As you enter Southwest Integrative Medicine Clinic, you will see that things work differently. Our doctors will spend time listening to the whole story, not just the symptoms that are bothering you today. We will investigate possible causes for your discomfort and develop a non-invasive holistic treatment plan that enhances your bodys ability to heal itself.

As integrative medicine doctors, we combine conventional with holistic and naturopathic medicine. We treat causes not symptoms. And, we prefer naturopathic treatments to pharmaceuticals.

Nutrition is an important component of many of our treatments because vitamins, minerals, and nutrients are not foreign to the body. They can be just as effective, or even more effective than conventional treatments. When a deficiency is present, a nutritional treatment plan can improve conditions such as diabetes, fatigue, obesity, and fibromyalgia.

Acupuncture has been used for thousands of years and has now become a popular, effective treatment for all types of health concerns. As a leading Phoenix acupuncture clinic, we help many patients stimulate healing, improving their fertility, weight loss, pain management, depression, digestion, and general health.

Hormone imbalance can affect numerous body functions without ever revealing the root cause. Because we use a holistic approach, we consider a wide array of paths to help you achieve optimal wellness.

Every Phoenix naturopathic doctor understands that the best thing we can do for our patients is provide guidance. At Southwest Integrative Medicine, we work with our patients to draw conclusions about the most appropriate treatment plan, whether it inolves acupuncture, hormone therapy, vitamin therapy, herbal medicine, or conventional treatments.

Serving Phoenix, Scottsdale, Fountain Hills, Mesa, Tempe, Cave Creek, Paradise Valley, and Carefree.

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Naturopathic Doctor Phoenix | Weight Loss Clinic ...

Recommendation and review posted by Bethany Smith

Our hormone levels decline with aging. We begin experiencing lack of energy, decrease in exercise tolerance and sexual drive. We gain weight, acquire heart disease and diabetes; we loose muscle strength, and our bones become fragile.

Such detrimental changes should not be ignored!

Weshould actively seek for ways how to continue to be and stay energetic and productive, even when years take toll on us.

Hormone Replacement Therapy (HRT) and, in particular, testosterone replacement has become increasingly popular among middle age men.

In addition to a healthy diet and active lifestyle, optimal hormone levels aid men to be at their best.

A recently published study, which included 930 men with coronary artery disease, showed that men who had a lower level of Testosterone (even borderline levels!) had almost twice higher chance of dying during seven years of follow-up. (Heart. 2010; 96:1821-1825)

At our clinic, we constantly review the most recent medical articles and strive to improve our protocols in order to bring you the best possible outcomes from your hormone therapy. Though subjective results may vary, most men on hormone replacement feel and function better than those who are not.

If you have any questions about Testosterone Replacement, DHEA, Thyroid or other hormone optimization, please CALL us today at (206) 792-5700 to discuss your personalized hormone replacement program.

We will carefully review your medical history and tailor a hormone replacement program right for you.

We can help YOU to feel your BEST!

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Home - Seattle Hormone Replacement Clinic for Men

Recommendation and review posted by Bethany Smith

Hormone Replacement Therapy Nutraceutical Imbalance Therapy IV Nutrient Therapy Medical Weight Loss Sexual Dysfunction Treatment GH Releasing Hormones You may be reading this because you are not your normal self. You are lethargic and your energy level is not what it was. Your body is becoming soft and flabby. You're having problems with focus and concentration. LEARN MORE Core Medical New York has an extensive menu of nutraceuticals, available via oral delivery or injection, that accelerate the anti-aging process in our patients. Our neutraceuticals range from high performance, gender-specific multi-vitamins to essential amino acids that can melt away body fat. LEARN MORE IV nutrient therapy is the process of giving vital nutrients to the body via the bloodstream. The nutrients can be distributed slowly with a syringe, as in the "Meyer's Cocktail," for five to fifteen minutes or by a slow drip that can last from thirty minutes to just over an hour. LEARN MORE Small doses of HCG, given to overweight individuals, decreases appetite, and assists in trimming off inches of fat, specifically around the hips, thighs, buttocks, and stomach in a few short weeks. LEARN MORE Core Clinic takes a multi-faceted approach to treating erectile dysfunction. The first step is an evaluation by one of Core's highly-trained physicians to identify what is causing erectile dysfunction. Upon completing the evaluation, an individualized treatment regimen is created by a Core physician. LEARN MORE Core Medical New York's objective in providing physician-supervised, adult Sermorelin growth hormone therapy, is to reverse the negative effects of aging and secure the extensive treatment benefits. LEARN MORE Core Medical New York is a group of professionals, dedicated to revolutionizing the anti-aging process. Core strives to bring an innovative approach to conquering the countless adverse effects of aging experienced by many adult men and women. We design for each client a customized program with the sole objective of improving their quality of life.

We also specialize in Erectile Dysfunction (ED) and Testosterone Replacement Therapy!

Call us today so we can help you out of the shadows of hormone imbalances! FOR A FREE CONSULTATION, CALL (844)NYC-CORE

These medicines are available only with a doctor's prescription. As such, you must be examined by our physician who will determine what products are medically necessary and provide you with instructions for proper use and administration. Core Medical New York will be happy to connect you with one of the many physicians in its network so you can learn more about our products and so that you, together with a qualified physician, can determine if our products are right for you. Please note that Core takes its responsibility to its patients very seriously and as such complies with all relevant statutes, rules and regulations, including but not limited to 21 U.S.C. 801-971 and 21 U.S.C. 301, et seq. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch or call 1-800-FDA-1088.

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Recommendation and review posted by Bethany Smith

An isolated cardiac muscle cell, beating

Cardiac muscle (heart muscle) is involuntary striated muscle that is found in the walls and histological foundation of the heart, specifically the myocardium. Cardiac muscle is one of three major types of muscle, the others being skeletal and smooth muscle. These three types of muscle all form in the process of myogenesis. The cells that constitute cardiac muscle, called cardiomyocytes or myocardiocytes, contain only three nuclei.[1][2][pageneeded] The myocardium is the muscle tissue of the heart, and forms a thick middle layer between the outer epicardium layer and the inner endocardium layer.

Coordinated contractions of cardiac muscle cells in the heart propel blood out of the atria and ventricles to the blood vessels of the left/body/systemic and right/lungs/pulmonary circulatory systems. This complex mechanism illustrates systole of the heart.

Cardiac muscle cells, unlike most other tissues in the body, rely on an available blood and electrical supply to deliver oxygen and nutrients and remove waste products such as carbon dioxide. The coronary arteries help fulfill this function.

Cardiac muscle has cross striations formed by rotating segments of thick and thin protein filaments. Like skeletal muscle, the primary structural proteins of cardiac muscle are myosin and actin. The actin filaments are thin, causing the lighter appearance of the I bands in striated muscle, whereas the myosin filament is thicker, lending a darker appearance to the alternating A bands as observed with electron microscopy. However, in contrast to skeletal muscle, cardiac muscle cells are typically branch-like instead of linear.

Another histological difference between cardiac muscle and skeletal muscle is that the T-tubules in the cardiac muscle are bigger and wider and track laterally to the Z-discs. There are fewer T-tubules in comparison with skeletal muscle. The diad is a structure in the cardiac myocyte located at the sarcomere Z-line. It is composed of a single T-tubule paired with a terminal cisterna of the sarcoplasmic reticulum. The diad plays an important role in excitation-contraction coupling by juxtaposing an inlet for the action potential near a source of Ca2+ ions. This way, the wave of depolarization can be coupled to calcium-mediated cardiac muscle contraction via the sliding filament mechanism. Cardiac muscle forms these instead of the triads formed between the sarcoplasmic reticulum in skeletal muscle and T-tubules. T-tubules play critical role in excitation-contraction coupling (ECC). Recently, the action potentials of T-tubules were recorded optically by Guixue Bu et al.[3]

The cardiac syncytium is a network of cardiomyocytes connected to each other by intercalated discs that enable the rapid transmission of electrical impulses through the network, enabling the syncytium to act in a coordinated contraction of the myocardium. There is an atrial syncytium and a ventricular syncytium that are connected by cardiac connection fibres.[4] Electrical resistance through intercalated discs is very low, thus allowing free diffusion of ions. The ease of ion movement along cardiac muscle fibers axes is such that action potentials are able to travel from one cardiac muscle cell to the next, facing only slight resistance. Each syncyntium obeys the all or none law.[5]

Intercalated discs are complex adhering structures that connect the single cardiomyocytes to an electrochemical syncytium (in contrast to the skeletal muscle, which becomes a multicellular syncytium during mammalian embryonic development). The discs are responsible mainly for force transmission during muscle contraction. Intercalated discs are described to consist of three different types of cell-cell junctions: the actin filament anchoring adherens junctions, the intermediate filament anchoring desmosomes , and gap junctions. They allow action potentials to spread between cardiac cells by permitting the passage of ions between cells, producing depolarization of the heart muscle. However, novel molecular biological and comprehensive studies unequivocally showed that intercalated discs consist for the most part of mixed-type adhering junctions named area composita (pl. areae compositae) representing an amalgamation of typical desmosomal and fascia adhaerens proteins (in contrast to various epithelia).[6][7][8] The authors discuss the high importance of these findings for the understanding of inherited cardiomyopathies (such as arrhythmogenic right ventricular cardiomyopathy).

Under light microscopy, intercalated discs appear as thin, typically dark-staining lines dividing adjacent cardiac muscle cells. The intercalated discs run perpendicular to the direction of muscle fibers. Under electron microscopy, an intercalated disc's path appears more complex. At low magnification, this may appear as a convoluted electron dense structure overlying the location of the obscured Z-line. At high magnification, the intercalated disc's path appears even more convoluted, with both longitudinal and transverse areas appearing in longitudinal section.[9]

In contrast to skeletal muscle, cardiac muscle requires extracellular calcium ions for contraction to occur. Like skeletal muscle, the initiation and upshoot of the action potential in ventricular muscle cells is derived from the entry of sodium ions across the sarcolemma in a regenerative process. However, an inward flux of extracellular calcium ions through L-type calcium channels sustains the depolarization of cardiac muscle cells for a longer duration. The reason for the calcium dependence is due to the mechanism of calcium-induced calcium release (CICR) from the sarcoplasmic reticulum that must occur under normal excitation-contraction (EC) coupling to cause contraction. Once the intracellular concentration of calcium increases, calcium ions bind to the protein troponin, which initiate extracellular fluid and intracellular stores, and skeletal muscle, which is only activated by calcium stored in the sarcoplasmic reticulum.

Until recently, it was commonly believed that cardiac muscle cells could not be regenerated. However, a study reported in the April 3, 2009 issue of Science contradicts that belief.[10] Olaf Bergmann and his colleagues at the Karolinska Institute in Stockholm tested samples of heart muscle from people born before 1955 who had very little cardiac muscle around their heart, many showing with disabilities from this abnormality. By using DNA samples from many hearts, the researchers estimated that a 20-year-old renews about 1% of heart muscle cells per year, and about 45 percent of the heart muscle cells of a 50-year-old were generated after he or she was born.

One way that cardiomyocyte regeneration occurs is through the division of pre-existing cardiomyocytes during the normal aging process.[11] The division process of pre-existing cardiomyocytes has also been shown to increase in areas adjacent to sites of myocardial injury. In addition, certain growth factors promote the self-renewal of endogenous cardiomyocytes and cardiac stem cells. For example, insulin-like growth factor 1, hepatocyte growth factor, and high-mobility group protein B1 increase cardiac stem cell migration to the affected area, as well as the proliferation and survival of these cells.[12] Some members of the fibroblast growth factor family also induce cell-cycle re-entry of small cardiomyocytes. Vascular endothelial growth factor also plays an important role in the recruitment of native cardiac cells to an infarct site in addition to its angiogenic effect.

Based on the natural role of stem cells in cardiomyocyte regeneration, researchers and clinicians are increasingly interested in using these cells to induce regeneration of damaged tissue. Various stem cell lineages have been shown to be able to differentiate into cardiomyocytes, including bone marrow stem cells. For example, in one study, researchers transplanted bone marrow cells, which included a population of stem cells, adjacent to an infarct site in a mouse model. Nine days after surgery, the researchers found a new band of regenerating myocardium.[13] However, this regeneration was not observed when the injected population of cells was devoid of stem cells, which strongly suggests that it was the stem cell population that contributed to the myocardium regeneration. Other clinical trials have shown that autologous bone marrow cell transplants delivered via the infarct-related artery decreases the infarct area compared to patients not given the cell therapy.[14]

Occlusion (blockage) of the coronary arteries by atherosclerosis and/or thrombosis can lead to myocardial infarction (heart attack), where part of the myocardium is injured due to ischemia (not receiving enough oxygen). This occurs because coronary arteries are functional end arteries - i.e. there is almost no overlap in the areas supplied by different arteries (anastomoses) so that if one fails, others cannot adequately perfuse the region, unlike in other tissues.

Certain viruses lead to myocarditis (inflammation of the myocardium). Cardiomyopathies are inherent diseases of the myocardium, many of which are caused by genetic mutations.

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Cardiac muscle - Wikipedia, the free encyclopedia

Recommendation and review posted by Bethany Smith

Abstract Introduction

Bone marrow mesenchymal stem cells (BMMSCs) are a heterogeneous population of postnatal precursor cells with the capacity of adhering to culture dishes generating colony-forming unit-fibroblasts (CFU-F). Here we identify a new subset of BMMSCs that fail to adhere to plastic culture dishes and remain in culture suspension (S-BMMSCs).

To catch S-BMMSCs, we used BMMSCs-produced extracellular cell matrix (ECM)-coated dishes. Isolated S-BMMSCs were analyzed by in vitro stem cell analysis approaches, including flow cytometry, inductive multiple differentiation, western blot and in vivo implantation to assess the bone regeneration ability of S-BMMSCs. Furthermore, we performed systemic S-BMMSCs transplantation to treat systemic lupus erythematosus (SLE)-like MRL/lpr mice.

S-BMMSCs are capable of adhering to ECM-coated dishes and showing mesenchymal stem cell characteristics with distinction from hematopoietic cells as evidenced by co-expression of CD73 or Oct-4 with CD34, forming a single colony cluster on ECM, and failure to differentiate into hematopoietic cell lineage. Moreover, we found that culture-expanded S-BMMSCs exhibited significantly increased immunomodulatory capacities in vitro and an efficacious treatment for SLE-like MRL/lpr mice by rebalancing regulatory T cells (Tregs) and T helper 17 cells (Th17) through high NO production.

These data suggest that it is feasible to improve immunotherapy by identifying a new subset BMMSCs.

Bone marrow mesenchymal stem cells (BMMSCs) are hierarchical postnatal stem/progenitor cells capable of self-renewing and differentiating into osteoblasts, chondrocytes, adipocytes, and neural cells [1,2]. BMMSCs express a unique surface molecule profile, including expression of STRO-1, CD29, CD73, CD90, CD105, CD146, Octamer-4 (Oct4), and stage-specific embryonic antigen-4 (SSEA4) [3,4]. It is generally believed that BMMSCs are negative for hematopoietic cell markers such as CD14 and CD34 [5-13]. BMMSCs have been widely used for tissue engineering [14-16]. Recently, a growing body of evidence has indicated that BMMSCs produce a variety of cytokines and display profound immunomodulatory properties [17-19], perhaps by inhibiting the proliferation and function of several major immune cells, such as natural killer cells, dendritic cells, and T and B lymphocytes [17-20]. These unique properties make BMMSCs of great interest for clinical applications in the treatment of different immune disorders [17,21-24].

BMMSCs are thought to be derived from the bone marrow stromal compartment, initially appearing as adherent, single colony clusters (colony-forming unit-fibroblasts [CFU-F]), and subsequently proliferating on culture dishes [25]. To date, the CFU-F assay has been considered one of the gold standards for determining the incidence of clonogenic BMMSC [26,27]. Since BMMSC are a heterogeneous population of stem cells, it is critical to identify whether BMMSC contain unique cell subsets with distinctive functions, analogous to the hematopoietic stem/progenitor cell system. In this study, we identified a subset of mouse BMMSCs in culture suspension and determined their immunomodulatory characteristics.

Female C3H/HeJ, C57BL/6J, and C3MRL-Faslpr/J mice were purchased from Jackson Laboratory (Bar Harbor, ME, USA). Female immunocompromised mice (Beige nude/nude XIDIII) were purchased from Harlan (Indianapolis, IN, USA). All animal experiments were performed under the institutionally approved protocols for the use of animal research (USC #10874 and 10941).

Anti Oct4, SSEA4, Runx2, OCN, active catenin and catenin were purchased from Millipore (Billerica, MA, USA). Anti alkaline phosphatase (ALP) antibody was purchased from Abcam (Cambridge, MA, USA). Anti Sca-1-PE, CD34-PE, CD34-FITC, CD45-PE, CD73-PE, CD4-PerCP, CD8-FITC, CD25-APC, CD3 and CD28 antibodies were purchased from BD Bioscience (San Jose, CA, USA). Anti Foxp3-PE, IL17-PE, and IFN-APC antibodies were purchased from eBioscience (San Diego, CA, USA). Unconjugated anti CD34, CD73, and CD105, NOS2 were purchased from Santa Cruz Biosciences (Santa Cruz, CA, USA). Anti actin antibody was purchased from Sigma (St. Louis, MO, USA).

The single suspension of bone marrow derived all nucleated cells (ANCs) from femurs and tibias were seeded at a density of 15 106 into 100 mm culture dishes (Corning, NY, USA) at 37C and 5% CO2. Non-adherent cells were removed after two days and attached cells were maintained for 16 days in alpha minimum essential medium (-MEM, Invitrogen, Grand Island, NY, USA) supplemented with 20% fetal bovine serum (FBS, Equitech-bio, Kerrville, TX, USA), 2 mM L-glutamine, 55 M 2-mercaptoethanol, 100 U/ml penicillin, and 100 g/ml streptomycin (Invitrogen). Colony-forming attached cells were passed once for further experimental use.

ECM coated dishes were prepared as described previously [28]. Briefly, 100% confluence of BMMSCs was cultured in medium with 100 nM L-ascorbic acid phosphate (Wako Pure Chemical, Richmond, VA, USA). After two weeks, cultures were washed with PBS and incubated with 0.005% Triton X-100 (Sigma) for 15 minutes at room temperature to remove cells. The ECM was treated with DNase I (100 units/ml; Sigma) for 1 hour at 37C. The ECM was washed with PBS three times and stored in 2 ml of PBS containing 100 U/ml penicillin, 100 g/ml streptomycin and 0.25 g/ml fungizone (Invitrogen) at 4C.

Bone marrow-derived ANCs (15 106) were seeded into 100 mm culture dishes and cultured for two days. The culture supernatant with floating cells was collected and centrifuged to obtain putative non-attached BMMSCs. The cells were re-seeded at indicated numbers on ECM-coated dishes. After 2 days, the floating cells in the cultures were removed with PBS and the attached cells on ECM were maintained for an additional 14 days. Colony-forming attached cells were passed once and sub-cultured on regular plastic culture dishes for further experiments. For some stem cell characterization analyses, we collected SSEA4 positive S-BMMSCs using the MACS magnetic separation system (Milteny Biotech, Auburn, CA, USA) and expanded in the cultures.

One million cells of ANCs from bone marrow were seeded on a T-25 cell culture flask (Nunc, Rochester, NY, USA). After 16 days, the cultures were washed with PBS and stained with 1% toluidine blue solution in 2% paraformaldehyde (PFA). A cell cluster that had more than 50 cells was counted as a colony under microscopy. The colony number was counted in five independent samples per each experimental group.

The proliferation of BMMSCs and S-BMMSCs was performed using the bromodeoxyuridine (BrdU) incorporation assay. Each cell population (1 104 cells/well) was seeded on two-well chamber slides (Nunc) and cultured for two to three days. The cultures were incubated with BrdU solution (1:100) (Invitrogen) for 20 hours, and stained with a BrdU staining kit (Invitrogen). BrdU-positive and total cell numbers were counted in ten images per subject. The BrdU assay was repeated in five independent samples for each experimental group.

A total of 0.5 106 cells of BMMSCs and S-BMMSCs was seeded on 60 mm culture dishes at the first passage. Upon reaching confluence, the cells were passaged at the same cell density. The population doubling was calculated at every passage according to the equation: log2 (number of harvested cells/number of seeded cells). The finite population doublings were determined by cumulative addition of total numbers generated from each passage until the cells ceased dividing.

BMMSCs or S-BMMSCs (0.2 106 cells) were incubated with 1 g of R-Phycoerythrin (PE). (PE)-conjugated antibodies or isotype-matched control immunoglobulin Gs (IgGs) (Southern Biotech, Birmingham, AL, USA) at 4C for 45 minutes. Samples were analyzed by a fluorescence-activated cell sorting (FACS)Calibur flow cytometer (BD Bioscience). For dual color analysis, the cells were treated with PE-conjugated and fluorescein isothiocyanate (FITC)-conjugated antibodies or isotype-matched control IgGs (1 g each). The cells were analyzed on FACSCalibur (BD Bioscience).

The cells subcultured on eight-well chamber slides (Nunc) (2 103/well) were fixed with 4% PFA. The samples were incubated with the specific or isotype-matched mouse antibodies (1:200) overnight at 4C, and treated with Rhodamine-conjugated secondary antibodies (1:400, Jackson ImmunoResearch, West Grove, PA, USA; Southern Biotechnology, Birmingham, AL, USA). Finally, chamber slides were mounted using Vectashield mounting medium containing 4', 6-diamidino-2-phenylindole (DAPI) (Vector Laboratories, Burlingame, CA, USA).

A total of 4.0 106 cells was mixed with hydroxyapatite/tricalcium phosphate (HA/TCP) ceramic powders (40 mg, Zimmer Inc., Warsaw, IN, USA) and subcutaneously transplanted into eight-week-old immunocompromised mice. After eight weeks, the transplants were harvested, fixed in 4% PFA and then decalcified with 5% ethylenediaminetetraacetic acid (EDTA; pH 7.4), followed by paraffin embedding. The paraffin sections were stained with H & E and analyzed by an NIH Image-J. The newly-formed mineralized tissue area from five fields was calculated and shown as a percentage to total tissue area.

BMMSCs and S-BMMSCs were cultured under osteogenic culture conditions containing 2 mM -glycerophosphate (Sigma), 100 M L-ascorbic acid 2-phosphate and 10 nM dexamethasone (Sigma). After induction, the cultures were stained with alizarin red or alkaline phosphatase.

For adipogenic induction, 500 nM isobutylmethylxanthine, 60 M indomethacin, 500 nM hydrocortisone, 10 g/ml insulin (Sigma), 100 nM L-ascorbic acid phosphate were added to the culture medium. After 10 days, the cultured cells were stained with Oil Red-O and positive cells were quantified by using an NIH Image-J. Total RNA was also isolated from cultures after 10 days induction for further experiments.

For chondrogenic induction, 1 106 cell pellets were cultured under chondrogenic medium containing 15% FBS, 1% ITS (BD), 100 nM dexamethasone, 2 mM pyruvate (SIGMA), and 10 ng/ml transforming growth factor beta 1 (TGF1) in (D)MEM (Invitrogen) for threeweeks. Cell pellets were harvested at three weeks post induction, fixed overnight with 4% PFA and then, sections were prepared for staining.

Extraction of total RNA and RT-PCR were performed according to standard procedures. Primer information is described in Additional materials and methods [see Additional file 1].

Additional file 1. Figures S1 to S8 and Additional materials and methods. Figure S1. ECM coated dish could capture a greater number of CFU-F. CFU-f number in ECM coated dish compared to regular dish. Figure S2. CD45-CD34-BMMSCs showed similar property with S-BMMSCs. (A) CFU-f number. (B) Flow cytometric analysis. Figure S3. S-BMMSCs extended survival rate of lethal dose of irradiated mice. The life span of irradiated mice. Figure S4. Osteoclast activity in S-BMMSC-treated MRL/lpr mice. (A) Osteoclast number. (B) sRANKL level. (C) CTX level. Figure S5. L-NMMA pre-treated BMMSC transplantation failed to ameliorate disease phenotype of MRL/lpr mice. (A) Anti dsDNA (IgG) level. (B) Anti dsDNA (IgM) level. (C) Urine protein level. (D) Tregs level. (E) Th17 level. (F) Ratio between Tregs/Th17. Figure S6. Inhibition of NO production in BMMSCs. (A) NO level with inhibitors. (B) iNOS level by western blot. Figure S7. Endogenous S-BMMSCs in mice bone marrow. (A) Cell sorting result. (B) CFU-f number. (C) Osteogenic differentiation in vitro. (D) NO level. Figure S8. Human bone marrow contains S-BMMSCs (hS-BMMSCs). (A) NO level. (B) Kynurenine production. (C) Kynurenine production in co-culture system. (D) T cell apoptosis induction by hS-BMMSCs. Additional materials and methods describe about TRAP staining, Histomotry, Rescue lethal dose irradiated mice, and Isolation of CD34+CD73+ double positive cells.

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A total of 20 g of protein was used and SDS-PAGE and western blotting were performed according to standard procedures. Detailed procedures are described in Additional materials and methods [see Additional file 1]. -actin on the same membrane served as the loading control.

BMMSCs and S-BMMSCs were cultured onto 35 mm low attach culture dishes (2 104/dish, STEMCELL Technologies, Vancouver, BC, V5Z 1B3, Canada) under hematopoietic differentiation medium (STEMCELL Technologies) with or without erythropoietin (EPO; 3 U/mL) for seven days. Whole bone marrow cells and linage negative bone marrow cells (Linage-cells) were used as positive controls. The results are representative of five independent experiments.

S-BMMSCs and BMMSCs were treated with 1 mM L-NG-monomethyl-arginine (L-NMMA) (Cayman Chemical, Ann Arbor, MI, USA) or 0.2 mM 1400 W (Cayman Chemical) to inhibit total nitric oxide synthase (NOS) or inducible nitric oxide synthase (iNOS), respectively.

BMMSCs (0.2 106/well) were cultured on 24-well plates with or without cytokines (IFN, 25 ng/ml; IL-1, 5 ng/ml, R&D Systems, Minneapolis, MN, USA) and chemicals (L-NMMA, 1 mM; 1400 W, 0.2 mM) at the indicated concentration and days. The supernatant from each culture was collected and nitric oxide concentration measured using a Total Nitric Oxide and Nitrate/Nitrite Parameter Assay kit (R&D Systems) according to the manufacturer's instruction.

The transwell system (Corning) was used for co-culture experiments. A total of 0.2 106 of S-BMMSCs or BMMSCs was seeded on each lower chamber. Activated spleen cells (1 106/chamber), which were pre-stimulated with plate-bound anti CD3 antibody (3 g/ml) and soluble anti CD28 antibody (2 g/ml) for two days, were loaded in the upper chambers. Both chambers were filled with a complete medium containing (D)MEM (Lonza, CH-4002 Basel, Switzerland) with 10% heat-inactivated FBS, 50 M 2-mercaptoethanol, 10 mM HEPES, 1 mM sodium pyruvate (Sigma), 1% non-essential amino acid (Cambrex, East Rutherford, NJ, USA), 2 mM L-glutamine, 100 U/ml penicillin and 100 mg/ml streptomycin. To measure the spleen cells viability, cell counting kit-8 (Dojindo Molecular Technologies, Rockville, MD, USA) was used. For apoptosis of spleen cells analyses, Annexin V-PE apoptosis detection kits I (BD Bioscience) were used and analyzed on FACSCalibur (BD Bioscience).

CD4+CD25- T-lymphocytes (1 106/well), collected using a CD4+CD25+ Treg isolation kit (Miltenyi Biotec), were pre-stimulated with plate-bound anti CD3 antibody (3 g/ml) and soluble anti CD28 antibody (2 g/ml) for two days. These activated T-lymphocytes were loaded on 0.2 106 BMMSCs or S-BMMSCs cultures with recombinant human TFG1 (2 ng/ml) (R&D Systems) and recombinant mouse IL2 (2 ng/ml) (R&D Systems). For Th17 induction, recombinant human TFG1 (2 ng/ml) and recombinant mouse IL6 (50 ng/ml) (Biolegend, San Diego, CA, USA) were added. After three days, cells in suspension were collected and stained with anti CD4-PerCP, anti CD8a-FITC, anti CD25-APC antibodies (each 1 g) for 45 minutes on ice under dark conditions. The cells were then stained with anti Foxp3-PE antibody (1 g) using a Foxp3 staining buffer kit (eBioscience) for cell fixation and permeabilization. For Th17, cells in suspension were stained with anti CD4-FITC (1g, Biolegend) for 45 minutes on ice under dark conditions followed by intercellular staining with anti-IL 17 antibody (1g, Biolegend) using a Foxp3 staining buffer kit. The cells were analyzed on FACSCalibur.

Under general anesthesia, C3H/HeJ-derived BMMSCs, S-BMMSCs, L-NMMA pre-treated BMMSCs (1 mM for five days), or CD34+/CD73+ double sorted cells (0.1 106 cells/10 g body weight) were infused into MRL/lpr mice via the tail vein at 10 weeks of age (n = 6 each group). In the control group, MRL/lpr mice received PBS (n = 5). All mice were sacrificed at two weeks post transplantation for further analysis. The protein concentration in urine was measured using a Bio-Rad Protein Assay (Bio-Rad, Hercules, CA, USA).

Peripheral blood serum samples were collected from mice. Autoantibodies, sRANKL and CTX were analyzed by ELISA using commercially available kits (anti-dsDNA antibodies and ANA; alpha diagnostics, albumin and sRANKL; R&D Systems, CTX; Nordic Bioscience Diagnostics, Herlev, Rigion Hovedstaden, Denmark) according to their manufactures' instructions. The results were averaged in each group. The intra-group differences were calculated between the mean values.

To detect Tregs, peripheral blood mononuclear cells (PBMNCs) (1 106) were treated with PerCP-conjugated anti-CD4, FITC-conjugated anti-CD8a, APC-conjugated anti-CD25 antibodies, and stained with R-PE-conjugated anti-Foxp3 antibody using a Foxp3 staining buffer kit (eBioscience). To measure Th17 cells, PBMNCs (1 106) were incubated with PerCP-conjugated anti-CD4, FITC-conjugated anti-CD8a, followed by treatment with R-PE-conjugated anti-IL-17 and APC-conjugated anti-IFN antibodies using a Foxp3 staining buffer kit. The cells were then analyzed on FACSCalibur .

Student's t-test was used to analyze statistical difference. P values less than 0.05 were considered significant.

To determine whether a subset of BMMSCs remain in culture suspension, ANCs (15 106 cells) from bone marrow were plated onto regular plastic culture dishes for two days and all non-attached cells were subsequently transplanted into immunocompromised mice subcutaneously using HA/TCP as a carrier. At eight weeks post-transplantation, newly formed bone was identified in the transplants by H & E staining (Figure 1A), suggesting that the BMMSC culture suspension may contain cells with a capacity to differentiate into bone forming cells. In vitro studies indicated that ECM produced by culture-expanded BMMSCs (BMMSC-ECM) could capture higher numbers of CFU-Fs when compared to plastic cultures [see Additional file 1, Figure S1] [28]. Thus, we collected culture supernatant with floating cells at two days post CFU-F culture and re-loaded it onto BMMSC-ECM-coated dishes (Figure 1B). A subset of BMMSCs in the suspension (S-BMMSCs) was able to adhere to the BMMSC-ECM and form CFU-F (Figure 1B), at a lower incidence compared to the number of CFU-F generated from regular BMMSCs (Figure 1C). In order to characterize the stem cell properties of S-BMMSCs, we collected SSEA4-positive S-BMMSCs and assessed their proliferation rate by BrdU incorporation. We found that S-BMMSCs had a significantly elevated BrdU uptake rate compared to regular BMMSCs (Figure 1D). In addition, we used a continuous cell culture assay to indicate that SSEA4-positive S-BMMSCs acquired a significantly increased number of population doublings (Figure 1E). These data imply that S-BMMSCs are distinct from regular BMMSCs in terms of attachment, proliferation, and self-renewal.

Figure 1. Identification of suspension BMMSCs (S-BMMSCs). (A) Hypothetical model indicates that bone marrow all nucleated cells (ANCs) were seeded at 15 106 into 100 mm culture dishes and incubated for two days at 37C with 5% CO2, and subsequently non-attached cells from culture suspension were transplanted into immunocompromised mice subcutaneously using hydroxyapatite tricalcium phosphate (HA) as a carrier for eight weeks. Newly formed bone (B) by osteoblasts (arrow heads) and associated connective tissue (C) were detected in this non-attached cell transplants by H & E staining. Bar = 100 m. (B) Hypothetical model of isolating S-BMMSCs. BMMSCs usually attach on culture dishes within two days; however, a small portion of BMMSCs in ANCs failed to attach to the dishes and remained in the suspension. The suspensions containing putative non-attached BMMSCs were collected and transferred to the extracellular matrix (ECM) coated dish with generating single colony clusters (CFU-F). These ECM-attached BMMSCs (S-BMMSCs) were sub-cultured on regular plastic culture dishes for additional experiments. (C) The number of plastic attached CFU-F from ANCs (1.5 106 cells) is more than seven-fold higher than that derived from BMMSC-ECM adherent S-BMMSCs. (D) Proliferation rates of S-BMMSCs and BMMSCs were assessed by BrdU incorporation for 24 hours. The percentage of positive cells is significantly increased in S-BMMSCs when compared to BMMSCs. (E) S-BMMSCs exhibit a significant increase in population doublings when compared to BMMSCs. The results are representative of five independent experiments. Scale bars = 50 m. ***P <0.001. The graph bar represents mean SD. BMMSCs, bone marrow mesenchymal stem cells; BrdU, bromodeoxyuridine; S-BMMSCs, BMMSCs in suspension; SD, standard deviation.

To examine the multipotent differentiation potential, we showed that S-BMMSCs are analogous to BMMSCs in their expression of alkaline phosphatase (ALP), mineralized nodule accumulation under the osteogenic inductive cultures, and bone regeneration when transplanted into immunocompromised mice using HA/TCP as a carrier (Figures 2A and 2B). Furthermore, we showed that S-BMMSCs were similar to regular BMMSCs in forming Oil red-O positive fat cells under adipogenic inductive conditions, which was associated with expression of the adipogenic genes, peroxisome proliferator-activated receptor gamma 2 (ppar2) and lipoprotein lipase (lpl) (Figures 2C and 2D). Parallel studies showed a similar capacity between S-BMMSCs and regular BMMSCs to differentiate into chondrocytes under chondrogenic inductive conditions, associated with the expression of proteoglycan, trichrome positive collagen, and type II collagen (Figure 2E). Collectively, these data confirm that S-BMMSCs are a subset of BMMSCs.

Figure 2. Multipotent differentiation of S-BMMSCs. (A) Alizarin Red S and alkaline phosphatase (ALP) staining showed that S-BMMSCs were similar to regular BMMSCs in osteogenic differentiation in vitro. (B) S-BMMSCs or regular BMMSCs (4 106 cells/transplant) were transplanted into immunocompromised mice using HA/TCP (HA) as a carrier for eight weeks. Bone formation was detected in S-BMMSC and BMMSC transplants, evidenced by H & E staining. HA, hydroxyapatite tricalcium phosphate; B, bone; M, bone marrow; CT, connective tissue. Bar = 50 m. (C-D) S-BMMSCs are capable of forming Oil Red O positive cells (C) and expression of ppar2 and lpl mRNA as seen in regular BMMSCs (D). Glyceraldehyde 3-phosphate dehydrogenase (gapdh) was used as an internal control. The results are representative of five independent experiments. Scale bars = 100 m. (E) Chondrogenic differentiation was assessed by Alcian blue staining for acidic sulfated mucosubstances, Pollak's Trichrome staining for collagen, and immunohistochemical staining for collagen type II. S-BMMSCs were able to differentiate into chondrocytes as observed in regular BMMSCs. Bar = 50 m. The results are representative of three independent experiments. The graph bar represents mean SD. BMMSCs, bone marrow mesenchymal stem cells; S-BMMSCs, BMMSCs in suspension; SD, standard deviation.

By flow cytometric analysis, S-BMMSCs expressed mesenchymal stem cell markers at the same level as regular BMMSCs (Figure 3A). Interestingly, 23.4% of S-BMMSCs expressed CD34, a hematopoietic stem cell (HSC) and endothelial cell marker, whereas 0.2% of BMMSCs expressed CD34 (Figure 3A). BMMSCs (21.4%) and S-BMMSCs (31.2%) expressed CD45, another hematopoietic marker, at passage 2 (Figure 3A). Both BMMSCs and S-BMMSCs were negative to CD11b antibody staining (data not shown), excluding the possibility that S-BMMSCs are derived from monocyte/macrophage lineage cells. Importantly, CD34+ S-BMMSCs co-expressed BMMSC-associated markers CD73 or Octamer-4 (Oct4), as evidenced by flow cytometric analysis (Figure 3B). Western blot analysis confirmed that S-BMMSCs expressed CD34, CD73, and CD105 (Figure 3C), and regular BMMSCs expressed CD73 and CD105 but lacked CD34 expression (Figure 3C). Whole bone marrow cells (BMC) were used as positive control. S-BMMSCs also showed a continued expression of CD34 from passage one to five; however, the expression levels appear reduced after passage three (Figure 3D). In order to further verify CD34 expression in S-BMMSCs, immunocytostaining analyses were performed to show co-expression of CD34 with mesenchymal markers CD73 (Figure 3E) in contrast to regular BMMSCs that were negative for anti-CD34 antibody staining (Figure 3E).

Figure 3. S-BMMSCs express CD34. (A) Flow cytometric analysis showed that regular BMMSCs fail to express CD34, but are positive for CD45 antibody staining (21.4%). However, S-BMMSCs express both CD34 (23.4%) and CD45 (31.2%). (B) Flow cytometric analysis also showed that CD34+ S-BMMSCs were positive for anti CD73 (13.8%) and Oct4 (13.4%) antibody staining. IgG isotype staining groups were used as negative controls. (C, D) Western blot analysis indicated that S-BMMSCs express CD34 and mesenchymal surface molecules CD73 and CD105. In contrast, regular BMMSCs only express CD73 and CD105 (C). S-BMMSCs express CD34 at passage one to five (D). -actin was used as a sample loading control. BMC, whole bone marrow ANC. (E) Immunocytostaining confirmed that S-BMMSCs are double positive for CD34/CD73 (triangle). Regular BMMSCs are negative for CD34 antibody staining and only positive for anti CD73 antibody staining. Bar = 100 m. (F) Both BMMSCs and S-BMMSCs failed to differentiate into hematopoietic lineage under hematopoietic inductive conditions with EPO (upper panel) or without EPO (lower panel). Whole bone marrow cells and lineage negative cells were used as positive (yellow arrowheads) control. Bar = 100 m. ANC, all nucleated cells; BMMSCs, bone marrow mesenchymal stem cells; EPO, erythropoietin; S-BMMSCs, BMMSCs in suspension.

It is generally believed that CD34 expression is associated with HSCs and endothelial populations. HSCs can differentiate into all the blood cell lineages and rescue lethally irradiated subjects. Thus, we cultured S-BMMSCs and regular BMMSCs in hematopoietic differentiation medium and determined that these mesenchymal cells failed to differentiate into a hematopoietic cell lineage compare to bone marrow cells that formed myeloid and erythroid colony forming clusters (Figure 3F). In addition, CD45-CD34-BMMSCs showed an ability similar to that of S-BMMSCs in colony forming and expressing surface marker as MSC [see Additional file 1, Figure S2]. Furthermore, we infused S-BMMSCs systemically to rescue lethally irradiated mice and found that S-BMMSCs, but not regular BMMSCs, could extend the lifespan of lethally irradiated mice [see Additional file 1, Figure S3]. However, S-BMMSCs failed to rescue lethally irradiated mice, as shown in the whole bone marrow cell group [see Additional file 1, Figure S3]. These data provid further evidence that CD34 expression in S-BMMSCs is not due to HSC contamination.

Since the immunomodulation property of MSCs is one of the essential factors for MSC characterization, allogenic S-BMMSC transplantation into MRL/lpr mice was performed (Figure 4A). Two weeks after transplantation, both S-BMMSCs and BMMSCs were capable of ameliorating SLE-induced glomerular basal membrane disorder (yellow arrow, Figure 4B) and reducing the urine protein level (Figure 4C). It appeared that S-BMMSCs were superior compared to BMMSCs in terms of reducing the overall urine protein levels (Figure 4C). As expected, MRL/lpr mice showed remarkably increased levels of autoantibodies, including anti-double strand DNA (dsDNA) IgG and IgM antibodies (Figures 4D and 4E) and anti-nuclear antibody (ANA; Figure 4F) in the peripheral blood serum. Although S-BMMSC and BMMSC infusion showed significantly decreased serum levels of anti-dsDNA IgG, IgM antibodies and ANA in peripheral blood (Figures 4D-F), S-BMMSCs showed a superior therapeutic effect in reducing anti-dsDNA IgG antibody and ANA levels when compared to BMMSCs (Figures 4D and 4F). Additionally, decreased serum albumin levels in MRL/lpr mice were recovered by S-BMMSC and BMMSC infusion (Figure 4G) but S-BMMSC treatment resulted in a more significant recovery than BMMSC treatment (Figure 4G). Next, flow cytometric analysis revealed that S-BMMSC showed more effectiveness in recovering the decreased level of CD4+CD25+Foxp3+ Tregs and increased the number of CD4+IL17+IFN- T-lymphocytes (Th17 cells) in peripheral blood when compared to BMMSCs (Figures 4H, 4I). In addition, highly passaged mouse S-BMMSCs failed to inhibit Th17 differentiation in vitro (data not shown) suggesting that mouse S-BMMSCs probably lose their immunomodulation property under long culture expansion.

Figure 4. S-BMMSCs showed superior therapeutic effect on SLE-like MRL/lpr mice. (A) Schema of BMMSC transplantation into MRL/lpr mice. (B) S-BMMSC and BMMSC treatment recover basal membrane disorder and mesangium cell over-growth in glomerular (G) (H&E staining). (C) S-BMMSC and BMMSC transplantation could reduce urine protein levels at two weeks post transplantation compared to the MRL/lpr group. S-BMMSCs offered a more significant reduction compared to BMMSCs. (D, E) The serum levels of anti-dsDNA IgG and IgM antibodies were significantly increased in MRL/lpr mice compared to controls (C3H). S-BMMSC and BMMSC treatments could reduce antibody levels but S-BMMSCs showed a superior treatment effect than BMMSC in reducing anti-dsDNA IgG antibody (D). (F) S-BMMSC and BMMSC treatments could reduce increased levels of anti nuclear antibody (ANA) in MRL/lpr mice. S-BMMSC showed a better effect in ANA reduction compared to BMMSC. (G) S-BMMSC and BMMSC treatments could increase the albumin level in MRL/lpr mice, which was decreased in controls. S-BMMSC treatments were more effective in elevating the albumin level compared to BMMSC treatment. (H) Flow cytometric analysis showed a reduced number of Tregs in MRL/lpr peripheral blood compared to control. BMMSC and S-BMMSC treatments elevated the number of Tregs. S-BMMSCs induced a more significant elevation of the Tregs level than BMMSCs. (I) Flow cytometric analysis showed an increased number of Th17 in MRL/lpr mice peripheral blood compared to control. Th17 were markedly decreased in BMMSC and S-BMMSC treated groups. S-BMMSC treatment induced a more significant reduction of Th17 cells than treatment with BMMSCs. *P <0.05; ** P <0.01; ***P <0.001. The graph bar represents mean SD. BMMSCs, bone marrow mesenchymal stem cells; Ig, immunoglobulin; S-BMMSCs, BMMSCs in suspension; SD, standard deviation; SLE, systemic lupus erythematosus; Tregs, regulatory T cells.

Furthermore, we showed that S-BMMSCs were superior to BMMSCs in terms of reducing increased numbers of tartrate-resistant acid phosphatase (TRAP) positive osteoclasts in the distal femur epiphysis of MRL/lpr mice [see Additional file 1, Figure S4A], elevated serum levels of sRANKL, a critical factor for osteoclastogenesis [see Additional file 1, Figure S4B] and bone resorption marker CTX [see Additional file 1, Figure S4C]. These data suggest that S-BMMSCs exhibit a superior therapeutic effect for SLE disorders compared to regular BMMSCs.

Recently, immunomodulatory properties were identified as an important stem cell characteristic of BMMSCs, leading to the utilization of systemic infused BMMSCs to treat a variety of immune diseases [19-21]. Here, we found that S-BMMSCs exhibited a significantly increased capacity for NO production compared to regular BMMSCs when treated with IFN and IL-1 (Figure 5A). It is known that NO plays a critical role in BMMSC-mediated immunosuppression [see Additional file 1, Figures S5A-F] [29]. Therefore, we assessed the functional role of high NO production in S-BMMSC-associated immunomodulatory properties. Spleen (SP) cells were activated by anti-CD3 and anti-CD28 antibodies for three days and then co-cultured with S-BMMSCs or regular BMMSCs in the presence of the general NOS inhibitor, L-NMMA or the iNOS inhibitor, 1400 W, using a Transwell culture system. The efficacy of L-NMMA and 1400 W to inhibit NO production in BMMSCs was verified [see Additional file 1, Figures S6A and 6B]. Although both S-BMMSCs and regular BMMSCs were capable of inhibiting cell viability of activated SP cells, S-BMMSCs showed a marked inhibition of SP cell viability over that of regular BMMSCs (Figure 5B). Moreover, both BMMSCs and S-BMMSCs induced SP cell apoptosis (Figure 5C). However, S-BMMSCs showed an elevated capacity in inducing activated SP cell apoptosis compared to regular BMMSCs (Figure 5C). Interestingly, when L-NMMA and 1400 W were added to the cultures, the number of apoptotic SP cells was significantly reduced in both S-BMMSC and regular BMMSC groups (Figure 5D and 5E). These in vitro experimental data suggested that NO production is an essential factor for BMMSC-mediated immunomodulation.

Figure 5. S-BMMSCs show up-regulated immunomodulatory properties through nitric oxide (NO) production. (A) NO levels in the supernatant of S-BMMSC and BMMSC culture were significantly higher in the INF-/IL-1 treated S-BMMSC group than in BMMSCs. (B-C) S-BMMSCs showed a significant reduction in the cell viability of activated SP cells compared to the cells cultured without BMMSCs (SP cell) and with BMMSCs (B). Both BMMSCs and S-BMMSCs showed a significantly increased rate of SP cell apoptosis compared to the SP cell only group but S-BMMSCs could induce higher SP cell apoptosis (C). (D-E) The induction of SP cell apoptosis by BMMSCs or S-BMMSCs was abolished in general NOS inhibitor L-NMMA-treated (D) and iNOS specific inhibitor 1400 W-treated (E) group. (F-H) Activated CD4+CD25- T-cells and S-BMMSCs or BMMSCs were co-cultured in the presence of TGF1 and IL-2 with or without NOS inhibitor for three days. The floating cells were stained for CD4+CD25+FoxP3+ regulatory T cells (Tregs). Both BMMSCs and S-BMMSC up-regulated Tregs but S-BMMSCs showed a significant effect in up-regulating Tregs. (F). Interestingly, L-NMMA and 1400 W treatments resulted in an abolishing of S-BMMSC-induced up-regulation of Tregs (G, H). (I) BMMSCs and S-BMMSCs could inhibit Th17 differentiation in vitro. S-BMMSC could inhibit it more effectively. (J, K) L-NMMA (J) or 1400 W (K) could abolish the inhibition of Th17 differentiation by BMMSCs or S-BMMSCs. The results are representative of at least three independent experiments. *P <0.05; **P <0.01; ***P <0.001. The graph bar represents mean SD. BMMSCs, bone marrow mesenchymal stem cells; iNOS, inducible nitric oxide synthase; L-NMMA, L-NG-monomethyl-arginine; NOS, nitric oxide synthase; S-BMMSCs, BMMSCs in suspension; SD, standard deviation; SP, spleen; Tregs, regulatory T cells.

Since up-regulation of CD4+CD25+Foxp3+ Tregs is required for immunotolerance [30], we tested Tregs up-regulation property of S-BMMSCs and BMMSCs in an in vitro co-culture system. When nave-T-cells were co-cultured with S-BMMSCs or regular BMMSCs in the presence of IL-2 and TGF-1, S-BMMSCs showed a significant up-regulation of Treg levels compared to regular BMMSCs (Figure 5F). Both L-NMMA and 1400 W were able to inhibit BMMSC- and S-BMMSC-induced up-regulation of Tregs, as shown by flow cytometric analysis (Figures 5G and 5H). Interestingly, the regulation effect on Tregs was more significant in the S-BMMSC group compared to the BMMSC group (Figure 5G and 5H). Moreover, both BMMSCs and S-BMMSCs could inhibit differentiation of Th17 in vitro, with a more prominent effect observed with S-BMMSC (Figure 5I). These inhibitions of Th17 differentiation were abolished by L-NMMA (Figure 5J) and 1400 W (Figure 5K). These data further verified the functional role of NO in S-BMMSC-induced immunomodulatory effect.

In order to identify whether there are functional endogenous S-BMMSCs, we used fluorescence activated cell sorting (FACS) to isolate CD34 and CD73 double-positive cells from bone marrow ANCs which resulted in the recovery of 3.77% double-positive cells [see Additional file 1, Figure S7A]. These CD34 and CD73 double-positive cells exhibited mesenchymal stem cell characteristics, including the capacity to form single colony clusters of fibroblast-like cells [see Additional file 1, Figure S7B], which could differentiate into osteogenic cells in vitro [see Additional file 1, Figure S7C]. These data indicated the feasibility of this approach to isolate S-BMMSC-like cells directly from bone marrow. We found that CD34+/CD73+ BMMSCs were analogous to S-BMMSCs in terms of having higher levels of NO production when compared to regular BMMSCs [see Additional file 1, Figure S7D] and reducing levels of urine protein, serum anti-dsDNA IgG and IgM antibodies in MRL/lpr mice (data not shown). These data indicate that endogenous S-BMMSCs could be isolated from bone marrow using CD34 and CD73 antibodies double sorting.

Additionally, we used the same BMMSC-ECM isolation approach to reveal the existence of human S-BMMSCs (hS-BMMSC) that possess stem cell properties including multipotent differentiation and self-renewal but lack expression of CD34 (data not shown). hS-BMMSCs showed elevated NO and kynurenine production which indicate high indoleamine 2,3-dioxygenase (IDO) activity when compared to regular BMMSCs [see Additional file 1, Figures S8A-C]. Thus, when activated T cells were co-cultured with hS-BMMSCs, AnnexinV-7 aminoactinomycinD (7AAD) double positive apoptotic SP cells were significantly elevated compared to BMMSCs [see Additional file 1, Figure S8D].

Adherent BMMSCs are able to proliferate and undergo osteogenic differentiation, providing the first evidence of CFU-F as precursors for osteoblastic lineage [25]. For over a few decades, the adherent CFU-F assay has been used as an effective approach to identify and select BMMSCs. In the current study, we showed that the adherent CFU-F assay collects the majority of clonogenic BMMSCs, but a subpopulation of BMMSCs is sustained in the culture suspension. This newly identified subpopulation of BMMSCs may be lost in the standard CFU-F assay for BMMSC isolation.

Due to the heterogeneity of the BMMSCs, there is no single, unique marker allowing for BMMSC isolation, rather an array of cell molecules are utilized to profile BMMSCs. It is widely accepted that BMMSCs express SH2 (CD105), SH3/SH4 (CD73), integrin 1 (CD29), CD44, Thy-1 (CD90), CD71, vascular cell adhesion molecule-1 (CD106), activated leukocyte cell adhesion molecule (CD166), STRO-1, GD2, and melanoma cell adhesion molecule (CD146) [5,7-13,31,32]. Nevertheless, it is believed that BMMSCs lack expression of hematopoietic surface molecules including CD34, integrin M (CD11b) and CD14. However, recent studies have implied that mouse BMMSCs might express the hematopoietic surface molecules, CD45 [28] and CD34 [33]. To ensure purity of S-BMMSCs, we used immune FACS to collect SSEA4+ S-BMMSCs for proliferation and differentiation assays in this study. Interestingly, previous experimental evidence appeared to support a notion that HSCs are capable of differentiating into mesenchymal cells [34] and osteoblastic lineage in vivo [35]. Thus, it is critical to clarify whether BMMSCs express hematopoietic associated surface molecules.

In this study, we have identified a novel subset of S-BMMSCs that failed to form adherent CFU-F in regular culture dishes, but were capable of adhering on mesenchymal stem cell-produced ECM and differentiating into osteoblasts, adipocytes and chondrocytes from both C3H/HeJ and C57BL/6J mice. S-BMMSCs co-expressed the HSC marker CD34 with the MSC markers CD73 and Oct4, excluding the potential of HSC contamination. Furthermore, S-BMMSCs were found to be distinct from HSC because they lacked the ability to differentiate into hematopoietic cell lineages in vitro and failed to rescue lethally-irradiated mice. The mechanism that may contribute to the up-regulated immunomodulatory function was associated with high NO production in S-BMMSCs and a NO-driven high Tregs level [36]. NO is a gaseous biological mediator with important roles in affecting T cell function [37].

This is the reason that S-BMMSCs showed a superior therapeutic effect in treating SLE mice.

One successful approach is to isolate cells that express specific molecules on their cell surfaces using monoclonal antibodies and cell sorting technologies. Enriched populations of BMMSCs have been isolated from human bone marrow aspirates using a STRO-1 monoclonal antibody in conjunction with antibodies against VCAM-1/CD106 [32], CD146 [11], low affinity nerve growth factor receptor/CD271, PDGR-R, EGF-R and IGF-1-R [38], fibroblast cell marker/D7-Fib [39] and integrin alpha 1/CD49a [40]. A more recent study has also identified molecules co-expressed by a CD271+ mesenchymal stem cell population including platelet derived growth factor receptor- (CD140b), human epidermal growth factor 2/ErbB2 (CD340) and frizzled-9 (CD349) [41]. Further cell separation based upon multi-parameter FACS identified a population of proposed mouse mesenchymal precursors with the composite phenotype Lin-CD45-CD31-Sca-1+[42]. Another recent study also identified and characterized an alternate population of primitive mesenchymal cells derived from adult mouse bone marrow, based upon their expression of the SSEA-1 [43]. All approaches used for BMMSC purification and isolation will undergo ex vivo expansion to enrich cell numbers for tissue regeneration or systemic therapies by plastic adherent assay. In addition to identifying a novel sub-population of BMMSCs that possess enhanced immunomodulatory properties when compared to regular BMMSCs, we showed that CD34+/CD73+ BMMSCs could be isolated directly from whole bone marrow and that CD34+/CD73+ BMMSCs are endogenous S-BMMSCs with higher NO production, and are superior in treating SLE-like mice when compared to regular BMMSCs.

Recently, non-adherent bone marrow cells (NA-BMCs) were identified [44,45]. The NA-BMSCs could be expanded in suspension and gave rise to multiple mesenchymal phenotypes, including osteoblasts, chondrocytes, and adipocytes in vitro, suggesting the presence of non-adherent BMMSCs in primary CFU-F cultures [45]. Although it has been reported that the NA-BMCs can rescue lethally-irradiated mouse recipients, our data indicated that S-BMMSCs only showed improved survival lifespan without a complete rescue of lethally-irradiated mice, compared to whole bone marrow transplantation. While the mechanism of S-BMMSC-mediated lifespan extension in lethally-irradiated mice is unknown, it is possible that S-BMMSCs have a more active interplay with hematopoietic cells than regular BMMSCs. It has been reported that granulocyte colony stimulating factor might promote BMMSCs into the circulation in humans [46], suggesting that non-attached BMMSCs may exist in vivo for specific functional needs. Added evidence indicated that osteocalcin-positive cells in circulation were able to differentiate into osteoblastic cells when cultured in the presence of TGF [47]. However, it is unknown whether S-BMMSCs are associated with circulating mesenchymal stem cells initially identified in mice, and this is very rare in humans.

A new subset of BMMSCs (S-BMMSCs) which failed to adhere to culture dishes possesses similar stem cell properties as those seen in BMMSCs, including CFU-F, stem cell markers, osto-, adipo-, and chondro-genic differentiation. However, S-BMMSC showed distinct features including expression of CD34 and a superior immunomodulation property through high NO production. These findings suggest that it is feasible to improve immunotherapy by identifying new subset BMMSCs.

7AAD: 7aminoactinomycineD; ALP: alkaline phosphatase; ANCs: all nucleated cells; BMMSCs: bone marrow mesenchymal stem cells; BrdU: bromodeoxyuridine; CFU-F: colony forming unit fibroblastic; CTX: C-terminal telopeptides of type I collagen; DAPI: 4', 6-diamidino-2-phenylindole; (D)MEM: (Dulbecco's) modified Eagle's medium; ECM: extracellular cell matrix; ELISA: enzyme-linked immunosorbent assay; EPO: erythropoietin; FACS: fluorescence-activated cell sorting; FBS: fetal bovine serums; FITC: fluorescein isothiocyanate; H & E: hematoxylin and eosin; HA/TCP: hydroxyapatite/tricalcium phosphate; HSC: hematopoietic stem cell; IDO: indoleamine 2,3-dioxygenase; IFN: interferon gamma; IgG: immunoglobulin G; IL-1: interleukin-1 beta; iNOS: inducible NOS; L-NMMA: L-NG-monomethyl-arginine; lpl: lipoprotein lipase; NF-B: nuclear factor-kappa B; NOS: nitric oxide synthase; PBMNCs: peripheral blood mononuclear cells; PBS: phosphate-buffered saline; PE: phycoerythrin; PFA: paraformaldehyde; ppar2: peroxisome proliferator-activated receptor gamma 2; RT-PCR: reverse transcriptase polymerase chain reaction; S-BMMSC: BMMSCs in suspension; SLE: systemic lupus erythematosus; SP: spleen; sRANKL: soluble runt-related NF-B ligand; SSEA: stage-specific embryonic antigen; TGF: transforming growth factor beta; Th17: T helper 17 cells; TRAP: tartrate-resistant acid phosphatase; Tregs: regulatory T cells.

The authors declare that they have no competing interests.

KA and YY: contributions to conception and design of experiments, acquisition of data, analysis and interpretation of data. TY, CC, LT, and YJ: contributions to acquisition of data, analysis and interpretation of data. XC and SG: contributions to drafting the manuscript and revising critically. SS: contributions to conception and design, drafting the manuscript, and giving final approval of the version to be published. All authors have read and approved the manuscript for publication.

We thank Dr. Tao Cai from NIH for discussions and critical reading of the manuscript. This work was supported by grants from the National Institute of Dental and Craniofacial Research, National Institutes of Health, Department of Health and Human Services (R01DE017449 and R01 DE019932 to S.S.).

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WHAT ARE STEM CELLS?

Stem cells are super unique in that they have the ability to go through numerous cycles and cell divisions while maintaining the undifferentiated state. Primarily, stem cells are capable of self-renewal and can transform themselves into other cell types of the same tissue. Their crucial role is to replenish dying cells and regenerate damaged tissue. Stem cells have a limited life expectation due to environmental and intrinsic stress factors. Because their life is endangered by internal and external stresses, stem cells have to be protected and supported to delay preliminary aging. In aged bodies, the number and activity of stem cells in reduced.

Until several years ago, the tart, unappealing breed of the Swiss-grown Uttwiler Sptlauber apples, did not seem to offer anything of value. That was until Swiss scientists discovered the unusual longevity of the stem cells that kept these apples alive months after other apples shriveled and fell off their trees. In the rural region of Switzerland, home of these magical apples, it was discovered that when the unpicked apples or tree bark was punctured, Swiss Apple trees have the ability to heal themselves and last longer than other varieties. What was the secret to these apples prolonged lives?

These scientists got to work to find out. What they revealed was that apple stem cells work just like human stem cells, they work to maintain and repair skin tissue. The main difference is that unlike apple stem cells, skin stem cells do not have a long lifespan, and once they begin depleting, the signs of aging start kicking in (in the forms of loose skin, wrinkles, the works). Time to harness these apple stem cells into anti aging skin care! Not so fast. As mentioned, Uttwiler Sptlauber apples are now very rare to the point that the extract can no longer be made in a traditional fashion. The great news is that scientists developed a plant cell culture technology, which involves breeding the apple stem cells in the laboratory.

Human stem cells on the skins epidermis are crucial to replenish the skin cells that are lost due to continual shedding. When epidermal stem cells are depleted, the number of lost or dying skin cells outpaces the production of new cells, threatening the skins health and appearance.

Like humans, plants also have stem cells. Enter the stem cells of the Uttwiler Sptlauber apple tree, whose fruit demonstrates an exceptionally long shelf-life. How can these promising stem cells help our skin?

Studies show that apple stem cells boosts production of human stem cells, protect the cell from stress, and decreases wrinkles. How does it work? The internal fluid of these plant cells contains components that help to protect and maintain human stem cells. Apple stem cells contain metabolites to ensure longevity as the tree is known for the fact that its fruit keep well over long periods of time.

When tested in vitro, the apple stem cell extract was applied to human stem cells from umbilical cords and was found to increase the number of the stem cells in culture. Furthermore, the addition of the ingredient to umbilical cord stem cells appeared to protect the cells from environmental stress such as UV light.

Apple stem cells do not have to be fed through the umbilical cord to benefit our skin! The extract derived from the plant cell culture technology is being harnessed as an active ingredient in anti aging skincare products. When delivered into the skin nanotechnology, the apple stem cells provide more dramatic results in decreasing lines, wrinkles, and environmental damage.

Currently referred to as The Fountain of Youth, intense research has proved that with just a concentration level of 0.1 % of the PhytoCellTec (apple stem cell extract) could proliferate a wealth of human stem cells by an astounding 80%! These wonder cells work super efficiently and are completely safe. Of the numerous benefits of apple stems cells, the most predominant include:

Skin Layers

Skin Cell Activity Before

Skin Cell Activity After 1 Hour

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Apple Stem Cells - Sonya Dakar Skin Clinic

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Stem cells play many important roles in our bodies from embryonic development through adulthood.

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Stem cells can now be created from differentiated cells.

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Learn about some different types of stem cells and their potential for treating diseases.

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Send activating signals to stem cells and watch them get to work!

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Stem cell therapies have been curing diseases for decades.

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Researchers are working on new ways to use stem cells in medicine.

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New developments in research are changing the conversation about stem cells.

Supported by a Science Education Partnership Award (SEPA) Grant No. R25RR023288 from the National Center for Research Resources, a component of the NIH. The contents provided here are solely the responsibility of the authors and do not necessarily represent the official views of NIH.

APA format: Genetic Science Learning Center (2014, June 22) Stem Cells. Learn.Genetics. Retrieved September 25, 2015, from http://learn.genetics.utah.edu/content/stemcells/ MLA format: Genetic Science Learning Center. "Stem Cells." Learn.Genetics 25 September 2015 <http://learn.genetics.utah.edu/content/stemcells/> Chicago format: Genetic Science Learning Center, "Stem Cells," Learn.Genetics, 22 June 2014, <http://learn.genetics.utah.edu/content/stemcells/> (25 September 2015)

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Stem Cells - Learn Genetics

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An even more advanced technique for solving inherited hair loss in the future is gene therapy. Gene therapy is the process of changing genes of existing cells in the body, and thereby altering cell function. It is a medical treatment still in its infancy, and there have only been a few recent examples of gene therapy working. But it is a potential future baldness treatment method worth exploring.

Gene therapy requires learning how an inherited medical condition occurs at the DNA molecule level, and then going in and fixing it. With gene therapy, the hair follicles with DHT-sensitive cells could be changed into follicles with DHT-resistant cells, and the hair follicles would continue to grow new hairs for a lifetime. But gene therapy involves several very difficult to achieve steps. The first step is figuring out which of the tens of thousands of genes on strands of DNA are involved in the characteristic to be altered, and the second step is figuring out how exactly the target genes are to be changed, so that they give instructions for making the slightly different proteins that will achieve the desired effect. The third step is getting the target cells in the living organism to incorporate the new and improved genes as replacements for the old undesirable genes.

Gene Identification:

Figuring out which genes are involved in the genetic condition to be changed is not an easy task. Despite all the advances in mapping genes in recent years, we are still very far away from knowing what most of these genes do. We certainly do not have a good understanding of all of the genes that affect the cycle of hair growth, and especially which genes are responsible for inherited hair loss. It is most likely that several genes are responsible for making proteins that cause certain hair follicles to be DHT-sensitive.

Future studies will likely involve comparing the genes and resulting proteins in different follicles from a single individual. In a given individual with androgenetic alopecia (pattern hair loss), some hair follicle cells will express the characteristic of DHT-resistance (the follicles at the back of the scalp), while other hair follicles on the same person will express the characteristic of DHT-sensitivity (at the hairline, for example). Both follicles contain cells with identical DNA, but they express different characteristics. So identifying the responsible genes will be tricky. And even after we identify these genes, we have to figure out how to change them ever so slightly so they will make proteins that create DHT-resistant hair follicles. But scientists have been making progress in gene identification.

Modifying Genes:

In a paper presented in the January 30, 1998 issue of the journal "Science", researchers led by Angela Christiano, PhD identified a defect in a single gene responsible for a rare type of inherited baldness called generalized atrichia observed in a Pakistani family, in which affected individuals are born with infant hair that falls out and never grows back. Shortly after birth, affected individuals are completely hairless. The gene, called hairless, was mapped in humans to chromosome 8p21, and was the first example of a single gene defect being identified as a hair loss cause. Christiano was careful to point out that this was just a first step towards identifying genes that affect hair loss. (Science, January 30,1998, vol 279, No. 5351)

Later in the same year, in a paper presented in the September 11, 1998 issue of the "American Journal of Human Genetics", Christiano's team reported on members of a family of Irish Travelers who also exhibited congenital atrichia, in which affected individuals are born with infant hair that falls out and never grows back. Genetic analysis of the Irish Travelers revealed that a mutation of the hairless gene was again responsible for the hair loss condition, however the mutation was different from the one that resulted in hair loss in the Pakistani family.

In a paper reported in the November 25 1998 issue of "Cell", researchers led by Elaine Fuchs, PhD induced the formation of new hair follicles in mice that were genetically engineered to constantly produce a stabilized form of a protein called beta-catenin. Beta-catenin is a multi-functional protein, which signals a variety of cellular functions, but is normally quickly degraded within a cell after being produced. Researchers altered the mouse gene that contains instructions for making the beta-catenin protein in such a way that the beta-catenin produced was resistant to being broken down. The resulting accumulation of beta-catenin caused a massive growth of new hair follicles to grow in normal mouse skin, until there were hair follicles branching from existing hair follicles. Eventually the mice also developed hair follicle tumors as a result of over-expressing beta-catenin. (Fuchs, university of Chicago 1998) (Gat, Dermatology Focus Vol. 19, No. 2, Summer 2000).

In the October 1999 issue of "The Journal of Clinical Investigation", researchers led by Ronald Crystal MD forced resting hair follicles of mice into the growth phase by exposing cells to larger than normal quantities of a protein produced by the Sonic Hedgehog Gene (abbreviated Shh).

The papers presented by these three groups of genetic researchers reveal the complexity of the task of understanding the genetic basis for inherited hair loss, and reveal the monumental task of figuring out how to correct the condition at the molecular level. In the first case, Angela Christiano's team identified a gene that can cause total hair loss when mutated in either of two different ways. In the second example, the team led by Elaine Fuchs mutated a gene in such a way that it coded for the creation of a slightly different protein that caused massive new hair follicle creation. And the third example showed that increasing the exposure to a naturally occurring protein could signal hair follicles to shift from the resting phase into the growth phase. And while all of these genes and their respective proteins appear to play some role in hair follicles, they are also known to affect other cells and systems in the body. Genetics is very complicated.

But suppose that at some point in the future we develop an adequately complete understanding of how all the genes, and their respective proteins, affect inherited hair loss. And suppose that we can also determine how exactly we want to alter the genes so that the proteins they make result in hair follicles that are DHT-resistant, rather than DHT sensitive, but without causing unwanted side effects.

Changing Genes in Living Cells and Living Organisms:

The third challenge of gene therapy is delivering the new-and-improved genes to the target cells, and then to have those cells use the new genes to make the corresponding new proteins, and then to have the altered cells express the desired characteristic.

The correct target cells are critical to successful gene therapy. If mature cells are altered, the benefits of the gene therapy go away after those cells wear out and are replaced with new cells having the original DNA. For a long-lasting effect, stem cells are targeted. When successful, the altered stem cells will then create altered transient amplifying cells, which in turn will create altered specialized cells that will express the desired characteristics.

The most common altered gene-delivery method involves using crippled viruses to insert desired genes into the target cells. Outside of the laboratory, viruses are tiny organisms that infect cells by replacing some of the cell's DNA with virus DNA. After infection by a virus, a cell begin to make the proteins the virus DNA tells it to make, causing the expression of various diseases. Scientists use the virus infection mechanism to deliver desirable DNA.

First, they cripple the virus DNA so that it cannot reproduce or cause harmful effects, but is still able to insert new DNA into target cells. The desired genes are spliced onto to the virus DNA, and the viruses insert the new DNA into the target cells. The viruses can be injected directly to the location where the stem cells are, or the stem cells may be cultured in a laboratory, altered by viruses containing the new DNA, and then the altered stem cells can be placed back into the organism.

There are many areas of gene therapy that need refinement. Identifying genes, determining exactly how to change them to code for the desired proteins, avoiding an immune response when the viruses are injected directly into the organism, getting an adequate quantity of target cells to take up the altered DNA regardless of how it is delivered, and getting the cells to express the characteristics coded by the altered genes, once the new DNA is inserted, all need more work. But forward progress is being made.

Read more:
Gene Therapy - American Hair Loss Association

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James K. Adams, Professor of Biology, Dalton State College

Andrew D. Warren, Yale Peabody Museum of Natural History

mybutterflybugs

mybutterflybugs

Kim Davis, Mike Stangeland, and Andrew Warren, Butterflies of America

In the realm of genetic anomalies found in living organisms perhaps none is more visually striking than bilateral gynandromorphism, a condition where an animal or insect contains both male and female characteristics, evenly split, right down the middle. While cases have been reported in lobsters, crabs and even in birds, it seems butterflies and moths lucked out with the visual splendor of having both male and female wings as a result of the anomaly. For those interested in the science, heres a bit from Elise over at IFLScience:

In insects the mechanism is fairly well understood. A fly with XX chromosomes will be a female. However, an embryo that loses a Y chromosome still develops into what looks like an adult male, although it will be sterile. Its thought that bilateral gynandromorphism occurs when two sperm enter an egg. One of those sperm fuses with the nucleus of the egg and a female insect develops. The other sperm develops without another set of chromosomes within the same egg. Both a male and a female insect develop within the same body.

Above are some great examples of bilateral gynandromorphism, but follow the links above and below for many more. (via Live Science, The Endless Airshow, Butterflies of America, IFLScience)

See related posts on Colossal about butterflies, genetics.

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Spectacular Genetic Anomaly Results in Butterflies with ...

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Every December, thousands of physicians attend what is by far the largest anti-aging conference in the world: the A4M (American Academy of Anti-Aging Medicine) conference in Las Vegas, Nevada. I have attended many of these conferences, most recently in 2012 and 2013. I will report mainly on the 2013 conference, but will include a few relevant presentations made at the 2012 A4M conference.

Nathan Bryan, PhD, (Assistant Professor of Molecular Medicine, School of Medicine, University of Texas Health Science Center) is a nitric oxide expert. Nitric oxide is a short-lived signaling molecule composed of nitrogen and oxygen. Dr. Bryan pointed to three theories of aging, all of which he said are controlled by nitric oxide: telomere shortening, mitochondrial dysfunction, and loss of stem cell function.

Telomeres are the ends of chromosomes that shorten with age, causing cells to become inactive when the telomeres become too short. Nitric oxide synthases, a group of enzymes that catalyze the formation of nitric oxide, stimulate the activity of the enzyme that keeps telomeres from shortening in endothelial cells (cells lining blood vessels).1,2

Mitochondria are organelles in cells that produce energy. Nitric oxide stimulates the creation of new mitochondria, notably in heart muscle.3

Stem cells can prevent tissue aging by regenerating damaged and worn-out tissues. Dr. Bryan said that nitric oxide synthase is required to stimulate mobilization and differentiation of stem cells,4 and that older patients dont respond well to stem cell therapy due to reduced availability of nitric oxide.

In addition to these aging processes, reduced nitric oxide availability leads to insulin resistance.5 And with age, the endothelial cells lining blood vessels show a reduced capacity to produce the nitric oxide that causes blood vessels to dilateone of the symptoms of endothelial dysfunction.6

Endothelial dysfunction contributes to high blood pressure and atherosclerosis and precedes atherosclerosis years before the disease manifests.7 Endothelial dysfunction tends to occur in men at an earlier age than it occurs in women.8

Pomegranate protects cardiovascular health by augmenting nitric oxide, which supports the functioning of endothelial cells that line the arterial walls. Nitric oxide signals vascular smooth muscle to relax, thereby increasing blood flow through arteries and veins.

Scientists have known for some time that oxidized LDL (low-density lipoprotein) can reduce the expression of nitric oxide synthase, the enzyme that produces nitric oxide from an amino acid called arginine. Recently, they discovered that pomegranate juice enhances the bioactivity of nitric oxide synthase in endothelial cells. Furthermore, pomegranates antioxidant properties protect nitric oxide from oxidative destruction, thus augmenting its biological actions.9,10

An Italian study examined the role of pomegranate juice in nitric oxide synthase activity in artery sections that had already developed atherosclerosis. In these segments, blood forcing its way around atherosclerotic plaque buildup exerts significant stress on arterial walls. This stress reduces nitric oxide synthase expression and sets the stage for the formation of yet more plaque.

The researchers selected mice with a genetic predisposition to developing atherosclerosis. They put the mice in one of the groups on a high-fat diet, let arterial disease develop for six months, and then added pomegranate juice to the experimental groups drinking water for 24 weeks. The placebo group was given plain drinking water.11

Pomegranate not only increased the expression of nitric oxide synthase in both healthy and atherosclerotic blood vessels, but increased it the most in blood vessels with the most plaque buildup. The list below shows the increase in nitric oxide synthase expression that occurred in response to pomegranate:8

Pomegranates ability to increase nitric oxide synthase resulted in a significant reduction in atherosclerotic lesions.11

Mark C. Houston, MD, (Associate Clinical Professor of Medicine, Vanderbilt University School of Medicine, and Director of the Hypertension Institute, Saint Thomas Hospital and Health Services) said that high blood pressure is due to three stressors to the endothelial cells that line blood vessels: inflammation, oxidative stress, and immune dysfunction.

Dr. Houston said that endothelial dysfunction precedes high blood pressure by decades.12 Once high blood pressure develops, blood vessel disease gets worse, creating a vicious cycle.13 To the extent that inflammation is part of this vicious cycle, high blood pressure is an inflammatory disease.14

Dr. Houston described different methods of measuring blood pressure. Manual measurement of blood pressure in a medical office is the worst method. The white-coat response (anxiety in reaction to medical professionals) can result in an elevated blood pressure reading leading to unnecessary drug therapy.15 This effect can be eliminated by the use of an automated device.16 Even better is a blood pressure monitoring device that can be worn over a 24-hour period.17 Patients whose blood pressure does not decrease while sleeping are more likely to have a stroke.18 Unfortunately, wearing a blood pressure monitoring device at night can often disturb sleep, undermining the accuracy of the reading.19

Dr. Houston has had great success in getting his patients off blood pressure drugs with his program of diet, exercise, weight reduction, and supplements. After six months of his treatment protocol, 62% of his high blood pressure patients were able to stop taking drugs.20 According to Dr. Houston, the average American is consuming about 10 times the minimum requirement for sodium, and is consuming two times as much sodium as potassium. Consuming five times more potassium than sodium is recommended. For blood pressure reduction, Dr. Houston also recommends omega-3 fatty acids (especially DHA), a monounsaturated fat (such as olive oil), vitamin C, vitamin D, lycopene, pycnogenol, coenzyme Q10, and 500 to 1,000 mg per day of magnesium.20

Abraham Morgentaler, MD, (Associate Clinical Professor of Urology, Harvard Medical School) has helped revolutionize testosterone replacement for older men. Prior to the 1990s, it was commonly believed that administering testosterone increased the risk of prostate cancer. Dr. Morgentaler began questioning this belief when he found evidence of prostate cancer in biopsies in men having low testosterone. In 1996, he published a paper in the Journal of the American Medical Association, which documented prostate cancer in 11 (14%) of 77 men with low testosterone.21 This result suggested to him that low testosterone is a risk factor rather than a protective factor for prostate cancer.

A decade later he was able to report that clinical trials with testosterone replacement therapy showed no increase in risk of prostate cancer.22High serum testosterone is not associated with a risk of developing prostate cancer.23,24 Testosterone replacement therapy does not even increase cancer in men with a high risk of prostate cancer.25,26

Dr. Morgentaler hypothesized that testosterone can facilitate prostate cancer if given to men with extremely low levels of testosterone. But this effect quickly reaches saturation due to the limited number of testosterone receptors. His analogy is that once a plant is receiving enough water, additional water does not make the plant grow more.27

Whereas normal blood testosterone is typically well above 450 ng/dL, saturation is estimated to occur at 230 ng/dL total serum testosterone.28 For this reason, a man with serum testosterone of 250 or 300 ng/dL would be testosterone deficient, but would be above the level at which testosterone therapy could increase prostate cancer risk. An estimated 20% of men have low testosterone by age 50, while half of men have low testosterone by age 80.29 Low testosterone levels are associated with decreased muscle mass, low bone density, central obesity, insulin resistance, low energy, decreased cardiovascular health, low libido, and irritability. Also, it is associated with increased mortality in the elderly population.29,30

In 2004, Dr. Morgentaler was writing a review of evidence for the safety of testosterone replacement therapy31 when it occurred to him to search for the basis of earlier beliefs that testosterone therapy would increase prostate cancer risk. He discovered the source to be a single study based on a single unrepresentative patient in 1941 by Nobel Laureate Charles Brenton Huggins.32

Dr. Morgentaler gave presentations at both the 2012 and 2013 A4M. About 85% of his 2013 presentation was identical to his 2012 presentation. Most of the new material in his 2013 presentation was a response to a recent article claiming that testosterone therapy increases cardiovascular disease risk.33 Dr. Morgentaler cited evidence to the contrary,29,34 calling the study flawed. His opinion was shared by other scientists.35,36

Joseph Maroon, MD, (Professor of Neurological Surgery, University of Pennsylvania School of Medicine) addressed the question, Should you allow your child to play football? Dr. Maroon cited the risks, but also extoled the benefits, which are not as easily scientifically documented.

Between 1980 and 2006, out of millions of players, there were 1,866 documented deaths or survived cardiac arrests in American competitive athletics; 56% of these deaths were due to cardiovascular disease, compared to 22% caused by trauma.37 Cardiovascular deaths in athletes under age 40 are usually due to inherited conditions.38 Retired professional football players, however, suffer more cardiovascular disease than the general population their same age.39 The injury rate among American high school athletes in the 2005-2006 school year was highest in football (4.36 per 1,000 athletes), followed by wrestling (2.5 per 1,000 for boys).40 Dr. Maroon stated that injuries from riding bicycles exceeded those from football and asked, Should you allow your child to ride a bicycle?

Dr. Maroon has devoted a great deal of attention to the subject of concussion. Long-term consequences of concussion include brain pathology from tau protein that is similar to what is seen in Alzheimers disease.41,42 Dr. Maroon recommended omega-3 fatty acids to reduce possible effects of concussion.43,44 He also referred to the Lystedt Law, passed in Washington State in 2009 (and subsequently passed in most other states), requiring that athletes under the age of 18 who have experienced a concussion during a practice or game be prohibited from further participation until cleared by a medical professional.45 The majority of coaches were already avoiding returning an athlete to play too soon after a suspected concussion.46

Dr. Maroons concluding remarks included a personal testimony regarding the benefits to health and character resulting from his lifelong participation in athletics. He contrasted the alarming growth of childhood obesity with the health benefits, social skills, and leadership skills that arise from athletic competition. He quoted General Douglas MacArthur, who wrote, Upon the fields of friendly strife are sown the seeds that upon other fields, on other days, will bear the fruits of victory.

Daniel Amen, MD, (Psychiatrist and Medical Director of Amen Clinics, Inc.) spoke at the 2012 Las Vegas A4M conference with a message that conflicted with Dr. Maroons. Dr. Amen said that, You should only allow your kids to play tackle football if you dont like them. He added that brain damage can occur even without concussion, referring to disrupted white matter found in the brains of soccer players rather than swimmers.

Dr. Amen specializes in SPECT (Single Photon Emission Computed Tomography), which uses gamma rays to image the brain. He has established that SPECT is superior to other brain imaging techniques, namely CT (Computed Tomography) or MRI (Magnetic Resonance Imaging), for the detection of mild traumatic brain injury.47 SPECT accuracy in diagnosis of Alzheimers disease may be as high as 88%.48 Dr. Amen is critical of other psychiatrists for not examining the organ which they are studyingthe brain.49 Dr. Amen believes he has established that SPECT can reveal undetected brain traumas, brain toxicities, and other maladies leading to psychiatric symptoms.50 Dr. Amen has determined that overweight and obese persons have smaller brain volume and reduced brain blood flow.51,52 Dr. Amen has also shown reduced blood flow in the brains of retired professional football players, which he says is consistent with a pattern of chronic brain trauma.53 Dr. Amen said that helmets prevent skull fracture, but not brain injury. The skull is hard, whereas the brain is soft and when there is trauma to the head, the soft brain slams up against bony ridges. In his experience, many psychiatric problems can be traced to undetected head traumas. He reported improved blood flow in retired professional football players who he treated with fish oil, multiple vitamins, ginkgo, alpha lipoic acid, and N-acetyl-cysteine.54

Michael Murphy, PhD, (Group Leader, Medical Research Council Mitochondrial Biology Unit, Cambridge, England) said that many aging-related diseases are the result of increasingly dysfunctional mitochondria (the organelles that provide energy to cells). Because getting drugs or nutraceuticals into mitochondria can be difficult, Dr. Murphy (as a mitochondrial biochemist) designed a new antioxidant molecule tailored for entering mitochondria.55,56 He called his new molecule MitoQ.57 Modeling a variety of diseases in mice and rats, Dr. Murphy demonstrated the potential benefit of MitoQ against cardiac ischemia-reperfusion,58 sepsis,59 diabetic nephropathy,60 multiple sclerosis,61 inflammatory bowel disease,62 metabolic syndrome,63 and alcohol-induced liver damage.64 MitoQ became the first molecule designed to reduce mitochondrial oxidative damage to enter phase II clinical trials. One trial, intended to reduce Parkinsons disease, failed to show any benefit,65 probably because the neuron damage in the patients was already too great for the chemical to have an effect. But the other trial, on hepatitis C, demonstrated that MitoQ could decrease liver inflammation in patients suffering from the disease.66 Future clinical trials are planned.

John Cline, MD, (Medical Director, Cline Medical Center, Nanaimo, BC, Canada) described his methods of detoxification. Dr. Cline is more representative of alternative medicine than the other presenters. Chelation therapy (removal of toxic metals from the blood) is part of his practice. Dr. Cline also recommended infrared saunas for elimination of toxic metals from the body.67 Arsenic, cadmium, lead, and mercury are toxic metals that have no known beneficial effect in humans, but which can be removed from the body through sweating.68

The human body normally detoxifies chemicals through two-step metabolic processing in the liver, described as phase I and phase II biotransformation. First, phase I causes a chemical alteration of the toxin through oxidation, reduction, or hydrolysis. Then phase II causes conjugation (linking) of the parent molecule or the products of phase I to another molecule, such as glutathione or sulfate.69,70 Phase II results in products that are much less toxic, water soluble, and easily excreted. But the products of phase I metabolism can be more toxic than the original toxin. To protect against the toxic products of phase I, Dr. Cline recommended magnesium, zinc, folic acid, vitamin C, and B vitamins. For phase II products, he recommended whey protein, N-acetyl-cysteine, glycine, pantothenic acid, magnesium, and TMG (trimethylglycine). Dr. Cline gave no citations to justify these claims.

Dr. Cline also advocates promoting forgiveness for stress-reduction and health.71 Unforgiveness is distinguished from anger by continuing rumination about the hurtful experience and offending person.72 As general advice for detoxification, Dr. Cline suggested drinking pure water, eating organic foods, avoiding amalgam dental fillings, and being cautious when eating fish (due to mercury toxicity).

Kathleen Collins, PhD, (Professor, Department of Molecular and Cellular Biology, University of California, Berkeley) spoke at the 2012 A4M about the potential for monitoring telomere length in medicine. Telomeres are strands of DNA at the ends of chromosomes that shorten with each cell division. When telomeres become too short, cells no longer divideand this effect is considered to be a cause of aging.73

Dr. Collins achieved fame by showing that defects in telomerase (the enzyme that lengthens telomeres) are linked with a genetic disease called dyskeratosis congenita, which is associated with bone marrow failure.74 Later it was shown that short telomeres could be used as a means of identifying patients who have the genetic defect leading to bone marrow failure.75 Dr. Collins said there is evidence that telomere length could be used as a diagnostic tool to identify women who have genetic defects that make them at high risk for developing breast cancer.76,77 She noted that short telomeres can be indicative of an unhealthy lifestyle, including smoking, obesity, consumption of processed meats, and a low intake of vitamin D or omega-3 fatty acids.78 Dr. Collins believes that measuring telomere length could be a useful tool in the coming age of molecular medicine based on the genomic, metabolic, and antibody profile of individual patients.79 But she said that too often, the average telomere length is used as a diagnostic tool rather than the lengths of the shortest telomeres in cells. Determining the length of the shortest telomeres is important because it is the shortest telomeres that cause cells to become dysfunctional.80,81 At the conference, Dr. Collins was representing the company Life Length (www.lifelength.com), which specializes in measuring shortest telomeres. Dr. Collins was occupying the Life Length booth in the A4M exhibit hall.

Mark Rosenberg, MD, (Physician, Institute for Healthy Aging, Boca Raton, Florida) noted that although telomerase is present in the great majority of cancer cells, short telomeres can lead to cancer by causing chromosome abnormalities.82 A study of average telomere length of white blood cells showed that the group of people with the lowest third of telomere lengths were three times more likely to get cancer and two times as likely to die of cancer over a 10-year period as people in the highest third of telomere lengths.83 Similarly, persons whose white blood cell telomeres are short have a higher risk of developing coronary heart disease,84,85 and are eight times more likely to die of infectious disease.84 Mice that were bred to be cancer resistant had their life spans increased by the telomerase enzyme (which lengthened their telomeres).86

There is a concern that lengthening telomeres by increasing telomerase activity can facilitate cancer. But mice whose telomerase activity was increased by gene therapy at 1-year or 2-years of age had a 24 or 13% (respectively) increase in median life span without increased cancer risk.87 In adult mice, at least, increasing telomerase activity had health benefits without increased cancer risk, which could be a promising sign for humans. The health benefits for the mice included increased insulin sensitivity and improved neuromuscular coordination.87 Dr. Rosenberg gave evidence of increased telomere length in people who take supplements. Average white blood cell telomere length was 5% longer for women who took multivitamin supplements, and higher dietary intakes of vitamins C and E were also associated with longer telomeres.88 Longer telomeres were associated with higher plasma levels of folic acid, vitamin D, and omega-3 fatty acids, as well as higher dietary intake of magnesium and curcumin.89

William Andrews, PhD, (Founder and President of Sierra Sciences) believes that human health and longevity without risk of cancer can be achieved by activating telomerase, the enzyme that lengthens telomeres. He noted that telomerase is active in lobsters, which continue to grow throughout their whole lives, rather than ceasing to grow at an age of maturity.90 But lobsters do not get cancer, even in polluted waters that increase cancer in fish and molluscs.91 Dr. Andrews created his company Sierra Sciences for the purpose of discovering chemicals that could increase the activity of telomerase enzyme.92 Telomerase preferentially lengthens the shortest telomeres in human cells.93 The highest potency substance Dr. Andrews has found so far is a chemical that stimulates telomerase activity to 16% of the amount that would be required to make cells immortal. He believes that with $30 million he could achieve 100%.92

If you have any questions on the scientific content of this article, please call a Life Extension Health Advisor at 1-866-864-3027.

See the article here:
The Las Vegas A4M Conference - Life Extension

Recommendation and review posted by Bethany Smith

BACKGROUND:

Data of the literature demonstrated controversial results of a correlation between transsexualism and genetic mutations.

To evaluate the hormone and gene profile of male-female (M-F) transsexual.

Thirty M-F transsexuals aged 24-39. Seventeen had already undergone sex reassignment surgery, 13 were awaiting. All subjects had been undergoing estrogen and antiandrogen therapy. We studied hormones of the hypothalamus- pituitary-testicular axis, thyroid and adrenal profile, GH basal and after GHRH stimulation, IGF-I. The gene study analyzed SRY, AR, DAX1, SOX9, AZF region of the Y chromosome.

Pre-surgery subjects had elevated PRL, reduced testosterone and gonadotropins. Post-surgery subjects showed reduced androgens, a marked increase in LH and FSH and normal PRL. Cortisol and ACTH were similar to reference values in pre- and post-surgery patients. There was a marked increase in the baseline and post-stimulation GH values in 6 of the 13 pre-surgery patients, peaking at T15. IGF-I was similar to reference values in both groups except for one post-surgery patient, whose level was below the normal range. There were no polymorphisms in the amplified gene region for SOX9, and a single nucleotide synonimous polymorphism for DAX1. No statistically significant differences were seen in the mean of CAG repeats between controls and transsexual subjects. SRY gene was present in all subjects. Qualitative analysis of the AZFa, AZFb, and AZFc regions did not reveal any microdeletions in any subject.

This gender disorder does not seem to be associated with any molecular mutations of some of the main genes involved in sexual differentiation.

See the article here:
Hormone and genetic study in male to female transsexual ...

Recommendation and review posted by Bethany Smith

Endocrinology (from Greek , endon, "within"; , krn, "to separate"; and -, -logia) is a branch of biology and medicine dealing with the endocrine system, its diseases, and its specific secretions known as hormones. It is also concerned with the integration of developmental events proliferation, growth, and differentiation, and the psychological or behavioral activities of metabolism, growth and development, tissue function, sleep, digestion, respiration, excretion, mood, stress, lactation, movement, reproduction, and sensory perception caused by hormones. Specializations include behavioral endocrinology[1][2][3] and comparative endocrinology.

The endocrine system consists of several glands, all in different parts of the body, that secrete hormones directly into the blood rather than into a duct system. Hormones have many different functions and modes of action; one hormone may have several effects on different target organs, and, conversely, one target organ may be affected by more than one hormone.

In the original 1902 definition by Bayliss and Starling (see below), they specified that, to be classified as a hormone, a chemical must be produced by an organ, be released (in small amounts) into the blood, and be transported by the blood to a distant organ to exert its specific function. This definition holds for most "classical" hormones, but there are also paracrine mechanisms (chemical communication between cells within a tissue or organ), autocrine signals (a chemical that acts on the same cell), and intracrine signals (a chemical that acts within the same cell).[4] A neuroendocrine signal is a "classical" hormone that is released into the blood by a neurosecretory neuron (see article on neuroendocrinology).

Examples of amine hormones

Examples of steroid hormones

Griffin and Ojeda identify three different classes of hormone based on their chemical composition:[5]

Amines, such as norepinephrine, epinephrine, and dopamine (catecholamines), are derived from single amino acids, in this case tyrosine. Thyroid hormones such as 3,5,3-triiodothyronine (T3) and 3,5,3,5-tetraiodothyronine (thyroxine, T4) make up a subset of this class because they derive from the combination of two iodinated tyrosine amino acid residues.

Peptide hormones and protein hormones consist of three (in the case of thyrotropin-releasing hormone) to more than 200 (in the case of follicle-stimulating hormone) amino acid residues and can have a molecular mass as large as 30,000 grams per mole. All hormones secreted by the pituitary gland are peptide hormones, as are leptin from adipocytes, ghrelin from the stomach, and insulin from the pancreas.

Steroid hormones are converted from their parent compound, cholesterol. Mammalian steroid hormones can be grouped into five groups by the receptors to which they bind: glucocorticoids, mineralocorticoids, androgens, estrogens, and progestogens. Some forms of vitamin D, such as calcitriol, are steroid-like and bind to homologous receptors, but lack the characteristic fused ring structure of true steroids.

The earliest study of endocrinology began in China.[6] The Chinese were isolating sex and pituitary hormones from human urine and using them for medicinal purposes by 200 BCE.[6] They used many complex methods, such as sublimation of steroid hormones.[6] Another method specified by Chinese textsthe earliest dating to 1110specified the use of saponin (from the beans of Gleditschia sinensis) to extract hormones, but gypsum (containing calcium sulfate) was also known to have been used.[6]

Although most of the relevant tissues and endocrine glands had been identified by early anatomists, a more humoral approach to understanding biological function and disease was favoured by the ancient Greek and Roman thinkers such as Aristotle, Hippocrates, Lucretius, Celsus, and Galen, according to Freeman et al.,[7] and these theories held sway until the advent of germ theory, physiology, and organ basis of pathology in the 19th century.

In 1849, Arnold Berthold noted that castrated cockerels did not develop combs and wattles or exhibit overtly male behaviour.[8] He found that replacement of testes back into the abdominal cavity of the same bird or another castrated bird resulted in normal behavioural and morphological development, and he concluded (erroneously) that the testes secreted a substance that "conditioned" the blood that, in turn, acted on the body of the cockerel. In fact, one of two other things could have been true: that the testes modified or activated a constituent of the blood or that the testes removed an inhibitory factor from the blood. It was not proven that the testes released a substance that engenders male characteristics until it was shown that the extract of testes could replace their function in castrated animals. Pure, crystalline testosterone was isolated in 1935.[9]

The Graves' disease was named after Irish doctor Robert James Graves,[10] who described a case of goiter with exophthalmos in 1835. The German Karl Adolph von Basedow also independently reported the same constellation of symptoms in 1840, while earlier reports of the disease were also published by the Italians Giuseppe Flajani and Antonio Giuseppe Testa, in 1802 and 1810 respectively,[11] and by the English physician Caleb Hillier Parry (a friend of Edward Jenner) in the late 18th century.[12]Thomas Addison was first to describe Addison's disease in 1849.[13]

In 1902 William Bayliss and Ernest Starling performed an experiment in which they observed that acid instilled into the duodenum caused the pancreas to begin secretion, even after they had removed all nervous connections between the two.[14] The same response could be produced by injecting extract of jejunum mucosa into the jugular vein, showing that some factor in the mucosa was responsible. They named this substance "secretin" and coined the term hormone for chemicals that act in this way.

Joseph von Mering and Oskar Minkowski made the observation in 1889 that removing the pancreas surgically led to an increase in blood sugar, followed by a coma and eventual deathsymptoms of diabetes mellitus. In 1922, Banting and Best realized that homogenizing the pancreas and injecting the derived extract reversed this condition.[15] The hormone responsible, insulin, was not discovered until Frederick Sanger sequenced it in 1953.

Neurohormones were first identified by Otto Loewi in 1921.[16] He incubated a frog's heart (innervated with its vagus nerve attached) in a saline bath, and left in the solution for some time. The solution was then used to bathe a non-innervated second heart. If the vagus nerve on the first heart was stimulated, negative inotropic (beat amplitude) and chronotropic (beat rate) activity were seen in both hearts. This did not occur in either heart if the vagus nerve was not stimulated. The vagus nerve was adding something to the saline solution. The effect could be blocked using atropine, a known inhibitor to heart vagal nerve stimulation. Clearly, something was being secreted by the vagus nerve and affecting the heart. The "vagusstuff" (as Loewi called it) causing the myotropic (muscle enhancing) effects was later identified to be acetylcholine and norepinephrine. Loewi won the Nobel Prize for his discovery.

Recent work in endocrinology focuses on the molecular mechanisms responsible for triggering the effects of hormones. The first example of such work being done was in 1962 by Earl Sutherland. Sutherland investigated whether hormones enter cells to evoke action, or stayed outside of cells. He studied norepinephrine, which acts on the liver to convert glycogen into glucose via the activation of the phosphorylase enzyme. He homogenized the liver into a membrane fraction and soluble fraction (phosphorylase is soluble), added norepinephrine to the membrane fraction, extracted its soluble products, and added them to the first soluble fraction. Phosphorylase activated, indicating that norepinephrine's target receptor was on the cell membrane, not located intracellularly. He later identified the compound as cyclic AMP (cAMP) and with his discovery created the concept of second-messenger-mediated pathways. He, like Loewi, won the Nobel Prize for his groundbreaking work in endocrinology.[17]

Although every organ system secretes and responds to hormones (including the brain, lungs, heart, intestine, skin, and the kidney), the clinical specialty of endocrinology focuses primarily on the endocrine organs, meaning the organs whose primary function is hormone secretion. These organs include the pituitary, thyroid, adrenals, ovaries, testes, and pancreas.

An endocrinologist is a physician who specializes in treating disorders of the endocrine system, such as diabetes, hyperthyroidism, and many others (see list of diseases below).

The medical specialty of endocrinology involves the diagnostic evaluation of a wide variety of symptoms and variations and the long-term management of disorders of deficiency or excess of one or more hormones.

The diagnosis and treatment of endocrine diseases are guided by laboratory tests to a greater extent than for most specialties. Many diseases are investigated through excitation/stimulation or inhibition/suppression testing. This might involve injection with a stimulating agent to test the function of an endocrine organ. Blood is then sampled to assess the changes of the relevant hormones or metabolites. An endocrinologist needs extensive knowledge of clinical chemistry and biochemistry to understand the uses and limitations of the investigations.

A second important aspect of the practice of endocrinology is distinguishing human variation from disease. Atypical patterns of physical development and abnormal test results must be assessed as indicative of disease or not. Diagnostic imaging of endocrine organs may reveal incidental findings called incidentalomas, which may or may not represent disease.

Endocrinology involves caring for the person as well as the disease. Most endocrine disorders are chronic diseases that need lifelong care. Some of the most common endocrine diseases include diabetes mellitus, hypothyroidism and the metabolic syndrome. Care of diabetes, obesity and other chronic diseases necessitates understanding the patient at the personal and social level as well as the molecular, and the physicianpatient relationship can be an important therapeutic process.

Apart from treating patients, many endocrinologists are involved in clinical science and medical research, teaching, and hospital management.

Endocrinologists are specialists of internal medicine or pediatrics. Reproductive endocrinologists deal primarily with problems of fertility and menstrual functionoften training first in obstetrics. Most qualify as an internist, pediatrician, or gynecologist for a few years before specializing, depending on the local training system. In the U.S. and Canada, training for board certification in internal medicine, pediatrics, or gynecology after medical school is called residency. Further formal training to subspecialize in adult, pediatric, or reproductive endocrinology is called a fellowship. Typical training for a North American endocrinologist involves 4 years of college, 4 years of medical school, 3 years of residency, and 2 years of fellowship. Adult endocrinologists are board certified by the American Board of Internal Medicine (ABIM) or the American Osteopathic Board of Internal Medicine (AOBIM) in Endocrinology, Diabetes and Metabolism.

In North America the principal professional organizations of endocrinologists include The Endocrine Society,[18] the American Association of Clinical Endocrinologists,[19] the American Diabetes Association,[20] the Lawson Wilkins Pediatric Endocrine Society,[21] and the American Thyroid Association.[22]

In the United Kingdom, the Society for Endocrinology[23] and the British Society for Paediatric Endocrinology and Diabetes[24] are the main professional organisations. The European Society for Paediatric Endocrinology[25] is the largest international professional association dedicated solely to paediatric endocrinology. There are numerous similar associations around the world.

Because endocrinology encompasses so many conditions and diseases, there are many organizations that provide education to patients and the public. The Hormone Foundation is the public education affiliate of The Endocrine Society and provides information on all endocrine-related conditions. Other educational organizations that focus on one or more endocrine-related conditions include the American Diabetes Association, National Osteoporosis Foundation, Human Growth Foundation, American Menopause Foundation, Inc., and Thyroid Foundation of America.

A disease due to a disorder of the endocrine system is often called a "hormone imbalance", but is technically known as an endocrinopathy or endocrinosis. Such disease can be treated by increasing or reducing the hormone which has become imbalanced.

See the article here:
Endocrinology - Wikipedia, the free encyclopedia

Recommendation and review posted by Bethany Smith

What is arthritis?

Arthritis is a general term that literally means "inflammation of the joints." The most common form of arthritis is osteoarthritis, which is caused by wear and tear on joint cartilage. Another form is rheumatoid arthritis, which causes joint inflammation due to an immune system disorder. This section only addresses osteoarthritis.

Osteoarthritis affects nearly 27 million Americans and is the most common cause of long-term disability. It is caused by degeneration of the cartilage in joints. Osteoarthritis, also called degenerative joint disease, not only reduces elasticity and lubrication in the joints, but weakens muscles and loosens ligaments. This degeneration of cartilage can occur in any joints, but is most common in the knees, hips, hands, neck, and lower back.

The biggest risk factors for osteoarthritis are simply aging and joint use, but osteoarthritis can also be due to obesity, injury, nutritional factors, metabolic disorders, and genetics.

Most people over age 60 have osteoarthritis to some degree, but its severity varies. Even people in their 20s and 30s can get osteoarthritis. In people over 50, more women than men get osteoarthritis.

Symptoms of osteoarthritis most often develop gradually and include:

The degree of arthritis seen on x-ray studies or arthroscopy doesn't directly correlate with the level of pain or disability someone experiences.

Conventional treatments for arthritis begin with protecting the joint from progressive joint degeneration, increasing joint movement, and providing pain control so that the individual can maintain a healthy, active lifestyle. When pain and disability from arthritis increase, surgery is an option.

Treatments that focus on pain control include:

When pain from arthritis cannot be controlled with medication, surgery is sometimes an option. The most common surgeries done for arthritis are:

Lifestyle changes that protect the joint from progressive cartilage degeneration include:

Studies done on people with mild to moderate osteoarthritis consistently show that regular exercise, including aerobics, strength training, and range of motion/flexibility, improves pain, increases walking tolerance, and decreases self-assessed disability.

This especially applies to those with knee arthritis. Using a cane, walker, or wedged insoles to help distribute the weight on joints can be helpful.

Staying physically active when you have arthritis is important because arthritis pain is typically worse after excessive activity as well as inactivity.

It is important to eliminate activities that cause joint wear and tear, such as running and high-impact aerobics.

Optimizing weight to reduce stress on the joints is important for both prevention and for decreasing symptoms and progression of disease. Losing weight helps reduce stress and strain on joints. In fact, for every pound of weight loss there is a four pound reduction in the load exerted on the knee.

In one study, a 10% weight loss led to a 28% improvement in function. Weight loss appears to alleviate more than just direct mechanical stress, because lowering body mass also improves the course of disease in the hand and wrist joints. Also, diabetics experience more severe osteoarthritis than those without diabetes, so if you have type 2 diabetes, losing weight could improve your arthritis both on its own and by possibly eliminating your diabetes.

An anti-inflammatory dietthat is, one low in saturated fats like red meat, dairy, and fried foodmay help reduce the inflammatory process in the joints. Increasing Omega-3 fatty acids may also help this balance. Some individuals may have symptomatic improvement with the elimination of nightshades (tomatoes, potatoes, eggplant, peppers, tobacco). A 2-3 week trial is worth considering.

In several US survey studies, many older patients with arthritis reported using complementary and alternative treatments. The most commonly used treatments were massage therapy (57%) and chiropractic (21%). The use of complementary therapies for arthritis was most common among those who considered themselves in poorer health and who also used traditional healthcare resources more.

Multiple studies have been done on the use of acupuncture for the pain of osteoarthritis. In a recent trial of almost 600 patients with knee arthritis, 26 weeks of acupuncture were compared to education sessions. Those receiving acupuncture showed significant improvement in function at 8 weeks, and in pain reduction at 26 weeks.

Mindfulness-Based Stress Reduction (MBSR) is a program of meditation and gentle yoga that has been scientifically validated. It is currently used in more than 200 hospitals and medical centers to complement the medical management of chronic pain and stress-related disorders. Research has studied individuals with many different kinds of pain (not just arthritis) and shown dramatic reductions in pain levels and an enhanced ability of individuals to cope with pain that may not go away.

Yoga is a holistic discipline, including mental, physical, and breathwork practices. A pilot study has shown that yoga may provide a feasible treatment option for obese patients over 50 years old and offers potential reductions in pain and disability caused by knee osteoarthritis.

The level of effectiveness of manual therapy with arthritis is under-researched; however, there are clinical reports of effectiveness, and some early studies are very promising.

One study of over 100 patients with osteoarthritis in the hip compared a five-week manual therapy program, including manipulations and joint mobilization, to an exercise program. Eighty-one percent of individuals had general perceived improvement after manual therapies, while only 50% experienced that in the exercise group. Patients in the manual therapy group had significantly better outcomes on pain, stiffness, hip function, and range of motion. These improvements lasted through at least 29 weeks.

There have been limited studies on the effectiveness of osteopathic manipulation alone. However, studies of osteopathy combined with conventional medical care show that the combination was more effective than conventional medical care alone for individuals with chronic pain syndromes from degenerative joint disease.

Early studies have shown massage therapy to be efficacious in the treatment of osteoarthritis of the knee, though long-term-costs studies have not yet been done.

Ice massage can be used to improve range of motion and strength of the knee, and improve function. Cold packs may be used to decrease swelling.

There are some naturally occurring substances with anti-inflammatory effects and a lower risk of gastrointestinal bleeding than NSAIDs. As with any medications, these should ideally be used for limited periods of healing, not for indefinite, long-term use.

Typical doses for each botanical are indicated below. However, you should talk with your healthcare provider before adding botanicals to your health regimen and ask about the right dosage for you.

Many people who suffer from arthritis experience either severe chronic pain or moderate chronic pain with occasional episodes of severe pain. Since the degree of pain and disability is highly influenced by an individual's perception of pain and not necessarily correlated with the degree of cartilage degeneration, a treatment plan that includes both conventional and integrative therapies can be very effective. As always, you should make sure that you communicate and share your treatment plan with all of your care providers.

Since obesity increases the risk for osteoarthritis of the knee and hip, maintaining ideal weight or losing excess weight may help prevent osteoarthritis of the knee and hip or decrease the rate of progression once osteoarthritis is established.

Acupuncture for pain relief may reduce the need pain medications, such as NSAIDs.

Maintaining activity as much as possible is helpful to delay disability and improve quality of life. A regular exercise program with stretching, strength training, and endurance and aerobic activities is important. Yoga is a good base activity for many people.

A regular meditation or relaxation practice can help you cope with pain, as can a self-reflection practice that honestly addresses emotional awareness and health.

More here:
Arthritis | Taking Charge of Your Health & Wellbeing

Recommendation and review posted by simmons

Contemporary Examples

Is that your spider sense tingling, or is that your arthritis?

And of course if you do have arthritis or other problems that make it hard to use a traditional grinder, this is a huge help.

Before Medicare, older people were trapped in wheelchairs, crippled by arthritis.

His arthritis, he told me, had been conquered by these weird maneuvers.

Nightshades have been associated with arthritis, fibromyalgia, autoimmune conditions and headaches.

Historical Examples

Tinkering with the diet has never been known to do any good for arthritis deformans and often does harm.

He knows the aspirin will not cure the arthritis, but he wants to alleviate the symptom.

Strangles occurs in the young principally and is not a frequent cause of synovitis or arthritis in the adult animal.

But you are in an advanced stage of arthritis deformans of the soul.

In hallux valgus, the metatarso-phalangeal joint of the great toe undergoes changes characteristic of arthritis deformans.

British Dictionary definitions for arthritis Expand

Derived Forms

arthritic (rtk) adjective, noun

Usage note

Rather than talking about an arthritic or arthritics, it is better to talk about a person with arthritis and people with arthritis

Word Origin

C16: via Latin from Greek: see arthro-, -itis

Word Origin and History for arthritis Expand

"inflammation of a joint," 1540s, from medical Latin arthritis, from Greek (nosos) arthritis "(disease) of the joints," from arthritis, fem. of arthrites (adj.) "pertaining to joints" (Greek nosos is a fem. noun), from arthron "a joint" (see arm (n.1)).

arthritis in Medicine Expand

arthritis arthritis (r-thr'ts) n. pl. arthritides (-thrt'-dz') Inflammation of a joint or joints resulting in pain and swelling. Also called articular rheumatism.

arthritis in Science Expand

Acute or chronic inflammation of one or more joints, usually accompanied by pain and stiffness, resulting from infection, trauma, degenerative changes, autoimmune disease, or other causes. See also osteoarthritis, rheumatoid arthritis.

arthritis in Culture Expand

The inflammation of tissues in the joints (such as osteoarthritis and rheumatoid arthritis), usually resulting in pain and stiffness.

View original post here:
Arthritis | Define Arthritis at Dictionary.com

Recommendation and review posted by simmons

Arthritis is inflammation of a body joint. The two most common types are osteoarthritis (also known as degenerative joint disease) and rheumatoid arthritis (RA). Osteoarthritis occurs in older adults or after trauma and is caused in part by degeneration of the joint and increases with age. RA is an autoimmune disease that often occurs in younger adults where the bodys own defenses attack the joint lining.

Your doctor will likely conduct a complete physical and may perform blood tests to look for inflammation to help diagnose your condition. Additional tests may include bone x-ray, CT, MRI, or ultrasound. Treatment will depend on the type, severity and location of the arthritis and may include medication, therapy or surgery.

Arthritis means inflammation of one or more joints in the body. A joint is an area where two or more bones make contact and move against each other. The underlying cause varies with specific types of arthritis. There are over 100 forms of arthritis with the two most common being osteoarthritis and rheumatoid arthritis. Osteoarthritis, also known as degenerative joint disease, is caused in part by degeneration of parts of the joint such as cartilage and increases with age. The increasing wear and breakdown on parts of the affected joint can result in reactive inflammation. Rheumatoid arthritis (RA), on the other hand, is an autoimmune disease where the bodys own defenses attack the normal joint lining. In this type of arthritis, the inflammation of the lining of the joint develops first and over time damages the component parts of the joint. Other relatively common causes of arthritis include trauma, abnormal limb alignment, infections, autoimmune conditions other than rheumatoid arthritis and abnormal deposits in the joints, such as in gout.

Some type of arthritis affects over 40 million people in the United States. More than half of those people have degenerative joint disease. Almost 60 percent of those affected by arthritis are women. While arthritis mainly occurs in adults, children can be at risk of certain types of arthritis such as those caused from injury and autoimmune diseases. Although any joint in the body can be affected, particular forms of arthritis have a tendency to occur in certain parts of the body. For example, rheumatoid arthritis commonly affects the wrists and knuckles, feet, neck, and larger joints in the limbs while degenerative joint disease may affect the thumb bases, finger joints, knees, hips, shoulders, and lower spine.

Symptoms of arthritis include:

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When diagnosing arthritis, your doctor will likely do a complete physical examination of your entire body, including your spine, joints, skin and eyes. You may undergo blood tests to detect inflammation. In cases where an infection or gout is suspected, it may be useful to draw some fluid from a joint with a needle in order to analyze the contents of the material. In addition, your physician may order one or more of the following imaging tests:

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Treatment for arthritis depends on the type, severity and location of the disorder. Common treatments include:

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Read the rest here:
Arthritis - RadiologyInfo.org

Recommendation and review posted by simmons

Future of the Life Science Industry - Innovation and Opportunities

The 18th Annual Conference of Chinese Bioscience Association October 10, 2015, Crown Plaza, Foster City, CA

We have invited industry and academia leaders to speak in this conference. Confirmed speakers include (no particular order):

Registration (including banquet style lunch):

CBA members registration:

Annual Conference CBA member rate Link

Non-CBA members registration:

Please use the bottom PayNow to pay.

Video highlights from 2014 Annual Conference at YouTube Link

2015 CBA Annual Conference Tentative Agenda

Oct 10, 2015 at Crowne Plaza Hotel, Foster City, California

Dr. Radoje (Rade) Drmanac, BGI

Dr. Jacqueline Law, Genentech

Dr. Lennart Mucke, Gladstone Institute of Neurological Disease

Dr. Tim Hoey, OncoMed

Dr. Janet Xiao, MoFo

Dr. Hiromitsu Nakauchi, Stanford

Dr. Scott Liu, CEO of Henlius Biotech

Dr. Xi Zhao-Wilson, BioMarker Pharmaceuticals

Dr. Licen Xu, Thermo Fisher

Dr. Ruhong Jiang, Applied Stem Cell

Link:
Chinese Bioscience Association | CBA: Biotech, Life ...

Recommendation and review posted by sam

Many women are unable to conceive and deliver a healthy baby due to genetic factors. Sometimes this is due to an inherited chromosome abnormality. Other times it is because of a single-gene defect passed from parent to child.

In addition, if other women in your family have had problems conceiving due to premature menopause, endometriosis or other factors, you may be at increased risk of the same problems.

Chromosomally abnormal embryos have a low rate of implantation in the mothers uterus, often leading to miscarriages. If an abnormal embryo does implant, the pregnancy may still result in miscarriage or the birth of a baby with physical problems, developmental delay, or mental retardation.

There are several kinds of chromosome abnormalities:

Translocation is the most common of these. Although a parent who carries a translocation is frequently normal, his or her embryo may receive too much or too little genetic material, and a miscarriage often results.

Couples with specific chromosome defects may benefit from pre-implantation genetic diagnosis (PGD) in conjunction with in vitro fertilization (IVF).

Down syndrome is usually associated with advanced maternal age and is a common example of aneuploidy. Down syndrome is caused by having an extra number-21 chromosome (three instead of two). It is also referred to as trisomy 21.

More information about genetics and chromosomes is available at the Web page Genetics Made Simple.

More rare is the existence of an inherited genetic disease due to abnormal genes or mutations. Chromosome analysis of the parents blood identifies such an inherited genetic cause in less than 5 percent of couples.

Single-gene abnormalities are mutations caused by changes in the DNA sequence of a gene, which produce proteins that allow cells to work properly. Gene mutations alter the functioning of cells due to a lack of a protein.

Single-gene disorders usually indicate a family history of a specific genetic disease such as cystic fibrosis (CF) an incurable and fatal disease affecting the mucous glands of vital organs and Tay Sachs, also a fatal disorder, in which harmful quantities of a fatty substance build up in tissues and nerve cells in the brain.

Though generally rare, these diseases are usually devastating to a family. Fortunately, much progress has been made in detection through pre-implantation genetic diagnosis (PGD) in conjunction with in vitro fertilization (IVF).

Although a couple may otherwise have no fertility problems, IVF and PGD can work together to spare mother and father from heartache in cases where there is a known single-gene family history.

Learn more about Genetics

Read more here:
Female Infertility Genetic Causes | RSC New Jersey

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SOURCE CVSL Inc.

LYON, France, Sept. 18, 2015 /PRNewswire/ -- Agel Enterprises, a company within the CVSL Inc. (NYSE MKT: CVSL) family of direct-to-consumer brands, today introduced what it expects will become the next generation of skin care.

It is a unique and revolutionary system called "Caspi" that uses stem cell extract from the finest Siberian Sturgeon caviar and 24 karat gold which is intended to make skin appear more youthful by helping encourage the growing layer of skin to produce youthful-looking skin tissue. The skin may actually appear firmer and more radiant over time, with fewer lines and wrinkles.

The new skin care system was unveiled today in Lyon, France, at Agel's annual worldwide convention. Today's announcement was made by John Rochon Jr., CVSL's vice chairman, who said of the new products, "I believe this is the most important and most dramatic skin care advance of the past 50 years."

"We believe Caspi is unlike anything the beauty market has ever seen. Caspi's exclusive formula literally takes skin care back to the very basis and core of young, healthy skin. The egg is the ultimate source of youth, purity and life. Using caviar stem cell extract for skin care is a unique innovation," added Mr. Rochon.

"If a new product is so good that it actually can change the way a person looks, to the point that their friends see a visible difference, it opens huge earning and recruiting opportunities for the entrepreneurs who are lucky enough to sell it," said Mr. Rochon. "We believe Caspi is the kind of breakthrough that can launch a whole new level of income growth for our independent sales force."

Caspi consists of a three-part beauty regimen:

Developed by a team of highly-respected cosmetic chemists, Caspi combines the highest quality natural ingredients. Unlike ordinary skin care products that are little more than masks, the new productgoes to the very source of life and regeneration -- and combines it with the ultimate symbols of luxury: caviar and gold.

Caspi is available exclusively through the Agel independent sales force. Agel is a global seller of nutritional products in gel form as well as a skin care line, operating in 40 countries.

"We are absolutely thrilled that Agel now has what we believe to be the most exciting skin care line in the world," said Jeff Higginson, Agel's co-CEO. "From the packaging to the product itself, it is simply extraordinary. We expect that when customers try it,they will never be satisfied with other skin care products again. It is an incredible product."

About CVSL

CVSL is a growing platform of direct-to-consumer brands. Within CVSL, each company retains its own separate brand identity, sales force and compensation plan. CVSL companies currently include The Longaberger Company, a 42-year old maker of hand-crafted baskets and other home decor items; Your Inspiration At Home, an award-winning maker of hand-crafted spices and other gourmet food items from around the world; Tomboy Tools, a direct seller of tools designed for women as well as home security systems; Agel Enterprises, a global seller of nutritional products in gel form as well as a skin care line, operating in 40 countries; Paperly, which offers a line of custom stationery and other personalized products; My Secret Kitchen, a U.K.-based seller of gourmet food products; Uppercase Living, which offers an extensive line of customizable vinyl expressions for display on walls in the home; and Kleeneze, a UK-based seller of cleaning, health, beauty, home, outdoor and a variety of other products. CVSL also includes Happenings, a lifestyle publication and marketing company.

Cautionary Note Regarding Forward-Looking Statements:

This press release contains forward-looking statements that involve risks and uncertainties. All statements other than statements of historical fact contained in this press release are forward-looking statements. We have attempted to identify forward-looking statements by terminology including "anticipate," "believe," "can," "continue," "could," "estimate," "expect," "intend," "may," "plan," "potential," "predict," "project," "should," or "will" or the negative of these terms or other comparable terminology. Although we do not make forward-looking statements unless we believe we have a reasonable basis for doing so, we cannot guarantee their accuracy. These statements include statements about the growth of CVSL, the anticipated customer results after they try the products and the impact of the new skin care line on the beauty market. These statements are subject to a number of risks and uncertainties, including our ability to unveil the product line when anticipated, the customer demand for the products and the risks outlined under "Risk Factors" in CVSL's Annual Report on Form 10-K/A for its fiscal year ended December 31, 2014 and those risks discussed in other documents we file with the Securities and Exchange Commission, which may cause our actual results, levels of activity, performance, or achievements expressed or implied by these forward-looking statements to differ materially from expectations. Except as required by law, we undertake no obligation to update or revise publicly any of the forward-looking statements after the date of this press release to conform our statements to actual results or changed expectations.

CVSL Media Contact: Russell Mack (rmack@cvsl.us.com) CVSL Investor Relations Contact: Tucker Gagan (tucker.gagan@cvsl.us.com)

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Last year, Patricia Beals was told she'd need a double knee replacement to repair her severely arthritic knees or she'd probably spend the rest of her life in a wheelchair.

Hoping to avoid surgery, Beals, 72, opted instead for an experimental treatment that involved harvesting bone marrow stem cells from her hip, concentrating the cells in a centrifuge and injecting them back into her damaged joints.

"Almost from the moment I got up from the table, I was able to throw away my cane," Beals says. "Now I'm biking and hiking like a 30-year-old."

A handful of doctors around the country are administering treatments like the one Beals received to stop or even reverse the ravages of osteoarthritis. Stem cells are the only cells in the body able to morph into other types of specialized cells. When the patient's own stem cells are injected into a damaged joint, they appear to transform into chondrocytes, the cells that go on to produce fresh cartilage. They also seem to amplify the body's own natural repair efforts by accelerating healing, reducing inflammation, and preventing scarring and loss of function.

Christopher J. Centeno, M.D., the rehab medicine specialist who performed Beals' procedure, says the results he sees from stem cell therapy are remarkable. Of the more-than-200 patients his Bloomfield, Colo., clinic treated over a two-year period, he says, "two thirds of them reported greater than 50 percent relief and about 40 percent reported more than 75 percent relief one to two years afterward."

According to Centeno, knees respond better to the treatment than hips. Only eight percent of his knee patients opted for a total knee replacement two years after receiving a stem cell injection. The complete results from his clinical observations will be published in a major orthopedic journal later this year.

The Pros and Cons

The biggest advantage stem cell injections seem to offer over more invasive arthritis remedies is a quicker, easier recovery. The procedure is done on an outpatient basis and the majority of patients are up and moving within 24 hours. Most wear a brace for several weeks but still can get around. Many are even able to do some gentle stationary cycling by the end of the first week.

There are also fewer complications. A friend who had knee replacement surgery the same day Beals had her treatment developed life-threatening blood clots and couldn't walk for weeks afterwards. Six months out, she still hasn't made a full recovery.

Most surgeries don't go so awry, but still: Beals just returned from a week-long cycling trip where she covered 20 to 40 miles per day without so much as a tweak of pain.

As for risks, Centeno maintains they are virtually nonexistent.

"Because the stem cells come from your own body, there's little chance of infection or rejection," he says.

Not all medical experts are quite so enthusiastic, however. Dr. Tom Einhorn, chairman of the department of orthopedic surgery at Boston University, conducts research with stem cells but does not use them to treat arthritic patients. He thinks the idea is interesting but the science is not there yet.

"We need to have animal studies and analyze what's really happening under the microscope. Then, and only then, can you start doing this with patients," he says.

The few studies completed to date have examined how stem cells heal traumatic injuries rather than degenerative conditions such as arthritis. Results have been promising but, as Einhorn points out, the required repair mechanisms in each circumstance are very different.

Another downside is cost: The injections aren't approved by the FDA, which means they aren't covered by insurance. At $4,000 a pop -- all out of pocket -- they certainly aren't cheap, and many patients require more than one shot.

Ironically, one thing driving up the price is FDA involvement. Two years ago, the agency stepped in and stopped physicians from intensifying stem cells in the lab for several days before putting them back into the patient. This means all procedures must be done on the same day, no stem cells may be preserved and many of the more expensive aspects of the treatment must be repeated each time.

Centeno says same day treatments often aren't as effective, either.

But despite the sky-high price tag and lack of evidence, patients like Beals believe the treatment is nothing short of a miracle. She advises anyone who is a candidate for joint replacement to consider stem cells first.

"Open your mind up and step into it," she says. "Do it. It's so effective. It's the future and it works."

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Induced pluripotent stem cells (iPSCs) are adult cells that have been genetically reprogrammed to an embryonic stem celllike state by being forced to express genes and factors important for maintaining the defining properties of embryonic stem cells. Although these cells meet the defining criteria for pluripotent stem cells, it is not known if iPSCs and embryonic stem cells differ in clinically significant ways. Mouse iPSCs were first reported in 2006, and human iPSCs were first reported in late 2007. Mouse iPSCs demonstrate important characteristics of pluripotent stem cells, including expressing stem cell markers, forming tumors containing cells from all three germ layers, and being able to contribute to many different tissues when injected into mouse embryos at a very early stage in development. Human iPSCs also express stem cell markers and are capable of generating cells characteristic of all three germ layers.

Although additional research is needed, iPSCs are already useful tools for drug development and modeling of diseases, and scientists hope to use them in transplantation medicine. Viruses are currently used to introduce the reprogramming factors into adult cells, and this process must be carefully controlled and tested before the technique can lead to useful treatment for humans. In animal studies, the virus used to introduce the stem cell factors sometimes causes cancers. Researchers are currently investigating non-viral delivery strategies. In any case, this breakthrough discovery has created a powerful new way to "de-differentiate" cells whose developmental fates had been previously assumed to be determined. In addition, tissues derived from iPSCs will be a nearly identical match to the cell donor and thus probably avoid rejection by the immune system. The iPSC strategy creates pluripotent stem cells that, together with studies of other types of pluripotent stem cells, will help researchers learn how to reprogram cells to repair damaged tissues in the human body.

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What are induced pluripotent stem cells? [Stem Cell ...

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Bioscience

The science of living things human, animal and plant has long been a field in which Kansas has strengths. The state has a strong foundation in some areas of the biosciences and is well situated to take advantage of emerging opportunities in others. From the nationally recognized drug discovery and development enterprise at University of Kansas and Kansas companies, to the states historical agricultural leadership, to the selection of Kansas as home to the National Bio and Agro-Defense Facility, Kansas is ripe for bioscience growth.

With over 16,000 people employed in the biosciences and industry leaders calling our state home, we are working with our partners statewide to offer comprehensive support for world-class research, commercialization, and business expansion in the bioscience industry. The Kansas Bioscience Authority, created by the Kansas Economic Growth Act of 2004, can provide financial resources and customized support services to help address strategic issues critical to the success of emerging Kansas bioscience enterprises. KansasBio, a not-for-profit organization serving as the voice of the biosciences in Kansas, enhances the business and research climate, and works with state leaders to attract and retain bioscience talent, companies and funding.

Kansas invests in companies and universities working in bioscience sectors where Kansas has established leadership and expertise and the resources needed to benefit from new opportunities. Those include the following areas:

ANIMAL HEALTH

The animal health sector involves the production, marketing and use of domestic animals in agriculture, entertainment and companionship. Kansas is part of the renowned Kansas City Animal Health Corridor, home to one-third of the worlds animal health industry. Kansas seeks to leverage these strengths by attracting new animal health companies and expanding existing ones, encouraging research collaborations that will lead to novel products, and build the foreign animal disease expertise that led to Kansas selection as the site of the National Bio and Agro-Defense Facility to protect our nations food supply.

HUMAN HEALTH

This sector encompasses work to safeguard and improve health with new drugs, therapies and medical devices. Kansas robust human health sector, from basic research to drug and device innovation to outstanding clinical care, provides benefits to Kansans and others worldwide. Clinical research for human health is a major emphasis for our state as Kansas is part of a bi-state region that ranks in the top five nationally for its concentration of clinical research firms. Kansas looks to work with companies who can bring drugs and devices to market faster and less expensively than traditional methods, provide new ways to diagnose disease and attract a growing share of the federal governments research investment.

BIO ENERGY Work in this sector focuses on creating fuel and chemicals out of biological material, often plant matter such as corn or switchgrass. Bioenergy products are easier on the environment and can help wean our nation from oil dependency. In this sector, Kansas hopes to develop the supply chain of feedstocks for bioenergy production, and drive collaborations that will lead to new businesses and products.

AG & BIO-BASED PRODUCTS

Kansas is known for its strong agricultural sector. Agriculture and products derived from crops will continue to play a key role in the states economy, particularly in rural communities. These industries have a global reach, too Kansas agricultural roots prime the state for advances in plant biology to help feed and clothe the world. Our state seeks advance new technologies, support innovative research, create new jobs and further advance Kansas leadership in these sectors.

Our commitment to the biosciences is strong and continues to grow. Let us show you how your company will benefit.

TRANSPORTATION ADVANTAGES

Whether by highway, rail or air, Kansas offers excellent transportation and marketing advantages for your business. Because were central and because weve focused on building and maintaining an outstanding infrastructure, its easier and cheaper to ship to and from Kansas. Were home to numerous production facilities, warehouses and distribution centers that have found shipping raw materials and finished goods is more profitable when youre located in the nations heartland.

Kansas strategic location, at the convergence of I-35 and I-70, places it at the crossroads of America. Our central location and excellent transportation network with access to interstate rail, trucking and air corridors put businesses within next-day freight service of 70 percent of the U.S.Highways Kansas ranks sixth for quality and access to transportation in all modes for getting products to market and for transporting individuals. We also rank third nationally in total road mileage with approximately 140,000 total road and street miles and over 10,000 highway miles. Thanks to our states proximity to major markets, our transit times and shipping rates for common carriers can compete with any in the country. Kansas motor carrier regulations, covering truck and trailer size and weight, mirror many federal guidelines.

Rail Service Kansas ranks in the top 10 in the United States in railroad mileage with almost 4,800 miles of track, 2.23 percent of all U.S. railroad miles. Our four Class I and 13 Class III secondary rail carriers ensure freight service to virtually anywhere in Kansas, since the countless tons of grain grown here have for decades mandated a comprehensive rail system.

Over 900 incorporated and unincorporated cities stand along Kansas tracks. Many communities are served by more than one railroad, and businesses in several cities can take advantage of reciprocal switching agreements between railroads. The Kansas City area, a convenient first stop en route to all major marketing regions, ranks as the second leading rail center in the nation.

Air Service Kansas City International Airport (KCI) and the Wichita Mid-Continent Airport are the largest airports serving the state, providing businesses with immediate access to major markets nationwide. KCI serves as the primary commercial airport for a four-state area for both passenger and air cargo service. These two airports contain state-of-the-art cargo handling facilities, main-deck loaders capable of handling the worlds largest freighter aircraft and an extensive highway system just minutes away to provide businesses with quick access to goods and markets.Inland Waterways The Port of Catoosa, an inland seaport located near Tulsa, Okla., is approximately 50 miles from the Kansas border. It is a year-round, economical alternative to other means of travel and is especially advantageous to businesses manufacturing large goods.

FOREIGN TRADE ZONES

Foreign trade zones (FTZs) in Kansas provide a duty-free and quota-free entry point for foreign goods into specific areas under customs supervision for an unlimited period of time. Kansas offers a variety of sites managed by grantees in Kansas City (Zone 17) and Wichita (Zone 161).

Kansas has taken advantage of the new Alternative Site Framework (ASF) foreign trade zone designation intended to provide greater flexibility and expedite access to the benefits of the Foreign Trade Zone program. As a result, a company in the designated region is not restricted to a site specific FTZ, as the entire county is eligible for FTZ benefits under the ASF designation. This streamlined approach offers a quicker turnaround time and lower cost, allowing grantees to locate zone designation where companies are located.

The Kansas City FTZ has a number of Magnet and Usage-Driven sites, including a five-acre site with 220,000 square feet of above-ground covered space; a second five-acre site with a 26,000 square-foot warehouse, a 50,000 square-foot warehouse, 21 acres in the Leavenworth Area Business Center and over 1,000 acres at two locations in Topeka: Forbes Field/Topeka Air Industrial Park and Phillip Billard Airport/Industrial Park. The new ASF procedures were adopted for a five-county area including Douglas, Johnson, Leavenworth, Miami, and Wyandotte that allow for a six-week approval process for certain types of designations with a significant reduction in the companys out of pocket expenses.

The Wichita FTZ has received approval to use the new ASF procedures for a central region that includes Butler, Harvey, McPherson, Reno, Saline, Sedgwick and Sumner counties. The new system makes it faster and less expensive for area businesses to establish their facilities as foreign trade zones, with an estimated turnaround time of 30 to 40 days. Existing Magnet sites include 120 acres and 800,000 square feet of covered warehouse and assembly space in Wichita.

Goods brought into a zone or sub-zone may be stored, manipulated or mixed with domestic or foreign materials used in manufacturing processes or exhibited for sale. Anything shipped out of a zone into the United States customs territory is then subject to duties. Goods reshipped to foreign nations are never subject to U.S. customs duties.

SKILLED AND EDUCATED LABOR

One of the positive factors in the expansion of the Kansas economy is the Kansas worker. A highly motivated and well-educated workforce is ready to assist your firm. Though much of the states 2.9 million population is concentrated in its metropolitan areas, firms locating in any region of the state will find a high-quality workforce ready to put its talents to work.

Kansas education system is one of the best in the nation and a powerful factor contributing to the success of many businesses. Our education system has resulted in an adept, well-skilled and highly trainable labor force. The high school graduation rate and percentage of the population with a bachelors degree are both well above the national average. Kansas ranks in the top third nationally for percent of adults with a college degree and average ACT score. Kansas higher education system includes six Board of Regents universities, 26 community and technical colleges statewide and one municipal college. Both the University of Kansas and Kansas State University have well-known specialties in medical, pharmaceutical, bioscience, animal and food science.

Kansas is also a right-to-work state. This has helped the labor costs in Kansas stay below the national average. The current union membership percentage in Kansas is 6.8 percent, well below the U.S. average. In addition, we have multiple workforce training programs and initiatives for companies new to Kansas or Kansas businesses needing to expand or restructure. Our training programs can offer direct financial assistance to train your workforce, and our workforce development professionals can assist in the recruitment of labor to staff your new business. .COMPETITIVE UTILITY RATES

Kansas possesses a built-in advantage over other states when it comes to meeting your energy needs. With one of the largest natural gas fields in the world, Kansas is among the nations leading producers of natural gas. Also, our statewide power costs are competitive with the national average.

POSITIVE BUSINESS CLIMATE

In an ongoing effort to improve the states business climate, Kansas lawmakers continue to find ways to reduce the cost of living and doing business in this state. Living costs are relatively low in Kansas at 8.7 percent below the national average, making our state one of the most affordable in the nation. Kansas housing is affordable, too, with the median value of owner-occupied housing more than 16.7 percent below the national average. In addition, Kansas ranks 15th overall for business competitiveness based on ten key economic factors, including workforce, education and transportation.

MORE INFORMATION ON BIOSCIENCE IN KANSAS CAN BE FOUND AT:

Kansas Bioscience Authority Animal Health

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Bioscience - Kansas Department of Commerce

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The recent sequencing of the human genome has accelerated scientific discoveries in genetics related to medicine and animal and plant science. Research universities in Georgia, supported by government funding and collaborations with private industry, conduct leading-edge research that contributes to improved prevention, diagnosis, and treatment of genetically caused diseases. The Georgia Research Alliance, a university, business, and government partnership, has been a key supporter of genetics research through eminent scholars, research laboratories and equipment, and technology incubators. Newborn Genetics Screening The state of Georgia has paid for newborn genetics screening since 1978. The program, developed in collaboration with the Emory University School of Medicine's Department of Human Genetics and Genetics Laboratory, tests all Georgia newborns for thirteen inherited diseases, including metabolic diseases. Emory, located in Atlanta, is one of the nation's leading research and treatment centers for inherited diseases, including lysosomal enzyme diseases, fragile X syndrome, and Down syndrome. Emory scientists are leaders in developing new enzyme replacement therapies for children born with Gaucher disease and Fabry disease, screening and treatment for maple syrup urine disease, and FISH technology (fluorescence in situ hybridization, which allows physicians to look for chromosomal abnormalities under a microscope). Emory's large staff of genetics counselors works with parents and prospective parents at centers throughout the state. In addition, genetics counseling and screening to predict adult cancers has developed rapidly since scientists discovered altered genes that increase the risk of breast, ovarian, and colon cancers. University Genetics Research Several of Georgia's research universities have extensive research centers focused on genetics. The Department of Human Genetics at the Emory University School of Medicine includes both laboratory research and clinical treatment programs in one of the largest academic genetics departments in the nation. Emory has the world's largest research program on fragile X syndrome to be funded by the National Institutes of Health (NIH). The gene responsible for fragile X syndrome, the most common cause of inherited mental retardation, was discovered by Emory professor Steven T. Warren, who led an international team of scientists. Warren and his team also have developed screening techniques and are working on potential new therapies for fragile X syndrome, which affects 3,500 individuals in Georgia either directly or as carriers. Emory geneticist Stephanie Sherman's discovery of what is known as the "Sherman Paradox," in which genetic diseases caused by the triplet repeat of amino acids are not passed on to offspring with the usual probabilities common among most genetic disorders, has been invaluable in helping physicians predict risk for these genetic diseases. Through support from the NIH, scientists at Emory and the Centers for Disease Control and Prevention have conducted sixteen years of research on the causes and clinical consequences of Down syndrome through the Atlanta Down Syndrome Project. All Atlanta-area newborns with Down syndrome and their parents are eligible to participate in the project. In 2000 the NIH expanded the Atlanta project into the National Down Syndrome Project by adding five other research centers (in Arkansas, California, Iowa, New Jersey, and New York). The Department of Genetics at the University of Georgia (UGA) in Athens includes many faculty who teach genetics to undergraduate and graduate students. Graduate research and training includes molecular genetics, evolutionary biology, and genomics. Four genetics faculty members are also members of the prestigious National Academy of Sciences.

The UGA Center for Applied Genetic Technologies (CAGT) brings together diverse expertise in plant and animal genomics, DNA markers, and transformation (a process of genetic alteration) and provides state-of-the-art facilities and instrumentation. Within CAGT are research labs and the Georgia BioBusiness Center incubator, which supports start-up companies in the biosciences by providing them access to management expertise and sophisticated instrumentation.

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Genetics in Georgia | New Georgia Encyclopedia

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ARTHRITIS OVERVIEW

Arthritis refers to inflammation of a joint. The inflammation can affect any of the important structures inside a joint, including the joint lining (synovium), bones, cartilage, or supporting tissues. Common symptoms of arthritis include pain, stiffness, and swelling of the joint. The condition may affect one or several joints throughout the body.

There are many possible causes of arthritis, although some are much more common than others. Some types of arthritis respond well to treatment and resolve without any lingering effects, whereas other types of arthritis are more difficult to control and can be disabling.

This topic provides an overview of arthritis; more detailed information about the various types of arthritis is also available. (See 'Where to get more information' below.)

ARTHRITIS CAUSES

There are many possible causes of arthritis, including age-related wear and tear, infections, autoimmune conditions, injuries, and others. Topic reviews that discuss specific types of arthritis are available separately. (See 'Where to get more information' below.)

ARTHRITIS SYMPTOMS

Joint symptomsThe most common symptoms of arthritis include joint pain and stiffness. There may also be joint tenderness, swelling, and limited movement of one or more joints. The skin over the joint is sometimes red and warm.

There are two main types of arthritis: inflammatory and noninflammatory. Examples of inflammatory arthritis include infectious arthritis, rheumatoid arthritis, and gout. An example of noninflammatory arthritis is osteoarthritis, the most common type of arthritis. The location, timing, and pattern of joint pain, as well as the presence of swelling and symptoms outside the joint (such as rash), can help to distinguish between inflammatory and noninflammatory arthritis.

Inflammatory arthritisInflammatory arthritis usually causes joint stiffness with rest, especially morning stiffness. Certain types of inflammatory arthritis, such as rheumatoid arthritis and the arthritis of systemic lupus erythematosus (SLE), affect joints symmetrically (ie, affect the same joints on both sides of the body).

Noninflammatory arthritisNoninflammatory arthritis usually causes pain that is aggravated by movement and weightbearing and is relieved by rest. Joints on one or both sides of the body may be affected.

ARTHRITIS DIAGNOSIS

The process of diagnosing arthritis involves several steps. A medical history and physical examination usually provide the most helpful information; laboratory tests, imaging tests (such as x-rays), and other tests are sometimes needed.

Laboratory and imaging testsLaboratory and imaging tests are sometimes, but not always, needed to determine the cause of arthritis.

Blood tests may be recommended. For example, if rheumatoid arthritis or systemic lupus erythematosus (SLE) is suspected, it can be helpful to test the blood for antibodies that are commonly present in these diseases. Examples include the rheumatoid factor (RF) for rheumatoid arthritis and the antinuclear antibody (ANA) for SLE.

Testing of the fluid inside a joint, called the synovial fluid, is often helpful in determining the cause of a persons arthritis. After making the skin numb, the fluid is removed by inserting a needle inside the joint and withdrawing a sample of fluid. This procedure is sometimes called a joint tap. Analysis of the joint fluid is particularly helpful in confirming that the arthritis is inflammatory and in establishing a diagnosis of septic arthritis (due to bacterial infection), gout, or pseudogout.

X-rays provide detailed pictures of bones. Other imaging tests, such as ultrasound, magnetic resonance imaging (MRI), and computed tomography (CT scan), provide images of the tissues inside and surrounding the joints. One or more of these imaging tests may be recommended to detect erosions (bone damage due to arthritis), fractures, calcium deposits, or changes in the shape of a joint.

For many types of arthritis, changes in the joint are not visible on x-ray for months or even years. However, x-rays are often useful to monitor over time.

WHEN TO SEEK HELP

Some signs and symptoms of arthritis require urgent medical care. If you have one or more swollen joints and any of the following, you should seek medical care as soon as possible.

Fever

Weight loss

An inability to function due to joint pain

An overall sense of feeling ill

Sudden weakness of specific muscle groups

ARTHRITIS TREATMENT

The treatment of arthritis depends upon the specific cause (see "Patient information: Osteoarthritis treatment (Beyond the Basics)" and "Patient information: Rheumatoid arthritis treatment (Beyond the Basics)"). Common treatments include physical and occupational therapy, pain relievers (such as acetaminophen), antiinflammatory medications (such as ibuprofen), and medications that suppress the immune system (such as prednisone or methotrexate).

WHERE TO GET MORE INFORMATION

Your healthcare provider is the best source of information for questions and concerns related to your medical problem.

This article will be updated as needed on our web site (www.uptodate.com/patients). Related topics for patients, as well as selected articles written for healthcare professionals, are also available. Some of the most relevant are listed below.

Patient level informationUpToDate offers two types of patient education materials.

The BasicsThe Basics patient education pieces answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials.

Patient information: Bursitis (The Basics) Patient information: Ganglion cyst (The Basics) Patient information: Osteoarthritis (The Basics) Patient information: Arthritis and exercise (The Basics) Patient information: Knee replacement (The Basics) Patient information: Hip replacement (The Basics) Patient information: Knee pain (The Basics) Patient information: Hand pain (The Basics) Patient information: Hip pain in older people (The Basics) Patient information: Rheumatoid arthritis (The Basics) Patient information: Rheumatoid arthritis and pregnancy (Beyond the Basics) Patient information: Juvenile rheumatoid arthritis (The Basics) Patient information: Gout (The Basics) Patient information: Calcium pyrophosphate deposition disease (pseudogout) (The Basics) Patient information: Psoriatic arthritis in adults (The Basics) Patient information: Psoriatic arthritis in children (The Basics) Patient information: Reactive arthritis (The Basics) Patient information: Septic arthritis (The Basics)

Beyond the BasicsBeyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are best for patients who want in-depth information and are comfortable with some medical jargon.

Patient information: Osteoarthritis symptoms and diagnosis (Beyond the Basics) Patient information: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics) Patient information: Gout (Beyond the Basics) Patient information: Pseudogout (Beyond the Basics) Patient information: Systemic lupus erythematosus (SLE) (Beyond the Basics) Patient information: Ankylosing spondylitis and other spondyloarthritis (Beyond the Basics) Patient information: Psoriatic arthritis (Beyond the Basics) Patient information: Reactive arthritis (Beyond the Basics) Patient information: Osteoarthritis treatment (Beyond the Basics) Patient information: Rheumatoid arthritis treatment (Beyond the Basics) Patient information: Joint infection (Beyond the Basics)

Professional level informationProfessional level articles are designed to keep doctors and other health professionals up-to-date on the latest medical findings. These articles are thorough, long, and complex, and they contain multiple references to the research on which they are based. Professional level articles are best for people who are comfortable with a lot of medical terminology and who want to read the same materials their doctors are reading.

Arthritis associated with gastrointestinal disease Clinical manifestations of rheumatoid arthritis Clinical manifestations and diagnosis of psoriatic arthritis Diagnosis and differential diagnosis of rheumatoid arthritis Imaging techniques for evaluation of the painful joint Evaluation of the adult with monoarthritis Evaluation of the adult with polyarticular pain General principles of management of rheumatoid arthritis in adults Overview of the systemic and nonarticular manifestations of rheumatoid arthritis Septic arthritis in adults Specific viruses that cause arthritis Treatment of psoriatic arthritis Non-radiographic axial spondyloarthritis, undifferentiated spondyloarthritis, and peripheral spondyloarthritis

The following organizations also provide reliable health information.

National Library of Medicine (www.nlm.nih.gov/medlineplus/arthritis.html, available in Spanish)

National Institute of Arthritis and Musculoskeletal and Skin Diseases (301) 496-8188 (www.niams.nih.gov/Health_Info/Arthritis/default.asp)

National Institute on Aging (www.nia.nih.gov/health/publication/arthritis-advice, available in Spanish)

American College of Rheumatology (404) 633-3777 (http://http://www.rheumatology.org/Practice/Clinical/Patients/Information_for_Patients/)

The Arthritis Foundation (800) 283-7800 (www.arthritis.org)

Patient SupportThere are a number of online forums where patients can find information and support from other people with similar conditions.

About.com Arthritis Forum (http://arthritis.about.com/forum)

Literature review current through: Aug 2015. | This topic last updated: Mon Jun 09 00:00:00 GMT 2014.

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Arthritis - UpToDate

Recommendation and review posted by simmons

Current evidence strongly indicates that some people diagnosed with arthritis are in fact suffering from low-grade fluoride poisoning.

Joint pain and stiffness are well known symptoms of excessive fluoride intake. According to the U.S. Department of Health and Human Services, too much fluoride causes chronic joint pain and arthritic symptoms. (DHHS 1991). U.S. health authorities have long dismissed the relevance of this by insisting that fluoride only causes arthritic symptoms in patients with advanced forms of skeletal fluorosis, a bone disease caused by fluoride.Modern research clearly shows, however, that fluoride-induced joint pains can occur in theabsence of obvious skeletal fluorosis. This makes fluorides effects on joints extremely difficult to differentiate from common forms of arthritis. In fact, research has found that fluoride can be a direct cause of osteoarthritis, with or without the presence of classic skeletal fluorosis. (Bao 2003; Savas 2001; Tartatovskaya 1995; Czerwinski 1988; Chen 1988).

In cases where fluoride is the cause of a persons arthritic problems, reduction in daily fluoride intake for a period of several weeks or months can eliminate the symptoms in the absence of medical treatment. Correct diagnosis is thus critical to effective recovery.

Chronic fluoride exposure can cause a bone disease known as skeletal fluorosis. In the classic type of skeletal fluorosis, the lower spine and pelvis develop a hyper-dense bone condition known as osteosclerosis. U.S. health authorities have long ascribed to the view that this spinal osteosclerosiswill be evident on x-rayif a persons joint pains are caused by fluoride. When spinal osteosclerosis is absent, therefore, doctors have traditionally dismissed the possibility that a patients joint pain could be caused by fluoride.

Research, however, has nowrepeatedly shownthat fluoride can cause joint pain and stiffness, including frank osteoarthritis,before bone changes in the spine are detectable on x-ray. The traditional criteria for diagnosing skeletal fluorosis thus results in people with fluoride-induced joint problems being misdiagnosed as suffering from arthritis. The extent of this misdiagnosis remains unknown.

According to U.S. health authorities, a daily dose of 10 mg of fluoride for over 10 years is sufficient to cause crippling skeletal fluorosis. (NRC 1993). Since crippling skeletal fluorosis represents the most severe stage of the disease (a stage where bone changes are readily detectable in the spine), common sense alone should indicate that earlier stages of fluorosis can be produced by doses lower than 10 mg/day.No systematicresearch, however, has been conducted in the United States or any other fluoridating country to determine how low the arthritic dose might be, and how this dose varies based on an individuals age, nutritional status, health status, and exposure to repetititve stress.

Although there has been a lack of systematic research (in western countries), acase studypublished inThe Lancetfound that daily doses of 6 to 9 mg per day were sufficient to cause arthritis in an avidtea-drinker. (Cook 1971). The subject of the study, anEnglish woman witha 25-year history of debilitatingarthritis, experienced complete reliefin her symptoms within 6 months of stopping her tea consumption. In light of the womans recovery, the author concluded that some cases of pain diagnosed as rheumatism or arthritis may be due to subclinical fluorosis which is not radiologically demonstrable.

More recent, more comprehensive, research from China confirms thatdoses lower than 10 mg/day can cause early stages of fluorosis as well as osteoarthritis. In 2000, a group of Chinese health agencies conducted a large-scale study to determine the daily doses of fluoride that cause the various phases of fluorosis. (Experts Group 2000). They found thatdoses of 6.2 to 6.6 mg/day were consistently sufficient to produce x-ray evidence of skeletal fluorosis which is significant since fluoride can cause chronic joint pain prior to the development of x-ray changes. It stands to reason, therefore, that doses less than 6 mg/day may cause arthritic symptoms.

Another large-scale study from China recently investigated whether the incidence ofosteoarthritic symptomsrates in a population are increased in areas with elevated fluoride levels. (Ge 2006). After examining over 7,000 individuals from six regions, the authors found that the rate of osteoarthritis was significantly increased at water fluoride levels of just1.7 ppm a concentration that would be associated with daily doses in the 5 to 6 mg/day range.(Ge 2006) The following figure displays the rate of pain and rigidity in the knee and vertebrae that the study found:

The U.S. Department of Health and Human Services has estimated that adults living in fluoridated communities routinely ingest between 1.6 and 6.6 mg of fluoride per day. (DHHS 1991). In other words, the doses that many American adults routinely ingest overlap the doses that modern research indicates can cause arthritic symptoms and the early stages of skeletal fluorosis.

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Fluoride Action Network | Arthritis

Recommendation and review posted by simmons