosterone-from-pain-pills-by-jeffrey...

Male Menopause, Low Testosterone and Robert Brannigan MD
http://jeffreydach.com/2010/10/07/male-menopause-low-testosterone-and-robert-...

Testosterone, PSA and Prostate Cancer, Myths and Misconceptions
http://www.bioidenticalhormones101.com/Testosterone_PSA_Prostate.html

PSA and Testosterone - Part Two - A Medical Myth
http://www.bioidenticalhormones101.com/Low_Testosterone_PSA_Two.html

low, testosterone, male, aging, fatigue, jeffrey dach, hcg, mortality, florida, hollywood, davie, video

Links to Buy Books on Amazon

http://www.amazon.com/Bioidentical-Hormones-101-Jeffrey-Dach/dp/1462034993
http://www.amazon.com/Natural-Medicine-101-Medical-Information/dp/1439211221/...

Office Location:
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
office telephone 954-792-4663

Low Testosterone in Males on You Tube by Jeffrey Dach MD

Fri, 20 Jan 2012 10:01:26 -0500

Low Testosterone in Males Four Part Series on You Tube by Jeffrey Dach MD

The Low Testosterone Condition in older Males may cause symptoms of fatigue, and depression and is associated with increased mortality and responds well to testosterone supplementation. Originally taped Dec 16, 2011 on radio show Staying Healthy with Dr Dach, Jeffrey Dach MD WWNN AM147O Boca Raton Florida

part one http://youtube.com/watch?v=TYQL190w3UQ

part two http://youtube.com/watch?v=YLBMOwIwo5w

part three http://youtube.com/watch?v=VrJRHLj38mg

part four http://youtube.com/watch?v=bho83jvbfOc

Articles with related interest:

Symptoms of Low Testosterone

Low Testosterone Diagnosis and Treatment by Jeffrey Dach MD

Low Testosterone Could Be Killing You

Low Testosterone From Pain Pills by Jeffrey Dach MD

Male Menopause, Low Testosterone and Robert Brannigan MD

Testosterone, PSA and Prostate Cancer, Myths and Misconceptions

PSA and Testosterone - Part Two - A Medical Myth

Office Location:
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
office telephone 954-792-4663

Low Level Lasers, Part Two by Dr Jeffrey Dach MD

Sun, 15 Jan 2012 17:01:08 -0500

Low Level Lasers, Part Two.

Clinical Applications

by Jeffrey Dach MD

Part One of this series reviewed the mechanism of how low level lasers interact at the cellular level . The coherent laser light in the near infrared wavelength is absorbed readily by cytochrome C oxidase located in the inner mitochondrial membrane. This is thought to be an ancient remnant of the ability of photosynthetic bacteria to absorb light and convert it into usable energy for cellular use.

Above left image: Mitochondria with illuminated inner membrane. This is the location of Cytochrome C oxidase which absorbs the red light.

EndoSymbiotic Theory of Lynn Margulis

Where did mitochondria come from?

One theory is that mitochondria originated from the bacterial world, incorporated into multicelled organisms in a symbiotic relationship. This idea was proposed as the endosymbiotic theory by Lynn Margulis, a biologist at Berkely in her 1970 book, the Origin of Eucaryotic Cells (1) . This explains why the primitive mechanism for light absorption is retained by our mitochondria.

Accelerated Wound Healing

A 2004 paper by Dr Janis T. Eellsa appeared in Mictochondrion stating that mitochondrial signal transduction accelerates wound and retinal healing by near-infrared light therapy. The authors state, "Photobiomodulation by light in the red to near infrared range (630–1000 nm) using low energy lasers or light-emitting diode (LED) arrays has been shown to accelerate wound healing, improve recovery from ischemic injury in the heart and attenuate degeneration in the injured optic nerve. Recent evidence indicates that the therapeutic effects of red to near infrared light result, in part, from intracellular signaling mechanisms triggered by the interaction of NIR light with the mitochondrial photoacceptor molecule cytochrome c oxidase.

We have also shown that NIR-LED treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients. Photobiomodulation improves wound healing in genetically diabetic mice by upregulating genes important in the promotion of wound healing.

Upregulates Gene Expression

Gene discovery studies conducted using microarray technology documented a significant upregulation of gene expression in pathways involved in mitochondrial energy production and antioxidant cellular protection. These findings provide a link between the actions of red to near infrared light on mitochondrial oxidative metabolism in vitro and cell injury in vivo.

Mitochondrial Dysfunction

Based on these findings and the strong evidence that mitochondrial dysfunction is involved in the pathogenesis of numerous diseases processes, we propose that NIR-LED photobiomodulation represents an innovative and non-invasive therapeutic approach for the treatment of tissue injury and disease processes in which mitochondrial dysfunction is postulated to play a role including diabetic retinopathy, age-related macular degeneration, Leber’s hereditary optic neuropathy and Parkinson’s disease." (2)

What Happens After the Coherent Light is Absorbed by the Mitochondria?

Not only is light energy utilized in the production of ATP (usable cellular energy), the light energy triggers a cascade which initiates the healing process.

Low Level Laser light accelerates wound healing, provides pain relief, improves the immune system and helps nerve regeneration. Low-energy coherent light in the red and infra-red range activates the mitochondrial respiratory chain components, and initiates a signaling cascade that promotes healing, and new cell growth. Cytochrome C oxidase is the molecule which absorbs the light in the inner membrane of the mitochondria. This protein contains four active metal centers, two iron and two copper molecules, which absorb light, thereby increasing mitochondrial respiration and ATP synthesis.

Clinical Conditions Which Benefit from Coherent Light, (LLLT) Low Level Laser Therapy

    Acute and chronic pain
    Arthritis
    Back pain
    Bursitis
    Carpal Tunnel
    Fibromyalgia
    Tennis Elbow
    Ligament sprains
    Muscle strain
    Soft tissue injuries
    Tendonitis
    Tennis elbow
    Rotator cuff
    Shoulder, knee and hip pain
    Neuropathy
    Trigeminal Neuralgia, Facial nerve pain
    Peyronies Disease- reduce scar formation
    Carpal Tunnel Syndrome

Wound Healing (9) Animal studies show light-dose dependent increase in collagen levels during the post-wounding days. The histological examination show significant increase in collagen deposition along with the reduced edema, leukocytes, increased granulation tissue, and fibroblast number in the optimal laser dose treated group compared to the non-illuminated controls. (9)

Thor Laser paper on Wound Healing pdf file

Nerve Regeneration : (8) Sciatic nerve transection studies in rates shows healing with larger fibers and larger axon diameter with LLLT (8)

Diabetic Gangrene and Ulcers (3) LLLT accelerates healing of diabetic gangrene and ulcers. (3)

Herpes Simplex (4) LLLT reduces lesion outbreak frequency and intensity. (4)

Herpes Zoster Outbreaks (Shingles)(5) LLLT reduces pain and lesions of herpes zoster servingas an effective treatment, while conventional medicine has little to offer. (5)

Post Radiation Mucositis (6) LLLT found to reduce severity of oral mucosal ulcerations and pain after chmotherapy and raidation therapy for head and neck cancers. (6)

Achilles Tendinitis (7): LLLT found safer and more effective than NSAID Drugs (7)

Tennis Elbow

Osteoarthritis and Rheumatoid Arthritis

Fingernail and ToeNail Fungus

Dermatology- Acne: LLLT was effective in treatment of acne (11)

Head trauma, stroke

Conclusion:

Low level laser is an excellent method for healing sports injuries, the musclo-tendinous system. In addition there are multiple clinicial applications for healing the nervous system, intractable nerve pain, chronic viral illness (herpes) and fungal illnes (nail fungus). The future of this modality is indeed very bright.(10) Low level laser is an emerging clincical paradigm. (12)   Dr Huang and Hamblin conclude with this: " LLLT is used by physical therapists, dentists, dermatologists, rheumatologists, and other specialists, as well as general practitioners. Laser therapy is also widely used in veterinary and sports medicine, and in rehabilitation clinics. Ongoing preclinical studies and clinical trials are using LLLT to treat serious and potentially fatal injuries and diseases including heart attacks and coronary artery disease, nerve regeneration and spinal cord injury, stroke, traumatic brain injuries, and degenerative neurological disorders such as Alzheimer's and Parkinson's diseases. (12)

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
954-792-4663
www.jeffreydach.com
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www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com

Links and References

1) http://evolution.berkeley.edu/evolibrary/article/history_24

ENDOSYMBlOTlC THEORY - Evolutionist Lynn Margulis showed that a major organizational event in the history of life probably involved the merging of two or more lineages through symbiosis. Lynn Margulis       Symbiotic microbes = eukaryote cells?
Mitochondria, for example, are wriggly bodies that generate the energy required for metabolism. To Margulis, they looked remarkably like bacteria.

"She knew that scientists had been struck by the similarity ever since the discovery of mitochondria at the end of the 1800s. Some even suggested that mitochondria began from bacteria that lived in a permanent symbiosis within the cells of animals and plants. There were parallel examples in all plant cells. Algae and plant cells have a second set of bodies that they use to carry out photosynthesis. Known as chloroplasts, they capture incoming sunlight energy. The energy drives biochemical reactions including the combination of water and carbon dioxide to make organic matter. Chloroplasts, like mitochondria, bear a striking resemblance to bacteria. Scientists became convinced that chloroplasts (below right), like mitochondria, evolved from symbiotic bacteria — specifically, that they descended from cyanobacteria (above right), the light-harnessing small organisms that abound in oceans and fresh water.
When one of her professors saw DNA inside chloroplasts, Margulis was not surprised. After all, that's just what you'd expect from a symbiotic partner. Margulis spent much of the rest of the 1960s honing her argument that symbiosis (see figure, below) was an unrecognized but major force in the evolution of cells. In 1970 she published her argument in The Origin of Eukaryotic Cells. "

(2) http://www.lighttherapysystems.eu/images/AcceleratedHealing.pdf
Mitochondrion 4 (2004) 559–567
Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy. by Janis T. Eellsa,*, Margaret T.T. Wong-Rileyb, James VerHoevec, Michele Henryd, Ellen V. Buchmane, Mary P. Kanee, Lisa J. Gouldf, Rina Dasg, Marti Jettg, Brian D. Hodgsonh, David Margolisi, Harry T. Whelane
aDepartment of Health Sciences, College of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA bDepartment of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53201, USA

Photobiomodulation by light in the red to near infrared range (630–1000 nm) using low energy lasers or light-emitting diode (LED) arrays has been shown to accelerate wound healing, improve recovery from ischemic injury in the heart and attenuate
degeneration in the injured optic nerve. Recent evidence indicates that the therapeutic effects of red to near infrared light result, in part, from intracellular signaling mechanisms triggered by the interaction of NIR light with the mitochondrial photoacceptor molecule cytochrome c oxidase.

We have demonstrated that NIR-LED photo-irradiation increases the production of cytochrome oxidase in cultured primary neurons and reverses the reduction of cytochrome oxidase activity produced by metabolic inhibitors.

We have also shown that NIR-LED treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients.

Photobiomodulation improves wound healing in genetically diabetic mice by upregulating genes important in the promotion of wound healing.

More recent studies have provided evidence for the therapeutic benefit of NIRLED treatment in the survival and functional recovery of the retina and optic nerve in vivo after acute injury by the
mitochondrial toxin, formic acid generated in the course of methanol intoxication.

Gene discovery studies conducted using microarray technology documented a significant upregulation of gene expression in pathways involved in mitochondrial energy production and antioxidant cellular protection. These findings provide a link between the actions of red to near infrared light on mitochondrial oxidative metabolism in vitro and cell injury in vivo. Based on these findings and the strong evidence that
mitochondrial dysfunction is involved in the pathogenesis of numerous diseases processes, we propose that NIR-LED photobiomodulation represents an innovative and non-invasive therapeutic approach for the treatment of tissue injury and
disease processes in which mitochondrial dysfunction is postulated to play a role including diabetic retinopathy, age-related macular degeneration, Leber’s hereditary optic neuropathy and Parkinson’s disease.

(3) http://www.ncbi.nlm.nih.gov/pubmed/9892822
Forsch Komplementarmed. 1998;5(5):244-247.
Healing of Bone Affections and Gangrene with Low-Intensity Laser Irradiation in Diabetic Patients Suffering from Foot Infections.
Schindl M, Schindl A, Pölzleitner D, Schindl L.

Two consecutive diabetic male patients with gangrene, osteomyelitis, and bone fractures. Helium-neon laser irradiation (36 J/cm2 ) 50 min/day. MAIN OUTCOME PARAMETER: Healing of gangrene and corticalis lesion as well as remineralisation of bone affections. Within a mean period of 14 weeks not only a complete healing of the diabetic gangrenes but also a radiographically determined reestablishment of corticalis and remineralisation of preexisting bone affections could be achieved.
CONCLUSION: We therefore conclude that low-intensity laser irradiation should be further tested as an additional beneficial therapeutic modality for the healing of gangrene and bone affections in diabetic patients.

(4)
http://www.ncbi.nlm.nih.gov/pubmed/22047597

Photomed Laser Surg. 2011 Nov 2. [Epub ahead of print]
The Effect of 670-nm Low Laser Therapy on Herpes Simplex Type 1.
Muñoz Sanchez PJ, Capote Femenías JL, Díaz Tejeda A, Tunér J.
Source 1 Leonardo Fernández Sánchez Dental Clinic , Cienfuegos, Cuba .
Abstract

Abstract Objective: The purpose of this work was to study the effect of low-level laser therapy (LLLT) on the healing and relapse intervals in patients with recurrent labial herpes simplex infections. Background data: Several pharmaceuticals are available to reduce symptoms and improbé healing of labial herpes, but only LLLT has been reported to significantly influence the length of the recurrence period. Material and methods: In an initial study, 232 patients with herpes simplex type 1 virus symptoms were consecutively selected for either LLLT or conventional therapy, including acyclovir cream or tablets. One of the dentists was responsible for the diagnosis, a second dentist for the treatment, and and a third for the evaluation, to allow for a semi-blinded procedure. Patients in the laser group received 670-nm laser irradiation, 40 mW, 1.6 J, 2.04 J/cm(2), 51 mW/cm(2) per blister in the prodromal stage and 4.8 J in the crust and secondarily infected stages, plus 1.2 J at the C2-C3 vertebrae. Patients were monitored daily during the first week to control healing, and monthly for 1 year to check on recurrence. In a consecutive study, 322 patients receiving LLLT were followed during 5 years to observe the period of ocurrences.

Results: An obvious effect of LLLT was found for both initial healing and for the length of the recurrence periods. Conclusions: LLLTof herpes simples virus 1 (HSV-1) appears to be an effective treatment modality without any observed side effects.

(5) http://naturalhealthpartners.pro/images/laser_and_herpes_zoser_simplex.pdf

Herpes Zoster (Shingles): A Therapy at Last November 2005

Low Intensity Laser Therapy when properly applied has an infinite ability to heal. Along with a number of systemic, dermatological and musculoskeletal problems, we may be able to now add shingles to the list of conditions where Low Intensity Laser Therapy may be applied as an effective therapy. Over the past two years at our rehabilitation centre, we have treated a number of patients afflicted with this sometimes severe viral infection and have been universally successful in treating these conditions. Excellent Before and After Treatment Photos showing resolution of lesions.

(6) http://www.ncbi.nlm.nih.gov/pubmed/21660670

Support Care Cancer. 2011 Aug;19(8):1069-77. Epub 2011 Jun 10.
A systematic review with meta-analysis of the effect of low-level laser therapy (LLLT) in cancer therapy-induced oral mucositis. Bjordal JM, Bensadoun RJ, Tunèr J, Frigo L, Gjerde K, Lopes-Martins RA. Centre for Evidence-Based Practice, Bergen University College-HiB, Moellendalsvn. 6, 5009, Bergen, Norway.

The purpose of this study is to review the effects of low-level laser therapy (LLLT) in the prevention and treatment of cancer therapy-induced oral mucositis (OM).
METHODS: A systematic review and meta-analysis of randomised placebo-controlled trials of LLLT performed during chemotherapy or radiation therapy in head and neck cancer patients.

We found 11 randomised placebo-controlled trials with a total of 415 patients; methodological quality was acceptable at 4.10 (SD ± 0.74) on the 5-point Jadad scale. The relative risk (RR) for developing OM was significantly (p = 0.02) reduced after LLLT compared with placebo LLLT (RR = 2.03 (95% CI, 1.11 to 3.69)). This preventive effect of LLLT improved to RR = 2.72 (95% CI, 1.98 to 3.74) when only trials with adequate doses above 1 J were included. For treatment of OM ulcers, the number of days with OM grade 2 or worse was significantly reduced after LLLT to 4.38 (95% CI, 3.35 to 5.40) days less than placebo LLLT. Oral mucositis severity was also reduced after LLLT with a standardised mean difference of 1.33 (95% CI, 0.68 to 1.98) over placebo LLLT. All studies registered possible side-effects, but they were not significantly different from placebo LLLT.

CONCLUSIONS: There is consistent evidence from small high-quality studies that red and infrared LLLT can partly prevent development of cancer therapy-induced OM. LLLT also significantly reduced pain, severity and duration of symptoms in patients with cancer therapy-induced OM.

(7) http://www.ncbi.nlm.nih.gov/pubmed/21910734
Photochem Photobiol. 2011 Nov-Dec;87(6):1447-52. doi: 10.1111/j.1751-1097.2011.00999.x. Epub 2011 Oct 7.
Infrared (810 nm) low-level laser therapy in rat achilles tendinitis: a consistent alternative to drugs. by Marcos RL, Leal Junior EC, Messias Fde M, de Carvalho MH, Pallotta RC, Frigo L, dos Santos RA, Ramos L, Teixeira S, Bjordal JM, Lopes-Martins RÁ.
Source : Laboratory of Pharmacology and Experimental Therapeutics, Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP-Brazil.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used and can reduce musculoskeletal pain in spite of the cost of adverse reactions like gastrointestinal ulcers or cardiovascular events. The current study investigates if a safer treatment such as low-level laser therapy (LLLT) could reduce tendinitis inflammation, and whether a possible pathway could be through inhibition of either of the two-cyclooxygenase (COX) isoforms in inflammation. Wistar rats (six animals per group) were injected with saline (control) or collagenase in their Achilles tendons. Then, we treated them with three different doses of IR LLLT (810 nm; 100 mW; 10 s, 30 s and 60 s; 3.57 W cm(-2); 1 J, 3 J, 6 J) at the sites of the injections, or intramuscular diclofenac, a nonselective COX inhibitor/NSAID. We found that LLLT dose of 3 J significantly reduced inflammation through less COX-2-derived gene expression and PGE(2) production, and less edema formation compared to nonirradiated controls. Diclofenac controls exhibited significantly lower PGE(2) cytokine levels at 6 h than collagenase control, but COX isoform 1-derived gene expression and cytokine PGE(2) levels were not affected by treatments. As LLLT seems to act on inflammation through a selective inhibition of the COX-2 isoform in collagenase-induced tendinitis, LLLT may have potential to become a new and safer nondrug alternative to coxibs.

(8) http://www.ncbi.nlm.nih.gov/pubmed/22009383
Lasers Med Sci. 2011 Oct 19. [Epub ahead of print]
Low-level laser therapy improves repair following complete resection of the sciatic nerve in rats. Medalha CC, Di Gangi GC, Barbosa CB, Fernandes M, Aguiar O, Faloppa F, Leite VM, Renno AC.   Source Department of Bioscience, Federal University of São Paulo (UNIFESP), Avenida Ana Costa 95, CEP 04021-001, Santos, SP, Brazil,

The aim of this study is to analyze the effects of low-level laser therapy (LLLT) on the regeneration of the sciatic nerve in rats following a complete nerve resection. Male Wistar rats were divided into a control injury group, injury groups irradiated with a 660-nm laser at 10 or 50 J/cm(2), and injury groups irradiated with an 808-nm laser at 10 or 50 J/cm(2). Treatment began 24 h following nerve resection and continued for 15 days. Using the sciatic functional index (SFI), we show that the injured animals treated with 660 nm at 10 and 50 J/cm(2) had better SFI values compared with the control injury and the 808-nm groups. Animals irradiated with the 808-nm laser at 50 J/cm(2) show higher values for fiber density than do control animals. In addition, axon and fiber diameters were larger in animals irradiated with 660 nm at 50 J/cm(2) compared to the control group. These findings indicate that 660-nm LLLT is able to provide functional gait recovery and leads to increases in fiber diameter following sciatic nerve resection.

(9) http://www.ncbi.nlm.nih.gov/pubmed/22174176

J Biophotonics. 2011 Dec 15. doi: 10.1002/jbio.201100089. [Epub ahead of print]
Spectroscopic and histological evaluation of wound healing progression following Low Level Laser Therapy (LLLT). Prabhu V, Rao SB, Chandra S, Kumar P, Rao L, Guddattu V, Satyamoorthy K, Mahato KK . Biophysics Unit, Manipal Life Sciences Centre, Manipal University, Manipal 576104, Karnataka, India.

The present study focuses on the evaluation of the effect of He-Ne laser on tissue regeneration by monitoring collagen synthesis in wound granulation tissues in Swiss albino mice using analysis of laser induced fluorescence (LIF) and light microscopy techniques.

The spectral analyses of the wound granulation tissues have indicated a dose dependent increase in collagen levels during the post-wounding days. The histological examinations on the other hand have also shown a significant increase in collagen deposition along with the reduced edema, leukocytes, increased granulation tissue, and fibroblast number in the optimal laser dose treated group compared to the non-illuminated controls.

(10) Lasers From Head to Toe
http://www.pharmacytimes.com/publications/issue/2011/May2011/Lasers-from-Head-to-Toe-Will-New-Procedures-Change-the-Face-of-Pharmacy-

Lasers from Head to Toe: Will New Procedures Change the Face of Pharmacy?
Published Online: Monday, May 16th, 2011
Jeannette Y. Wick, RPh, MBA, FASCP

(11) Acne
http://www.ncbi.nlm.nih.gov/pubmed/10809858
Br J Dermatol. 2000 May;142(5):973-8.
Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris. Papageorgiou P, Katsambas A, Chu A. Source Unit of Dermatology, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, DuCane Road, London W12 0NN, U.K.
Abstract

In this study we have evaluated the use of blue light (peak at 415 nm) and a mixed blue and red light (peaks at 415 and 660 nm) in the treatment of acne vulgaris. One hundred and seven patients with mild to moderate acne vulgaris were randomized into four treatment groups: blue light, mixed blue and red light, cool white light and 5% benzoyl peroxide cream. Subjects in the phototherapy groups used portable light sources and irradiation was carried out daily for 15 min. Comparative assessment between the three light sources was made in an observer-blinded fashion, but this could not be achieved for the use of benzoyl peroxide. Assessments were performed every 4 weeks. After 12 weeks of active treatment a mean improvement of 76% (95% confidence interval 66-87) in inflammatory lesions was achieved by the combined blue-red light phototherapy; this was significantly superior to that achieved by blue light (at weeks 4 and 8 but not week 12), benzoyl peroxide (at weeks 8 and 12) or white light (at each assessment). The final mean improvement in comedones by using blue-red light was 58% (95% confidence interval 45-71), again better than that achieved by the other active treatments used, although the differences did not reach significant levels. We have found that phototherapy with mixed blue-red light, probably by combining antibacterial and anti-inflammatory action, is an effective means of treating acne vulgaris of mild to moderate severity, with no significant short-term adverse effects.

(12) http://spie.org/x35504.xml?ArticleID=x35504
Biomedical Optics & Medical Imaging. Low-level laser therapy: an emerging clinical paradigm. Ying-Ying Huang, Michael Hamblin, and Aaron C.-H. Chen Improved understanding of the fundamental cellular and molecular mechanisms is broadening the technique's mainstream use for many ailments. 9 July 2009, SPIE Newsroom. DOI: 10.1117/2.1200906.1669

Cytochrome c oxidase is a photoacceptor, absorbing light at a peak spectrum of 630-670nm (red spectrum). This particular molecule is responsible for ensuring that the Respiratory Chain goes to completion. The Respiratory Chain harvests electrons from O2 and NADH passing them along through a series of Redox reactions, ultimately producing ATP and H2O. Cytochrome c oxidase promotes the electron flow along the Respiratory Chain between Complexes III and IV.

pubs.acs.org/cen/news/85/i12/8512notw4.html
Chemical & Engineering News March 19, 2007 Volume 85, Number 12 p. 13 Enzyme Catalysis Electron-Starved Enzyme Cytochrome c oxidase model mimics natural electron-limited conditions SChematic model of cytochrome C oxidase

www.bioflexlaser.com/research/abstracts.php

Abstracts The number of positive peer-reviewed publications which support the application of Laser Therapy continues to grow. Meditech has selected a number of abstracts from these publications and have grouped them by pathology for your review. We regularly update the abstracts as they become available with the intention of keeping you informed on current research findings.

www.lindsaylaser.com/ClinicalReviews.html

Downloads/Clinical Reviews Lindsay Medical Laser Therapy ...Improving Quality of Life, One Patient at a time! articles on low level laser

www.nirtherapy.com/studies/index.php www.lindsaylaser.com/files/Clinical%20Reviews/Nerve_regen/Trigeminal_neuralgia.pdf

LLT for trigerminal neuralgia

www.lindsaylaser.com/files/Clinical%20Reviews/WoundHealing/03_Venous_Ulcer_Israel.pdf

www.thelancet.com/journals/lancet/article/PIIS0140-6736%2809%2961522-1/fulltext?elsca1=PPV-TL&elsca2=email&elsca3=segment

The Lancet, Volume 374, Issue 9705, Pages 1897 - 1908, 5 December 2009

Efficacy of low-level laser therapy in the management of neck pain: a systematic review and meta-analysis of randomised placebo or active-treatment controlled trials Dr Roberta T Chow MBBS a Corresponding AuthorEmail Address, Prof Mark I Johnson PhD b, Prof Rodrigo AB Lopes-Martins PhD c, Prof Jan M Bjordal PT d e Summary

Background Neck pain is a common and costly condition for which pharmacological management has limited evidence of efficacy and side-effects. Low-level laser therapy (LLLT) is a relatively uncommon, non-invasive treatment for neck pain, in which non-thermal laser irradiation is applied to sites of pain. We did a systematic review and meta-analysis of randomised controlled trials to assess the efficacy of LLLT in neck pa in. Methods We searched computerised databases comparing efficacy of LLLT using any wavelength with placebo or with active control in acute or chronic neck pain. Effect size for the primary outcome, pain intensity, was defined as a pooled estimate of mean difference in change in mm on 100 mm visual analogue scale. Findings We identified 16 randomised controlled trials including a total of 820 patients. In acute neck pain, results of two trials showed a relative risk (RR) of 1·69 (95% CI 1·22—2·33) for pain improvement of LLLT versus placebo. Five trials of chronic neck pain reporting categorical data showed an RR for pain improvement of 4·05 (2·74—5·98) of LLLT. Patients in 11 trials reporting changes in visual analogue scale had pain intensity reduced by 19·86 mm (10·04—29·68). Seven trials provided follow-up data for 1—22 weeks after completion of treatment, with short-term pain relief persisting in the medium term with a reduction of 22·07 mm (17·42—26·72). Side- effects from LLLT were mild and not different from those of placebo. Interpretation We show that LLLT reduces pain immediately after treatment in acute neck pain and up to 22 weeks after completion of treatment in patients with chronic neck pain.

Comparison between Wound Healing in Induced Diabetic and Non diabetic Rats after Low-Level Laser Therapy Aug 2006, Vol. 24, No. 4: 474-479 Sylvia Bicalho Rabelo , D.D.S., M.S.D. Instituto de Pesquisa e Desenvolvimento (IP&D), Universidade do Vale do Paraiba

Systemic Eï¬€ects of Low-Intensity Laser Irradiation on Skin Micro circulation in Patients with Diabetic Microangiopathy. Andreas Schindl, Georg Heinze, Martin Schindl, Heidemarie Pernerstorfer-Schönd and Liesbeth Schindl. Microvascular Research Volume 64, Issue 2, September 2002, Pages 240-246

Eï¬€ects of near-infrared low-level laser irradiation on micro circulation. Yasuyo Maegawa, MD, Toshiyuki Itoh, MD, PhD, Toyoshi Hosokawa, MD, PhD, Kazuhiro Yaegashi, MD, PhD, Mayumi Nishi, MD, PhD. Lasers in Surgery and Medicine Volume 27 Issue 5, Pages 427 – 437

Symptomatic Reversal of Peripheral Neuropathy in Patients with Diabetes. Alan B. Kochman, Dale H. Carnegie, and Thomas J. Burke. Journal of the American Podiatric Medical Association Volume 92 Number 3 125-130 2002

-----------------------------------------

www.ncbi.nlm.nih.gov/pubmed/18665762

Photomed Laser Surg. 2008 Aug;26(4):323-8.

Low-intensity light therapy: exploring the role of redox mechanisms.
Tafur J, Mills PJ. Source Department of Psychiatry, Behavioral Medicine Laboratory, University of California at San Diego, La Jolla, California 92093-0804, USA. jtafur@ucsd.edu Abstract

Low-intensity light therapy (LILT) appears to be working through newly recognized photoacceptor systems. The mitochondrial electron transport chain has been shown to be photosensitive to red and near-infrared (NIR) light. Although the underlying mechanisms have not yet been clearly elucidated, mitochondrial photostimulation has been shown to increase ATP production and cause transient increases in reactive oxygen species (ROS). In some cells, this process appears to participate in reduction/oxidation (redox) signaling. Redox mechanisms are known to be involved in cellular homeostasis and proliferative control. In plants, photostimulation of the analogous photosynthetic electron transport chain leads to redox signaling known to be integral to cellular function. In gene therapy research, ultraviolet lasers are being used to photostimulate cells through a process that also appears to involve redox signaling. It seems that visible and near visible low-intensity light can be used to modulate cellular physiology in some nonphotosynthetic cells, acting through existing redox mechanisms of cellular physiology. In this manner, LILT may act to promote proliferation and/or cellular homeostasis. Understanding the role of redox state and signaling in LILT may be useful in guiding future therapies, particularly in conditions associated with pro-oxidant conditions.

www.ncbi.nlm.nih.gov/pubmed/19272168

J Biomed Sci. 2009 Jan 12;16:4. Molecular mechanisms of cell proliferation induced by low power laser irradiation.

Gao X, Xing D. Source MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, South China Normal University, Guangzhou 510631, PR China. gaoxj@scnu.edu.cn Abstract Low power laser irradiation (LPLI) promotes proliferation of multiple cells, which (especially red and near infrared light) is mainly through the activation of mitochondrial respiratory chain and the initiation of cellular signaling. Recently, the signaling proteins involved in LPLI-induced proliferation merit special attention, some of which are regulated by mitochondrial signaling. Hepatocyte growth factor receptor (c-Met), a member of tyrosine protein kinase receptors (TPKR), is phosphorylated during LPLI-induced proliferation, but tumor necrosis factor alpha (TNF-alpha) receptor has not been affected. Activated TPKR could activate its downstream signaling elements, like Ras/Raf/MEK/ERK, PI3K/Akt/eIF4E, PI3K/Akt/eNOS and PLC-gamma/PKC pathways. Other two pathways, DeltaPsim/ATP/cAMP/JNK/AP-1 and ROS/Src, are also involved in LPLI-induced proliferation. LPLI-induced cell cycle progression can be regulated by the activation or elevated expressions of cell cycle-specific proteins. Furthermore, LPLI induces the synthesis or release of many molecules, like growth factors, interleukins, inflammatory cytokines and others, which are related to promotive effects of LPLI.

www.ncbi.nlm.nih.gov/pubmed/10902741

Int J Radiat Biol. 2000 Jun;76(6):863-70.

Specific helium-neon laser sensitivity of the purified cytochrome c oxidase.
Pastore D, Greco M, Passarella S. Source Dipartimento di Scienze Animali, Vegetali e dell'Ambiente, Università del Molise, Campobasso, Italy. Abstract PURPOSE: In order to gain some insight into the mechanism of interaction between Helium-Neon (He-Ne) laser light and mitochondrial cytochromes, the sensitivity of cytochrome electron transfer activity to He-Ne laser was tested. MATERIALS AND METHODS: Irradiation of solutions containing either purified cytochromes or dissolved rat liver mitochondria was carried out (wavelength 632.8 nm, fluence rate 10 mW cm(-2), fluence 2 J cm(-2)); the irradiation conditions were the ones able to affect cytochrome c oxidase (COX) activity in mitochondria (Pastore et al., 1994). RESULTS: Cytochrome c oxidation catalysed by COX was affected by He-Ne laser irradiation of the purified enzyme. This result was obtained from measurements of the pseudo-first-order kinetic constant and from determinations of the turnover number of the enzyme, performed at different cytochrome c/COX ratios. Consistently, the kinetic parameters of COX changed. On the contrary, no alteration in the rate of electron transfer catalysed by either cytochrome c or bc1 complex was found. CONCLUSIONS: This study shows that purified COX is a specific target of He-Ne laser light; therefore, COX may be considered to be a mitochondrial photo-acceptor.

www.nature.com/nrm/journal/v9/n7/box/nrm2434_BX1.html

Box 1 | The role of cytochrome c in respiration From the following article:
Cytochrome c: functions beyond respiration
Yong-Ling P. Ow, Douglas R. Green, Zhenyue Hao & Tak W. Mak Nature Reviews Molecular Cell Biology 9, 532-542 (July 2008) One of the essential molecules of the electron-transport chain is cytochrome c (grey circle). Cytochrome c accepts electrons from Complex III and diffuses to Complex IV (cytochrome oxidase), where it donates the electrons to O2, converting O2 to H2O. Cytochrome c first forms as apocytochrome c, which is produced by translation and co-translational modification in the cytosol. Apocytochrome c then translocates to the mitochondrial intermembrane space where the haem moiety is covalently attached by cytochrome c haem lyase to form holocytochrome c. Concurrently, the partially extended conformation of apocytochrome c becomes the more compact structure of holocytochrome c.

sandwalk.blogspot.com/2007/08/heme-groups.html Cytochrome c is a major player in membrane associated electron transport systems in bacteria and mitochondria and in photosynthesis. images

users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CellularRespiration.html

images for mitohondria and respiration

The Electron Transport Chain

The electron transport chain consists of 3 complexes of integral membrane proteins the NADH dehydrogenase complex (I) the cytochrome c reductase complex (III) the cytochrome c oxidase complex (IV) and two freely-diffusible molecules ubiquinone cytochrome c that shuttle electrons from one complex to the next. The electron transport chain accomplishes: the stepwise transfer of electrons from NADH (and FADH2) to oxygen molecules to form (with the aid of protons) water molecules (H2O); (Cytochrome c can only transfer one electron at a time, so cytochrome c oxidase must wait until it has accumulated 4 of them before it can react with oxygen.) harnessing the energy released by this transfer to the pumping of protons (H+) from the matrix to the intermembrane space. Approximately 20 protons are pumped into the intermembrane space as the 4 electrons needed to reduce oxygen to water pass through the respiratory chain. The gradient of protons formed across the inner membrane by this process of active transport forms a miniature battery. The protons can flow back down this gradient, reentering the matrix, only through another complex of integral proteins in the inner membrane, the ATP synthase complex (as we shall now see). The energy released as electrons pass down the gradient from NADH to oxygen is harnessed by three enzyme complexes of the respiratory chain (I, III, and IV) to pump protons (H+) against their concentration gradient from the matrix of the mitochondrion into the intermembrane space (an example of active transport). As their concentration increases there (which is the same as saying that the pH decreases), a strong diffusion gradient is set up. The only exit for these protons is through the ATP synthase complex. As in chloroplasts, the energy released as these protons flow down their gradient is harnessed to the synthesis of ATP. Why do mitochondria have their own genome? Many of the features of the mitochondrial genetic system resemble those found in bacteria. This has strengthened the theory that mitochondria are the evolutionary descendants of a bacterium that established an endosymbiotic relationship with the ancestors of eukaryotic cells early in the history of life on earth. However, many of the genes needed for mitochondrial function have since moved to the nuclear genome. The recent sequencing of the complete genome of Rickettsia prowazekii has revealed a number of genes closely related to those found in mitochondria. Perhaps rickettsias are the closest living descendants of the endosymbionts that became the mitochondria of eukaryotes.

http://www.laserpointerpro.com/5mw-650nm-ultra-powerful-red-laser-pointer-p-210.html

5mW 650nm Ultra Powerful Red Laser Pointer

http://www.laserpointerpro.com/5mw-650nm-openback-ultra-powerful-red-laser-pointer-pen-p-219.html

http://pubs.acs.org/cen/news/85/i12/8512notw4.html
Chemical & Engineering News. March 19, 2007     Volume 85, Number 12    p. 13
Enzyme Catalysis Electron-Starved Enzyme Cytochrome c oxidase model mimics natural electron-limited conditions SChematic model of cytochrome C oxidase

http://mail.sott.net/articles/show/223040-Extinction-Metamorphosis-Evolutionary-Apoptosis-and-Genetically-Programmed-Species-Mass-Death

Extinction, Metamorphosis, Evolutionary Apoptosis, and Genetically Programmed Species Mass Death Rhawn Joseph, Ph.D. Journal of Cosmology Thu, 15 Oct 2009 07:58 CDT

http://mail.sott.net/articles/show/223040-Extinction-Metamorphosis-Evolutionary-Apoptosis-and-Genetically-Programmed-Species-Mass-Death

Oxygenation and Mitochondria

---------------------- Literature review -------------------------

www.laserscenarfusion.com/articles/newlllt.pdf

Our latest LLLT literature review with abstracts including muscle fatigue, TMJ, myofacial pain, acne and a possible application for morphine withdrawal. selected pubmed references from this pdf file:

---------------
increases ATP in lymphocytes
----------------

www.ncbi.nlm.nih.gov/pubmed/18922088

Photomed Laser Surg. 2008 Oct;26(5):451-3.

Intracellular ATP level increases in lymphocytes irradiated with infrared laser light of wavelength 904 nm. Benedicenti S, Pepe IM, Angiero F, Benedicenti A. Source Department of Medical Science, Dentistry, and Biophysics, University of Genoa, Milan, Italy. stefano.benediceneti@tiscali.it Abstract

OBJECTIVE: Red and near-infrared laser irradiation is reported to have a range of biological effects on cultured cells and different tissues, leading to the hypothesis that laser light can affect energy metabolism. Increased adenosine triphosphate (ATP) synthesis has been reported in cultured cells and rat brain tissue after irradiation at 632.8 nm and 830 nm, respectively. This study investigated whether diode pulsed laser irradiation enhances ATP production in lymphocytes.

MATERIALS AND METHODS: Aliquots (500 microL) of an extract of cultured lymphocytes of the Molt-4 cell line were irradiated with diode laser light (lambda = 904 nm, pulsed mode, 6 kHz frequency) with an average emission power of 10 mW for 60 min. A Spectra Physics M404 power meter was used to measure light intensity. Controls were treated similarly but not irradiated. The amount of ATP was measured by the luciferin-luciferase bioluminescent assay. RESULTS: The amount of ATP in irradiated cell cultures was 10.79 +/- 0.15 microg/L (SD; n = 10), and in non-irradiated cell cultures it was 8.81 +/- 0.13 microg/L (SD; n = 10).

The average percentage increase of irradiated versus control cell cultures was about 22.4% +/- 0.56% SD (p < 0.001).

CONCLUSION: This significant increase is probably due to laser irradiation; it cannot be attributed to any thermal effect, as the temperature during irradiation was maintained at 37.0 degrees +/- 0.5 degrees C. Thus the therapeutic effects of the biostimulating power of this type of laser are identified and its indications may be expanded. Increases nitric oxide

www.ncbi.nlm.nih.gov/pubmed/18922087?dopt=Citation

Photomed Laser Surg. 2008 Oct;26(5):443-9.

Role of nitric oxide in the visible light-induced rapid increase of human skin microcirculation at the local and systemic levels: II. healthy volunteers. Samoilova KA, Zhevago NA, Petrishchev NN, Zimin AA. Source Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia. samoilova3@yandex.ru Abstract

OBJECTIVE: The aim of this study is to evaluate the skin microcirculation increase seen in healthy volunteers after a single exposure to polychromatic visible (pVIS) light, and to prove the role of nitric oxide (NO) in the development of this effect.

BACKGROUND DATA: Improvement of microcirculation is one of the most important effects of laser and pVIS light therapy; however, its mechanism of action remains unknown. A main role in the regulation of vascular tone is known to be played by NO. It is produced by NO-synthase (NOS) located in membranes of many cells, including endothelial and blood cells. NOS, a biopteroflavohemoprotein, absorbs pVIS light, resulting in its activation.

MATERIALS AND METHODS: The central area of the dorsal side of the right hand (24 cm2) of 42 volunteers was irradiated for 5 min with pVIS light from a Q-light (385-750 nm, 95% polarization, 40 mW/cm2, 12 J/cm2). Then for 90 min, the blood flow rate (Qas) was measured eight times, both in the area of the irradiation (local effect) and in the non-irradiated left hand (systemic effect) by using a high-frequency ultrasound Doppler device, recording Qas in human skin to a depth up to 5 mm. In the central area of the right hand of 14 volunteers an NOS inhibitor, N-monomethyl-L-arginine (L-NMMA, 0.1% solution), was iontophoretically administered prior to exposure, whereas in 10 other subjects it was administered to the left hand with subsequent exposure of the right hand.

RESULTS: As soon as 2 min after exposure, Qas in the irradiated area rose on average by 32%, and in 20 min by 45%; it then decreased and in 90 min returned to the initial level. A statistically significant Qas increase in the non-irradiated hand was recorded in 5 min (+9%), and in 20 min it reached a maximum level (+39%), and 90 min later it decreased to the initial values. The presence of L-NMMA in the light-exposed area completely blocked the photoinduced rise of microcirculation, both in the irradiated and in non-irradiated hand; however, its administration to the non-irradiated hand did not prevent these effects.

CONCLUSION: The increase in skin microcirculation produced by pVIS light at the local and systemic levels is due to activation of NO synthesis in the irradiated area.

-------
full text Free Mechanism of Benefits of Low Level Lasers-
Activates Mitochondrial respiration-

www.ncbi.nlm.nih.gov/pubmed/21814580
PLoS One. 2011;6(7):e22453. Epub 2011 Jul 21.

Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts.

Chen AC, Arany PR, Huang YY, Tomkinson EM, Sharma SK, Kharkwal GB, Saleem T, Mooney D, Yull FE, Blackwell TS, Hamblin MR. Source Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America. BACKGROUND: Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear.

METHODOLOGY/PRINCIPAL FINDINGS: In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm(2) and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration.

CONCLUSION: We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT.
--------------------------------------
FUll text- nice intro and review by Harvard prof
--------------------------------

www.ncbi.nlm.nih.gov/pmc/articles/PMC2939452/?tool=pubmed

Lasers Surg Med. 2010 August; 42(6): 447–449.
Introduction to Experimental and Clinical Studies Using Low-Level Laser (Light) Therapy (LLLT)

Michael R. Hamblin, PhD, Associate Professor Michael R. Hamblin, Harvard Medical School; *Correspondence to: Michael R Hamblin, PhD, Assistant Professor, Harvard Medical School

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Photoceutical for stem cell growth and regeneration
-----------------------------

From a Stem Cell COmpany:

www.ncbi.nlm.nih.gov/pmc/articles/PMC2830167/?tool=pubmed

J Transl Med. 2010; 8: 16.
Lasers, stem cells, and COPD
Feng Lin,#1 Steven F Josephs,#1 Doru T Alexandrescu,#2 Famela Ramos,1 Vladimir Bogin,3 Vincent Gammill,4 Constantin A Dasanu,5 Rosalia De Necochea-Campion,6 Amit N Patel,7 Ewa Carrier,6 and David R Kooscorresponding author1

The medical use of low level laser (LLL) irradiation has been occurring for decades, primarily in the area of tissue healing and inflammatory conditions. Despite little mechanistic knowledge, the concept of a non-invasive, non-thermal intervention that has the potential to modulate regenerative processes is worthy of attention when searching for novel methods of augmenting stem cell-based therapies. Here we discuss the use of LLL irradiation as a "photoceutical" for enhancing production of stem cell growth/chemoattractant factors, stimulation of angiogenesis, and directly augmenting proliferation of stem cells. The combination of LLL together with allogeneic and autologous stem cells, as well as post-mobilization directing of stem cells will be discussed. "A pubmed search for "low level laser therapy" yields more than 1700 results, yet before stumbling across this concept, none of us, or our advisors, have ever heard of this area of medicine."

--------------------------- Nuclear Factor Kappa Beta -------------------------- www.researchersworld.com/vol2/issue3/Paper_6.pdf

THE BIOLOGY OF NUCLEAR FACTOR KAPPA BETA (NFkB IN HEALTH AND PATHOLOGY by Carlos Kusano Bucalen Ferrari, Biomedical Research Group, Institute of Biological and Health Sciences (ICBS), “Campus Universitário do Araguaia”, “Universidade Federal de Mato Grosso” (UFMT), Barra do Garças, MT, Brazil.

www.ncbi.nlm.nih.gov/pubmed/15175863
J Mol Med (Berl). 2004 Jul;82(7):434-48. Epub 2004 Jun 3.
Nuclear factor-kappaB: its role in health and disease.
Kumar A, Takada Y, Boriek AM, Aggarwal BB. Source Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. axkumar@bcm.tmc.edu Abstract Nuclear factor-kappaB (NF-kappa is a major transcription factor that plays an essential role in several aspects of human health including the development of innate and adaptive immunity. The dysregulation of NF-kappaB is associated with many disease states such as AIDS, atherosclerosis, asthma, arthritis, cancer, diabetes, inflammatory bowel disease, muscular dystrophy, stroke, and viral infections. Recent evidence also suggests that the dysfunction of NF-kappaB is a major mediator of some human genetic disorders. Appropriate regulation and control of NF-kappaB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NF-kappaB related human diseases. This review summarizes the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention

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www.drkaslow.com/html/low_level_lasers__lllt_.html

cold laser article dr kaslow place into blog roll

---------- Q LAser dr Lytle _----------------

“Use Mode 1 to re-energize muscle, ligament and tendon cells for healing wounds and injuries or for reducing pain and inflammation; Mode 1 also benefits tendonitis, arthritis, burns, sprains, cuts, bruises, muscle pulls, sore throat, and any pain or inflammation.” • “Use Mode 2 to re-energize brain and heart cells and to normalize brain neuropeptides and heart cell energy.” • “Use Mode 3 as a multi-organ cell re-energizer that cycles through 29 different frequencies proven effective and beneficial for healing, and to benefit inflammation or disorders of all internal, and for the treatment of any unknown condition.” [Note: The proprioceptive points are (1) just in front of the ear over the TMJ, (2) under the angle of the jaw, (3) two inches below the collar bone, and (4) one inch up from the rounded angle of the shoulder blade (scapula).]

www.humanenergyscience.com/uploads/Dr_Lytle_s_audio_4-10.pdf

OSTEOARTHRITIS and the LOW LEVEL LASER
A Transcript of Dr. Lytle’s webinar April 2010

www.21CenturyMedicineChest.com/blog/Joint_Pain
(runtime 59:03) Dr. Irina: Why did you choose osteoarthritis as the basis of your first FDA clinical trials? What were the results of the trials? And we get the exciting news\ www.laserlightinstitute.info/healinglight.pdf

Healing Light by Dr. Larry Lytle
----------------------------------------------
www.21centurydoc.com/tag/soft-laser
21st Century Doc - 21st Century Medicine at your Fingertips

www.scribd.com/doc/66068978/Electrotherapeutic-Devices-Principles-Design-and-Applications

Electrotherapeutic DevicesPrinciples, Design, and Applications --------------------

-------------------------------------------
full pdf

qvchealth.info/clients/931/documents/MuscleRepair_Silveira.pdf
Journal of Photochemistry and Photobiology B: Biology 95 (2009) 89–92

Evaluation of mitochondrial respiratory chain activity in muscle healing by low-level laser therapy

Paulo C.L. Silveira a,*, Luciano Acordi da Silva a, Daiane B. Fraga b, Tiago P. Freitas b, Emilio L. Streck b, Ricardo Pinho a Background: Recent studies demonstrate that low-level laser therapy (LLLT) modulates many biochemical processes, especially the decrease of muscle injures, the increase in mitochondrial respiration and ATP synthesis for accelerating the healing process. Objective: In this work, we evaluated mitochondrial respiratory chain complexes I, II, III and IV and succinate dehydrogenase activities after traumatic muscular injury. Methods: Male Wistar rats were randomly divided into three groups (n = 6): sham (uninjured muscle), muscle injury without treatment, muscle injury with LLLT (AsGa) 5 J/cm2. Gastrocnemius injury was induced by a single blunt-impact trauma. LLLT was used 2, 12, 24, 48, 72, 96, and 120 hours after muscle- trauma.

Results: Our results showed that the activities of complex II and succinate dehydrogenase after 5 days of muscular lesion were significantly increased when compared to the control group. Moreover, our results showed that LLLT significantly increased the activities of complexes I, II, III, IV and succinate dehydrogenase, when compared to the group of injured muscle without treatment.

Conclusion: These results suggest that the treatment with low-level laser may induce an increase in ATP synthesis, and that this may accelerate the muscle healing process.

www.thorlaser.com/downloads/research/Biphasic-Dose-Response-in-Low-Level-Light-Therapy-Harvard.pdf

Formerly Nonlinearity in Biology, Toxicology, and Medicine Copyright © 2009 University of Massachusetts

BIPHASIC DOSE RESPONSE IN LOW LEVEL LIGHT THERAPY Ying-Ying Huang Michael R. Hamblin, BAR 414, Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston,

www.theragem.com/harvardstudy.pdf www.photobiology.info/Hamblin.html MECHANISMS OF LOW LEVEL LIGHT THERAPY
Michael R. Hamblin Department of Dermatology, Harvard Medical School, BAR 414 Wellman Center for Photomedicine, Massachusetts General Hospital 40 Blossom Street, Boston MA 02114 hamblin@helix.mgh.harvard.edu

www.mgh.harvard.edu/wellman/people/mhamblin.asp
www.photobiology.info/ spie.org/x35504.xml?ArticleID=x35504

Biomedical Optics & Medical Imaging Low-level laser therapy: an emerging clinical paradigm
Ying-Ying Huang, Michael Hamblin, and Aaron C.-H. Chen 9 July 2009, SPIE Newsroom. DOI: 10.1117/2.1200906.1669
Improved understanding of the fundamental cellular and molecular mechanisms is broadening the technique's mainstream use for many ailments. 9 July 2009, SPIE Newsroom. DOI: 10.1117/2.1200906.1669

www.molecularneurodegeneration.com/content/4/1/26 Reduced axonal transport in Parkinson's disease cybrid neurites is restored by light therapy Patricia A Trimmer1*, Kathleen M Schwartz1, M Kathleen Borland1, Luis De Taboada2, Jackson Streeter2 and Uri Oron3

www.photothera.com/technology/neurothera
The NeuroThera® Laser System is under development for the treatment of ischemic stroke and is not approved for sale or distribution in the United States or internationally. The NeuroThera® Laser System is an investigational device that seeks to improve neurological outcomes via noninvasive delivery of near-infrared (NIR) laser energy called Transcranial Laser Therapy (TLT) into the brain. The system consists of a moveable console, a fiber optic cable, and a handpiece. A trained clinician uses the handpiece to direct the TLT to twenty predetermined treatment sites on the patient’s scalp. The total procedure time is approximately 2-3 hours. The Company believes that the NeuroThera® Laser System may offer a compelling option for the treatment of acute ischemic stroke up to twenty-four hours following onset of stroke symptoms.

www.nature.com/jid/journal/v127/n8/full/5700826a.html
www.ncbi.nlm.nih.gov/pubmed/17446900

J Invest Dermatol. 2007 Aug;127(8):2048-57. Epub 2007 Apr 19.

Helium-neon laser irradiation stimulates cell proliferation through photostimulatory effects in mitochondria.

Hu WP, Wang JJ, Yu CL, Lan CC, Chen GS, Yu HS. Source Faculty of Biotechnology and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract Previous reports have shown that cellular functions could be influenced by visual light (400-700 nm). Recent evidence indicates that cellular proliferation could be triggered by the interaction of a helium-neon laser (He-Ne laser, 632.8 nm) with the mitochondrial photoacceptor-cytochrome c oxidase.

Our previous studies demonstrated that He-Ne irradiation induced an increase in cell proliferation, but not migration, in the melanoma cell line A2058 cell. The aim of this study was to investigate the underlying mechanisms involved in photostimulatory effects induced by an He-Ne laser. Using the A2058 cell as a model for cell proliferation, the photobiologic effects induced by an He-Ne laser were studied. He-Ne irradiation immediately induced an increase in mitochondrial membrane potential (delta psi(mt)), ATP, and cAMP via enhanced cytochrome c oxidase activity and promoted phosphorylation of Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) expressions. He-Ne irradiation-induced A2058 cell proliferation was significantly abrogated by the addition of delta psi(mt) and JNK inhibitors. Moreover, treatment with an He-Ne laser resulted in delayed effects on IL-8 and transforming growth factor-beta1 release from A2058 cells.

These results suggest that He-Ne irradiation elicits photostimulatory effects in mitochondria processes, which involve JNK/AP-1 activation and enhanced growth factor release, and ultimately lead to A2058 cell proliferation.

www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm246619.htm
March 3, 2011 WARNING LETTER CERTIFIED MAILRETURN RECEIPT REQUESTED
Refer to MIN 11-14 Robert L. Lytle, DDS, PhD President, 2035, Inc.
Managing Limited Partner, QLaser Healing Light LP 520 Kansas City Street, Suite 100 Rapid City, South Dakota 57701

Dear Dr. Lytle: During an inspection of your firm located in Rapid City, South Dakota, on May 25 - 27, 2010, an investigator from the United States Food and Drug Administration (FDA) learned that your firms 2035, Inc. and QLaser Healing Light LP are marketing the Q10 Laser and 808 Enhancer Probe in the United States without marketing clearance or approval, in violation of the Federal Food, Drug, and Cosmetic Act (the Act). Q1000 Laser and 660 Enhancer Probe A review of our records indicates that we cleared a premarket notification (510(k)) for the Q1000 Laser and 660 Enhancer Probe (QLaser System), K080513, with an intended use “for providing temporary relief of pain associated with osteoarthritis of the hand, which has been diagnosed by a physician or other licensed medical professional.”

www.accessdata.fda.gov/cdrh_docs/pdf8/K080513.pdf
Re: K080513 Trade/Device Name: QLaser System Regulation Number: 21 CFR 890.5500 Regulation Name: Infrared lamp Regulatory Class: II Product Code: NHN Dated: January 9, 2009 Received: January 12, 2009

------------------------

lyphedema
- --------------------------

www.riancorp.com/

RianCorp has completed the only randomised double blind clinical trial testing the effects of LLLT on lymphoedema/lymphedema in the world.7 Fleet St, Richmond, South Australia 5033 The LTU-904 models are infra-red lasers operating at a wavelength of 904 nanometers. This invisible wavelength penetrates deeply into tissue (much deeper than the often used red laser operating in the visible red region).

www.rifkinmedicalproducts.com/ RIFKIN MEDICAL PRODUCTS,LLC call 203-758-6569 The LTU-904 laser is only ONLY lymphoedema treatment that has been trialled in a randomised double blind study. The laser works very effectively in about 30% of patients and with some effect in about 50% of patients.

------------------------
www.henrylahore.com/Health/LLLT%20800%20nm%20gets%20into%20spinal%20cord%20July%202009.PDF

Photomedicine and Laser Surgery Volume 27, Number 3, 2009 ª Mary Ann Liebert, Inc. Pp. 379–380 Guest Editorial*

The Potential of Light Therapy for Central Nervous System Injury and Disease

Juanita J. Anders, Ph.D. Department of Anatomy, Physiology and Genetics Uniformed Services University of the Health Sciences 4301 Jones Bridge Rd. Bethesda, MD 20814 Juanita J. Anders

--------------------------------

www.isan.troitsk.ru/dls/publ/tiinaabs2005.pdf

Absorption measurements of a cell monolayer relevant to phototherapy:
Reduction of cytochrome c oxidase under near IR radiation

Tiina I. Karu a,*, Lydmila V. Pyatibrat a, Sergei F. Kolyakov b, Natalya I. Afanasyeva c
Journal of Photochemistry and Photobiology B: Biology 81 (2005) 98–106 a Institute of Laser and Information Technologies of Russian Academy of Sciences, Troitsk, Pionerskaya Street 2, Moscow Region 142190, Russian Federation b Institute of Spectroscopy of Russian Academy of Sciences, Troitsk, Moscow Region 142190, Russian Federation c Spectrooptical Sensing Inc., Portland, OR 97205, USA Received 26 April 2005; accepted 20 July 2005

Phototherapy uses monochromatic light in the optical region of 600–1000 nm to treat in a non-destructive and non-thermal fashion various soft-tissue and neurological conditions. This kind of treatment is based on the ability of light red-to-near IR to alter cellular metabolism as a result of its being absorbed by cytochrome c oxidase. To further investigate the involvement of cytochrome c oxidase as a photoacceptor in the alteration of the cellular metabolism,

Jeffrey Dach MD
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Low Level Laser Medicine of the Future, Part One

Sun, 15 Jan 2012 17:01:53 -0500

Low Level Laser Medicine of the Future, Part One

I recently learned about Low Level Laser at a meeting in Orlando. Dr. Larry Lytle presented a nice talk on the low energy laser device for various medical applications. This information was new to me as it probably is for you as well.

Left Image: Sky with laser beams, with three lasers beams projected into the sky courtesy of Wikimedia Commons.

A Patient with Severe Degenerative Arthritis

One of out family members has severe degenerative arthritis of the knee, so we picked up a low level laser device from Dr Lytle with the idea of using it on the knee. . MRI scans showed advanced degenerative changes, destruction of knee cartilage, and fluid in the joint, and the knee was inflamed, and painful.

Left Image: QLaser Device Courtesy of Dr Lytle and QLaser Company

Offering a Knee Replacement

The knee was bad enough for the orthopedic surgeon to offer a knee replacement.

Low Level Laser for the Knee

We applied the low level laser light to the knee, and noticed prompt improvement with less pain and inflammation. With daily treatments, the knee continued to improve with elimination of pain. The knee replacement operation is no longer needed.

What is Low Level Laser?   And Why Haven't I Heard About It?

You are probably thinking, "if low level laser is so great, why haven't I heard about it"? The answer is that the FDA, working on behalf of the drug industry, has been diligently suppressing information about it. The device relieves pain and inflammation directly competing with the drug industry. Dr Lytle received FDA warning letters demanding removal of information from his web site about uses of the low level laser. Fortunately, this newsletter can fill in the missing information deleted by the FDA.

What Are Low Level Lasers ?

Invented in 1967, LASER stands for Light Amplification and Stimulated Emission. This is a device which produces light which is In-Phase and all the Same Frequency, also called Coherent Light. This differs from incoherent light from the sun or a light bulb, this type of light is out of phase and has differing frequencies.

Since invention in 1967, lasers have become commonplace in medical, industrial and even household uses. For example, there are low level lasers in your CD player, in the supermarket barcode reader, and in your optical mouse.

Low level lasers for personal medical use are also available, approved as safe by the FDA, and available for sale to the public without a prescription. These can be seen in popular mail order catalogs, and can even be ordered from Amazon.

Of course, we make the important distinction between safe low energy lasers and the more dangerous high energy lasers which can cut through metal. Medical lasers are used by surgeons to cut tissue in the operating room. High Energy Lasers are obviously dangerous and require more regulation.

Energy- Where Does It Come From ? Photosynthesis from Light

All energy in living organisms comes from light energy (from the sun) harnessed by photosynthesis. In higher organisms, such as us humans, we eat the plants and utilize plant energy in the form of carbon double bonds in a reaction called oxidation. This same oxidation provides us with energy from "fossil fuel" such as coal, oil and gasoline which are another source of energy stored up from plant photosynthesis. An "oxidative" chemical reaction occurs when we use fossil fuel, and "burn" a log in the fire place, or run our car engine with gasoline.

The Proto-Porphyrin Ring- This Absorbs Light Energy

Left Image: Proto-porphyrin Basic Ring Structure - notice the four central nitrogen atoms. This structure absorbs light and is present as hemoglobin, chlorophyll, and all cytochromes. Central metal atoms such as Fe , Mg and Cu enhance ability to absorb light energy.

How Our Cells Make Energy

Normally, the mitochondria in trillions of our cells use food to make energy. Food is the carbon compounds we eat. The carbon double bond is the energy source and provides energy in a process called oxidation (also called Fatty Acid Oxidation or oxidative phosphorylation). Oxygen is combined with carbon (from our food) to liberate the energy in the double bond in "burning" of carbon to carbon dioxide and water.

Photosynthesis in Mitochondria ?

Another dormant pathway of energy production also exists. Our mitochondria retain the ability to absorb energy from light. The more primitive machinery of "photosynthesis" lies dormant in mitochondria, ready to be re-awakened. The mitochondria can absorb and utilize energy directly from light photons in the infrared spectrum. This machinery is very similar to photosynthesis of plants and bacteria.

Living Organisms Absorb and Utilize Light Energy - Photosynthesis

Left Image: Chlorophyll found in bacteria. Notice the Proto-Porphyrin Ring with central (Mg) Magnesium, surrounded by four nitrogen atoms. This structure absorbs light energy.

We are all familiar with photosynthesis, the ability of plants to convert sunlight into usable energy. The leafy green color comes from chlorophyll, the light absorptive molecule. The chemical structure of chlorophyll is strikingly similar to hemoglobin, both contain a proto-porphyrin ring, and a central metal atom. Chlorophyll contains magnesium (Mg) in the center. Hemoglobin contains iron (Fe), and Cytochrome C oxidase contains both Fe and Copper. Mitochondria contain light absorbing compounds called cytochromes which contain the same proto-porphyrin ring structure as chlorophyll, allowing for light absorption . (see image below)

Left Image : Cytochrome C Oxidase in the mitochondria. Notice similarity of ring structure to chlorophyll. Central Magnesium has been replace with a central Iron (Fe). There is also a copper (Cu) add-on at top. This structure absorbs light energy.

Where in the cell is the light absorbed ? Cytochrome C Oxidase

Recent studies show that light photons are absorbed in the mitochondria by a protein called cytochrome c oxidase, which is involved in energy production. Cytochrome c oxidase is a photo-acceptor, absorbing light at a peak spectrum of 630-670nm (red light). Cytochrome C oxidase is a large protein which contains two Iron molecules and two Copper molecules in its center .   These metals atoms have outer shell electrons which absorb electromagnetic radiation (also known as a light photons).

Activating Cytochrome C Oxidase in the Mitochondria

Left Image: Mitochondria with illuminated inner membrane showing electrical energy production.

Once the outer electrons of the central metal atom absorb light energy, these electrons will then move to higher-energy orbitals, making a transition to a higher-energy state. This is useful since the job of Cytochrome Oxidase is energy production and the increased energy spills out in the final product as ATP.

Thus we have a process of converting light energy to usable cellular ATP (Adenine Triphosphate) which is the currency of energy in the cell. This shares remarkable molecular similarities to photosynthesis in plants and bacteria.

Thanks to low level laser devices, we can now deliver photon energy to mitochondria of deeper areas of the body such as joints, the spine and brain. This "energizes" the mitochondria, and increased cellular energy production activates the healing process.

Gene Expression and Cell Signalling

However, increased mitochondria energy is only where the process begins. This is only the first step which triggers cell signalling for growth and healing. In addition, there is increased microcirculation from nitric oxide synthesis, there is activation of fibroblasts and macrophages. There is stimulation of new blood vessel growth. There is up-regulation of hundred of genes which are involved in transcription of growth and proliferation factors such as nuclear factor kappa beta, VEGF (vascular endothelial growth factor), and the JNK gene is activated as well with promoted phosphorylation of Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) expressions. Bottom line is this induces a healing reaction.

For Part Two of this series, CLICK HERE.

Jeffrey Dach MD
7450 Griffin Road, SUite 190
Davie, Fl 33314
954-792-4663
www.jeffreydach.com
www.drdach.com
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www.bioidenticalhormones101.com
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Links and References

http://pubs.acs.org/cen/news/85/i12/8512notw4.html
Chemical & Engineering News. March 19, 2007     Volume 85, Number 12    p. 13
Enzyme Catalysis Electron-Starved Enzyme Cytochrome c oxidase model mimics natural electron-limited conditions SChematic model of cytochrome C oxidase

http://mail.sott.net/articles/show/223040-Extinction-Metamorphosis-Evolutionary-Apoptosis-and-Genetically-Programmed-Species-Mass-Death

Extinction, Metamorphosis, Evolutionary Apoptosis, and Genetically Programmed Species Mass Death Rhawn Joseph, Ph.D. Journal of Cosmology Thu, 15 Oct 2009 07:58 CDT

http://mail.sott.net/articles/show/223040-Extinction-Metamorphosis-Evolutionary-Apoptosis-and-Genetically-Programmed-Species-Mass-Death

Oxygenation and Mitochondria

---------------------- Literature review -------------------------

www.laserscenarfusion.com/articles/newlllt.pdf

Our latest LLLT literature review with abstracts including muscle fatigue, TMJ, myofacial pain, acne and a possible application for morphine withdrawal. selected pubmed references from this pdf file:

---------------
increases ATP in lymphocytes
----------------

www.ncbi.nlm.nih.gov/pubmed/18922088

Photomed Laser Surg. 2008 Oct;26(5):451-3.

Intracellular ATP level increases in lymphocytes irradiated with infrared laser light of wavelength 904 nm. Benedicenti S, Pepe IM, Angiero F, Benedicenti A. Source Department of Medical Science, Dentistry, and Biophysics, University of Genoa, Milan, Italy. stefano.benediceneti@tiscali.it Abstract

OBJECTIVE: Red and near-infrared laser irradiation is reported to have a range of biological effects on cultured cells and different tissues, leading to the hypothesis that laser light can affect energy metabolism. Increased adenosine triphosphate (ATP) synthesis has been reported in cultured cells and rat brain tissue after irradiation at 632.8 nm and 830 nm, respectively. This study investigated whether diode pulsed laser irradiation enhances ATP production in lymphocytes.

MATERIALS AND METHODS: Aliquots (500 microL) of an extract of cultured lymphocytes of the Molt-4 cell line were irradiated with diode laser light (lambda = 904 nm, pulsed mode, 6 kHz frequency) with an average emission power of 10 mW for 60 min. A Spectra Physics M404 power meter was used to measure light intensity. Controls were treated similarly but not irradiated. The amount of ATP was measured by the luciferin-luciferase bioluminescent assay. RESULTS: The amount of ATP in irradiated cell cultures was 10.79 +/- 0.15 microg/L (SD; n = 10), and in non-irradiated cell cultures it was 8.81 +/- 0.13 microg/L (SD; n = 10).

The average percentage increase of irradiated versus control cell cultures was about 22.4% +/- 0.56% SD (p < 0.001).

CONCLUSION: This significant increase is probably due to laser irradiation; it cannot be attributed to any thermal effect, as the temperature during irradiation was maintained at 37.0 degrees +/- 0.5 degrees C. Thus the therapeutic effects of the biostimulating power of this type of laser are identified and its indications may be expanded. Increases nitric oxide

www.ncbi.nlm.nih.gov/pubmed/18922087?dopt=Citation

Photomed Laser Surg. 2008 Oct;26(5):443-9. Role of nitric oxide in the visible light-induced rapid increase of human skin microcirculation at the local and systemic levels: II. healthy volunteers. Samoilova KA, Zhevago NA, Petrishchev NN, Zimin AA. Source Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia. samoilova3@yandex.ru Abstract

OBJECTIVE: The aim of this study is to evaluate the skin microcirculation increase seen in healthy volunteers after a single exposure to polychromatic visible (pVIS) light, and to prove the role of nitric oxide (NO) in the development of this effect.

BACKGROUND DATA: Improvement of microcirculation is one of the most important effects of laser and pVIS light therapy; however, its mechanism of action remains unknown. A main role in the regulation of vascular tone is known to be played by NO. It is produced by NO-synthase (NOS) located in membranes of many cells, including endothelial and blood cells. NOS, a biopteroflavohemoprotein, absorbs pVIS light, resulting in its activation.

MATERIALS AND METHODS: The central area of the dorsal side of the right hand (24 cm2) of 42 volunteers was irradiated for 5 min with pVIS light from a Q-light (385-750 nm, 95% polarization, 40 mW/cm2, 12 J/cm2). Then for 90 min, the blood flow rate (Qas) was measured eight times, both in the area of the irradiation (local effect) and in the non-irradiated left hand (systemic effect) by using a high-frequency ultrasound Doppler device, recording Qas in human skin to a depth up to 5 mm. In the central area of the right hand of 14 volunteers an NOS inhibitor, N-monomethyl-L-arginine (L-NMMA, 0.1% solution), was iontophoretically administered prior to exposure, whereas in 10 other subjects it was administered to the left hand with subsequent exposure of the right hand.

RESULTS: As soon as 2 min after exposure, Qas in the irradiated area rose on average by 32%, and in 20 min by 45%; it then decreased and in 90 min returned to the initial level. A statistically significant Qas increase in the non-irradiated hand was recorded in 5 min (+9%), and in 20 min it reached a maximum level (+39%), and 90 min later it decreased to the initial values. The presence of L-NMMA in the light-exposed area completely blocked the photoinduced rise of microcirculation, both in the irradiated and in non-irradiated hand; however, its administration to the non-irradiated hand did not prevent these effects.

CONCLUSION: The increase in skin microcirculation produced by pVIS light at the local and systemic levels is due to activation of NO synthesis in the irradiated area.

-------
full text Free Mechanism of Benefits of Low Level Lasers-
Activates Mitochondrial respiration-

www.ncbi.nlm.nih.gov/pubmed/21814580
PLoS One. 2011;6(7):e22453. Epub 2011 Jul 21.

Low-level laser therapy activates NF-kB via generation of reactive oxygen species in mouse embryonic fibroblasts.

Chen AC, Arany PR, Huang YY, Tomkinson EM, Sharma SK, Kharkwal GB, Saleem T, Mooney D, Yull FE, Blackwell TS, Hamblin MR. Source Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America. BACKGROUND: Despite over forty years of investigation on low-level light therapy (LLLT), the fundamental mechanisms underlying photobiomodulation at a cellular level remain unclear.

METHODOLOGY/PRINCIPAL FINDINGS: In this study, we isolated murine embryonic fibroblasts (MEF) from transgenic NF-kB luciferase reporter mice and studied their response to 810 nm laser radiation. Significant activation of NF-kB was observed at fluences higher than 0.003 J/cm(2) and was confirmed by Western blot analysis. NF-kB was activated earlier (1 hour) by LLLT compared to conventional lipopolysaccharide treatment. We also observed that LLLT induced intracellular reactive oxygen species (ROS) production similar to mitochondrial inhibitors, such as antimycin A, rotenone and paraquat. Furthermore, we observed similar NF-kB activation with these mitochondrial inhibitors. These results, together with inhibition of laser induced NF-kB activation by antioxidants, suggests that ROS play an important role in the laser induced NF-kB signaling pathways. However, LLLT, unlike mitochondrial inhibitors, induced increased cellular ATP levels, which indicates that LLLT also upregulates mitochondrial respiration.

CONCLUSION: We conclude that LLLT not only enhances mitochondrial respiration, but also activates the redox-sensitive NFkB signaling via generation of ROS. Expression of anti-apoptosis and pro-survival genes responsive to NFkB could explain many clinical effects of LLLT.
--------------------------------------
FUll text- nice intro and review by Harvard prof
--------------------------------

www.ncbi.nlm.nih.gov/pmc/articles/PMC2939452/?tool=pubmed

Lasers Surg Med. 2010 August; 42(6): 447–449.
Introduction to Experimental and Clinical Studies Using Low-Level Laser (Light) Therapy (LLLT)

Michael R. Hamblin, PhD, Associate Professor Michael R. Hamblin, Harvard Medical School; *Correspondence to: Michael R Hamblin, PhD, Assistant Professor, Harvard Medical School

-------------------
Photoceutical for stem cell growth and regeneration
-----------------------------

From a Stem Cell COmpany:

www.ncbi.nlm.nih.gov/pmc/articles/PMC2830167/?tool=pubmed

J Transl Med. 2010; 8: 16.
Lasers, stem cells, and COPD
Feng Lin,#1 Steven F Josephs,#1 Doru T Alexandrescu,#2 Famela Ramos,1 Vladimir Bogin,3 Vincent Gammill,4 Constantin A Dasanu,5 Rosalia De Necochea-Campion,6 Amit N Patel,7 Ewa Carrier,6 and David R Kooscorresponding author1

The medical use of low level laser (LLL) irradiation has been occurring for decades, primarily in the area of tissue healing and inflammatory conditions. Despite little mechanistic knowledge, the concept of a non-invasive, non-thermal intervention that has the potential to modulate regenerative processes is worthy of attention when searching for novel methods of augmenting stem cell-based therapies. Here we discuss the use of LLL irradiation as a "photoceutical" for enhancing production of stem cell growth/chemoattractant factors, stimulation of angiogenesis, and directly augmenting proliferation of stem cells. The combination of LLL together with allogeneic and autologous stem cells, as well as post-mobilization directing of stem cells will be discussed. "A pubmed search for "low level laser therapy" yields more than 1700 results, yet before stumbling across this concept, none of us, or our advisors, have ever heard of this area of medicine."

--------------------------- Nuclear Factor Kappa Beta -------------------------- www.researchersworld.com/vol2/issue3/Paper_6.pdf

THE BIOLOGY OF NUCLEAR FACTOR KAPPA BETA (NFkB IN HEALTH AND PATHOLOGY by Carlos Kusano Bucalen Ferrari, Biomedical Research Group, Institute of Biological and Health Sciences (ICBS), “Campus Universitário do Araguaia”, “Universidade Federal de Mato Grosso” (UFMT), Barra do Garças, MT, Brazil.

www.ncbi.nlm.nih.gov/pubmed/15175863
J Mol Med (Berl). 2004 Jul;82(7):434-48. Epub 2004 Jun 3.
Nuclear factor-kappaB: its role in health and disease.
Kumar A, Takada Y, Boriek AM, Aggarwal BB. Source Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA. axkumar@bcm.tmc.edu Abstract Nuclear factor-kappaB (NF-kappa is a major transcription factor that plays an essential role in several aspects of human health including the development of innate and adaptive immunity. The dysregulation of NF-kappaB is associated with many disease states such as AIDS, atherosclerosis, asthma, arthritis, cancer, diabetes, inflammatory bowel disease, muscular dystrophy, stroke, and viral infections. Recent evidence also suggests that the dysfunction of NF-kappaB is a major mediator of some human genetic disorders. Appropriate regulation and control of NF-kappaB activity, which can be achieved by gene modification or pharmacological strategies, would provide a potential approach for the management of NF-kappaB related human diseases. This review summarizes the current knowledge of the physiological and pathophysiological functions of NF-kappaB and its possible role as a target of therapeutic intervention

-----------------------------------------------------------------

www.drkaslow.com/html/low_level_lasers__lllt_.html

cold laser article dr kaslow place into blog roll

---------- Q LAser dr Lytle _----------------

“Use Mode 1 to re-energize muscle, ligament and tendon cells for healing wounds and injuries or for reducing pain and inflammation; Mode 1 also benefits tendonitis, arthritis, burns, sprains, cuts, bruises, muscle pulls, sore throat, and any pain or inflammation.” • “Use Mode 2 to re-energize brain and heart cells and to normalize brain neuropeptides and heart cell energy.” • “Use Mode 3 as a multi-organ cell re-energizer that cycles through 29 different frequencies proven effective and beneficial for healing, and to benefit inflammation or disorders of all internal, and for the treatment of any unknown condition.” [Note: The proprioceptive points are (1) just in front of the ear over the TMJ, (2) under the angle of the jaw, (3) two inches below the collar bone, and (4) one inch up from the rounded angle of the shoulder blade (scapula).]

www.humanenergyscience.com/uploads/Dr_Lytle_s_audio_4-10.pdf

OSTEOARTHRITIS and the LOW LEVEL LASER
A Transcript of Dr. Lytle’s webinar April 2010

www.21CenturyMedicineChest.com/blog/Joint_Pain
(runtime 59:03) Dr. Irina: Why did you choose osteoarthritis as the basis of your first FDA clinical trials? What were the results of the trials? And we get the exciting news\ www.laserlightinstitute.info/healinglight.pdf

Healing Light by Dr. Larry Lytle
----------------------------------------------
www.21centurydoc.com/tag/soft-laser
21st Century Doc - 21st Century Medicine at your Fingertips

www.scribd.com/doc/66068978/Electrotherapeutic-Devices-Principles-Design-and-Applications

Electrotherapeutic DevicesPrinciples, Design, and Applications --------------------

-------------------------------------------
full pdf

qvchealth.info/clients/931/documents/MuscleRepair_Silveira.pdf
Journal of Photochemistry and Photobiology B: Biology 95 (2009) 89–92

Evaluation of mitochondrial respiratory chain activity in muscle healing by low-level laser therapy

Paulo C.L. Silveira a,*, Luciano Acordi da Silva a, Daiane B. Fraga b, Tiago P. Freitas b, Emilio L. Streck b, Ricardo Pinho a Background: Recent studies demonstrate that low-level laser therapy (LLLT) modulates many biochemical processes, especially the decrease of muscle injures, the increase in mitochondrial respiration and ATP synthesis for accelerating the healing process. Objective: In this work, we evaluated mitochondrial respiratory chain complexes I, II, III and IV and succinate dehydrogenase activities after traumatic muscular injury. Methods: Male Wistar rats were randomly divided into three groups (n = 6): sham (uninjured muscle), muscle injury without treatment, muscle injury with LLLT (AsGa) 5 J/cm2. Gastrocnemius injury was induced by a single blunt-impact trauma. LLLT was used 2, 12, 24, 48, 72, 96, and 120 hours after muscle- trauma.

Results: Our results showed that the activities of complex II and succinate dehydrogenase after 5 days of muscular lesion were significantly increased when compared to the control group. Moreover, our results showed that LLLT significantly increased the activities of complexes I, II, III, IV and succinate dehydrogenase, when compared to the group of injured muscle without treatment.

Conclusion: These results suggest that the treatment with low-level laser may induce an increase in ATP synthesis, and that this may accelerate the muscle healing process.

www.thorlaser.com/downloads/research/Biphasic-Dose-Response-in-Low-Level-Light-Therapy-Harvard.pdf

Formerly Nonlinearity in Biology, Toxicology, and Medicine Copyright © 2009 University of Massachusetts

BIPHASIC DOSE RESPONSE IN LOW LEVEL LIGHT THERAPY Ying-Ying Huang Michael R. Hamblin, BAR 414, Wellman Center for Photomedicine, Massachusetts General Hospital, 40 Blossom Street, Boston,

www.theragem.com/harvardstudy.pdf www.photobiology.info/Hamblin.html MECHANISMS OF LOW LEVEL LIGHT THERAPY
Michael R. Hamblin Department of Dermatology, Harvard Medical School, BAR 414 Wellman Center for Photomedicine, Massachusetts General Hospital 40 Blossom Street, Boston MA 02114 hamblin@helix.mgh.harvard.edu

www.mgh.harvard.edu/wellman/people/mhamblin.asp
www.photobiology.info/ spie.org/x35504.xml?ArticleID=x35504

Biomedical Optics & Medical Imaging Low-level laser therapy: an emerging clinical paradigm
Ying-Ying Huang, Michael Hamblin, and Aaron C.-H. Chen 9 July 2009, SPIE Newsroom. DOI: 10.1117/2.1200906.1669
Improved understanding of the fundamental cellular and molecular mechanisms is broadening the technique's mainstream use for many ailments. 9 July 2009, SPIE Newsroom. DOI: 10.1117/2.1200906.1669

www.molecularneurodegeneration.com/content/4/1/26 Reduced axonal transport in Parkinson's disease cybrid neurites is restored by light therapy Patricia A Trimmer1*, Kathleen M Schwartz1, M Kathleen Borland1, Luis De Taboada2, Jackson Streeter2 and Uri Oron3

www.photothera.com/technology/neurothera
The NeuroThera® Laser System is under development for the treatment of ischemic stroke and is not approved for sale or distribution in the United States or internationally. The NeuroThera® Laser System is an investigational device that seeks to improve neurological outcomes via noninvasive delivery of near-infrared (NIR) laser energy called Transcranial Laser Therapy (TLT) into the brain. The system consists of a moveable console, a fiber optic cable, and a handpiece. A trained clinician uses the handpiece to direct the TLT to twenty predetermined treatment sites on the patient’s scalp. The total procedure time is approximately 2-3 hours. The Company believes that the NeuroThera® Laser System may offer a compelling option for the treatment of acute ischemic stroke up to twenty-four hours following onset of stroke symptoms.

www.nature.com/jid/journal/v127/n8/full/5700826a.html
www.ncbi.nlm.nih.gov/pubmed/17446900

J Invest Dermatol. 2007 Aug;127(8):2048-57. Epub 2007 Apr 19.

Helium-neon laser irradiation stimulates cell proliferation through photostimulatory effects in mitochondria.

Hu WP, Wang JJ, Yu CL, Lan CC, Chen GS, Yu HS. Source Faculty of Biotechnology and Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract Previous reports have shown that cellular functions could be influenced by visual light (400-700 nm). Recent evidence indicates that cellular proliferation could be triggered by the interaction of a helium-neon laser (He-Ne laser, 632.8 nm) with the mitochondrial photoacceptor-cytochrome c oxidase.

Our previous studies demonstrated that He-Ne irradiation induced an increase in cell proliferation, but not migration, in the melanoma cell line A2058 cell. The aim of this study was to investigate the underlying mechanisms involved in photostimulatory effects induced by an He-Ne laser. Using the A2058 cell as a model for cell proliferation, the photobiologic effects induced by an He-Ne laser were studied. He-Ne irradiation immediately induced an increase in mitochondrial membrane potential (delta psi(mt)), ATP, and cAMP via enhanced cytochrome c oxidase activity and promoted phosphorylation of Jun N-terminal kinase (JNK)/activator protein-1 (AP-1) expressions. He-Ne irradiation-induced A2058 cell proliferation was significantly abrogated by the addition of delta psi(mt) and JNK inhibitors. Moreover, treatment with an He-Ne laser resulted in delayed effects on IL-8 and transforming growth factor-beta1 release from A2058 cells.

These results suggest that He-Ne irradiation elicits photostimulatory effects in mitochondria processes, which involve JNK/AP-1 activation and enhanced growth factor release, and ultimately lead to A2058 cell proliferation.

www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm246619.htm
March 3, 2011 WARNING LETTER CERTIFIED MAILRETURN RECEIPT REQUESTED
Refer to MIN 11-14 Robert L. Lytle, DDS, PhD President, 2035, Inc.
Managing Limited Partner, QLaser Healing Light LP 520 Kansas City Street, Suite 100 Rapid City, South Dakota 57701

Dear Dr. Lytle: During an inspection of your firm located in Rapid City, South Dakota, on May 25 - 27, 2010, an investigator from the United States Food and Drug Administration (FDA) learned that your firms 2035, Inc. and QLaser Healing Light LP are marketing the Q10 Laser and 808 Enhancer Probe in the United States without marketing clearance or approval, in violation of the Federal Food, Drug, and Cosmetic Act (the Act). Q1000 Laser and 660 Enhancer Probe A review of our records indicates that we cleared a premarket notification (510(k)) for the Q1000 Laser and 660 Enhancer Probe (QLaser System), K080513, with an intended use “for providing temporary relief of pain associated with osteoarthritis of the hand, which has been diagnosed by a physician or other licensed medical professional.”

www.accessdata.fda.gov/cdrh_docs/pdf8/K080513.pdf
Re: K080513 Trade/Device Name: QLaser System Regulation Number: 21 CFR 890.5500 Regulation Name: Infrared lamp Regulatory Class: II Product Code: NHN Dated: January 9, 2009 Received: January 12, 2009

------------------------

lyphedema
- --------------------------

www.riancorp.com/

RianCorp has completed the only randomised double blind clinical trial testing the effects of LLLT on lymphoedema/lymphedema in the world.7 Fleet St, Richmond, South Australia 5033 The LTU-904 models are infra-red lasers operating at a wavelength of 904 nanometers. This invisible wavelength penetrates deeply into tissue (much deeper than the often used red laser operating in the visible red region).

www.rifkinmedicalproducts.com/ RIFKIN MEDICAL PRODUCTS,LLC call 203-758-6569 The LTU-904 laser is only ONLY lymphoedema treatment that has been trialled in a randomised double blind study. The laser works very effectively in about 30% of patients and with some effect in about 50% of patients.

------------------------
www.henrylahore.com/Health/LLLT%20800%20nm%20gets%20into%20spinal%20cord%20July%202009.PDF

Photomedicine and Laser Surgery Volume 27, Number 3, 2009 ª Mary Ann Liebert, Inc. Pp. 379–380 Guest Editorial*

The Potential of Light Therapy for Central Nervous System Injury and Disease Juanita J. Anders, Ph.D. Department of Anatomy, Physiology and Genetics Uniformed Services University of the Health Sciences 4301 Jones Bridge Rd. Bethesda, MD 20814 Juanita J. Anders

--------------------------------

www.isan.troitsk.ru/dls/publ/tiinaabs2005.pdf

Absorption measurements of a cell monolayer relevant to phototherapy: Reduction of cytochrome c oxidase under near IR radiation Tiina I. Karu a,*, Lydmila V. Pyatibrat a, Sergei F. Kolyakov b, Natalya I. Afanasyeva c
Journal of Photochemistry and Photobiology B: Biology 81 (2005) 98–106 a Institute of Laser and Information Technologies of Russian Academy of Sciences, Troitsk, Pionerskaya Street 2, Moscow Region 142190, Russian Federation b Institute of Spectroscopy of Russian Academy of Sciences, Troitsk, Moscow Region 142190, Russian Federation c Spectrooptical Sensing Inc., Portland, OR 97205, USA Received 26 April 2005; accepted 20 July 2005

Phototherapy uses monochromatic light in the optical region of 600–1000 nm to treat in a non-destructive and non-thermal fashion various soft-tissue and neurological conditions. This kind of treatment is based on the ability of light red-to-near IR to alter cellular metabolism as a result of its being absorbed by cytochrome c oxidase. To further investigate the involvement of cytochrome c oxidase as a photoacceptor in the alteration of the cellular metabolism,

Jeffrey Dach MD
7450 Griffin Road, SUite 190
Davie, Fl 33314
954-792-4663
www.jeffreydach.com
www.drdach.com
www.naturalmedicine101.com
www.bioidenticalhormones101.com
www.truemedmd.com

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Bioidentical Hormones Prevent Osteoarthritis

Sun, 15 Jan 2012 17:01:28 -0500

Bioidentical Hormones
Prevent and Reverse Osteoarthritis

by Jeffrey Dach MD

Hormonal Decline Leads to Degenerative Disease

One of the basic concepts of "Anti-Aging Medicine" is that hormonal decline leads to the onset of degenerative diseases. On the top on the list is degenerative osteoarthritis, a common form of progressive joint destruction from years of wear and tear. Recent medical research shows that menopausal estrogen deficiency is a causative factor in developing degeneration of the joints.

Anti-Aging Medicine accepts the idea that hormonal replacement is beneficial for preventing the various degenerative diseases of aging, such as the joint degeneration of osteo-arthritis. Bioidentical Hormone Supplementation not only reduces risk for developing degenerative disease, it also reduces over-all mortality.

Above left image: Xray of knee showing early osteoarthritis courtesy of wikimedia commons.

Mainstream Medicine Says Hormonal Decline is NORMAL

This is vehemently denied by Mainstream Institutional Medicine which clings to the politically acceptable yet incorrect thesis, that hormonal decline DOES NOT lead to degenerative disease, and does not require treatment.   These "mainstream medical institutions" consider low hormone levels of aging to be "NORMAL".

Mainstream Medicine is a Vending Machine and a Mouthpiece for the Drug Industry

Mainstream medicine marches to the tune of the pharmaceutical industry, and a major source of profit for the drug industry comes from "Blockbuster Drugs" used to treat degenerative diseases, such as anti-inflammatory NSAID drugs for treatment of osteo-arthritis.

The drug industry views bio-identical hormone replacement as a direct threat to profits from its pipeline of blockbuster drugs. Since Mainstream Medicine serves as a vending machine and a mouthpiece for the drug industry, it is no surprise that bio-identical hormones have been neglected, ignored and even rejected by Institutional Medicine.

Growing Baby Boomer Population in Hormonal Decline

Imagine a growing population of baby boomer generation retirees, over the age of 50, all on their way to hormonal decline and degenerative diseases such as osteoarthritis, coronary artery disease, osteoporosis, immune and cognitive function decline. Imagine the beneficial outcome if this entire population was given bio-identical hormones? These aging baby boomers and retirees would no longer need many of the drugs freely prescribed by their doctor for degenerative disease, eliminating a large chunk of profit for the pharmaceutical industry. In addition these people would live longer in good health, bankrupting the government Medicare and Social Security programs. Obviously, this is politically unacceptable.   Above left image: Typical changes of osteoarthritis of the finger joints, courtesy of wikimedia commons.

Osteo-arthritis and Estrogen Replacement

Osteoarthritis increases dramatically in women after menopause suggesting that estrogen deficiency increases risk of osteoarthritis. Studies of women who take estrogen replacement therapy after menopause consistently report reduced risk for osteoarthritis when compared to women not using estrogen replacement. This suggests a role for estrogen supplements for prevention of osteoarthritis in women after age 50. (15)

A nice summary article by Dr. Herrero- Beaumont from Spain came out in the 2009 Seminars in Arthritis and Rheumatism. (1) This author reviewed the medical literature from 1952 to 2008 and found three causes for osteoarthritis :

1) genetic
2) menopause-related Estrogen deficiency
3) aging

In another publication in 2009 Arthritis Research and Therapy, Dr Herrero Beaumont says: "There is now increasing evidence that estrogens influence the activity of joint tissues through complex molecular pathways that act at multiple levels."(2)

Estrogen Replacement Reduces Osteoarthritis of the HIP by 43%

A 1996 study on estrogen replacement and osteoarthritis published in the Archives of Internal Medicine, entitled, " Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women" was from Dr Genant at the University of California, San Francisco.(3) This study examined 4,366 post-menopausal women over the age of 65. Hip X-Rays were used to assess osteoarthritis of the hip joint.    They found that women who took oral estrogen had a 38% reduced risk osteoarthritis (OA) of the hip. Women who used Estrogen for 10 years or longer had a 43% reduction in OA of the hip. The authors concluded that " Postmenopausal estrogen replacement therapy may protect against OsteoArthritis (OA) of the hip." (3)

Framingham Study - Arthritis of the Knee Reduced by 60%

The Framingham Study on Arthritis of the Knee was published in Arthritis and Rheum in 1998 by Dr Zhang of Boston University School of Medicine entitled, "Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study. " (4) Their study examined whether estrogen replacement therapy (ERT) prevents worsening of radiographic knee osteoarthritis (OA) in elderly women.

They followed 551 post-menopausal women (over the age of 63) over 8 years with serial weight bearing AP knee X-Rays, looking for worsening of osteoarthritis over time. The authors found a 60% decrease in osteo-arthritis in the estrogen users compared to non-users.(4)

Above left image: Hip replacement could be prevented by Estrogen Replacement, image courtesy of wikimedia commons

Women's Health Initiative WHI- Lower Incidence of Joint Replacements

Published in 2006, the WHI data showed that women receiving Premarin (oral estrogen alone) had 12% lower rates for joint replacement for osteoarthritis.(5)

Genetic Causes of Arthritis

GENETIC CAUSES OF Osteoarthritis- Disturbed Estrogen Metabolism

A study was published in 2010 in the journal Osteoarthritis Cartilage by Dr Riancho from Spain entitled," Common variations in estrogen-related genes are associated with severe large-joint osteoarthritis: a multicenter genetic and functional study." (6)

The authors explored the association of genetic abnormalities with severe osteoarthritis (OA) in 3147 patient who were compared to 2,381 normal controls . The authors examined two abnormal genes which reduce estrogen activity. These are the genes for the Aromatase Enzyme, and gene for the estrogen receptor (ER-Alpha, estrogen receptor alpha), and their association with severe osteoarthritis (OA) of the lower limbs.

Women with unfavourable genotypes had 60% increased risk for knee OA. The authors conclude, "Common genetic variations of the aromatase and ER genes are associated with the risk of severe OA of the large joints of the lower limb in a sex-specific manner. These results are consistent with the hypothesis that estrogen activity may influence the development of large-joint OA."(6) Thus, the genetic studies also indicate the importance of estrogen in preserving joints and preventing osteoarthritis.

Cellular Mechanisms of Estrogen on Cartilage

Dr Tanko from Denmark summarized three decades of medical research in an article published in 2008 in Climacteric entitled, "Review of cellular mechanisms conferring the indirect and direct effects of estrogen on articular cartilage." (8) The authors state, " Estrogen receptors have been identified in articular chondrocytes from various animals and humans." They conclude: "The effects of estrogen on articular cartilage further corroborate the due consideration of estrogen therapy for maintaining not only bone but also cartilage health in postmenopausal women." . (8)

Animal Studies

Estrogen Replacement in Monkeys Prevents OA

A study published in Arthritis Rheumatism 2002 entitled,"Effects of long-term estrogen replacement therapy on osteoarthritis severity in monkeys", by Dr Ham from the University of Minnesota, examined estrogen replacement therapy (ERT) on the severity of osteoarthritis (OA) of the knee joint in postmenopausal female monkeys (after surgical removal of the ovaries).(7)

After three years of estrogen treatment, using Premarin, the monkeys were sacrificed and knee joints examined histologically. The authors found that cartilage lesions of osteoarthritis (OA) were significantly less severe in the animals given estrogen replacement (ERT) compared with those in the control group. The authors concluded," These results demonstrate that long-term estrogen replacement (ERT) significantly reduces the severity of osteoarthritis (OA).(7)

Ovarectomized Mice Treated with Estrogen

A 2006 study by Tanko from Denmark published in Arthritis Rheumatism found that estrogen prevented joint and cartilage degradation in an animal model with mice. This article was entitled,"Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: implications of the time of initiation."(9) The authors found that "treatment of the animals with estrogen counters the acceleration of type-two collagen degradation and these benefits can be maximized by early initiation after menopause. The protective effect of estrogen seems to involve direct inhibition of the catabolic function of chondrocytes." (9)

Pig Studies

Similarly in pigs, researchers found estrogen prevents cartilage degradation. This study was published by Claassen from Germany in 2002 Annals of Anatomy, entitleded, " The effect of estrogens and dietary calcium deficiency on the extracellular matrix of articular cartilage in Göttingen miniature pigs." (10) Their study investigated how estrogen deficiency affects the articular cartilage .   They found that in animals with estrogen deficiency, the articular cartilage underwent degradation, i.e. similar changes to those observed in physiologically aging cartilage.(10)

Electron Microscope Study of Estrogen Deficiency Induced Arthritis in the Guinea Pig

A guinea pig study by Dr Dai from China was published in the Chinese medical Literature, in 2005, entitled,"The relationship of the expression of estrogen receptor in cartilage cell and osteoarthritis induced by bilateral ovariectomy in guinea pig." (11)

The authors used the scanning electron microscope (SEM) and transmission electron microscope (TEM) to analyze cartilage degeneration in joints after ovariectomy, which produces estrogen deficiency in the animals. The authors looked at estrogen receptors and serum levels of estrogen. They indeed found estrogen receptors (ER) in the cartilage of the guinea pigs. They also found Joint Cartilage degeneration detected by electron microscopy at 6 weeks, with severe degenerative lesions at 12 weeks after removal of ovaries compared to the control group. The author concludes that , "bilateral ovariectomy in the guinea pig leads to severe osteoarthritis ".(11)

Ovarectomized Sheep Treated With Estradiol Implants

Published in 1997 in Osteoarthritis Cartilage, a study entitled," Biochemical effects of estrogen on articular cartilage in ovariectomized sheep" by Dr AS Turner from Colorado State University, looked at estrogen replacement with estradiol implants in ovarectomized sheep.(12)   After twelve months, the articular cartilage from the knee joints were carefully evaluated. Ovarectomy, with its attendant estrogen deficiency had a significant deleterious effect on articular cartilage.   Treatment with estradiol, a bioidentical hormone, reversed these deleterious effects, and maintained structural integrity of the joints. (12)

Another sheep study published in 2005 in Osteoarthritis Cartilage, entitled, "Ovariectomy alters the structural and biomechanical properties of ovine femoro-tibial articular cartilage and increases cartilage iNOS", by Dr MA Cake MA from Australia examined the effect of estrogen depletion (ovariectomy) on articular cartilage of the joints, and the production nitric oxide synthase (iNOS). (13)

At 26 weeks after removal of the ovaries, the joints were studied histologicaly, and amounts for nitric oxide (NO) studied. In the estrogen deficient animals, cartilage thickness was reduced, along with arthritic changes and upregulated nitric oxide production. (13) The authors conclude, "estrogen depletion caused regional thinning of femoro-tibial cartilage, with biomechanical and histological changes suggestive of a disturbance in proteoglycan and collagen."(13)

Animal Model Summary Paper

In 2008, Dr Sniekers of the Netherlands summarized all preceding animal studies in a report published in Osteoarthritis Cartilage, entitled," Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment - a systematic approach." (14)

The author noted that the prevalence of osteoarthritis (OA) increases dramatically in women after the age of 50 with onset of menopausal estrogen deficiency. Animal models are useful to evaluate this. The author found eleven out of 14 animal studies showed that ovarectomy (surgically induced estrogen deficiency) resulted in cartilage damage, indicating considerable evidence for a relation between cartilage degeneration and estrogen deficiency (ovarectomy) in animals. (14)

Conclusion

The animal and human studies now provide overwhelming evidence for the importance of estrogen replacement after menopause for the prevention, and/or reversal of osteoarthritis.

Articles with related interest:

Menopausal Arthritis

Articles on Bioidentical Hormones By Jeffrey Dach MD

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Links and References

1) www.ncbi.nlm.nih.gov/pubmed/19589561

Semin Arthritis Rheum. 2009 Oct;39(2):71-80.
Epub 2009 Jul 9.

Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics.

Herrero-Beaumont G, Roman-Blas JA, Castañeda S, Jimenez SA. Source Bone and Joint Research Unit, Service of Rheumatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain.

Osteoarthritis (OA) has been historically divided into primary and secondary. Primary OA has been defined as an idiopathic condition developing in previously undamaged joints in the absence of an obvious causative mechanism. During the last few years a large amount of evidence has provided new insights into the biochemistry and molecular biology of cartilage, subchondral bone, and other articular tissues, which suggest distinct etiopathogenetic mechanisms in some forms of primary OA. OBJECTIVE: To propose an etiopathogenic classification of primary OA in the light of the significant progress in the understanding of the disease.

METHODS: A review of the literature was performed by searching the Medline and PubMed databases from 1952 to November 2008 using the following keywords: genetic alteration, heritability, estrogen, menopause, and aging either alone or in various combinations with joint, cartilage, subchondral bone, synovium, ligaments, muscle, tendons, OA, and osteoporosis.

RESULTS: Numerous studies have shown that genetic alterations, menopause-related estrogen deficiency, and aging play crucial roles in the molecular pathophysiological events involved in the process of cartilage and joint damage and thus in development of OA.

We propose classifying primary OA into 3 distinct although interrelated subsets:
type I OA, genetically determined;
type II OA, estrogen hormone dependent;
and type III OA, aging related.

CONCLUSIONS: The 3 proposed subsets of OA display distinct etiological, clinical, and therapeutic characteristics and should therefore no longer be considered to be "Primary OA."

2) www.ncbi.nlm.nih.gov/pmc/articles/PMC2787275/?tool=pubmed
FULL TEXT - Arthritis Res Ther. 2009; 11(5): 241.

Osteoarthritis associated with estrogen deficiency

Jorge A Roman-Blas,1,2 Santos Castañeda,3 Raquel Largo,1 and Gabriel Herrero-Beaumontcorresponding author1 1Bone and Joint Research Unit, Service of Rheumatology, Fundación Jiménez Díaz, Universidad Autónoma, Madrid 28040, Spain

Osteoarthritis (OA) affects all articular tissues and finally leads to joint failure. Although articular tissues have long been considered unresponsive to estrogens or their deficiency, there is now increasing evidence that estrogens influence the activity of joint tissues through complex molecular pathways that act at multiple levels.

3) www.ncbi.nlm.nih.gov/pubmed/8862099
Arch Intern Med. 1996 Oct 14;156(18):2073-80.

Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women.

Study of Osteoporotic Fractures Research Group. Nevitt MC, Cummings SR, Lane NE, Hochberg MC, Scott JC, Pressman AR, Genant HK, Cauley JA. Source Department of Epidemiology and Biostatistics, University of California, San Francisco, USA.

Abstract OBJECTIVE: To determine whether postmenopausal estrogen replacement therapy is associated with a reduced risk of radiographic findings of osteoarthritis (OA) of the hip. DESIGN: Cross-sectional study.

SUBJECTS: White women (N = 4366; age, > or = 65 years) who were participants in a cohort study of osteoporotic fractures.

MEASUREMENTS AND METHODS: Radiographs of the pelvis that were obtained in all subjects were assessed for radiographic features of OA of the hip on a summary scale of 0 (none) to 4 (severe OA). Postmenopausal estrogen use was assessed by interview. The association of current and past oral estrogen use with OA of the hip was analyzed by using logistic regression, adjusting for potential confounding variables (eg, indicators of osteoporosis and correlates of estrogen use).

RESULTS: Five hundred thirty-nine women (12.3%) had mild or greater radiographic findings of OA of the hip in at least 1 hip, and 214 women (4.9%) had moderate to severe findings; 17% and 24% of the women were current and past users of oral estrogen, respectively. Women who were currently using oral estrogen had a significantly reduced risk of any OA of the hip (adjusted odds ratio [OR], 0.62; 95% confidence interval [CI], 0.49-0.86) and moderate to severe manifestation of disease (OR, 0.54; 95% CI, 0.33-0.88). Current users who had taken estrogen for 10 years or longer had a greater reduction in the risk of any OA of the hip (OR, 0.57; 95% CI, 0.40-0.82) compared with that of users for less than 10 years (OR, 0.75; 95% CI, 0.47-1.24). Current estrogen use for 10 years or longer was associated with a nonsignificant trend for a reduced risk of moderate to severe symptomatic disease (OR, 0.59; 95% CI, 0.28-1.29).

CONCLUSION: Postmenopausal estrogen replacement therapy may protect against OA of the hip in elderly white women.

4) www.ncbi.nlm.nih.gov/pubmed/9778229
Arthritis Rheum. 1998 Oct;41(10):1867-73.

Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study.

Zhang Y, McAlindon TE, Hannan MT, Chaisson CE, Klein R, Wilson PW, Felson DT. Source Boston University School of Medicine, Massachusetts, USA.

Abstract OBJECTIVE: To examine whether estrogen replacement therapy (ERT) prevents worsening of radiographic knee osteoarthritis (OA) in elderly women. METHODS: A total of 551 women ages 63-91 years (mean age 71) in the Framingham Study were followed up from biennial examination 18 (1983-1985) to examination 22 (1992-1993). Data on postmenopausal ERT were obtained every 2 years. Subjects were classified into 3 groups according to their estrogen use at biennial examination 18: never users (n = 349), past users (n = 162), and current users (n = 40). Women received anteroposterior weight-bearing knee radiographs at examinations 18 and 22. Using the Kellgren and Lawrence criteria, global radiographic knee OA was assessed, (grade range 0-4) and individual radiographic features, such as osteophytes and joint space narrowing, were scored from 0 to 3. Worsening was defined as either development of radiographic OA that was not present at baseline (incident OA) or progression of baseline radiographic OA by > or =1 Kellgren and Lawrence grade (progressive OA). Potential confounding factors included age, body mass index, weight change, smoking, knee injury, physical activity level, and bone mineral density at the femoral neck. RESULTS: During 8 years of followup, 17.4% of knee radiographic scores worsened by 1 grade and 5.8% by 2 or 3 grades among never users of ERT.

Among current estrogen users, only 11.7% of knee radiographic scores worsened by 1 grade and none worsened by more than 1 grade. After adjusting for age and other potential confounding factors, the relative risk of incident radiographic knee OA in comparison with never users of estrogen was 0.8 (95% confidence interval [95% CI] 0.5-1.4) in past users and 0.4 (95% CI 0.1-3.0) in current users. Current use of estrogen also showed a trend toward decreased risk of progressive knee OA compared with never use (odds ratio [OR] 0.5, 95% CI 0.1-2.9). When both incident and progressive radiographic knee OA cases were combined, current ERT use had a 60% decreased risk compared with never use (OR 0.4, 95% CI 0.1-1.5).

5) www.ncbi.nlm.nih.gov/pubmed/17009251

Effect of hormone therapy on risk of hip and knee joint replacement in the Women's Health Initiative. Cirillo DJ, Wallace RB, Wu L, Yood RA. Arthritis Rheum. 2006 Oct;54(10):3194-204. University of Iowa College of Public Health, Iowa City, IA 52242, USA.

To determine the effect of hormone therapy on arthroplasty rates.

METHODS: We examined data from the Women's Health Initiative placebo-controlled, double-blind, randomized trials. Community-dwelling women ages 50-79 years were enrolled at 40 US clinics. Women with prior arthroplasty were excluded, yielding a sample size of 26,321 subjects. Women who had had hysterectomies (n = 10,272) were randomly assigned to receive 0.625 mg/day conjugated equine estrogens (n = 5,076), or placebo (n = 5,196), with a mean followup of 7.1 years. Those who had not had hysterectomies (n = 16,049) were randomly assigned to receive estrogen plus progestin (n = 8,240), given as 0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate, or placebo (n = 7,809), with a mean followup of 5.6 years. Participants reported hospitalizations, and arthroplasties were identified by procedure codes. Arthroplasties due to hip fracture were censored. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (95% CIs) using intent-to-treat methods and outcome of time to first procedure.

RESULTS: In the estrogen-alone trial, women receiving hormone therapy had significantly lower rates of any arthroplasty (HR 0.84 [95% CI 0.70- 1.00], P = 0.05).

CONCLUSION: These data suggest that hormone therapy may influence joint health, but this observed decrease in risk may be limited to unopposed estrogen and may possibly be more important in hip than in knee osteoarthritis.

GENETIC CAUSES OF Osteoarthritis

6) www.ncbi.nlm.nih.gov/pubmed/20417295

Osteoarthritis Cartilage. 2010 Jul;18(7):927-33.

Common variations in estrogen-related genes are associated with severe large-joint osteoarthritis: a multicenter genetic and functional study. Riancho JA, García-Ibarbia C, Gravani A, Raine EV, Rodríguez-Fontenla C, Soto-Hermida A, Rego-Perez I, Dodd AW, Gómez-Reino JJ, Zarrabeitia MT, Garcés CM, Carr A, Blanco F, González A, Loughlin J. Source Servicio de Medicina Interna, Hospital UM Valdecilla-IFIMAV, Universidad de Cantabria, RETICEF, Santander, Spain. rianchoj@unican.es Abstract

OBJECTIVE: Several lines of evidence suggest that estrogens influence the development of osteoarthritis (OA). The aim of this study was to explore the association of two common polymorphisms within the aromatase (CYP19A1) and estrogen receptor (ER) alpha (ESR1) genes with severe OA of the lower limbs.

METHODS: The rs1062033 (CYP19A1) and rs2234693 (ESR1) single nucleotide polymorphisms were genotyped in 5528 individuals (3147 patients with severe hip or knee OA, and 2381 controls) from four centres in Spain and the United Kingdom. Gene expression was measured in femoral bone samples from a group of patients.

RESULTS: In the global analysis, both polymorphisms were associated with OA, but there was a significant sex interaction. The GG genotype at rs1062033 was associated with an increased risk of knee OA in women [odds ratio (OR) 1.23; P=0.04]. The CC genotype at rs2234693 tended to be associated with reduced OA risk in women (OR 0.76, P=0.028, for knee OA; OR=0.84, P=0.076 for hip OA), but with increased risk of hip OA in men (OR 1.28; P=0.029). Women with unfavourable genotypes at both loci had an OR of 1.61 for knee OA (P=0.006). The rs1062033 genotype associated with higher OA risk was also associated with reduced expression of the aromatase gene in bone.

CONCLUSIONS: Common genetic variations of the aromatase and ER genes are associated with the risk of severe OA of the large joints of the lower limb in a sex-specific manner. These results are consistent with the hypothesis that estrogen activity may influence the development of large-joint OA.

Estrogen Replacement in Ovarectomized Monkeys Prevents OA

7) www.ncbi.nlm.nih.gov/pubmed/12124881

Arthritis Rheum. 2002 Jul;46(7):1956-64.

Effects of long-term estrogen replacement therapy on osteoarthritis severity in cynomolgus monkeys. Ham KD, Loeser RF, Lindgren BR, Carlson CS. Source Dpartment of Veterinary Pathology, College of Veterinary Medicine, University of Minnesota, St. Paul, 55108, USA. hamx0012@tc.umn.edu Abstract

OBJECTIVE: To determine the effects of long-term estrogen replacement therapy (ERT) on the severity of osteoarthritis (OA) of the knee joint in surgically postmenopausal (bilaterally ovariectomized) female monkeys. A secondary aim was to evaluate the effect of soy phytoestrogen (SPE) treatment on the severity of OA.

METHODS: Feral adult female cynomolgus macaques were ovariectomized bilaterally and then randomly divided into 3 age- and weight-matched treatment groups. For 3 years, the first group received ERT with conjugated equine estrogens, the second group received SPE, and the third group received no treatment (controls). At necropsy, histologic lesions of OA were graded, and the area and thickness of cartilage and subchondral bone were measured. The data were summarized by principal components analysis, and the resulting factors and individual variables were compared using analysis of variance and analysis of covariance (age and weight as covariates).

RESULTS: Cartilage lesions of OA were significantly less severe in the animals given ERT compared with those in the control group. This treatment effect remained significant when adjusted for age and weight. The factor representing subchondral bone was significantly higher, but the number of osteophytes was lower, in the ERT group compared with the control group. SPE treatment had no significant effect on cartilage or bone lesions of OA.

CONCLUSION: These results demonstrate that long-term ERT significantly reduces the severity of OA lesions in this animal model.

8) www.ncbi.nlm.nih.gov/pubmed/18202960

Climacteric. 2008 Feb;11(1):4-16.

An update review of cellular mechanisms conferring the indirect and direct effects of estrogen on articular cartilage. Tankó LB, Søndergaard BC, Oestergaard S, Karsdal MA, Christiansen C. Source Nordic Bioscience, Herlev, Denmark. Abstract

OBJECTIVE: To review cellular mechanisms that have been proposed to mediate the indirect and direct effects of estrogen on articular cartilage, and to outline the remaining clinical questions that need to be clarified before utilizing the beneficial effects of estrogen for the prevention of osteoarthritis in early postmenopausal women.

DESIGN: Summary of original research papers and reviews listed in Pubmed (1980-2007).

RESULTS: Estrogen receptors have been identified in articular chondrocytes from various animals and humans. Molecular studies showed that estrogen can elicit genomic and rapid non-genomic effects on various cell types, including chondrocytes, and the latter effects are only inducible in females. In addition to direct effects, estrogen can also affect the homeostasis of articular cartilage by modulating the expression/production of different molecules such as various growth factors, inflammatory cytokines, matrix metalloproteinases, and reactive oxygen species. Moreover, in vivo observation argues for the notion that inhibition of subchondral bone turnover is also part of the mechanisms by which estrogen (and antiresorptive agents in general) can protect against joint degradation. Published studies undertaken at cellular, tissue, and in vivo levels illustrate that the effect of estrogen on cartilage may depend on the dose applied, the administration route, the time of initiation, and whether it is combined with a progestin.

CONCLUSIONS: The herein reviewed direct and indirect effects of estrogen on articular cartilage further corroborate the due consideration of estrogen therapy for maintaining not only bone but also cartilage health in postmenopausal women. Future studies in postmenopausal women are needed to clarify whether the efficacy of estrogen therapy can be further optimized by using other forms of estrogen, other progestins, or by initiating the therapy in the peri- or early postmenopausal period.

Animal Studies

9) www.ncbi.nlm.nih.gov/pubmed/16871544
Arthritis Rheum. 2006 Aug;54(8):2441-51.

Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: implications of the time of initiation. Oestergaard S, Sondergaard BC, Hoegh-Andersen P, Henriksen K, Qvist P, Christiansen C, Tankó LB, Karsdal MA. Source Nordic Bioscience, Herlev, Denmark.

Abstract OBJECTIVE: To investigate how the time of initiation influences the effects of estrogen therapy on type II collagen (CII) turnover and the structural integrity of articular cartilage in ovariectomized rats and to determine whether estrogen exerts direct effects on the catabolic function of chondrocytes ex vivo.

METHODS: A total of 46 Sprague-Dawley rats were distributed into 1 of the following treatment groups:
1) ovariectomy,
2) ovariectomy plus early estrogen therapy,
3) ovariectomy plus delayed estrogen therapy, or
4) sham operation.

Cartilage turnover was estimated by measuring the serum levels of C-telopeptide of type II collagen (CTX-II). Cartilage lesions at week 9 were quantified using a published scoring technique. The presence of the CTX-II epitope in articular cartilage was assessed by immunohistochemistry. The effects of estrogen (1 -100 nM) on chondrocytes were investigated in bovine cartilage explants subjected to catabolic cytokines (tumor necrosis factor alpha [TNFalpha] and oncostatin M [OSM]).

RESULTS: In ovariectomized rats, estrogen therapy evoked significant decreases in serum CTX-II independently of the time of initiation; yet, delayed initiation resulted in diminished efficacy in terms of preventing cartilage lesions. CTX-II fragments were present in articular cartilage, colocalizing with early lesions at the cartilage surface. In untreated animals, the early relative increases in serum CTX-II were proportional to the severity of cartilage lesions at week 9 (r = 0.73, P < 0.01). Estrogen significantly and dose- dependently countered CTX-II release from TNFalpha plus OSM-stimulated cartilage explants ex vivo.

CONCLUSION: Our results suggest that estrogen counters the acceleration of CII degradation and related structural alterations, and these benefits can be maximized by early initiation after menopause. The protective effect of estrogen seems to involve direct inhibition of the catabolic function of chondrocytes.

10) www.ncbi.nlm.nih.gov/pubmed/11936193
Ann Anat. 2002 Mar;184(2):141-8.
The effect of estrogens and dietary calcium deficiency on the extracellular matrix of articular cartilage in Göttingen miniature pigs. Claassen H, Hornberger F, Scholz-Ahrens K, Schünke M, Schrezenmeir J, Kurz B. Source Anatomisches Institut der Universität Kiel, Germany.

Abstract Clinical observations have suggested that estrogens are involved in the pathogenesis of postmenopausal osteoarthritis (OA). However, positive and negative associations between the incidence of OA and serum estrogen concentrations have been reported.

In contrast to this, osteoporosis is regarded as a disease with a strong estrogen-dependent component. Moreover, there is an interaction between estrogen and calcium deficiency: calcium supplementation potentiates the effect of estrogen therapy. The present study was designed to investigate how estrogen deficiency affects the articular cartilage depending on calcium supply. The distribution of different types of glycosaminoglycans and collagens can be used as an indicator for extracellular matrix changes induced by estrogen deficiency. Different levels of dietary calcium were therefore fed to intact and ovariectomized Göttingen miniature pigs for one year before articular cartilage was harvested. The histochemical staining for heavy sulfated glycosaminoglycans in the extracellular matrix of ovariectomized miniature pigs, especially of those fed with a low calcium diet, was stronger in comparison to intact animals. In intact animals type II-collagen was immunodetected in all zones of unmineralized and mineralized articular cartilage, while immunostaining for this protein was negative to weak in the deep radiated fiber zone of ovariectomized minipigs.

These results suggest that the synthesis of heavy sulfated glycosaminoglycans and immunohistochemically detectable type II-collagen is possibly influenced by estrogen
deficiency.

In conclusion, under estrogen deficiency, the extracellular matrix of articular cartilage underwent similar changes to those observed in physiologically aging cartilage where keratan sulfate is increased as a heavy sulfated glycosaminoglycan.

11) www.ncbi.nlm.nih.gov/pubmed/16696325

J Huazhong Univ Sci Technolog Med Sci. 2005;25(6):683-6.

The relationship of the expression of estrogen receptor in cartilage cell and osteoarthritis induced by bilateral ovariectomy in guinea pig. Dai G, Li J, Liu X, Liu Q, Liu C. Source Department of Orthopaedics, Oilu Hospital Affiliated Shan Dong University, Jinan 250012, China.

Abstract To investigate the estrogen receptor (ER) expression in cartilage cell in the development of osteoarthritis induced by bilateral ovariectomy in guinea pig and to find their relationship. 30 two-month-old female guinea pigs were randomly divided into two groups (n = 15 each): sham operation (control) group and ovariectomized group (OVX);

Scanning electron microscope (SEM) and transmission electron microscope (TEM) were obtained to analysis the cartilage degeneration of the hind limb knee joint after 6 and 12 weeks of ovariectomy. Dextran-Coated-Charcoal (DCC) was taken to quantitively detect the expression of ER. The serum levels of estrogen and gestone were detected by immune contest assay.

The results showed that ER do exist in the cartilages of the guinea pigs, with higher expression in the control group than in OVX group at the same time point (P < 0.05). It was increased also at 12 th week after operation than that of preoperation. The blood serum levels of estrogen and gestone showed a similar tendency to the expression of ER. Joint cartilage degeneration detected by SEM and TEM could be found at 6 th week, but severe degenerative lesions at 12 th week in the OVX group compared with the control group (P < 0.01).

The data suggested that bilateral ovariectomy in guinea pig lead to severe osteoarthritis which might be related to the lower serum level of estrogen and the downregulation of the expression of ER in the cartilage also.

12) www.ncbi.nlm.nih.gov/pubmed/9010879

Osteoarthritis Cartilage. 1997 Jan;5(1):63-9.

Biochemical effects of estrogen on articular cartilage in ovariectomized sheep.
Turner AS, Athanasiou KA, Zhu CF, Alvis MR, Bryant HU. Source Department of Clinical Sciences, Colorado State University, Ft. Collins 80523, USA.

Abstract Cartilage is a sex-hormone-sensitive tissue but the role of estrogen in the pathogenesis of osteoarthritis (OA) remains controversial. In this study, intrinsic material properties and thickness of articular cartilage of the knee joint of ovariectomized (OVX) and estrogen-treated sheep were measured. Skeletally mature ewes (N = 36, same breed, same housing 4-5 years old) were divided into; sham treated (n = 9), OVX (N = 13), OVX plus one estradiol implant (OVXE; N = 10) and OVX plus two estradiol implants (OVX2E; N = 4).

Twelve months following sham procedure or OVX, sheep were euthanized and articular cartilage from a total of 216 points in the left femorotibial (knee) joints was tested for aggregate modulus, Poisson's ratio, permeability, thickness and shear modulus (six sites per sheep). When all of the sites in each knee were grouped together, OVX had a significant effect on articular cartilage. The sham cartilage of all sites grouped together had a larger aggregate modulus (P = 0.001) and a larger shear modulus (P = 0.054) than the OVX tissue. No statistically significant differences were seen for permeability and thickness between OVX, sham, OVXE and OVX2E. Differences existed in biomechanical properties at the different sites that were tested. Overall, no one location tended to be lowest or highest for all variables. This biomechanical study suggests that OVX may have a detrimental effect on the intrinsic material properties of the articular cartilage of the knee, even though the cartilage of the OVX animals appeared normal.

Treatment with estradiol implants ameliorated these deleterious effects and may have helped maintain the tissue's structural integrity. Our study supports epidemiological studies of OA in women after menopause. The protective effect of estrogen and it's therapeutic effect remain to be further defined. This model may allow the relationship of estrogen and estrogen antagonists to be studied in greater detail, and may be valuable for the study of the pathogenesis and therapies of OA of postmenopausal women, particularly in its early stages.

13) www.ncbi.nlm.nih.gov/pubmed/16154775

Osteoarthritis Cartilage. 2005 Dec;13(12):1066-75. Epub 2005 Sep 9.

Ovariectomy alters the structural and biomechanical properties of ovine femoro-tibial articular cartilage and increases cartilage iNOS. Cake MA, Appleyard RC, Read RA, Smith MM, Murrell GA, Ghosh P. Source School of Veterinary and Biomedical Sciences, Murdoch University, WA, Australia.

Abstract OBJECTIVE: To examine the effect of oestrogen depletion produced by surgical ovariectomy on the structural and biomechanical properties of ovine femoro-tibial articular cartilage (AC), and the production of inducible nitric oxide synthase (iNOS) and nitrotyrosine by these tissues. METHODS: Six aged ewes were surgically ovariectomised (OVX), while six were used as unoperated controls. Dynamic biomechanical indentation testing of tibial plateau AC was performed at 26 weeks post-op. Histological sections of medial tibial plateau and lateral tibial plateau (LTP), medial and lateral femoral condyles (MFC, LFC) and patellar AC were examined for histopathology, toluidine blue staining intensity, and patterns of collagen birefringence intensity. Immunoreactivity for iNOS and nitrotyrosine was assessed in full-thickness biopsy plugs of LFC and patellar AC, and patellar AC explants were cultured to determine in vitro NO release.

RESULTS: Phase lag was reduced overall in LTP-AC of OVX sheep (10.9+/-2.2 degrees vs 12.1+/-2.3 degrees ; P<0.0001). Cartilage thickness was reduced in the LTP of OVX sheep (P=0.0002), in association with localised changes in dynamic shear modulus. Toluidine blue staining intensity was reduced in the patella, LFC, and MFC. Histological examination revealed greater histopathology scores in the MFC of OVX animals, and altered collagen birefringence intensity plots in the LTP. Immunostaining for iNOS was increased in patella AC (P=0.008), whilst nitrotyrosine immunoreactivity was increased in patella (P=0.03) and LFC (P<0.0001) AC. NO release by patellar AC explants was also elevated.

CONCLUSIONS: Oestrogen depletion induced by OVX caused regional thinning of femoro-tibial cartilage, with biomechanical and histological changes suggestive of a disturbance in the content and/or structural organisation of the proteoglycan and collagen macromolecular assembly. The observed up-regulation of cartilage iNOS suggests a possible mechanism for these matrix changes.

ANimal Model Summary

14) www.ncbi.nlm.nih.gov/pubmed/18280756

Osteoarthritis Cartilage. 2008 May;16(5):533-41. Epub 2008 Feb 15.

Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment - a systematic approach. Sniekers YH, Weinans H, Bierma-Zeinstra SM, van Leeuwen JP, van Osch GJ. Source Department of Orthopaedics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Abstract

OBJECTIVE: The prevalence of osteoarthritis (OA) increases dramatically in women after the age of 50. Animal models are used to study the effects of hormone depletion [by ovariectomy (OVX)] and estrogen treatment on OA. This review summarizes these animal studies, in order to get a better insight in the role of hormones on OA.

METHOD: The literature was systematically reviewed until May 2007. The results were divided into two parts: the effect of OVX on cartilage, and the effect of estrogen treatment on cartilage. Only studies with an appropriate control group (e.g., sham-operated) were included.

RESULTS AND DISCUSSION: Eleven out of 16 animal studies showed that OVX resulted in cartilage damage. When only studies using sexually mature animals were included, we saw that 11 out of 14 studies showed a detrimental effect, indicating considerable evidence for a relation between cartilage degeneration and OVX in mature animals. The effect of estrogen treatment was inconclusive with only 11 out of 22 animal studies reporting a beneficial effect on cartilage, whereas all six studies administering selective estrogen receptor modulators (SERMs) after OVX described protective effects. The discrepancy between the studies may be caused by the large variation in experimental set-up. We suggested a list of quality criteria for animal models since standardisation of design and outcome parameters of animal experiments may help to compare different studies and to gain better insight in the role of hormones in the osteoarthritic process.

HUMAN

15)

www.ncbi.nlm.nih.gov/pubmed/9608332

Curr Opin Rheumatol. 1998 May;10(3):269-72.

The effects of estrogen on osteoarthritis.

Felson DT, Nevitt MC. Source Boston University School of Medicine, Multipurpose Arthritis and Musculoskeletal Diseases Center, MA 02118-2526, USA.

Abstract The prevalence of osteoarthritis is higher in women than men, and in women it increases dramatically in the years after menopause. These observations and others reporting a painful form of hand osteoarthritis after the menopause suggest that loss of estrogen at the time of menopause increases a woman's risk of getting osteoarthritis. This article reviews biologic evidence for hormone sensitivity of cartilage, animal studies testing the effect of estrogen on the joints of ovariectomized animals, and human epidemiologic and clinical studies evaluating endogenous estrogen levels and estrogen replacement therapy and their relation to the occurrence of osteoarthritis. Overall the evidence for a role of estrogen in osteoarthritis is conflicting. Epidemiologic studies of women who take estrogen replacement therapy, however, consistently report that these women have a lower prevalence of osteoarthritis than women not taking estrogen, suggesting a possible therapeutic role for estrogen in osteoarthritis.

PEMF - Pulsed Electro MAgnetic Fields

www.ncbi.nlm.nih.gov/pubmed/16023006

J Orthop Res. 2005 Jul;23(4):899-908. Epub 2005 Mar 17.

Pulsed electromagnetic fields reduce knee osteoarthritic lesion progression in the aged Dunkin Hartley guinea pig. Fini M, Giavaresi G, Torricelli P, Cavani F, Setti S, Canè V, Giardino R. Source Department of Experimental Surgery, Codivilla-Putti Research Institute, Rizzoli Institute of Orthopaedics, Via di Barbiano, 1/10, 40136 Bologna, Italy.

Abstract An experimental in vivo study was performed to test if the effect of Pulsed Electromagnetic Fields (PEMFs) on chondrocyte metabolism and adenosine A2a agonist activity could have a chondroprotective effect on the knee of Dunkin Hartley guinea-pigs of 12 months with spontaneously developed osteoarthritis (OA).

After a pilot study, 10 animals were randomly divided into two groups: PEMF-treated group (6 h/day for 3 months) and Sham-treated group. Microradiography and histomorphometry were performed on the entire articular surface of knee joints used in evaluating chondropathy severity, cartilage thickness (CT), cartilage surface Fibrillation Index (FI), subchondral bone plate thickness (SBT) and histomorphometric characteristics of trabecular epiphyseal bone. The PEMF-treated animals showed a significant reduction of chondropathy progression in all knee examined areas (p<0.05). CT was significantly higher (p<0.001) in the medial tibia plateaus of the PEMF-treated group when compared to the Sham-treated group. The highest value of FI was observed in the medial tibia plateau of the Sham-treated group (p<0.05). Significant lower values were observed in SBT of PEMF-treated group in comparison to Sham-treated group in all knee examined areas (p<0.05). The present study results show that PEMFs preserve the morphology of articular cartilage and slower the progression of OA lesions in the knee of aged osteoarthritic guinea pigs. The chondroprotective effect of PEMFs was demonstrated not only in the medial tibial plateau but also on the entire articular surface of the knee.

www.ncbi.nlm.nih.gov/pubmed/17459652

Biomed Pharmacother. 2008 Dec;62(10):709-15. Epub 2007 Apr 3.

Effect of pulsed electromagnetic field stimulation on knee cartilage, subchondral and epyphiseal trabecular bone of aged Dunkin Hartley guinea pigs.

Fini M, Torricelli P, Giavaresi G, Aldini NN, Cavani F, Setti S, Nicolini A, Carpi A, Giardino R. Source Laboratory of Experimental Surgery, Research Institute Codivilla-Putti, Rizzoli Orthopaedic Institute, Bologna, Italy.

Abstract It has been demonstrated that pulsed electromagnetic field (PEMF) stimulation has a chondroprotective effect on osteoarthritis (OA) progression in the knee joints of the 12-month-old guinea pigs. The aim of the present study was to discover whether the therapeutic efficacy of PEMFs was maintained in older animals also in more severe OA lesions. PEMFs were administered daily (6 h/day for 6 months) to 15-month-old guinea pigs. The knee joints (medial and lateral tibial plateaus, medial and lateral femoral condyles) were evaluated by means of a histological/histochemical Mankin modified by Carlsson grading score and histomorphometric measurements of cartilage thickness (CT), fibrillation index (FI), subchondral bone thickness (SBT) and epiphyseal bone microarchitecture (bone volume: BV/TV; trabecular thickness: Tb.Th; trabecular number: Tb.N; trabecular separation: Tb.SP). Periarticular knee bone was also evaluated with dual X-ray absorptiometry (DXA). PEMF stimulation significantly changed the progression of OA lesions in all examined knee areas. In the most affected area of the knee joint (medial tibial plateau), significant lower histochemical score (p<0.0005), FI (p<0.005), SBT (p<0.05), BV/TV (p<0.0005), Tb.Th (p<0.05) and Tb.N (p<0.05) were observed while CT (p<0.05) and Tb.Sp (p<0.0005) were significantly higher than in SHAM-treated animals. DXA confirmed the significantly higher bone density in SHAM-treated animals.

Even in the presence of severe OA lesions PEMFs maintained a significant efficacy in reducing lesion progression.

Low Level Laser for OA

www.integralnatmed.com/pdf/LLLT_Knee_Osteoarthritis_Photomedicine_2009.pdf

Photomedicine and Laser Surgery Volume 27, Number 4, 2009

The Effect of Low-Level Laser in Knee Osteoarthritis: A Double-Blind, Randomized, Placebo-Controlled Trial Be´ la Heged}us, M.D.,1 La´ szlo´ Viharos, Ph.D.,2 Miha´ ly Gervain, Ph.D.,3 and Ma´ rta Ga´ lfi, Ph.D.4 Introduction:

Low-level laser therapy (LLLT) is thought to have an analgesic effect as well as a biomodulatory effect on microcirculation. This study was designed to examine the pain-relieving effect of LLLT and possible microcirculatory changes measured by thermography in patients with knee osteoarthritis (KOA). Materials and Methods: Patients with mild or moderate KOA were randomized to receive either LLLT or placebo LLLT. Treatments were delivered twice a week over a period of 4wk with a diode laser (wavelength 830 nm, continuous wave, power 50mW) in skin contact at a dose of 6 J=point. The placebo control group was treated with an ineffective probe (power 0.5mW) of the same appearance. Before examinations and immediately, 2 wk, and 2 mo after completing the therapy, thermography was performed (bilateral comparative thermograph by AGA infrared camera); joint flexion, circumference, and pressure sensitivity were measured; and the visual analogue scale was recorded. Results: In the group treated with active LLLT, a significant improvement was found in pain (before treatment [BT]: 5.75; 2 mo after treatment : 1.18); circumference (BT: 40.45; AT: 39.86); pressure sensitivity (BT: 2.33; AT: 0.77); and flexion (BT: 105.83; AT: 122.94). In the placebo group, changes in joint flexion and pain were not significant. Thermographic measurements showed at least a 0.58C increase in temperature—and thus an improvement in circulation compared to the initial values. In the placebo group, these changes did not occur.

Conclusion: Our results show that LLLT reduces pain in KOA and improves microcirculation in the irradiated area.

torontopainrelief.com/articles/Laser%20Therapy%20for%20Treatment%20of%20Arthritic%20Knees%20-%20A%20Clinical%20.pdf

Laser therapy for the treatment of arthritic knees: a clinical study F. Kahna, R. Liboroa and F. Saraga*a a Meditech Laser Rehabilitation Centre, 415 Horner Ave, Toronto, ON, Canada, M8W4W3 ABSTRACT In a follow-up clinical study to our previously published 2006 SPIE conference proceeding, we analyzed a cross-section of patients treated for a variety of knee problems that present at our Meditech Laser Rehabilitation Clinics on a daily basis. Of the 98 patients with knee pathologies included in this study, 63% presented with degenerative osteoarthritis. On average 11 treatments, each 30-45 minutes in duration, were administered for the individual patient resulting in a significant improvement rate in excess of 92%. Laser Therapy is active at both the cellular and systemic levels activating a variety of mechanisms including cartilage regeneration, DNA synthesis, improved microcirculation and an analgesic and anti-inflammatory effect.

iv.iiarjournals.org/content/18/5/585.full.pdf
in vivo 18: 585-592 (2004)

Effect of Low-level Laser Therapy on Osteoarthropathy in Rabbit

HYUNG-JIN CHO1, SUNG-CHUL LIM2,3, SU-GWAN KIM4, YOUNG-SOO KIM1, SEONG-SOO KANG1, SEOK-HWA CHOI5, YONG-SEONG CHO6 and CHUN-SIK BAE1,7 1College of Veterinary Medicine and 7Biotechnology Research Institute, Chonnam National University, Gwangju; 2Department of Pathology, 3Research Center for Resistant Cells, Chosun University, Medical School, Gwangju; 4Department of Oral and Maxillofacial Surgery, Oral Biology Research Institute, College of Dentistry, Chosun University, Gwangju; 5College of Veterinary Medicine, Chungbuk National University, Cheongju; Conversely, the 4-week treatment group showed chondrocyte replacement, with sometimes close to normal articular cartilage on the articular surface. These results suggest that LLLT was effective in the treatment of chemically-induced OA.

mend.endojournals.org/content/19/4/833.full

Minireviews Mechanisms of Estrogen Receptor Signaling: Convergence of Genomic and Nongenomic Actions on Target Genes Linda Björnström and Maria Sjöberg- Author Affiliations Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden

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