DIM (diindolylmethane), is a food-based compound found in cruciferous vegetables like broccoli, cabbage, cauliflower and Brussels sprouts.Studies have shown that it has the ability to reduce the risk of certain cancers, especiallythose influenced by excessive estrogen levels, such as breast, uterine and prostate. DIM can also stimulatefat breakdown and encourage an increase in muscle mass. I can attest, through my own personal experience supplementing with DIM as well as that of quite a few clients (both male and female), that DIM effectively modulates estrogen metabolism helping to do away with uncomfortable symptoms of PMS, perimenopause and prostate issues.

The following excerpt comes from Dr. Scott Rollins, MD, founder and Medical Director at the Integrative Medicine Center of Western Colorado (http://imcwc.com/news/index.php?id=3271124400587032289). Thisis a very well-written and comprehensive account of the effects of DIM and how to best use this supplement to make the most out of its incredible benefits:

Lower your risk of cancer, help lose weight and build muscle all remarkable benefits of a simple food supplement called DIM. For men or women, DIM is something to consider as part of an overall supplement program.

DIM, or diindolylmethane, is a plant based compound found in cruciferous vegetables, such as brussel sprouts,cabbage, broccoli and cauliflower. DIM has been shown in studies to reduce the risk of certain cancers, especiallythose driven by abnormally high estrogen levels, such as breast, uterus and prostate cancer. DIM can also stimulate the breakdown of fat while encouraging muscle development.

Estrogen hormones are naturally found in men and women and have many benefits such as preserving artery healthand brain function while fighting oxidative free radical damage. Higher estrogen levels found in women cause thefemale body shape with breast and hip development. Many women are estrogen dominant however, meaning theyhave too much estrogen accumulating in the body for the complementary progesterone to balance.

Natural estrogen dominance occurs as women near menopause, starting even ten years prior to menopause, where theyoften dont make as much progesterone to balance their estrogen. Symptoms such breast pain, water retention, heavypainful menstrual cycles, or irritable anxious moods are typical bothersome symptoms. Estrogens over-stimulation ofbreasts and uterus tissue can lead to breast cysts or adenomas and uterine growths both unpleasant and potentiallydangerous physical outcomes are too often accompanied by worrisome mammograms and hysterectomies.

Some women have estrogen dominance throughout their life for various reasons, such as low thyroid, high cortisol,exposure to environmental estrogen-like chemicals, or impaired detoxification pathways for estrogen.

Men often suffer from estrogen overload as well. With normal aging our testosterone levels drop as the conversion toestrogen increases, leading to a falling ratio of testosterone to estrogen. Higher estrogen levels in men lead to weightgain, loss of muscle mass, feminization of the body, further decreases in already falling testosterone levels, andincrease the risk of diseases such as heart disease and prostate cancer. The enzyme that normally converts testosteroneto estrogen is most abundant in fat, so as men put on weight the cycle of falling testosterone and rising estrogen simply picks up steam!

There are two main pathways in the liver for our estrogen to be normally metabolized and excreted. One pathwayleads to very good metabolites called 2-hydroxy estrogens. The other pathway leads to bad metabolites called 4 or 16-hydroxy estrogens. DIM stimulates the favorable 2-hydroxy pathway for estrogen metabolism and this is how DIMworks to improve our health.DIM is not a hormone, nor is it a hormone replacement. It is a plant compound that will improve our hormonebalance. By improving the metabolism of our natural estrogens DIM will help lower high levels of estrogen in thebody. This alone can help remedy estrogen dominant conditions and restore a healthy estrogen/testosterone ratio inmen and women.The favorable 2-hydroxy metabolites promoted by DIM are potent anti-oxidants and help prevent muscle breakdownafter exercise, as evidenced by female athletes having less muscle tissue breakdown after intense exercise than men.By reducing the estrogen dominance and also reducing the accumulation of cancer-promoting 4/16-hydroxymetabolites DIM can help lower the risk of cancer.The 2-hydroxy metabolites help increase the active testosterone levels in men and women by displacing inactiveprotein-bound testosterone to its active free portion. This leads to significant improvements in the ability to buildmuscle and enjoy the benefits of testosterone including better mood, increased stamina, endurance, sex drive anderectile function.The accumulation of fat around the belly, hips and buttocks is partly due to excess estrogen levels combined withfalling testosterone levels. DIM will help lower excess estrogen and promote the fat-burning 2-hydroxy metabolites.This can help you achieve a leaner body with less body fat.

View original post here:
DIM for Hormone Balance - Healthy by Nature

Recommendation and review posted by simmons

These hormones are associated with aging and aging absolutely affects ones weight. Metabolism slows, hormone levels change, and vigorous activity becomes more difficult. However, there is evidence that behavioral changes account for a greater proportion of weight gain than physiological changes.

As we grow older, we usually grow in wealth and free timetime to eat out, relax at home, or take vacations. Menopause also plays a role. One long-term, ongoing study of women before, during, and after menopause (the Rancho Bernardo Womens Study) has shown that women tend to gain weight more rapidly during and after menopause.

To many peoples surprise, average weight gain is more rapid in those not taking hormones than in those taking hormones. But it bears repeatingweight gain tends to occur in women during and after menopause, whether or not they choose hormone replacement therapy (HRT).

According to the Postmenopausal Estrogen and Progestin Intervention (PEPI) Trial, women on placebo experienced a much larger weight gain than those receiving supplemental hormones, but even they experienced a small weight gain during the three years of the trial (J Clin Endocrinolog Metab. 1997; 82: 1549-1556). While the women on placebo gained an average of 4.6 lbs., the women taking estrogen alone gained 1.5 lbs. The estrogen administered was the type found in Premarin and Prempro. The women taking estrogen along with a progestin, either cyclically to approximate a natural cycle or continuously also gained weight2.9 lbs. with cyclical Provera and 2.0 lbs. with a type taken daily. Those assigned to a micronized progesterone gained 2.9 lbs.

Medroxyprogesterone acetate (Provera) is the most common progestin prescribed in HRT. It is the progestin component of HRT that is most often associated with bloating and weight gain. Progestins are various synthetic versions of progesterone, the hormone secreted by the ovaries during the second half of the menstrual cycle if ovulation has occurred.

Progesterone, often considered a fattening steroid hormone, promotes fat synthesis and storage, as this would contribute to a successful pregnancy. Pregnancy requires a tremendous expenditure of energy (i.e. calories) and progesterone, whose name suggests its function (pro=for, gest=gestation), facilitates this in several ways. It increases appetite and slows down intestinal transit time, thus allowing more of the digested nutrients to be absorbed. It can also sometimes decrease insulin sensitivity (the action of insulin at the cellular level), resulting in a degree of insulin resistance which can elevate blood sugar. This conserves glucose for the fetus for growth and development, though at the expense of the mother. Progesterone can also result in the retention of sodium and water, which also contributes to weight gain. However in a non-pregnant state, the increased glucose resulting from the increased absorption of an increased amount of food is absorbed by fat cells causing weight gain. The levels of progesterone during pregnancy are, however, much higher than the levels normally found during the luteal phase of the menstrual cycle and are also higher than the progestins supplied in HRT.

Further, women with a uterus should not take estrogen without a progestin, since this increases the risk of endometrial cancer significantly. For those women who cannot tolerate progestins, an annual endometrial biopsy (usually an office procedure) is recommended if they choose to take estrogen. Whether or not such surveillance adequately prevents cancer has yet to be determined; further study is needed.

Estrogen can also promote sodium (salt) and water retention, increasing blood volume which is important in pregnancy since it increases delivery of nutrients etc. to the fetus. But in a non-pregnant state it can result in weight gain. The weight gain is often temporary since the body eventually adjusts to shifts in fluid. Haarbo and Associates reported that abdominal fat deposition is significantly lower in HRT users. Although all women in this Finnish study gained weight, the HRT users gained less weight and fat overall than non-users. Further, removal of the ovaries in mice, resulting in a lack of estrogen and progesterone similar to the hormonal situation in post-menopausal women, results in massive weight gain due, at least partially, to a greatly increased food intake. Administration of estradiol results in a return of food intake to normal levels and a consequent weight loss.

In women administration of GnRH agonists such as Lupron and other drugs which have the effect of shutting down the ovary are also notorious for causing weight gain, often a large amount (more than can be explained by an increased appetite). The exact mechanism underlying this remains unclear, as does the mechanism underlying menopausal weight gain.

In conclusion, its probably not the fault of the hormone replacement medication that most women gain weight through menopause. Having said that, we often see women whose weight gain was very closely associated with starting hormone therapy. Like most things, some women likely develop much more significant side effects than others do. Its interesting to note that women in some countries tend to lose weight during and after menopause. This is very closely related to activity and diet changes. For instance, in Southeast Asia, women raising young children have more access to food and are less active than their older counterparts who return to work in the factories or fields.

More:
Does hormone replacement medication ... - Lindora Clinic

Recommendation and review posted by simmons

Femme Clinique is Bellevues premier life enhancement clinic for women who want to get more from life. From sexual enhancement to healthy aging and longevity we can help you maximize your potential from the inside out using bio-identical hormone therapies.

In todays world we are constantly being exposed to chemicals that can severely affect the hormone milieu. When your hormones are out of imbalance you may experience symptoms which can range from uncontrollable weight gain or loss to severe fatigue and low mood.

An obvious symptom of hormonal imbalance is PMS (premenstrual syndrome) which is usually due to a progesterone and/or estrogen deficiency. Hormones effect everything including how we feel and think. Progesterone can help improve relaxation and sleep and estrogen is important for mental clarity. A more extreme example of estrogen deficiency is Alzheimers disease.

Another problem is that as we age our hormones tend to decline (ie menopause). Many women are afraid to do hormone replacement because they have been told it might increase their risk of cancer. The truth is that science has advanced. We can now measure hormone levels accurately and decrease cancer risks. Also, all the studies that showed increase risks were from studies using horse hormones. Premarin is a horse hormone mix.

Using hormone therapies that help your body restore balance can help you regain your optimal health. Bioidentical hormone therapies have been used for thousands of years to help women regain health and vigor for life. The Chinese used bioidentical hormones 1,000 years ago in 1025 AD. Your naturally produces hormones and bio-identical hormones are identical to the hormones your body produces.

We can help you balance your hormones with lifestyle, diet, exercise, and bio-identical hormones. For example, if you are post-menopause then you may need need to apply an estrogen cream topically daily. In addition, some women need a little testosterone cream. While women need much less testosterone than men, you still naturally produced a little testosterone when you were younger. Progesterone, oxytocin, testosterone, estrogen, and thyroid hormones are all important to have in balance.

Pamela Smith, MD, MPH discusses disease prevention

If you are looking for a holistic solution to health aging and balancing your hormones naturally, then theNatural Hormone Replacement Therapyis right for you. This treatment program is designed to help you balance the key hormones Progesterone, Oxytocin, Testosterone, Estrogen, Thyroid, and more.

Your physician can help you determine how best to balance your hormones to increase your wellness and reduce your health risks. Becoming a patient is easy and your first visit includes labs and thorough review of your top health concerns and health history. Based on your specific needs your physician will recommend specific treatments and possibly additional lab testing. Our services are concierge so we invite you to contact us with any questions or concerns throughout the process.

Call (425) 274-2777 with any questions, to schedule, or schedule your new patient visit (we accept most insurance) online:

See the original post:
FEMME CLINIQUE - Bio-Identical Hormone Therapy Clinic ...

Recommendation and review posted by sam

1. Introduction

Bone marrow is a complex tissue containing hematopoietic cell progenitors and their progeny integrated within a connective-tissue network of mesenchymal-derived cells known as the stroma (1). The stroma cells, or Mesenchymal stem cells (MSCs), are multi-potent progenitor cells that constitute a minute proportion of the bone marrow, represented as a rare population of cells that makes up 0.001 to 0.01% of the total nucleated cells. They represent 10-fold less abundance than the haematopoietic stem cells (2), which contributes to the organization of the microenvironment supporting the differentiation of hematopoietic cells (3). MSC are present in tissues of young, as well as, adult individuals (4, 5), including the adipose tissue, umbilical cord blood, amniotic fluid and even peripheral blood (1, 6-8). MSCs were characterized over thirty years ago as fibroblast-like cells with adhesive properties in culture (9, 10). The term MSC has become the predominant term in the literature since the early 90s (11), after which their research field has grown rapidly due to the promising therapeutic potential, resulting in an increased frequency of clinical trials in the new millennium at an explosive rate.

As data accumulated, there was a need to establish a consensus on the proper definition of the MSCs. The International Society for Cellular Therapy has recommended the minimum criteria for defining multi-potent human MSCs (12, 13). The criteria included: (i) cells being adherent to plastic under standard culture conditions; (ii) MSC being positive for the expression of CD105, CD73 and CD90 and negative for expression of the haematopoietic cell surface markers CD34, CD45, CD11a, CD19 or CD79a, CD14 or CD11b and histocompatibility locus antigen (HLA)-DR; (iii) under a specific stimulus, MSC differentiate into osteocytes, adipocytes and chondrocytes in vitro. These criteria presented properties to purify MSC and to enable their expansion by several-fold in-vitro, without losing their differentiation capacity. When plated at low density, MSCs form small colonies, called colony-forming units of fibroblasts (CFU-f), and which correspond to the progenitors that can differentiate into one of the mesenchymal cell lineages (14, 15). It has been reported lately that MSCs are able to differentiate into both mesenchymal, as well as, non-mesenchymal cell lineages, such as adipocytes, osteoblasts, chondrocytes, tenocytes, skeletal myocytes, neurones and cells of the visceral mesoderm, both in vitro and in vivo (16, 17).

All cells have half-lives and their natural expiration must be matched by their replacement; MSCs, by proliferating and differentiating, can be the proposed source of these new replacement cells as characterized in their differentiation capacity. This replacement hypothesis mimics the known sequence of events involved in the turnover and maintenance of blood cells that are formed from haematopoietic stem cells (HSCs) (18). Unlike HSCs, MSCs can be culture-expanded ex vivo in up to 40 or 50 cell doublings without differentiation (19). A dramatic decrease in MSC per nucleated marrow cell can be observed when the results are grouped by decade, thus showing a 100-fold decrease from birth to old age. Being pericytes present in all vascularized tissues, the local availability of MSC decreases substantially as the vascular density decreases by one or two orders of magnitude with age (20). In recent years, the discovery of MSCs with properties similar, but not identical, to BM-MSCs has been demonstrated in the stromal fraction of the connective tissue from several organs, including adipose tissue, trabecular bone, derma, liver and muscle (21-24). It is important to note that the origin of MSCs might determine their fate and functional characteristics (25). Studies of human bone marrow have revealed that about one-third of the MSC clones are able to acquire phenotypes of pre-adipocytes, osteocytes and chondrocytes (16). This is in concordance with data showing that 30% of the clones from bone marrow have been found to exhibit a trilineage differentiation potential, whereas the remainder display a bi-lineage (osteo-chondro) or uni-lineage (osteo) potential (26). Moreover, MSC populations derived from adipose tissue and derma present a heterogeneous differentiation potential; indeed, only 1.4% of single cells obtained from adipose-derived adult stem cell (ADAS) populations were tri-potent, the others being bi-potent or unipotent (27).

Mesenchymal Stem Cells have been shown to possess immunomodulatory characteristics, as described through the inhibition of T-cell proliferation in vitro (28-30). These observations have triggered a huge interest in the immunomodulatory effects of MSCs. The in vitro studies have been complemented in vivo, where both confirmed the immunosuppressive effect of MSC. MSC activating stimuli in vitro, appears to include the secretion of cytokines and the interaction with other immune cells in the presence of proinflammatory cytokines (Fig 1) (31). Primarily, the in vivo effect has been originally shown in a baboon model, in which infusion of ex vivoexpanded matched donor or third-party MSCs delayed the time to rejection of histo-incompatible skin grafts (29). The delay indicated a potential role for MSC in the prevention and treatment of graft-versus-host disease (GVHD) in ASCT, in organ transplantation to prevent rejection, and in autoimmune disorders. Recently, MSCs were used to successfully treat a 9-year-old boy with severe treatment-resistant acute GVHD, further confirming the potent immunosuppressive effect in humans (32). The immunosuppressive potential has no immunologic restriction, whether the MSCs are autologous with the stimulatory or the responder lymphocytes or the MSCs are derived from a third party. The degree of MSC suppression is dose dependent, where high doses of MSC are inhibitory, whereas low doses enhance lymphocyte proliferation in MLCs (33). Broadly, MSC modulate cytokine production by the dendritic and T cell subsets DC/Th1 and DC/Th2 (34), block the antigen presenting cell (APC) maturation and activation (35), and increase the proportion of CD4+CD25+ regulatory cells in a mixed lymphocyte reaction (36).

Potential mechanisms of the MSC interactions with immune cells. Mesenchymal stem cells (MSCs) can inhibit both the proliferation and cytotoxicity of resting natural killer (NK) cells, as well as, their cytokine production by releasing prostaglandin E2 (PGE2), indoleamine 2,3-dioxygenase (IDO) and soluble HLA-G5 (sHLA-G5). Killing of MSCs by cytokine-activated NK cells involves the engagement of cell-surface receptors (Thick blue line) expressed by NK cells with its ligands expressed on MSCs. MSCs inhibit the differentiation of monocytes to immature myeloid dendritic cells (DCs), bias mature DCs to an immature DC state, inhibit tumour-necrosis factor (TNF) production by DCs and increase interleukin-10 (IL-10) production by plasmacytoid DCs (pDCs). MSC-derived PGE2 is involved in all of these effects. Immature DCs are susceptible to activated NK cell-mediated lysis. MSC Direct inhibition of CD4+ T-cell function depends on their release of several soluble molecules, including PGE2, IDO, transforming growth factor-1 (TGF1), hepatocyte growth factor (HGF), inducible nitric-oxide synthase (iNOS) and haem-oxygenase-1 (HO1). MSC inhibition of CD8+ T-cell cytotoxicity and the differentiation of regulatory T cells mediated directly by MSCs are related to the release of sHLA-G5 by MSCs. In addition, the upregulation of IL-10 production by pDCs results in the increased generation of regulatory T cells through an indirect mechanism. MSC-driven inhibition of B-cell function seems to depend on soluble factors and cellcell contact. Finally, MSCs dampen the respiratory burst and delay the spontaneous apoptosis of neutrophils by constitutively releasing IL-6.

Dendritic cells have the elementary role of antigen presentation to nave T cells upon maturation, which in turn induce the proinflammatory cytokines. Immature DCs acquire the expression of co-stimulatory molecules and upregulate expression of MHC-I and II, as well as, other cell-surface markers (CD11c and CD83). Mesenchymal stem cells have profound effect on the development of DC, where in the presence of MSC, the percentage of DC with conventional phenotype is reduced, while that of plasmacytoid DC is increased, therefore biasing the immune system toward Th2 and away from Th1 responses in a PGE-2 dependent mechanism (37). Furthermore, MSCs inhibit the up-regulation of CD1a, CD40, CD80, CD86, and HLA-DR during DC differentiation and prevent an increase of CD40, CD86, and CD83 expression during DC maturation (38). When mature DCs are incubated with MSCs they have a decreased cell-surface expression of MHC class II molecules, CD11c, CD83 and co-stimulatory molecules, as well as, decreased interleukin-12 (Il-12) production, thereby impairing the antigen-presenting function of the DCs (Fig 1) (39, 40). MSCs can also decrease the pro-inflammatory potential of DCs by inhibiting their production of tumour-necrosis factor (TNF-) (40). Furthermore, plasmacytoid DCs (pDCs), which are specialized cells for the production of high levels of type-I IFN in response to microbial stimuli, upregulate production of the anti-inflammatory cytokine IL-10 after incubation with MSCs (34). These observations indicate a potent anti-inflammatory and immunoregulatory effect for MSC in vitro and potentially in vivo.

Natural killer (NK) cells are key effector cells of the innate immunity in anti-viral and anti-tumor immune responses through their Granzyme B mediated cytotoxicity and the production of pro-inflammatory cytokines (41). NK-mediated target cell lysis results from an antigen-ligand interaction realized by activating NK-cell receptors, and associated with reduced or absent MHC-I expression by the target cell (42). MSCs can inhibit the cytotoxic activity of resting NK cells by down-regulating expression of NKp30 and natural-killer group 2, member D (NKG2D), which are activating receptors involved in NK-cell activation and target-cell killing (Fig 1) (43). Resting NK cells proliferate and acquire strong cytotoxic activity when cultured with IL-2 or IL-15, but when incubated with MSC in the presence of these cytokines, resting NK-cell, as well as, pre-activated NK cell proliferation and IFN- production are almost completely abrogated (44, 45). It is worth noting that although the susceptibility of NK cells to MSC mediated inhibition is potent, the pre-activated NK cells showed more resistance to the immunosuppressive effect of MSC compared to resting NK cells (43). The susceptibility of human MSCs to NK-cell-mediated cytotoxicity depends on the low level of cell-surface expression of MHC class I molecules by MSCs and the expression of several ligands, that are recognized by activating NK-cell receptors. Autologous and allogeneic MSC were susceptible to lysis by NK cells (43), where NK cell-mediated lysis was inversely correlated with the expression of HLA class I on MSC (46). Incubation of MSCs with IFN- partially protected them from NK-cell-mediated cytotoxicity, through the up-regulation of expression of MHC-I molecules on MSCs (43). Taken together, a possible dynamic interaction between NK cells and MSC in vivo exists, where the latter partially inhibit activated MSC, without compromising their ability to kill MSC, reflecting on an interaction tightly regulated by IFN- concentration.

Neutrophils play a major role in innate immunity during the course of bacterial infections, where they are activated to kill foreign infectious agents and accordingly undergo a respiratory burst. MSCs have been shown to dampen the respiratory burst and to delay the spontaneous apoptosis of resting and activated neutrophils through an IL-6-dependent mechanism (47). MSC had no effect on neutrophil phagocytosis, expression of adhesion molecules, and chemotaxis in response to IL-8, f-MLP, or C5a (47). Stimulation with bacterial endotoxin induces chemokine receptor expression and mobility of MSCs, which secrete large amounts of inflammatory cytokines and recruit neutrophils in an IL-8 and MIF-dependent manner. Recruited and activated neutrophils showed a prolonged lifespan, an increased expression of inflammatory chemokines, and an enhanced responsiveness toward subsequent challenge with LPS, which suggest a role for MSCs in the early phases of pathogen challenge, when classical immune cells have not been recruited yet (48). Furthermore, MSC have shown the capability to mediate the preservation of resting neutrophils, a phenomenon that might be important in those anatomical sites, where large numbers of mature and functional neutrophils are stored, such as the bone marrow and lungs (49).

T-cells are major players of the adaptive immune response. After T-cell receptor (TCR) engagement, T cells proliferate and undergo numerous effector functions, including cytokine release and, in the case of CD8+ T cells (CTL), cytotoxicity. Abundant reports have shown that T-cell proliferation stimulated with polyclonal mitogens, allogeneic cells or specific antigen is inhibited by MSCs (28, 29, 50-56). The observation that MSCs can reduce T cell proliferation in vitro is mirrored by the in vivo finding through infusions of hMSCs that control GVHD following bone marrow transplantation. Nevertheless, there is no demonstrable correlation between the measured effects of MSCs in vitro and their counter effect in vivo due to the lack of universality of methodology correlating the in vitro findings with the in vivo therapeutic potential.

MSC inhibition of T-cell proliferation is not MHC restricted, since it can be mediated by both autologous and allogeneic MSCs and depends on the arrest of T-cells in the G0/G1 phase of the cell cycle (55, 57). Thus, MSCs do not promote T-cell apoptosis, but instead maintain T cell survival upon subjection to overstimulation through the TCR and upon commitment to undergo CD95CD95-ligand-dependent activation-induced cell death (57). MSC effects on T cell proliferation in vitro appear to have both contact-dependent and contact-independent components (58). Inhibition of T-cell proliferation by MSCs leads to decreased IFN- secretion in vitro and in vivo associated with increased IL-4 production by T helper 2 (TH2) cells (34, 59). Taken together, there is an implication for a shift from a pro-inflammatory state characterized by IFN- secretion to an anti-inflammatory state characterized by IL-4 secretion (Fig 1). An imperative role for effector T-cell is the MHC restricted killing of virally-infected or of allogeneic cells mediated via CD8+ CTLs, and which is down-regulated by MSC (60).

Regulatory T cells (Tregs), a subpopulation of T cells, are vital to keep the immune system in check, help avoid immune-mediated pathology and contain unrestricted expansion of effector T-cell populations, which results in maintaining homeostasis and tolerance to self antigens. Tregs are currently identified by co-expression of CD4 and CD25, expression of the transcription factor FoxP3, production of regulatory cytokines IL-10 and TGF-, and ability to suppress proliferation of activated CD4+CD25+ T cells in co-culture experiments. Differential expression of CD127 (-chain of the IL-7 receptor) enable flow cytometry-based separation of human Tregs from CD127+ non-regulatory T-cells (61). MSCs have been reported to induce the production of IL-10 by pDCs, which, in turn, trigger the generation of regulatory T cells (Fig 1) (34, 40). Furthermore, Tregs secrete TGF- and when used in vitro, TGF- in combination with IL-2 directs the differentiation of T-cells into Tregs, while Tregs suppress the proliferation of TCR-dependent proliferation of effector CD25null or CD25low T-cells in a non-autologous fashion. Also TGF- alters angiogenesis following injury in experiments using MSC (62). In addition, after co-culture with antigen-specific T-cells, MSCs can directly induce the proliferation of regulatory T-cells through release of the immunomodulatory HLA-G isoform HLA-G5 (Fig 1) (63). Taken together, MSCs can modulate the intensity of an immune response by inhibiting antigen-specific T-cell proliferation and cytotoxicity and promoting the generation of regulatory T-cells.

Antibody producing B-cells constitute the second main cell type involved in adaptive immunity. Interactions between MSCs and B-cells have produced controversial results attributable to the inconsistent experimental conditions used (31, 55, 64). Initial reports on mice suggested that MSC exercise a dampening effect on the proliferation of B-cells (64), which is in concordance with most published works to date (31, 55, 64). Furthermore, MSCs can also inhibit B-cell differentiation and constitutive expression of chemokine receptors via the release of soluble factors and cell-cell contact mediated possibly by the Programmed Cell Death 1 (PD-1) and its ligand (31, 64). The addition of MSCs, at the beginning of a mixed lymphocyte reaction (MLC), considerably inhibited immunoglobulin production in standard MLC, irrespective of the MSC dose employed, which suggests that third-party MSC are able to suppress allo-specific antibody production, consequently, overcoming a positive cross-match in sensitized transplant recipients (65). However, other in vitro studies have shown that MSCs could support the survival, proliferation and differentiation to antibody-secreting cells of B-cells from normal individuals and from pediatric patients with systemic lupus erythematosus (66, 67). A major mechanism of B-cell suppression was hMSC production of soluble factors, as indicated by transwell experiments, where hMSCs inhibited B-cell differentiation shown as significant impairment of IgM, IgG, and IgA production. CXCR4, CXCR5, and CCR7 B-cell expression, as well as chemotaxis to CXCL12, the CXCR4 ligand, and CXCL13, the CXCR5 ligand, were significantly down-regulated by hMSCs, suggesting that these cells affect chemotactic properties of B-cells (Fig 1). B-cell costimulatory molecule expression and cytokine production were unaffected by hMSCs (64). Regardless of the controversial in vitro effects, B-cell response is mainly a T-cell dependent mechanism, and thus its outcome is significantly influenced by the MSC-mediated inhibition of T-cell functions. More recently, Corcione et al have shown that systemic administration of MSCs to mice affected by experimental autoimmune encephalomyelitis (EAE), a prototypical disease mediated by self-reactive T cells, results in striking disease amelioration mediated by the induction of peripheral tolerance (52). In addition, it has been shown that tolerance induction by MSCs may occur also through the inhibition of dendritic-cell maturation and function (34, 35), thus suggesting that activated T cells are not the only targets of MSCs.

Low concentrations of IFN- upregulate the expression of MHC-II molecules by MSCs, which indicates that they could act as antigen presenting cells (APCs) early in an immune response, when the level of IFN- are low (68, 69). However, this process of MHC-II expression by MSCs, along with the potential APC characteristics, was reversed as IFN- concentrations increased. These observations could suggest that MSCs function as conditional APC in the early phase of an immune response, while later switch into an immunosuppressive function (68). Since bone marrow might be a site for the induction of T-cell responses to blood-borne antigens (70), and since MSC are derived from the stromal progenitor cells that reside in the bone marrow, therefore, MSC express a yet unidentified role in the control of the immune response physiology of the bone marrow. Dendritic cells are the main APC for T-cell responses, and MSC-mediated suppression of DC maturation would prohibit efficient antigen presentation and thus, the clonal expansion of T-cells. Direct interactions of MSCs with T-cells in vivo could lead to the arrest of T-cell proliferation, inhibition of CTL-mediated cytotoxicity and generation of CD4+ regulatory T-cells. As a consequence, impaired CD4+ T-cell activation would translate into defective T-cell help for B-cell proliferation and differentiation to antibody-secreting cells.

The hMSCs express few to none of the B7-1/B7-2 (CD80/CD86) costimulatorytype molecules; this appears to contribute, at least in part, to their immune privilege characteristic. Mechanisms that lead to immune tolerance rely on interrelated pathways that involve complex cross talk and cross regulation of T-cells and APCs by one another. Both soluble mediators and modulation exerted via complex networks of cytokines and costimulatory molecules appear to play a role in MSC regulation of T cells, and these mechanisms invoke both contact-dependent and -independent pathways.

Although many of the studies use MSC-conditioned medium, both contact-dependent and -independent mechanisms are probably invoked in the therapeutic use of MSCs (20, 71). In addition to cytokines, the network of costimulatory molecules is hypothesized to play a prominent role in modulating tolerance and inflammation. MSCs down-regulate the expression of costimulatory molecules (30, 72, 73). The discovery of new functions for B7 family members, together with the identification of additional B7 and CD28 family members, is revealing new ways in which the B7:CD28 family may regulate T-cell activation and tolerance. Not only do CD80/86:CD28 interactions promote initial T-cell activation, they also regulate self-tolerance by supporting CD4+CD25+ Treg homeostasis (74-76). Cytotoxic T-lymphocyte antigen 4 (CTLA-4) can exert inhibitory effects in both B7-1/B7-2dependent and independent fashions. B7-1 and B7-2 can signal bi-directionally through engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells (77). The B7 family membersinducible co-stimulator (ICOS) ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1)are expressed on professional APC cells, while B7-H4 and B7-H1 are expressed on hMSCs and on cells within non-lymphoid organs. These observations may provide a new means for regulating T-cell activation and tolerance in peripheral tissues (31, 71, 78). ICOS and PD-1 are expressed upon T-cell-induction, and they regulate previously activated T-cells (79). Both the ICOS:ICOSL pathway and the PD-1:PD-L1/PD-L2 pathway play a critical role in regulating T-cell activation and tolerance (79). There is consensus that both CTLA-4 and PD-1 inhibit T-cell and B-cell activation and may play a crucial role in peripheral tolerance (79, 80). Both CTLA-4 and PD-1 functions are associated with Rheumatoid Arthritis (RA) and other autoimmune diseases. PD-1 is over expressed on CD4+ T cells in the synovial fluid of RA patients (81). Whether or not these costimulatory molecules are critical mediators of MSC-mediated immune suppression and/or tolerance in vivo is still under current investigation.

Studies have shown that MSCs escape the immune system, and this makes them a potential therapeutic tool for various transplantation procedures. MSCs express intermediate levels of HLA major histocompatibility complex (MHC) class I molecules (16, 50, 82, 83), while they do not express HLA class II antigens of the cell surface. However, HLA class II is readily detectable by Western blot on whole-cell lysates of unstimulated adult MSCs, thus suggesting that MSCs contain intracellular deposits of HLA class II allo-antigens (83). Cell-surface expression can be induced by treatment of the cells with IFN- for 1 or 2 days. Unlike adult MSCs, the fetal liver derived cells have no intracellular nor cell surface HLA class II expression (84), but incubation with IFN- initiated their intracellular expression followed by surface expression. Differentiation of MSCs into their mesodermal lineages of bone, cartilage, or adipose tissue, both in adult and fetal MSCs continued to express HLA-I, but not class II (84). Undifferentiated MSCs in vitro fail to elicit a proliferative response from allogeneic lymphocytes, thus suggesting that the cells are not inherently immunogenic (28, 30, 50). When pre-cultured with IFN- for full HLA class II expression, MSCs still escape recognition by allo-reactive T-cells, (83, 84) as is the case with MSCs differentiated adipocytes, osteoblasts, and chondrocytes. Limited in vivo data demonstrate the persistence of allogeneic MSCs into immunocompetent hosts after transplantation. In one patient treated with MSCs, DNA of donor MSC could not be detected in any organ at autopsy few weeks after the infusion, while in another patient receiving MSCs from two donors, the donor DNA from both donors was detected in lymph node and colon, the target organs of GVHD, within weeks after infusion (85). Data from our lab indicated that MSC were undetectable after two weeks in an allogeneic system (86). Therefore, the question of whether MSCs are recognized by an intact allogeneic immune system in vivo remains open, although the in vitro data support the theory that MSCs escape the immune system. MSCs do not express FAS ligand or costimulatory molecules, such as B7-1, B7-2, CD40, or CD40L (50). When costimulation is inadequate, T-cell proliferation can be induced by the addition of exogenous costimulation. However, MSCs differ from other cell types, and no T-cell proliferation can be observed when they are cultured with HLA-mismatched lymphocytes in the presence of a CD28-stimulating antibody (50). However, in agreement with the in vitro data, infusion or implantation of allogeneic and MHC-mismatched MSCs into baboons has been well tolerated (87-89). Unique immunologic properties of MSCs were also suggested by the fact that engraftment of human MSCs occurred after intra-uterine transplantation into sheep, even when the transplantation was performed after the fetuses became immunocompetent (90). MSC mainly fail to activate T-cells and show to be targets for CD8+ T cell-cytotoxicity, althought controversial (60). Phyto-hemagglutinin (PHA) blasts, generated to react against a specific donor, will lyse chromium-labeled mononuclear cells from that individual but it will not lyse MSCs derived from the same donor. Furthermore, killer cell inhibitory receptor (KIR ligand)mismatched natural killer cells do not lyse MSCs (60). Thus, MSCs, although incompatible at the MHC, tend to escape the immune system.

Although MSCs are transplantable across allogeneic barriers, a delayed type hypersensitivity reaction can lead to rejection in xenogenic models of human MSCs injected into immunocompetent rats (91). In this study, MSCs were identified in the heart muscle of severe compromised immune deficiency rats, in contrast to that of immunocompetent rats. In the latter group, peripheral blood lymphocytes proliferated after re-stimulation with human MSCs in vitro, thus suggesting cellular immunization. Such a proliferative response in vitro has not been detected in humans treated with intravenous (IV) infusion of allogeneic MSCs (Le Blanc and Ringdn, unpublished data, 2004).

Several studies have acknowledged the immunosuppressive activities of MSCs, but the underlying mechanisms are far from being fully characterized. The initial step in the interaction between MSCs and their target cells involves cellcell contact mediated by adhesion molecules, in concordance with studies showing the dependence of T-cell proliferation on the engagement of PD-1 by its ligand (31). Several soluble immunosuppressive factors, either produced constitutively by MSCs or released following cross-talk with target cells have been reported, including nitric oxide and indoleamine 2,3-dioxygenase (IDO), which are only released by MSC after IFN- stimulation with target cells (92, 93), and thus not in a constitutive manner. IDO induces the depletion of tryptophan from the local environment, which is an essential amino acid for lymphocyte proliferation. MSC-derived IDO was reported as a requirement to inhibit the proliferation of IFN--producing TH1 cells (92) and together with prostaglandin E2 (PGE-2) to block NK-cell activity (Fig 1) (44). In addition, IFN-, alone or in combination with TNF-, IL-1 or IL-1, stimulates the production of chemokines by mouse MSCs that attract T-cells and stimulate the production of inducible nitric-oxide synthase (iNOS), which in turn inhibits T-cell activation through the production of nitric oxide (56). It is worth noting that MSCs from IFN- receptor (IFN--R1) deficient mice do not have immunosuppressive activity, which highlights the vital role of IFN- in the immunosuppressive function of MSC (56).

Additional soluble factors, such as transforming growth factor-1 (TGF-1), hepatocyte growth factor (HGF), IL-10, PGE-2, haem-oxygenase-1 (HO1), IL-6 and soluble HLA-G5, are constitutively produced by MSCs (28, 34, 51, 63, 94) or secreted in response to cytokines released by target cells upon interacting with MSC. TNF- and IFN- have been shown to stimulate the production of PGE-2 by MSCs above constitutive level (34). Furthermore, IL-6 was shown to dampen the respiratory burst and to delay the apoptosis of human neutrophils by inducing phosphorylation of the transcription factor signal transducer and activator of transcription 3 (47), and to inhibit the differentiation of bone-marrow progenitor cells into DCs (95).

The failure to reverse suppression, when neutralizing antibodies against IL-10, TGF- and IGF were added to MLR reactions does point to the possibility that MSC may secrete as yet uncharacterized immunosuppressive factors (93). Galectin-1 and Galectin-3, newly characterized lectins, are constitutively expressed and secreted by human bone marrow MSC. Inhibition of galectin-1 and galectin-3 gene expression with small interfering RNAs abrogated the suppressive effect of MSC on allogeneic T-cells (Fig 1) (96). The restoration of T-cell proliferation in the presence of - lactose indicates that the carbohydrate-recognition domain of galectins is responsible for the immunosuppression of T-cells and highlights an extracellular mechanism of action for the MSC-secreted galectins. In this respect, the inhibition of T-cell proliferation could result from either direct effects of galectin-1 and galectin-3 on T cells and/or through a direct or an indirect on effect on dendritic cells (97).

HLA-G5 represents another important molecule involved in MSC mediated regulation of the immune response, where its production has been shown to suppress T-cell proliferation, as well as NK-cell and T-cell cytotoxicity, while promoting the generation of Tregs (63, 98). HLA-G protein expression is constitutive and the level is not modified upon stimulation by allogeneic lymphocytes in MSC/MLR. HLA-G5 is detected on MSCs by real-time reverse-phase polymerase chain reaction, immune-fluorescence, flow cytometry and enzyme-linked immunosorbent assay in the supernatant (99). Cell contact between MSCs and activated T-cells induces IL-10 production, which, in turn, stimulates the release of soluble HLA-G5 by MSCs (63). It is worth nothing that none of these molecules have an exclusive role and that MSC-mediated immune-regulation is a redundant system that is mediated by several molecules.

One important characteristic of hMSCs is their ability to suppress inflammation resulting from injury, as well as, resulting from allogeneic solid organ transplants, and autoimmune disease. Consistent with in vitro studies, murine allogeneic MSCs are effective cellular therapy models in the treatment of murine models of human disease (52, 100-102). Several studies have documented the substantial clinical improvements observed in animal models, when MSC were systemically introduced as a therapy in mouse models of multiple sclerosis (102, 103), inflammatory bowel disease (104-106), infarct, stroke, and other neurologic diseases (107, 108), as well as diabetes (109). These findings strongly suggest that xenogeneic hMSCs are not immunologically recognized by various immunocompetent mouse models of disease and are able to home to sites of inflammation. However, the mechanisms behind the immunosuppressive actions at the site of inflammation and its association with the homing activity have not yet been completely elucidated.

Nitric Oxide (NO) mediate its effect partly through phosphorylation of Stat-5, which results in suppression of T- cell proliferation, partly through the inhibition of NO synthase or the inhibition of prostaglandin synthesis. This reveals the MSC-dependent effects on proliferation. Although indoleamine-2, 3-dioxygenase (IDO) has been hypothesized to be critical in mediating the effect of NO, neutralizing IDO by using a blocking antibody did not interfere with NOs suppressive effects (93, 110).

Within an in vivo setting, injury, inflammation, and/or foreign cells can lead to T-cell activation, which results in those T-cells producing proinflammatory cytokines including, but not limited to, TNF-, IFN-, IL-1, and IL-1. Combinations of cytokines may also induce cell production of chemokines, some of which bind to CXCR3-R expressing cells (including T cells) that co-localize with MSCs. MSCs then produce NO, which inhibits Stat-5 phosphorylation, thereby leading to cell-cycle arrest (and thus halting T cell proliferation) (Fig 1) (110). In addition, iNOS appears to be important in mouse MSC in vivo effects. MSCs from mice that lack iNOS (or IFN-R1) are unable to suppress GVHD. In contrast to mouse MSCs that use NO in mediating their immune-suppressive effect, hMSCs and MSCs from non-human primates appear to mediate their immune-suppressive effects via IDO (56). There is some controversy about whether the effect of IDO results from local depletion of tryptophan, or from the accumulation of tryptophan metabolites (which is suggested by data showing that use of a tryptophan antagonist, 1-methyl-L tryptophan, restored allo-reactivity that would otherwise have been suppressed by MSCs). In addition to its effect on the JAK-STAT pathway, NO may also influence mitogen activated protein kinase and nuclear factor B, which would cause a reduction in the gene expression of proinflammatory cytokines.

The clinical experience with and the safety of MSCs is of utmost interest for their wide therapeutic applications. The pioneering in vivo studies with MSC focused on the engraftment facilitation for the haematopoietic stem cells (111). Further work also focused on the regenerative functions of MSC in terms of functional repair of damaged tissues (112). Hypoimmunogenicity of MSC provided a critical advantage in their use for clinical and therapeutic purposes in vitro (50), followed by pre-clinical studies (29) and reaching the human clinical studies (32) with the use of allogeneic donors. Allogeneic MSC have proved to be an option with major advantages in clinical use, since the use of autologous MSC is hindered by the limited time frame for clonal expansion and the costly in vitro proliferation. However, some sub-acute conditions, such as autoimmune diseases, might allow the use of autologous MSCs and their culture in vitro. It is worth noting that some reports have recently challenged the belief that allogeneic MSCs are poorly immunogenic (113, 114), indicating that in some cases an autologous MSC source could be advantageous. Recent reports have shown that MSCs from patients with autoimmune disease have a normal capability to support hematopoiesis, (115) and to exercise immunomodulatory functions (116), and to show a normal phenotypic characteristics (117).

The perspective role of adult stem cells in degenerative disease conditions, where there is progressive tissue damage and an inability to repair, possibly due to the depletion of stem cell populations or functional alteration, has been considered. In cases of osteoarthritis, a disease of the joints where there is progressive and irreversible loss of cartilage characterized by changes in the underlying bone, Murphy et al showed that the proliferative capacity of the MSC was substantially reduced, and this was independent of the harvest site from patients with end-stage OA undergoing joint replacement surgery (118). In this study the marrow samples were harvested both from the site of surgery (either the hip or the knee) and also from the iliac crest. These effects were apparently disease-related, and not age-related. However, the data suggest that susceptibility to OA and perhaps other degenerative diseases may be due to the reduced mobilization or proliferation of stem cells. In addition, successfully recruited cells may have a limited capacity to differentiate, leading to defective tissue repair. Alternatively, the altered stem cell activity may be in response to the elevated levels of inflammatory cytokines seen in OA, which was confirmed by several other investigators (119, 120).

Similarly, the functional impairment of the anti-proliferative effect of MSCs derived from patients with aplastic anaemia (121) or multiple myeloma (122) might be resulting from an intrinsic abnormality in the microenvironment of the bone marrow, which is consistent with the possible use of autologous MSC for therapeutic purposes.

With the knowledge of the homing capacity of MSC and their capacity to engraft into the recipients bone after systemic administration, MSCs have been utilized to treat children with severe osteogenesis imperfecta, leading to improved parameters of increased growth velocity and total body mineral content associated with fewer fractures (123). Systemic infusion of allogeneic MSCs also led to encouraging bone marrow recovery in patients with tumors following chemotherapy (123). The immunosuppressive effect of infused MSCs has been successfully shown in acute, severe graft-versus-host disease (GvHD) (32). The probable effect of MSC was the inhibition of donor T-cell reactivity to histocompatibility antigens of the recipient tissue. Currently, there is no successful therapy for steroid-refractory acute GVHD. The possible role of MSCs in this context is therefore of potential interest. Le Blanc et al reported a case of grade IV acute GVHD of the gut and liver in a patient who had undergone ASCT with cells from an unrelated female donor (32). The patient was unresponsive to all types of immunosuppression drugs. When the patient was infused with 2x 106 MSCs per kilogram from his HLA-haploidentical mother, his GVHD responded with a decline in bilirubin and normalization of stools. After the MSC infusion, DNA analysis of his bone marrow showed the presence of minimal residual disease (124). When immunosuppression was discontinued, the patient again developed severe acute GVHD, with its associated symptoms within a few weeks.

Modulation of host allo-reactivity led to accelerated bone-marrow recovery in patients co-transplanted with MSCs and haplo-identical HSCs (125). Clinical trials are being conducted on the immunomodulatory potential of MSCs in the treatment of Crohns disease, with the potential for those cells to contribute to the regeneration of gastrointestinal epithelial cells (126).

As described previously, MSCs are characterized by their hypoimmunogenicity. In 2000, data from several research groups demonstrated long-term allo-MSC engraftment in a variety of non-cardiac tissues in the absence of immunosuppression (88, 90). On the basis of these observations, investigators began to look into the possibility of allo-MSCs engraftment into affected myocardium in rats, and later in swine, where allo-MSCs were found to readily engraft in necrotic myocardium and favorably alter ventricular function (2). The allo-MSC engraftment occurred without evidence of immunologic rejection or lymphocytic infiltration in the absence of assisted immunosuppressive therapy emphasizing some of the apparent advantages of these cells over other cell populations for cellular cardiomyoplasty. The immunologically privileged status of MSCs was also observed in xenogeneic setting, where Saito et al injected MSC intravenously from C57BL/6 mice into immunocompetent adult Lewis rats (127). When these animals were later subjected to MIs, murine MSCs could be identified in the region of necrosis, and these cells expressed muscle specific proteins not present before coronary ligation.

Consistent with results from in vitro studies, murine allogeneic MSCs are effective in the treatment of murine models of human disease (52, 103, 128). Several studies have reported clinical improvements in mouse models of multiple sclerosis and amyotrophic lateral sclerosis, inflammatory bowel disease, stroke, diabetes, infarct and GVHD using I.V. injected xenogeneic hMSCs rather than allogeneic MSCs (108, 109). A major advantage in using hMSCs in mouse models of human disease is that the possibility of gathering mechanistic data through measuring biomarkers from body fluids or using noninvasive imaging technology, which may prove to be an advantage in clinical studies when applied on humans.

In experiments designed to study the trafficking of hMSCs, investigators used mouse models of severe erosive polyarthritis characterized by an altered transgene allele that results in chronic over-expression of TNF- and which resemble human RA patients (60, 72). The motive behind utilizing these mice models was to investigate similarities in MSC homing with mouse models of chronic asthma and acute lung injury. Injected hMSC revealed a reduction in ankle arthritis parameters associated with decrease appendage related erythema, possibly due to the MSC localization to ankle joints as revealed by bioluminescence (129). Similar observations for inducing tolerance were made using adipose-derived MSC, where Treg were induced in RA PBMC and in mouse models of arthritis (36, 130). Furthermore, studies of rheumatoid arthritis T-cells showed a down-regulation of effector response using adipose-derived MSCs (131). Variations in this potential described by the capability of MSCs to down-regulate collagen-induced arthritis, and in the ability to induce Tregs, depend on the source of MSC (mouse vs. human) and its characteristics (primary isolate of MSC line), which reflect on difference in function compared to primary expanded MSC (132). Other studies reported that in the collagen-induced model of arthritis, mice infused with MSCs have increased numbers of CD4+CD25+ cells that express FoxP3 and thus reveal a Treg phenotype (20). Recent data on collagen-induced arthritis model, where murine MSCs did not reveal therapeutic benefits against arthritis in vivo, but did show anti-proliferative effect in vitro suggest that there is no appropriate in vitro measures that can be accurately extrapolated into a potential therapeutic utility of MSCs in vivo, and that mouse MSCs show difference in functional characteristics to hMSC in terms of immunoregulatory capacity (133).

MSCs immunological properties appeared to have potential therapeutic advantages in other forms of autoimmune diseases, especially in type 1 diabetes. In NOD mouse model, several physiological defects that aim to maintain peripheral and central tolerance contribute to the development of autoimmune diabetes. These defects are summed up as a combination of immune cell dysfunction (including T-cell, NK cells, B-cells, and dendritic cells), associated with the presence of inflammatory cytokine milieu (134). MSCs possess specific immunomodulatory properties capable of halting autoimmunity through immunomodulation processes described in this chapter. The processes might be through a direct effect via the presentation of differential levels of negative costimulatory molecules and the secretion of regulatory cytokines that affect regulatory T-cells/autoreactive T-cells. Furthermore, MSCs could modulate the immunological dysregulation observed in antibody producing B-cells and cytotoxic NK cells. Dendritic cells have been shown to be defective in NOD mice characterized by higher levels of costimulation with a potential capability to shift to a TH-1 type of immune response.

In an experimental mouse model of diabetes induced by streptozotocin, it was observed that MSCs promoted the endogenous repair of pancreatic islets and renal glomeruli (109). Similarly, co-infusion of MSCs and bone-marrow cells inhibited the proliferation of -cell-specific T-cells isolated from the pancreas of diabetic mice and restored insulin and glucose levels through the induction of recipient-derived pancreatic -cell regeneration in the absence of trans-differentiation of MSCs (135). These studies show that the in vivo administration of MSCs is clinically efficacious through the modulation of pathogenic - and T-cell responses and through potent bystander effects on the target tissue.

The timing of MSC infusion seems to be a critical parameter in their therapeutic efficacy. In the EAE mouse model of multiple sclerosis, MSC systematically injected at disease onset ameliorated myelin oligodendrocyte glycoprotein (MOG)-induced EAE and further decreased the infiltration T-cells, B-cells and macrophages into the central nervous system (CNS). Furthermore, T cells isolated from the lymph nodes of MSC-treated mice did not proliferate after in vitro re-challenge with MOG peptide, which is an indication of the induction of T-cell anergy (52). Systematic injection of MSCs was found to inhibit the in vivo production of pathogenic plp-specific antibodies and to suppress the encephalitogenic potential of plp-specific T cells in passive-transfer experiments. In this model, the MSCs migrated to the lymphoid organs, as well as, to the inflamed CNS, where they exercised a protective effect on the neuronal axons in situ (135, 136). In these studies, the therapeutic effect of MSCs depended on the release of anti-apoptotic, anti-inflammatory and trophic molecules, as occurred in the case of stroke in rats (137), and, possibly, on the recruitment of local progenitors and their subsequent induction to differentiate into neural cells (138). As trophic effect, the MSCs appeared to favor oligo-dendrogenisis by neural precursor cells (139).

Several other studies have provided insights into the effects of MSCs mediated by cytokines. In a model of acute renal failure, the administration of MSCs increased the recovery of renal function through the inhibition of production of proinflammatory cytokines, such as Il-1, TNF and IFN, and through an anti-apoptotic effect on target cells (140). Along the same line, the anti-inflammatory activity of MSCs was revealed in a mouse model of lung fibrosis, where they inhibited the effects of IL-1-producing T cells and TNF-producing macrophages through the release of IL-1 receptor antagonist (IL-1RA) (141). The release of trophic factors such as the WNT-associated molecule secreted frizzled-related protein 2 (SFRp2), which leads to the rescue of ischemic cardiomyocytes and the restoration of ventricular functions represent another important function for MSC (142).

With all the promising therapeutic potential of MSC, there seems to be a growing concern about their association with tumors. The immunoregulatory and anti-proliferative effects of MSCs led to several studies investigating the inhibitory effect of MSCs on tumor growth. Inhibition or, more frequently, stimulation of tumor-cell proliferation in vitro and/or tumor growth in vivo by MSCs has been reported (143-145). The heterogeneous nature of the MSC populations and the different experimental tumor models used, contribute to the effect of tumors on MSC in which the microenvironment generated by tumors influence the behavior of MSCs (146). Two main mechanisms are probably involved in the enhancement of tumor growth by MSCs. First, the cell-to-cell cross-talk between MSCs and tumor cells contribute to tumor progression, thus integrating within the tumor stroma (147), and second, the suppressive effects of MSCs on the immune system of tumor-bearing hosts might facilitate tumorigenesis, as shown for the inhibition of melanoma rejection, possibly mediated by regulatory CD8+ T cells (144). Irrespective of the possible interactions between cancer cells, immune cells and MSCs, the potential risk of stimulating the growth cancer by MSCs must be considered.

As a whole, the data accumulated from preclinical and clinical data indicate that bone marrow-derived MSCs have, in addition to their therapeutic purposes in regenerative medicine, effects that can result from other characteristics, such as their anti-proliferative and anti-inflammatory properties. The immuno suppressive activity of MSCs provides means for inducing peripheral tolerance following systemic injection mediated through the inhibition of cell division, thereby preventing their responsiveness to antigenic triggers while maintaining them in a quiescent state. In addition, the clinical efficacy of MSCs in different experimental model seems to occur almost only during the acute phase of disease associated with limited trans-differentiation, which indicates that the therapeutic effectiveness of MSCs relies heavily on their ability to modify microenvironments. These modifications occur through the release of anti-inflammatory cytokines, and anti-apoptotic and trophic molecules that promote the repair and protection of damaged tissues, as well as, maintain the integrity of the immune cells.

Read more:
Mesenchymal Stem Cells: Immunology and Therapeutic ...

Recommendation and review posted by Bethany Smith

Conference Series LLCinvites all the participants from all over the world to attend '8th World Congress on Cell & Stem Cell Research during March 20-22, 2017 in Orlando, USA which includes prompt keynote presentations, Oral talks, Poster presentations and Exhibitions.

Stem cellsare cells originate in all multi-cellular organisms. They were isolated in mice in 1981 and in humans in 1998. In humans there are several types of stem cells, each with variable levels of potency. Stem cell treatments are a type of cell therapy that introduces new cells into adult bodies for possible treatment of cancer, diabetes, neurological disorders and other medical conditions. Stem cells have been used to repair tissue damaged by disease or age.

Objective

Stem Cell Research-2017 has the platform to fulfill the prevailing gaps in the transformation of this science of hope, to serve promptly with solutions to all in the need. Stem Cell Research 2017 will have an anticipated participation of 120+ delegates across the world to discuss the conference goal.

Success Story: Cell Science Conference Series

The success of the Cell Science conference series has given us the prospect to bring the gathering inOrlando,USA. Since its commencement in 2011 Cell Science series has witnessed around 750 researchers of great potentials and outstanding research presentations from around the world. Awareness of stem cells and its application is becoming popular among the general population. Parallel offers of hope add woes to the researchers of cell science due to the potential limitations experienced in the real-time.

About Organizers

Conference Series LLCis one of the leadingOpen Access publishersand organizers of international scientificconferences and events every year across USA, Europe & Asia Conference Series LLChas so far organized 3000+Global Conferenceseries Events with over 600+ Conferences, 1200+ Symposiums and 1200+ Workshops on Medical, Pharma, Engineering, Science, Technology and Business with 700+ peer-reviewed open accessjournalsin basic science, health, and technology. OMICS International is also in association with more than 1000 International scientific and technological societies and associations and a team of 30,000 eminent scholars, reputed scientists as editorial board members.

Scientific Sessions

Stem Cell Research-2017 will encompass recent researches and findings in stem cell technologies, stem cell therapies and transplantations, current understanding of cell plasticity in cancer and other advancements in stem cell research and cell science.Stem Cell Research-2017 will be a great platform for research scientists and young researchers to share their current findings in this field of applied science. The major scientific sessions in Stem Cell Research-2017will focus on the latest and exciting innovations in prominent areas of cell science and stem cell research.

Target Audience:

Eminent personalities, Directors, CEO, President, Vice-president, Organizations, Associations heads and Professors, Research scientists, Stem Cell laboratory heads, Post-docs, Students other affiliates related to the area of Stem cell research, stem cell line companies can be as Target Audience.

8th World Congress on Cell & Stem Cell Research

The success of the 7 Cell Science conferences series has given us the prospect to bring the gathering one more time for our 8thWorld Congress 2017 meet in Orlando, USA. Since its commencement in 2011 cell science series has perceived around 750 researchers of great potentials and outstanding research presentations around the globe. The awareness of stem cells and its application is increasing among the general population that also in parallel offers hope and add woes to the researchers of cell science due to the potential limitations experienced in the real-time.

Stem Cell Research-2017has the goal to fill the prevailing gaps in the transformation of this science of hope to promptly serve solutions to all in the need.World Congress 2017 will have an anticipated participation of 100-120 delegates from around the world to discuss the conference goal.

History of Stem cells Research

Stem cells have an interesting history, in the mid-1800s it was revealed that cells were basically the building blocks of life and that some cells had the ability to produce other cells. Efforts were made to fertilize mammalian eggs outside of the human body and in the early 1900s, it was discovered that some cells had the capacity to generate blood cells. In 1968, the first bone marrow transplant was achieved successfully to treat two siblings with severe combined immunodeficiency. Other significant events in stem cell research include:

1978: Stem cells were discovered in human cord blood 1981: First in vitro stem cell line developed from mice 1988: Embryonic stem cell lines created from a hamster 1995: First embryonic stem cell line derived from a primate 1997: Cloned lamb from stem cells 1997: Leukaemia origin found as haematopoietic stem cell, indicating possible proof of cancer stem cells

Funding in USA:

No federal law forever did embargo stem cell research in the United States, but only placed restrictions on funding and use, under Congress's power to spend. By executive order on March 9, 2009, President Barack Obama removed certain restrictions on federal funding for research involving new lines of humanembryonic stem cells. Prior to President Obama's executive order, federal funding was limited to non-embryonic stem cell research and embryonic stem cell research based uponembryonic stem celllines in existence prior to August 9, 2001. In 2011, a United States District Court "threw out a lawsuit that challenged the use of federal funds for embryonic stem cell research.

Members Associated with Stem Cell Research:

Discussion on Development, Regeneration, and Stem Cell Biology takes an interdisciplinary approach to understanding the fundamental question of how a single cell, the fertilized egg, ultimately produces a complex fully patterned adult organism, as well as the intimately related question of how adult structures regenerate. Stem cells play critical roles both during embryonic development and in later renewal and repair. More than 65 faculties in Philadelphia from both basic science and clinical departments in the Division of Biological Sciences belong to Development, Regeneration, and Stem Cell Biology. Their research uses traditional model species including nematode worms, fruit-flies, Arabidopsis, zebrafish, amphibians, chick and mouse as well as non-traditional model systems such as lampreys and cephalopods. Areas of research focus include stem cell biology, regeneration, developmental genetics, and cellular basis of development, developmental neurobiology, and evo-devo (Evolutionary developmental biology).

Stem Cell Market Value:

Worldwide many companies are developing and marketing specialized cell culture media, cell separation products, instruments and other reagents for life sciences research. We are providing a unique platform for the discussions between academia and business.

Global Tissue Engineering & Cell Therapy Market, By Region, 2009 2018

$Million

Why to attend???

Stem Cell Research-2017 could be an outstanding event that brings along a novel and International mixture of researchers, doctors, leading universities and stem cell analysis establishments creating the conference an ideal platform to share knowledge, adoptive collaborations across trade and world, and assess rising technologies across the world. World-renowned speakers, the most recent techniques, tactics, and the newest updates in cell science fields are assurances of this conference.

A Unique Opportunity for Advertisers and Sponsors at this International event:

http://stemcell.omicsgroup.com/sponsors.php

UAS Major Universities which deals with Stem Cell Research

University of Washington/Hutchinson Cancer Center

Oregon Stem Cell Center

University of California Davis

University of California San Francisco

University of California Berkeley

Stanford University

Mayo Clinic

Major Stem Cell Organization Worldwide:

Norwegian Center for Stem Cell Research

France I-stem

Stem Cell & Regenerative Medicine Ctr, Beijing

Stem Cell Research Centre, Korea

NSW Stem Cell Network

Monash University of Stem Cell Labs

Australian Stem Cell Centre

Target Audience:

Eminent personalities, Directors, CEO, President, Vice-president, Organizations, Associations heads and Professors, Research scientists, Stem Cell laboratory heads, Post-docs, Students other affiliates related to the area of Stem cell research, stem cell line companies can be as Target Audience

Market Analysis of Stem Cell Therapy:

The global market for stem cell products was $3.8 billion in 2011. This market is expected to reach nearly $4.3 billion in 2012 and $6.6 billion by 2016, increasing at a compound annual growth rate (CAGR) of 11.7% from 2011 to 2016.

Americas is the largest region of global stem cell market, with a market share of about $2.0 billion in 2013. The region is projected to increase to nearly $3.9 billion by 2018, with a CAGR of 13.9% for the period of 2013 to 2018

Europe is the second largest segment of the global stem cell market and is expected to grow at a CAGR of 13.4% reaching about $2.4 billion by 2018 from nearly $1.4 billion in 2013.

Figure 2:Global Market

Companies working for Stem Cells:

Company

Location

Business Type

Cynata Therapeutics

Armadale, Australia

Stem Cell Manufacturing Technology

Mesoblast

Melbourne, Australia

Regenerative Medicine

Activartis

Vienna, Austria

Dendritic Cell-Based Cancer Immunotherapy

Aposcience

Vienna, Austria

Treatments composed of mixture of cytokines, growth factors and other active components

Cardio3 Biosciences

Mont-Saint-Guibert, Belgium

Stem Cell Differentiation

Orthocyte (BioTime)

Alameda, CA

Cellular Therapies

Capricor

Beverly Hills, CA

Stem Cell Heart Treatments

Life Stem Genetics

Beverly Hills, CA

Autologous stem cell therapy

International Stem Cell

Carlsbad, CA

Proprietary Stem Cell Induction

Targazyme

Carlsbad, CA

Cell Therapy

DaVinci Biosciences

Costa Mesa, CA

Cellular Therapies

Invitrx Therapeutics

Irvine, CA

Autologous Stem Cell Therapy, Therapeutic & Cosmetic

Stem Cell Softwares :

Products Manufactured By Industry Related to Stem Cell:

Excerpt from:
Worlds leading Stem Cell Conference | Global Meetings ...

Recommendation and review posted by Bethany Smith

Persons using assistive technology might not be able to fully access information in this file. For assistance, please send e-mail to: mmwrq@cdc.gov. Type 508 Accommodation and the title of the report in the subject line of e-mail.

Prepared by

Bin Chen, PhD

MariBeth Gagnon, MS

Shahram Shahangian, PhD

Nancy L. Anderson, MMSc

Devery A. Howerton, PhD

D. Joe Boone, PhD

Division of Laboratory Systems, National Center for Preparedness, Detection, and Control of Infectious Diseases, Coordinating Center for Infectious Diseases

The material in this report originated in the Coordinating Center for Infectious Diseases, Mitchell L. Cohen, MD, Director; National Center for Preparedness, Detection, and Control of Infectious Diseases, Rima Khabbaz, MD, Director; and the Division of Laboratory Systems, Roberta B. Carey, PhD, Acting Director.

Corresponding preparer: Bin Chen, PhD, Division of Laboratory Systems, National Center for Preparedness, Detection, and Control of Infectious Diseases, Coordinating Center for Infectious Diseases, 1600 Clifton Road NE, MS G-23, Atlanta, GA 30329. Telephone: 404-498-2228; Fax: 404-498-2215; E-mail: bkc1@cdc.gov.

Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) regulations, laboratory testing is categorized as waived (from routine regulatory oversight) or nonwaived based on the complexity of the tests; tests of moderate and high complexity are nonwaived tests. Laboratories that perform molecular genetic testing are subject to the general CLIA quality systems requirements for nonwaived testing and the CLIA personnel requirements for tests of high complexity. Although many laboratories that perform molecular genetic testing comply with applicable regulatory requirements and adhere to professional practice guidelines,specific guidelines for quality assurance are needed to ensure the quality of test performance. To enhance the oversight of genetic testing under the CLIA framework,CDC and the Centers for Medicare & Medicaid Services (CMS) have taken practical steps to address the quality management concerns in molecular genetic testing,including working with the Clinical Laboratory Improvement Advisory Committee (CLIAC). This report provides CLIAC recommendations for good laboratory practices for ensuring the quality of molecular genetic testing for heritable diseases and conditions. The recommended practices address the total testing process (including the preanalytic,analytic,and postanalytic phases),laboratory responsibilities regarding authorized persons,confidentiality of patient information,personnel competency,considerations before introducing molecular genetic testing or offering new molecular genetic tests,and the quality management system approach to molecular genetic testing. These recommendations are intended for laboratories that perform molecular genetic testing for heritable diseases and conditions and for medical and public health professionals who evaluate laboratory practices and policies to improve the quality of molecular genetic laboratory services. This report also is intended to be a resource for users of laboratory services to aid in their use of molecular genetic tests and test results in health assessment and care. Improvements in the quality and use of genetic laboratory services should improve the quality of health care and health outcomes for patients and families of patients.

Genetic testing encompasses a broad range of laboratory tests performed to analyze DNA, RNA, chromosomes, proteins, and certain metabolites using biochemical, cytogenetic, or molecular methods or a combination of these methods. In 1992, the regulations for the Clinical Laboratory Improvement Amendments of 1988 (CLIA) were published and began to be implemented. Since that time, advances in scientific research and technology have led to a substantial increase both in the health conditions for which genetic defects or variations can be detected with molecular methods and in the spectrum of the molecular testing methods (1). As the number of molecular genetic tests performed for patient testing has steadily increased, so has the number of laboratories that perform molecular genetic testing for heritable diseases and conditions (2,3). With increasing use in clinical and public health practices, molecular genetic testing affects persons and their families in every life stage by contributing to disease diagnosis, prediction of future disease risk, optimization of treatment, prevention of adverse drug response, and health assessment and management. For example, preconception testing for cystic fibrosis and other heritable diseases has become standard practice for the care of women who are either pregnant or considering pregnancy and are at risk for giving birth to an infant with one of these conditions (4). DNA-based diagnostic testing often is crucial for confirming presumptive results from newborn screening tests, which are performed forapproximately95% of the 4 million infants born in the United States each year (5,6). In addition, pharmacogenetic and pharmacogenomic tests, which identify individual variations in single-nucleotide polymorphisms, haplotype markers, or alterations in gene expression, are considered essential for personalized medicine, which involves customizing medical care on the basis of genetic information (7).

The expanding field of molecular genetic testing has prompted measures both in the United States and worldwide to assess factors that affect the quality of performance and delivery of testing services, the adequacy of oversight and quality assurance mechanisms, and the areas of laboratory practice in need of improvement. Problems that could affect patient testing outcomes that have been reported include inadequate establishment or verification of test performance specifications, inadequate personnel training or qualifications, inappropriate test selection and specimen submission, inadequate quality assurance practices, problems in proficiency testing, misunderstanding or misinterpretation of test results, and other concerns associated with one or more phases of the testing process (8--11).

Under CLIA, laboratory testing is categorized as waived testing or nonwaived (which includes tests of moderate and high complexity) based on the level of testing complexity. Laboratories that perform molecular genetic testing are subject to general CLIA requirements for nonwaived testing and CLIA personnel requirements for high-complexity testing; no molecular genetic test has been categorized as waived or moderate complexity. Many laboratories also adhere to professional practice guidelines and voluntary or accreditation standards, such as those developed by the American College of Medical Genetics (ACMG), the Clinical and Laboratory Standards Institute (CLSI), and the College of American Pathologists (CAP), which provide specific guidance for molecular genetic testing (12--14). In addition, certain state programs, such as the New York State Clinical Laboratory Evaluation Program (CLEP), have specific requirements that apply to genetic testing laboratories in their purview (15). However, no specific requirements exist at the federal level for laboratory performance of molecular genetic testing for heritable diseases and conditions.

Since 1997, CDC and the Centers for Medicare & Medicaid Services (CMS) have worked with other federal agencies, professional organizations, standard-setting organizations, CLIAC, and other advisory committees to promote the quality of genetic testing and improve the appropriate use of genetic tests in health care. To enhance the oversight of genetic testing under CLIA, CMS developed a multifaceted action plan aimed at providing guidelines, including the good laboratory practice recommendations in this report, rather than prescriptive regulations (16). Many of the activities in the action plan have been implemented or are in progress, including 1) providing CMS and state CLIA surveyors with guidelines and technical training on assessing genetic testing laboratories for compliance with applicable CLIA requirements, 2) developing educational materials on CLIA compliance for genetic testing laboratories, 3) collecting data on laboratory performance in genetic testing, 4) working with CLIAC and standard-setting organizations on oversight concerns, and 5) collaborating with CDC and the Food and Drug Administration (FDA) on ongoing oversight activities (16). This plan also was supported by the Secretary's Advisory Committee on Genetics, Health, and Society (SACGHS) in its 2008 report providing recommendations regarding future oversight of genetic testing (1).

The purposes of this report are to 1) highlight areas of molecular genetic testing that have been recognized by CLIAC as needing specific guidelines for compliance with existing CLIA requirements or needing quality assurance measures in addition to CLIA requirements and 2) provide CLIAC recommendations for good laboratory practices to ensure the quality of molecular genetic testing for heritable diseases and conditions. These recommendations are intended primarily for genetic testing that is conducted to diagnose, prevent, or treat disease or for health assessment purposes. The recommendations are distinct from the good laboratory practice regulations for nonclinical laboratory studies under FDA oversight (21 CFR Part 58) (17).The recommended laboratory practices provide guidelines for ensuring the quality of the testing process (including the preanalytic, analytic, and postanalytic phases of molecular genetic testing), laboratory responsibilities regarding authorized persons, confidentiality of patient information, and personnel competency. The recommendations also address factors to consider before introducing molecular genetic testing or offering new molecular genetic tests and the quality management system approach in molecular genetic testing. Implementation of the recommendations in laboratories that perform molecular genetic testing for heritable diseases and conditions and an understanding of these recommendations by users of laboratory services are expected to prevent or reduce errors and problems related to test selection and requests, specimen submission, test performance, and reporting and interpretation of results, leading to improved use of molecular genetic laboratory services, better health outcome for patients, and in many instances, better health outcomes for families of patients. In future reports, recommendations will be provided for good laboratory practices focusing on other areas of genetic testing, such as biochemical genetic testing, molecular cytogenetic testing, and somatic genetic testing.

With the completion of the human genome project, discoveries linking genetic mutations or variations to specific diseases and biologic processes are frequently reported (18). The rapid progress in biomedical research, accompanied by advances in laboratory technology, have led to increased opportunities for development and implementation of new molecular genetic tests. For example, the number of heritable diseases and conditions for which clinical genetic tests are available more than tripled in 8 years, from 423 diseases in November 2000 to approximately 1,300 diseases and conditions in October 2008 (2,19). Molecular genetic testing is performed not only to detect or confirm rare genetic diseases or heritable conditions (20) but also to detect mutations or genetic variations associated with more common and complex conditions such as cancer (21,22), coagulation disorders (23), cardiovascular diseases (24), and diabetes (25). As the rapid pace of genetic research results in a better understanding of the role of genetic variations in diseases and health conditions, the development and clinical use of molecular genetic tests continues to expand (26--28).

Despite considerable information gaps regarding the number of U.S. laboratories that perform molecular genetic tests for heritable diseases and conditions and the number of specific genetic tests being performed (1), molecular genetic testing is one of the areas of laboratory testing that is increasing most rapidly. Molecular genetic tests are performed by a broad range of laboratories, including laboratories that have CLIA certificates for chemistry, pathology, clinical cytogenetics, or other specialties or subspecialties (11). Although nationwide data are not available, data from state programs indicate considerable increases in the numbers of laboratories that perform molecular genetic tests. For example, the number of approved laboratories in the state of New York that perform molecular genetic testing for heritable diseases and conditions increased 36% in 6 years, from 25 laboratories in February 2002 to 34 laboratories in October 2008 (29).

Although comprehensive data on the annual number of molecular genetic tests performed nationwide are not available, industry reports indicate a steady increase in the number of common molecular genetic tests for heritable diseases and conditions, such as mutation testing for cystic fibrosis and factor V Leiden thrombophilia (3). The number of cystic fibrosis mutation tests has increased significantly since 2001, pursuant to the recommendations of the American College of Obstetricians and Gynecologists and ACMG for preconception and prenatal carrier screening (30,31). The DNA-based cystic fibrosis mutation tests are now considered to be some of the most commonly performed genetic tests in the United States and have become an essential component of several state newborn screening programs for confirming presumptive screening results of infants (32). The overall increase in molecular genetic testing from 2006 to 2007 worldwide has been reported to be 15% in some market analyses, outpacing other areas of molecular diagnostic testing (33).

In 1988, Congress enacted Public Law 100-578, a revision of Section 353 of the Public Health Service Act (42 U.S.C. 263a) that amended the Clinical Laboratory Improvement Act of 1967 and required the Department of Health and Human Services (HHS) to establish regulations to ensure the quality and reliability of laboratory testing on human specimens for disease diagnosis, prevention, or treatment or for health assessment purposes. In 1992, HHS published CLIA regulations that describe requirements for all laboratories that perform patient testing (34). Facilities that perform testing for forensic purposes only and research laboratories that test human specimens but do not report patient-specific results are exempt from CLIA regulations (34). CMS (formerly the Health Care Financing Administration) administers the CLIA laboratory certification program in conjunction with FDA and CDC. FDA is responsible for test categorization, and CDC is responsible for CLIA studies, convening CLIAC, and providing scientific and technical support to CMS. CLIAC was chartered by HHS to provide recommendations and advice regarding CLIA regulations, the impact of CLIA regulations on medical and laboratory practices, and modifications needed to CLIA standards to accommodate technological advances.

In 2003, CMS and CDC published CLIA regulatory revisions to reorganize and revise CLIA requirements for quality systems for nonwaived testing and the laboratory director qualifications for high-complexity testing (35). The revised regulations included facility administration and quality system requirements for every phase of the testing process (35). Requirements for the clinical cytogenetics specialty also were reorganized and revised. Other genetic tests, such as molecular genetic tests, are not recognized as a specialty or subspecialty under CLIA. However, because these tests are considered high complexity, laboratories that perform molecular genetic testing for heritable diseases and conditions must meet applicable general CLIA requirements for nonwaived testing and the personnel requirements for high-complexity testing (36).

To enhance oversight of genetic testing under CLIA, CMS developed a plan to promote a comprehensive approach for effective application of current regulations and to provide training and guidelines to surveyors and laboratories that perform genetic testing (16). CDC and CMS also have been assessing the need to revise and update CLIA requirements for proficiency testing programs and laboratories, taking into consideration the need for improved performance evaluation for laboratories that perform genetic testing (37).

Studies and reports since 1997 have revealed a broad range of concerns related to molecular genetic testing for heritable diseases and conditions, including safe and effective translation of research findings into patient testing, the quality of test performance and results interpretation, appropriate use of testing information and services in health management and patient care, the adequacy of quality assurance measures, and concerns involving the ethical, legal, economic, and social aspects of molecular genetic testing (1,9,22,38,39). Some of these concerns are indicative of the areas of laboratory practice that are in need of improvement, such as performance establishment and verification, proficiency testing, personnel qualifications and training, and results reporting (1,9,11,22,39).

Studies have indicated that although error rates associated with different areas of laboratory testing vary (40), the overall distribution of errors reported in the preanalytic, analytic, and postanalytic phases of the testing process are similar for many testing areas, including molecular genetic testing (9,11,39,40). The preanalytic phase encompasses test selection and ordering and specimen collection, processing, handling, and delivery to the testing site. The analytic phase includes selection of test methods, performance of test procedures, monitoring and verification of the accuracy and reliability of test results, and documentation of test findings. The postanalytic phase includes reporting test results and archiving records, reports, and tested specimens (41).

Studies have indicated that errors are more likely to occur during the preanalytic and postanalytic phases of the testing process than during the analytic phase, with most errors reported for the preanalytic phase (40,42--44). In the preanalytic phase, inappropriate selection of laboratory tests has been a significant source of errors (42,43). Misuse of laboratory services, such as unnecessary or inappropriate test requests, might lead to increased risk for medical errors, adverse patient outcome, and increased health-care costs (43). Although no study has determined the overall number of molecular genetic tests performed that could be considered unwarranted or unnecessary, a study of the use and interpretation of adenomatous polyposis coli gene (APC) testing for familial adenomatous polyposis and other heritable conditions associated with colonic polyposis indicated that 17% of the cases evaluated did not have valid indications for testing (22).

Although data are limited, studies also indicate that improvements are needed in the analytic phase of molecular genetic testing. A study of the frequency and severity of errors associated with DNA-based genetic testing revealed that errors related to specimen handling in the laboratory and other analytic steps ranged from 0.06% to 0.12% of approximately 92,000 tests evaluated (39). A subsequent meta-analysis indicated that these self-reported error rates were comparable to those detected in nongenetic laboratory testing (40). An analysis of performance data from the CAP molecular genetic survey program during 1995--2000 estimated the overall error rate for cystic fibrosis mutation analysis to be 1.5%, of which approximately 50% of the errors occurred during the analytic or postanalytic phases of testing (45). Unrecognized sequence variations or polymorphisms also could affect the ability of molecular genetic tests to detect or distinguish the genotypes being analyzed, leading to false-positive or false-negative test results. Such problems have been reported for some commonly performed genetic tests such as cystic fibrosis mutation analysis and testing for HFE-associated hereditary hemochromatosis (46,47).

The postanalytic phase of molecular genetic testing involves analysis of test results, preparation of test reports, and results reporting. The study on the use of the APC gene testing and interpretation of test results indicated that lack of awareness among health-care providers of APC test limitations was a primary reason for misinterpretation of test results (22). In a study assessing the comprehensiveness and usefulness of reports for cystic fibrosis and factor V Leiden thrombophilia testing, physicians in many medical specialties considered reports that included information beyond that specified by the general CLIA test report requirements to be more informative and useful than test reports that only met CLIA requirements; additional information included patient race/ethnicity, clinical history, reasons for test referral, test methodology, recommendations for follow-up testing, implications for family members, and suggestions for genetic counseling (48). Consistent with these findings, international guidelines for quality assurance in molecular genetic testing recommend that molecular genetic test reports be accurate, concise, and comprehensive and communicate all essential information to enable effective decision-making by patients and health care professionals (49).

Proficiency testing is a well-established practice for monitoring and improving the quality of laboratory testing (50,51) and is a key component of the external quality assessment process. Studies have indicated that using proficiency testing samples that resemble actual patient specimens could improve monitoring of laboratory performance (50,52--54). Participation in proficiency testing has helped laboratories reduce analytic deficiencies, improve testing procedures, and take steps to prevent future errors (55--59).

CLIA regulations have not yet included proficiency testing requirements for molecular genetic tests. Laboratories that perform molecular genetic testing must meet the general CLIA requirement to verify, at least twice annually, the accuracy of the genetic tests they perform (493.1236[c]) (36). Laboratories may participate in available proficiency testing programs for the genetic tests they perform to meet this CLIA alternative performance assessment requirement. Proficiency testing participation correlates significantly with the quality assurance measures in place among laboratories that perform molecular genetic testing (9,10). Because proficiency testing is a rigorous external assessment for laboratory performance, in 2008, SACGHS recommended that proficiency testing participation be required for all molecular genetic tests for which proficiency testing programs are available (1). Formal molecular genetic proficiency testing programs are available only for a limited number of tests for heritable diseases and conditions; in addition, the samples provided often are purified DNA, which do not typically require performance of all steps of the testing process, such as nucleic acid extraction and preparation (60). For many genetic conditions that are either rare or for which testing is performed by one or a few laboratories, substantial challenges in developing formal proficiency testing programs have been recognized (1).

Development of effective alternative performance assessment approaches to proficiency testing is essential for ensuring the quality of molecular genetic testing (1). Professional guidelines have been developed for laboratories to evaluate and monitor test performance when proficiency testing programs are not available (61). However, reports of the CAP molecular pathology on-site inspections indicate that deficiencies related to participation in interlaboratory comparison or alternative performance assessment are among the most frequently identified deficiencies, accounting for 3.9% of all deficiencies cited (62).

The ability of a test to diagnose or predict risk for a particular health condition is the test's clinical validity, which often is measured by clinical (or diagnostic) sensitivity, clinical (or diagnostic) specificity, and predictive values of the test for a given health condition. Clinical validity can be influenced by factors such as the prevalence of the disease or health condition, penetrance (proportion of persons with a mutation causing a particular disorder who exhibit clinical symptoms of the disorder), and modifiers (genetic or environmental factors that might affect the variability of signs or symptoms that occur with a phenotype of a genetic alteration). For genetic tests, clinical validity refers to the ability of a test to detect or predict the presence or absence of a particular disease or phenotype and often corresponds to associations between genotypes and phenotypes (1,28,63--69). The usefulness of a test in clinical practice, referred to as clinical utility, involves identifying the outcomes associated with specific test results (28). Clinical validity and clinical utility should be assessed individually for each genetic test because the implications might vary depending on the health condition and population being tested (38).

As advances in genomic research and technology result in rapid development of new genetic tests, concerns have been raised that certain tests, particularly predictive genetic tests, could become available without adequate assessment of their validity, benefits, and utility. Consequently, health professionals and consumers might not be able to make a fully informed decision about whether or how to use these tests. In 1997, a task force formed by a National Institutes of Health (NIH)--Department of Energy workgroup recommended that laboratories that perform patient testing establish clinical validity for the genetic tests they develop before offering them for patient testing and carefully review and document evidence of test validity if the test has been developed elsewhere (70). This recommendation was later included in a report of the Secretary's Advisory Committee on Genetic Testing (SACGT), which was established in 1998 to advise HHS on medical, scientific, ethical, legal, and social concerns raised by the development and use of genetic tests (38).

Public concerns about inadequate knowledge or documentation of the clinical validity of certain genetic tests were also recognized by SACGHS, the advisory committee that was established by HHS in 2002 to supersede SACGT (1). SACGHS recommended the development and support of sustainable public-private collaborations to fill the gaps in knowledge of the analytic validity, clinical validity, clinical utility, economic value, and population health impact of molecular genetic tests (1). Collaborative efforts that have been recognized include the Evaluation of Genomic Applications in Practice and Prevention (EGAPP) program, a CDC initiative to establish and evaluate a systematic, evidence-based process for assessing genetic tests and other applications of genomic technology in transition from research to clinical practice and public health (71), and the Collaboration, Education, and Test Translation (CETT) Program, which is overseen by the NIH Office of Rare Diseases to promote the effective transition of potential genetic tests for rare diseases from research settings into clinical settings (72).

The increase in direct-to-consumer (DTC) genetic testing (i.e., genetic tests offered directly to consumers with no health-care provider involvement) has raised concerns about the potential risks or misuses of certain genetic tests (73). As of October 2008, consumers could directly order laboratory tests in 27 states; in another 10 states, consumer-ordered tests are allowed under defined circumstances (74). As DTC genetic tests become increasingly available, various genetic profile tests have been marketed directly to the public that claim to answer questions regarding cardiovascular risks, drug metabolism, dietary arrangements, and lifestyles (73). In addition, DTC advertisements have caused a substantial increase in the demand for molecular genetic tests, such as those for hereditary breast and ovarian cancers (75,76). Although allowing easy access to the testing services, DTC genetic testing has raised concerns about the potential for inadequate pretest decision-making, misunderstanding of test results, access to tests of questionable clinical value, lack of necessary follow-up, and unexpected additional responsibilities for primary care physicians (77--80). Both the government and professional organizations have developed educational materials that provide guidance to consumers, laboratories, genetics professionals, and professional organizations regarding DTC genetic tests (80--82).

Studies indicate that qualifications of laboratory personnel, including training and experience, are critical for ensuring quality performance of genetic testing, because human error has the greatest potential influence on the quality of laboratory test results (9,83,84). A study of laboratories in the United States that perform molecular genetic testing suggested that laboratory adherence to voluntary quality standards and guidelines for genetic testing was significantly associated with laboratories directed or supervised by persons with board certification in medical genetics (9). Results of an international survey revealed a similar correlation between the quality assurance practices of a molecular genetic testing laboratory and the formal training of the laboratory director (10). Overall, the concerns recognized in publications and documented cases support the need to have trained, qualified personnel at all levels to ensure the quality of all phases of the genetic testing process.

To monitor and assess the scope and growth of molecular genetic testing in the United States, data were collected and analyzed from scientific articles, government reports, the CMS CLIA database, information from state programs, studies by professional groups, publicly available directories and databases of laboratories and laboratory testing, industry reports, and CDC studies (1--3,5,6,9,29,38,83,85--88). To evaluate factors in molecular genetic testing that might affect testing quality and to identify areas that would benefit from quality assurance guidelines, various documents were considered, including professional practice guidelines, CAP laboratory accreditation checklists, CLSI guidelines, state requirements, and international guidelines and standards (12--15,49,61,89--95).

Since 1997, CLIAC has provided HHS with recommendations on approaches needed to ensure the quality of genetic testing (37). At the February 2007 CLIAC meeting, CLIAC asked CDC and CMS to clarify critical concerns in genetic testing oversight and to provide a status report at the subsequent CLIAC meeting. At the September 2007 CLIAC meeting, CDC presented an overview of the regulatory oversight and voluntary measures for quality assurance of genetic testing and described a plan to develop and publish educational material on good laboratory practices. CDC solicited CLIAC recommendations to address concerns that presented particular challenges related to genetic testing oversight, including establishment and verification of performance specifications, control procedures for molecular amplification assays, proficiency testing, genetic test reports, personnel competency assessment, and the definition of genetic tests. CLIAC recommended convening a workgroup of experts in genetic testing to consider these concerns and provide input for CLIAC deliberation.

The CLIAC Genetic Testing Good Laboratory Practices Workgroup was formed. The workgroup conducted a series of meetings on the scope of laboratory practice recommendations needed for genetic testing and suggested that recommendations first be developed for molecular genetic testing for heritable diseases and conditions. The workgroup evaluated good laboratory practices for all phases of the genetic testing process after reviewing professional guidelines, regulatory and voluntary standards, accreditation checklists, international standards and guidelines, and other documents that provided general or specific quality standards applicable to molecular genetic testing for heritable diseases and conditions (1,12--15,36,41,49,61,80,82,91--109). The workgroup also reviewed information on the HHS-approved and other certification boards for laboratory personnel and the number of persons certified in each of the specialties for which certification is available (110--118). Workgroup suggestions were reported to CLIAC at the September 2008 committee meeting. The CLIAC recommendations were formed on the basis of the workgroup report and additional CLIAC recommendations. The committee recommended that CDC include the CLIAC-recommended good laboratory practices for molecular genetic testing in the planned publication. Summaries of CLIAC meetings and CLIAC recommendations are available (37).

The following recommended good laboratory practices are for areas of molecular genetic testing for heritable diseases and conditions in need of guidelines for complying with existing CLIA requirements or in need of additional quality assurance measures. These recommendations are not intended to encompass the entire realm of laboratory practice; they are meant to provide guidelines for specific quality concerns in the performance and delivery of laboratory services for molecular genetic testing for heritable diseases and conditions.

These recommendations address laboratory practices for the total testing process, including the preanalytic, analytic, and postanalytic phases of molecular genetic testing. The recommendations for the preanalytic phase include guidelines for laboratory responsibilities for providing information to users of laboratory services, informed consent, test requests, specimen submission and handling, test referrals, and preanalytic systems assessment. The recommendations for the analytic phase include guidelines for establishment and verification of performance specifications, quality control procedures, proficiency testing, and alternative performance assessment. The recommendations for the postanalytic phase include guidelines for test reports, retention of records and reports, and specimen retention. The recommendations also address responsibilities of laboratories regarding authorized persons, confidentiality of patient information and test results, personnel competency, factors to consider before introducing molecular genetic testing or offering new molecular genetic tests, and the potential benefits of the quality management system approach in molecular genetic testing. Recommendations are provided in relation to applicable provisions in the CLIA regulations and, when necessary, are followed by a description of how the recommended practices can be used to improve quality assurance and quality assessment for molecular genetic testing. A list of terms and abbreviations used in this report also is provided (Appendix A).

Laboratories are responsible for providing information regarding the molecular genetic tests they perform to users of their services; users include authorized persons under applicable state law, health-care professionals, patients, referring laboratories, and payers of laboratory services. Laboratories should review the genetic tests they perform and the procedures they use to provide and update the recommended test information that follows. At a minimum, laboratories should ensure that the test information is available from accessible sources such as websites, service directories, information pamphlets or brochures, newsletters, instructions for specimen submission, and test request forms. Laboratories that already provide the information from these sources should continue to do so. However, laboratories also might decide to provide the information more directly to their users (e.g., by telephone, e-mail, or in an in-person meeting) and should determine the situations in which such direct communication is necessary. The complexity of language used should be appropriate for the particular laboratory user groups (e.g., for patients, plain language understandable by the general public).

Test selection, test performance, and specimen submission. Laboratories should provide information regarding the molecular genetic tests they perform to users of their services to facilitate appropriate test selection and requests, specimen handling and submission, and patient care. Each laboratory that performs molecular genetic testing for heritable diseases and conditions should provide the following information to its users:

--- Intended use of the test, including the nucleic acid target of the test (e.g., genes, sequences, mutations, or polymorphisms), the purpose of testing (e.g., diagnostic, preconception, or predictive), and the recommended patient populations

--- Indications for testing

--- Test method to be used, presented in user-friendly language in relation to the performance specifications and the limitations of the test (with Current Procedural Terminology [CPT] codes included when appropriate)

--- Specifications of applicable performance characteristics, including information on analytic validity and clinical validity

--- Limitations of the test

--- Whether testing is performed with an FDA-approved or FDA-cleared test system, with a laboratory-developed test or test system that is not approved or cleared by FDA, or with an investigational test under FDA oversight

Cost. When possible and practical, laboratories should provide users with information on the charges for molecular genetic tests being performed. Estimating the expenses that a patient might incur from a particular genetic test might be difficult for certain laboratories and providers because fee schedules of individual laboratories can vary depending on the health-care payment policy selections of each patient. However, advising the patient and family members of the financial implications of the tests, whenever possible, facilitates informed decision-making.

Discussion. Under CLIA, laboratories are required to develop and follow written policies and procedures for specimen submission and handling, specimen referral, and test requests (42 CFR 493.1241 and 1242). Laboratories must ensure positive identification and optimum integrity of specimens from the time of collection or receipt through the completion of testing and reporting of test results (42 CFR 493.1232). In addition, laboratories that perform nonwaived testing must ensure that a qualified clinical consultant is available to assist laboratory clients with ordering tests appropriate for meeting clinical expectations (42 CFR 493.1457[b]). The recommended laboratory practices in this report describe laboratory responsibilities for ensuring appropriate test requests and specimen submission for the molecular genetic tests they perform, in addition to laboratory responsibilities for meeting CLIA requirements. The recommendations emphasize the role of laboratories in providing specific information needed by users before decisions are made regarding test selection and ordering, based on consideration of several factors.

First, molecular genetic tests for heritable diseases and conditions are being rapidly developed and increasingly used in health-care settings. Users of laboratory services need the ability to easily access information regarding the intended use, performance specifications, and limitations of the molecular genetic tests a laboratory offers to determine appropriate testing for specific patient conditions.

Second, many molecular genetic tests are performed using laboratory-developed tests or test systems. The performance specifications and limitations of the testing might vary among laboratories, even for the same disease or condition, depending on the specific procedures used. Users of laboratory services who are not provided information related to the appropriateness of the tests being considered might select tests that are not indicated or cannot meet clinical expectations.

Third, for many heritable diseases and conditions, test performance and interpretation of test results require information regarding patient race/ethnicity, family history, and other pertinent clinical and laboratory information. Informing users before tests are ordered of the specific patient information needed by the laboratory should facilitate test requests and allow prompt initiation of appropriate testing procedures and accurate interpretation of test results.

Finally, providing information to users on performance specifications and limitations of tests before test selection and ordering prepares users of laboratory services for understanding test results and implications. CLIA test report requirements (42 CFR 493.1291[e]) indicate that laboratories are required to provide users of their services, on request, with information on laboratory test methods and the performance specifications the laboratory has established or verified for the tests. However, for molecular genetic tests for heritable diseases and conditions, laboratories should provide test performance information to users before test selection and ordering, rather than waiting for a request after the test has been performed. The information provided in the preanalytic phase must be consistent with information included on test reports.

Providing molecular genetic testing information to users before tests are selected and ordered should improve test requests and specimen submission and might reduce unnecessary or unwarranted testing. The recommended practices also might increase informed decision-making, improve interpretation of results, and improve patient outcome.

A person who provides informed consent voluntarily confirms a willingness to undergo a particular test, after having been informed of all aspects of the test that are relevant to the patient's decision (49). Informed consent for genetic testing or specific types of genetic tests is required by law in certain states; as of June 2008, 12 states required that informed consent be obtained before a genetic test is requested or performed (119). In addition, certain states (e.g., Massachusetts, Michigan, Nebraska, New York, and South Dakota) have included required informed consent components in their statutes [97,120--123]) (Appendix B). These state statutes can be used as examples for laboratories in other states that are developing specific informed consent forms. Professional organizations recommend that informed consent be obtained for testing for many inherited genetic conditions (12,13). CLIA regulations have no requirements for laboratory documentation of informed consent for requested tests; however, medical decisions for patient diagnosis or treatment should be based on informed decision-making (124). Regardless of whether informed consent is required, laboratories that perform molecular genetic tests for heritable diseases and conditions should be responsible for providing users with the information necessary to make informed decisions.

Informed consent is in the purview of the practice of medicine; the persons authorized to order the tests are responsible for obtaining the appropriate level of informed consent (67). Unless mandated by state or local requirements, obtaining informed consent before performing a test generally is not considered a laboratory responsibility. For molecular genetic testing for heritable diseases and conditions, not all tests require written patient consent before testing (125). However, when informed consent for patient testing is recommended or required by law or other applicable requirements as a method for documenting the process and outcome of informed decision-making, laboratories should ensure that certain practices are followed:

Laboratories should refer to professional guidelines for additional information regarding informed consent for molecular genetic tests and should consider available models when developing the content, format, and procedures for documentation of patient consent.

CLIA requirements (42 CFR 493.1241[c]) specify that laboratories that perform nonwaived testing must ensure that the test request solicits the following information: 1) the name and address or other suitable identifiers of the authorized person requesting the test and (if applicable) the person responsible for using the test results, or the name and address of the laboratory submitting the specimen, including (if applicable) a contact person to enable reporting of imminently life-threatening laboratory results or critical values; 2) patient name or a unique patient identifier; 3) sex and either age or date of birth of the patient; 4) the tests to be performed; 5) the source of the specimen (if applicable); 6) the date and (if applicable) time of specimen collection; and 7) any additional information relevant and necessary for a specific test to ensure accurate and timely testing and reporting of results, including interpretation (if applicable). For molecular genetic testing for heritable diseases and conditions, laboratories must comply with these CLIA requirements and should solicit the following additional information on test requests:

Patient name and any other unique identifiers needed for testing. CLIA test request requirements indicate that laboratories must solicit patient names or unique patient identifiers on test requests (42 CFR 493.1241[c][2]). Laboratories that perform molecular genetic testing for heritable diseases and conditions should ensure that at least two unique identifiers are solicited on these test requests, which should include patient names, when possible, and any other unique identifiers needed to ensure patient identification. In certain situations (e.g., compatibility testing for which donor names are not always provided to the laboratory), an alternative unique identifier is appropriate.

Date of birth. CLIA requirements specify that test requests must solicit the sex and either age or date of birth of the patient (42 CFR 493.1241[c][3]). For molecular genetic testing for heritable diseases and conditions, patient date of birth is more informative than age and should be obtained when possible.

Indications for testing, relevant clinical and laboratory information, patient race/ethnicity, family history, and pedigree. Obtaining information on indications for testing, relevant clinical or laboratory information, patient racial/ethnic background, family history, and pedigree is critical for selecting appropriate test methods, determining the mutations or variants to be tested, interpreting test results, and timely reporting of test results. Genetic conditions often have different disease prevalences with various mutation frequencies and distributions among racial/ethnic groups. Unique, or private, mutations or genotypes might be present only in specific families or can be associated with founder effects (i.e., gene mutations observed in high frequency in a specific population because of the presence of the mutation in a single ancestor or small number of ancestors in the founding population). Family history and other relevant clinical or laboratory information are often important for determining whether the test requested might meet the clinical expectations, including the likelihood of identifying a disease-causing mutation. Specific race/ethnicity, family history, and other pertinent information to be solicited on a test request should be determined according to the specific disease or condition for which the patient is being tested. Laboratories should consider available guidelines for requesting and obtaining this additional information and determine circumstances in which more specific patient information is needed for particular genetic tests (126,127). Although this information is not specified in CLIA, the regulations provide laboratories the flexibility to determine and solicit relevant and necessary information for a specific test (42 CFR 493.1241[c][8]). The recommended test request components also are consistent with many voluntary professional and accreditation guidelines (12--14).

Documentation of informed consent. Methods for indicating and documenting informed consent on a test request might include a statement, text box, or check-off box on the test request form to be signed or checked by the test requestor; a separate form to be signed as part of the test request; or another method that complies with applicable requirements and adheres to professional guidelines. In addition, when state or local laws or regulations specify that patient consent must be obtained regarding the use of tested specimens for quality assurance or other purposes, the test request must include a way for the test requestor to indicate the decision of the patient. Laboratories also might determine that other situations merit documentation of consent before testing.

CLIA requires laboratories to establish and follow written policies and procedures for patient preparation, specimen collection, specimen labeling (including patient name or unique patient identifier and, when appropriate, specimen source), specimen storage and preservation, conditions for specimen transportation, specimen processing, specimen acceptability and rejection, and referral of specimens to another laboratory (42 CFR 493.1242). If a laboratory accepts a referral specimen, appropriate written instructions providing information on specimen handling and submission must be available to the laboratory clients. The following recommendations are intended to help laboratories that perform molecular genetic testing meet general CLIA requirements and to provide additional guidelines on quality assurance measures for specimen submission, handling, and referral for molecular genetic testing. Before test selection and ordering, laboratories that perform molecular genetic testing should provide their users with instructions on specimen collection, handling, transport, and submission. Information on appropriate collection, handling, and submission of specimens for molecular genetic tests should include the following:

Criteria for specimen acceptance or rejection. Laboratories should have written criteria for acceptance or rejection of specimens for the molecular genetic tests they perform and should promptly notify the authorized person when a specimen meets the rejection criteria and is determined to be unsuitable for testing. The criteria should include information on determining the existence of and addressing the following situations:

Retention and exchange of information throughout the testing process. Information on test requests and test reports is a particularly important component of the complex communication between genetic testing laboratories and their users. Laboratories should have policies and procedures in place to ensure that information needed for selection of appropriate test methods, test performance, and results interpretation is retained throughout the entire molecular genetic testing process. This recommendation is based on CLIAC recognition of instances in which information on test requests or test reports was removed by electronic or other information systems during specimen submission, results reporting, or test referral. CLIA requires laboratories to ensure the accuracy of test request or authorization information when transcribing or entering the information into a record system or a laboratory information system (42 CFR 493.1241[e]). For molecular genetic tests, information on test requests and test reports should be retained accurately and completely throughout the testing process.

Specimen referral. CLIA requires laboratories to refer specimens for any type of patient testing to CLIA-certified laboratories or laboratories that meet equivalent requirements as determined by CMS (42 CFR 493.1242[c]). Examples of laboratories that meet equivalent requirements include Department of Veterans Affairs laboratories, Department of Defense laboratories, and laboratories in CLIA-exempt states.

Laboratories must have written policies and procedures for assessing and correcting problems identified in test requests, specimen submission, and other preanalytic steps of molecular genetic testing (42 CFR 493.1249). The preanalytic systems assessment for molecular genetic testing should include the following practices:

CLIA requires laboratories to establish or verify the analytic performance of all nonwaived tests and test systems before introducing them for patient testing and to determine the calibration and control procedures of tests based on the performance specifications verified or established. Before reporting patient test results, each laboratory that introduces an unmodified, FDA-cleared or FDA-approved test system must 1) demonstrate that the manufacturer-established performance specifications for accuracy, precision, and reportable range of test results can be reproduced and 2) verify that the manufacturer-provided reference intervals (or normal values) are appropriate for the laboratory patient population (42 CFR 493.1253). Laboratories are subject to more stringent requirements when introducing 1) FDA-cleared or FDA-approved test systems that have been modified by the laboratory, 2) laboratory-developed tests or test systems that are not subject to FDA clearance or approval (e.g., standardized methods and textbook procedures), or 3) test systems with no manufacturer-provided performance specifications. In these instances, before reporting patient test results, laboratories must conduct more extensive procedures to establish applicable performance specifications for accuracy, precision, analytic sensitivity, analytic specificity; reportable range of test results; reference intervals, or normal values; and other performance characteristics required for test performance.

Although laboratories that perform molecular genetic testing for heritable diseases and conditions must comply with these general CLIA requirements, additional guidelines are needed to assist with establishment and verification of performance specifications for these tests. The recommended laboratory practices that follow are primarily intended to provide specific guidelines for establishing performance specifications for laboratory-developed molecular genetic tests to ensure valid and reliable test performance and interpretation of results. The recommendations also might be used by laboratories to verify performance specifications of unmodified FDA-cleared or FDA-approved molecular genetic test systems to be introduced for patient testing.

Factors that should be considered when developing performance specifications for molecular genetic tests include the intended use of the test; target genes, sequences, and mutations; intended patient populations; test methods; and samples to be used (99). The following five steps should be considered general principles for establishing performance specifications of each new molecular genetic test:

Samples for establishment of performance specifications. Establishment of performance specifications should be based on an adequate number, type, and variety of samples to ensure that test results can be interpreted for specific patient conditions and that the limitations of the testing and test results are known. When selecting samples, the following factors should be considered:

Analytic performance specifications. Laboratories should determine performance specifications for all of the following analytic performance characteristics for molecular genetic tests that are not cleared or approved by FDA before introducing the tests for patient testing:

Accuracy. Accuracy is commonly defined as "closeness of the agreement between the result of a measurement and a true value of the measurand" (128). For qualitative molecular genetic tests, laboratories are responsible for verifying or establishing the accuracy of the method used to identify the presence or absence of the analytes being evaluated (e.g., mutations, variants, or other targeted nucleic acids). Accuracy might be assessed by testing reference materials, comparing test results against results of a reference method, comparing split-sample results with results obtained from a method shown to provide clinically valid results, or correlating research results with the clinical presentation when establishing a test system for a new analyte, such as a newly identified disease gene (96).

Precision. Precision is defined as "closeness of agreement between independent test results obtained under stipulated conditions" (129). Precision is commonly determined by assessing repeatability (i.e., closeness of agreement between independent test results for the same measurand under the same conditions) and reproducibility (i.e., closeness of agreement between independent test results for the same measurand under changed conditions). Precision can be verified or established by assessing day-to-day, run-to-run, and within-run variation (as well as operator variance) by repeat testing of known patient samples, quality control materials, or calibration materials over time (96).

Analytic sensitivity. Practice guidelines vary in their definitions of analytic sensitivity; certain guidelines consider analytic sensitivity to be the ability of an assay to detect a given analyte, or the lower limit of detection (LOD) (93), whereas guidelines for molecular genetic testing for heritable diseases consider analytic sensitivity to be "the proportion of biological samples that have a positive test result or known mutation and that are correctly classified as positive" (12). However, determining the LOD of a molecular genetic test or test system is often needed as part of the performance establishment and verification (93). To avoid potential confusion among users and the general public in understanding the test performance and test results, laboratories should review and follow applicable professional guidelines before testing is introduced and ensure the guidelines are followed consistently throughout performance establishment and verification and during subsequent patient testing. Analytic sensitivity should be determined for each molecular genetic test before the test is used for patient testing.

Analytic specificity. Analytic specificity is generally defined as the ability of a test method to determine only the target analytes to be detected or measured and not the interfering substances that might affect laboratory testing. Interfering substances include factors associated with specimens (e.g., specimen hemolysis, anticoagulant, lipemia, and turbidity) and factors associated with patients (e.g., clinical conditions, disease states, and medications) (96). Laboratories must document information regarding interfering substances and should use product information, literature, or the laboratory's own testing (96). Accepted practice guidelines for molecular genetic testing, such as those developed by ACMG, CAP, and CLSI, define analytic specificity as the ability of a test to distinguish the target sequences, alleles, or mutations from other sequences or alleles in the specimen or genome being analyzed (12--14). The guidelines also address documentation and determination of common interfering substances specific for molecular detection (e.g., homologous sequences, contaminants, and other exogenous or endogenous substances) (12--14). Laboratories should adhere to these specific guidelines in establishing or verifying analytic specificity for each of their molecular genetic tests.

Reportable range of test results. As defined by CLIA, the reportable range of test results is "the span of test result values over which the laboratory can establish or verify the accuracy of the instrument or test system measurement response" (36). The reportable range of patient test results can be established or verified by assaying low and high calibration materials or control materials or by evaluating known samples of abnormally high and low values (96). For example, laboratories should assay quality control or reference materials, or known normal samples, and samples containing mutations to be detected for targeted mutation analyses. For analysis of trinucleotide repeats, laboratories should include samples representing the full range of expected allele lengths (130).

Reference range, or reference interval (i.e., normal values). As defined by CLIA, a reference range, or reference interval, is "the range of test values expected for a designated population of persons (e.g., 95% of persons that are presumed to be healthy [or normal])" (36). The CMS Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services provides general guidelines regarding the use of manufacturer-provided or published reference ranges appropriate for the patient population and evaluation of an appropriate number of samples to verify manufacturer claims or published reference ranges (96). For all laboratory-developed tests, the laboratory is responsible for establishing the reference range appropriate for the laboratory patient population (including demographic variables such as age and sex) and specimen types (96). For molecular genetic tests for heritable diseases and conditions, normal values might refer to normal alleles in targeted mutation analyses or the reference sequences for sequencing assays. Laboratories should be aware that advances in knowledge and testing technology might affect the recognition and documentation of normal sequences and should keep an updated database for the molecular genetic tests they perform.

Quality control procedures. CLIA requires laboratories to determine the calibration and control procedures for nonwaived tests or test systems on the basis of the verification or establishment of performance specifications for the tests (42 CFR 493.1253[b][3]). Laboratories that perform molecular genetic tests must meet these requirements and, for every molecular genetic test to be introduced for patient testing, should consider the recommended quality control practices.

Documentation of information on clinical validity. Laboratories should ensure that the molecular genetic tests they perform are clinically usable and can be interpreted for specific patient situations. Laboratory responsibilities for clinical validity include the following:

Although CLIA regulations do not include validation of clinical performance specifications of new tests or test systems, laboratories are required to ensure that the tests being performed meet clinical expectations. For tests of high complexity, such as molecular genetic tests, laboratory directors and technical supervisors are responsible for ensuring that the testing method is appropriate for the clinical use of the test results and can provide the quality of results needed for patient care (36). Laboratory directors and clinical consultants must ensure laboratory consultations are available for laboratory clients regarding the appropriateness of the tests ordered and interpretation of test results (36). Documentation of available clinical validity information helps laboratories that perform molecular genetic testing to fulfill their responsibilities for consulting with health-care professionals and other users of laboratory services, especially regarding tests that evaluate germline mutations or variants that might be performed only once during a patient's lifetime.

Establishing clinical validity is a continuous process and might require extended studies and involvement of many disciplines (38). The recommendations in this report emphasize the responsibility of laboratories that perform molecular genetic testing to document available information from medical and scientific research studies on the intended patient populations to be able to perform testing and provide results interpretation appropriate for specific clinical contexts. Laboratory directors are responsible for using professional judgment to evaluate the results of such studies as applied to newly discovered gene targets, especially those of a predictive or incompletely penetrant nature, in considering potential new tests. The recommendations in this report are consistent with the voluntary professional and accreditation guidelines of ACMG, CLSI, and CAP for molecular genetic testing (12--14,93,94).

General quality control practices. The analytic phase of molecular genetic testing often includes the following steps: specimen processing; nucleic acid extraction, preparation, and assessment; enzymatic reaction or amplification; analyte detection; and recording of test results. Laboratories that perform molecular genetic testing must meet the general CLIA requirements for nonwaived testing (42 CFR 493.1256) (36), including the following applicable quality control requirements:

--- At least two control materials of different concentrations for each quantitative procedure

--- A negative control material and a positive control material for each qualitative procedure

--- A negative control material and a control material with graded or titered reactivity, respectively, for each test procedure producing graded or titered results

--- Two control materials, including one that is capable of detecting errors in the extraction process, for each test system that has an extraction phase

--- Two control materials for each molecular amplification procedure and, if reaction inhibition is a substantial source of false-negative results, a control material capable of detecting the inhibition

Specific quality control practices. Specific quality control practices are necessary for ensuring the quality of molecular genetic test performance. The following recommendations include specific guidelines for meeting the general CLIA quality control requirements and additional measures that are more stringent or explicit than the CLIA requirements for monitoring and ensuring the quality of the molecular genetic testing process:

Alternative control procedures. Ideally, laboratories should use control materials to monitor the entire testing process, but such materials are not always practical or available. Appropriate alternative control procedures depend on the specific test and the control materials needed. Following are examples of accepted alternative control procedures when control materials are not available:

The CMS Survey Procedures and Interpretive Guidelines for Laboratories and Laboratory Services provides general guidelines for alternative control procedures and encourages laboratories to use multiple mechanisms for ensuring testing quality (96). Following are examples of procedures that, when applicable, should be followed by laboratories that perform molecular genetic testing:

Unidirectional workflow for molecular amplification procedures. CLIA requires laboratories to have procedures in place to monitor and minimize contamination during thetesting process and to ensure a unidirectional workflow for amplification procedures that are not contained in closed systems (42 CFR 493.1101) (36). In this context, a closed system is a test system designed to be fully integrated and automated to purify, concentrate, amplify, detect, and identify targeted nucleic acid sequences. Such a modular system generates test results directly from unprocessed samples without manipulation or handling by the user; the system does not pose a risk for cross-contamination because amplicon-containing tubes and compartments reamain completely closed during and after the testing process. For example, according to CLIA regulations, an FDA-cleared or FDA-approved test system that contains amplification and detection steps in sealed tubes that are never opened or reopened during or after the testing process and that is used as provided by the manufacturer (i.e., without any modifications) is considered a closed system.

The requirement for a unidirectional workflow, which includes having separate areas for specimen preparation, amplification, product detection, and reagent preparation, applies to any testing that involves molecular amplification procedures. The following recommendations provide more specific guidelines for laboratories that perform molecular genetic testing for heritable diseases and conditions using amplification procedures that are not in a closed system:

Laboratories should recognize that methods such as PCR amplification, whole genome amplification, or subcloning to prepare quality control materials might be a substantial source of laboratory contamination. These laboratories should have the following specific procedures to monitor, detect, and prevent cross-contamination:

These practices also should be considered by laboratories that purchase amplified materials for use as control materials, calibration materials, or competitors.

Proficiency testing is an important tool for assessing laboratory competence, evaluating the laboratory testing process, and providing education for the laboratory personnel. For certain analytes and testing specialties for which CLIA regulations specifically require proficiency testing, proficiency testing is provided by private-sector and state-operated programs that are approved by HHS because they meet CLIA standards (42 CFR Part 493). These approved programs also may provide proficiency testing for genetic tests and other tests that are not on the list of regulated analytes and specialties (131). Although the CLIA regulations do not have proficiency testing requirements specific for molecular genetic tests, laboratories that perform genetic tests must comply with the general requirements for alternative performance assessment for any test or analyte not specified as a regulated analyte to, at least twice annually, verify the accuracy of any genetic test or procedure they perform (42 CFR 493.1236[c]). Laboratories can meet this requirement by participating in available proficiency testing programs for the genetic tests they perform (132).

The following recommended practices provide more specific and stringent measures than the current CLIA requirements for performance assessment of molecular genetic testing. The recommendations should be considered by laboratories that perform molecular genetic testing to monitor and evaluate the ongoing quality of the testing they perform:

Proficiency testing samples. When possible, proficiency testing samples should resemble patient specimens; at a minimum, samples resembling patient specimens should be used for proficiency testing for the most common genetic tests. When proficiency testing samples are provided in the form of purified DNA, participating laboratories do not perform all the analytic steps that occur during the patient testing process (e.g., nucleic acid extraction and preparation). Such practical limitations should be recognized when assessing proficiency testing performance. Laboratories are encouraged to enroll in proficiency testing programs that examine the entire testing process, including the preanalytic, analytic, and postanalytic phases.

See original here:
Good Laboratory Practices for Molecular Genetic Testing ...

Recommendation and review posted by Bethany Smith

Embryonic stem cells, as their name suggests, are derived from embryos. Most embryonic stem cells are derived from embryos that develop from eggs that have been fertilized in vitroin an in vitro fertilization clinicand then donated for research purposes with informed consent of the donors. They are not derived from eggs fertilized in a woman's body.

Growing cells in the laboratory is known as cell culture. Human embryonic stem cells (hESCs) aregenerated by transferringcells from a preimplantation-stage embryointo a plastic laboratory culture dish that contains a nutrient broth known as culture medium. The cells divide and spread over the surface of the dish. In the original protocol, the inner surface of the culture dish was coated with mouse embryonic skin cellsspecially treated so they will not divide. This coating layer of cells is called a feeder layer. The mouse cells in the bottom of the culture dish provide the cells a sticky surface to which they can attach. Also, the feeder cells release nutrients into the culture medium. Researchers have nowdevised ways to grow embryonic stem cells without mouse feeder cells. This is a significant scientific advance because of the risk that viruses or other macromolecules in the mouse cells may be transmitted to the human cells.

The process of generating an embryonic stem cell line is somewhat inefficient, so lines are not produced each time cells from the preimplantation-stage embryo are placed into a culture dish. However, if the plated cells survive, divide and multiply enough to crowd the dish, they are removed gently and plated into several fresh culture dishes. The process of re-plating or subculturing the cells is repeated many times and for many months. Each cycle of subculturing the cells is referred to as a passage. Once the cell line is established, the original cells yield millions of embryonic stem cells. Embryonic stem cells that have proliferated in cell culture for six or more months without differentiating, are pluripotent, and appear genetically normal are referred to as an embryonic stem cell line. At any stage in the process, batches of cells can be frozen and shipped to other laboratories for further culture and experimentation.

At various points during the process of generating embryonic stem cell lines, scientists test the cells to see whether they exhibit the fundamental properties that make them embryonic stem cells. This process is called characterization.

Scientists who study human embryonic stem cells have not yet agreed on a standard battery of tests that measure the cells' fundamental properties. However, laboratories that grow human embryonic stem cell lines use several kinds of tests, including:

As long as the embryonic stem cells in culture are grown under appropriate conditions, they can remain undifferentiated (unspecialized). But if cells are allowed to clump together to form embryoid bodies, they begin to differentiate spontaneously. They can form muscle cells, nerve cells, and many other cell types. Although spontaneous differentiation is a good indication that a culture of embryonic stem cells is healthy, the process is uncontrolled and therefore an inefficient strategy to produce cultures of specific cell types.

So, to generate cultures of specific types of differentiated cellsheart muscle cells, blood cells, or nerve cells, for examplescientists try to control the differentiation of embryonic stem cells. They change the chemical composition of the culture medium, alter the surface of the culture dish, or modify the cells by inserting specific genes. Through years of experimentation, scientists have established some basic protocols or "recipes" for the directed differentiation of embryonic stem cells into some specific cell types (Figure 1). (For additional examples of directed differentiation of embryonic stem cells, refer to the 2006 NIH stem cell report.)

Figure 1. Directed differentiation of mouse embryonic stem cells. Click here for larger image. ( 2008 Terese Winslow)

If scientists can reliably direct the differentiation of embryonic stem cells into specific cell types, they may be able to use the resulting, differentiated cells to treat certain diseases in the future. Diseases that might be treated by transplanting cells generated from human embryonic stem cells include diabetes, traumatic spinal cord injury, Duchenne's muscular dystrophy, heart disease, and vision and hearing loss.

Previous|III. What are embryonic stem cells?|Next

Excerpt from:
What are embryonic stem cells? [Stem Cell Information]

Recommendation and review posted by simmons

2009

"A UK and Canadian team have manipulated human skin cells to act like embryonic stem cells without using viruses making them safer for use in humans.

"Study leader Dr. Keisuke Kaji, from the Medical Research Council Centre for Regenerative Medicine at the University of Edinburgh, said nobody, including himself, had thought it was really possible. 'It is a step towards the practical use of reprogrammed cells in medicine, perhaps even eliminating the need for human embryos as a source of stem cells,' he said."

--

"'Ethical' stem cell creation hope," BBC News, March 1, 2009, http://news.bbc.co.uk/2/hi/health/7914976.stm

***

"A groundbreaking medical treatment that could dramatically enhance the body's ability to repair itself has been developed by a team of British researchers. The therapy, which makes the body release a flood of stem cells into the bloodstream, is designed to heal serious tissue damage caused by heart attacks and even repair broken bones.

"A possible danger with some other stem cell therapies in the pipeline is their use of embryonic stem cells. Because these can turn into any type of tissue, there is a risk they could grow into cancer cells when injected into patients. [This] treatment uses stem cells that can only grow into blood vessels, bone and cartilage, so the risk of causing cancer is removed."

--

I. Sample, "Revolutionary stem cell therapy boosts body's ability to heal itself," The Guardian (United Kingdom) , January 8, 2009, http://www.guardian.co.uk/science/2009/jan/08/stem-cells-bone-marrow-heart-attack

***

"Controversial research into the use of 'hybrid' human-animal embryos to make stem cells is in danger of stalling because of a lack of funding, British scientists claim.

"Since the furore broke scientists have developed a cheap and powerful new technique in which adult skin cells are reprogrammed to create cells that are almost identical to stem cells. Researchers have already used the technique to make so-called induced pluripotent stem (iPS) cells for patients with diabetes, muscular dystrophy and Down's syndrome.

[Quoting Harry Moore, head of reproductive biology at Sheffield University] 'What has happened is the field has moved on. You could argue that iPS cells are a more important area than hybrids now.' "

--

I. Sample, "Rival stem cell technique takes the heat out of hybrid embryo debate," The Guardian. January 13, 2009, http://www.guardian.co.uk/science/2009/jan/13/hybrid-embryos-stem-cells

***

"A dose of their own stem cells 'reset' the malfunctioning immune system of patients with early-stage multiple sclerosis and, for the first time, reversed their disability.

'This is the first study to actually show reversal of disability,' said Richard Burt, an associate professor in the division of immunotherapy at Northwestern, and the lead author of the study published yesterday in the British journal, the Lancet Neurology. 'Some people had complete disappearance of all symptoms.' "

--

R. Waters, "Dose of Own Stem Cells Reverses Patients' Multiple Sclerosis," Bloomberg News, January 30, 2009, http://www.bloomberg.com/apps/news?pid=20601124&sid=akHXxf3bS3TY&refer=home

***

"A new study suggests that adult bone marrow stem cells can be used in the construction of artificial skin. The findings mark an advancement in wound healing and may be used to pioneer a method of organ reconstruction."

--

"Study Uses Bone Marrow Stem Cells to Regenerate Skin," Physorg, January 14, 2009, http://www.physorg.com/news151166956.html

***

2008

"The reality is that the bulk of today's stem-cell research relies on adult stem cells taken from bone marrow, blood, skeletal muscles, body fat and umbilical cord blood. Scientists have even managed to coax adult skin cells to mimic the versatility of embryonic stem cells, which can grow virtually any cell or tissue in the human body. Unlike embryonic stem cells, though, these adult stem cells are being tested in humans right now, with very real possibilities to change the way various diseases are treated in the next five to 10 years."

--

T. Wheeler, "Stem cells mature," Beacon Journal (Akron, Ohio), April 6, 2008.

***

"For the first time, scientists at Children's Hospital of Pittsburgh of UPMC have discovered a unique population of adult stem cells derived from human muscle that could be used to treat muscle injuries and diseases such as heart attack and muscular dystrophy.

"Because this is an autologous transplant, meaning from the patient to himself, there is not the risk of rejection you would have if you took the stem cells from another source

"Myoendothelial cells also showed no propensity to form tumors, a concern with other stem cell therapies."

--

"Pittsburgh scientists identify human source of stem cells with potential to repair muscle damaged by disease or injury," Children's Hospital of Pittsburgh, September 4, 2007, http://www.pslgroup.com/dg/28732E.htm.

***

2007

"An Ecuadorian stem cellexpert said on September 24 that transplants of autologous adult bone marrow stem cells restored some function in spinal cord injury (SCI) patients who have been paralyzed for an average of four years, some up to 22 years.

"Of the 25 patients who provided more than three months and up to 14 months follow up: 15 gained the ability to stand up, 10 could walk on the parallels with braces, seven could walk without braces and five could walk with crutches. Three patients recovered full bladder control, and 10 patients regained some form of sexual function. No adverse events or abnormal reactions to implantation were observed.

'By implanting an adult's own bone marrow stem cells, we've seen significant improvements in the quality of life for those who suffer from spinal cord injuries,' said Francisco Silva, executive vice president of research and development for PrimeCell Therapeutics."

--

"Marrow Stem Cell Transplants Restore Spinal Cord Functions," Stem Cell Business News, Sept. 24, 2007, http://www.stemcellresearchnews.com/absolutenm/anmviewer.asp?a=867&z=15

***

"In recent years, scientists have discovered that red bone marrow is the body's Swiss Army repair kit. It contains a traveling laboratory of cells that can heal the liver, heart, kidneys, leg arteries, pancreas, and even ovaries and the brain. Up to 40 percent of the liver can be regrown from stem cells found in bone marrow, researchers at New York University School of Medicine, Yale University School of Medicine and Sloan-Kettering Cancer Center found."

--

B. J. Fikes, "Body parts Bone marrow: The body's repair kit," North County Times (San Diego, CA), May 20, 2006, http://www.nctimes.com/lifestyles/health-med-fit/article_0bcace84-44ac-51bc-99a0-b1bf6ddb6d21.html

***

2006

"The results of a study published in the April issue of Stem Cells and Development suggest that human stem cells derived from bone marrow are predisposed to develop into a variety of nerve cell types, supporting the promise of developing stem cell-based therapies to treat neurodegenerative disorders such as Parkinson's disease and multiple sclerosis.

"When transplanted into the central nervous system, [these cells] will develop into a variety of functional neural cell types, making them a potent resource for cell-based therapy."

--

"New Findings Support Promise of Using Stem Cells to Treat Neurodegenerative Diseases," Business Wire, May 1, 2006, http://findarticles.com/p/articles/mi_m0EIN/is_2006_May_1/ai_n16135565/

2005

"A team of Texas and British researchers says it has produced large amounts of embryoniclike stem cells from umbilical cord blood, potentially ending the ethical debate affecting stem-cell research -- the need to kill human embryos. The international researchers said the cells -- called cord-blood-derived-embryoniclike stem cells, or CBEs -- have the ability to turn into any kind of body tissue, like embryonic stem cells do, and can be mass-produced using technology derived from NASA.... "Scientists believe the ability to replicate tissue could lead to the development of ways to replace organs as well as treat life-threatening diseases such as diabetes, Alzheimer's and Parkinson's, which have been the focus of stem-cell research." -- J. Price, "Advance made in stem-cell debate," The Washington Times, August 20, 2005, http://www.washingtontimes.com/national/20050820-122747-2417r.htm

* * *

"Various studies that have been conducted around the world, including a limited number performed in the United States, have suggested that when patients with heart failure receive stem cells taken from their bone marrow, their hearts show signs of improved function and recovery." -- "Stem Cells With Heart Bypass Surgery Trial To Begin At University Of Pittsburgh," ScienceDaily, August 25, 2005, http://www.sciencedaily.com/releases/2005/08/050825070117.htm

* * * "Researchers in Boston have isolated a kind of cell from human bone marrow that they say has all the medical potential of human embryonic stem cells.... "Tufts University researchers used specialized cell-sorting machines to pluck the peculiar cells from samples of bone marrow obtained from different donors. Tests suggested the cells are capable of morphing into many, and perhaps all, of the various kinds of cells that make up the human body. ...

"When a batch of the newly identified marrow cells were injected into the hearts of rats that had experienced heart attacks, some of the cells turned into new heart muscle while others became new blood vessels to support the ailing hearts. ...

"'I think embryonic stem cells are going to fade in the rearview mirror of adult stem cells,' said Douglas W. Losordo, the Tufts cardiologist who left the effort.... Bone marrow, he said, 'is like a repair kit. Nature provided us with these tools to repair organ damage.'"

-Rick Weiss, "Marrow Has Cells Like Stem Cells, Tests Show," Washington Post, Feburary 2, 2005, p. A3, at http://www.washingtonpost.com/wp-dyn/articles/A55369-2005Feb1.html .

* * * "[Erica] Nader, 26, of Farmington Hills, Mich., was the first American to travel to Portugal, in March 2003, for experimental sugery for spinal cord injury. She was injured in July 2001 in an auto accident... She was paralyzed from the top of her arms down. "In the procedure...a team of doctors opened Nader's spinal cord to clear out any scar tissue.... Then, using a long tube, they took a sample of olfactory mucosal cells from the ridge of her nose.... These cells are among the body's richest supply of adult stem cells and are capable of becoming any type of cell, depending on where they are implanted. In this case, these adult stem cells were to take on the job of neurons, or nerve cells, once implanted in the spinal cord at the site of an injury. ... "And after three years, magnetic imaging resonance tests show that the cells indeed promote the development of new blood cells and synapses, or connections between nerve cells, says Dr. Carlos Lima, chief of the Lisbon team. ... "Dr. Pratas Vital, one of two neurosurgeons on the team, calls the transplanted cells spinal cord autografts, a term that indicates the cells come from a person's own body, not fetal or embryonic stem cells. ...

"[Erica] is much stronger and much more capable of lifting her arms, bending her knees on a slanted exercise board and standing erect. ... Once, she was paralyzed from her biceps down. Now, she can push herself off an exercise ball, do arm lifts and help raise herself off a floor mat. ... In the past six weeks, she's started to walk in leg braces with a walker or on a treadmill." -Patricia Anstett, "Paraplegic improving after stem-cell implant," The Indianapolis Star, January 16, 2005, at http://www.indystar.com/articles/5/209449-5235-047.html.

* * * 2004

"[E]vidence from three different labs the University of Minnesota, the Robert Wood Johnson Medical School in New Jersey, and Argonne National Laboratory outside Chicago have found three different ASCs [adult stem cells] that may be completely plastic. ... As the team leader at the Robert Wood Johnson School, Ira Black, told me, 'In aggregate, our study and various others do support the idea that one [adult stem cell] can give rise to all types of tissue.' ...

-Michael Fumento, "The Adult Answer," National Review Online, December 20, 2004, at http://www.nationalreview.com/comment/fumento200412200902.asp.

* * * "Scientists have transplanted adult stem cells from the bone marrow of rats into the brains of rat embryos and found that thousands of the cells survive into adulthood, raising the possibility that someday developmental abnormalities could be prevented or treated in the womb. "Dr. Ira Black, chairman of the department of neuroscience at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, said the cells took on the properties of brain cells, migrating to specific regions and taking up characteristics of neighboring cells. ... "Black and his colleagues used a specific type of bone marrow cell called a stromal cell, taken from the leg bones of adult rats. 'We see this potentially as an appropriate treatment for prenatal disease, mental retardation and congenital conditions,' Black said. The hope is that a patient's own bone barrow might someday be the source for replacing brain cells lost to illness and brain trauma, experts say, eliminating the need to use human embryonic stem cells. "In a separate study, Dr. Alexander Storch of the University of Ulm, Germany, recently took bone marrow and stromal cells from six healthy people and converted the cells into immature neural stem cells. ... 'A single cell culture could grow all major brain cell types,' said Storch, who used specific growth factors to help them differentiate. ...Storch is now transplanting the cells into mice with multiple sclerosis, Parkinson's disease and stroke symptoms. In the stroke study, the labeled adult stromal cells migrated to the area surrounding the stroke damage, he said. They had all of the chemical, electrical and functional properties of brain cells." -Jamie Talan, "Stem cell transplant a success," Newsday, May 12, 2004, at http://www.mult-sclerosis.org/news/May2004/SuccessfulRatStemCellTransplant.html.

* * * "'Cord blood stem cells have the same capacity to cure disease as do embryonic stem cells, as they can become any cell in the body...,' said Dr. William Schmidt, Jr., an oncologist with the Charleston Cancer Center in N. Charleston, SC. "'The use of umbilical cord blood stem cells in the treatment of disease is one of the most prominent advancements in medicine today. Developments in this field will revolutionize medicine and disease treatment,' said Dr. [Roger] Markwald [Professor and Chair of the Department of Cell Biology and Anatomy at the Medical University of South Carolina]."

-Press Release, "CureSource Issues Statement on Umbilical Cord Blood Stem Cells vs. Embryonic Stem Cells," May 12, 2004, at http://home.businesswire.com/portal/site/altavista/index.jsp?ndmViewId=news_view&newsId=20040512005909&newsLang=en.

* * * "California scientists have found that neural stem cells can target and track deadly brain tumor cells. ...The discovery by researchers at Cedars-Sinai's Maxine Dunitz Neurosurgical Institute in Los Angeles means that neural stem cells may someday be effective 'delivery systems' to transport cancer-killing gene and immune products. ... "'We have previously demonstrated the uncanny ability of neural stem cells to seek out and destroy satellites of tumor cells in the brain,' said John S. Yu, senior author of the study and co-director of the Comprehensive Brain Tumor Program a Cedars-Sinai. '...With this knowledge, we hope to expedite the translation of this powerful and novel strategy for the clinical benefit of patients with brain tumors.'" -Press release, "Neural stem cells may help fight cancer," May 5, 2004, at http://www.nlm.nih.gov/medlineplus/news/fullstory_17570.html. * * * "'We're not trying to change the [adult stem] cells in any way before we put them in the body. These are very early precursor cells. They have the potential to become almost anything, and they adapt quickly once they're inside,' said [Tulane University Center for Gene Therapy research professor Dr. Brian] Butcher. Tests on rats with damaged spines have shown that cell growth occurs in the spine [after adult stem cell injection] and allows the animals to walk again. ... "Using adult stem cells sidesteps some of the legal and ethical issues involved in using fetal...or embryonic stem cells.... And there may be other benefits as well. 'We're not against stem-cell research of any kind,' said Butcher. 'But we think there are advantages to using adult stem cells. For example, with embryonic stem cells, a significant number become cancer cells, so the cure could be worse than the disease. And they can be very difficult to grow, while adult stem cells are very easy to grow.' "But perhaps the biggest advantage to adult stem cells is that they sidestep immunological concerns because the cells used to treat a patient come from his or her own body."

-Heather Heilman, "Great Transformations," The Tulanian, Spring 2004, at http://www2.tulane.edu/article_news_details.cfm?ArticleID=5155.

* * * "Had a major heart attack? In the not-too-distant future, doctors may be able to use stem cells to regenerate damaged heart muscle. And here's the exciting part: They can do it using stem cells that aren't extracted from human embryos. "[G]iven the controversy over harvesting cells from embryos, doctors have been exploring other possibilities. The payoff: A team from the University of Texas M.D. Anderson Cancer Center in Houston recently repaired heart muscles in animals by injecting them with stem cells extracted from human blood. It's the stem-cell equivalent of Columbus reaching America: Not only would cells harvested from one's own body eliminate the risk that they would be rejected, but obtaining them would be a simple, painless proposition. "'This work gives us a way to get the cells that's as easy as giving a blood sample,' says Edward Yeh, M.D., lead author of the study. The real mind boggler is what the stem cells might mean to the 1.2 million Americans who suffer heart attacks each year." -Special Report, "Good news about bad things that happen to your parents," USA Weekend magazine, March 5-7, 2004, p. 6, at http://www.usaweekend.com/04_issues/040307/040307aging.html#heart. * * * 2003

"Scientists in Canada have turned adult skin cells into the building blocks of brain cells --opening the way for their use in new therapies for such incurable diseases. The discovery, by a team at the University of Toronto, is particularly exciting as it promises to provide a readily accessible and ethically neutral source of neural stem cells -- the precursors of nerve and brain tissue. "While other groups have managed to create these cells before, they have generally required the use of adult stem cells from bone marrow, which are difficult and painful to extract, or embryonic stem cells, which require the destruction of a human embryo. "If the Toronto technique is perfected for clinical use it would allow neural stem cells to be made from a patient's skin, ensuring a perfect genetic match that would not be rejected by the body. The cells would then be transplanted into the brains of people with neurological disorders, to replace, for example, the specialized dopamine neurons that are lost in Parkinson's disease." -Oliver Wright, "Patients' Own Skin Cells Turned into Potential Alzheimer's Treatment," The Times (London), December 10, 2003, Home News, p. 8.

* * * "Massachusetts General Hospital researchers have harnessed newly discovered cells from an unexpected source, the spleen, to cure juvenile diabetes in mice, a surprising breakthrough that could soon be tested in local patients and open a new chapter in diabetes research... "'This shows there might be a whole new type of therapy that we haven't tapped into,' said Dr. Denise Faustman, MGH immunology lab director and lead author of the new study, which appears today in the journal Science. 'We've figured out how to regrow an adult organ'." -R. Mishra, "Juvenile diabetes cured in lab mice," The Boston Globe, November 14, 2003, p. A2. * * * "There is now an emerging recognition that the adult mammalian brain, including that of primates and humans, harbours stem cell populations suggesting the existence of a previously unrecognised neural plasticity to the mature CNS [central nervous system], and thereby raising the possibility of promoting endogenous neural reconstruction... Since large numbers of stem cells can be generated efficiently in culture, they may obviate some of the technical and ethical limitations associated with the use of fresh (primary) embryonic neural tissue in current transplantation strategies." -T. Ostenfeld and C. Svendsen, "Recent advances in stem cell neurobiology," Advances and Technical Standards in Neurosurgery, vol. 28 (2003), p. 3. * * * "Stem cells in our bone marrow usually develop into blood cells, replenishing our blood system. However, in states of emergency, the destiny of some of these stem cells may change: They can become virtually any type of cell liver cells, muscle cells, nerve cells responding to the body's needs. Prof. Tsvee Lapidot and Dr. Orit Kollet of the Weizmann Institute's Immunology Department have found how the liver, when damaged, sends a cry for help to these stem cells. 'When the liver becomes damaged, it signals to stem cells in the bone marrow, which rush to it and help in its repair as liver cells,' says Lapidot...

"The findings could lead to new insights into organ repair and transplants, especially liver-related ones. They may also uncover a whole new stock of stem cells that can under certain conditions become liver cells. Until a few years ago only embryonic stem cells were thought to possess such capabilities. Understanding how stem cells in the bone marrow turn into liver cells could one day be a great boon to liver repair as well as an alternative to the use of embryonic stem cells." -"Weizmann Institute scientists find that stem cells in the bone marrow become liver cells," EurakAlert, August 11, 2003, at http://www.eurekalert.org/pub_releases/2003-08/wi-wis_1081103.php.

* * * I.S. Abuljadayel, Chief Scientific Officer of Tri-Stem Inc., on his study published in the July 2003 Current Medical Research and Opinion on producing pluripotent stem cells from adult blood cells:

"This new technology offers a viable option for the generation of large numbers of pluripotent stem cells. These are likely to have many clinical and research applications. The source material is blood, the most accessible tissue in our body which can be extracted by simple venipuncture or aphaeresis. The procedure raises no ethical concerns and removes the need to resort to embryos or aborted fetuses. The technology is also cost-effective, donor-friendly producing relatively large quantities of stem cells within a short time, which could eventually save patient lives and shorten patient waiting lists." -"Stem cell-like plasticity induced in mature mononuclear cells," Reuters Health, July 7, 2003.

* * * "This is an example of promising experimental therapies involving stem cells from bone marrow. Until just a few years ago, conventional wisdom held that only embryonic stem cells could turn into any cell in the body. But that thinking began to change as studies showed that stem cells from bone marrow could become heart, muscle, nerve, or liver cells. Now, the results of clinical trials conducted in Britain, Germany and Brazil show that heart patients injected with their own bone marrow cells benefit from the treatment."

-N. Touchette,"Bone Marrow Stem Cells Heal the Heart," Genome News Network, May 2, 2003, at http://www.genomenewsnetwork.org/articles/05_03/sc_heart.shtml * * * "Stem cells from bone marrow can transform into insulin-producing cells, scientists have shown, suggesting a future cure for diabetes... "Transplants of pancreatic cells have been tried between people, but the supplies are restricted and recipients have to take strong anti-rejection medication. Embryonic stem cells have also been converted into insulin-producing cells, but also produce immune-rejection, in addition to ethical concerns. But taking bone marrow cells from a patient, developing them into beta cells and then reimplanting them would have none of these difficulties. Also, much of the technology for bone marrow transplantation is already well developed, says study leader Mehboob Hussain, at the New York University School of Medicine. "'I am absolutely excited by the potential applications of our findings,' he said. 'In our body, there is an additional, easily available source of cells that are capable of becoming insulin-producing cells.'" -S. Bhattacharya, "Bone marrow experiments suggest diabetes cure," NewScientist.com News Service, March 17, 2003, at http://www.newscientist.com/news/news.jsp?id=ns99993508. * * * 2002

"The use of human embryonic stem cells has been confronted with major obstacles because of bio-ethical and political issues involved obtaining them, as well as the suggestion that embryonic stem cells may lack appropriate developmental instructions, making them potentially less feasible for engrafting into adult tissue... "As compared to embryonic stem cells, adult derived stem cells are endowed with additional developmental instructions and may be better suited for therapeutic purposes. According to [Dr. Shahin Rafii of Cornell University Medical College], 'We are approaching a day when a patient's own stem cells can be induced to divide and develop into tissue that can replace that which is diseased or destroyed, making overcrowded organ transplant lists and rejection of foreign tissues a thing of the past'." -"Mechanism For Regulation Of Adult Stem Cells Found," UniSci - Daily University Science News, May 31, 2002, at http://unisci.com/stories/20022/0531021.htm * * * On the versatility of adult hematopoietic (blood-producing) stem cells, HSCs: "[R]ecent studies have suggested that a subpopulation of HSCs may have the ability to contribute to diverse cell types such as hepatocytes, myocytes, and neuronal cells, especially following induced tissue damage... These surprising findings contradict the dogma that adult stem cells are developmentally restricted." -K. Bunting and R. Hawley, "The tao of hematopoietic stem cells: toward a unified theory of tissue regeneration," Scientific World Journal, April 10, 2002, p. 983.

* * * 2001

Commenting on a study by researchers at New York University, Yale and Johns Hopkins: "'There is a cell in the bone marrow that can serve as the stem cell for most, if not all, of the organs in the body,' says Neil Theise, M.D., Associate Professor of Pathology at NYU School of Medicine... '(t)his study provides the strongest evidence yet that the adult body harbors stem cells that are as flexible as embryonic stem cells'." -"Researchers Discover the Ultimate Adult Stem Cell," ScienceDaily Magazine, May 4, 2001, at http://www.sciencedaily.com/releases/2001/05/010504082859.htm * * * "Umbilical cords discarded after birth may offer a vast new source of repair material for fixing brains damaged by strokes and other ills, free of the ethical concerns surrounding the use of fetal tissue, researchers said Sunday."

Excerpt from:
Scientific Experts Agree Embryonic Stem Cells Are ...

Recommendation and review posted by sam

Promoting Safe and Effective Genetic Testing in the United States Table of Contents Final Report of the Task Force on Genetic Testing

The Task Force was created by the National Institutes of Health-Department of Energy Working Group on Ethical, Legal and Social Implications of Human Genome Research.

September 1997

EDITORS Neil A. Holtzman, M.D., MPH Michael S. Watson, Ph.D.

ACKNOWLEDGEMENTS

EXECUTIVE SUMMARY

ENSURING THE SAFETY AND EFFECTIVENESS OF NEW GENETIC TESTS

ENSURING THE QUALITY OF LABORATORIES PERFORMING GENETIC TESTS

IMPROVING PROVIDERS' UNDERSTANDINGS OF GENETIC TESTING

GENETIC TESTING FOR RARE INHERITED DISORDERS

Chapter 1: INTRODUCTION

Chapter 2: ENSURING THE SAFETY AND EFFECTIVENESS OF NEW

Chapter 3: ENSURING THE QUALITY OF LABORATORIES PERFORMING GENETIC TESTS

Chapter 4: IMPROVING PROVIDERS' UNDERSTANDINGS OF GENETIC TESTING

Chapter 5: GENETIC TESTING FOR RARE INHERITED DISORDERS

Chapter 6: SUMMARY AND CONCLUSIONS

Appendix 1: Individuals and Organizations Who Provided Comments to the Task Force

Appendix 2: Response of the Task Force to the Food and Drug Administration's Proposed Rule on Analyte Specific Reagents

Appendix 3: State of the Art of Genetic Testing in the United States: Survey of Biotechnology Companies and Nonprofit Clinical Laboratories and Interviews of Selected Organizations

Appendix 4: Informational Materials about Genetic Tests

Appendix 5: The History of Newborn Phenylketonuria Screening in the U.S.

Appendix 6: Scientific Advances and Social Risks: Historical Perspectives of Genetic Screening Programs for Sickle Cell Disease, Tay-Sachs Disease, Neural Tube Defects and Down Syndrome, 1970-1997

GLOSSARY

Top of page

Last Reviewed: October 1, 2012

Continue reading here:
Genetic Testing Report - genome.gov

Recommendation and review posted by sam

Genetic testing looks for changes in a person's genes, chromosomes, or in the levels of certain important proteins.

Types of genetic tests include:

Once the DNA is separated out, scientists hunt for the gene along the DNA strand to see if it looks abnormal.

Another type of chromosome test, called FISH analysis (fluorescent in situ hybridization), can find small changes in the chromosomes that may be missed by the karyotype.

A newer type of chromosome test is called array CGH. It is a very sensitive test and can also find small changes in the chromosomes.

You may find companies offering home genetics testing kits on the Internet. These do-it-yourself test kits have not been proven to be accurate, and they may not even be testing for what they claim to be. You should talk to a genetics professional before you purchase or use this type of kit.

Sources:

"What Is Genetic Testing?" About Genetic Services. 19 Mar 2004. GeneTests. 21 Jan 2008

Burton, Jess, & Jon Turney. The Rough Guide to Genes & Cloning. London: Rough Guides Ltd., 2007.

"Frequently Asked Questions About Genetic Testing." Genetics and Genomics for Patients and the Public. 17 Dec 2007. National Human Genome Research Institute. 21 Jan 2008

2016 About, Inc. All rights reserved.

Read this article:
What Is Genetic Testing -- Information About Genetic Testing

Recommendation and review posted by Bethany Smith

Our Associate Medical Director, Professor Jeremy Pearson,discusses the parallels between todays news about treating paralysis and our hopes for mending broken hearts.

21 October 2014

This morning I woke to the news that a paralysed man could walk again. A medical miracle had been performed thanks to laboratory and clinical research. But when you break down the scientific journey thats got us to this point, you realise it isnt a miracle at all but decades of dedication and excellent science. This is the journey our funded researchers are on now as they work towards repairing and regenerating hearts damaged by heart attack.

A University College London (UCL) researcher, Professor Geoffrey Raisman, has been the driving force behind the paralysis breakthrough. Back in 1985 he discovered special cells in the nose that have a unique ability for allowing new nerve cells to grow. Almost three decades later, after developing a technique through studies in rats, we now have a potential treatment to regenerate a severed spinal cord.

This breakthrough is an excellent example of how persistence pays off in medical research. Laboratory science youre helping us to fund now could become a patient treatment in the future but the researchers need time and they need continued funding.

Professor Raisman was searching for a solution to a problem that seemed unsolvable something that our funded researchers can relate to. Right now, once a heart is damaged, like the spinal cord, it cannot be repaired. The heart doesnt spontaneously repair itself. A damaged heart cant pump blood around the body as well as it should, which can lead to heart failure. Heart failure can be severely disabling and prevent people carrying out basic tasks like going to the shops or washing without becoming totally exhausted.

Right now a BHF Professor Paul Riley(pictured) is moving us closer to a solving our unsolvable problem. In 2011, while at UCL, Professor Riley showed in mice how heart muscle can be regenerated in the adult heart after damage. Now at Oxford, he and his team are further investigating the outer layer of the heart, where these regenerative heart cells lie. We hope this work will eventually lead to a treatment that could be given to people after a heart attack to trigger the repair of any damage and prevent heart failure.

Due to difficulties in securing funding Professor Raismans progress was perhaps delayed by many years. With your support we hope to accelerate the progress that Professor Riley and his fellow researchers are making. We have already committed to funding 7.5 million across three Centres of Regenerative Medicine, one led by Professor Riley, that bring top researchers together with a common aim of repairing damaged heart muscle and blood vessels. And now we hope to raise a further 10 million towards a dedicated regenerative medicine facility for Professor Riley and his colleagues at Oxford.

This facility, called the Institute of Developmental and Regenerative Medicine, will bring experts from three separate disciplines under one roof where they can share facilities, ideas and resources making new treatments a reality much sooner.

Continue reading here: Regenerative medicine

.

Read more:
Regenerative medicine IPS Cell Therapy IPS Cell Therapy

Recommendation and review posted by sam

Jewish Genetics: Abstracts and Summaries Part 1: Jewish Populations Last Update: April 26, 2016 Family TreeDNA: Genetic Testing Service Get genetically tested to discover your relationship to other families, other Jews, and other ethnic groups. Projects you might qualify to join include "Gesher Galicia - Jewish DNA Project", "JewishGen Belarus SIG DNA Project", "JewishGen Hungarian SIG DNA Project", "German Jewish Gersig DNA Project", "Jewish Frankfurt", "Sephardic Heritage DNA Project", "Jews of Rhodes Project", "The Jewish R1b Project", "Ashkenazi Levite R1a1", and "Jewish E Project". Order a DNA kit from FTDNA's headquarters in the USA This page collects Y-DNA and mtDNA data and analysis related to traditionally Rabbinical Jewish populations of the world, including: Ashkenazim (Jews of Northern and Eastern Europe) Sephardim (Spanish and Portuguese Jews) Mizrakhim (Middle Eastern Jews) Italkim (Italian Jews) Caucasian Mountain Jews (Dagestani and Azerbaijani Jews) Georgian Jews Indian Jews North African Jews Yemenite Jews Ethiopian Jews Steven Bray's study, 2010 Steven M. Bray, Jennifer G. Mulle, Anne F. Dodd, Ann E. Pulver, Stephen Wooding, and Stephen T. Warren. "Signatures of founder effects, admixture, and selection in the Ashkenazi Jewish population." Proceedings of the National Academy of Sciences of the United States of America (PNAS) 107:37 (September 14, 2010): pages 16222-16227. 471 unrelated Ashkenazim were genotyped. Among the comparative populations were 1705 continental Europeans and 1251 European-Americans. Also used for comparison were 3 Middle Eastern populations: Palestinian Arabs, Druze, and Bedouins. Abstract: "The Ashkenazi Jewish (AJ) population has long been viewed as a genetic isolate, yet it is still unclear how population bottlenecks, admixture, or positive selection contribute to its genetic structure. Here we analyzed a large AJ cohort and found higher linkage disequilibrium (LD) and identity-by-descent relative to Europeans, as expected for an isolate. However, paradoxically we also found higher genetic diversity, a sign of an older or more admixed population but not of a long-term isolate. Recent reports have reaffirmed that the AJ population has a common Middle Eastern origin with other Jewish Diaspora populations, but also suggest that the AJ population, compared with other Jews, has had the most European admixture. Our analysis indeed revealed higher European admixture than predicted from previous Y-chromosome analyses. Moreover, we also show that admixture directly correlates with high LD, suggesting that admixture has increased both genetic diversity and LD in the AJ population. Additionally, we applied extended haplotype tests to determine whether positive selection can account for the level of AJ-prevalent diseases. We identified genomic regions under selection that account for lactose and alcohol tolerance, and although we found evidence for positive selection at some AJ-prevalent disease loci, the higher incidence of the majority of these diseases is likely the result of genetic drift following a bottleneck. Thus, the AJ population shows evidence of past founding events; however, admixture and selection have also strongly influenced its current genetic makeup."

Excerpts from page 16222:

"The Ashkenazi Jewish (AJ) population has long been viewed as a genetic isolate, kept separate from its European neighbors by religious and cultural practices of endogamy (1). [...] Y-chromosome studies also indicate only a low amount of admixture with neighboring Europeans (8-10). [...] Consistent with recent reports (13, 20, 23-25), principal component analysis (PCA) using these combined datasets confirmed that the AJ individuals cluster distinctly from Europeans, aligning closest to Southern European populations along the first principal component, suggesting a more southern origin, and aligning with Central Europeans along the second, consistent with migration to this region (Fig. S1)."

Excerpts from page 16223:

"The higher diversity in the AJ population was paralleled by a lower inbreeding coefficient, F, indicating the AJ population is more outbred than Europeans, not inbred, as has long been assumed (P < 1e-7) (Table 1). The greater genetic variation among the AJ population was further confirmed using a pairwise identity-by-state (IBS) permutation test, which showed that average pairs of AJ individuals have significantly less genomewide IBS sharing than pairs of EA or Euro individuals (empirical P value < 0.05). Thus, our results show that the AJ population is more genetically diverse than Europeans. [...] We also compared the genome-wide haplotype structure between the AJ and European populations using a haplotype modeling algorithm (26), which models phased haplotypes as edges that pass through nodes at each SNP across the genome. The number of nodes in the model is correlated to the genetic variation, and the number of edges per node is inversely correlated to the haplotype length. Using this model, we found that the AJ population has a greater number of nodes (0.88-1.11% more) but fewer edges per node (3.82-4.76% fewer) compared with the Europeans (P < 1e-50) (Table S2), indicating both higher genetic variation and longer haplotypes in the AJ population, consistent with our previous results. [...] We removed SNPs in high LD and measured the mean heterozygosity per locus across the combined Middle Eastern populations (Bedouin, Palestinian, and Druze) and found that the AJ population had higher heterozygosity (0.3121 vs. 0.3053, P < 1e-23). Other reports showing no increased heterozygosity in the AJ relative to Middle Eastern populations (13, 22) were probably limited by lower AJ sample sizes, which our dataset overcomes. Thus, the increased genetic diversity and LD appear consistent with admixture rather than founding effects. [...] To evaluate admixture in the AJ population, we investigated the similarity between AJ and HGDP populations using PCA as well as a population clustering algorithm (32). Both analyses show that AJ individuals cluster between Middle Eastern and European populations (Fig. 2 A and B and Fig. S2A), corroborating other recent reports (13, 20, 22, 23, 25). Interestingly, our population clustering reveals that the AJ population shows an admixture pattern subtly more similar to Europeans than Middle Easterners (Fig. 2 A and C, Lower), while also verifying that the Ashkenazi Jews possess a unique genetic signature clearly distinguishing them from the other two regions (Fig. 2C, Upper). The fixation index, FST, calculated concurrently to the PCA, confirms that there is a closer relationship between the AJ and several European populations (Tuscans, Italians, and French) than between the AJ and Middle Eastern populations (Fig. S2B)."

Excerpts from pages 16223-16224:

"Although the proximity of the AJ and Italian populations could be explained by their admixture prior to the Ashkenazi settlement in Central Europe (13), it should be noted that different demographic models may potentially yield similar principal component projections (33); thus, it is also consistent that the projection of the AJ populations is primarily the outcome of admixture with || Central and Eastern European hosts that coincidentally shift them closer to Italians along principle component axes relative to Middle Easterners."

Excerpts from page 16224:

"We used the combined Palestinian and Druze populations to represent the Middle Eastern ancestor and tested three different European groups as the European ancestral population (SI Materials and Methods). Using these proxy ancestral populations, we calculated the amount of European admixture in the AJ population to be 35 to 55%. Previous estimates of admixture levels have varied widely depending on the chromosome or specific locus being considered (18), with studies of Y-chromosome haplogroups estimating from 5 to 23% European admixture (8, 9). Our higher estimate is in part a result of the use of different proxies for the Jewish ancestral population."

Excerpts from page 16226:

"Multiple studies have found that the 'lactase-persistence' allele at the LCT locus was selected for in Northern Europeans, with the selective sweep presumably occurring at the time of the domestication of cattle 2,000 to 20,000 y ago (42, 43). The absence of this allele in our data would suggest that the selective sweep was complete before the Ashkenazi establishment in Europe. Moreover, the prevalence of lactase deficiency in Ashkenazi Jews has been estimated at 60 to 80% (44), further corroborating the lack of selection for the LCT locus in the AJ population. [...] Intriguingly, the AJ population has long been known to have lower levels of alcoholism than other groups (16, 46), with one study showing that Jewish males have a 2.5-fold lower lifetime rate of alcohol abuse/dependence compared with non-Jews (47). [...] Our results, together with a recent study showing that variation in the ALDH2 promoter affects alcohol absorption in Jews (48), now suggest that genetic factors and selective pressure at the ALDH2 locus may have contributed to the low levels of alcoholism."

Quinn Eastman of Emory University with ScienceDaily staff. "Analysis of Ashkenazi Jewish Genomes Reveals Diversity, History." ScienceDaily (August 27, 2010). Excerpts:

"Common Genetic Threads Link Thousands of Years of Jewish Ancestry." ScienceDaily (June 4, 2010). Excerpts:

Razib Khan. "Genetics and the Jews." Discover Magazine - Gene Expression (June 6, 2010).

"Dienekes Pontikos". "Two Major Groups of Living Jews." dienekes.blogspot.com (June 3, 2010).

Alla Katsnelson. Jews worldwide share genetic ties: But analysis also reveals close links to Palestinians and Italians." Nature.com (June 3, 2010). Excerpts:

Sharon Begley. "The DNA of Abraham's Children." Newsweek Web Exclusive (June 3, 2010). Excerpts:

Andrea Anderson. "Study Points to Shared Genetic Patterns amongst Jewish Populations." GenomeWeb News (June 3, 2010). Excerpts:

Nicholas Wade. "In DNA, New Clues to Jewish Roots." The New York Times (May 14, 2002): F1 (col. 1). Excerpts:

Mark G. Thomas, Michael E. Weale, Abigail L. Jones, Martin Richards, Alice Smith, Nicola Redhead, Antonio Torroni, Rosaria Scozzari, Fiona Gratrix, Ayele Tarekegn, James F. Wilson, Cristian Capelli, Neil Bradman, and David B. Goldstein. "Founding Mothers of Jewish Communities: Geographically Separated Jewish Groups Were Independently Founded by Very Few Female Ancestors." The American Journal of Human Genetics 70:6 (June 2002): 1411-1420. The study collected mtDNA from about 600 Jews and non-Jews from around the world, including 78 Ashkenazic Jews and Georgians, Uzbeks, Germans, Berbers, Ethiopians, Arabs, etc. 17.9% of sampled Iraqi Jews have an mtDNA pattern known as U3, compared to 2.6% of Ashkenazic Jews, 0.9% of Moroccan Jews, 1.7% of ethnic Berbers, 1.1% of ethnic Germans, 0.0% of Iranian Jews, 0.0% of Georgian Jews, 0.0% of Bukharian Jews, 0.0% of Yemenite Jews, 0.0% of Ethiopian Jews, 0.0% of Indian Jews, 0.0% of Syrian Arabs, 0.0% of Georgians, 0.0% of Uzbeks, 0.0% of Yemeni Arabs, 0.0% of Ethiopians, 0.0% of Asian Indians, 0.0% of Israeli Arabs. (According to Vincent Macaulay, U3 is found also among some Turks, Iraqis, Caucasus tribes, Alpine Europeans, North Central Europeans, Kurds, Azerbaijanis, Eastern Mediterranean Europeans, Central Mediterranean Europeans, Western Mediterranean Europeans, and southeastern Europeans.) Another pattern, called Haplotype I, was found among 12.1% of Bukharan Jews, 2.6% of Ashkenazic Jews, 1.8% of Iraqi Jews, 1.3% of Iranian Jews, 1.1% of ethnic Germans, and 2.4% of ethnic Asian Indians, and none of the other groups among individuals tested. (According to Vincent Macaulay, Haplotype I is found also among some Northeastern Europeans, North Central Europeans, Caucasus tribes, Northwestern Europeans, and Scandinavians.) Yet another pattern, called Haplotype J1, was found among 12.5% of Iraqi Jews, 2.7% of Iranian Jews, 9.2% of Yemenite Jews, and 1.7% of Israeli Arabs, and none of the other groups among individuals tested. (According to Vincent Macaulay, Haplotype J1 is found also among some Iraqi Arabs, Bedouins, Palestinian Arabs, and Azerbaijanis.) To compare with Vincent Macaulay's research on mtDNA, visit Supplementary data from Richards et al. (2000). Abstract:

Martin Richards. "Beware the gene genies." The Guardian (February 21, 2003). Excerpts:

Page 1104: "It is worth mentioning that, on the basis of protein polymorphisms [which are not to be confused with Y chromosome polymorphisms], most Jewish populations cluster very closely with Iraqis (Livshits et al. 1991) that the latter, in turn, cluster very closely with Kurds (Cavalli-Sforza et al. 1994)."

At Table 1: Y Chromosome Haplogroup Distribution, it is indicated that 11.6 percent of Muslim Kurds and 9.4 percent of Bedouins also have Eu 19 chromosomes; hence, genetic drift rather than admixture with East Europeans may theoretically explain Eu 19's presence among Ashkenazi Jews. On the other hand, the origin of Eu 19 (now known as R1a1) is from eastern Europe thousands of years ago, perhaps the kurgan culture, and is found in much higher quantities among Slavs (like Sorbs, Belarusians, Ukrainians, and Poles) than any Middle Eastern tribe. For further data consult figure 1 in Ornella Semino, et al., "The genetic legacy of Paleolithic Homo sapiens sapiens in extant Europeans: a Y chromosome perspective," Science 290(5494) (Nov. 10, 2000): 1155-1159, as well as the 2003 Levite study referenced here. [Update added December 21, 2013: The Ashkenazic Levite variety of R1a1, sometimes called R1a-M582, was later found to be from an Iranian source rather than an East European source.]

In Figure 3 of Nebel et al.'s 2001 paper, it can be seen that while some Muslim Kurds possess the Cohen Modal Haplotype (at a frequency of 0.011), and even some Palestinian Arabs do (at a frequency of 0.021), more Muslim Kurds (0.095) have a haplotype that is a different Y DNA lineage, with a different allele number in one of the six microsatellite locis. Figure 3 is also interesting since it shows that 0.021 of Palestinian Arabs have the Cohen Modal Haplotype.

Judy Siegel. "Genetic evidence links Jews to their ancient tribe." Jerusalem Post (November 20, 2001). Excerpts:

"Study: North African, Iraqi Jewry nearly genetic twins." Jerusalem Post (November 19, 2001). Excerpts:

Tamara Traubman. "Study finds close genetic connection between Jews, Kurds." Ha'aretz (November 21, 2001). Excerpts:

"The Jewish World: This Week in Israel." Global Jewish Agenda (Jewish Agency for Israel, November 22, 2001). Excerpts:

"Evrei i kurdi - brat'ya po genam." MIGnews.com (Media International Group)

Max Gross. "'A Certain People': Study Confirms Deep Similarities Among Jews." Forward (August 16, 2002): B11. Excerpts:

"Jews and Arabs Share Recent Ancestry." Science Now (American Academy for the Advancement of Science, October 30, 2000). In the last sentence, it is admitted that European Jews mixed with groups residing in Europe. Excerpts:

Judy Siegel. "Experts find genetic Jewish-Arab link." Jerusalem Post (November 6, 2000). Despite its merits, this study uses a small sample size and an improbable set of test subjects. It is puzzling that the Northern Welsh were tested, because it's obvious that they are farther away from European Jews than Arabs. Why were they tested instead of the Serbs, Romanians, Italians, or Austrians - groups which, unlike the Welsh, had significant contact with Jews over the centuries? The selection of groups influences the results of any genetics study. Notice, however, that even according to this test, somewhere between 20 and 30 percent of the Jews do NOT have paternal-line ancestry from Israel. Excerpts:

Nicholas Wade. "Scientists Rough Out Humanity's 50,000-Year-Old Story." The New York Times (November 14, 2000). Excerpts:

Tamara Traubman. "A new study shows that the genetic makeup of Jews and Arabs is almost identical, and that both groups share common prehistoric ancestors." Ha'aretz (2000). Excerpts:

Nadine Epstein. "Family Matters: Funny, We Don't Look Jewish." Hadassah Magazine 82:5 (January 2001). Excerpts:

The assertion of Ostrer that Yiddish comes from Alsace and Rhineland has been debunked by solid research showing that Yiddish derives from Bavaria. Yiddish is clearly a form of High German, too, and not Low German. Epstein's article demonstrates a lack of linguistic knowledge.

Christopher Hitchens. "The Part-Jewish Question: Double the Pleasure or Twice the Pain? Of 'Semi-Semites' and Those Who Fear Them." Forward (January 26, 2001). Excerpts:

Hillel Halkin. "Wandering Jews -- and Their Genes." Commentary 110:2 (September 2000): 54-61. Excerpts:

Michael F. Hammer, Alan J. Redd, Elizabeth T. Wood, M. R. Bonner, Hamdi Jarjanazi, Tanya Karafet, A. Silvana Santachiara-Benerecetti, Ariella Oppenheim, Mark A. Jobling, Trefor Jenkins, Harry Ostrer, and Batsheva Bonn-Tamir. "Jewish and Middle Eastern non-Jewish Populations Share a Common Pool of Y-chromosome Biallelic Haplotypes.", PNAS 97:12 (June 6, 2000): 6769-6774. Summary:

According to Mark Jobling, "Jews are the genetic brothers of Palestinians, Lebanese, and Syrians".

Some revealing comments from the study's geneticists: Dina Kraft's May 9, 2000 article in the Associated Press quotes Hebrew University geneticist Howard Cedar who "said even though Y chromosomes are considered the best tool for tracing genetic heritage, researchers still don't know what the history is behind the variations. As a result, it is difficult to draw conclusions about genetic affinity.." The article also quotes Batsheva Bonne-Tamir, a Tel Aviv University geneticist, who "cautioned that the techniques were new and that until the human genome is mapped, it will be difficult to be certain about the conclusions."

"To say that Jews are somehow homogeneous across the entire diaspora is completely fallacious," says Ken Jacobs of the University of Montreal. "There is so much incredible genetic heterogeneity within the Jewish community -- any Jewish community." Jewish people simply don't exhibit the genetic homogeneity that [Kevin] MacDonald ascribes to them, Jacobs says. According to an Jacobs' views as summarized in an article in the New Times Los Angeles Online (April 20-26, 2000), "Witness For The Persecution" by Tony Ortega: "The only Jewish subgroup that does show some homogeneity -- descendants of the Cohanim, or priestly class -- makes up only about 2 percent of the Jewish population. Even within the Cohanim, and certainly within the rest of the Jewish people, there's a vast amount of genetic variation that simply contradicts MacDonald's most basic assertion that Jewish genetic sameness is a sign that Judaism is an evolutionary group strategy." In H-ANTISEMITISM, Ken Jacobs added: "Hammer's Jewish samples are heavily skewed towards the Kohanim... This is bound to reduce within-population variance in the Jewish sample... I pointed out solely that the data reported for the Jewish samples in the recent PNAS were remarkably similar to those published previously in studies of which Hammer was a co-author, the focus of which was the Kohanim... There is an ahistorical aspect to this work, as well as a serious conflation of genes, ethnicity, and religious belief. For example, as used in Hammer's study, the distinction between 'Syrian' and 'Palestinian' is based on fairly recent geo-political constructs that have little or no bearing on the patterns of gene flow in the region prior to 1000 CE.... In the original Lemba study, the complex of Y-chromosome genes was found in 45% of Kohanim among Ashkenazim, the percentage was 56% of Kohanim among the Sepharad, and 53% among the Buba clan of the Lemba. Among non-Kohanim the average Jewish % for this gene complex is less than 5%. One does not have to understand the lingo to see that there was inbreeding in one part of the dispersed Jewish communities and a certain level of outbreeding in the rest."

John Tooby, Professor of Anthropology at the University of California at Santa Barbara, is quoted in an article for Slate's "Culturebox" by Judith Shulevitz as saying: "The notion that Jews are a genetically distinct group doesn't make it on the basis of modern population genetics."

Chris Garifo. "U of A researcher heads breakthrough genetic study." Jewish News of Greater Phoenix 52:37 (May 19, 2000). Excerpts:

Ivan Oransky. "Tracing Mideast Roots Back to Isaac and Ishmael: Study of Y Chromosome Suggests a Common Ancestry for Jews and Arabs." The Forward (May 19, 2000). Excerpts:

Hillary Mayell. "Genetic Link Established Between Jews and Arabs." National Geographic News (May 10, 2000).

"Jews and Arabs are 'genetic brothers'." BBC News (May 10, 2000). Excerpts:

Nicholas Wade. "Y Chromosome Bears Witness to Story of the Jewish Diaspora." The New York Times (May 9, 2000): F4 (col. 1). Excerpts:

Norton Godoy. "Judeus e rabes: irmos." Isto (2000).

R. Highfield. "Jews, Arabs share ancestral link, study says." Calgary Herald (May 9, 2000): A19.

Marilynn Larkin. "Jewish-Arab affinities are gene-deep." The Lancet 355 (2000): 1699.

Maggie Fox. "Middle Eastern Roots: Shared Y Chromosome Illustrates Genetic Map of the Past." Reuters (May 9, 2000).

Joel J. Elias. "The Genetics of Modern Assyrians and their Relationship to Other People of the Middle East." Assyrian Health Network (July 20, 2000). Excerpts:

"North African Jews show slightly elevated membership in the k2 component prevalent in African populations. Similarly, in the Ashkenazi Jews, the proportion of the largely European k5 component is somewhat larger than that in the Sephardi Jews (23% vs. 16%). Within the Ashkenazi Jews from Eastern and Central Europe, we do see a signal (2.2%) of components common in East Asia that are less visible in Ashkenazi Jews from Western Europe or European Sephardi Jews (0.6%)."

Excerpts from page 882:

"Admixture demonstrates the connection of Ashkenazi, North African, and Sephardi Jews, with the most similar non-Jewish populations to Ashkenazi Jews being Mediterranean Europeans from Italy (Sicily, Abruzzo, Tuscany), Greece, and Cyprus. When subtracting the k5 component, which perhaps originates in Ashkenazi and Sephardi Jews from admixture with European hosts, the best matches for membership patterns of the Ashkenazi Jews shift to the Levant: Cypriots, Druze, Lebanese, and Samaritans. [...] Considering the IBD threshold of 3 Mb for shared segments, Ashkenazi Jews are expected to show no significant IBD sharing with any population from which they have been isolated for [approximately more than] 20 generations. [...] Ashkenazi Jews show significant IBD sharing only with Eastern Europeans, North African Jews, and Sephardi Jews."

Agence France-Presse. "Study confirms Jewish Middle East origins." Sydney Morning Herald, June 11, 2010. Excerpt:

Alla Katsnelson. "Genes link Jewish communities, take 2." Nature: The Great Beyond (June 9, 2010). Excerpt:

Razib Khan. "Genetics and the Jews (it's still complicated.)" Discover Magazine - Gene Expression (June 10, 2010). Excerpts:

Excerpts from the body of the article:

Martin Richards. "New information is discovered about the ancestry of Ashkenazi Jews." Press release released October 8, 2013. Excerpts:

Nicholas Wade. "Genes Suggest European Women at Root of Ashkenazi Family Tree." The New York Times (October 9, 2013). Excerpts:

Jon Entine. "Ashkenazi Jewish Women Descended Mostly from Italian Converts, New Study Asserts." Genetic Literacy Project (October 8, 2013). Excerpts:

Kate Yandell. "Genetic Roots of the Ashkenazi Jews." The Scientist Magazine (October 8, 2013). Excerpts:

Eva Fernndez, Alejandro Prez-Prez, Cristina Gamba, Eva Prats, Pedro Cuesta, Josep Anfruns, Miquel Molist, Eduardo Arroyo-Pardo, and Daniel Turbn. "Ancient DNA Analysis of 8000 B.C. Near Eastern Farmers Supports an Early Neolithic Pioneer Maritime Colonization of Mainland Europe through Cyprus and the Aegean Islands." PLoS Genetics 10:6 (June 5, 2014): e1004401. Some ancient skeletons from the "Pre-Pottery Neolithic B" ("PPNB") sites at Tell Halula and Tell Ramad in what's now Syria had the "K" mtDNA haplogroup. This PPNB population genetically clusters with the modern-day Ashkenazi Jews, Csng people, and the population of Cyprus, who all have high frequencies of "K". (Modern Syrians are in a different cluster.) The evidence weighs against Costa et al.'s interpretation that the "K" haplogroups that Ashkenazim possess reflect European ancestors rather than Middle Eastern ones. Fernndez et al. wrote:

Shai Carmi, Ethan Kochav, Ken Y. Hui, Xinmin Liu, James Xue, Fillan Grady, Saurav Guha, Kinnari Upadhyay, Semanti Mukherjee, B. Monica Bowen, Joseph Vijai, Ariel Darvasi, Kenneth Offit, Laurie J. Ozelius, Inga Peter, Judy H. Cho, Harry Ostrer, Gil Atzmon, Lorraine N. Clark, Todd Lencz, and Itsik Pe'er. "The Ashkenazi Jewish Genome." A paper presented at the annual meeting of The American Society of Human Genetics (ASHG) in October 22-26, 2013 in Boston, Massachusetts. The researchers sequenced 128 complete genomes from Ashkenazi Jews. From their results they estimate that about 55 percent plus or minus 2 percentage points of Ashkenazi ancestry derives from European peoples.

Shai Carmi, Ken Y. Hui, Ethan Kochav, Xinmin Liu, James Xue, Fillan Grady, Saurav Guha, Kinnari Upadhyay, Dan Ben-Avraham, Semanti Mukherjee, B. Monica Bowen, Tinu Thomas, Joseph Vijai, Marc Cruts, Guy Froyen, Diether Lambrechts, Stphane Plaisance, Christine Van Broeckhoven, Philip Van Damme, Herwig Van Marck, Nir Barzilai, Ariel Darvasi, Kenneth Offit, Susan Bressman, Laurie J. Ozelius, Inga Peter, Judy H. Cho, Harry Ostrer, Gil Atzmon, Lorraine N. Clark, Todd Lencz, and Itsik Pe'er. "Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins." Nature Communications 5 (September 9, 2014): article number 4835. The complete genomes of 128 Ashkenazi Jewish individuals were examined. Based on their analysis, the authors estimate that Ashkenazi Jews are about 46-50% of European origin, sharing ancestry with Western Europeans like the Flemish, who were also sampled in this study. The authors state that the other contributing population to Ashkenazic genetics are Middle Easterners. Their model suggests the present Ashkenazic population was founded after a bottleneck that occurred 25 to 32 generations ago, that is about "600-800 years" ago. The Ashkenazim have higher heterozygosity than non-Jewish Europeans yet descend from "a recent bottleneck of merely ~350 individuals." Page 63 of their "Supplementary Information" under "Reasons for increased heterozygosity" asserts "Additionally, AJ genomes were shown to have ~3% West-African ancestry." This is highly questionable as the authors cite not their own data to support this claim, but rather the methodologically-flawed study "The history of African gene flow into Southern Europeans, Levantines, and Jews" by Moorjani et al. that appeared in PLoS Genetics 7 in 2011. Most other admixture tests have shown zero or at most 0.1% Sub-Saharan West African/Negroid) ancestry in Ashkenazi individuals, and only tiny amounts of East African as well. Neither the Supplementary Information provided by Carmi et al. nor their main article discuss the evidence for small amounts of East Asian and Slavic ancestry in Eastern Ashkenazi Jews. Excerpt from the Abstract:

Karen Kaplan. "DNA ties Ashkenazi Jews to group of just 330 people from Middle Ages." Los Angeles Times (September 9, 2014). Excerpts:

Jesse Emspak. "Oy Vey! European Jews Are All 30th Cousins, Study Finds." LiveScience (September 9, 2014). Excerpts:

Alkes L. Price, Johannah Butler, Nick Patterson, Cristian Capelli, Vincenzo L. Pascali, Francesca Scarnicci, Andres Ruiz-Linares, Leif Groop, Angelica A. Saetta, Penelope Korkolopoulou, Uri Seligsohn, Alicja Waliszewska, Christine Schirmer, Kristin Ardlie, Alexis Ramos, James Nemesh, Lori Arbeitman, David B. Goldstein, David E. Reich, and Joel N. Hirschhorn. "Discerning the Ancestry of European Americans in Genetic Association Studies." Public Library of Science Genetics (PLoS Genetics) (January 2008). Sampled Southern Italians (Sicilians as well as those on the mainland), and other Europeans - 4,198 individuals in all. Excerpts:

Chao Tian, Roman Kosoy, Rami Nassir, Annette Lee, Pablo Villoslada, Lars Klareskog, Lennart Hammarstrm, Henri-Jean Garchon, Ann E. Pulver, Michael Ransom, Peter K. Gregersen, and Michael F. Seldin. "European Population Genetic Substructure: Further Definition of Ancestry Informative Markers for Distinguishing among Diverse European Ethnic Groups." Molecular Medicine vol. 15(11-12) (November 2009), pages 371-383. Sampled people from Italy (Lombards, Tuscans, Sardinians, Southern Italian-Americans living in New York) and Ashkenazi Jews to genotype them for 300,000 autosomal SNPs. Excerpts:

Chao Tian, Robert M. Plenge, Michael Ransom, Annette Lee, Pablo Villoslada, Carlo Selmi, Lars Klareskog, Ann E. Pulver, Lihong Qi, Peter K. Gregersen, and Michael F. Seldin. "Analysis and Application of European Genetic Substructure Using 300 K SNP Information." Public Library of Science Genetics (PLoS Genetics) (January 2008). Abstract excerpt:

Michael F. Seldin, Russell Shigeta, Pablo Villoslada, Carlo Selmi, Jaakko Tuomilehto, Gabriel Silva, John W. Belmont, Lars Klareskog, and Peter K. Gregersen. "European Population Substructure: Clustering of Northern and Southern Populations." Public Library of Science Genetics (PLoS Genetics) 2(9) (September 2006). Abstract:

Talia Bloch. "One Big, Happy Family: Litvaks and Galitzianers, Lay Down Your Arms; Science Finds Unity in the Jewish Gene Pool." Forward (August 22, 2007). Excerpts:

Anna C. Need, Dalia Kasperaviiute, Elizabeth T. Cirulli, and David B. Goldstein. "A genome-wide genetic signature of Jewish ancestry perfectly separates individuals with and without full Jewish ancestry in a large random sample of European Americans." Genome Biology 10(1) (2009): R7 (electronically published on January 22, 2009). Excerpts:

Marc Haber, Dominique Gauguier, Sonia Youhanna, Nick Patterson, Priya Moorjani, Laura R. Botigu, Daniel E. Platt, Elizabeth Matisoo-Smith, David F. Soria-Hernanz, R. Spencer Wells, Jaume Bertranpetit, Chris Tyler-Smith, David Comas, and Pierre A. Zalloua. "Genome-Wide Diversity in the Levant Reveals Recent Structuring by Culture." PLoS Genetics 9(2) (February 28, 2013): e1003316. Participants in this study about the Levant region of West Asia included Sephardi Jews, Ashkenazi Jews, Palestinians, Lebanese Christians, Lebanese Druze, Lebanese Muslims, Syrians, Jordanians, Bedouins, Cypriots, Armenians, Saudis, Yemenis, Iranians, and multiple European, East/South/Central Asian, and African populations. Ashkenazi Jews and Sephardi Jews were found to be closely related to each other and more closely related to Lebanese than Palestinians are. Excerpts:

Doron M. Behar, Ene Metspalu, Toomas Kivisild, Alessandro Achilli, Yarin Hadid, Shay Tzur, Luisa Pereira, Antonio Amorim, Llus Quintana-Murci, Kari Majamaa, Corinna Herrnstadt, Neil Howell, Oleg Balanovsky, Ildus A. Kutuev, Andrey Pshenichnov, David Gurwitz, Batsheva Bonne-Tamir, Antonio Torroni, Richard Villems, and Karl Skorecki. "The Matrilineal Ancestry of Ashkenazi Jewry: Portrait of a Recent Founder Event." American Journal of Human Genetics 78 (2006): 487-497. Abstract:

Judy Siegel. "40% Ashkenazim come from matriarchs." Jerusalem Post (January 13, 2006). Excerpts:

Nicholas Wade. "New Light on Origins of Ashkenazi in Europe." The New York Times (January 14, 2006): A12. Excerpts:

Malcolm Ritter. "Study: Most Ashkenazi Jews from four women." Associated Press (January 12, 2006). Excerpts:

Maggie Fox. "Study finds why Jewish mothers are so important." Reuters (January 13, 2006). Excerpts:

Donald Macintyre. "3.5 million Ashkenazi Jews 'traced to four female ancestors'." The Independent (January 14, 2006).

"'Four mothers' for Europe's Jews." BBC News (January 13, 2006). Excerpts:

Hillel Halkin. "Jews and Their DNA." Commentary Magazine 126:2 (September 2008): beginning on page 37. Excerpts:

David B. Goldstein. "In Jewish Genetic History, the Known Unknowns." Forward (August 28, 2009). Excerpts:

Almut Nebel, Dvora Filon, Marina Faerman, Himla Soodyall, and Ariella Oppenheim. "Y chromosome evidence for a founder effect in Ashkenazi Jews." European Journal of Human Genetics 13:3 (March 2005): 388-391. Preceded by advance electronic publication on November 3, 2004. This study focuses on one of the two main non-Mideastern Y-DNA lineages among Ashkenazic Jewish men: haplogroup R1a1 (the other is haplogroup Q). Abstract:

Mait Metspalu, Doron M. Behar, Y. Baran, Saharon Rosset, N. Kopelman, Bayazit Yunusbayev, A. Gladstein, Michael F. Hammer, Shay Tzur, E. Halperin, Karl Skorecki, Richard Villems, and Noah A. Rosenberg. "No indication of Khazar genetic ancestry among Ashkenazi Jews." A paper presented at the annual meeting of The American Society of Human Genetics (ASHG) in October 22-26, 2013 in Boston, Massachusetts. Some of the comparisons here are of questionable utility since the Khazars did not descend originally from the ancient peoples of the Caucasus and there is no proof that modern Caucasus peoples are descended from Khazars. So, the study doesn't directly test for Khazarian descent. Excerpts from the Abstract:

Doron M. Behar, Daniel Garrigan, Matthew E. Kaplan, Zahra Mobasher, Dror Rosengarten, Tatiana M. Karafet, Lluis Quintana-Murci, Harry Ostrer, Karl Skorecki, and Michael F. Hammer. "Contrasting patterns of Y chromosome variation in Ashkenazi Jewish and host non-Jewish European populations." Human Genetics 114:4 (March 2004): 354-365. 442 Ashkenazi Jews were sampled for this study and differentiated according to geographic, religious, and ethno-historical subcategories like "Byelorussian Jews" and "Dutch Jews". In Table 2 on page 357 we see that the mutation lineage designation R-M17, corresponding to haplogroup R1a1 (most often found among Ashkenazi Levites), is found at a frequency of 0.075 among the Ashkenazi Jews as a whole in this study, and at a frequency of 0.264 among the Non-Jewish Europeans (French, Germans, Austrians, Hungarians, Poles, Romanians, and Russians) in the study. Excerpts:

Doron M. Behar, Michael F. Hammer, Daniel Garrigan, Richard Villems, Batsheva Bonne-Tamir, Martin Richards, David Gurwitz, Dror Rosengarten, Matthew Kaplan, Sergio Della Pergola, Lluis Quintana-Murci, and Karl Skorecki. "MtDNA evidence for a genetic bottleneck in the early history of the Ashkenazi Jewish population." European Journal of Human Genetics 12:5 (May 2004): 355-364. (Advance online publication on January 14, 2004.) An observer who read the study indicates that the study shows that approximately 60 percent of European Jewish maternal roots come from European sources, with the other 40 percent from Middle Eastern or Asian roots. Abstract excerpt:

Bayazit Yunusbayev, Mait Metspalu, Mari Jrve, Ildus A. Kutuev, Siiri Rootsi, Ene Metspalu, Doron M. Behar, Krt Varendi, Hovhannes Sahakyan, Rita Khusainova, Levon Yepiskoposyan, Elza K. Khusnutdinova, Peter A. Underhill, Toomas Kivisild, and Richard Villems. "The Caucasus as an asymmetric semipermeable barrier to ancient human migrations." Molecular Biology and Evolution For future print publication. First published online on September 13, 2011. Among many other peoples of the Caucasus, 10 Mountain Jews were sampled to evaluate their haplogroups. These Mountain Jews' Y-DNA haplogroups were as follows: 3 belonged to haplogroup J1e*, 4 to J2a*, 1 to J2a2*, and 2 to L2. These haplogroups suggest overwhelmingly Near Eastern ancestry for the Mountain Jews' paternal lineages (represented by the J haplogroups) and a smaller South Asian element (represented by the L haplogroup).

Dror Rosengarten. "Y Chromosome Haplotypes Among Members of the Caucasus Jewish Communities." Proceedings of the 6th International Conference on Ancient DNA and Associated Biomolecules, July 21-25, 2002. Abstract excerpt:

Stefania Bertoncini, Kazima Bulayeva, Gianmarco Ferri, Luca Pagani, Laura Caciagli, Luca Taglioli, Igor Semyonov, Oleg Bulayev, Giorgio Paoli, and Sergio Tofanelli. "The Dual Origin of Tati-Speakers from Dagestan as Written in the Genealogy of Uniparental Variants." American Journal of Human Biology 24:4 (July/August 2012): pages 391-399. First published online on January 24, 2012. They genetically tested the Y-DNA and mtDNA of two Tat-speaking peoples who live in Daghestan in southern Russia: the Mountain Jews (also called Juhurim) and Muslim Tats. The two communities speak different dialects of the Tat language. The genetics of the Jewish and Muslim Tat speakers were found to be quite different, with the authors saying that they "do not reflect a common ancestry." The Mountain Jews were shown to be "a group with tight matrilineal genetic legacy who separated early from other Jewish communities." In the section "Analysis of paternal lineages", the authors indicate that the dominant Y-DNA haplogroup in Mountain Jews is G-M201 (3M285, P15, and M287), representing 36.8% of their total paternal lineages. The Mountain Jews' branch of G doesn't match the G sublineages of "two major Caucasian linguistic domains" nor does their branch cluster with the G STR Y-DNA haplotypes of Ashkenazim that were reported in Behar et al. 2004 and Hammer et al. 2009. The researchers were surprised that the Mountain Jews' kinds of G "can be separated into at least two divergent clades falling many mutational steps away from any G haplotype ever published before [...] One of these clades is defined by a very peculiar incomplete allele, DYS448*17.4, most likely the results of a deletion external to the repeat units." They also make this observation: "In the MJ [Mountain Jews], the highest level of haplotype sharing (lowest DHS values at the nine-locus level of analysis) was observed with autochthonous groups from Dagestan (Tabasarans, Kubachians, and Laks) and the Jews from Afghanistan". The Y-DNA haplogroup that Mountain Jews share with Tabasarans, called J1*-M267, isn't the same haplogroup that's shared between Muslim Tats and Tabarasans; the two lineages are not even close.

Felice L. Bedford. "Sephardic signature in haplogroup T mitochondrial DNA." European Journal of Human Genetics 20 (2012): 441-448. First released electronically on November 23, 2011. Excerpts from the Abstract:

Christopher L. Campbell, Pier F. Palamara, Maya Dubrovsky, Laura R. Botigu, Marc Fellous, Gil Atzmon, Carole Oddoux, Alexander Pearlman, Li Hao, Brenna M. Henn, Edward Burns, Carlos D. Bustamante, David Comas Martnez, Eitan Friedman, Itsik Pe'er, and Harry Ostrer. "North African Jewish and non-Jewish populations form distinctive, orthogonal clusters." Proceedings of the National Academy of Sciences USA (PNAS). Scheduled for print publication. First published online on August 6, 2012. This investigates the roots of five Jewish populations from North Africa (Moroccan, Algerian, Tunisian, Djerban, and Libyan Jews) and compares them to various Jewish and non-Jewish groups. The researchers found evidence that North African Jews descend from ancient Israelites as well as North African converts to Judaism and confirmed that they intermarried with Sephardic Jews who settled there during the Inquisition era. The degree to which the North African Jewish groups descend from Europeans varied. The study was able to separate Moroccan and Algerian Jews from Djerban and Libyan Jews. The PCA analysis and structure analysis showed that non-Jews of North Africa have more sub-Saharan African ancestry than Jews from North Africa do, confirming earlier studies like Behar et al. 2008.

Dan Even. "International genetic study traces Jewish roots to ancient Middle East." Ha'aretz (August 8, 2012). Excerpts:

A. L. Non, A. Al-Meeri, R. L. Raaum, L. F. Sanchez, and C. J. Mulligan. "Mitochondrial DNA reveals distinct evolutionary histories for Jewish populations in Yemen and Ethiopia." American Journal of Physical Anthropology 144:1 (January 2011): pages 1-10. First published online on July 7, 2010. This study of mtDNA included 45 Yemenite Jewish participants, 41 Ethiopian Jewish paticipants, 50 Yemenite non-Jewish participants, and some Ethiopian non-Jewish participants who speak Semitic language(s). The results showed Yemenite Jews and Ethiopian Jews both have high frequencies of "sub-Saharan African L haplogroups [...] indicating a significant African maternal contribution unlike other Jewish Diaspora populations. However, no identical haplotypes were shared between the Yemenite and Ethiopian Jewish populations, suggesting very little gene flow between the populations and potentially distinct maternal population histories." The authors explain that Ethiopian Jews are maternally Ethiopian rather than Israelite in origin, but they think Yemenite Jews partially have "potential descent from ancient Israeli exiles" and don't believe they have much ethnic Yemenite ancestry.

Noah A. Rosenberg, Eilon Woolf, Jonathan K. Pritchard, Tamar Schaap, Dov Gefel, Isaac Shpirer, Uri Lavi, Batsheva Bonn-Tamir, Jossi Hillel, and Marcus W. Feldman. "Distinctive genetic signatures in the Libyan Jews." Proceedings of the National Academy of Sciences USA (PNAS) 98:3 (January 30, 2001): 858-863. (Mirror) Excerpts:

Yedael Y. Waldman , Arjun Biddanda , Natalie R. Davidson, Paul Billing-Ross, Maya Dubrovsky, Christopher L. Campbell, Carole Oddoux, Eitan Friedman, Gil Atzmon, Eran Halperin, Harry Ostrer, and Alon Keinan. "The Genetics of Bene Israel from India Reveals Both Substantial Jewish and Indian Ancestry." PLoS ONE 11:3 (March 24, 2016): e0152056. Autosomal DNA analysis shows that the Bene Israel community of western India was formed by intermarriage between Middle Eastern Jewish men and local Indian women. 18 Bene Israel individuals were compared with hundreds of representatives of Jewish and non-Jewish populations. They have increased lengths of identical-by-descent matches with Jewish populations from outside of India, including Mizrahi Jews, compared to any other population within India or Pakistan. A weakness of this study is that it doesn't compare the Bene Israel against any non-Jewish population from the eastern Middle East (Iran/Iraq area).

Aleza Goldsmith. Jews and Arabs share genes, Stanford research scientist says." Jewish Bulletin of Northern California (March 9, 2001). Excerpts:

Peter A. Underhill, P. Shen, A. A. Lin, L. Jin, G. Passarino, W. H. Yang, E. Kauffman, Batsheva Bonn-Tamir, J. Bertranpetit, P. Francalacci, M. Ibrahim, T. Jenkins, J. R. Kidd, S. Q. Mehdi, M. T. Seielstad, R. S. Wells, A. Piazza, R. W. Davis, M. W. Feldman, Luigi Luca Cavalli-Sforza, and P. J. Oefner. "Y chromosome sequence variation and the history of human populations." Nature Genetics 26 (2000): 358-361. Sequence information for the 167 Y chromosome markers.

View post:
Jewish Genetics, Part 1: Jewish Populations (Ashkenazim ...

Recommendation and review posted by simmons

By Ian M. Chapman, MBBS, PhD

NOTE: This is the Consumer Version. CONSUMERS: Click here for the Professional Version

NOTE: This is the Consumer Version. DOCTORS: Click here for the Professional Version

Hypopituitarism is an underactive pituitary gland that results in deficiency of one or more pituitary hormones.

Hypopituitarism can be caused by several factors, including certain inflammatory disorders, a tumor of the pituitary gland, or an insufficient blood supply to the pituitary gland.

Symptoms depend on what hormone is deficient and may include short height, infertility, intolerance to cold, fatigue, and an inability to produce breast milk.

The diagnosis is based on measuring the blood levels of hormones produced by the pituitary gland and on imaging tests done on the pituitary gland.

Treatment focuses on replacing deficient hormones with synthetic ones but sometimes includes surgical removal or irradiation of any pituitary tumors.

Hypopituitarism, an uncommon disorder, can be caused by a number of factors, including a pituitary tumor or an insufficient blood supply to the pituitary gland.

DELATESTRYL

PARLODEL

CRINONE

CORTEF, SOLU-CORTEF

No US brand name

NOTE: This is the Consumer Version. CONSUMERS: Click here for the Professional Version

NOTE: This is the Consumer Version. DOCTORS: Click here for the Professional Version

See more here:
Hypopituitarism - Hormonal and Metabolic Disorders - Merck ...

Recommendation and review posted by simmons

As we age, our stem cells lose their potency. Your skin's ability to repair itself just isn't what it used to be. The result can be fine lines, wrinkles, age spots, and sagging skin. But non-embryonic stem cells -- the same stem cells active early in life -- are highly potent. Lifeline stem cell serums tap into the potency of these stem cells to help renew your skin's appearance.

Scientists at Lifeline Skin Care discovered that human non-embryonic stem cell extracts can help fight the look of fine lines, wrinkles and age spots. These stem cell extracts are mixed with powerful moisturizers and other carefully selected ingredients to help slow the signs of aging. And Lifeline stem cell serums were born.

The first types of human stem cells to be studied by researchers were embryonic stem cells, donated from in vitro fertilization labs. But because creating embryonic stem cells involves the destruction of a fertilized human embryo, many people have ethical concerns about the use of such cells.

Lifeline Skin Care (through its parent company, International Stem Cell Corporation) is the first company in the world to discover how to create human non-embryonic stem cells -- and how to take extracts from them. As a result, you need never be concerned that a viable human embryo was damaged or destroyed to create these extraordinary skin care products.

The non-embryonic stem cells in Lifeline stem cell serums are derived from unfertilized human oocytes (eggs) which are donated to ISCO from in vitro fertilization labs and clinics.

Lifeline Skin Care's exclusive skin care products are a combination of several discoveries and unique high-technology, with patent-pending formulations.

Original post:
Stem Cell Serums Visibly Renew Skin / Lifeline Skin Care Blog

Recommendation and review posted by Bethany Smith

Int J Biomater. 2012; 2012: 926059.

1Department of Surgery, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239, USA

2Hagey Laboratory for Pediatric Regenerative Medicine, Department of Surgery, Stanford University, 257 Campus Drive, Stanford, CA 94305, USA

3Department of Surgery, Plastic and Reconstructive Surgery Division, Division of Burn Surgery, University of Michigan Health Systems, 1500 East Medical Center Drive, Ann Arbor, MI 48104, USA

4The Biomaterials and Advanced Drug Delivery (BioADD) Laboratory, Stanford University, 300 Pasteur Drive, Grant Building, Room S380, Stanford, CA 94305, USA

Academic Editor: Kadriye Tuzlakoglu

Received 2012 Jan 15; Accepted 2012 Apr 8.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Stem cell-based therapies offer tremendous potential for skin regeneration following injury and disease. Functional stem cell units have been described throughout all layers of human skin and the collective physical and chemical microenvironmental cues that enable this regenerative potential are known as the stem cell niche. Stem cells in the hair follicle bulge, interfollicular epidermis, dermal papillae, and perivascular space have been closely investigated as model systems for niche-driven regeneration. These studies suggest that stem cell strategies for skin engineering must consider the intricate molecular and biologic features of these niches. Innovative biomaterial systems that successfully recapitulate these microenvironments will facilitate progenitor cell-mediated skin repair and regeneration.

Skin serves as the interface with the external world and maintains key homeostatic functions throughout life. This regenerative process is often overlooked until a significant exogenous and/or physiologic insult disrupts our ability to maintain skin homeostasis [1]. Complications of normal repair often result in chronic wounds, excessive scarring, or even malignant transformation, cutaneous diseases that contribute substantially to the global health burden [2, 3]. As human populations prone to inadequate healing (such as the aged, obese, and diabetics) continue to expand, novel therapies to treat dysfunctional skin repair and regeneration will become more critical.

Tissue regeneration has been demonstrated in multiple invertebrate and vertebrate species [4]. In humans, even complex tissues can regenerate without any permanent sequelae, such as liver, nerves, and skin. Although the typical result after significant organ injury is the formation of scar, regeneration after extensive skin and soft tissue trauma has been reported, most notably after digit tip amputation [5]. It is well accepted that human skin maintains the ability to regenerate; the question for researchers and clinicians is how to harness this potential to treat cutaneous injury and disease.

The integumentary system is a highly complex and dynamic system composed of myriad cell types and matrix components. Numerous stem cell populations have been identified in skin and current research indicates that these cells play a vital role in skin development, repair, and homeostasis [1, 6, 7]. In general, stem cells are defined by their ability to self-renew and their capacity to differentiate into function-specific daughter cells. These progenitor cells have been isolated from all skin layers (epidermis, dermis, hypodermis) and have unique yet complimentary roles in maintaining skin integrity. The promise of regenerative medicine lies in the ability to understand and regulate these stem cell populations to promote skin regeneration [4].

Wound healing is a highly regulated process that is thought to be mediated in part by stem cells [8, 9]. This has prompted researchers to examine the use of stem cells to augment skin repair following injury. Preclinical studies have suggested that the secretion of paracrine factors is the major mechanism by which stem cells enhance repair [10, 11]. Consistent with this hypothesis, conditioned media from mesenchymal stem cells (MSCs) have been shown to promote wound healing via activation of host cells [11, 12]. Clinical studies have suggested that topical delivery of MSCs may improve chronic wound healing [1315] and multiple groups have demonstrated the benefit of using recombinant cytokines (many of which are known to be secreted by stem cells) in patients with recalcitrant wounds [16]. However, more research is needed to determine the mechanisms by which stem cell therapies might improve wound healing in humans.

For example, the extent of stem cell engraftment and differentiation following topical delivery remains unclear. In one study, bone-marrow-derived allogeneic MSCs injected into cutaneous wounds in mice were shown to express keratinocyte-specific proteins and contributed to the formation of glandular structures after injury [17]. Although long-term engraftment was poor (only 2.5% of MSCs remained engrafted after four weeks), levels of secreted proangiogenic factors were greater in MSC-treated wounds. Our laboratory has demonstrated that local injection of allogeneic MSCs improved early wound closure in mice but that injected MSCs contributed to less than 1% of total wound cells after four weeks [18]. Taken together, these studies suggest that the benefits observed with stem cell injections are the result of early cytokine release rather than long-term engraftment and differentiation.

One potential reason for the transient presence of exogenous stem cells is the absence of proper contextual cues after cells are delivered into the wound. The dynamic microenvironment, or niche, of stem cells is responsible for regulating their stem-like behavior throughout life [19, 20]. This niche is comprised of adjacent cells (stem and nonstem cells), signaling molecules, matrix architecture, physical forces, oxygen tension, and other environmental factors (). A useful analogy is the seed versus soil paradigm in which seeds (stem cells) will only thrive in the proper chemical and physical soil environment (wound bed) [4]. Clearly, we need to better define what these niches are and how they dictate cell behavior to fully realize the potential of progenitor cell therapies.

Potential components of the skin stem cell niche. Features common to skin stem cell niches include dynamic regulation of matrix ligands, intercellular interactions, and biochemical gradients in the appropriate three-dimensional contexts. Engineered biomaterials ...

The epidermis is comprised of at least three major stem cell populations: the hair follicle bulge, the sebaceous gland, and the basal layer of interfollicular epithelium [21]. Because these subpopulations are responsible for regulating epithelial stratification, hair folliculogenesis, and wound repair throughout life [22], the epidermis has become a model system to study regeneration. Elegant lineage tracing and gene mapping experiments have elucidated key programs in epidermal homeostasis. Specifically, components of the wingless-type (Wnt)/-catenin, sonic hedgehog (Shh), and transforming growth factor (TGF)-/bone morphogenetic protein (BMP) pathways appear to be particularly relevant to epidermal stem cell function [1, 22, 23]. Microarray analyses have even indicated that hair follicle stem cells share some of the same transcriptomes as other tissue-specific stem cells [24], suggesting that conserved molecular machinery may control how environmental stimuli regulate the stem cell niche [25].

Epithelial stem cells from the bulge, sebaceous gland, and basal epithelium have common features, including expression of K5, K14, and p63, and their intimate association with an underlying basement membrane (BM) [26]. These cells reside in the basal layer of stratified epithelium and exit their niche during differentiation [26]. This process is mediated in part by BM components such as laminin and cell surface transmembrane integrins that control cell polarity, anchorage, proliferation, survival, and motility [27, 28]. Epithelial progenitor cells are also characterized by elevated expression of E-cadherin in adherens junctions and reduced levels of desmosomes [29], underscoring the importance of both extracellular and intercellular cues in stem cell biology.

In addition to complex intraepithelial networks, signals from the dermis (e.g., periodic expression of BMP2 and BMP4) are thought to regulate epithelial processes [30]. Dermal-derived stem cells may even differentiate into functional epidermal melanocytes [31], suggesting that mesenchymal-epithelial transitions may underlie skin homeostasis, as has been shown in hepatic stem cells [32]. Recently, it has been demonstrated that irreversibly committed progeny from an epithelial stem cell lineage may be recycled and contribute back to the regenerative niche [33], further highlighting the complexity of the epidermal regeneration.

In contrast to the highly cellular nature of the epidermis, the dermis is composed of a heterogeneous matrix of collagens, elastins, and glycosaminoglycans interspersed with cells of various embryonic origin. Recent studies suggest that a cell population within the dermal papilla of hair follicles may function as adult dermal stem cells. This dermal unit contains at least three unique populations of progenitor cells differentiated by the type of hair follicle produced and the expression of the transcription factor Sox2 [34]. Sox2-expressing cells are associated with Wnt, BMP, and fibroblast growth factor (FGF) signaling whereas Sox2-negative cells utilize Shh, insulin growth factor (IGF), Notch, and integrin pathways [35, 36]. Skin-derived precursor (SKP) cells have also been isolated from dermal papillae and can be differentiated into adipocytes, smooth myocytes, and neurons in vitro [37, 38]. These cells are thought to originate in part from the neural crest and have been shown to exit the dermal papilla niche and contribute to cutaneous repair [39].

Researchers have also demonstrated that perivascular sites in the dermis may act as an MSC-like niche in human scalp skin [40]. These perivascular cells express both NG2 (a pericyte marker) and CD34 (an MSC and hematopoietic stem cell marker) and are predominantly located around hair follicles. Perivascular MSC-like cells have been shown to protect their local matrix microenvironment via tissue-inhibitor-of-metalloproteinase (TIMP-) mediated inhibition of matrix metalloproteinase (MMP) pathways, suggesting the importance of the extracellular matrix (ECM) niche in stem cell function [41]. Interestingly, even fibroblasts have been shown to maintain multilineage potential in vitro and may play important roles in skin regeneration that have yet to be discovered [42, 43].

The ability to harvest progenitor cells from adipose tissues is highly appealing due to its relative availability (obesity epidemic in the developed world) and ease of harvest (lipoaspiration). Secreted cytokines from adipose-derived stem cells (ASCs) have been shown to promote fibroblast migration during wound healing and to upregulate VEGF-related neovascularization in animal models [44]. ASCs have even been harvested from human burn wounds and shown to engraft into cutaneous wounds in a rat model [45]. Although these multipotent cells have only been relatively recently identified, they exhibit significant potential for numerous applications in skin repair [46].

ASCs are often isolated from the stromal vascular fraction (SVF) of homogenized fat tissue. These multipotent cells are closely associated with perivascular cells and maintain the potential to differentiate into smooth muscle, endothelium, adipose tissue, cartilage, and bone [47, 48]. Researchers have attempted to recreate the ASC niche using fibrin matrix organ culture systems to sustain adipose tissue [49]. Using this in vitro system, multipotent stem cells were isolated from the interstitium between adipocytes and endothelium, consistent with the current hypothesis that ASCs derive from a perivascular niche.

Detailed immunohistological studies have demonstrated that stem cell markers (e.g., STRO-1, Wnt5a, SSEA1) are differentially expressed in capillaries, arterioles, and arteries within adipose tissue, suggesting that ASCs may actually be vascular stem cells at diverse stages of differentiation [50]. Adipogenic and angiogenic pathways appear to be concomitantly regulated and adipocytes secrete multiple cytokines that induce blood vessel formation including vascular endothelial-derived growth factor (VEGF), FGF2, BMP2, and MMPs [51, 52]. Additionally, cell surface expression of platelet-derived growth factor receptor (PDGFR) has been linked to these putative mural stem cells [53]. Reciprocal crosstalk between endothelial cells and ASCs may regulate blood vessel formation [54] and immature adipocytes have been shown to control hair follicle stem cell activity through PDGF signaling [55]. Taken together, these studies indicate that the ASC niche is intimately associated with follicular and vascular homeostasis but further studies are needed to precisely define its role in skin homeostasis [48].

Strategies to recapitulate the complex microenvironments of stem cells are essential to maximize their therapeutic potential. Biomaterial-based approaches can precisely regulate the spatial and temporal cues that define a functional niche [56]. Sophisticated fabrication and bioengineering techniques have allowed researchers to generate complex three-dimensional environments to regulate stem cell fate. As the physicochemical gradients, matrix components, and surrounding cells constituting stem cell niches in skin are further elucidated (), tissue engineered systems will need to be increasingly scalable, tunable, and modifiable to mimic these dynamic microenvironments [5761]. A detailed discussion of different biomaterial techniques for tissue engineering is beyond the scope of this paper, but we refer to reader to several excellent papers on the topic [6270].

Skin-specific stem cells and putative features of their niche.

One matrix component thought to regulate interactions between hair follicle stem cells and melanocyte stem cells is the hemidesmosomal collagen XVII [71]. Collagen XVII controls their physical interactions and maintains the self-renewal capacity of hair follicles via TGF-, indicating that biomaterial scaffolds containing collagen XVII may be necessary for stem cell-mediated hair follicle therapies. Another matrix component implicated in the hair follicle niche is nephronectin, a protein deposited into the underlying basement membrane by bulge stem cells to regulate cell adhesion via 81 integrins [72]. Hyaluronic acid fibers have been incorporated into collagen hydrogels to promote epidermal organization following keratinocyte seeding [73], and in vitro studies have demonstrated the critical role of collagen IV in promoting normal epithelial architecture when keratinocytes are grown on fibroblast-populated dermal matrices [74]. These studies collectively suggest that tissue engineered matrices for skin regeneration will need to recapitulate the complex BM-ECM interactions that define niche biology [75].

The role of MSCs in engineering skin equivalents has been studied using either cell-based or collagen-based dermal equivalents as the scaffolding environment [76]. When these constructs were grown with keratinocytes in vitro, only the collagen-based MSCs promoted normal epidermal and dermal structure, leading the authors to emphasize the necessity of an instructive biomaterial-based scaffold to direct stem cell differentiation, proliferation, paracrine activity [and] ECM deposition [76]. Our laboratory has reported that MSCs seeded into dermal-patterned hydrogels maintain greater expression of the stem cell transcription factors Oct4, Sox2, and Klf4 as compared to those grown on two-dimensional surfaces [18]. MSCs seeded into these niche-like scaffolds also exhibited superior angiogenic properties compared to injected cells [18], indicating that stem cell efficacy may be enhanced with biomaterial strategies to recapitulate the niche. Another study demonstrated that ASC delivery in natural-based scaffolds (dermis or small intestine submucosa) resulted in improved wound healing compared to gelatin-based scaffolds, suggesting the importance of biologically accurate architecture for stem cell delivery [77].

Researchers have developed novel three-dimensional microfluidic devices to study perivascular stem cell niches in vitro [78]. For example, MSCs seeded with endothelial cells in fibrin gels were able to induce neovessel formation within microfluidic chambers through 61 integrin and laminin-based interactions. Fibrin-based gels have also been used to study ASC and endothelial cell interactions in organ culture [49] and to control ASC differentiation in the absence of exogenous growth factors, demonstrating the importance of the three-dimensional matrix environment in regulating the ASC niche [79]. These studies indicate that the therapeutic use of ASCs in skin repair will likely be enhanced with biomaterial systems that optimize these cell-cell and cell-matrix contacts.

Finally, it must be recognized that the wound environment is exceedingly harsh and often characterized by inflammation, high bacterial loads, disrupted matrix, and/or poor vascularity. In this context, it should not be surprising that injection of naked stem cells into this toxic environment does not produce durable therapeutic benefits. Our laboratory has shown that the high oxidative stress conditions of ischemic wounds can be attenuated with oxygen radical-quenching biomaterial scaffolds that also deliver stem cells [80]. Other researchers have shown that oxygen tension, pH levels, and even wound electric fields may influence stem cell biology, suggesting that the future development of novel sensor devices will allow even finer control of chemical microgradients within engineered niches [70, 81]. It is also important to acknowledge that current research on niche biology has been performed largely in culture systems or rodent models, findings that will need to be rigorously confirmed in human tissues before clinical use.

As interdisciplinary fields such as material science, computer modeling, molecular biology, chemical engineering, and nanotechnology coordinate their efforts, multifaceted biomaterials will undoubtedly be able to better replicate tissue-specific niche environments. Recent studies suggest that the cells necessary for skin regeneration are locally derived [5], indicating that adult resident cells alone may have the ability to recreate skin (). Thus, the ability to engineer the proper environment for skin stem cells truly has the potential to enable regenerative outcomes. We believe that next-generation biomaterial scaffolds will not only passively deliver stem cells but also must actively modify the physicochemical milieu to create a therapeutic niche.

Locally derived skin stem cells may harbor the potential to regenerate skin. Stem cells populations have been identified in various niches throughout the skin, including the epidermal stem cell in the hair follicle bulge, sebaceous glands, and interfollicular ...

Current research indicates that skin regeneration is highly dependent upon interactions between resident progenitor cells and their niche. These microenvironmental cues dictate stem cell function in both health and disease states. Early progress has been made in elucidating skin compartment-specific niches but a detailed understanding of their molecular and structural biology remains incomplete. Biomaterials will continue to play a central role in regenerative medicine by providing the framework upon which to reconstruct functional niches. Future challenges include the characterization and recapitulation of these dynamic environments using engineered constructs to maximize the therapeutic potential of stem cells.

Articles from International Journal of Biomaterials are provided here courtesy of Hindawi Publishing Corporation

Originally posted here:
Stem Cell Niches for Skin Regeneration

Recommendation and review posted by sam

Stem Cell Technology represents a major breakthrough in anti-aging and regenerative skin care, by protecting, strengthening, and replenishing our own human skin cells. Where Peptides stimulate different functions acting as messengers to skin cells, stem cell technology improves the life of the core of the cell. Working in synergy with peptides, they enhance the effectiveness of peptides and other active ingredients.

Antiaging effects - The stem cells in our skin have a limited life expectancy due to DNA damage, aging and oxidative stress. As our own skin stem cells age, they become more difficult to repair and replenish. Protection of our stem cells becomes more and more beneficial as our skin ages, and with the advent of stem cells, we are now able to delay the natural aging process even further than before.

Expected benefits of stem cells technology for regenerative skin care:

Stem Cell Replenishing Serum Featuring a potent concentration of apple and edelweiss plant stem cells, state-of-the-art peptides, and other cutting edge ingredients, the Stem Cell Replenishing Serum is thoroughly formulated to produce age defying results, restoring the youthful look and vitality to aging skin.

Stem Cell Moisturizing Cream Also featuring a healthy concentration of apple and edelweiss plant stem cells, peptides, and numerous botanical extracts, the Stem Cell Moisturizing Cream is formulated to produce age defying results while also helping to maintain healthy and youthful looking skin as a daily moisturizer.

Our Stem Cell Applications:

LPAR Stem Cell Products contain a wide variety of stem cells with healthy and potent concentrations in order to deliver the results skin care consumers strive for. The first stem cell ingredient discovered and produced is a liposomal preparation based on the stem cells of a rare Swiss apple. The revolutionary active ingredient, Malus Domestica by PhytoCellTec is based on a high tech plant cell culture technology. It has been proven to protect the longevity of skin stem cells and provide significant anti-wrinkle effects. Since the discovery and the worldwide success of Apple Stem Cells introduction to the cosmetic and skin care marketplace, other new and exciting stem cell ingredients have been discovered to provide extraordinary results for all skin types.

We were proud to be the first skin care line to offer the ground-breaking combination of Apple and Edelweiss stem cells, and are dedicated to formulating the best new and existing stem cell ingredients into our product line as the technology continues to develop.

To inquire about purchasing LPAR Stem Cell products. visit our Retail Locator page.

Featuring a luxurious and potent blend of three major botanical stem cells (Apple, Gardenia Jasminoides, Echinacea Angustifolia) two state-of-the-art peptides (Nutripeptides, Matrixyl synthe6), and numerous botanical extracts and minerals, the Stem Cell Nourishing Mask is thoroughly formulated to nourish, firm, and energize mature skin. Total Stem Cell Concentration: 5.5% - Total Peptide Concentration: 9.0%

Directions: Using fingertips, apply on clean, dry skin twice weekly. Avoid the eye area. The mask can be left on the skin for prolonged periods (during the day or overnight). Allow at least 10-15 minutes for the mask to penetrate the skin before rinsing with water or applying additional product For external use only.

Ingredients: Water (Aqua), Glycerin, Glyceryl Acrylate/Acrylic Acid Copolymer, Hydrolyzed Rice Protein (Nutripeptides), Sodium Hyaluronate, Hydroxypropyl Cyclodextrin, Palmitoyl Tripeptide-38 (Matrixyl synthe6), Biosaccharide Gum-1, Olea Europaea (Olive) Fruit Oil, Gardenia Jasminoides Meristem Cell Culture, Xanthan Gum, Malus Domestica Fruit Cell Culture, Lecithin, Porphyridium Polysaccharide, Echinacea Angustifolia Meristem Cell Culture, Carbomer, Triethanolamine, Mentha Pipertita (Peppermint) Extract, Camellia Sinensis (Green Tea) Leaf Extract, Palmaria Palmata (Dulce) Extract, Chamomilla Recutita (Matricaria) Flower Extract, Phenoxyethanol, Caprylyl Glycol, Ethylhexylglycerin, Hexylene Glycol, Copper PCA, Zinc PCA, Dipotassium Glycyrrhizate, Olea Europaea (Olive) Fruit Extract, Aloe Barbadensis Leaf Juice Powder, Fragrance (Parfum)

Featuring a plant and fruit stem cell enhanced blend of three major stem cells (Apple, Edelweiss, Alpine Rose), state-of-the-art peptides (Eyeseryl, Nutripeptides), the Stem Cell Eye Therapy is an advanced eye formula designed to nourish, firm, and increase skin elasticity and skin smoothness around the eye area. Total Stem Cell Concentration: 6.75% - Total Peptide Concentration: 11.0%

Directions: Using fingertips, apply product around both eyes on clean, dry skin once or twice daily before applying a moisturizer or night cream. For external use only.

Ingredients: Water, Acetyl Tetrapeptide-5 (Eyeseryl), Sodium Hyaluronate, Hydrolyzed Rice Protein (Nutripeptides), Glycerin, Leontopodium Alpinum Meristem Cell Culture (Edelweiss Stem Cells), Xanthan Gum, Malus Domestica Fruit Cell Culture (Apple Stem Cells), Lecithin, Porphyridium Polysaccharide, Camellia Sinensis (Green Tea) Leaf Extract, Cucumis Sativus (Cucumber) Fruit Extract, Phenoxyethanol, Caprylyl Glycol, Ethylhexylglycerin, Hexylene Glycol, Carbomer, Triethanolamine, Rhododendron Ferrugineum Leaf Cell Culture Extract (Alpine Rose Stem Cells) Isomalt, Sodium Benzoate, Lactic Acid, Sodium Polystyrene Sulfonate, Allantoin, Copper PCA, Aloe Barbadensis Leaf Juice Powder

Plant stem cells represent a major breakthrough in skin care, launching the beginning of a new system of treating the skin...by protecting and replenishing the building blocks of what makes up our own skin: Stem Cells. Rather than working around the natural aging process of our skin stem cells, we now have the technology available to improve the life of our skins most important and central component.

Featuring a potent combination of apple, edelweiss, and grape stem cells, state-of-the-art peptides, and other cutting edge ingredients, the Stem Cell Replenishing Serum is thoroughly formulated to produce age defying results, restoring the youthful look and vitality to aging skin.

Directions: Apply with fingertips on clean, dry skin once or twice daily. Avoid the eye area by approximately 1 cm. Suitable for mature skin types. For external use only.

Ingredients: Water (Aqua), Glycerin, Dipeptide Diaminobutyroyl Benzylamide Diacetate, Acetyl Octapeptide-3, Malus Domestica Fruit Cell Culture (Apple Stem Cells), Hydrolyzed Ceratonia Siliqua Seed Extract, Palmitoyl Tripeptide-5, PEG-8 Dimethicone, Saccharide Isomerate, Imperata Cylindrica (Root) Extract, Polysorbate 20, Leontopodium Alpinum Meristem Cell Culture (Edelweiss Stem Cells), Leucojum Aestivum Bulb Extract, Triethanolamine, Carbomer, Xanthan Gum, Vitis Vinifera Fruit Cell Extract (Grape Stem Cells), Isomalt, Sodium Benzoate, Lecithin, Disodium EDTA, Allantoin, Aloe Barbadensis Leaf Juice Powder, Phenoxyethanol, Caprylyl Glycol, Ethylhexylglycerin, Hexylene Glycol, PEG-8-Carbomer, Fragrance (Parfum)

Plant stem cells represent a major breakthrough in skin care, launching the beginning of a new system of treating the skin...by protecting and replenishing the building blocks of what makes up our own skin: Stem Cells. Rather than working around the natural aging process of our skin stem cells, we now have the technology available to improve the life of our skins most important and central component.

Featuring a healthy concentration and a diverse group of stem cells (apple, edelweiss, grape), peptides, and numerous botanical extracts, the Stem Cell Moisturizing Cream is formulated to produce age-defying results, while also helping to maintain healthy and youthful looking skin as a daily moisturizer.

Directions: For mature skin and/or skin conditioning, apply onto clean, dry skin with fingertips once daily. Avoid the eye. For external use only.

Ingredient Highlights: Plant/Fruit Stem Cells 4% - Malus Domestica (Apple Stem Cells) - Leontopodium Alpinum Cell Culture Extract (Edelweiss Stem Cells) - Vitis Vinifera Fruit Cell Extract (Grape Stem Cells)

Ingredients: Water (Aqua), Glycerin, Isopropyl Myristate, Caprylic/Capric Triglyceride, Cetearyl Olivate, Sorbitan Olivate, Sorbitol, Saccharide Isomerate, Sodium Hyaluronate, Leucojum Aestivum Bulb Extract, Malus Domestica Fruit Cell Extract (Apple Stem Cells), Leontopodium Alpinum Meristem Cell Culture (Edelweiss Stem Cells), Vitis Vinifera Fruit Cell Extract (Grape Stem Cells), Crambe Abyssinica Seed Oil, Dimethicone, Cetyl Alcohol, Imperata Cylindrica (Root) Extract, Acetyl Octapeptide-3 (SNAP-8), Dipeptide Diaminobutyroyl Benzylamide Diacetate(SYN-AKE), Palmitoyl Tripeptide-3 (SYN-COL), Hydrolyzed Ceratonia Siliqua Seed Extract, Aloe Barbadensis Leaf Juice Powder, Olea Europaea (Olive) Leaf Extract, Glyceryl Stearate, Xantham Gum, Cetyl Palmitate, Sorbitan Palmitate, Bisabolol, Tocopheryl Acetate, Fragrance, Phenoxyethanol, Caprylyl Glycol, Ethylhexyglycerin, Hexylene Glycol, PEG-8, Carbomer, Lecithin, Isomalt, Sodium Benzoate, Disodium EDTA

[ pH: 5.00 ]

Featuring high concentrations of Vitamin C (Tetrahexyldecyl Ascorbate), Orange Stem Cells, and Peptides, this is a multi-beneficial cream with state-of-the-art actives formulated to deliver significant and lasting results.

Tetrahexyldecyl Ascorbate is a stable, oil soluble form of Vitamin C that penetrates deeper into the skin than traditional ascorbic acid based Vitamin C. It's a proven skin lightener, a powerful Anti-Oxidant, DNA protector, and increases collagen synthesis more effectively than ascorbic acid. Orange Stem Cells work to increase elasticity and skin resistance to the dermis, which increase firmness and diminish wrinkles while also working synergistically with peptides to further increase skin elasticity and collagen support.

How to Use: Smooth a pearl sized drop onto the face once daily (morning or evening). Avoid the eye area while applying. Follow with Solar Protection if used during the day.

Ingredients: Water (Aqua), Tetrahexyldecyl Ascorbate (Vitamin C Ester), Glycerin, Hexyl Laurate, Caprylic/Capric Triglyceride, Butylene Glycol, Sorbitol, Stearic Acid, Glyceryl Stearate, PEG-100 Stearate, Cetyl Alcohol, Sorbitan Stearate, Polysorbate 60, Acetyl Hexapeptide-8, Sodium Hyaluronate, Squalane, Dimethicone, PPG-12/SMDI Copolymer, Citrus Aurantium Dulcis Callus Culture Extract (Orange Stem Cells), Tocopheryl Acetate, Cetearyl Ethylhexanoate, Linoleic Acid, Glycine Soja (Soybean) Sterols, Phospholipids, Di-PPG-2 Myreth-10 Adipate, Retinol, Polysorbate 20, Hydrolyzed Glycosaminoglycans, Alcohol, Ectoin, Lecithin, Cyclotetrapeptide-24 Aminocyclohexane Carboxylate, Glucosamine HCl, Algae Extract, Yeast Extract, Urea, Micrococcus Lysate, Plankton Extract, Arabidopsis Thaliana Extract, Magnesium Aluminum Silicate, Xanthan Gum, Phenoxyethanol, Caprylyl Glycol, Ethylhexylglycerin, Hexylene Glycol, Disodium EDTA, Citrus Aurantium Dulcis (Orange) Peel Oil

[ pH: 4.7 ]

The Vitamin C Stem Cell Mask combines a potent blend of Vitamin C Ester (Tetrahexyldecyl Ascorbate), highly concentrated plant and fruit stem cells (Argan, Sea Fennel), and Aldenine, a unique peptide that acts as a cellular detoxifier and a collagen III booster.

Directions: Apply on clean, dry skin. Avoid the eye area. The mask may be left on the skin (i.e. during the day or overnight), or it may be rinsed off with lukewarm water after 10 - 15 minutes. Suitable for mature skin types.

Ingredients: Water (Aqua), Tetrahexyldecyl Ascorbate, Kaolin, Glycerin, Glyceryl Stearate, Sorbitan Olivate, Cetearyl Olivate, Cetyl Palmitate, Sorbitol, Sorbitan Palmitate, Stearic Acid, Caprylic/Capric Triglyceride, Cyclopentasiloxane, Cyclhexasiloxane, Carthamus Tinctorius (Safflower) Seed Oil, Punica Granatum Extract, Butylene Glycol, Ananas Sativus (Pineapple) Fruit Extract, Carica Papaya Fruit Extract, Hydrolyzed Wheat Protein, Hydrolyzed Soy Protein, Tripeptide-1, Argania Spinosa (Argan Stem Cells) Sprout Cell Extract, Crithmum Maritimum (Sea Fennel Stem Cells) Callus Culture Filtrate, Oligopeptide-68, Sodium Oleate, Phenoxyethanol, Caprylyl Glycol, Ethylhexylglycerin, Hexylene Glycol, Polyacrylamide, C13-14 Isoparaffin, Laureth-7, Isomalt, Hydrogenated Lecithin, Lecithin, Sodium Benzoate, Allantoin, Citrus Aurantium Dulcis (Orange) Peel Oil, Magnesium Aluminum Silicate, Xanthan Gum, Disodium EDTA

[ pH: 6.00 ]

Originally designed to prepare and increase the skins receptiveness to our Professional Peptide Peel, the Premier Peptide Serum has gone on to become our most powerful anti-wrinkle product for year-round home care due to its high concentration and diversity of peptides. Composed of a total concentration of 65% peptides, the Premier Peptide Serum is a state of the art facial serum expertly formulated to reduce the signs of aging, energizing mature skin.

The Intensive Clarifying Peptide Cream is a unique and high potency moisturizing cream formulated with an abundance of natural skin lighteners, peptides, and botanical extracts that combine to clarify and firm mature skin, while effectively minimizing fine lines and wrinkles.

The Collagen Peptide Complex builds off of our original Collagen Copper Activating Complex, and includes an advanced formulation of peptides, including Syn-Coll, a small but powerful peptide that stimulates collagen synthesis at a cellular level, helping to compensate for any collagen deficit in the skin.

Boasting a remarkable collection of natural and innovative ingredients from exotic plants and enhanced peptides, the neck firming cream has been designed & tested to firm and energize mature skin, while providing increased smoothness and elasticity to the often neglected neck area.

Providing sufficient hydration is the most essential way to keep our skin healthy and youthful. While many of our products assist in hydrating the skin, hydration is the main focus of the Nano-Peptide B5 Complex, acting as the foundation for your home care regimen. Fortified with Sodium Hyaluronate (30%) and Pantothenic acid, it provides an especially deep and complete hydration. Because of the presence of peptides, it also assists in tightening and firming the skin while allowing for maximum absorption and effectiveness.

Designed for mature skin, this sophisticated moisturizer promotes cell renewal, stimulating the dermis layer of the skin with a high potency blend of peptides (Argireline, Matrixyl, & Biopeptide-CLTM) and botanical extracts that make it a particularly refined and effective moisturizing cream for age management.

The A&M Eye Recovery Therapy is an advanced age management treatment, applying the most tried and true peptides and delivery systems; Argireline & Matrixyl, to the highly wrinkle prone and fragile eye area, providing diminished wrinkle depth, and increased firmness and elasticity. The peptide Eyeliss is added to further enhance this treatment by counteracting skin slackening, puffiness, and decreasing irritation.

The A&M Facial Recovery Therapy is an advanced age-management treatment that blends the most tried and true peptides and delivery systems; Argireline & Matrixyl. Stimulating the deeper layers of the skin, the A&M Facial Recovery Therapy provides diminished wrinkle depth, as well as an increase in skin elasticity and firmness.

Originally designed to prepare and increase the skins receptiveness to our Professional Peptide Peel, the Premier Peptide Serum has gone on to become our most powerful anti-wrinkle product for year-round home care due to its high concentration and diversity of peptides. Composed of a total concentration of 65% peptides, the Premier Peptide Serum is a state of the art facial serum expertly formulated to reduce the signs of aging, energizing mature skin.

Directions: For mature skin types; apply at least three weeks before beginning the Lucrece Professional Peptide Peel treatment, and use twice a day leading up to the Peel. For year round application, apply once per day after the Collagen Peptide Complex. Avoid the eye area by at least 1 cm during application.

Peptides: SYN-AKE: A small peptide (Dipeptide Diaminobutyroyl Benzylamide Diacetate) that mimics the activity of Waglerin 1, a polypeptide that is found in the venom of the Temple Viper, Tropidolaemus wagleri. Clinical trials have shown SYN-AKE is capable of reducing wrinkle depth by inhibiting muscle contractions. SNAP-8: An anti-wrinkle (Acetyl Octapeptide-3) elongation of the famous Hexapeptide Argireline. The study of the basic biochemical mechanisms of anti-wrinkle activity led to the revolutionary Hexapeptide which has taken the cosmetic world by storm. ARGIRELINE: (Acetyl Hexapeptide-8) MATRIXYL: (Palmitoyl Pentapeptide-4) REGU-AGE: (Hydrolyzed Rice Bran Protein - Oxido Reductases - Soybean Protein) BIOPEPTIDE CL: (Palmitoyl Oligopeptide) RIGIN: (Palmitoyl Tetrapeptide-7) EYELISS: (Dipeptide-2 & Palmitoyl Tetrapeptide-7) INYLINE: (Acetyl Hexapeptide 30)

Other Ingredients: Water, Sodium Hyaluronate, Spiraea Ulmaria Flower Extract & Centella Asiatica Extract & Echinacea Purpurea Extract, Phenoxyethanol & Benzyl Alcohol & Potassium Sorbate & Tocopherol, Meadowsweet, Hydrocotyl Extract, Leucojum Aestivum Bulb Extract, Amino Acids, Diazolidinyl Urea, Imperata Cylindrica Extract, SMDI Copolymer, Hydroxyethylcellulose

[ pH: 5.00 ]

This unique and high potency moisturizing cream is formulated with an abundance of natural skin lighteners, peptides, and botanical extracts that combine to help clarify and energize mature skin.

Directions: Smooth a pearl size drop onto the face, gently massaging in with fingertips once per day (morning), avoiding the eye area. Follow with solar protection if applicable.

Skin Lightening Agents: Mulberry Bark, Saxifrage Extract, Grape Extract, Scutellaria Root Extracts, Vitamin C Ester (Tetrahexyldecyl Ascorbate), Emblica Fruit Extract, Licorice Root Extract.

Ingredients: Water (Aqua), Saxifrage Extract & Grape Extract & Butylene Glycol & Water & Mulberry Bark Extract & Scutellaria Root Extract, Prunus Amygdalus Dulcis (Sweet Almond) Oil, Caprylic/Capric Triglycerides, Sesamum Indicum (Sesame) Seed Oil, Cetearyl Olivate & Sorbitan Olivate, Glycerin, Palmitoyl Pentapeptide-4 (Matrixyl), Tetrahexyldecyl Ascorbate (C-Ester), Glyceryl Stearate & PEG 100 Stearate, Stearic Acid, Theobroma Cocao (Cocoa) Seed Butter, PPG-12/SMDI Copolymer, Butyrospermum Parkii (Shea) Butter, Tocopheryl Acetate (Vitamin E), Phyllanthus Emblica Fruit Extract, Palmitoyl Tripeptide-5 (Syn-Coll), Triethanolamine, Phenoxyethanol, Mangifera Indica (Mango) Seed Butter, Darutoside, Tricholoma Matsutake Singer (Mushroom) Extract, Imperata Cylindrica (Root) Extract, Fragrance (Parfum), Glucosamine HCL & Algae Extract & Yeast Extract & Urea, Retinyl Palmitate (Vitamin A), Centella Asiatica Extract & Echinacea Purpurea Extract, Xanthan Gum, Arctostaphylos Uva Ursi Leaf Extract, Glycyrrhiza Glabra Root Extract, Magnesium Aluminum Silicate, Disodium EDTA

[ pH: 5.75 ]

Specializing in firming the skin, the Collagen Peptide Complex builds off of our original Collagen Copper Activating Complex, and adds a combination of (5) major peptides, helping to keep the skin looking its youngest and most alive, as it works to firm, and add elasticity & texture to the skin. For best results, apply directly after the Nano-Peptide B5 Complex.

Directions: Apply a liberal amount on clean, dry face using fingertips, and massage into the skin. Let dry, and follow with a moisturizer and sun-block if used during the day, or the Vitamin A Facial Cream + III if used at night. Warning: For mature skin only. If redness occurs, lessen use to once or twice per week. If reactions persist, discontinue use.

Ingredients: Water (Aqua), Dipalmitoylhydroxyproline, Glycerin, Palmitoyl Tetrapeptide-7 (Rigin), Palmitoyl Oligopeptide (Biopeptide-CL), Butylene Glycol, Yeast (Faex Extract), Hydrocotyl Extract & Coneflower Extract, Aloe Barbadensis Leaf Extract, Palmitoyl Tripeptide-5 (Syn-Coll), Acetyl Hexapeptide-8 (Argireline), Palmitoyl Pentapeptide-4 (Matrixyl), Panthenol, Phenoxyethanol & Caprylyl Glycol & Ethylhexylglycerin & Hexylene Glycol, Triethanolamine, Carbomer, Decarboxy Carsonine HCI, Citrus Grandis (Grapefruit) Seed Extract, Copper PCA, Olea Europaea (Olive) Leaf Extract, Disodium EDTA

[ pH: 5.50 ]

Boasting a remarkable collection of natural and innovative ingredients from exotic plants and enhanced peptides, the neck firming cream has been designed & tested to firm and energize mature skin, while providing increased smoothness and elasticity to the often neglected neck area.

Directions: On clean dry skin, apply onto the neck area with fingertips in an upward motion. Apply twice a day, or as needed.

Key Ingredients: Bio-Bustyl: Stimulates cell metabolism, promotes collagen synthesis, and enhances fibroblast (collagen-producing cell) proliferation. INCI: Glyceryl Polymethacrylate, Soy Protein Ferment, PEG-8, & Palmitoyl Oligopeptide Polylift: Using a cross-linking technology, biopolymerization, Polylift reinforces the natural lifting effect of sweet almond proteins, providing a smooth firmness & radiance to the surface of the skin. INCI: Prunus Amygdalus Dulcis (Sweet Almond) Seed Extract.

Ingredients: Deionized Water, Prunus Amygdalus Dulcis (Sweet Almond Oil), Caprylic/Capric Triglycerides, Sesamum Indicum (Sesame) Seed Oil, Simmondsia (Jojoba) Seed Oil/ Buxus Chinensis, Cetearyl Alcohol, Dicetyl Phosphate, Ceteth-10 Phosphate, Palmitoyl Oligopeptide, Palmitoyl Tetrapeptide-7, Prunus Amygdalus Dulcis Seed Extract, Terminalia Catappa Leaf Extract & Sambucus Nigra Flower Extract & PVP & Tannic Acid, Glyceryl Polymethacrylate & Rahnella/ Soy Protein Ferment & PEG-8 & Palmitoyl Oligopeptide, Glycerin, Glyceryl Stearate & PEG 100 Stearate, Biosaccharide Gim-1, PPG-12/ SMDI Copolymer, Phyllanthus Emblica Fruit Extract, Stearic Acid, Centella Asiatica Extract & Darutosidetriethanolamine, Tocopheryl Acetate, Magnifera Indica (Mango) Seed Butter, Glycerin & Aqua & Lysolecithin & Perilla Frutescens Seed Oil, Xantham Gum, Retinyl Palmitate, Tetrahexyldecyl Ascorbate (Vitamin C Ester), Echinacea Purpurea Extract, Imperata Cylindrica (Root) Extract, Glycyrrhiza Glabra Root Extract, Magnesium, Aluminum Silicate, Disodium EDTA

[ pH: 6.25 ]

Hydration is the most essential way to keep our skin healthy feeling and healthy looking. While many of our products assist in hydrating the skin, hydration is the main focus for this product, making it an essential for all skin types. Fortified with Hyaluronic (30%) and Panthenol (Vitamin B5), the Nano-Peptide B5 Complex provides an especially deep and complete hydration. With the addition of peptides, it also assists in tightening and firming the skin while allowing for maximum absorption and effectiveness.

The Nano-Peptide B5 Complex should be applied directly after cleansing the skin, as the 2nd step in skin care regimens for all skin types (morning & night). For best results, age management regimens should follow with the Stem Cell Replenishing Serum and/or the Collagen Peptide Complex before moisturizing.

Directions: Apply a healthy amount on clean, dry skin. May be used around the eye area.

Key Ingredients: Palmitoyl Pentapeptide-4: Stimulates the skins fibroblasts to rebuild the extra-cellular matrix, including the synthesis of Collagen I and Collagen IV, fibronectin and of Glycosaminoglycans. It also stimulates the production of the dermal matrix (Collagen I & III) resulting in a significant reduction of wrinkles and fine lines. Acetyl Hexapeptide-8: Reduces facial wrinkle depth and the signs of skin aging resulting from facial movements and facial muscle contraction by halting the release of neurotransmitters from SNARE and catecholamine complexes, (which can also induce formation of wrinkles and fine lines to the skin). Hyaluronic Acid (30%): Penetrates deep into the skin, providing ample moisture Panthenol: Enhances formation of skin pigments for younger looking skin, and contains deep penetrating properties that allow a more complete hydration.

Other Ingredients: Water (Aqua), Hyaluronic Acid, Panthenol (Vitamin B5), MDI Complex, Palmitoyl Pentapeptide-4, Acetyl Hexapeptide-8, Phenoxyethanol, Hydrolyzed Wheat Protein, Butylene Glycol, Hydrocotyl & Coneflower Extract, Glycosaminoglycans.

[ pH: 5.5 ]

Designed for mature, sun damaged, and/or dehydrated skin, the Anti-Wrinkle Facial Cream is a peptide enriched moisturizer focused on increasing skin firmness & elasticity, and fortifying the skin with anti-oxidants & botanical extracts to facilitate healthy feeling and healthy looking skin.

Directions: Smooth a pearl size drop onto the face, massage into skin thoroughly. For use in the morning (recommended), follow with solar protection.

Ingredients: Water (Aqua), Glycerin, Dimethicone, Caprylic/Capric Triglycerides, C12-15 Alkyl Benzoate, Linoleic Acid & Glycine Soja (Soybean) Sterols & Phospholipids, Acetyl Hexapeptide-8, Butylene Glycol & Carbomer & Polysorbate 20 & Palmitoyl Pentapeptide-4, Cetearyl Alcohol & Dicetyl Phosphate & Ceteth-10 Phosphate, Glyceryl Stearate & PEG 100 Stearate, PPG-12/ SMDI Copolymer, Phyllanthus Emblica Fruit Extract, Darutoside, Cocoa Butter, Cetyl Alcohol, Butyrospermum Parkii (Shea Butter), Saccharomyces/Xylinum Black Tea Ferment & Glycerin & Hydroxyethylcellulose, Glucoseamine HCL & Algae Extract & Saccharomyces Cerevisiae (Yeast Extract) & Urea, Steareth-20 & Palmitoyl Tetrapeptide-7, Centella Asiatica Extract & Echinacea Purpurea Extract, Hydrolyzed Vegetable Protein, Imperata Cylindrica (Root) Extract & PEG-8 & Carbomer, Phenoxyethanol & Caprylyl Glycol & Ethylhexylglycerin & Hexylene Glycol, Polyglyceryl Methacrylate & Propylene Glycol & Palmitoyl Oligopeptide, Cyclopentasiloxane & Dimethicone, Stearic Acid, Mangifera Indica (Mango) Seed Butter, Tocopheryl Acetate, Glycyrrhiza Glabra Root Extract, Arctostaphylos Uva Ursi Leaf Extract, Chlorella Vulgaris Extract, Corallina Officinalis Extract, Dipotassium Glycyrrhizate, PEG-8 & Tocopherol & Ascorbyl Palmitate & Ascorbic Acid & Citric Acid, Disodium EDTA, Magnesium Aluminum Silicate, Xanthan Gum, Triethanolamine, Retinyl Palmitate, Lavandula Angustifolia (Lavender) Oil

[ pH: 5.75 ]

This advanced eye care treatment is expertly formulated to diminish the depth, increase firmness & elasticity, and to counteract skin slackening to the highly wrinkle prone and fragile eye area. Featuring (4) major peptides (Argireline, Matrixyl, Eyeliss, & Regu-age), the A&M Eye Recovery Therapy is our most potent eye treatment, and is recommended for mature skin.

Directions: Using fingertips, massage to surrounding eye areas affected by wrinkles due to muscle contractions. Also use in the nasal labial area. For best results, apply once per evening, followed by the A&M Facial Recovery Therapy, and/or the Vitamin A Facial Cream + III.

Ingredients Highlights: Palmitoyl Pentapeptide-4 (Matrixyl): Stimulates the skins fibroblasts to rebuild the extra-cellular matrix, including the synthesis of Collagen I and Collagen IV, fibronectin and of Glycosaminoglycans. It also stimulates the production of dermal matrix (Collagen I & III) resulting in a significant reduction of wrinkles and fine lines of the skin. Acetyl Hexapeptide-8 (Argireline): Reduces facial wrinkle depth and the signs of skin aging resulting from facial movements and facial muscle contraction by halting the release of neurotransmitters from SNARE and catecholamine complexes, (which can also induce formation of wrinkles and fine lines to the skin). Dipeptide-2 & Palmitoyl Tetrapeptide-7 (Eyeliss): Combats the effect of tiredness and hypertension, as well as the natural effects of aging, which contribute to the formation of bags under the eyes, Eyeliss is an outstanding anti-aging ingredient. Soy Peptides & Hydrolyzed Rice Bran Extract (Regu-Age): A highly active complex of specially purified soy and rice peptides and biotechnologically derived yeast protein, Regu-Age effectively addresses dark circles and puffiness around the eyes.

Other Ingredients: Water, Sodium Hyaluronate, Centella Asiatica Extract & Echinacea Purpurea Extract, Xanthan Gum-Chondrus Crispus & Glucose, Lecithin & Dipalmitoyl Hydroxyproline, Imperata Cylindrica Extract, PEG-8 Dimethicone, Cyclomethicone

[ pH: 6.25 ]

An advanced age management treatment that blends the most tried and true peptides and delivery systems, Argireline & Matrixyl, helping to prevent skin aging induced by repeated facial movement caused by excessive catecholamine release. Stimulating the deeper layers of the skin, the A&M Facial Recovery Therapy provides diminished wrinkle depth, as well as an increase in the elasticity and firmness of the skin. Recommend for mature skin types.

Directions: Using fingertips apply to facial areas and massage into skin once per evening, allowing it to absorb into the skin. Apply directly after the A&M Eye Recovery Therapy.

Ingredients Highlights: Palmitoyl Pentapeptide-4: Stimulates the skins fibroblasts to rebuild the extra-cellular matrix, including the synthesis of Collagen I and Collagen IV, fibronectin and of Glycosaminoglycans. It also stimulates the production of dermal matrix (Collagen I & III) resulting in a significant reduction of wrinkles and fine lines of the skin. Acetyl Hexapeptide-8: Reduces facial wrinkle depth and the signs of skin aging resulting from facial movements and facial muscle contraction by halting the release of neurotransmitters from SNARE and catecholamine complexes, (which can also induce formation of wrinkles and fine lines to the skin).

Other Ingredients: Deionized Water, Sodium Hyaluronate, Lecithin & Dipalmitoyl Hydroxyproline, Hydrocotyl & Coneflower Extracts, Glycosaminoglycans, Glucosamine HCI & Alagae Extract & Yeast Extract & Urea, Magnesium Ascorbyl Phosphate, Glycine HCL, Retinyl Palmitate

[ pH: 6.25 ]

Addressing the multiple problems of sun and age damaged skin, the Intensive Clarifying Facial Cream + III is a glycolic acid based moisturizer featuring three potent skin lighteners; Kojic Acid, Licorice, and Hydro- quinone (2%), which quickly & effectively treat hyperpigmentation & discolorations.

Vitamin C Ester (Tetrahexyldecyl Ascorbate) is a stable, oil-soluble form of Vitamin C, providing high level skin lightening, enhanced collagen synthesis, and increased DNA & UV protection with higher absorption capabilities and less irritating than Ascorbic Acid.

Because of how well it protects the skins collagen fibers, ascorbic acid based Vitamin C is widely considered one of the most effective antioxidants for skin rejuvenation & revitalization. The 20% Vitamin C Lightening drops combine a potent concentration of ascorbic acid with aloe, green tea leaf extract, and mushroom extract. *Also available is our original Vitamin C Serum, containing a milder blend of ascorbic acid (14%).

The Anti-Wrinkle Eye Cream contains a high potency blend of peptides, including EyelissTM & Regu-age (in addition to Argireline & Matrixyl) which work synergistically to improve firmness, elasticity, and reduce puffiness & dark circles around the eye area.

Addressing the multiple problems of sun and age damaged skin, the Intensive Clarifying Facial Cream + III moisturizer combines three powerful lightening. Agents: Hydroquinone, Kojic Acid, & Licorice, with Alpha Lipoic Acid, Vitamin C, & Co-enzyme Q10, minimizing fine lines, evening skin tone, and naturally exfoliating the outer layer of the skin while providing a 15 sun protection factor (SPF).

Directions: Smooth a pearl sized drop onto the face once or twice daily. Avoid eye area. If used during the day, apply additional sun protection if skin is in contact with the sun for an extended period (twenty minutes or more).

Active Ingredients: Octyl Methoxycinnamate - 7.5% Octyl Salcylate - 5% Glycolic Acid - 4% Benzophenone - 3% Hydroquinone - 2%

Inactive Ingredients: Deionized Water, Glyceryl Stearate & PEG-100 Stearate, Ascorbic Acid (Vitamin C), Alpha Lipoic Acid, Co-enzyme Q 10, Kojic Acid, Cetyl Alcohol, Licorice, Palmitic Acid, Octyl Salcylate, Phenoxyethanol, Tocopheryl Acetate, Essential Oil of Rosewood, Disodium tEDTA

[ pH: 4.5 ]

Vitamin C Ester is a stable, oil-soluble form of Vitamin C, providing high level Skin Lightening, enhanced Collagen Synthesis, and increased DNA & UV protection with higher absorption capabilities than Ascorbic Acid.

Directions: On clean, dry skin, apply four to five drops directly onto the face once a day, avoiding the eye area.

Ingredients: Cyclomethicone, Tetrahexyldecyl Ascorbate (Vitamin C Ester 10%), PPG-12/SMDI Copolymer, Santalum Album Extract, Phellodendrone Amurense Bark Extract, Barley Extract, Jojoba Seed Oil/Buxus Chinensis, Tocopheryl Acetate, Phenoxyethanol, Tricholoma Matsutake Singer (Mushroom Extract), Ascorbyl Palmitate, Bisabolol

[ pH: 7.0 ]

Ascorbic acid based Vitamin C is widely considered one of the most effective antioxidants for rejuvenating mature skin due to its ability to protect the skins collagen fibers, and for its ability to help inhibit melanin production, creating a lightening effect to the skin. The 20% Vitamin C Lightening Drops combine a potent concentration of ascorbic acid with aloe, green tea extract, and an exotic mushroom extract (Tricholoma Matsutake Singer) for additional lightening.

Directions: On clean, dry skin apply four to five drops directly onto the face once daily. Avoid the eye area. Thoroughly wash hands after use. Though a light tingling sensation is normal, if irritation (redness) results after application, discontinue or reduce the frequency of use of the product.

Ingredients: Water (Aqua), Ascorbic Acid -20%, Ethoxydiglycol, Hydroxyethylcellulose, Phenoxyethanol, Polysorbate 20, Camellia Sinensis Leaf Extract, Aloe Barbadensis Leaf Extract, Mushroom Extract (Tricholoma Matsutake Singer)-Enzymes- Alcohol, Sodium Sulfite, Disodium EDTA

[ pH: 3.00 ]

The Anti-Wrinkle Eye Cream is formulated to reduce puffiness, enhances firmness, strengthens connective tissues, and to help diminish dark circles around the eye area. In contrast to the A&M Eye Recovery Therapy, the Anti-Wrinkle Eye Cream concentrates on the upper layers of the skin, making it a great day moisturizer for the eyes.

Directions: Apply around the eye area with the ring finger once daily. For best results, follow with a moisturizer and solar protection.

Read the original:
anti-aging stem cells - innovative treatments for skin ...

Recommendation and review posted by Bethany Smith

Skin is the soft outer covering of vertebrates. Other animal coverings, such as the arthropod exoskeleton have different developmental origin, structure and chemical composition. The adjective cutaneous means "of the skin" (from Latin cutis, skin). In mammals, the skin is an organ of the integumentary system made up of multiple layers of ectodermal tissue, and guards the underlying muscles, bones, ligaments and internal organs.[1] Skin of a different nature exists in amphibians, reptiles, and birds.[2] All mammals have some hair on their skin, even marine mammals like whales, dolphins, and porpoises which appear to be hairless. The skin interfaces with the environment and is the first line of defense from external factors. For example, the skin plays a key role in protecting the body against pathogens[3] and excessive water loss.[4] Its other functions are insulation, temperature regulation, sensation, and the production of vitamin D folates. Severely damaged skin may heal by forming scar tissue. This is sometimes discoloured and depigmented. The thickness of skin also varies from location to location on an organism. In humans for example, the skin located under the eyes and around the eyelids is the thinnest skin in the body at 0.5mm thick, and is one of the first areas to show signs of aging such as "crows feet" and wrinkles. The skin on the palms and the soles of the feet is 4mm thick and the back is 14mm thick and is the thickest skin in the body. The speed and quality of wound healing in skin is promoted by the reception of estrogen.[5][6][7]

Fur is dense hair.[8] Primarily, fur augments the insulation the skin provides but can also serve as a secondary sexual characteristic or as camouflage. On some animals, the skin is very hard and thick, and can be processed to create leather. Reptiles and fish have hard protective scales on their skin for protection, and birds have hard feathers, all made of tough -keratins. Amphibian skin is not a strong barrier, especially regarding the passage of chemicals via skin and is often subject to osmosis and diffusive forces. For example, a frog sitting in an anesthetic solution would be sedated quickly, as the chemical diffuses through its skin. Amphibian skin plays key roles in everyday survival and their ability to exploit a wide range of habitats and ecological conditions.[9]

Mammalian skin is composed of two primary layers:

The epidermis is composed of the outermost layers of the skin. It forms a protective barrier over the body's surface, responsible for keeping water in the body and preventing pathogens from entering, and is a stratified squamous epithelium,[10] composed of proliferating basal and differentiated suprabasal keratinocytes. The epidermis also helps the skin regulate body temperature.[citation needed]

Keratinocytes are the major cells, constituting 95% of the epidermis,[10] while Merkel cells, melanocytes and Langerhans cells are also present. The epidermis can be further subdivided into the following strata or layers (beginning with the outermost layer):[11]

Keratinocytes in the stratum basale proliferate through mitosis and the daughter cells move up the strata changing shape and composition as they undergo multiple stages of cell differentiation to eventually become anucleated. During that process, keratinocytes will become highly organized, forming cellular junctions (desmosomes) between each other and secreting keratin proteins and lipids which contribute to the formation of an extracellular matrix and provide mechanical strength to the skin.[12]Keratinocytes from the stratum corneum are eventually shed from the surface (desquamation).

The epidermis contains no blood vessels, and cells in the deepest layers are nourished by diffusion from blood capillaries extending to the upper layers of the dermis.

The epidermis and dermis are separated by a thin sheet of fibers called the basement membrane, and is made through the action of both tissues. The basement membrane controls the traffic of the cells and molecules between the dermis and epidermis but also serves, through the binding of a variety of cytokines and growth factors, as a reservoir for their controlled release during physiological remodeling or repair processes.[13]

The dermis is the layer of skin beneath the epidermis that consists of connective tissue and cushions the body from stress and strain. The dermis provides tensile strength and elasticity to the skin through an extracellular matrix composed of collagen fibrils, microfibrils, and elastic fibers, embedded in hyaluronan and proteoglycans.[12] Skin proteoglycans are varied and have very specific locations.[14] For example, hyaluronan, versican and decorin are present throughout the dermis and epidermis extracellular matrix, whereas biglycan and perlecan are only found in the epidermis.

It harbors many mechanoreceptors (nerve endings) that provide the sense of touch and heat. It also contains the hair follicles, sweat glands, sebaceous glands, apocrine glands, lymphatic vessels and blood vessels. The blood vessels in the dermis provide nourishment and waste removal from its own cells as well as for the epidermis.

The dermis is tightly connected to the epidermis through a basement membrane and is structurally divided into two areas: a superficial area adjacent to the epidermis, called the papillary region, and a deep thicker area known as the reticular region.

The papillary region is composed of loose areolar connective tissue.This is named for its fingerlike projections called papillae that extend toward the epidermis. The papillae provide the dermis with a "bumpy" surface that interdigitates with the epidermis, strengthening the connection between the two layers of skin.

The reticular region lies deep in the papillary region and is usually much thicker. It is composed of dense irregular connective tissue, and receives its name from the dense concentration of collagenous, elastic, and reticular fibers that weave throughout it. These protein fibers give the dermis its properties of strength, extensibility, and elasticity. Also located within the reticular region are the roots of the hair, sebaceous glands, sweat glands, receptors, nails, and blood vessels.

The hypodermis is not part of the skin, and lies below the dermis. Its purpose is to attach the skin to underlying bone and muscle as well as supplying it with blood vessels and nerves. It consists of loose connective tissue and elastin. The main cell types are fibroblasts, macrophages and adipocytes (the hypodermis contains 50% of body fat). Fat serves as padding and insulation for the body. Another name for the hypodermis is the subcutaneous tissue.

Microorganisms like Staphylococcus epidermidis colonize the skin surface. The density of skin flora depends on region of the skin. The disinfected skin surface gets recolonized from bacteria residing in the deeper areas of the hair follicle, gut and urogenital openings.

The epidermis of fish and of most amphibians consists entirely of live cells, with only minimal quantities of keratin in the cells of the superficial layer. It is generally permeable, and in the case of many amphibians, may actually be a major respiratory organ. The dermis of bony fish typically contains relatively little of the connective tissue found in tetrapods. Instead, in most species, it is largely replaced by solid, protective bony scales. Apart from some particularly large dermal bones that form parts of the skull, these scales are lost in tetrapods, although many reptiles do have scales of a different kind, as do pangolins. Cartilaginous fish have numerous tooth-like denticles embedded in their skin, in place of true scales.

Sweat glands and sebaceous glands are both unique to mammals, but other types of skin gland are found in other vertebrates. Fish typically have a numerous individual mucus-secreting skin cells that aid in insulation and protection, but may also have poison glands, photophores, or cells that produce a more watery, serous fluid. In amphibians, the mucus cells are gathered together to form sac-like glands. Most living amphibians also possess granular glands in the skin, that secrete irritating or toxic compounds.[15]

Although melanin is found in the skin of many species, in the reptiles, the amphibians, and fish, the epidermis is often relatively colourless. Instead, the colour of the skin is largely due to chromatophores in the dermis, which, in addition to melanin, may contain guanine or carotenoid pigments. Many species, such as chameleons and flounders may be able to change the colour of their skin by adjusting the relative size of their chromatophores.[15]

The epidermis of birds and reptiles is closer to that of mammals, with a layer of dead keratin-filled cells at the surface, to help reduce water loss. A similar pattern is also seen in some of the more terrestrial amphibians such as toads. However, in all of these animals there is no clear differentiation of the epidermis into distinct layers, as occurs in humans, with the change in cell type being relatively gradual. The mammalian epidermis always possesses at least a stratum germinativum and stratum corneum, but the other intermediate layers found in humans are not always distinguishable. Hair is a distinctive feature of mammalian skin, while feathers are (at least among living species) similarly unique to birds.[15]

Birds and reptiles have relatively few skin glands, although there may be a few structures for specific purposes, such as pheromone-secreting cells in some reptiles, or the uropygial gland of most birds.[15]

Skin performs the following functions:

Skin is a soft tissue and exhibits key mechanical behaviors of these tissues. The most pronounced feature is the J-curve stress strain response, in which a region of large strain and minimal stress exists, and corresponds to the microstructural straightening and reorientation of collagen fibrils.[18] In some cases the intact skin is prestreched, like wetsuits around the diver's body, and in other cases the intact skin is under compression. Small circular holes punched on the skin may widen or close into ellipses, or shrink and remain circular, depending on preexisting stresses.[19]

The term "skin" may also refer to the covering of a small animal, such as a sheep, goat (goatskin), pig, snake (snakeskin) etc. or the young of a large animal.

The term hides or rawhide refers to the covering of a large adult animal such as a cow, buffalo, horse etc.

Skins and hides from the different animals are used for clothing, bags and other consumer products, usually in the form of leather, but also as furs.

Skin from sheep, goat and cattle was used to make parchment for manuscripts.

Skin can also be cooked to make pork rind or crackling.

Go here to see the original:
Skin - Wikipedia, the free encyclopedia

Recommendation and review posted by Bethany Smith

Gene Therapy- An Overview

Gene Therapy is a processin which faulty genes are rectified by the use of several different techniques. The idea of Gene Therapy was coined in the 1950s almost directly after Watson and Crick discovery of unwinding the DNA double-helix. Scientists worked diligently, playing with the idea of being able to insert healthy genes in place of mutated ones which cause severe genetic disease.

According Anne Matthews, RN, phD, director of Genetic Counseling and Family Studies, statistics have shown that "approximately 4 million babies are born each year. About 3 to 4% will be born with a genetic disease or major birth defect."(Citation 8) These unpreventable and seemingly incurable genetic diseases are generally malicious, causing debilitating effects on the individuals as well as theirfamilies. Desperate for a cure, doctors and scientists experimented with many different methods, eventually discovering gene therapy.

This therapy is relatively new, so much research is still being done. Like all new medical techniques, the ethics of Gene Therapy are highly debated. While some people argue for Gene Therapy as a innovative new life-saving method, others believe that humans should have no role in tampering with natural creation. As of now there is no FDA (US Food and Drug Administration) regulated treatment or product that is for sale. However, research by top scientist and labs continue to experiment with over 400 clinical trials conducted in the United States. In thecomingyears scientist hope to test the vastopportunitiesthat gene therapy offers and make it anaccessibletreatment.

Here is the original post:
Gene Therapy

Recommendation and review posted by sam

If youre new to Quora, the question and answer website that rapidly seems to have trumpedYahoo Answers, youll be thrilled to hear its all brilliantly simple. People post a question that theyd like an answer to, and anyone from random people with an opinion to world-famous experts can post a reply, with the best answers quickly up-voted. While there are plenty of queries about Beyonc, NASA and conspiracy theories, there are also some interesting entries about hair loss, too.

One of the best threads is based around the question What are the genetics of Male Pattern Baldness? While it might only have garnered just two replies to date, one of these has attracted more than 4,000 views. And the fact that the answer comes from Adriana Heguy, who says she has worked in genetics and genomics for the past two decades probably helps.

The first thing that Ms Heguy does is caution how complex the science behindall this is. She also admits that the genetics of Androgenetic Alopecia (genetic baldness) is not really well understood. Acknowledging that genetic baldness is a highly heritable condition, so is most likely to be passed on through families, she does go on to explain that there is furtherevidence that non-genetic factors also play a part. Although she does not elaborate on these, this is likely a reference to issues which can exacerbate or trigger hair loss, such asstress, illness ordietary imbalances.

Of the specific genes thought to play a part in Male Pattern Baldness, Ms Heguy first mentions the androgen receptor (AR) gene. She points out that because this receptor is on the X chromosome which is inherited from your mother the myth persists that men need only look at the maternal line of their family tree to see if theyre likely to go bald or not.

But it (AR) is not the only gene involved, Ms Heguy explains, or even the main gene. There are genes in basically all chromosomes that have been implicated in Androgenetic Alopecia, and this is what makes it so difficult to unravel.

This fits researchers findings that it is, in fact, more likely any actively expressed genetic traits are likely to come from our fathers side of the family including hair loss. People are able to carry the genes for androgenetic alopeciawithout displaying any of the signs if these genes lie dormant and are not active, which can explain why sometimes hair loss appears to skip a generation.

Androgen receptors are also known as NR3C4 which stands for Nuclear Receptor subfamily 3, group C, member 4 and they control cell behaviour. When testosterone reacts with the enzyme5-alpha-reductase in a cell, it is converted into the androgen dihydrotestone (DHT) and, asthose with an inherited predisposition to male pattern baldness have an innate sensitivity to DHT,the hair miniaturisation process starts.

Male Pattern Baldness begins when the DHTgradually impedes hairgrowth by binding to the androgen receptors in the hair follicle and causing increasingly thinning hair, theneventually stops them from producing hair altogether. For this reason, successful treatment of Male Pattern Baldness ofteninvolves the use of a clinically-proven drug, finasteride 1mg,which inhibits the production of DHT.

A second product, and one that Belgravia hair loss specialists often recommend, particularly for stubborn areas such as a receding hairline, is the topical daily treatmenthigh strength minoxidil. When applied directly to the affected areas of the scalp as advised, thiscan encourage accelerated hair growth. This is most often used by Belgravias male clients as part of a comprehensive treatment course alongside finasteride and hair growth boosters to maximise the chances of seeing an improvement to both their hair loss and the condition of their hair.

While Ms Heguy admits that we are still far from a definitive cure forAndrogenetic Alopecia by which she presumably means a single-dose, one-off medication that will completely stop MPB before it has even started she does offer some hope to men who have already lost their hair to the condition: If there is any consolation for men distressed about hair loss, if it was a phenotype that was repulsive to females, the gene variants would have been weeded out a long time ago, by sexual selection. Many of us find bald heads very manly and attractive.

The Belgravia Centre is the leader in hair loss treatment in the UK, with two clinics based in Central London.If you are worried about hair loss you canarrange afree consultationwith a hair loss expert or complete ourOnline Consultation Formfrom anywhere in the UK or the rest of the world. View ourHair Loss Success Stories, which are the largest collection of such success stories in the world and demonstrate the levels of success that so many of Belgravias patients achieve. You can also phone020 7730 6666any time for our hair loss helpline or to arrange a free consultation.

Read more:
Scientist Explains the Genetics of Male Pattern Baldness

Recommendation and review posted by Bethany Smith

Bio-Identical

For years, women have coped with menopause through hormone replacement strategies that addressed the problem instead of the patient. Recently, hormone replacement therapy has been refined so that current therapies are tailored and delivered directly to the patient. Dr. Neera Bhatia is pleased to offer one such therapy, BioTE, that is at the forefront of this design process. BioTE is widely regarded as one of the superior bio-identical hormone replacement therapies available.

Dr. Bhatia's mission statement includes a focus on incorporating innovations that further patient welfare into her practice. With this commitment in mind, Dr. Bhatia is the ideal physician to guide patients through the process of bio-identical hormone replacement therapy. Through nearly 35 years in practice, Dr. Bhatia has seen the approach to hormone replacement therapy develop. Now, there is a solution for patients that she fully endorses and promotes BioTE pellets.

Briefly, bio-identical hormones are plant derived and biologically engineered to match the patient's own hormones. These hormones represent the most recent advancement in hormone replacement therapy and represents a solution for both women and men.

Exclusive Interview

Continued here:
San Antonio Natural Hormone Therapy Clinic | Bio-Identical ...

Recommendation and review posted by Bethany Smith

RATIONALE:

The regenerative potential of the heart is insufficient to fully restore functioning myocardium after injury, motivating the quest for a cell-based replacement strategy. Bone marrow-derived mesenchymal stem cells (MSCs) have the capacity for cardiac repair that appears to exceed their capacity for differentiation into cardiac myocytes.

Here, we test the hypothesis that bone marrow derived MSCs stimulate the proliferation and differentiation of endogenous cardiac stem cells (CSCs) as part of their regenerative repertoire.

Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow-derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit(+) CSCs increased 20-fold in MSC-treated animals versus controls (P<0.001), there was a 6-fold increase in GATA-4(+) CSCs in MSC versus control (P<0.001), and mitotic myocytes increased 4-fold (P=0.005). Porcine endomyocardial biopsies were harvested and plated as organotypic cultures in the presence or absence of MSC feeder layers. In vitro, MSCs stimulated c-kit(+) CSCs proliferation into enriched populations of adult cardioblasts that expressed Nkx2-5 and troponin I.

MSCs stimulate host CSCs, a new mechanism of action underlying successful cell-based therapeutics.

Read more from the original source:
Bone marrow mesenchymal stem cells stimulate cardiac stem ...

Recommendation and review posted by sam

Cells in animals and in plants that are capable of becoming any other type of cell in that organism and then reproducing more of those cells. Despite the fact that stem cell research is in its infancy, many cosmetics companies claim they are successfully using plant-based or human-derived stem cells in their anti-aging products. The claims run the gamut, from reducing wrinkles to repairing elastin to regenerating cells, so the temptation for consumers to try these products is intense.

The truth is that stem cells in skincare products do not work as claimed; they simply cannot deliver the promised results. In fact, they likely have no effect at all because stem cells must be alive to function as stem cells, and by the time these delicate cells are added to skincare products, they are long since dead and, therefore, useless. Actually, its a good thing that stem cells in skincare products cant work as claimed, given that studies have revealed that they pose a potential risk of cancer.

Plant stem cells, such as those derived from apples, melons, and rice, cannot stimulate stem cells in human skin; however, because they are derived from plants they likely have antioxidant properties. Thats good, but its not worth the extra cost that often accompanies products that contain plant stem cells. Its also a plus that plant stem cells cant work as stem cells in skincare products; after all, you dont want your skin to absorb cells that can grow into apples or watermelons!

There are also claims that because a plants stem cells allow a plant to repair itself or to survive in harsh climates, these benefits can be passed on to human skin. How a plant functions in nature is completely unrelated to how human skin functions, and these claims are completely without substantiation. It doesnt matter how well the plant survives in the desert, no matter how you slather such products on your skin, you still wont survive long without ample water, shade, clothing, and other skin-protective elements.

Another twist on the stem cell issue is that cosmetics companies are claiming they have taken components (such as peptides) out of the plant stem cells and made them stable so they will work as stem cells would or that they will influence the adult stem cells naturally present in skin. In terms of these modified ingredients working like stem cells, this theory doesnt make any sense because stem cells must be complete and intact to function normally. Using peptides or other ingredients to influence adult stem cells in skin is something thats being explored, but to date scientists are still trying to determine how that would work and how it could be done safely. For now, companies claiming theyve isolated substances or extracts from stem cells and made them stable are most likely not telling the whole story. Currently, theres no published, peer-reviewed research showing these stem cell extracts can affect stem cells in human skin.

Follow this link:
stem cells - Cosmetic Ingredient Dictionary: Cosmetics Cop ...

Recommendation and review posted by simmons

Educational Materials

Youth: Special Considerations

Transgender Terminology

Resources

Trans Affirming Therapists

Driver's License

Social Security

Passport

Peer Support Group: Being Me

Metamorphosis Medical Center and Dr. Kristen Vierregger are dedicated to improving the overall health and well-being of members of the transgender community by providing medically supervised hormone therapy in an atmosphere that is compassionate, safe, and understanding.

You will feel confident that you are receiving the best care and best medicine available for gender transitioning. We can customize your hormone experience to reach the level you desire. We understand that not everyone has the same goal or endpoint in their transition. Everyone is unique.

In the area of gender transitioning and hormone therapy, where myth and ignorance sometimes exceeds knowledge within the medical community, Dr. Vierregger provides expert, professional, and empathetic hormone therapy. She really listens to your needs.

We at Metamorphosis Medical Center understand that transitioning is much more than a physical or superficial journey; transitioning is a rebirth of an individual long buried under the layers of self or societys imposed expectations. Like all births, it can be long, difficult, and full of doubts at times, but we can help facilitate the joy and expectation of a new life, a new beginning, a metamorphosis.

Dr. Vierregger is the doctor in residence at the LBGT The Center OC Trans*ition Program as well as her private practice.

Google+

Go here to read the rest:
Transgender hormone therapy Clinic

Recommendation and review posted by simmons

A stem cell transplant is a treatment for some types of cancer. For example, you might have one if you have leukemia, multiple myeloma, or some types of lymphoma. Doctors also treat some blood diseases with stem cell transplants.

In the past, patients who needed a stem cell transplant received a bone marrow transplant because the stem cells were collected from the bone marrow. Today, stem cells are usually collected from the blood, instead of the bone marrow. For this reason, they are now more commonly called stem cell transplants.

A part of your bones called bone marrow makes blood cells. Marrow is the soft, spongy tissue inside bones. It contains cells called hematopoietic stem cells (pronounced he-mah-tuh-poy-ET-ick). These cells can turn into several other types of cells. They can turn into more bone marrow cells. Or they can turn into any type of blood cell.

Certain cancers and other diseases keep hematopoietic stem cells from developing normally. If they are not normal, neither are the blood cells that they make. A stem cell transplant gives you new stem cells. The new stem cells can make new, healthy blood cells.

The main types of stem cell transplants and other options are discussed below.

Autologous transplant. Doctors call this an AUTO transplant. This type of stem cell transplant may also be called high-dose chemotherapy with autologous stem cell rescue.

In an AUTO transplant, you get your own stem cells after doctors treat the cancer. First, your health care team collects stem cells from your blood and freezes them. Next, you have powerful chemotherapy, and rarely, radiation therapy. Then, your health care team thaws your frozen stem cells. They put them back in your blood through a tube placed in a vein (IV).

It takes about 24 hours for your stem cells to reach the bone marrow. Then they start to grow, multiply, and help the marrow make healthy blood cells again.

Allogeneic transplantation. Doctors call this an ALLO transplant.

In an ALLO transplant, you get another persons stem cells. It is important to find someone whose bone marrow matches yours. This is because you have certain proteins on your white blood cells called human leukocyte antigens (HLA). The best donor has HLA proteins as much like yours as possible.

Matching proteins make a serious condition called graft-versus-host disease (GVHD) less likely. In GVHD, healthy cells from the transplant attack your cells. A brother or sister may be the best match. But another family member or volunteer might work.

Once you find a donor, you receive chemotherapy with or without radiation therapy. Next, you get the other persons stem cells through a tube placed in a vein (IV). The cells in an ALLO transplant are not typically frozen. So, doctors can give you the cells as soon after chemotherapy or radiation therapy as possible.

There are 2 types of ALLO transplants. The best type for each patient depends his or her age and health and the type of disease being treated.

Ablative, which uses high-dose chemotherapy

Reduced intensity, which uses milder doses of chemotherapy

If your health care team cannot find a matched adult donor, there are other options. Research is ongoing to determine which type of transplant will work best for different patients.

Umbilical cord blood transplant. This may be an option if you cannot find a donor match. Cancer centers around the world use cord blood.

Parent-child transplant and haplotype mismatched transplant. These types of transplants are being used more commonly. The match is 50%, instead of near 100%. Your donor might be a parent, child, brother, or sister.

Your doctor will recommend an AUTO or ALLO transplant based mostly on the disease you have. Other factors include the health of your bone marrow and your age and general health. For example, if you have cancer or other disease in your bone marrow, you will probably have an ALLO transplant. In this situation, doctors do not recommend using your own stem cells.

Choosing a transplant is complicated. You will need help from a doctor who specializes in transplants. So you might need to travel to a center that does many stem cell transplants. Your donor might need to go, too. At the center, you talk with a transplant specialist and have an examination and tests. Before a transplant, you should also think about non-medical factors. These include:

Who can care for you during treatment

How long you will be away from work and family responsibilities

If your insurance pays for the transplant

Who can take you to transplant appointments

Your health care team can help you find answers to these questions.

The information below tells you the main parts of AUTO and ALLO transplants. Your health care team usually does the steps in order. But sometimes certain steps happen in advance, such as collecting stem cells. Ask your doctor what to expect before, during, and after a transplant.

A doctor puts a thin tube called a transplant catheter in a large vein. The tube stays in until after the transplant. Your health care team will collect stem cells through this tube and give chemotherapy and other medications through the tube.

You get injections of a medication to raise your number of white blood cells. White blood cells help your body fight infections.

Your health care team collects stem cells, usually from your blood.

Time: 1 to 2 weeks

Where its done: Clinic or hospital building. You do not need to stay in the hospital overnight.

Time: 5 to 10 days

Where its done: Clinic or hospital. At many transplant centers, patients need to stay in the hospital for the duration of the transplant, usually about 3 weeks. At some centers, patients receive treatment in the clinic and can come in every day.

Time: Each infusion usually takes less than 30 minutes. You may receive more than 1 infusion.

Where its done: Clinic or hospital.

Time: approximately 2 weeks

Where its done: Clinic or hospital. You might be staying in the hospital or you might not.

Time: Varies based on how the stem cells are collected

Where its done: Clinic or hospital

Time: 5 to 7 days

Where its done: Many ALLO transplants are done in the hospital.

Time: 1 day

Where its done: Clinic or hospital.

You take antibiotics and other drugs. This includes medications to prevent graft-versus-host disease. You get blood transfusions through your catheter if needed. Your health care team takes care of any side effects from the transplant.

After the transplant, patients visit the clinic frequently at first and less often over time.

Time: Varies

For an ablative transplant, patients are usually in the hospital for about 4 weeks in total.

For a reduced intensity transplant, patients are in the hospital or visit the clinic daily for about 1 week.

The words successful transplant might mean different things to you, your family, and your doctor. Below are 2 ways to measure transplant success.

Your blood counts are back to safe levels. A blood count is the number of red cells, white cells, and platelets in your blood. A transplant makes these numbers very low for 1 to 2 weeks. This causes risks of:

Infection from low numbers of white cells, which fight infections

Bleeding from low numbers of platelets, which stop bleeding

Tiredness from low numbers of red cells, which carry oxygen

Doctors lower these risks by giving blood and platelet transfusions after a transplant. You also take antibiotics to help prevent infections. When the new stem cells multiply, they make more blood cells. Then your blood counts improve. This is one way to know if a transplant is a success.

It controls your cancer. Doctors do stem cell transplants with the goal of curing disease. A cure may be possible for some cancers, such as some types of leukemia and lymphoma. For other patients, remission is the best result. Remission is having no signs or symptoms of cancer. After a transplant, you need to see your doctor and have tests to watch for any signs of cancer or complications from the transplant.

Talking often with the doctor is important. It gives you information to make health care decisions. The questions below may help you learn more about stem cell transplant. You can also ask other questions that are important to you.

Which type of stem cell transplant would you recommend? Why?

If I will have an ALLO transplant, how will we find a donor? What is the chance of a good match?

What type of treatment will I have before the transplant? Will radiation therapy be used?

How long will my treatment take? How long will I stay in the hospital?

How will a transplant affect my life? Can I work? Can I exercise and do regular activities?

How will we know if the transplant works?

What if the transplant doesnt work? What if the cancer comes back?

What are the side effects? This includes short-term, such as during treatment and shortly after. It also includes long-term, such as years later.

What tests will I need later? How often will I need them?

If I am worried about managing the costs of treatment, who can help me with these concerns?

Bone Marrow Aspiration and Biopsy

Making Decisions About Cancer Treatment

Donating Blood and Platelets

Donating Umbilical Cord Blood

Explore BMT

Be the Match: National Marrow Donor Program

Blood & Marrow Transplant Information Network

U.S. Department of Health and Human Services: Understanding Transplantation as a Treatment Option

National Bone Marrow Transplant Link

See the article here:
What is a Stem Cell Transplant (Bone Marrow Transplant ...

Recommendation and review posted by simmons

Dr.Chia graduated with Bachelor of Medicine and Bachelor of Surgery from the National University of Singapore in 1999, for which she was awarded the Singapore Medical Association Bronze Medal for being 2nd in the overall examination. She was also honored with the Dean's List Award, the Yeoh Khuan Joo Gold Medal (Surgery) and the Nestle Book Prize ( Paediatrics Clinical Clerkship). She decided to pursue her passion for internal medicine and completed her residency at the Singapore General Hospital. She obtained membership of the Royal College of Physicians of the United Kingdom in 2002. Following this, she embarked on her fel-lowship training in the field of Endocrinology at the Department of Endocrinology, Singapore General Hos-pital (SGH).

In 2004, whilst still pursuing her subspecialty training in Endocrinology, Dr Chia was given a research fellow-ship at the Cleveland Clinic Foundation, USA. During this one and a half year period, she conducted research on blood markers for the diagnosis and management of thyroid cancer, for which she was awarded the Merlin Bumpus Young Researcher Award (2nd prize) by the Cleveland Clinic Foundation. Upon her return to Singa-pore, she completed the rest of her Endocrinology fellowship in 2007, and was admitted as a Fellow of the Academy of Medicine, Singapore.

Dr Chia has always been passionate about teaching, and has been heavily involved with both undergraduate and postgraduate education. She was Chairman of the SGH Division of Medicine Medical Officer Education Committee from 2006 to 2008, as well as a Clinical Tutor at the Yong Lou Lin School of Medicine at the Na-tional University of Singapore.

Dr Chia has wide ranging interests particularly in thyroid disease and diabetes. She is the current chairman of the SGH Thyroid Group, a multidisciplinary association of physicians with an interest in the care of patients with thyroid cancer. She is the only endocrinologist in Sinapore so far to receive the specialist credential En-docrine Certification in Neck Ultrasound (ECNU) from the American Association of Clinical Endocrinologists (AACE). This rigorous credential is only awarded to endocrinologists who have satisfied a high standard for performing thyroid and neck ultrasounds, as well as ultrasound-guided biopsies of thyroid nodules.

Dr Chia also has a great interest in managing diabetes, and strongly believes in empowering both physician and patient in combating this growing problem. To this end, she has given numerous educational talks on dia-betes to the medical community, both internationally and locally. Besides this, Dr Chia also manages oste-oporosis, calcium disorders, obesity, polycystic ovarian disease, lipid disorders, pituitary and adrenal disorders and other hormonal evaluations. She is the incumbent honorary secretary of the Endocrine & Metabolic Soci-ety of Singapore and the Chapter of Endocrinologists, Academy of Medicine. She is an active member of The Endocrine Society (USA) and the American Association of Clinical Endocrinologists (AACE).

Read more from the original source:
The Endocrine Clinic | Singapore Hormone Specialists

Recommendation and review posted by Bethany Smith