Summary

Successful reprogramming of differentiated human somatic cells into a pluripotent state would allow creation of patient- and disease-specific stem cells. We previously reported generation of induced pluripotent stem (iPS) cells, capable of germline transmission, from mouse somatic cells by transduction of four defined transcription factors. Here, we demonstrate the generation of iPS cells from adult human dermal fibroblasts with the same four factors: Oct3/4, Sox2, Klf4, and c-Myc. Human iPS cells were similar to human embryonic stem (ES) cells in morphology, proliferation, surface antigens, gene expression, epigenetic status of pluripotent cell-specific genes, and telomerase activity. Furthermore, these cells could differentiate into cell types of the three germ layers in vitro and in teratomas. These findings demonstrate that iPS cells can be generated from adult human fibroblasts.

Embryonic stem (ES) cells, derived from the inner cell mass of mammalian blastocysts, have the ability to grow indefinitely while maintaining pluripotency (Evans and Kaufman, 1981andMartin, 1981). These properties have led to expectations that human ES cells might be useful to understand disease mechanisms, to screen effective and safe drugs, and to treat patients of various diseases and injuries, such as juvenile diabetes and spinal cord injury (Thomson etal., 1998). Use of human embryos, however, faces ethical controversies that hinder the applications of human ES cells. In addition, it is difficult to generate patient- or disease-specific ES cells, which are required for their effective application. One way to circumvent these issues is to induce pluripotent status in somatic cells by direct reprogramming (Yamanaka, 2007).

We showed that induced pluripotent stem (iPS) cells can be generated from mouse embryonic fibroblasts (MEF) and adult mouse tail-tip fibroblasts by the retrovirus-mediated transfection of four transcription factors, namely Oct3/4, Sox2, c-Myc, and Klf4 (Takahashi and Yamanaka, 2006). Mouse iPS cells are indistinguishable from ES cells in morphology, proliferation, gene expression, and teratoma formation. Furthermore, when transplanted into blastocysts, mouse iPS cells can give rise to adult chimeras, which are competent for germline transmission (Maherali etal., 2007, Okita etal., 2007andWernig etal., 2007). These results are proof of principle that pluripotent stem cells can be generated from somatic cells by the combination of a small number of factors.

In the current study, we sought to generate iPS cells from adult human somatic cells by optimizing retroviral transduction in human fibroblasts and subsequent culture conditions. These efforts have enabled us to generate iPS cells from adult human dermal fibroblasts and other human somatic cells, which are comparable to human ES cells in their differentiation potential in vitro and in teratomas.

Induction of iPS cells from mouse fibroblasts requires retroviruses with high transduction efficiencies (Takahashi and Yamanaka, 2006). We, therefore, optimized transduction methods in adult human dermal fibroblasts (HDF). We first introduced green fluorescent protein (GFP) into adult HDF with amphotropic retrovirus produced in PLAT-A packaging cells. As a control, we introduced GFP to mouse embryonic fibroblasts (MEF) with ecotropic retrovirus produced in PLAT-E packaging cells(Morita etal., 2000). In MEF, more than 80% of cells expressed GFP (FigureS1). In contrast, less than 20% of HDF expressed GFP with significantly lower intensity than in MEF. To improve the transduction efficiency, we introduced the mouse receptor for retroviruses, Slc7a1 (Verrey etal., 2004) (also known as mCAT1), into HDF with lentivirus. We then introduced GFP to HDF-Slc7a1 with ecotropic retrovirus. This strategy yielded a transduction efficiency of 60%, with a similar intensity to that in MEF.

The protocol for human iPS cell induction is summarized inFigure1A. We introduced the retroviruses containing human Oct3/4, Sox2, Klf4, and c-Myc into HDF-Slc7a1 (Figure1B; 8 105 cells per 100 mm dish). The HDF derived from facial dermis of 36-year-old Caucasian female. Six days after transduction, the cells were harvested by trypsinization and plated onto mitomycin C-treated SNL feeder cells (McMahon and Bradley, 1990) at 5 104 or 5 105 cells per 100 mm dish. The next day, the medium (DMEM containing 10% FBS) was replaced with a medium for primate ES cell culture supplemented with 4 ng/ml basic fibroblast growth factor (bFGF).

Induction of iPS Cells from Adult HDF

(A) Time schedule of iPS cell generation.

(B) Morphology of HDF.

(C) Typical image of non-ES cell-like colony.

(D) Typical image of hES cell-like colony.

(E) Morphology of established iPS cell line at passage number 6 (clone 201B7).

(F) Image of iPS cells with high magnification.

(G) Spontaneously differentiated cells in the center part of human iPS cell colonies.

(HN) Immunocytochemistry for SSEA-1 (H), SSEA-3 (I), SSEA-4 (J), TRA-1-60 (K), TRA-1-81 (L), TRA-2-49/6E (M), and Nanog (N). Nuclei were stained with Hoechst 33342 (blue). Bars = 200 m (BE, G), 20 m (F), and 100 m (HN).

Approximately two weeks later, some granulated colonies appeared that were not similar to hES cells in morphology (Figure1C). Around day 25, we observed distinct types of colonies that were flat and resembled hES cell colonies (Figure1D). From 5 104 fibroblasts, we observed 10 hES cell-like colonies and 100 granulated colonies (7/122, 8/84, 8/171, 5/73, 6/122, and 11/213 in six independent experiments, summarized in Table S1). At day 30, we picked hES cell-like colonies and mechanically disaggregated them into small clumps without enzymatic digestion. When starting with 5 105 fibroblasts, the dish was nearly covered with more than 300 granulated colonies. We occasionally observed some hES cell-like colonies in between the granulated cells, but it was difficult to isolate hES cell-like colonies because of the high density of granulated cells. The nature of the non-hES-like cells remains to be determined.

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Historians of homosexuality will judge much twentieth-century "science" harshly when they come to reflect on the prejudice, myth, and downright dishonesty that litter modern academic research on sexuality. Take, for example, the lugubrious statements of-once respected investigators. Here is Sandor Feldman, a well-known psychotherapist, in 1956:

Or consider the remarks of the respected criminologist Herbert Hendin:

The notion of the homosexual as a deeply disturbed deviant in need of treatment was the orthodoxy until only recently. Bernard Oliver, Jr., a psychiatrist specializing in sexual medicine, wrote in 1967 that Dr. Edmond Bergler feels that the homosexual's real enemy is not so much his perversion but [sic] ignorance of the possibility that he can be helped, plus his psychic masochism which leads him to shun treatment....

There is good reason to believe now, more than ever before, that many homosexuals can be successfully treated by psychotherapy, and we should encourage homosexuals to seek this help.[3]

Such views about the origin of homosexual preferences have become part of American political culture as well. When, in 1992, Vice-President Dan Quayle offered the view that homosexuality "is more of a choice than a biological situation.... It is a wrong choice,"[4] he merely reasserted the belief that homosexuality reflected psychological conditioning with little biological basis, and certainly without being influenced by a person's biological inheritance.

And now we have the much publicized spectacle--Time magazine has taken up the story in a dramatic feature entitled "Search for a Gay Gene"[5] --of homosexuality's origins being revealed in the lowly fruit fly, Drosophila.[6] Males and females of this, one has to admit, rather distant relation adopt courtship behavior that has led two researchers at the US National Institutes of Health to draw extravagant parallels with human beings.

Shang-Ding Zhang and Ward F. Odenwald found that what they took to be homosexual behavior among male fruit flies--touching male partners with forelegs, licking their genitalia, and curling their bodies to allow genital contact--could be induced by techniques that abnormally activated a gene called w (for "white," so called because of its effect on eye color). Widespread activation (or "expression") of the white gene in Drosophila produced male-to-male rituals that took place in chains or circles of five or more flies. If female fruit flies lurked nearby, male flies would only rarely be tempted away from their male companions. These findings, which have apparently been reproduced by others, have led the investigators to conclude that "w misexpression has a profound effect on male sexual behavior."

Zhang and Odenwald go on to speculate that the expression of w could lead to severe shortages of serotonin, an important chemical signal that enables nerve cells to communicate with one another. The authors conjecture that mass activation of w diminishes brain serotonin by promoting its use elsewhere in the body. Indeed, cats, rabbits, and rats all show some elements of "gay" behavior when their brain serotonin concentrations fall. Intriguing and, you might think, convincing evidence.

Yet, although w is found in modified form in human beings, it is a huge (and, it seems to me, a dangerous) leap to extrapolate observations from fruit flies to humans. In truth, when the recent data are interpreted literally we find that (a) the w gene induces male group sex behavior in highly ritualized linear or circular configurations, and (b) while these tend more toward homosexual than straight preferences, they are truly bisexual (as pointed out by Larry Thompson in Time). Zhang and Odenwald force their experimental results with fruit flies to fit their preconceived notions of homosexuality. How simplistic it seems to equate genital licking in Drosophila with complex individual and social homosexual behavior patterns in humans. Can notions of homosexuality apply uniformly across the biological gulf that divides human beings and insects? Such arguments by analogy seem hopelessly inadequate.

By contrast, the work of Simon LeVay, Dean Hamer, and a small group of researchers concerned to distinguish biological and genetic influences on sexual behavior has discredited much of the loose rhetoric that has been used about homosexuality. In August 1991, LeVay, a neuroscientist who now directs the Institute of Gay and Lesbian Education in southern California, published in the magazine Science findings from autopsies of men and women of known sexual preference. He found that a tiny region in the center of the brain--the interstitial nucleus of the anterior hypothalamus (INAH) 3--was, on average, substantially smaller in nineteen gay men who died from AIDS than among sixteen heterosexual men.[7]

The observation that the male brain could take two different forms, depending on one's sexual preference, was a stunning discovery. The hypothalamus-a small, intricate mass of cells lying at the base of the brain-was long believed to have a role in sexual behavior, but direct evidence that it did so was weak. Yet LeVay expressed caution. Although his data showed that human sexual preference "is amenable to study at the biological level," he noted that it was impossible to be certain whether the anatomical differences between the brains of gay and straight men were a cause or a consequence of their preference.[8]

In the thirteen persuasive essays that make up The Sexual Brain, LeVay takes account of the current bio-behavioral controversy over the science of sex. From the union of wiry sperm and bloated ovum to the child-rearing practices of mammals and humans, for which mothers are largely responsible, he writes (metaphorically), the "male is little more than a parasite who takes advantage of [the female's] dedication to reproduction." He goes on to draw from a wide range of sources to support his contentious assertion that "there are separate centers within the hypothalamus for the generation of male-typical and female-typical sexual behavior and feelings." He argues that a connection--the details of which remain mysterious--between brain and behavior exists through hormones such as testosterone.

The most convincing evidence he puts forward to support his view comes from women with congenital adrenal hyperplasia. This condition, in which masculine characteristics, such as androgenized genitalia, including clitoral enlargement and partially fused labia, become pronounced in women, is caused by excessive testosterone production and leads, in adulthood, to an increased frequency of lesbianism affecting up to half of all the women who have the condition. The theory, still unproven, that is proposed to explain these behavioral effects of hormones is that one or more chemical signals act during a brief early critical period in the development of most males to alter permanently both the brain and the pattern of their later adult behavior. Unless this hormonal influence is switched on, a female pattern of development will follow automatically.

What might be the origin of biological differences underlying male sexual preference? In 1993 Dean Hamer and his colleagues at the National Cancer Institute discovered a preliminary but nevertheless tantalizing clue.[9] Hamer began his painstaking search for a genetic contribution to sexual behavior by studying the rates of homosexuality among male relatives of seventy-six known gay men. He found that the incidence of homosexual preference in these family members was strikingly higher (13.5 percent) than the rate of homosexuality among the whole sample (2 percent). When he looked at the patterns of sexual orientation among these families, he discovered more gay relatives on the maternal side. Homosexuality seemed, at least, to be passed from generation to generation through women.

Maternal inheritance could be explained if there was a gene influencing sexual orientation on the X chromosome, one of the two human sex chromosomes that bear genes determining the sex of offspring.[10] Men have both X and Y chromosomes, while women have two X chromosomes. A male sex-determining gene, called SRY, is found on the Y chromosome. Indeed, the Y chromosome is the most obvious site for defining male sexuality since it is the only one of the forty-six human chromosomes to be found in men alone. The SRY gene is the most likely candidate both to turn on a gene that prevents female development and to trigger testosterone production. Since the female has no Y chromosome, she lacks this masculinizing gene. In forty pairs of homosexual brothers, Hamer and his team looked for associations between the DNA on the X chromosome and the homosexual trait. They found that thirty-three pairs of brothers shared the same five X chromosomal DNA "markers," or genetic signatures, at a region near the end of the long arm of the X chromosome designated Xq28.[11] The possibility that this observation could have occurred by chance was only 1 in 10,000.

LeVay takes a broad philosophical perspective in his discussion of human sexuality by placing his research in the context of animal evolution. Hamer, on the other hand, has written, with the assistance of the journalist Peter Copeland, a more focused popular account of his research. He conceived his project after reflecting on a decade of laborious research on yeast genes. Although the project was approved by the National Institutes of Health after navigating a labyrinthine course through government agencies, it remained rather meagerly funded.

Taken together, the scientific papers of both LeVay and Hamer and the books that their first reports have now spawned[12] make a forceful but by no means definitive case for the view that biological and genetic influences have an important--perhaps even decisive--part in determining sexual preference among males. LeVay writes, for example, that "...the scientific evidence presently available points to a strong influence of nature, and only a modest influence of nurture." But there is no broad scientific agreement on these findings. They have become mired in a quasi-scientific debate that threatens to let obscurantism triumph over inquiry. What happened?

To begin with, we must ask what LeVay and Hamer have not shown. LeVay has found no proof of any direct link between the size of INAH 3 and sexual behavior. Size differences alone prove nothing. He was also unable to exclude the possibility that AIDS has an influence on brain structure, although this seemed unlikely, since six of the heterosexual men he studied also had AIDS. Moreover, Hamer did not find a gene for homosexuality; what he discovered was data suggesting some influence of one or more genes on one particular type of sexual preference in one group of people. Seven pairs of brothers did not have the Xq28 genetic marker, yet these brothers were all gay. Xq28 is clearly not a sine qua non for homosexuality; it is neither a necessary nor a sufficient cause by itself.

And what about women? Although the genitalia of women as well as men are clearly biologically determined, no data exist to prove a genetic link, or a link based on brain structure, with female sexual preferences, whether heterosexual or homosexual. Finally, neither study has been replicated by other researchers, the necessary standard of scientific proof. Indeed, there is every reason to suppose that the INAH 3 data will be extremely difficult to confirm. Only a few years ago INAH 1 (located close to INAH 3) was also thought to be larger in men than in women. Two groups, including LeVay's, have failed to reproduce this result.

Most of these limitations are clearly acknowledged by both LeVay and Hamer in their original scientific papers and are reinforced at length in their books. But reactions to their findings have nevertheless been harshly critical. For instance, after pointing out several potential weaknesses in Hamer's study and criticizing his decision to publish in Science at a time when gay "lives are at stake," two biologists, Anne Fausto-Sterling and Evan Balaban, asked "whether it might not have been prudent for the authors and the editors of Science to have waited until more of the holes in the study had been plugged...."[13] Fortunately, their somewhat hysterical reaction has been followed by more careful comment by other scientists.[14]

Lack of prudence also characterized the response in the press. In London, the conservative Daily Telegraph ran the clumsy headline, "Claim that homosexuality is inherited prompts fears that science could be used to eradicate it." Another story began, "A lot of mothers are going to feel guilty," while another was entitled "Genetic tyranny."

These headlines are part of the popular rhetoric about DNA, which supposes that a gene represents an irreducible and immutable unit of the human self. The correlation between a potentially active gene and a behavior pattern is assumed to indicate cause and effect. Was Hamer himself guilty of over-interpretation? In his original paper, he went to extraordinary lengths to qualify his findings. He and his co-authors offer no fewer than ten statements advising a cautious reading of their data, and they note that "replication and confirmation of our results are essential." Neither the hyperbolic press response with its relentless message of genetic determinism nor the ill-judged scientific criticism was appropriate.

Nevertheless, there are three conceptual issues raised by these reports --namely, heritability, sexual categorization, and the meaning of the phrase "biological basis of behavior" --which have been largely ignored in the scramble to publish instant analyses of the findings of LeVay and Hamer, among others.

Heritability is a measure of the resemblance between relatives; it is expressed as the proportion of variability in an observable characteristic that can be attributed to genetic factors. Eye color, for example, is 100 percent heritable, whereas we know that most behavioral traits have genetic contributions of well below 50 percent. Heritability is a quarrelsome issue among geneticists, and its proportional value is often quoted without the necessary qualifications. Variation in any trait is accounted for by the influence of genes (including, importantly, the interaction among genes), environment (the family and one's wider life experience), and the interaction between one or more genes and one or more environmental variables. The standard measure of heritability is the sum of all genetic influences, and it ignores potentially complex interactions--for example, the influence of the family milieu on the behavioral expression of a gene influencing sexual preference. The most common error made by those who discuss genetic contributions to behavior is to forget that heritability is a property only of the population under study at one particular time. It cannot be generalized to characterize the behavior itself.

When we apply these considerations to Hamer's data, we make a surprising discovery. If we accept his own hypothesis of the relation between the Xq28 marker and the behavioral trait, the maximum heritability of homosexuality in the group he studied is 67 percent, which may seem a remarkably high figure. Yet this group was a particularly selected one: the seventy-six study participants openly acknowledged being gay, and had volunteered for the study. What Hamer's results do not tell us is what the influence of the Xq28 marker in the general population might be. He infers from various mathematical calculations "that Xq28 plays some role in about 5 to 30 percent of gay men." But he admits that this is merely a preliminary estimate and that accurate measuring of Xq28 heritability in the general population remains to be done. In fact, a frequent criticism of Hamer's Science paper was that he did not measure the incidence of Xq28 markers among heterosexual brothers of gay sibling pairs. Without this information, it is impossible to guess the influence of any genes that might be located at Xq28. Their effects will be unpredictable at best, and any interaction with the environment will assume critical importance.

At this point, science inches uneasily toward dogma and diatribe. Hamer cites Richard Lewontin's Not in Our Genes[15] as one of his early inspirations to change the direction of his research. Hamer writes that he

knew that [Lewontin] had criticized the idea that behavior is genetic, arguing instead that it is a product of class-based social structures....Why was Lewontin, a formidable geneticist, so determined not to believe that behavior could be inherited? He couldn't disprove the genetics of behavior in a lab, so he wrote a political polemic against it.

Indeed, Lewontin has frequently provided cogent arguments against the view that heritability can help delineate the effects of genes on human behavior.[16] He has described the separation of behavioral variation into genetic and environmental contributions and the interaction between the two as "illusory."[17] For him and his co-writers, such a model "cannot produce information about causes of phenotypic difference," i.e., differences in observable physical and mental traits. The precise meaning of heritability forces the inevitable conclusion, Lewontin has written, that whatever proportion is quoted, it "is nearly equivalent to no information at all for any serious problem in human genetics."

Imagine Dean Hamer's astonishment, therefore, when he received a letter from Richard Lewontin in 1992. A Harvard professor teaching genetics and behavior had invited Hamer to submit a pamphlet describing his research as an example of "conceptual advances" in "modern behavior genetic studies." He had willingly complied, but only later discovered that it had been ruled "scientifically unacceptable" by Ruth Hubbard, an emeritus professor at the Harvard Biological Laboratories deeply skeptical about determinism. In his letter, Hamer writes, Lewontin

went on to theorize that human behaviors must be "very, very far from the genes" because "there are some at least that we know for sure are not influenced by genes as, for example, the particular language one speaks." That made about as much sense as saying that since some people eat tacos and some eat hamburgers, there is no biological drive to eat.

Hamer, tongue firmly in cheek, offered to give Lewontin's students a lecture on how good research into behavior genetics is done. Lewontin accepted. On the day of his scheduled talk, Hamer faced not only Lewontin but also Ruth Hubbard and Evan Balaban (a co-author of the hostile letter later published in Science). Hamer described his methods carefully and stressed that his research could identify only potential genetic influences and not isolate specific genetic causes of behavior. At the end of the lecture, Lewontin indicated that he had no dispute with Hamer after all, and left the classroom without further comment. One wonders from this if Lewontin has modified his views on studying genetic contributions to human behavior.

Although it is true that heritability is only a crude measure of genetic influence, it remains a valuable research tool if, as one scientist has said, the researchers realize that

genetic influence on behavior appears to involve multiple genes rather than one or two major genes, and nongenetic sources of variance are at least as important as genetic factors....This should not be interpreted to mean that genes do not affect human behavior; it only demonstrates that genetic influence on behavior is not due to major-gene effects.[18]

More importantly, one can move beyond the "lump sum" theory of genetic influences to study the way in which genes affect behavior over time, or to discover how a gene influences different but possibly related behaviors, for instance both sexual preference and aggression.

Lewontin also cited the "terrible mischief" that could result from a research program based on heritability as his reason to suggest stopping "the endless search for better methods of estimating useless quantities."" Hamer agrees that precise genetic determinacy is an impossible goal; his 1993 article for Science on DNA markers also ended with an unusual admonition:

We believe that it would be fundamentally unethical to use [this] information to try to assess or alter a person's current or future sexual orientation, either heterosexual or homosexual, or other normal attributes of human behavior. Rather, scientists, educators, policy-makers, and the public should work together to ensure that such research is used to benefit all members of society.

If scientists who have opposed research on heritability would accept that it can have, when it is carried out in this spirit, an important place in the study of behavior, that would add much-needed weight to calls to expand, and improve, research on human sexuality.

Although Hamer and LeVay have both expressed cautious confidence in their results, they are evidently uneasy about their own categorizations of men as either gay or straight. Hamer writes that,

In truth, I don't think that there is such a thing as "the" rate of homosexuality in the population at large. It all depends on the definition, how it's measured, and who is measured.

Classifying sexuality into homosexual and heterosexual categories may have benefits of simplicity for researchers, but how closely does this division fit the real world? Poorly is the answer. Sexual behavior and styles of life among men and women vary from day to day and year to year, and a conclusion about whether or not sexual experience is characterized as homosexual frequently depends on the definition one uses.[20] The slippery nature of our crude categories should alert us to beware of conclusions about groups labeled as "homosexual" or "heterosexual."

Moreover, the concept of sexuality itself cannot easily be analyzed. It exists at several levels--chromosomal, genital, brain, preference, gender self-image, gender role, and a range of subtle influences on behavior (hair color, eye color, and many more). Each of these can be grouped together with the others to produce a single measurable component on a scale, devised by Alfred Kinsey in the 1940s, that allegedly shows a person's degree of homosexual preference. Hamer used this scale somewhat uncritically to categorize his volunteers. Stephen Levine, a medical expert on sexual behavior, has noted that the conflated and crude Kinsey scale "does not do justice to the diversity among homosexual women and men."[21]

One of Hamer's severest critics, Anne Fausto-Sterling, a developmental geneticist at Brown University, has tried to extend sexual categories beyond the binary divisions of male and female[(22] She suggests adding three more groups based on "intersex" humans: herms (true hermaphrodites who possess one testis and one ovary), merms (individuals who have testes, no ovaries, but some female genitalia), and ferms (who have ovaries, no testes, but some male characteristics). This attempt to create multiple categories is, however, futile. It tries to systematize the un-systematizable by proposing a neatly divided-up continuum of sexuality, while, in fact, very different and mutually exclusive factors may be at work in particular cases. It is an impossible and intellectually misguided task.

Two major studies examining the historical origins of modern sexual categories show how social groupings that evolve over time can mislead one into supposing that inherent biological classes exist in some unchangeable sense. Michel Foucault chronicled the history of sexual norms by concentrating on the fluid notion of "homosexuality."[23] He denounced what he called "Freud's conformism" in taking heterosexuality to be the normal standard in psychoanalysis. He concluded:

We must not forget that the psychological, psychiatric, medical category of homosexuality was constituted from the moment it was characterized--Westphal's famous article of 1870 on "contrary sexual sensations" can stand as its date of birth[24]--less by a type of sexual relations than by a certain quality of sexual sensibility.... The sodomite had been a temporary aberration; the homosexual was now a species.

This analysis, it seems to me, points to a critical error in the research of both Hamer and LeVay. Both, in spite of their qualifications, adopt the idea of the homosexual as a physical "species" different from the heterosexual. But there are no convincing historical grounds for this view. As Foucault points out, at the time of Plato,

People did not have the notion of two distinct appetites allotted to different individuals or at odds with each other in the same soul; rather, they saw two ways of enjoying one's pleasure...

The cultural historian Jonathan Katz has recently attacked the naive partitioning of sexual orientation by tracing the dominance of the norm--heterosexuality --throughout history.[25] He provides a convincing argument that the "just-is hypothesis" of heterosexuality--i.e., that the word corresponds to a true behavioral norm--is an "invented tradition." He shows that the categories of gay and straight are gradually dissolving as notions of the family become more various. Basing his view more on intuition than on sociological evidence, he predicts "the declining significance of sexual orientation."

The final issue that has confused the interpretation of research into sexuality is the meaning of "biological influence." Unfortunately, both LeVay and Hamer, in their effort to popularize their findings, ignore the subtlety of this question. As has been noted, LeVay is unambiguous about his own position on biological determinism,

The most promising area for exploration is the identification of genes that influence sexual behavior and the study of when, where, and how these genes exert their effects.

Both researchers ignore the central issue in the debate over nature and nurture. The question is: How do genes get you from a biochemical program that instructs cells to make proteins to an unpredictable interplay of behavioral impulses--fantasy, courtship, arousal, sexual selection--that constitutes "sexuality"? The question remains unresolved. The classic fall-back position is to claim that genes merely provide a basis, at most a predisposition, to a particular behavior. But such statements lack a precise or testable meaning.

Perhaps we are asking the wrong question when we set out to find whether there is a gene for sexual orientation. We know that genes are responsible for the development of our lungs, larynx, mouth, and the speech areas of our brain. And we understand that this complexity cannot be collapsed into the notion of a gene for "talking." Similarly, what possible basis can there be for concluding that there is a single gene for sexuality, even though we accept that there are genes that direct the development of our penises, vaginas, and brains? This analogy is not to deny the importance of genes, but merely to recast their role in a different conceptual setting, one devoid of dualist prejudice.

The search for a single dominant gene--the "O-GOD" (one gene, one disorder) hypothesis--that would influence a behavioral variant is likely to be fruitless. Many different genes, together with many different environmental factors, will interact in unpredictable ways to guide behavioral preferences. Each component will contribute small quanta of influence. One result of such a quantum theory of behavior is that it makes irrelevant the overstretched speculations of both Hamer and LeVay about why a gene for homosexuality still exists when it apparently has little apparent survival value in evolutionary terms. The quest for a teleological explanation to identify a reason for the existence of a "gay gene" becomes pointless when one understands that there is not now, and never was, a single and final reason for being gay or straight, or having any other identity along the continuum of sexual preference.

Does this complexity, together with an adverse and polarized social milieu, preclude successful research efforts concerning human sexuality? In 1974, Lewontin wrote that reconstruction of man's genetic past is "an activity of leisure rather than of necessity."[26] Perhaps so. But, as Robert Plomin argues, the value of studying inheritance in behavior lies in its importance

per se rather than in its usefulness for revealing how genes work. Some of society's most pressing problems, such as drug abuse, mental illness, and mental retardation, are behavioral problems. Behavior is also a key in health as well as illness, in abilities as well as disabilities, and in the personal pluses of life, such as sense of well-being and the ability to love and work.[27]

What research into human sexuality, then, lies ahead? Dean Hamer has repeated his initial work among male homosexuals in an entirely new group of families and has included a much-needed analysis of women. He has also compared the frequency of the Xq28 marker among pairs of gay siblings and their heterosexual brothers, important control data that he did not acquire the first time around. This work has been submitted to the journal Nature Genetics. Two other teams--one recently formed at the National Institutes of Health and a Canadian group that has reached some preliminary results--are attempting to replicate Hamer's initial findings. All Hamer will say about his latest data is that they have not discouraged him from continuing with his project.

To track down and sequence the DNA from one or more relevant genes at Xq28, from a total of about two hundred candidates, seems an almost insuperable task. To read the molecular script of DNA involves deciphering millions of constituent elements. Moreover, each gene will have to be studied individually and many more pairs of gay brothers will be needed to achieve this goal. The work will be extremely difficult for a single laboratory to undertake on its own. Hamer's request for a federally funded center for research into sexuality--a National Institute of Sexual Health--is therefore timely, for the study of differences between the sexes has reached a critical, though admittedly fragmented, stage and a coordinated research program would be valuable.

The concerns of such an institute should be broad. For example, it might have included the recent work reported from Yale which overturns the conventional view that language function is identical for both men and women.[28] By studying which brain areas were activated during various linguistic tasks, the Yale scientists found that women used regions in both their right and left brain cortices in certain instances, while men used only the left side of their brains. If functional brain differences for sophisticated behaviors exist between the sexes, the task for the future would be to link function to structure and to describe how both evolve from a background of genetic and environmental influence.

Inevitably, the idea of biological determinism carries with it the threat of manipulating the genes or the brain in order to adapt to the prevailing norm. As I have noted, Hamer was acutely aware of this possibility when he wrote his paper. But the prospects for pinpointing genetic risk have moved rapidly and worryingly forward with the recent availability of genetic screening techniques for, among other diseases, several cancers, including a small proportion of cancers of the breast, colon, and thyroid. Most such techniques are used without any current prospect for gene therapy or for any other effective treatment of the conditions identified. Geneticists such as Francis Collins, director of the Human Genome Project, have opposed unrestricted and unregulated screening techniques, describing their recent uses as "alarming"[29] because we are "treading into a territory which the genetics community has felt rather strongly is still [in the stage of] research." Hamer's fine words opposing genetic manipulation are likely to mean little in the marketplace if his work eventually leads to the isolation of a gene that has an effect on sexual preference, even if it has only a small effect that is present in only a limited number of people. US state legislatures are slowly responding to these issues. Colorado recently became the eleventh state to enact a law preventing information derived from genetic testing to be used in a discriminatory fashion.

In recognition of the emerging risks from dubious applications of preliminary discoveries, NIH launched a Task Force on Genetic Testing in April. The twenty-member committee includes representatives from industry, managed-care organizations, and patient-advocacy groups, and is chaired by Neil A. Holtzman, a professor of pediatrics and health policy at Johns Hopkins University. Far from being a friend to the hyperbolists, Holtzman has written that "physicians should be at the forefront of decrying florid genetic determinism and its dire implications for health and welfare reform."[30] His committee is charged with performing a two-year study of genetic technologies, which will look specifically at the accuracy, safety, reliability, and social implications of new testing procedures. This move is not without self-interest on the part of the geneticists at the NIH. Members of the US Congressional House Appropriations Committee, which closely monitors NIH spending, have said that they may freeze the Human Genome Project's $153 million grant if ethics issues are not given close attention.

But sex-based research has already run into political trouble. The Council for Citizens Against Government Waste has charged that some NIMH research is a misuse of taxpayer's money. Tom Schatz, CCAGW's president, has criticized twenty such studies, including one involving research into sex offenders. Rex Cowdry, acting director of the National Institute of Mental Health, argues that "for these grants, I think first you have to believe that the factors that motivate and control sexual behavior are worth knowing about...you have to believe that knowing more about how men and women are both similar and different is important."[31]

With such partisan pressures dominating the future of the research agenda, the circulation of uninformed opinions couched in scholarly prose is a cause for anxiety. In an otherwise superb and iconoclastic critique of the history of heterosexuality, Jonathan Katz ends with a sweeping and badly informed declaration:

Biological determinism is misconceived intellectually, as well as politically loathsome...Contrary to today's bio-belief, the heterosexual/homosexual binary is not in nature, but is socially constructed, therefore deconstructable.

LeVay and Hamer on the one hand, and Katz, on the other, evidently have taken completely antithetical positions. But Katz's extreme intellectual reductionism makes him as guilty as the more simplistic biologists and journalists who inflate claims about every new genetic discovery. After convincingly undermining the distinction between gay and straight, he then accepts the naive dualism of nature vs. nurture. It is such attempts as Katz's to put into opposition forces that are not in opposition which argue so strongly for planned research free from the ideological temptations that he succumbs to. Biological research into sexuality will indeed be misconceived if we assume that we already understand the differences between the sexes. In part the results of that research often contradict any such assumption. Katz demands that "we need to look less to oracles [presumably biological], and trust more in our desires, visions, and political organizing." But to take this path risks perpetuating a debate based on ignorance rather than one based on evidence.

It is true that the research of Hamer and LeVay presents technical and conceptual difficulties and that their preliminary findings obviously need replication or refutation. Yet their work represents a genuine epistemological break away from the past's rigid and withered conceptions of sexual preference. The pursuit of understanding about the origins of human sexuality --the quest to find an answer to the question, What does it mean to be gay and/or straight?--offers the possibility of eliminating what can be the most oppressive of cultural forces, the prejudiced social norm.

1 See Perversions: Psychodynamics and Therapy, edited by Sandor Lorand and Michael Balint (Ortolan Press, 1965; first edition, Random House, 1956), p. 75.

2 Quoted in Kenneth Lewes, The Psychoanalytic Theory of Male Homosexuality (Simon and Schuster, 1988), p. 188.

3 See Bernard J. Oliver, Jr., Sexual Deviation in American Society (College and University Press, 1967), p. 146.

4 See Karen de Witt, "Quayle Contends Homosexuality Is a Matter of Choice, Not Biology," The New York Times, September 14, 1992, p. A17.

5 See Larry Thompson, "Search for a Gay Gene," Time (June 12, 1995), pp. 60-61.

6 See Shang-Ding Zhang and Ward F. Odenwald, "Misexpression of the White (w) Gene Triggers Male-male Courtship in Drosophila," Proceedings of the National Academy of Sciences, USA, Vol. 92 (June 6, 1995), pp. 5525-5529.

7 See Simon LeVay, "A Difference in Hypothalamic Structure Between Heterosexual and Homosexual Men," Science (August 30, 1991), pp. 1034-1037.

8 The suprachiasmatic nucleus, also located in the hypothalamus, is larger in homosexual men than in either heterosexual men or women. The anterior commissure of the corpus callosum (a band of tissue that connects the right and left hemispheres of the brain) is also larger in gay men.

9 See Dean H. Hamer et al., "A Linkage Between DNA Markers on the X Chromosome and Male Sexual Orientation," Science (July 16, 1993), pp. 321-327.

10. The normal complement of human chromosomes is forty-six per individual, two of which are designated sex chromosomes. In the male, the sex chromosomal makeup is XY, while in the female it is XX. If a gene for homosexuality (Xh) was transmitted through the maternal line, one can see how the subsequent offspring would be affected.

(Chart omitted)

Suppose the unaffected female carrier for homosexuality (XXh) produced offspring with a non-Xh male (XY). Half of all female children would be carriers of Xh (like their mothers), while half of all male offspring would carry Xh unopposed by another X. The Xh trait -- homosexuality -- would then be able to express itself.

11 By chance, one would expect each pair of brothers to share half their DNA. So, assuming that there was no gene for homosexuality, one would expect twenty of the forty pairs of brothers to share the X chromosome marker.

12 LeVay has recently completed a second book in collaboration with Elisabeth Nonas--City of Friends--that surveys gay and lesbian culture; it will be published by MIT Press in November. He is currently working on Queer Science, a study of how scientific research has affected the lives of gays and lesbians.

13 See Anne Fausto-Sterling and Evan Balaban, "Genetics and Male Sexual Orientation," Science (September 3, 1993), p. 1257.

14 For example, see David Weatherall, Science and the Quiet Art (Norton, 1995) who notes that "these findings should not surprise us. Almost every condition...reveals a complex mixture of nature and nurture," p. 287.

15 See R.C. Lewontin, S. Rose, and L. J. Kamin, Not in Our Genes (Pantheon, 1984).

16 Lewontin is not a total skeptic about the importance of molecular genetics research in medicine. For instance, he accepts "that some fraction of cancers arise on a background of genetic predisposition." See R.C. Lewontin, "The Dream of the Human Genome," The New York Review (May 28, 1992), pp. 31-40.

17 See M. W. Feldman and R. C. Lewontin, "The Heritability Hang-up," Science (December 19, 1975), pp. 1163-1168.

18 See Robert Plomin, "The Role of Inheritance in Behavior," Science (April 13, 1990), pp. 183-188.

19 See R.C. Lewontin, "The Analysis of Variance and the Analysis of Causes," The American Journal of Human Genetics, Vol. 26 (1974), pp. 400-411.

20 For example, in a UK study (see Anne M. Johnson, "Sexual lifestyles and HIV risks," Nature [December 3, 1992], pp. 410-412), although only 1.4 percent of men reported a male partner during the past five years, 6.1 percent of men reported having experienced some same-gender behavior.

21 See Stephen B Levine, Sexual Life: A Clinician's Guide (Plenum, 1992). The Kinsey scale has seven levels ranging from exclusively heterosexual (0) to exclusively gay (6). Hamer applied this scale to four aspects of sexuality: self-identification, attraction, fantasy, and behavior.

22 See Anne Fausto-Sterling, "The Five Sexes: Why Male and Female Are Not Enough," The Sciences (March/April, 1993), pp. 20-24.

23 See Michel Foucault, The History of Sexuality, Vols. One and Two (Vintage, 1990).

24 Dr. K.F.O. Westphal became the first modern author to publish an account of what he described as a "contrary sexual feeling" (Die contrare Sexualempfindung), although the word homosexual was first used in a private letter written by Karl Maria Kertbeny on May 6, 1868. This linguistic history is described in detail by Jonathan Katz (see note 25).

25 See Jonathan Ned Katz, The Invention of Heterosexuality (Dutton, 1995).

26 R.C. Lewontin, "The Analysis of Variance and the Analysis of Causes," The American Journal of Human Genetics, Vol. 26 (1974), pp. 400-411.

27. Robert Plomin, "The Role of Inheritance in Behavior," Science (April 13, 1990), pp. 183-188.

28. See Bennett A. Shaywitz et al., "Sex differences in the functional organization of the brain for language," Nature (February 16, 1995), pp. 607-609.

29 See Gina Kolata, "Tests to Assess Risks for Cancer Raising Questions," The New York Times (March 27, 1995), p. A1.

30 See Neil A. Holtzman, "Genetics," Journal of the American Medical Association (April 26, 1995), pp. 1304-1306.

31 See "NIMH's Cowdry Defends Institute's Research Against Appropriations Committee, Watchdog Group Criticism," The Blue Sheet (March 29, 1995), pp. 5-6.

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What Is Gene Therapy?

Explore the what's and why's of gene therapy research, includingan in-depth look at the genetic disorder cystic fibrosis and how gene therapy could potentially be used to treat it.

Gene Delivery: Tools of the Trade

Explore the methods for delivering genes into cells.

Space Doctor

You are the doctor! Design and test gene therapy treatments with ailing aliens.

Challenges In Gene Therapy

Researchers hoping to bring gene therapy to the clinic face unique challenges.

Approaches To Gene Therapy

Beyond adding a working copy of a broken gene, gene therapy can also repair or eliminate broken genes.

Gene Therapy Successes

The future of gene therapy is bright. Learn about some of its most encouraging success stories.

Gene Therapy Case Study: Cystic Fibrosis

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Gene Therapy [Internet]. Salt Lake City (UT): Genetic Science Learning Center; 2012 [cited 2016 Aug 5] Available from http://learn.genetics.utah.edu/content/genetherapy/

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The heart is a muscular organ in humans and other animals, which pumps blood through the blood vessels of the circulatory system.[1] Blood provides the body with oxygen and nutrients, and also assists in the removal of metabolic wastes. The heart is located in the middle compartment of the mediastinum in the chest.[3]

In humans, other mammals, and birds, the heart is divided into four chambers: upper left and right atria; and lower left and right ventricles.[4][5] Commonly the right atrium and ventricle are referred together as the right heart and their left counterparts as the left heart. Fish in contrast have two chambers, an atrium and a ventricle, while reptiles have three chambers.[5] In a healthy heart blood flows one way through the heart due to heart valves, which prevent backflow.[3] The heart is enclosed in a protective sac, the pericardium, which also contains a small amount of fluid. The wall of the heart is made up of three layers: epicardium, myocardium, and endocardium.[7]

The heart pumps blood through the body. Blood low in oxygen from the systemic circulation enters the right atrium from the superior and inferior venae cavae and passes to the right ventricle. From here it is pumped into the pulmonary circulation, through the lungs where it receives oxygen and gives off carbon dioxide. Oxygenated blood then returns to the left atrium, passes through the left ventricle and is pumped out through the aorta to the systemic circulationwhere the oxygen is used and metabolized to carbon dioxide. In addition the blood carries nutrients from the digestive tract to various organs of the body, while transporting waste to the liver and kidneys. Normally with each heartbeat the right ventricle pumps the same amount of blood into the lungs as the left ventricle pumps to the body. Veins transport blood to the heart and carry deoxygenated blood - except for the pulmonary and portal veins. Arteries transport blood away from the heart, and apart from the pulmonary artery hold oxygenated blood. Their increased distance from the heart cause veins to have lower pressures than arteries.[3] The heart contracts at a resting rate close to 72 beats per minute.Exercise temporarily increases the rate, but lowers resting heart rate in the long term, and is good for heart health.

Cardiovascular diseases (CVD) are the most common cause of death globally as of 2008, accounting for 30% of deaths.[11][12] Of these more than three quarters follow coronary artery disease and stroke.[11] Risk factors include: smoking, being overweight, little exercise, high cholesterol, high blood pressure, and poorly controlled diabetes, among others.[13] Diagnosis of CVD is often done by listening to the heart-sounds with a stethoscope, ECG or by ultrasound.[3] Specialists who focus on diseases of the heart are called cardiologists, although many specialties of medicine may be involved in treatment.[12]

The human heart is situated in the middle mediastinum, at the level of thoracic vertebrae T5-T8. A double-membraned sac called the pericardium surrounds the heart and attaches to the mediastinum.[15] The back surface of the heart lies near the vertebral column, and the front surface sits behind to the sternum and rib cartilages.[7] The upper part of the heart is the attachment point for several large blood vessels - the venae cavae, aorta and pulmonary trunk. The upper part of the heart is located at the level of the third costal cartilage.[7] The lower tip of the heart, the apex, lies to the left of the sternum (8 to 9cm from the midsternal line) between the junction of the fourth and fifth ribs near their articulation with the costal cartilages.[7]

The largest part of the heart is usually slightly offset to the left side of the chest (though occasionally it may be offset to the right) and is felt to be on the left because the left heart is stronger and larger, since it pumps to all body parts. Because the heart is between the lungs, the left lung is smaller than the right lung and has a cardiac notch in its border to accommodate the heart.[7] The heart is cone-shaped, with its base positioned upwards and tapering down to the apex.[7] An adult heart has a mass of 250350 grams (912oz).[16] The heart is typically the size of a fist: 12cm (5in) in length, 8cm (3.5in) wide, and 6cm (2.5in) in thickness.[7] Well-trained athletes can have much larger hearts due to the effects of exercise on the heart muscle, similar to the response of skeletal muscle.[7]

The heart has four chambers, two upper atria, the receiving chambers, and two lower ventricles, the discharging chambers. The atria open into the ventricles via the atrioventricular valves, present in the atrioventricular septum. This distinction is visible also on the surface of the heart as the coronary sulcus. There is an ear-shaped structure in the upper right atrium called the right atrial appendage, or auricle, and another in the upper left atrium, the left atrial appendage. The right atrium and the right ventricle together are sometimes referred to as the right heart. Similarly, the left atrium and the left ventricle together are sometimes referred to as the left heart. The ventricles are separated from each other by the interventricular septum, visible on the surface of the heart as the anterior longitudinal sulcus and the posterior interventricular sulcus.

The cardiac skeleton is made of dense connective tissue and this gives structure to the heart. It forms the atrioventricular septum which separates the atria from the ventricles, and the fibrous rings which serve as bases for the four heart valves.[19] The cardiac skeleton also provides an important boundary in the heart's electrical conduction system since collagen cannot conduct electricity. The interatrial septum separates the atria and the interventricular septum separates the ventricles.[7] The interventricular septum is much thicker than the interatrial septum, since the ventricles need to generate greater pressure when they contract.[7]

The heart, showing valves, arteries and veins. The white arrows shows the normal direction of blood flow.

The heart has four valves, which separate its chambers.[7] The valves ensure blood flows in the correct direction through the heart and prevents backflow. Each valve consists of two to three cusps. The valves between the atria and ventricles connected to cartilaginous strings called chordae tendinae which in turn connect to muscles on the heart wall called papillary muscles.

The valves between the atria and ventricles are called the atrioventricular valves. Between the right atrium and the right ventricle is the tricuspid valve. The tricuspid valve has three cusps, which connect to chordae tendinae and three papillary muscles named the anterior, posterior, and septal muscles, after their relative positions. The mitral valve lies between the left atrium and left ventricle. It is also known as the bicuspid valve due to its having two cusps, an anterior and a posterior cusp. These cusps are also attached via chordae tendinae to two papillary muscles projecting from the ventricular wall.

The papillary muscles extends from the walls of the heart to the chordae tendinae of valves. These muscles prevent the valves from falling too far back when they close.[22]During the relaxation phase of the cardiac cycle, the papillary muscles are also relaxed and the tension on the chordae tendineae is slight. As the heart chambers contract, so do the papillary muscles. This creates tension on the chordae tendineae, helping to hold the cusps of the atrioventricular valves in place and preventing them from being blown back into the atria.[7][g]

Two additional semilunar valves sit at the exit of each of the ventricles. The pulmonary valve is located at the base of the pulmonary artery. This has three cusps which are not attached to any papillary muscles. When the ventricle relaxes blood flows back into the ventricle from the artery and this flow of blood fills the pocket-like valve, pressing against the cusps which close to seal the valve. The semilunar aortic valve is at the base of the aorta and also is not attached to papillary muscles. This too has three cusps which close with the pressure of the blood flowing back from the aorta.[7]

The right heart consists of two chambers, the right atrium and the right ventricle, separated by a valve, the tricuspid valve.[7]

The right atrium receives blood almost continuously from the body's two major veins, the superior and inferior venae cavae. A small amount of blood from the coronary circulation also drains into the right atrium via the coronary sinus, which is immediately above and to the middle of the opening of the inferior vena cava.[7] In the wall of the right atrium is an oval-shaped depression known as the fossa ovalis, which is a remnant of an opening in the fetal heart known as the foramen ovale.[7] Most of the internal surface of the right atrium is smooth, the depression of the fossa ovalis is medial, and the anterior surface has prominent ridges of pectinate muscles, which are also present in the right atrial appendage.[7]

The right atrium is connected to the right ventricle by the tricuspid valve.[7] The walls of the right ventricle are lined with trabeculae carneae, ridges of cardiac muscle covered by endocardium. In addition to these muscular ridges, a band of cardiac muscle, also covered by endocardium, known as the moderator band reinforces the thin walls of the right ventricle and plays a crucial role in cardiac conduction. It arises from the lower part of the interventricular septum and crosses the interior space of the right ventricle to connect with the inferior papillary muscle.[7] The right ventricle tapers into the pulmonary trunk, into which it ejects blood when contracting. The pulmonary trunk branches into the left and right pulmonary arteries that carry the blood to each lung. The pulmonary valve lies between the right lung and the pulmonary trunk.[7]

The left heart has two chambers: the left atrium, and the left ventricle, separated by the mitral valve.[7]

The left atrium receives oxygenated blood back from the lungs via one of the four pulmonary veins. The left atrium has an outpouching called the left atrial appendage. Like the right atrium, the left atrium is lined by pectinate muscles.[23] The left atrium is connected to the left ventricle by the mitral valve.[7]

The left ventricle is much thicker as compared with the right, due to the greater force needed to pump blood to the entire body. Like the right ventricle, the left also has trabeculae carneae, but there is no moderator band. The left ventricle pumps blood to the body through the aortic valve and into the aorta. Two small openings above the aortic valve carry blood to the heart itself, the left main coronary artery and the right coronary artery.[7]

The heart wall is made up of three layers: the inner endocardium, middle myocardium and outer epicardium. These are surrounded by a double-membraned sac called the pericardium.

The innermost layer of the heart is called the endocardium. It is made up of a lining of simple squamous epithelium, and covers heart chambers and valves. It is continuous with the endothelium of the veins and arteries of the heart, and is joined to the myocardium with a thin layer of connective tissue.[7] The endocardium, by secreting endothelins, may also play a role in regulating the contraction of the myocardium.[7]

The middle layer of the heart wall is the myocardium, which is the cardiac muscle a layer of involuntary striated muscle tissue surrounded by a framework of collagen. The cardiac muscle pattern is elegant and complex, as the muscle cells swirl and spiral around the chambers of the heart, with the outer muscles forming a figure 8 pattern around the atria and around the bases of the great vessels, and inner muscles formining a figure 8 around the two ventricles and proceed toward the apex. This complex swirling pattern allows the heart to pump blood more effectively.[7]

There are two types of cells in cardiac muscle: muscle cells which have the ability to contract easily, and pacemaker cells of the conducting system. The muscle cells make up the bulk (99%) of cells in the atria and ventricles. These contractile cells are connected by intercalated discs which allow a rapid response to impulses of action potential from the pacemaker cells. The intercalated discs allow the cells to act as a syncytium and enable the contractions that pump blood through the heart and into the major arteries.[7] The pacemaker cells make up 1% of cells and form the conduction system of the heart. They are generally much smaller than the contractile cells and have few myofibrils which gives them limited contractibility. Their function is similar in many respects to neurons.[7] Cardiac muscle tissue has autorhythmicity, the unique ability to initiate a cardiac action potential at a fixed rate spreading the impulse rapidly from cell to cell to trigger the contraction of the entire heart.[7]

The pericardium surrounds the heart. It consists of two membranes: an inner serous membrane called the epicardium, and an outer fibrous membrane. Blood vessels and nerves reach the cardiac muscle from the epicardium.[7] These help influence the heart rate.[7] These enclose the pericardial cavity which contains the pericardial fluid that lubricates the surface of the heart.

Heart tissue, like all cells in the body, need to be supplied with oxygen, nutrients and a way of removing metabolic wastes. This is achieved by the coronary circulation, which includes arteries, veins, and lymphatic vessels, Blood circulates through the coronary circulation cyclically, in peaks and troughs relating to the heart muscle's relaxation or contraction.[7]

Heart tissue receives blood from two arteries which arise just above the aortic valve. These are the left main coronary artery and the right coronary artery. The left main coronary artery splits shortly after leaving the aorta into two vessels, the left anterior descending and the left circumflex artery. The left anterior descending artery supplies heart tissue and the front, outer side, and the septum of the left ventricle. It does this by smaller branching arteries - diagonal and septal branches. The left circumflex supplies the back and underneath of the left ventricle. The right coronary artery supplies the right atrium, right ventricle, and lower posterior sections of the left ventricle. The right coronary artery also supplies blood to the atrioventricular node (in about 90% of people) and the sinoatrial node (in about 60% of people). The right coronary artery runs in a groove at the back of the heart and the left anterior descending artery runs in a groove at the front. There is significant variation between people in the anatomy of the arteries that supply the heart The arteries divide at their furtherst reaches into smaller branches that join together at the edges of each arterial distribution.[7]

The coronary sinus is a large vein that drains into the right atrium, and receives most of the venous drainage of the heart. It receives blood from the great cardiac vein (receiving the left atrium and both ventricles), the posterior cardiac vein (draining the back of the left ventricle), the middle cardiac vein (draining the bottom of the left and right ventricles), and small cardiac veins. The anterior cardiac veins drain the front of the right ventricle and drain directly into the right atrium.[7]

Small lymphatic networks called plexuses exist beneath each of the three layers of the heart. These networks collect into a main left and a main right trunk, which travel up the groove between the ventricles that exists on the heart's surface, receiving smaller vessels as they travel up. These vessels then travel into the atrioventricular groove, and receive a third vessel which drains the section of the left ventricle sitting on the diaphragm. The left vessel joins with this third vessel, and travels along the pulmonary artery and left atrium, ending in the inferior tracheobronchial node. The right vessel travels along the right atrium and the part of the right ventricle sitting on the diaphragm. It usually then travels in front of the ascending aorta and then ends in a brachiocephalic node.

The heart is the first functional organ to develop and starts to beat and pump blood at about three weeks into embryogenesis. This early start is crucial for subsequent embryonic and prenatal development.

The heart derives from splanchnopleuric mesenchyme in the neural plate which forms the cardiogenic region. Two endocardial tubes form here that fuse to form a primitive heart tube known as the tubular heart.[28] Between the third and fourth week, the heart tube lengthens, and begins to fold to form an S-shape within the pericardium. This places the chambers and major vessels into the correct alignment for the developed heart. Further development will include the septa and valves formation and remodelling of the heart chambers. By the end of the fifth week the septa are complete and the heart valves are completed by the ninth week.[7]

Before the fifth week, there is an opening in the fetal heart known as the foramen ovale. The foramen ovale allowed blood in the fetal heart to pass directly from the right atrium to the left atrium, allowing some blood to bypass the lungs. Within seconds after birth, a flap of tissue known as the septum primum that previously acted as a valve closes the foramen ovale and establishes the typical cardiac circulation pattern. A depression in the surface of the right atrium remains where the foramen ovale once walls, called the fossa ovalis.[7]

The embryonic heart begins beating at around 22 days after conception (5 weeks after the last normal menstrual period, LMP). It starts to beat at a rate near to the mother's which is about 7580 beats per minute (bpm). The embryonic heart rate then accelerates and reaches a peak rate of 165185 bpm early in the early 7th week (early 9th week after the LMP).[29][30] After 9 weeks (start of the fetal stage) it starts to decelerate, slowing to around 145 (25) bpm at birth. There is no difference in female and male heart rates before birth.[31]

The heart functions as a pump in the circulatory system to provide a continuous flow of blood throughout the body. This circulation consists of the systemic circulation to and from the body and the pulmonary circulation to and from the lungs. Blood in the pulmonary circulation exchanges carbon dioxide for oxygen in the lungs through the process of respiration. The systemic circulation then transports oxygen to the body and returns carbon dioxide and relatively deoxygenated blood to the heart for transfer to the lungs.[7]

The right heart collects deoxygenated blood from two large veins, the superior and inferior venae cavae. Blood collects in the right and left atrium continuously.[7] The superior vena cava drains blood from above the diaphragm and empties into the upper back part of the right atrium. The inferior vena cava drains the blood from below the diaphragm and empties into the back part of the atrium below the opening for the superior vena cava. Immediately above and to the middle of the opening of the inferior vena cava is the opening of the thin-walled coronary sinus.[7] Additionally, the coronary sinus returns deoxygenated blood from the myocardium to the right atrium. The blood collects in the right atrium. When the right atrium contracts, the blood is pumped through the tricuspid valve into the right ventricle. As the right ventricle contracts, the tricuspid valve closes and the blood is pumped into the pulmonary trunk through the pulmonary valve. The pulmonary trunk divides into pulmonary arteries and progressively smaller arteries throughout the lungs, until it reaches capillaries. As these pass by alveoli carbon dioxide is exchanged for oxygen. This happens through the passive process of diffusion.

In the left heart, oxygenated blood is returned to the left atrium via the pulmonary veins. It is then pumped into the left ventricle through the mitral valve and into the aorta through the aortic valve for systemic circulation. The aorta is a large artery that branches into many smaller arteries, arterioles, and ultimately capillaries. In the capillaries, oxygen and nutrients from blood are supplied to body cells for metabolism, and exchanged for carbon dioxide and waste products.[7] Capillary blood, now deoxygenated, travels into venules and veins that ultimately collect in the superior and inferior vena cavae, and into the right heart.

The cardiac cycle refers to a complete heartbeat which includes systole and diastole and the intervening pause. The cycle begins with contraction of the atria and ends with relaxation of the ventricles. Systole refers to contraction of the atria or ventricles of the heart contract. Diastole is when the atria or ventricles relax and fill with blood. The atria and ventricles work in concert, so in systole when the ventricles are contracting, the atria are relaxed and collecting blood. When the ventricles are relaxed in diastole, the atria contract to pump blood to the ventricles. This coordination ensures blood is pumped efficiently to the body.[7]

At the beginning of the cardiac cycle, in early diastole, both the atria and ventricles are relaxed. Since blood moves from areas of high pressure to areas of low pressure, when the chambers are relaxed, blood will flow into the atria (through the coronary sinus and the pulmonary veins). As the atria begin to fill, the pressure will rise so that the blood will move from the atria into the ventricles. In late diastole the atria contract, pumping more blood into the ventricles. This causes a rise in pressure in the ventricles. As the ventricles reach systole, blood will be pumped into the pulmonary artery (right ventricle) or aorta (left ventricle).

When the atrioventricular valves (tricuspid and mitral) are open, during blood flow to the ventricles, the aortic and pulmonary valves are closed to prevent backflow into the ventricles. When the ventricular pressure is greater than the atrial pressure the tricuspid and mitral valves will shut. When the ventricles contract the pressure forces the aortic and pulmonary valves open. As the ventricles relax, the aortic and pulmonary valves will close in response to decreased pressure.

Cardiac output (CO) is a measurement of the amount of blood pumped by each ventricle (stroke volume) in one minute. This is calculated by multiplying the stroke volume (SV) by the beats per minute of the heart rate (HR). So that: CO = SV x HR.[7] The cardiac output is normalized to body size through body surface area and is called the cardiac index.

The average cardiac output, using an average stroke volume of about 70mL, is 5.25 L/min, with a normal range of 4.08.0 L/min.[7] The stroke volume is normally measured using an echocardiogram and can be influenced by the size of the heart, physical and mental condition of the individual, sex, contractility, duration of contraction, preload and afterload.[7]

Preload refers to the filling pressure of the atria at the end of diastole, when they are at their fullest. A main factor is how long it takes the ventricles to fillif the ventricles contract faster, then there is less time to fill and the preload will be less.[7] Preload can also be affected by a person's blood volume. The force of each contraction of the heart muscle is proportional to the preload, described as the Frank-Starling mechanism. This states that the force of contraction is directly proportional to the initial length of muscle fiber, meaning a ventricle will contract more forcefully, the more it is stretched.[7]

Afterload, or how much pressure the heart must generate to eject blood at systole, is influenced by vascular resistance. It can be influenced by narrowing of the heart valves (stenosis) or contraction or relaxation of the peripheral blood vessels.[7]

The strength of heart muscle contractions controls the stroke volume. This can be influenced positively or negatively by agents termed inotropes. These can be either conditions or drugs. Positive inotropes that cause stronger contractions include high blood calcium and drugs such as Digoxin, which will act to stimulate the sympathetic nerves in the fight-or-flight response. Negative inotropes causing weaker contractions include high blood potassium, hypoxia, acidosis, and drugs such as beta blockers and calcium channel blockers.

The normal rhythmical heart beat, called sinus rhythm, is established by the sinoatrial node, the heart's pacemaker. Here an electrical signal is created that travels through the heart, causing the heart muscle to contract.

The sinoatrial node is found in the upper part of the right atrium near to the junction with the superior vena cava.[33] The electrical signal generated by the sinoatrial node travels through the right atrium in a radial way that is not completely understood. It travels to the left atrium via Bachmann's bundle, such that both left and right atria contract together.[34][35][36] The signal then travels to the atrioventricular node. This is found at the bottom of the right atrium in the atrioventricular septumthe boundary between the right atrium and the left ventricle. The septum is part of the cardiac skeleton, tissue within the heart that the electrical signal cannot pass through, which forces the signal to pass through the atrioventricular node only.[7] The signal then travels along the bundle of His to left and right bundle branches through to the ventricles of the heart. In the ventricles the signal is carried by specialized tissue called the Purkinje fibers which then transmit the electric charge to the cardiac muscle.[37]

The normal resting heart rate is called the sinus rhythm, created and sustained by the sinoatrial node, a group of pacemaking cells found in the wall of the right atrium. Cells in the sinoatrial node do this by creating an action potential. The cardiac action potential is created by the movement of specific electrolytes into and out of the pacemaker cells. The action potential then spreads to nearby cells.

When the sinoatrial cells are resting, they have a negative charge on their membranes. However a rapid influx of sodium ions causes the membrane's charge to become positive. This is called depolarisation and occurs spontaneously.[7] Once the cell has a sufficiently high charge, the sodium channels close and calcium ions then begin to enter the cell, shortly after which potassium begins to leave it. All the ions travel through ion channels in the membrane of the sinoatrial cells. The potassium and calcium only start to move out of and into the cell once it has a sufficiently high charge, and so are called voltage-gated. Shortly after this, the calcium channels close and potassium channels open, allowing potassium to leave the cell. This causes the cell to have a negative resting charge and is called repolarization. When the membrane potential reaches approximately 60 mV, the potassium channels close and the process may begin again.[7]

The ions move from areas where they are concentrated to where they are not. For this reason sodium moves into the cell from outside, and potassium moves from within the cell to outside the cell. Calcium also plays a critical role. Their influx through slow channels means that the sinoatrial cells have a prolonged "plateau" phase when they have a positive charge. A part of this is called the absolute refractory period. Calcium ions also combine with the regulatory protein troponin C in the troponin complex to enable contraction of the cardiac muscle, and separate from the protein to allow relaxation.[39]

The normal sinus rhythm of the heart, giving the resting heart rate, is influenced by the autonomic nervous system through sympathetic and parasympathetic nerves.[40] These arise from two paired cardiovascular centres in the medulla oblongata.The vagus nerve of the parasympathetic nervous system acts to decrease the heart rate, and nerves from the sympathetic trunk act to increase the heart rate. These come together in the cardiac plexus near the base of the heart. Without parasympathetic input which normally predominates, the sinoatrial node would generate a heart rate of about 100 bpm.[7]

The nerves from the sympathetic trunk emerge through the T1-T4 thoracic ganglia and travel to both the sinoatrial and atrioventricular nodes, as well as to the atria and ventricles. The ventricles are more richly innervated by sympathetic fibers than parasympathetic fibers. Sympathetic stimulation causes the release of the neurotransmitter norepinephrine (also known as noradrenaline) at the neuromuscular junction of the cardiac nerves. This shortens the repolarization period, thus speeding the rate of depolarization and contraction, which results in an increased heart rate. It opens chemical or ligand-gated sodium and calcium ion channels, allowing an influx of positively charged ions.[7] Norepinephrine binds to the beta1 receptor. High blood pressure medications are used to block these receptors and so reduce the heart rate.[7]

The cardiovascular centres receive input from a series of receptors including proprioreceptors, baroreceptors, and chemoreceptors, plus stimuli from the limbic system. Through a series of reflexes these help regulate and sustain blood flow. For example, increased physical activity results in increased rates of firing by various proprioreceptors located in muscles, joint capsules, and tendons. With increased rates of firing, the parasympathetic stimulation may decrease or sympathetic stimulation may increase as needed in order to increase blood flow.[7]

Similarly, baroreceptors are stretch receptors located in the aortic sinus, carotid bodies, the venae cavae, and other locations, including pulmonary vessels and the right side of the heart itself. Rates of firing from the baroreceptors represent blood pressure, level of physical activity, and the relative distribution of blood. The cardiac centers monitor baroreceptor firing to maintain cardiac homeostasis, a mechanism called the baroreceptor reflex. With increased pressure and stretch, the rate of baroreceptor firing increases, and the cardiac centers decrease sympathetic stimulation and increase parasympathetic stimulation. As pressure and stretch decrease, the rate of baroreceptor firing decreases, and the cardiac centers increase sympathetic stimulation and decrease parasympathetic stimulation.[7]

There is a similar reflex, called the atrial reflex or Bainbridge reflex, associated with varying rates of blood flow to the atria. Increased venous return stretches the walls of the atria where specialized baroreceptors are located. However, as the atrial baroreceptors increase their rate of firing and as they stretch due to the increased blood pressure, the cardiac center responds by increasing sympathetic stimulation and inhibiting parasympathetic stimulation to increase heart rate. The opposite is also true.[7]

In addition to the autonomic nervous system, other factors can impact on this. These include epinephrine, norepinephrine, and thyroid hormones; levels of various ions including calcium, potassium, and sodium; body temperature; hypoxia; and pH balance. Factors that increase the heart rate can include release of norepinephrine, hypoxemia, low blood pressure and dehydration, a strong emotional response, a higher body temperature, and metabolic and hormonal factors such as a low potassium or sodium level or stimulus from thyroid hormones.[7] Decreased body temperature, relaxation, and metabolic factors can also contribute to a decrease in heart rate.[7]

The resting heart rate of a newborn can be 129 beats per minute (bpm) and this gradually decreases until maturity.[41] The adult resting heart rate ranges from 60 to 100 bpm. Exercise and fitness levels, age and basal metabolic rate can all affect the heart rate. An athlete's heart rate can be lower than 60 bpm. During exercise the rate can be 150 bpm with maximum rates reaching from 200 to 220 bpm.[7]

One of the simplest methods of assessing the heart's condition is to listen to it using a stethoscope.[7] Typically, healthy hearts have only two audible heart sounds, called S1 and S2. The first heart sound S1, is the sound created by the closing of the atrioventricular valves during ventricular contraction and is normally described as "lub". The second heart sound, S2, is the sound of the semilunar valves closing during ventricular diastole and is described as "dub".[7] Each sound consists of two components, reflecting the slight difference in time as the two valves close.[42] S2 may split into two distinct sounds, either as a result of inspiration or different valvular or cardiac problems.[42] Additional heart sounds may also be present and these give rise to gallop rhythms. A third heart sound, S3 usually indicates an increase in ventricular blood volume. A fourth heart sound S4 is referred to as an atrial gallop and is produced by the sound of blood being forced into a stiff ventricle. The combined presence of S3 and S4 give a quadruple gallop.[7]

Heart murmurs are abnormal heart sounds which can be either pathological or benign.[43] One example of a murmur is Still's murmur, which presents a musical sound in children, has no symptoms and disappears in adolescence.[44]

A different type of sound, a pericardial friction rub can be heard in cases of pericarditis where the inflamed membranes can rub together.[45]

Cardiovascular diseases, which include diseases of the heart, are the leading cause of death worldwide.[46] The majority of cardiovascular disease is noncommunicable and related to lifestyle and other factors, becoming more prevalent with ageing.[46] Heart disease is a major cause of death, accounting for an average of 30% of all deaths in 2008, globally.[11] This rate varies from a lower 28% to a high 40% in high-income countries.[12] Doctors that specialise in the heart are called cardiologists. Many other medical professionals are involved in treating diseases of the heart, including doctors such as general practitioners, cardiothoracic surgeons and intensivists, and allied health practitioners including physiotherapists and dieticians.[47]

Coronary artery disease is also known as ischemic heart disease, is caused by atherosclerosis a build-up of plaque along the inner walls of the arteries which narrows them, reducing the blood flow to the heart.[48] A stable plaque may cause chest pain (angina) or breathlessness during exercise or at rest, or no symptoms at all. A ruptured plaque can block a blood vessel and lead to ischaemia of the heart muscle, causing unstable angina or a heart attack. In the worst case this may cause cardiac arrest, a sudden and utter loss of output from the heart.Obesity, high blood pressure, uncontrolled diabetes, smoking and high cholesterol can all increase the risk of developing atherosclerosis and coronary artery disease.[46][48]

Heart failure is where the heart can't beat enough blood to meet the needs of the body.[48] It is generally a chronic condition, associated with age, that progresses gradually.Each side of the heart can fail independently of the other, resulting in heart failure of the right heart or the left heart. Left heart failure can also lead to right heart failure (cor pulmonale) by increasing strain on the right heart. If the heart is unable to pump sufficient blood, it may accumulate throughout the body, causing breathlessness in the lungs (pulmonary congestion; pulmonary edema), swelling (edema) of the feet or other gravity-dependent areas, decrease exercise tolerance, or cause other clinical signs such as an enlarged liver, cardiac murmurs, or a raised jugular venous pressure. Common causes of heart failure include coronary artery disease, valve disorders and diseases of cardiac muscle.

Cardiomyopathy is a noticeable deterioration of the heart muscle's ability to contract, which can lead to heart failure. The causes of many types of cardiomyopathy are poorly understood; some identified causes include alcohol, toxins, systemic disease such as sarcoidosis, and congenital conditions such as HOCM. The types of cardiomyopathy are described according to how they affect heart muscle. Cardiomyopathy can cause the heart to become enlarged (hypertrophic cardiomyopathy), constrict the outflow tracts of the heart (restrictive cardiomyopathy), or cause the heart to dilate and impact on the effiency of its beating (dilated cardiomyopathy). HOCM is often undiagnosed and can cause sudden death in young athletes.[7]

Heart murmurs are abnormal heart sounds which can be either related to disease or benign, and there are several kinds. There are normally two heart sounds, and abnormal heart sounds can either be extra sounds, or "murmurs" related to the flow of blood between the sounds. Murmurs are graded by volume, from 1) the quietest, to 6) the loudest, and evaluated by their relationship to the heart sounds, position in the cardiac cycle, and additional features such as their radiation to other sites, changes with a person's position, the frequency of the sound as determined by the side of the stethoscope by which they are heard, and site at which they are heard loudest.Phonocardiograms can record these sounds,[7] and echocardiograms are generally required for their diagnosis. Murmurs can result from valvular heart diseases due to narrowing (stenosis), or regurgitation of any of the main heart valves, such as aortic stenosis, mitral regurgitation or mitral valve prolapse. They can also result from a number of other disorders, including atrial and ventricular septal defects. Two common and infective causes of heart murmurs, are infective endocarditis and rheumatic fever, particularly in developing countries. Infective endocarditis involves colonisation of a heart valve, and rheumatic fever involves an initial bacterial infection by Group A streptococcus followed by a reaction against heart tissue that resembles the streptococcal antigen.

Abnormalities in the normal sinus rhythm of the heart can prevent the heart from effectively pumping blood, and are generally identified by ECG. These cardiac arrhythmias can cause an abnormal but regular heart rhythm, such as a rapid heart rate (tachycardia, classified as arising from above the ventricles or from the ventricles) or a slow heart rate (bradycardia); or may result in irregular rhythms. Tachycardia is generally defined as a heart rate faster than 100 beats per minute, and bradycardia as a heart rate slower than 60.Asystole is the cessation of heart rhythm. A random and varying rhythm is classified as atrial or ventricular fibrillation depending if the electrical activity originates in the atria or the ventricles. Abnormal conduction can cause a delay or unusual order of contraction of the heart muscle. This can be a result of a disease process, such as heart block, or congenital, such as Wolff-Parkinson-White syndrome.

Diseases may also affect the pericardium which surrounds the heart, which when inflammed is called pericarditis. This may result from infective causes (such as glandular fever, cytomegalovirus, coxsackievirus, tuberculosis or Q fever), systemic disorders such as amyloidosis or sarcoidosis, tumours, high uric acid levels, and other causes. This inflammation affects the ability of the heart to pump effectively. When fluid builds up in the pericardium this is called pericardial effusion, which when it causes acute heart failure is called cardiac tamponade. This may be blood from a traumatic injury or fluid from an effusion. This can compress the heart and adversely affect the function of the heart. The fluid can be removed from the pericardial sac using a syringe in a procedure called pericardiocentesis.

The heart can be affected by congenital diseases. These include failure of the developmental foramen ovale to close, present in up to 25% of people;[60]ventricular or atrial septal defects, congenital diseases of the heart valves (e.g. congenital aortic stenosis) or disease relating to blood vessels or blood flow from the heart (such as a patent ductus arteriosus or aortic coarctation).; Harrisons 14581465 These may cause symptoms at a variety of ages. If unoxygenated blood travels directly from the right to the left side of the heart, it may be noticed at birth, as it may cause a baby to become blue (cyanotic) such as Tetralogy of Fallot. A heart problem may impact a child's ability to grow. Some causes rectify with time and are regarded as benign. Other causes may be incidentally detected on a cardiac examination. These disorders are often diagnosed on an echocardiogram.

Heart disease is diagnosed by the taking of a medical history, a cardiac examination, and further investigations, including blood tests, echocardiograms, ECGs and imaging. Other invasive procedures such as cardiac catheterisation can also play a role.

The cardiac examination includes inspection, feeling the chest with the hands (palpation) and listening with a stethoscope (auscultation).[64] It involves assessment of signs that may be visible on a person's hands (such as splinter haemorrhages), joints and other areas. A person's pulse is taken, usually at the radial artery near the wrist, in order to assess for the rhythm and strength of the pulse. The blood pressure is taken, using either a manual or automatic sphygmomanometer or using a more invasive measurement from within the artery. Any elevation of the jugular venous pulse is noted. A person's chest is felt for any transmitted vibrations from the heart, and then listened to with a stethoscope. A normal heart has two hearts sounds - additional heart sounds or heart murmurs may also be able to be heard and may point to disease. Additional tests may be conducted to assess a person's heart murmurs if they are present, and peripheral signs of heart disease such as swollen feet or fluid in the lungs may be assessed.

Using surface electrodes on the body, it is possible to record the electrical activity of the heart. This tracing of the electrical signal is the electrocardiogram (ECG) or (EKG). An ECG is a bedside test and usually requires the placement of ten leads on the body. This produces a "12 lead" ECG (three extra leads are calculated mathematically, and one lead is a ground).

There are five prominent features on the ECG: the P wave (atrial depolarisation), the QRS complex (atrial repolarisation and ventricular depolarisation) and the T wave (ventricular repolarisation).[7] These reflect the summed action potential of the heart's muscle cells as they contract. A downward deflection on the ECG implies cells are becoming more negative in charge ("depolarising"), whereas an upward inflection implies cells are becoming more positive ("repolarising"). The ECG is a useful tool in detecting rhythm disturbances and in detecting insufficient blood supply to the heart.[64] Sometimes abnormalities are not immediately visible on the ECG. Testing when exercising can be used to provoke an abnormality, or an ECG can be worn for a longer period such as a 24-hour Holter monitor if a suspected rhythm abnormality is not present at the time of assessment.

Several imaging methods can be used to assess the anatomy and function of the heart, including ultrasound (echocardiography), angiography, CT scans, MRI and PET. An echocardiogram is an ultrasound of the heart used to measure the heart's function, assess for valve disease, and look for any abnormalities. Echocardiography can be conducted by a probe on the chest ("transthoracic") or by a probe in the esophagus ("transoesophageal"). A typical echocardiography report will include information about the width of the valves noting any stenosis, whether there is any backflow of blood (regurgitation) and information about the blood volumes at the end of systole and diastole, including an ejection fraction, which describes how much blood is ejected from the left and right ventricles after systole. Ejection fraction can then be obtained by dividing the volume ejected by the heart (stroke volume) by the volume of the filled heart (end-diastolic volume).[66] Echocardiograms can also be conducted under circumstances when the body is more stressed, in order to examine for signs of lack of blood supply. This cardiac stress test involves either direct exercise, or where this is not possible, injection of a drug such as dobutamine.

CT scans, chest X-rays and other forms of imaging can help evaluate the heart's size, evaluate for signs of pulmonary oedema, and indicate whether there is fluid around the heart. They are also useful for evaluating the aorta, the major blood vessel which leaves the heart.

A number of medications are used to treat diseases of the heart, or ameliorate symptoms.

For diseases of the heart rate or rhythm, a number of different antiarrhythmic agents are used. These may interfere with electrolyte channels and thus the cardiac action potential (such as calcium channel blockers, sodium channel blockers), interfere with stimulation of the heart by the sympathetic nervous system (beta blockers), or interfere with the movement of sodium and potassium across the cell membrane, such as digoxin.[67] Other examples include atropine for slow rhythms, and amiodarone for irregular rhythms. Such medications are not the only way of treating diseases of heart rate or rhythm. In the context of a new-onset irregular heart rhythm (atrial fibrillation), immediate electrical cardioversion may be attempted. For a slow heartbeat or heart block, a pacemaker or defibrillator may be inserted. The acuity of onset often affects how a rhythm disturbance is managed, as does whether a rhythm causes hemodynamic instability, such as low blood pressure or symptoms. An instigating cause is investigated for, such as a heart attack, medication, or metabolic problem.

For ischaemic heart disease, treatment also includes amelioration of symptoms. This includes GTN, beta blockers and, in the context of an acute event, stronger pain relief such as morphine and other opiates. Many of these drugs have additional protective benefits, by decreasing the sympathetic tone on the heart that occurs with the pain, or by dilating blood vessels (GTN).

Treatment of heart disease includes primary and secondary prevention to prevent the occurrence or worsening of symptoms and atherosclerosis. This includes recommendations to cease smoking, decrease alcohol consumption, increase exercise, and make modifications to their diet to decrease the consumption of fats and sugars. Medications may also be given to help better control concurrent diabetes. Statins or other drugs such as fibrates may also be given to decrease a person's cholesterol levels. Blood pressure medication may also be commenced or modified.

For many diseases of the heart, including atrial fibrillation and valvular disease, and after a heart operation, anticoagulation in the form of aspirin, warfarin, clopidogrel or novel oral anticoagulants is often given simultaneously, because of an increased risk of stroke or, in the context of a clotted heart vessel, rethrombosis.

Surgery, when considered necessary for diseases of the heart, can take place via an open operation or via small guidewires inserted via peripheral arteries ("percutaneous coronary intervention"). Percutaneous coronary intervention is usually used in the context of an acute coronary syndrome, and may be used to insert a stent.

Coronary artery bypass surgery is one such operation. In this operation, one or more arteries surrounding the heart that have become narrowed are bypassed. This is done by taking blood vessels harvested from another part of the body. Commonly harvested veins include the saphenous veins or the internal mammary artery. Because this operation involves the heart tissue, a machine is used so that blood can bypass the heart during the operation.

Heart valve repair or valve replacement are options for diseases of the heart valves.

Humans have known about the heart since ancient times, although its precise function and anatomy were not clearly understood.[71] From the primarily religious views of earlier societies towards the heart, ancient Greeks are considered to have been the primary seat of scientific understanding of the heart in the ancient world. [72][73][74]Aristotle considered the heart to be organ responsible for creating blood; Plato considered the heart as the source of circulating blood and Hippocrates noted blood circulating cyclically from the body through the heart to the lungs.[72][74]Erasistratos (304-250 BC) noted the heart as a pump, causing dilation of blood vessels, and noted that arteries and veins both radiate from the heart, becoming progressively smaller with distance, although he believed they were filled with air and not blood. He also discovered the heart valves.[72]

The Greek physician Galen (2nd century AD) knew blood vessels carried blood and identified venous (dark red) and arterial (brighter and thinner) blood, each with distinct and separate functions.[72] Galen, noting the heart as the hottest organ in the body, concluded that it provided heat to the body.[74] The heart did not pump blood around, the heart's motion sucked blood in during diastole and the blood moved by the pulsation of the arteries themselves. [74] Galen believed the arterial blood was created by venous blood passing from the left ventricle to the right through 'pores' between the ventricles.[71] Air from the lungs passed from the lungs via the pulmonary artery to the left side of the heart and created arterial blood. [74]

These ideas went unchallenged for almost a thousand years.[71][74]

The earliest descriptions of the coronary and pulmonary circulation systems can be found in the Commentary on Anatomy in Avicenna's Canon, published in 1242 by Ibn al-Nafis.[75] In his manuscript, al-Nafis wrote that blood passes through the pulmonary circulation instead of moving from the right to the left ventricle as previously believed by Galen.[76] His work was later translated into Latin by Andrea Alpago.[77]

In Europe, the teachings of Galen continued to dominate the academic community and his doctrines were adopted as the official canon of the Church. Andreas Vesalius questioned some of Galen's beliefs of the heart in De humani corporis fabrica (1543), but his magnum opus was interpreted as a challenge to the authorities and he was subjected to a number of attacks.[78]Michael Servetus wrote in Christianismi Restitutio (1553) that blood flows from one side of the heart to the other via the lungs.[78]

The breakthrough came with the publication of De Motu Cordis (1628) by the English physician William Harvey. Harvey's book completely describes the systemic circulation and the mechanical force of the heart, leading to an overhaul of the Galenic doctrines.[79]Otto Frank (18651944) was a German physiologist; among his many published works are detailed studies of this important heart relationship. Ernest Starling (18661927) was an important English physiologist who also studied the heart. Although they worked largely independently, their combined efforts and similar conclusions have been recognized in the name "FrankStarling mechanism".[7]

Although Purkinje fibers and the bundle of His were discovered as early as the 19th century, their specific role in the electrical conduction system of the heart remained unknown until Sunao Tawara published his monograph, titled Das Reizleitungssystem des Sugetierherzens, in 1906. Tawara's discovery of the atrioventricular node prompted Arthur Keith and Martin Flack to look for similar structures in the heart, leading to their discovery of the sinoatrial node several months later. These structures form the anatomical basis of the electrocardiogram, whose inventor, Willem Einthoven, was awarded the Nobel Prize in Medicine or Physiology in 1924.[80]

The first successful heart transplantation was performed in 1967 by the South African surgeon Christiaan Barnard at Groote Schuur Hospital in Cape Town. This marked an important milestone in cardiac surgery, capturing the attention of both the medical profession and the world at large. However, long-term survival rates of patients were initially very low. Louis Washkansky, the first recipient of a donated heart, died 18 days after the operation while other patients did not survive for more than a few weeks.[81] The American surgeon Norman Shumway has been credited for his efforts to improve transplantation techniques, along with pioneers Richard Lower, Vladimir Demikhov and Adrian Kantrowitz. As of March 2000, more than 55,000 heart transplantations have been performed worldwide.[82]

By the middle of the 20th century, heart disease had surpassed infectious disease as the leading cause of death in the United States, and it is currently the leading cause of deaths worldwide. Since 1948, the ongoing Framingham Heart Study has shed light on the effects of various influences on the heart, including diet, exercise, and common medications such as aspirin. Although the introduction of ACE inhibitors and beta blockers has improved the management of chronic heart failure, the disease continues to be an enormous medical and societal burden, with 30 to 40% of patients dying within a year of receiving the diagnosis.[83]

As one of the vital organs, the heart was long identified as the center of the entire body, the seat of life, or emotion, or reason, will, intellect, purpose or the mind.[84] The heart is an emblematic symbol in many religions, signifying "truth, consience or moral courage in many religions - the temple or throne of God in Islamic and Judeo-Christian thought; the divine centre, or atman, and the third eye of transcendent wisdom in Hinduism; the diamond of purity and essence of the Buddha; the Taoist centre of understanding."[84]

In the Hebrew Bible, the word for heart, lev, is used in these meanings, as the seat of emotion, the mind, and referring to the anatomical organ. It is also connected in function and symbolism to the stomach.[85]

An important part of the concept of the soul in Ancient Egyptian religion was thought to be the heart, or ib. The ib or metaphysical heart was believed to be formed from one drop of blood from the child's mother's heart, taken at conception.[86] To ancient Egyptians, the heart was the seat of emotion, thought, will, and intention. This is evidenced by Egyptian expressions which incorporate the word ib, such as Awi-ib for "happy" (literally, "long of heart"), Xak-ib for "estranged" (literally, "truncated of heart").[87] In Egyptian religion, the heart was the key to the afterlife. It was conceived as surviving death in the nether world, where it gave evidence for, or against, its possessor. It was thought that the heart was examined by Anubis and a variety of deities during the Weighing of the Heart ceremony. If the heart weighed more than the feather of Maat, which symbolized the ideal standard of behavior. If the scales balanced, it meant the heart's possessor had lived a just life and could enter the afterlife; if the heart was heavier, it would be devoured by the monster Ammit.[88]

The Chinese character for "heart", , derives from a comparatively realistic depiction of a heart (indicating the heart chambers) in seal script.[89] The Chinese word xn also takes the metaphorical meanings of "mind", "intention", or "core".[90]In Chinese medicine, the heart is seen as the center of shn "spirit, consciousness".[91] The heart is associated with the small intestine, tongue, governs the six organs and five viscera, and belongs to fire in the five elements.[92]

The Sanskrit word for heart is hd or hdaya, found in the oldest surviving Sanskrit text, the Rigveda. In Sanskrit, it may mean both the anatomical object and "mind" or "soul", representing the seat of emotion. Hrd may be a cognate of the word for heart in Greek, Latin, and English.[93][94]

Many classical philosophers and scientists, including Aristotle, considered the heart the seat of thought, reason, or emotion, often disregarding the brain as contributing to those functions.[95] The identification of the heart as the seat of emotions in particular is due to the Roman physician Galen, who also located the seat of the passions in the liver, and the seat of reason in the brain.[96]

The heart also played a role in the Aztec system of belief. The most common form of human sacrifice practiced by the Aztecs was heart-extraction. The Aztec believed that the heart (tona) was both the seat of the individual and a fragment of the Sun's heat (istli). To this day, the Nahua consider the Sun to be a heart-soul (tona-tiuh): "round, hot, pulsating".[97]

In Catholicism, there has been a long tradition of worship of the heart, stemming from worship of the wounds of Jesus Christ which gained prominence from the mid sixteenth century.[98] This tradition influenced the development of the medieval Christian devotion to the Sacred Heart of Jesus and the parallel worship of Immaculate Heart of Mary, made popular by John Eudes.[99]

The expression of a broken heart is a cross-cultural reference to grief for a lost one or to unfulfilled romantic love.

The notion of "Cupid's arrows" is ancient, due to Ovid, but while Ovid describes Cupid as wounding his victims with his arrows, it is not made explicit that it is the heart that is wounded. The familiar iconography of Cupid shooting little heart symbols is a Renaissance theme that became tied to Valentine's day.[84]

Animal hearts are widely consumed as food. As they are almost entirely muscle, they are high in protein. They are often included in dishes with other offal, for example in the pan-Ottoman kokoretsi.

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Unlike cell lines, primary cells are non-transformed, non-immortalized cells that are isolated directly from tissue. Closely mimicking a living model and yielding more biologically and physiologically relevant results, human primary cells have become an essential tool in the development of therapeutic treatments. Choose from an extensive range of fresh and cryopreserved peripheral blood products, as well as cryopreserved cord blood products, to incorporate into your research workflow.

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Human peripheral blood cells are isolated from adult whole blood or from a leukapheresis preparation produced using state-of-the-art apheresis systems. These apheresis collections, known as "Leuko Paks", contain very high concentrations of mononuclear cells and are available in the following Pak sizes: full, half and quarter Pak. Specific cell subsets are purified using STEMCELL's cell isolation products. Fresh whole blood products are collected directly into blood bags using acid-citrate-dextrose solution A (ACDA) or citrate-phosphate-dextrose (CPD) as the anticoagulant.

Human cord blood is collected using citrate-phosphate-dextrose (CPD) as the anticoagulant. Mononuclear cells are obtained by density gradient centrifugation. Specific cell subsets are obtained using STEMCELLs cell isolation products.

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Donor Screening: Donors are screened for HIV (1 & 2), Hepatitis B, and Hepatitis C. If the donor was screened within 90 days of donation the product will be shipped with negative test results from donor screening. If the donor was not screened within 90 days of collection, a test sample will be taken at the time of donation and the product will be shipped before the screening results are available. In the unlikely event that a test result is positive, the customer will be contacted as soon as possible (usually within 24-72 hours from the time of shipment).

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Donor Screening: Cord blood is only collected from mothers that have tested negative for HIV (1 & 2) and Hepatitis B during their pregnancy. Hepatitis C is tested for at the time of collection. Fresh cord blood products are shipped with negative test results for HIV (1 & 2) and Hepatitis B donor screening. Hepatitis C test results are not available at the time of shipment. In the unlikely event that the Hepatitis C test result is positive, the customer will be contacted as soon as possible (usually within 24-72 hours from the time of shipment).

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Primary Cells Overview - stemcell.com

Recommendation and review posted by simmons

See comment in PubMed Commons below N Engl J Med. 2012 Oct 18;367(16):1487-96. doi: 10.1056/NEJMoa1203517. Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL; Blood and Marrow Transplant Clinical Trials Network. Collaborators (182)

Horowitz MM, Carter SL, Confer DL, DiFronzo N, Wagner E, Merritt W, Wu R, Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Couban S, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Carter SL, Karanes C, Horowitz MM, Confer DL, Allen C, Colby C, Gurgol C, Knust K, Foley A, King R, Mitchell P, Couban S, Pulsipher MA, Ehninger G, Johnston L, Khan SP, Maziarz RT, McCarty JM, Mineishi S, Porter DL, Bredeson C, Anasetti C, Lee S, Waller EK, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Logan BR, Carter SL, Lee SJ, Waller EK, Anasetti C, Logan BR, Lee SJ, Stadtmauer E, Wingard J, Vose J, Lazarus H, Cowan M, Wingard J, Westervelt P, Litzow M, Wu R, Geller N, Carter S, Confer D, Horowitz M, Poland N, Krance R, Carrum G, Agura E, Nademanee A, Sahdev I, Cutler C, Horwitz ME, Kurtzberg J, Waller EK, Woolfrey A, Rowley S, Brochstein J, Leber B, Wasi P, Roy J, Jansen J, Stiff PJ, Khan S, Devine S, Maziarz R, Nemecek E, Huebsch L, Couban S, McCarthy P, Johnston L, Shaughnessy P, Savoie L, Ball E, Vaughan W, Cowan M, Horn B, Wingard J, Silverman M, Abhyankar S, McGuirk J, Yanovich S, Ferrara J, Weisdorf D, Faber E Jr, Selby G, Rooms LM, Porter D, Agha M, Anderlini P, Lipton J, Pulsipher MA, Pulsipher MA, Shepherd J, Toze C, Kassim A, Frangoul H, McCarty J, Hurd D, DiPersio J, Westervelt P, Shenoy S, Agura E, Culler E, Axelrod F, Chambers L, Senaldi E, Nguyen KA, Engelman E, Hartzman R, Sutor L, Dickson L, Nademanee A, Khalife G, Lenes BA, Eames G, Sibley D, Gale P, Antin J, Ehninger G, Newberg NR, Gammon R, Montgomery M, Mair B, Rossmann S, Wada R, Waxman D, Ranlett R, Silverman M, Herzig G, Fried M, Atkinson E, Weitekamp L, Bigelow C, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Miller JP, Price T, Young C, Hilbert R, Oh D, Cable C, Smith JW, Kalmin ND, Schultheiss K, Beck T, Lankiewicz MW, Sharp D.

Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia.

We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37).

The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse.

We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).

Survival after Randomization in the Intention-to-Treat Analysis

The P value is from a stratified binomial comparison at the 2-year point. The P value from a stratified log-rank test was also not significant. A total of 75 patients in each group were still alive at 36 months.

N Engl J Med. ;367(16):10.1056/NEJMoa1203517.

Outcomes after Transplantation, According to Study Group

Panel A shows the rate of overall survival, and Panel B the rate of disease-free survival. Panel C shows the incidence of death unrelated to relapse. Panel D shows the incidence of relapse. Panel E shows the incidence of neutrophil engraftment (>500 neutrophils per cubic millimeter), and Panel F the incidence of platelet engraftment (>20,000 platelets per cubic millimeter, without platelet transfusion during the prior 7 days). Panel G shows the incidence of acute graft-versus-host disease (GVHD) of grades II to IV, and Panel H the incidence of chronic GVHD. P values for the between-group differences in overall survival (Panel A) and disease-free survival (Panel B) are from a stratified binomial comparison at the 2-year point; P values from stratified log-rank tests for survival and disease-free survival were also not significant. All other P values shown are from stratified log-rank tests.

N Engl J Med. ;367(16):10.1056/NEJMoa1203517.

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Peripheral-blood stem cells versus bone marrow from ...

Recommendation and review posted by simmons

Abstract

Mesenchymal stem cells (MSCs) represent a promising tool for new clinical concepts in supporting cellular therapy. Bone marrow (BM) was the first source reported to contain MSCs. However, for clinical use, BM may be detrimental due to the highly invasive donation procedure and the decline in MSC number and differentiation potential with increasing age. More recently, umbilical cord blood (UCB), attainable by a less invasive method, was introduced as an alternative source for MSCs. Another promising source is adipose tissue (AT). We compared MSCs derived from these sources regarding morphology, the success rate of isolating MSCs, colony frequency, expansion potential, multiple differentiation capacity, and immune phenotype. No significant differences concerning the morphology and immune phenotype of the MSCs derived from these sources were obvious. Differences could be observed concerning the success rate of isolating MSCs, which was 100% for BM and AT, but only 63% for UCB. The colony frequency was lowest in UCB, whereas it was highest in AT. However, UCB-MSCs could be cultured longest and showed the highest proliferation capacity, whereas BM-MSCs possessed the shortest culture period and the lowest proliferation capacity. Most strikingly, UCB-MSCs showed no adipogenic differentiation capacity, in contrast to BM- and AT-MSCs. Both UCB and AT are attractive alternatives to BM in isolating MSC: AT as it contains MSCs at the highest frequency and UCB as it seems to be expandable to higher numbers.

Mesenchymal stem cells (MSCs) found in many adult tissues are an attractive stem cell source for the regeneration of damaged tissues in clinical applications because they are characterized as undifferentiated cells, able to self-renew with a high proliferative capacity, and possess a mesodermal differentiation potential [1].

Although bone marrow (BM) has been the main source for the isolation of multipotent MSCs, the harvest of BM is a highly invasive procedure and the number, differentiation potential, and maximal life span of MSCs from BM decline with increasing age [24]. Therefore, alternative sources from which to isolate MSCs are subject to intensive investigation.

One alternative source is umbilical cord blood (UCB), which can be obtained by a less invasive method, without harm for the mother or the infant [5]. However, controversy still exists whether full-term UCB can serve as a source for isolating multipotent MSCs: although some groups did not succeed in isolating MSCs [6, 7], we and other groups succeeded in isolating MSCs from full-term UCB [812].

Adipose tissue (AT) is another alternative source that can be obtained by a less invasive method and in larger quantities than BM. It has been demonstrated that AT contains stem cells similar to BM-MSCs, which are termed processed lipoaspirate (PLA) cells [13]. These cells can be isolated from cosmetic liposuctions in large numbers and grown easily under standard tissue culture conditions [13]. The multilineage differentiation capacity of PLA cells has been confirmed [13].

As BM-MSCs are best characterized, we asked whether MSCs derived from other sources share the characteristics of BM-MSCs. The aim of our study was to compare MSCs isolated from the three sources under identical in vitro conditions with respect to their morphology, frequency of colonies, expansion characteristics, multilineage differentiation capacity, immunophenotype, and success rate of isolating the cells.

We compared MSCs from BM and two alternative sources, namely UCB and AT, concerning basic MSC characteristics. All cells isolated from these three sources exhibited typical MSC characteristics: a fibroblastoid morphology, the formation of CFU-F, a multipotential differentiation capability, and the expression of a typical set of surface proteins. Whereas MSCs derived from the three sources expressed classic MSC marker proteins, but lacked hematopoietic and endothelial markers, we observed significant differences concerning the expression of CD90, CD105, and CD106. These molecules are described to be associated with hematopoiesis and cell migration [18 20]. It needs to be further investigated whether these molecules are functionally important for stroma and homing capacities. In a first approach, we created a comprehensive protein expression profile of undifferentiated UCB-MSCs, which will be extended to BM- and AT-MSCs and then correlated to functional properties [21].

Since the relevance of the observed differences of marker expression has not been properly investigated yet, differences concerning differentiation capacity seem to be more relevant for MSC quality at present. We demonstrated a multilineage differentiation capacity for BM- and AT-MSCs. Interestingly, UCB-MSCs could not be differentiated toward the adipogenic lineage, which was not related to the CFU-F origin. Actually, there are conflicting data concerning the adipogenic differentiation capacity of UCB-MSCs [9 12, 22, 23]. Nevertheless, we assume that UCB-MSCs are less sensitive toward the adipogenic differentiation (supported by results of Chang et al. [22]) which might be related to the ontogenetic age of these cells. This is further supported by the fact that adipocytes reside in adult human BM and AT but are absent in fetal BM and by the observation of an increased adipogenesis correlated with age [24]. Further comparative genomic or proteomic approaches are needed to assess the susceptibility toward adipogenesis of MSCs.

None of our UCB-MSCs showed adipogenic differentiation capacity, but all differentiated into both the chondro- and osteogenic lineages. In contrast, a tripotential differentiation capacity was observed for most AT samples but only for a few BM samples. One sample each of BM and AT was observed to undergo only the chondrogenic pathway. In accordance with this, a hierarchical or even restricted differentiation potential of MSCs has been reported [1, 13, 25].

In our study, investigations were limited to the mesodermal differentiation capacity. Based on recent reports, however, the spectrum of differentiation of MSCs does not seem to be restricted to this lineage. MSCs derived from all three tissues have been shown to differentiate into further mesodermal lineages and into endo- and ectodermal lineages as well [10 13, 26 33]. Comparative experiments need to be performed to assess responsiveness toward cardiomyogenic, endothelial, hepatic, neuronal, and pancreatic differentiation.

A high impact on clinical exploitation might be related to the abundance and expansion capacity of MSCs. Based on our results, both BM and AT are reliable sources for isolating and expanding MSCs in autologous settings since all preparations gave rise to MSCs. UCB, in contrast, had an isolation efficacy of a maximum of 63% [8]. We attribute these differences to the fact that MSCs are circulating in the prenatal organism and are residing in tissues of the adult [9]. Despite the low frequency of UCB-MSCs, the expansion potential was highest compared with other cell sources. Considering clinical applications, the resulting cell numbers may be similar to both BM and AT, which can be obtained at higher frequencies. One argument against AT might be the limited availability in some patients. However, we believe that due to the high frequency of AT-MSCs, also small fat reservoirs might be sufficient for MSC isolation. BM has been the main source for clinical application of MSCs, such as the treatment of osteogenesis imperfecta, graft versus host disease, and acute myocardial infarction [3436]. As the number, frequency, and differentiation capacity of BM-MSCs correlate negatively with age, they could be clinically inefficient when derived from elderly patients. In that case, an allogeneic approach would be required. In case a matching donor is required, BM or AT from HLA identical siblings, haplo-identical relatives, or HLA-screened donors might be best choice. Speculating on a off-the-shelf product requiring mass production, AT might be a solid starting basis due to the abundance, relatively easy harvest, and high MSCs frequency.

Transplantation of MSCs is currently a highly experimental procedure, resembling the early beginnings of hematopoietic stem cell transplantation. In the latter, BM has been replaced gradually by peripheral blood progenitor cells and umbilical cord blood. Also, in the field of MSCs, alternative sources are intensely investigated, and one day these new sources may replace BM. Taking into account all the advantages and disadvantages of the three sources discussed above, depending on the therapeutic indication, the clinical applications may be based on differentiation capacity, but more likely on the abundance, frequency, and expansion potential of the cells.

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Comparative Analysis of Mesenchymal Stem Cells from Bone ...

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Embryonic stem cells seen through a microscope. The study saw a 40% reduction in the size of scarred tissue on the patients hearts. Photograph: Mauricio Lima/AFP/Getty Images

People suffering from heart disease have been offered hope by a new study that suggests damaged tissue could be regenerated through a stem cell treatment injected into the heart during surgery.

The small-scale study, published in the Journal of Cardiovascular Translational Research, followed 11 patients who during bypass surgery had stem cells injected into their hearts near the site of tissue scars caused by heart attacks.

One of the trials most dramatic results was a 40% reduction in the size of scarred tissue. Such scarring occurs during a cardiac event such as a heart attack, and can increase the chances of further heart failure. The scarring was previously thought to be permanent and irreversible.

At the time of treatment, the patients were suffering heart failure and had a very high (70%) annual mortality rate. But 36 months after receiving the stem cell treatment all are still alive, and none have suffered a further cardiac event such as a heart attack or stroke, or had any readmissions for cardiac-related reasons.

According to the British Heart Foundation, while there are several treatments to help people with heart failure, there is no known cure, and in some cases a heart transplant may be the only option.

Twenty-four months after participants were injected with the stem cell treatment there was a 30% improvement in heart function, 40% reduction in scar size, and 70% improvement in quality of life, as judged by the Minnesota living with heart failure (MLHF) score.

Related: Brain damage could be repaired by creating new nerve cells

Quite frankly it was a big surprise to find the area of scar in the damaged heart got smaller, said Prof Stephen Westaby from John Radcliffe hospital in Oxford, who undertook the research at AHEPA university hospital in Thessaloniki, Greece, with Kryiakos Anastasiadis and Polychronis Antonitsis.

Westaby began theorising about the impact of stem cells on regenerating heart tissue and reducing scarring after observing how scar tissue on the hearts of babies who have had heart attacks and undergone heart failure disappeared by the time they reached adolescence, suggesting that residual stem cells might be able to repair the damaged tissue.

Its an early study and its difficult to make large-scale predictions based on small studies, said Ajan Reginald, the founder of Celixir, the company that produces the treatment. But even in a small study you dont expect to see results this dramatic.

These are 11 patients who were in advanced heart failure, they had had a heart attack in the past, multiple heart attacks in many cases. The life expectancy for these patients is less than two years, were excited and honoured that these patients are still alive.

Related: Nearly 2m people may have undiagnosed killer disease

Jeremy Pearson, the associate medical director at the British Heart Foundation (BHF), said: This very small study suggests that targeted injection into the heart of carefully prepared cells from a healthy donor during bypass surgery, is safe. It is difficult to be sure that the cells had a beneficial effect because all patients were undergoing bypass surgery at the same time, which would usually improve heart function.

A controlled trial with substantially more patients is needed to determine whether injection of these types of cells proves any more effective than previous attempts to improve heart function in this way, which have so far largely failed.

Westaby conceded that the improvement in patients health was partly due to the heart bypass surgery those in the study were undergoing, and said the next study would include a control group who undergo bypass but do not receive stem cell treatment, to measure exactly what impact the treatment has.

These patients came out of heart failure partly due to the bypass grafts of course, but we think it was partly due to the fact that they had a smaller area of scar [as a result of the stem cell treatment]. Certainly this finding of scar being reduced is quite fascinating, he said.

Westaby will commence a large-scale controlled study later this year at the Royal Brompton hospital in London, and Celixir hopes to make the Heartcel treatment available to patients in 2018 or 2019.

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Stem cell trial suggests damaged heart tissue could be ...

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Multipotent Cell-Secreted Extracellular Matrix Supports Cartilage Formation Histogen to present at International Cartilage Repair Society 2015

CHICAGO, May 8, 2015 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, will present new research on its human extracellular matrix (hECM) material in the promotion of cartilage regeneration during the International Cartilage Repair Society (ICRS) 2015 Meeting, taking place May 8-11, 2015 in Chicago, IL. The orthobiologic applications of all of Histogen's products are being developed by its worldwide joint venture, PUR Biologics LLC.

Histogen has previously shown that hypoxia-induced multipotent cells produce soluble and insoluble materials that contain components associated with stem cell niches in the body and with scarless healing. These proteins include a variety of laminins, osteonectin, decorin, hyaluronic acid, collagen type IV, SPARC, CXCL12, NID1, NID2, NOTCH2, tenascin, thrombospondin, fibronectin, versican, and fibrillin-2. In vitro studies further demonstrated that the CCM and ECM promote the adhesion, proliferation and migration of bone marrow-derived human mesenchymal stem cells (MSCs).

In this latest research, in vivo studies with the hECM were undertaken to determine their potential as orthobiologics. Rabbit studies demonstrated the potential of the hECM to promote regeneration and repair of full-thickness articular cartilage defects. Eight weeks following hECM treatment of femoral osteochondral defects, mature bone and hyaline cartilage formation was seen, exemplified by the presence of a tide mark and integration into the adjacent cartilage. This work is currently being repeated in a goat cartilage defect model, with similar results to date.

"The efficacy we have seen with the multipotent cell-secreted ECM in bone and cartilage regeneration is unprecedented," said Ryan Fernan, CEO of PUR Biologics. "The preclinical work overwhelmingly supports use of the material as an orthobiologic to reduce inflammation and promote cartilage regeneration in the articulating joint and intervertebral spinal disc. We look forward to entering human trials for these indications, as well as to continuing our research on utilizing the product for soft tissue repair in a variety of sports injuries."

Histogen's cell conditioned media (CCM) and hECM were also evaluated in an ex vivo rabbit intervertebral spinal disc model to study the effects of these materials in an environment where an extensive inflammatory response was induced by thrombin injection. Compared to untreated controls, both the CCM and ECM treatment significantly down regulated the expression of the inflammatory cytokine genes IL-1, IL-6, TNF-alpha, as well as the genes encoding the extracellular matrix degrading enzymes MMP3, and ADAMTS4, while upregulating aggrecan expression in the annulus fibrosus and nucleus pulposus tissue.

Dr. Gail Naughton, CEO of Histogen, will present "Human Cell Conditioned Media and Extracellular Matrix Reduce Inflammation and Support Hyaline Cartilage Formation" at the ICRS 2015 meeting in Chicago on May 9, 2015. Following the event, the presentation will be available upon request.

About PUR Biologics PUR Biologics is dedicated to providing regenerative biologic solutions to address musculoskeletal surgical needs, including spine, dental, ligament and medical device coating applications. In addition to distribution of approved allograft and biologic products, PUR is focused on development of next-generation orthopedic products based upon human protein and growth factor materials for bone and tissue regeneration. For more information visit http://www.purbiologics.com.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

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Novel Immunomodulatory Treatment Induces Apoptosis in Melanoma Histogen to present data at 2015 Society of Investigative Dermatology Annual Meeting

ATLANTA, May 6, 2015 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, will present new research on its 105F immunomodulatory treatment candidate for melanoma during the 2015 Society of Investigative Dermatology (SID) Annual Meeting, taking place May 6-9, 2015 in Atlanta, GA.

Histogen has previously shown that hypoxia-induced multipotent cells produce a soluble material with anti-oncologic properties, with potential benefit in the treatment of a wide range of cancers. Studies to characterize the active components of the material have identified a low molecular weight fraction (105F) which directly induces apoptosis, or controlled cell death, in 21 human cancer cell lines. In its latest research, Histogen sought to further examine the mechanism of action of 105F in melanoma through in vitro and in vivo studies.

After treatment with 105F, melanoma cells were shown to release Interleukin 6 (IL-6) and TNF a, pro-inflammatory cytokines acting as signals to the immune system. This induction of an immune "flare" in combination with tumor cell apoptosis could be critically important in recruiting immune cells to the tumor for cytotoxic attack.

"We were excited to see the dual activity of 105F, both directly inducing cancer cell death and activating an anti-tumorigenic immune response to reduce metastatic disease," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen. "These results represent a potential treatment for melanoma and other solid tumors that works through multiple channels to eliminate cancer cells, but is not toxic to the body's healthy cells."

An in vivo model of lung metastasis in C57Bl/6 mice further showed the efficacy of 105F in the treatment of melanoma. Daily intravenous injections of 105F over 14 days resulted in a significant (p=0.0049) reduction in lesions and marked immune cell infiltration as compared to controls.

Dr. Naughton will present "105F is a novel immunoadaptive treatment candidate for melanoma that induces apoptosis and the secretion of pro-inflammatory IL-6" at the 2015 SID Annual Meeting in Atlanta beginning May 6, 2015. Following the event, the presentation will be available upon request.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

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Histogen's Composition for Oncology Treatments Receives US Patent

SAN DIEGO, October 8, 2014 - Histogen Oncology, a company developing innovative cancer therapies based on Histogen's regenerative medicine technology, today announced that the United States Patent & Trademark Office has issued patent 12/363,479 entitled "Extracellular matrix compositions for the treatment of cancer" to Histogen.

The patent, which is the fifth U.S. patent issued to Histogen, covers the soluble and insoluble compositions of proteins and cofactors that are secreted by multipotent stem cells through Histogen's technology process for use in the treatment of cancer. The patent claims support of the use of the compositions alone or as a delivery system for traditional chemotherapeutic agents.

Through the recent formation and funding of the Histogen Oncology joint venture, research and development of the unique, naturally secreted compositions is progressing toward a Phase I clinical trial for end stage pancreatic cancer.

"We are pleased about the timely issuance of our U.S. patent for the treatment of cancer," said Dr. Gail K. Naughton, Histogen CEO and Chairman of the Board. "Our collaborations with top institutions continue to produce mounting evidence supporting the unique mechanism of action of our secreted material in preventing metastasis and reducing tumor load while having no toxic affect on normal cells."

Histogen's composition has shown effectiveness in inhibiting over 21 human cancer cell lines both in vitro as well as in animal models. The mechanism of action of the secreted material is through the induction of apoptosis (controlled cell death) primarily in malignant cells, so there is little to no toxicity to normal cells. Histogen Oncology is studying the efficacy of a small molecular weight fraction of the cell secreted composition as a stand alone treatment as well as in combination therapy to evaluate whether effectiveness can be demonstrated with less toxic drug doses.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen Oncology Created to Develop Novel Biologic Cancer Treatments Histogen, Inc. and Wylde, LLC Form Joint Venture

SAN DIEGO, July 8, 2014 - Histogen Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, has partnered with Southern California medical device group Wylde, LLC to create Histogen Oncology. This joint venture will focus on the development of unique cell-derived materials for cancer applications.

Under this joint venture, Histogen Oncology has acquired exclusive rights to Histogen's human multipotent cell conditioned media (CCM) and extracellular matrix (ECM) materials, as well as their derivatives, for oncology applications throughout North America. Histogen Oncology's initial clinical focus is pancreatic cancer, a highly treatment-resistant cancer in which a sub-fraction of the CCM has shown substantial preclinical promise.

"We have been very impressed with the results of Histogen's preliminary oncology work, not only because of the significant survival benefit but also because it is a naturally-derived material that is showing no toxicity," said Christopher Wiggins of Wylde, LLC. "There are so many patients out there who are not candidates for existing therapies due to the toxic nature of available drugs. This is particularly true in pancreatic cancer, where 80% of people diagnosed already have stage four disease."

In post-resection nude mouse models, intravenous treatment with the CCM sub-fraction resulted in prolonged survival by more than three fold in a majority of treated animals. In non-resection models, more than 50% of treated mice lived twice as long as the control. These results point to a potentially significant outcome for pancreatic cancer patients, and Histogen Oncology intends to progress the material toward a Phase I clinical trial for no-option pancreatic cancer patients in the coming 18 months.

Research on the mechanism responsible for cancer cell inhibition by the CCM shows the upregulation of Caspase 9 and cleaved Caspase 3, which causes cancer cells to enter apoptosis, or programmed cell death.

"The activity of the CCM sub-fraction is unique in a number of ways. Whereas most cancer therapies target rapidly dividing cells but not cancer stem cells, the inhibitory effect of this material is seen in malignant cells and circulating tumor cells as well," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen, Inc. "In addition, the activity is selective for malignant cells, supporting the proliferation of human dermal fibroblasts, embryonic stem cells and mesenchymal stem cells, while inhibiting tumor growth."

Histogen Oncology will be supported by Histogen's research group and funded by Wylde, LLC., made up of experts from the surgery and medical device industries. The creation of this joint venture allows for dedicated development of the CCM sub-fraction as a cancer treatment, as Histogen continues to allocate resources to the Company's revenue-generating aesthetic and promising therapeutic programs.

"We are extremely excited to fuel and push the next stage of development for this innovative and potentially life-saving therapy," said Wiggins. "The next generation of cancer treatment will have cell-signaling at its core, be beneficial in combination with existing therapies as well as stand alone, and provide an option to patients who currently have none. We believe Histogen's material has all of those characteristics and more."

About Histogen Aesthetics Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen Aesthetics Acquires CellCeuticals Biomedical Skin Treatments

SAN DIEGO, March 10, 2014 - Histogen Aesthetics, a subsidiary of regenerative medicine company Histogen, Inc. focused on skin care and cosmeceuticals, announced today that the Company has acquired the CellCeuticals Biomedical Skin Treatments line of skincare products.

Histogen Aesthetics will continue sales of the eleven existing CellCeuticals Biomedical Skin Treatments skincare products, while bringing new innovation to the line through the addition of a unique regenerative medicine technology, working to improve skin aging at a cellular level.

"We have long admired the science, clinical data and elegant formulas behind the CellCeuticals line, and see it as an ideal fit for our recently revitalized aesthetics subsidiary," said Dr. Gail K. Naughton, CEO and Chairman of Histogen, Inc. "We are very excited to begin infusing unique cell-signaling factors into the CellCeuticals regimen, to truly transform skin one cell at a time."

Dr. Naughton has spent more than 30 years in tissue engineering and regenerative medicine, and holds over 100 patents in the field. She founded Histogen in 2007, focused on developing therapies that work to stimulate the stem cells in the body to regenerate tissues and organs. Through this work, she has also seen how different compositions of human proteins can have cosmetic benefits, particularly in anti-aging and rejuvenation.

"I am pleased that the CellCeuticals Biomedical Skin Treatments will evolve, and see Histogen Aesthetics as an excellent home for this innovative product line," said Paul Scott Premo, co-founder of CellCeuticals Skin Care, Inc. "I believe the addition of this regenerative medicine technology will be the opportunity to introduce a new generation of products that are the vanguard of regenerative skin care."

The CellCeuticals system is made up of eleven distinctive products including the Extremely Gentle Skin Cleanser, CellGenesis Regenerative Skin Treatment, and PhotoDefense Color Radiance SPF55+ with proprietary and patented PhotoPlex technology. The line is currently available at retailers including QVC.com, Dermstore.com, and Nordstrom.com, as well as http://www.cellceuticalskincare.com.

About Histogen Aesthetics Histogen Aesthetics LLC, formed in 2008 as a subsidiary of Histogen, Inc., focuses on the development of innovative skin care products utilizing regenerative medicine technology. Histogen Aesthetics' technology is based on the expertise of founder Dr. Gail K. Naughton, in which fibroblasts are grown under unique conditions, producing a complex of naturally-secreted proteins and synergistic bio-products known to stimulate skin cells to regenerate and rejuvenate tissues. In 2014, Histogen Aesthetics acquired CellCeuticals Biomedical Skin Treatments, a line of scientifically-proven products that reactivate cells to help aging skin perform and look healthier and younger. For more information, visit http://www.cellceuticalskincare.com.

About Suneva Medical, Inc. Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process is also being researched for oncology applications, and in orthopedics through joint venture PUR Biologics, LLC. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen and Suneva Medical Expand License for Cell Conditioned Media-based Aesthetic Products Internationally

SAN DIEGO, CA, January 14, 2014 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, today announced that they have entered into an international license agreement with Suneva Medical, Inc. for physician-dispensed aesthetic products containing Histogen's proprietary multipotent cell conditioned media (CCM).

This agreement is an amendment to the existing license between Histogen and Suneva Medical, through which Suneva has exclusively licensed the Regenica skincare line within the United States since February 2012. Under the terms of the international agreement, Suneva Medical is now the exclusive licensee for the distribution of Regenica through the physician-dispensed channel in Europe, most of Asia, South America, Canada, Australia, and the Middle East.

"Not only has Suneva had sales success, but they have generated enthusiasm around the Regenica product line and our technology here in the US," said Gail K. Naughton, Ph.D., CEO and Chairman of the Board of Histogen. "We are excited about expanding our skincare partnership internationally, and look forward to an exciting year for Regenica."

Regenica contains Histogen's proprietary Multipotent Cell Conditioned Media, made up of soluble cell-signaing proteins and growth factors which support the body's epidermal stem cells and renew skin throughout life. Through Histogen's technology process, which mimics the embryonic environment including conditions of low oxygen and suspension, cells are triggered to become multipotent, and naturally produce these proteins associated with skin renewal and scarless healing.

"We believe that Regenica truly is the next generation in growth factor technology, and we are extremely pleased that the products will now have a presence around the world," said Nicholas L. Teti, Jr., Chairman and Chief Executive Officer of Suneva Medical. "Our relationship with Histogen in the US physician market has been a valuable asset to Suneva, and has laid the groundwork for international success."

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

About Suneva Medical, Inc. Suneva Medical, Inc. is a privately-held aesthetics company focused on developing, manufacturing and commercializing novel, differentiated products for the general dermatology and aesthetic markets. The company currently markets Artefill in the US, Korea, Singapore and Vietnam; Refissa and Regenica Skincare in the U.S.; and Bellafill in Canada. For more information, visit http://www.sunevamedical.com.

Regenica is a trademark of Suneva Medical, Inc. The Multipotent Cell Conditioned Media Complex is covered by U.S. patents #8,257,947 and #8,524,494.

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Multipotent Stem Cell Proteins Support Soft Tissue Regeneration Histogen to present data at TERMIS AM Annual Conference in Atlanta

ATLANTA, November 13, 2013 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, announced that Dr. Michael Zimber will give a podium presentation entitled "Human Multipotent Stem Cell Proteins Support Soft Tissue Regeneration" today at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) Americas Annual Meeting in Atlanta, GA.

Through its proprietary technology process that simulates the conditions of the embryonic environment, Histogen has developed a human extracellular matrix (hECM) material composed of stem cell-associated proteins including SPARC, decorin, collagens I,III,IV, V, fibronectin, fibrillin, laminins, and hyaluronic acid. The hECM's distinctive composition of growth factors and other proteins are known to stimulate stem cells in the body, regenerate tissues, and promote scarless healing.

Histogen sought to examine whether the hECM may promote scarless healing in full thickness wounds, similar to that seen in fetal healing, using a variety of forms of the material, including hollow spheres to maximize void fill volume. In preclinical studies, all hECM-treated wounds healed rapidly with minimum contractions, and the hECM microspheres had a statistically significant improvement in healing as compared to the controls (p<0.05) and produced a 25% thicker dermis. In addition, hECM applied topically after microneedling resulted in up to a 3X dermal thickening.

"We are very pleased that our propriety materials produced by hypoxia-induced human multipotent stem cells have shown significant healing results in both soft and hard tissues," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen. "These results open new therapeutic markets, show tremendous potential for our material in cutaneous wound care and orthopedics, as well as support the expansion of our aesthetic pipeline to include soft tissue fillers."

In addition to "Human Multipotent Stem Cell Proteins Support Soft Tissue Regeneration", Dr. Zimber will also be presenting "Human Multipotent Stem Cell Proteins Support Osteogenesis In Vitro" during the TERMIS AM Annual Meeting taking place November 10-13, 2013 in Atlanta. Following the event, these presentations will be available upon request.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Multipotent Stem Cell Proteins Support Rejuvenation while Inhibiting Skin Cancer Histogen to present data at TERMIS AP Annual Conference in Shanghai

San Diego, October 24, 2013 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, announced that the Company's Chairman and CEO, Dr. Gail Naughton, will present today at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) Asia Pacific Annual Meeting in Shanghai, China.

Through its proprietary technology process that simulates the conditions of the embryonic environment, Histogen is uniquely able to trigger the de-differentiation of skin cells into multipotent stem cells without genetic manipulation. The cells express key stem cell markers including Oct4, Sox2 and Nanog, and secrete a distinctive composition of growth factors and other proteins known to stimulate stem cells in the body, regenerate tissues, and promote scarless healing.

It is the soluble and insoluble compositions of multipotent proteins and growth factors resulting from this process that have been shown to both promote skin regeneration and induce controlled cell death in multiple skin cancers.

"The anti-aging and rejuvenation benefits of human multipotent stem cell proteins have been shown in several clinical studies, and have resulted in the material's use as a thriving next-generation ingredient for skin care," said Dr. Naughton. "In parallel, we have also been studying the anti-cancer activity of these proteins, and have shown that, just as in the embryonic environment, they support normal tissue growth while resulting in the controlled death of cancer cells".

In vitro studies performed with Histogen's material have shown reduction in Squamous Cell Carcinoma (SCC), Basal Cell Carcinoma, and Melanoma cell number through the mechanism of apoptosis, or controlled cell death, induced by the upregulation of Caspase in these cancer cells. In one in vivo model, melanoma load was reduced by up to 80% versus the control (p<0.05) by the addition of the insoluble multipotent stem cell proteins, and a dose response curve was seen. Similar inhibition was seen with SCC. In subcutaneous mouse experiments, tumor growth was inhibited by 70-90%.

"Human Multipotent Stem Cell Proteins Stimulate Skin Regeneration While Inducing Skin Cancer Cell Apotosis" will be presented by Dr. Naughton during the TERMIS AP Annual Meeting taking place October 23-26, 2013 in Shanghai. Further information and data on the ability of multipotent stem cell proteins to induce apoptosis in skin cancers can be found in the publication Journal of Cancer Therapy at file.scirp.org/Html/1-8901700_33923.htm.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Histogen to present at 2013 STEM CELL MEETING ON THE MESA

San Diego, October 11, 2013 - Histogen, Inc., a regenerative medicine company developing therapies for conditions including hair loss and cancer, announced today that Histogen CEO Gail K. Naughton, Ph.D. will give a company presentation at the 3rd Annual Regen Med Partnering Forum, part of the Stem Cell Meeting on the Mesa to be held October 14-16 in La Jolla, CA.

Histogen's solutions are based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. The technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of proteins that have been shown to support stem cell growth and differentiation.

"It is an exciting time for Histogen, as we continue to move the technology forward with expanded partnerships in skincare, compelling clinical data in both male and female hair loss, and early but exciting results in orthopedics," said Dr. Naughton. "We look forward to sharing our story during the Stem Cell Meeting on the Mesa, and to progressing our products even further through growing relationships with industry leaders and through our potential merger with Stratus Media to form publicly-traded Restorgenex."

Organized by the Alliance for Regenerative Medicine (ARM), the California Institute for Regenerative Medicine (CIRM) and the Sanford Consortium for Regenerative Medicine, the 2013 Stem Cell Meeting on the Mesa is a three-day conference aimed at bringing together senior members of the regenerative medicine industry with the scientific research community to advance stem cell science into cures. The Regen Med Partnering Forum, held October 14 &15 at the Estancia La Jolla Hotel, is the only partnering meeting organized specifically for the regenerative medicine and advanced therapies industry.

The following are specific details regarding Histogen's presentation at the conference:

Event: Regen Med Partnering Forum - 2013 Stem Cell Meeting on the Mesa Date: October 14, 2013 Time: 3:15pm Location: Estancia La Jolla Hotel & Spa, 9700 North Torrey Pines Road, La Jolla

A live video webcast of all company presentations will be available at: stemcellmeetingonthemesa.com/webcast and will also be published on ARM's website shortly after the event. Histogen will also make a copy of Dr. Naughton's presentation available at http://www.histogen.com.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Stratus Media Group and Histogen Execute Letter of Intent for Biotechnology Merger

LOS ANGELES, October 07, 2013 - Stratus Media Group, Inc. (OTCQB:SMDI) announced today that it was planning to expand its entrance into the biotechnology industry with the execution of a letter of intent between the Company and Histogen, Inc., a regenerative medicine company developing innovative therapies for conditions including hair loss and cancer.

The non-binding letter of intent outlines the primary terms of a merger of San Diego-based Histogen into Stratus, to be renamed Restorgenex Corporation. The letter of intent has been approved by the board of directors of both companies, and the parties are engaged in completing a formal merger agreement.

Histogen's solutions are based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. The technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of proteins that have been shown to support stem cell growth and differentiation. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products.

"Histogen's technology platform opens a spectrum of potential product opportunities in both aesthetics and therapeutics, an ideal fit with our vision for Restorgenex," said Sol J. Barer, Ph.D., who will assume the position of Chairman of the Board of Restorgenex effective November 1, 2013. "The expertise of the Histogen team in developing regenerative products from concept to market, along with the success Histogen has already found in skincare partnering, will add significant value to our Company."

Following successful completion of this proposed merger, the company's goal is to build Restorgenex into a world-class cosmeceutical and pharmaceutical company in the large and expanding fields of dermatology and hair restoration. The parties intend to move toward a formal merger agreement in which Histogen would become a wholly-owned subsidiary, Histogen founder Gail K. Naughton, Ph.D. would assume the position of Chief Executive Officer of Restorgenex, and the corporate headquarters of Restorgenex would be located in San Diego. The merger will require, among other things, the satisfaction of customary closing conditions including the approval of Histogen's shareholders.

"I am very excited about the potential of a merger between Histogen and Restorgenex, and look forward to moving into the next stage," said Dr. Naughton. "It is an honor to be working with biotechnology visionaries Dr. Sol Barer and Isaac Blech, and to have them recognize the promise of Histogen's products is a true testament to the unique and exciting nature of our technology."

Dr. Naughton has spent more than 25 years extensively researching the tissue engineering process, holds more than 95 U.S. and foreign patents, and has been honored for her pioneering work in the field by prestigious organizations including receiving the Intellectual Property Owners Association Inventor of the Year Award.

Prior to founding Histogen in 2007, Dr. Naughton oversaw the design and development of the world's first up-scaled manufacturing facility for tissue engineered products, was pivotal in raising over $350M from the public market and corporate partnerships, and brought four human cell-based products from concept through FDA approval and market launch as President of Advanced Tissue Sciences.

"I believe the potential acquisition of Histogen, and the expertise and vision Dr. Naughton will bring as Chief Executive Officer will be a tremendous asset in ushering the Company into the biotechnology industry," said Jerold Rubinstein, current Chairman and Chief Executive Officer of Stratus.

http://www.histogen.com http://www.stratusmediagroup.com

Forward-Looking Statements Statements in this press release relating to plans, strategies, projections of results, and other statements that are not descriptions of historical facts may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and the Securities Acts of 1933 and 1934. Forward-looking information is inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors. Although the company's management believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee future results, performance or achievements. The company has no obligation to update these forward-looking statements.

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Recommendation and review posted by sam

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Recommendation and review posted by simmons

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Recommendation and review posted by Bethany Smith

When it comes to health, hormones and gut bacteria have a much bigger effect than many people realize. In fact, these two factors can destroy health even if everything else (diet, supplements, etc.) is optimized.

Conversely, regulatinghormones and fixing gut bacteria can do a lot to boost health, even if not all the other factors are optimal. In fact, there are even studies about using certain hormone reactions to heal brain trauma.

If you doubt the very real power of hormones to affect everything from mood, to weight, to bowel health, ask the nearest pregnant woman if shes noticed any difference in these areas since becoming pregnant. Or ask the nearest 13 year old girl carefully

What factor contributes to weight gain during pregnancy? Hormone balance.

What causes weight fluctuations, bloating and other health symptoms throughout the course of a month? Hormones.

What causes men to naturally put on muscle more easily or lose weight more quickly? Hormones.

What is a huge contributing factor of growth in children? Hormones.

What controls ovulation, reproduction, pregnancy, etc? Hormones.

Yes, when it comes to losing weight or improving health, what do we focus on? Calories or micronutrients or diets. Those with symptoms likefatigue, skin issues, weight gain, weight around the middle, trouble sleeping, always sleeping, PMS, endometriosis, infertility, PCOS or other issues may find that addressing hormones is vital for recovery.

Hormones are your bodys chemical messengers. They travel in your bloodstream to tissues and organs. They work slowly, over time, and affect many different processes, including metabolism, sexual function, reproduction, mood and much more.

Endocrine glands, which are special groups of cells, make hormones. The major endocrine glands are the pituitary, pineal, thymus, thyroid, adrenal glands and pancreas. In addition, men produce hormones in their testes and women produce them in their ovaries. (source)

Hormones are produced in a complex process, but depend on beneficialfats and cholesterol, so lack of these important dietary factors can cause hormone problems simply because the body doesnt have the building blocks to make them. Toxins containing chemicals that mimic these building blocks or that mimic the hormones themselves are also problematic because the body can attempt to create hormones using the wrong building blocks. Mutant estrogen anyone?

Ive heard so many cases lately of people who have improved diet, started exercising, etc. but are still not losing weight or improving their health markers. After talking to many of these people, it seems that the factor they all have in common is an underlying problem with hormone balance.

Ive written about Leptin and thyroid hormones before, and these are just a small piece in the complicated hormone system in the body. In a given day or month, a womans body will have fluctuations in hormones like estrogen, progesterone, cortisol, lutenizing hormone, prolactin, oxytocin, leptin, ghrelin, thyroid hormones, melatonin, serotonin and others.

The endocrine system is a complex system that we will probably never completely understand, but there are some basic things you can do to boost your bodys ability to create and balance hormones:

Ivetalked about this before, but the body is simply not meant to consume the man-made fats found in vegetable oils. The fat content of the human body is largely saturated fat, with only about 3% of thebodys fat coming from other types.

The 3% of the body made up of polyunsaturated fats contains both Omega-3 fats and Omega-6 fats in about a 50:50 balance. This ratio is extremely important for health, and it is often ignored. Seed based vegetable oils (like canola oil, soybean oil, etc.) are very high in Omega-6 fats and low in Omega-3 fats. Since the 1950s, these seed based oils have replaced many sources of saturated fats and Omega-3s in the diet. This is one of the reasons that most people are not getting enough vital Omega-3 fatty acids from their diet.

Not only are we consuming way too many omega-6 fatty acids from polyunsaturated vegetable oils, but we are not consuming enough beneficial Omega-3s and saturated fats. These types of fats are vital for proper cell function and especially for hormone function, as these are literally the building blocks for hormone production. When we dont give the body adequate amounts of these fats, it must use what is available, relying on lower quality polyunsaturated fats.

The trouble is that polyunsaturated fats are less stable and oxidize easily in the body, which can lead to inflammation and mutations within the body. Emerging evidence suggests that that this inflammation can occur in arterial cells (potentially increasing the chance of clogged arteries), skin cells (leading to skin mutations) and reproductive cells (which may be connected to PCOS and other hormone problems).

Other types of fats, especially saturated fats, are vital for hormone health and balance as the body uses fats as building blocks for hormones. As this article explains:

When these important saturated fatty acids are not readily available, certain growth factors in the cells and organs will not be properly aligned. This is because the various receptors, such as G-protein receptors, need to be coupled with lipids in order to provide localization of function.

The messages that are sent from the outside of the cell to the inner part of the cell control many functions including those activated by, for example, adrenaline in the primitive mammalian fight/flight reactions. When the adrenal gland produces adrenaline and the adrenaline (beta-adrenergic) receptor communicates with the G-protein and its signal cascade, the parts of the body are alerted to the need for action; the heart beats faster, the blood flow to the gut decreases while the blood flow to the muscles increases and the production of glucose is stimulated.

The G-proteins come in different forms; the alpha subunit is covalently linked to myristic acid and the function of this subunit is important for turning on and off the binding to an enzyme called adenylate cyclase and thus the amplification of important hormone signals.

When researchers looked at the fatty acid composition of the phospholipids in the T-cells (white blood cells), from both young and old donors, they found that a loss of saturated fatty acids in the lymphocytes was responsible for age-related declines in white blood cell function. They found that they could correct cellular deficiencies in palmitic acid and myristic acid by adding these saturated fatty acids.

For this reason,Coconut Oilis amazing for hormone health. It provides the necessary building blocks for hormone production, can assist weight loss, reduce inflammation, and even has antimicrobial and antibacterial properties.My favorite way to consume it is toblend into coffeeor tea.This is the highest quality one Ive found. Other quality sources of fats include avocados, animal fats, olive oil, grass fed meats, pastured eggs, and raw dairy (for those who tolerate it). Quality seafood is also very important, as it is natures best source of naturally occurring Omega-3s.

Bottom line: Dont eat fats like vegetable oil, peanut oil, canola oil, soybean oil, margarine, shortening, or other chemically altered fats. Choose fats like coconut oil, real butter, olive oil (dont heat it!) and animal fats (tallow, lard) from healthy sources instead and eat lots of high Omega-3 fish.

I love coffee a lot, but the truth is that too much caffeine can wreakhavocon the endocrine system, especially if there are other hormone stressors involved, like pregnancy, presence of toxins, beneficial fat imbalance or stress.

Cut down the coffee if you can, or replace with beneficial herbal teas (here are my ten favorite DIY recipes). If you cant or wont cut the coffee, use it as a way to sneak in your beneficial fats by adding 1 tablespoon coconut oil to each cup and blending in the blender to emulsify. It is like a latte but with healthy fats! Here is the recipe I use and the only way I drink coffee.

Harmful chemicalsfound in pesticides, plastics, household cleaners, and even mattresses can contain hormone disrupting chemicals that mimic hormones in the body and keep the body from producing real hormones. Things likehormonal birth control can (obviously) do the same thing.

For those with a hormone imbalance or who are struggling to get pregnant, avoiding these unnecessary chemicalsis very important! Cook in glass or non-coated metal pans (no non-stick or teflon) and avoid heating or storing foods in plastic. Find organic produce and meat whenever possible and dont use chemical pesticides or cleaners. Hereis arecipe for a natural cleaner.

Here are some additional tips for avoiding indoor toxins:

Beauty products are another source of chemical exposure for many people. There are tens of thousands of chemicals in the personal care products we encounter daily, and most of these chemicals have not been tested for long-term safety. Avoiding these products can make a tremendous difference in achieving hormone balance. Start by making simple switches like homemade deodorant, and homemade lotion and even DIY makeup if youre feeling adventurous. Check out my full index of natural beauty recipes here.

I cant emphasize this one enough!Without adequatesleep, hormones will not be in balance. Period. (This is the one I struggle with the most!)

While youre sleeping, your body is extremely active removing toxins, recharging the mind, and creating hormones. Skimping on sleep, even for one night, can have a tremendous impact on hormones and even one night of missed or shortened sleep can create the hormone levels of a pre-diabetic (source).

Try some of these tips to help improve sleep::

Unfortunately, we live in a world where the food supply is often depleted of nutrients due to over-farming, the water is often contaminated with chemicals, and even the air can contain compounds that cause havoc in the body.

Ideally, we could get all of our nutrients from food, properly hydrate from water, and get enough Vitamin D from the sun on a daily basis. Wed get magnesium from the ocean and not get deficient in the first place since wed be consuming adequate minerals from eating fresh seafood. Since this is rarely the case, supplements can sometimes be needed! Ive sharedthe basic supplements that I take before, butcertain supplements are especially helpful for hormone balance.

NOTE: Make sure to check with your doctor or health care professional before taking any new supplements, especially if you are on medications or contraceptives.

Maca A hormone boosting tuber in the radish family with a long history of use in Peru. Women who use this often see improvements in fertility, reduction in PMS and better skin/hair. It can help men with sperm production, testosterone levels and muscle composition.Maca is a good source ofminerals and essential fatty acids, which is one of the ways it supports hormone balance. It is available inpowder form(least expensive option) or incapsules. Maca should be discontinued during pregnancy.

Magnesium Magnesium is vital for hundreds of functions within the human body and many of us are deficient in this master mineral (heres how to tell if you are). There are several different ways to getMagnesium:Inpowder form with a product like Natural Calmso that you can vary your dose and work up slowly,ionic liquid formcan be added to food and drinks and dose can be worked up slowly,ortransdermal form by using Magnesium oilapplied to the skin (this is my favorite method). Topical applicationis often the most effective option for those with a damaged digestive tract or severe deficiency.

Vitamin D & Omega-3s A pre-hormone is supportive of hormone function. Bestobtained from the sunif possible, or from aD3 supplementorCod Liver Oil(a good source of Omega-3 and Vitamin D and what I do in the winter). Make sure not to get too much, and optimally, get Serum Vitamin D levels checked to monitor levels.

Gelatin or Collagen-a great source of minerals and necessary amino acids. Gelatin and collagen powderssupport hormone production and digestive healthin various ways. Gelatin powder can actually gel and is useful in recipes like homemade jello and probiotic marshmallows, while collagen protein does not gel but is easily added to soups, smoothies, coffee, tea or any other food. (I get both gelatin powder and collagen peptides from here)

Natural Progesterone Cream PMS and menstrual troubles are often linked to specific hormone imbalances. Especially for those with short cycles or short second phase of their cycle (ovulation through start of menses), progesterone can be the issue. Ive seen people add only natural progesterone cream and see symptoms greatly reduce. If you do use progesterone cream, do you own research, make sure you have a goodbrand that is soy-freeand only use for the second half of your cycle (ovulation through menses). Check with a doctor or professional before using any hormone supplement.

For those withhormone imbalance, intense extended exercise can actually make the problem worse in the short term. Sleep is muchmore important, at least during the balancing phase, so focusing on relaxing exercises like walking or swimming and avoiding the extended running, cardio, and exercise videos, can help the body in the short term.

I personally likeRebounding, which is great gentle exercise and has additional health benefits.

While extended cardio can be bad, short bursts of heavy lifting (kettlebells, deadlifts, squats, lunges) can be beneficial since they trigger a cascade of beneficial hormone reactions. Aim for a few sets (5-7) at a weight that really challenges you, but make sure to get help with form and training if you havent done these before as bad form can be harmful.

Certain herbs and plants can also help the body bring hormones into balance. Of course, it is important to talk to a doctor before taking these, especially if a person is on hormonal contraceptives or other medications. Some herbs that Ive personally used are:

Vitex/Chaste Tree Berry Nourishes the pituitary gland and helps lengthen the luteal phase. It lowers prolactin and raises progesterone. For some women, this alone will improve symptoms.

Red Raspberry LeafA well know fertility herb that is also helpful in reducing PMS and cramping. It has a high nutrient profile and is especially high in calcium and is a uterine tonic. It is available incapsuleform, but makes an excellent hot or cold tea.

Adaptogens- Herbs that help the body handle stress and support the adrenals. They are a great and natural way to work toward hormone balance for many people. This is a good primer on understanding adaptogens.

The digestive system has much more of an impact on hormones than many of us realize. Not only is the digestive tract the source of many vital neurotransmitters in the body, butan imbalance in the gut can translate to an imbalance in neurotransmitter and hormones. Serotonin, a necessary neurotransmitter for sleep/stress balance is more concentrated in the gut than even in the brain! 70% of the immune system is found in the gut and it is quite literally the motherboard of many functions in the body. Even thyroid health has been linked to gut health.

What Hippocrates knew thousands of years ago seems just as true today that all disease beginsin the gut. Those who struggle with gut problems may have trouble ever achieving hormone balance without first addressing gut health. (This is the most comprehensive program Ive ever seen for addressing gut healthissues.)

Leptin is a master hormone, and if it is out of balance or if you are resistant to it, no other hormones will balance well. Fixing leptin will also help boost fertility, make weight loss easier, improve sleep, and lower inflammation. Dr. Jack Kruse, a neurosurgeon, has a whole system for getting leptin into balance.

The infographic below is a quick overview of steps to balance your hormones. Pin it or share it to save for later!

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Source: Wellness Mama

Have you struggled with hormone problems? What helped you? Share below!

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How to Balance Hormones Naturally | Wellness Mama

Recommendation and review posted by sam

Lime, bearing the scientific name Citrus Aurantifolia, has been used for ages in the treatment of various ailments.The first fruit that comes to mind in terms of medicinal uses is the reliable lime. This sour citrus fruit can do what many advanced medicines cannot. Lime is consumed throughout the world in the form of sorbet, beverages, refreshing cocktails, pickles, jams, jellies, snacks, candies, sugar boiled confections and in cooking. The oil extracted from its peel or skin is extensively used in soft drink concentrates, body oils, cosmetic products, hair oils, toothpastes, toilet and beauty soaps, disinfectants, mouth washes, deodorants and innumerable other products. There are many varieties of lime found all over the world, particularly in the tropical and the Mediterranean climates. Lets take a look at the benefits and medicinal uses of lime,am sure you would be amazed. Scurvy: Lime is very well-known as a cure for scurvy, the disease which is caused from a deficiency of vitamin-C. It is characterized by frequent infections that show as normal cold symptoms, cracked lips and lip corners, ulcers on the tongue and in the mouth. You can also spot scurvy from spongy, swollen and bleeding gums. Since its cause is a deficiency of vitamin-C, its remedy is none other than vitamin-C, and lime is full of this this essential vitamin. In the past, soldiers and sailors were given lime to keep them safe from scurvy, which was a horrible and potentially fatal disease back then. Even now, it is distributed among the workers working in polluted environments like furnaces, painting shops, heat treatments, cement factories, mines, and other dangerous work environments to protect them from scurvy. Skin Care: Lime juice and its natural oils are very beneficial for skin when consumed orally or applied externally. It rejuvenates the skin, keeps it shining, protects it from infections and reduces body odor due to the presence of a large amount of vitamin-C and Flavonoids. Those are both class-1 anti oxidants, and have antibiotic and disinfectant properties. When applied externally on skin, its acids scrub out the dead cells, cures dandruff, rashes, and bruises. It can also be used to create a refreshing bathing experience if its juice or oil is mixed into your bathing water.

Digestion: Lime has an irresistible scent which causes your mouth to water and this actually aids primary digestion (the digestive saliva floods your mouth even before you taste it). The natural acidity in lime does the rest. While they break down of the macro molecules of the food, the Flavonoids, the compounds found in the fragrant oils extracted from lime, stimulate the digestive system and increase secretion of digestive juices, bile and acids. This flood of flavonoids also stimulate the peristaltic motion. This is the reason behind lemon pickle with lunch and dinner being a traditional practice in India and various neighboring countries in that region.

Constipation: Primarily, the ample amount of acids present in lime helps clear the excretory system by washing and cleaning off the tracts, just as some acids are used to clean floors and toilets. The roughage in lime is also helpful in easing constipation, but the most beneficial element is the high acidity. An overdose of lime juice with salt also acts as an excellent purgative without any side effects, thereby providing relief from constipation.

Diabetes: According to the American Diabetes Association, limes and other citrus fruits are considered a diabetes super food for a number of reasons. Mainly, the high levels of soluble fiber found in limes make it an ideal dietary aid to help regulate the bodys absorption of sugar into the bloodstream, reducing the occurrence of blood sugar spikes that are a serious risk to to diabetic patients. Also, limes and other citrus fruits have a low glycemic index, which means that they will not cause unexpected spikes in glucose levels, in addition to the benefits of soluble fibers effect.

Heart Disease: That same soluble fiber which can help diabetics maintain their blood sugar levels can also lower blood pressure and eliminate the presence of LDL cholesterol (bad cholesterol). Furthermore, soluble fiber can cut down on inflammation of the blood vessels, which is a known preventative measure against heart disease, heart attacks, and strokes.

Peptic Ulcer:In addition to vitamin-C, lime contains special compounds called Flavonoids (Limonoids such as Limonin Glucoside) which have antioxidant, anti-carcinogenic, antibiotic and detoxifying properties that stimulate the healing process of peptic and oral ulcers.

Respiratory Disorders: The flavonoid-rich oil that is extracted from limes is extensively used in anti-congestive medicines such as balms, vaporizers, and inhalers due to the presence of Kaempferol. Just scratching the peel of a lime and inhaling it gives immediate relief for congestion and nausea.

Arthritis: One of the many causes of arthritis is an excess of uric acid that builds up in the body. Uric acid is one of the waste products that normal urination will clear out of the body, but unfortunately, when too much builds up, it can make the pain and inflammation from arthritis even worse. The citric acid found in citrus fruits like limes is a solvent in which uric acid can dissolve, increasing the amounts that are eliminated in the urine. Citrus fruits in general have anti-inflammatory properties, and can be used for a number of inflammation issues.

Eye Care: Vitamin-C again! Its anti oxidant properties protect eyes from aging and macular degeneration. On top of that, flavonoids help protect them from infections.

Fever: If someone is suffering from a fever, limes and lime juice can be of great importance. Citrus fruits in general have fever-reducing qualities, and if the fever is very high, the patients diet should be restricted to lemon juice and water. However, if the fever is mild to moderate, other fruit juices, particularly citrus juices like lime juice, can be administered in order to bring the fever back a manageable level. Vitamin-C, found in high concentrations in citrus fruits, naturally lowers the temperature of the body.

Gout: There are two main causes of gout. The first source is the accumulation of free radicals in the body, and the second is accumulation of toxins in the body, primarily uric acid. Limes can help prevent both of these causes. It is a wonderful source of antioxidants & detoxifiers (vitamin-C & Flavonoids) which reduce the number of free radicals as well as detoxifying the body.

Gums: The root cause of gum problems is a deficiency of vitamin-C (Scurvy, which gives bleeding and spongy gums) and microbial growth. Sometimes, the ulcers come from physical trauma. In all of these situations, limes can help. Its vitamin-C cures scurvy, Flavonoids inhibit microbial growth and potassium and Flavonoids help heal ulcers and wounds.

Piles: Since lime helps heal ulcers and wounds in the digestive system and excretory system while providing relief from constipation, it eradicates all the root causes of piles. Piles are a different term for hemorrhoids, an uncomfortable condition that occurs in the anal region and can result in bleeding and discomfort both during excretion and general activity. It can also lead to certain forms of cancer, and limes can help prevent their formation or recurrence.

Cholera: Although it has disappeared in many parts of the world, cholera is still a dangerous and deadly disease in some places on the planet, and luckily, limes and other citrus fruits can help defend against this often fatal condition. The lime juice, when added to potentially infected water, proved to be a very effective disinfectant, and even when it was consumed regularly after someone had been exposed to cholera-infected water, fatalities were reduced. Numerous studies were done on this application of lime juice, particularly following the horrible outbreak of cholera in Guinea-Bissau in 1994.

Weight Loss: A glass of warm water with a full limes worth of juice in it is an excellent weight reducer as well as a brilliant refresher and antioxidant drink. The citric acid present in lime is an excellent fat burner. You can consume two glasses a day and see legitimate and remarkable results within a week.

Urinary Disorders: The high potassium content of limes is very effective in removal of the toxic substances and the precipitates which get deposited in kidneys and the urinary bladder. The disinfectant properties of limes also help cure infections in the urinary system. Furthermore, it stops prostrate growth (very common in males above 40) and clears blockage of urine that can come from calcium deposits in the urinary tract.

Other Benefits: It is a good appetizer and digestive. It can help to cure rheumatism, prostate and colon cancer, cholera, arteriosclerosis, fatigue and even high fevers (contrary to popular belief). The best part of it is that it has no negative side effects!

THANKS FOR VISITING....PLEASE SHARE AFTER READING .....LEAVE YOUR COMMENTS AND QUESTIONS BELOW....

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Recommendation and review posted by sam

There are several ways adult stem cells can be isolated, most of which are being actively explored by our researchers.

1) From the body itself: Scientists are discovering that many tissues and organs contain a small number of adult stem cells that help maintain them. Adult stem cells have been found in the brain, bone marrow, blood vessels, skeletal muscle, skin, teeth, heart, gut, liver, and other (although not all) organs and tissues. They are thought to live in a specific area of each tissue, where they may remain dormant for years, dividing and creating new cells only when they are activated by tissue injury, disease or anything else that makes the body need more cells.

Adult stem cells can be isolated from the body in different ways, depending on the tissue. Blood stem cells, for example, can be taken from a donors bone marrow, from blood in the umbilical cord when a baby is born, or from a persons circulating blood. Mesenchymal stem cells, which can make bone, cartilage, fat, fibrous connective tissue, and cells that support the formation of blood can also be isolated from bone marrow. Neural stem cells (which form the brains three major cell types) have been isolated from the brain and spinal cord. Research teams at Childrens, headed by leading scientists Stuart Orkin, MD and William Pu, MD, both affiliate members of the Stem Cell Program, recently isolated cardiac stem cells from the heart.

Isolating adult stem cells, however, is just the first step. The cells then need to be grown to large enough numbers to be useful for treatment purposes. The laboratory of Leonard Zon, MD, director of the Stem Cell Program, has developed a technique for boosting numbers of blood stem cells thats now in Phase I clinical testing.

2) From amniotic fluid: Amniotic fluid, which bathes the fetus in the womb, contains fetal cells including mesenchymal stem cells, which are able to make a variety of tissues. Many pregnant women elect to have amniotic fluid drawn to test for chromosome defects, the procedure known as amniocentesis. This fluid is normally discarded after testing, but Childrens Hospital Boston surgeon Dario Fauza, MD, a Principal Investigator at Childrens and an affiliate member of the Stem Cell Program, has been investigating the idea of isolating mesenchymal stem cells and using them to grow new tissues for babies who have birth defects detected while they are still in the womb, such as congenital diaphragmatic hernia. These tissues would match the baby genetically, so would not be rejected by the immune system, and could be implanted either in utero or after the baby is born.

3) From pluripotent stem cells: Because embryonic stem cells and induced pluripotent cells (iPS cells), which are functionally similar, are able to create all types of cells and tissues, scientists at Childrens and elsewhere hope to use them to produce many different kinds of adult stem cells. Laboratories around the world are testing different chemical and mechanical factors that might prod embryonic stem cells or iPS cells into forming a particular kind of adult stem cell. Adult stem cells made in this fashion would potentially match the patient genetically, eliminating both the problem of tissue rejection and the need for toxic therapies to suppress the immune system.

4) From other adult stem cells: A number of research groups have reported that certain kinds of adult stem cells can transform, or differentiate, into apparently unrelated cell types (such as brain stem cells that differentiate into blood cells or blood-forming cells that differentiate into cardiac muscle cells). This phenomenon, called transdifferentiation, has been reported in some animals. However, its still far from clear how versatile adult stem cells really are, whether transdifferentiation can occur in human cells, or whether it could be made to happen reliably in the lab.

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Where Do We Get Adult Stem Cells? | Boston Children's Hospital

Recommendation and review posted by sam

Cells Weekly is a digest of the most interesting news and events in stem cell research, cell therapy and regenerative medicine. Cells Weekly is posted every Sunday night!

1. Proliferation of unproved stem cell clinics in US The biggest buzz this week was a study by @LeighGTurner and @pknoepfler on stem cell clinics in US. This is very interesting study, which Id highly recommend you to read! Forget about stem cell tourism, all you need to do now is to look across the street or open glossy magazine at airplane. They are everywhere:

Using rigorous Internet-based key word searches (see Supplemental Information for details), we found 351 U.S. businesses engaged in direct-to-consumer marketing of stem cell interventions offered at 570 clinics. For each business, we collected the company name, location(s), website address, advertised stem cell types, and diseases, injuries, and other conditions that clinics claim to treat with stem cell interventions. (Table S1 lists and describes all of the businesses we identified).

The authors did a lot of work and they are also open to suggestions for clinics database and improvements in methodology. Also read about this study on the Niche blog.

2. Failure of Phase 3 cardiac cell therapy trial This week Belgian company Celyad released headline results of their Phase 3 cardiac cell therapy pan-European trial CHART-1. It was efficacy assessment of auto- bone marrow MSC, induced in cardiac lineage, on 271 patients with chronic ischemic heart failure. Primary endpoints of the study were missed. So, study is failed. However, post-hoc analysis showed 60% of patient subgroup with significant efficacy, measured by primary endpoint. Companys press release has a positive spin and most media outlets called the results of the trial mixed or even promising. The fate of so-called C-CURE cell therapy now will depend on discussion with EMA in Europe. Company still may attempt to commercialize it and/ or continue with re-designed trial in US. In any case Celyad would not proceed with C-CURE without partner. Unfortunately for Celyad, dropping of the companys value by investors for more than a third, will make a search for potential partner very hard.

3. Stem cell professionals divided for 2 camps in best regulation debate Article in STAT nicely summarized recent debate on the best rergulatory framework for stem cell-based therapies in US. In the first camp, proponents of so-called Regrow Act and anyone else (for example, president of CIRM, Randy Mills), who supports reformation of FDA to accelerate approvals and ease regulation in general. In the second camp, professionals, who are opposing simple ease of current FDA regulation. In this camp, we can see such professional organizations as ISSCR, ARM and some patient advocacy groups. As the example of second camp, you can read Knoepflers op-ed in the San Francisco Chronicle. Very interesting debate! Let me know what do you think in comments.

4. More clinical trials updates The results of the Phase 2 ALS trial, sponsored by NeuralStem were published online in Neurology on June 29, 2016. 15 patients, divided for 5 treatments groups, underwent experimental procedures in 3 different US centers. Even though there were 2 cases of serious adverse events observed and 2 deaths (attributed to disease progression) before 270 days, procedure deemed to be safe and well tolerated in general. Important conclusion experimental treatment was not clinically beneficial. However, as it was highlighted by investigators, the trial was not designed and powered to assess efficacy.

Last year, US-based company Cytori had 2 cardiac cell therapy trials, called ATHENA 1 and 2. Both trials were terminated last year, due to safety concerns and business considerations. Recently, company published available data, generated from both trials. 31 patients were included in analysis (28 from ATHENA 1 and 3 from ATHENA 2) 17 in cell therapy group and 14 in placebo group. Patients with chronic myocardial ischemia received 40 or 80 millions of autologous adipose tissue-derived stromal vascular fraction cells, processed from lipoaspirates at point of care with Celution system. Serious adverse events in 2 patients (related to procedure, but not related to cells) triggered stopping rule and studies were suspended. FDA allowed to continue after amendment, however company decided to terminate trials. In relation to safety, ATHENA 1 did not meet primary endpoint, measured by major adverse cardiac events (MACE) 35.3% in cell therapy group versus 21.4% in placebo. Some efficacy endpoints, specified in ATHENA 2 were met at some time points. The authors concluded that studies were feasible with suggestion of benefit.

5. Caution about new gene therapy trials Two recent proposals for new gene therapy trials in US, evaluated by NIH Recombinant DNA Advisory Committee (RAC) caused concerns about safety. Nature editorial this week covered proposals of Dimension Therapeutics and University of Pennsylvania, saying it must proceed with caution. Links about proposal for the first CRISPR-based application in human, you can look in previous Cells Weekly. Here is decision on Dimensions proposal:

After some discussion, the RAC voted unanimously to approve the trial. However, that came with a long list of conditions, including that the treatment first be tested in a second animal species. The researchers disagree with most of the conditions, believing that more expensive animal trials will add nothing. They feel that they are being held to a different standard from most trials. Dimension still plans to submit an application to the US Food and Drug Administration (FDA) later this year to start a clinical trial. It is unclear how heavily the RACs recommendations weigh into FDA decisions, but Wadsworth says that the company will conduct its trials overseas if necessary. These patients have been waiting a long time, he says.

6. Is FDA really holding stem cell therapy developers? Based on the recent post on California Stem Cell Report, the answer is YES. This opinion was voiced by CIRMs president Randy Mills several times. Ive asked Jan Nolta (IND submitter) on twitter FDA request of $330k pigs experiments and she said that it makes sense to do and $330k was misquoted.

Do you guys have any good examples when FDA was unreasonably holding developers with their INDs and trials progression? Please comment!

7. MSC and cancer friends or foes? New interesting data came up this week about impact of MSC-based therapy on carcinogenesis. Researchers found that in breast tumor model coinjection and distant injection of MSC has different impact on tumor growth:

Unlike previous reports, this is the first study reporting that MSCs may exert opposite roles on tumor growth in the same animal model by modulating the host immune system, which may shed light on the potential application of MSCs as vehicles for tumor therapy and other clinical applications.

8. New methods and protocols: Osteogenic differentiation of bioprinted constructs consisting of human adipose-derived stem cells (PLoS ONE) Bone marrow is a reservoir for cardiac resident stem cells (Sci Rep) Multiple genetically engineered humanized microenvironments in a single mouse (Biomater Res) Xenotransplantation of human fetal cardiac progenitor cells is useless in porcine model of ischemic heart failure (PLoS ONE) Feeding strategies in expansion of human pluripotent stem cells in stirred tank bioreactors (Stem Cells TM)

Tagged as: cells weekly

Read more from the original source:
Stem Cell Assays Reproducible Research on Stem Cells

Recommendation and review posted by Bethany Smith

low hormone levels

Specializing in Hormone Replacement Therapy (HRT), Testosterone Replacement Therapy (TRT) and Human Growth Hormone Therapy (HGH), Elite HRToffers the most up to date treatment options available to optimize your physical and emotional health to the highest level possible, helping you to get your edge back.

Our fully personalized age management and wellness programs, incorporating Physician prescribed Hormone Replacement Therapy (HRT), wellness coaching and program monitoring will help to slow down and even reverse the signs and symptoms of aging so you can look and feel your absolute best at any age. How you look and feel as you age is entirely up to you, you can make the years to come the best years of your life. Take the first step toward a fitter, younger and healthier you. Our team of expert Physicians and wellness consultants are here to guide you every step of the way. Together, well help you to look better, feel younger and stay healthier.

Call us for a free private consultation, your call is completely confidential and no obligation is required, youll be glad you did. Prefer information via email? Submit your questions and concerns using one of our contact forms. One of our Physicians or wellness consultants will respond right away.

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Hormone Replacement Therapy Boca Raton - Hormone Doctor ...

Recommendation and review posted by simmons

Is hormone therapy (HRT) making a comeback?

A few years ago, the use of hormone replacement therapy (HRT) looked like a medical mess. For decades, women were told that HRT -- usually a combination of estrogen and progestin -- was good for them during and after menopause. Then the 2002 results of the Women's Health Initiative study seemed to show just the opposite: hormone replacement therapy actually had life-threatening risks such as heart attacks, strokes, and cancer.

"Women felt betrayed," says Isaac Schiff, MD, chief of obstetrics and gynecology at Massachusetts General Hospital in Boston. "They were calling their doctors, saying, 'How could you put me on this drug which causes heart attacks, strokes, and cancer?'"

Almost overnight, standard medical practice changed. Doctors stopped prescribing hormone replacement therapy and 65% of women on HRT quit, according to Schiff.

But some experts say hormone replacement therapy may be coming back. All along HRT remained an important treatment for menopause symptoms like hot flashes. And now, a number of recent studies show that hormone replacement therapy may have protective benefits for women who are early in menopause.

"I think we swung too positive on hormone therapy in the past and then we went too negative," says Schiff, who is also chair of the American College of Obstetricians and Gynecologists Task Force on Hormone Therapy. "Now we're trying to find a balance in between."

"We're definitely in a gray zone of uncertainty about hormone therapy," says Jacques Rossouw, MD, project officer for the federal Women's Health Initiative (WHI). "But when you're uncertain, you have to err on the side of safety."

While Rossouw concedes that new studies show some preventative benefit for younger women, he says any potential benefit is very slight. And, he notes, there is no evidence that any benefit would last if women kept taking hormones as they got older.

But increasing numbers of researchers say there should be a place for hormone replacement therapy as a preventive treatment for limited periods as it may help prevent disease in younger women around the age of menopause.

"We have evidence that hormone therapy can prevent heart disease, hip fractures, and osteoporosis, and that it cuts the risk of developing diabetes by 30% in younger women," says Shelley R. Salpeter, MD, a clinical professor of medicine at Stanford University's School of Medicine.

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Hormone Replacement Therapy - WebMD

Recommendation and review posted by sam

This article is about the medical therapy. For the cell type, see Stem cell.

Stem-cell therapy is the use of stem cells to treat or prevent a disease or condition.

Bone marrow transplant is the most widely used stem-cell therapy, but some therapies derived from umbilical cord blood are also in use. Research is underway to develop various sources for stem cells, and to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes, heart disease, and other conditions.

Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and to human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.

For over 30 years, bone marrow has been used to treat cancer patients with conditions such as leukaemia and lymphoma; this is the only form of stem-cell therapy that is widely practiced.[1][2][3] During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. It is this side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.[4]

Another stem-cell therapy called Prochymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids.[5] It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.[6]

The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.[7]

In 2014, the European Medicines Agency recommended approval of Holoclar, a treatment involving stem cells, for use in the European Union. Holoclar is used for people with severe limbal stem cell deficiency due to burns in the eye.[8]

In March 2016 GlaxoSmithKline's Strimvelis (GSK2696273) therapy for the treatment ADA-SCID was recommended for EU approval.[9]

Stem cells are being studied for a number of reasons. The molecules and exosomes released from stem cells are also being studied in a effort to make medications.[10]

Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's, Amyotrophic lateral sclerosis, and Alzheimer's disease.[11][12][13] There have been preliminary studies related to multiple sclerosis.[14][15]

Healthy adult brains contain neural stem cells which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorder.[16][17][18]

Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. A small clinical trial was underway in Scotland in 2013, in which stem cells were injected into the brains of stroke patients.[19]

Clinical and animal studies have been conducted into the use of stem cells in cases of spinal cord injury.[20][21][22]

The pioneering work[23] by Bodo-Eckehard Strauer has now been discredited by the identification of hundreds of factual contradictions.[24] Among several clinical trials that have reported that adult stem-cell therapy is safe and effective, powerful effects have been reported from only a few laboratories, but this has covered old[25] and recent[26] infarcts as well as heart failure not arising from myocardial infarction.[27] While initial animal studies demonstrated remarkable therapeutic effects,[28][29] later clinical trials achieved only modest, though statistically significant, improvements.[30][31] Possible reasons for this discrepancy are patient age,[32] timing of treatment[33] and the recent occurrence of a myocardial infarction.[34] It appears that these obstacles may be overcome by additional treatments which increase the effectiveness of the treatment[35] or by optimizing the methodology although these too can be controversial. Current studies vary greatly in cell-procuring techniques, cell types, cell-administration timing and procedures, and studied parameters, making it very difficult to make comparisons. Comparative studies are therefore currently needed.

Stem-cell therapy for treatment of myocardial infarction usually makes use of autologous bone-marrow stem cells (a specific type or all), however other types of adult stem cells may be used, such as adipose-derived stem cells.[36] Adult stem cell therapy for treating heart disease was commercially available in at least five continents as of 2007.[citation needed]

Possible mechanisms of recovery include:[11]

It may be possible to have adult bone-marrow cells differentiate into heart muscle cells.[11]

The first successful integration of human embryonic stem cell derived cardiomyocytes in guinea pigs (mouse hearts beat too fast) was reported in August 2012. The contraction strength was measured four weeks after the guinea pigs underwent simulated heart attacks and cell treatment. The cells contracted synchronously with the existing cells, but it is unknown if the positive results were produced mainly from paracrine as opposed to direct electromechanical effects from the human cells. Future work will focus on how to get the cells to engraft more strongly around the scar tissue. Whether treatments from embryonic or adult bone marrow stem cells will prove more effective remains to be seen.[37]

In 2013 the pioneering reports of powerful beneficial effects of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies.[38] Critics report that of 48 reports there seemed to be just five underlying trials, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578 patient randomized trial and as a 391 patient observational study. Other reports required (impossible) negative standard deviations in subsets of patients, or contained fractional patients, negative NYHA classes. Overall there were many more patients published as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.[39]

One of the most promising benefits of stem cell therapy is the potential for cardiac tissue regeneration to reverse the tissue loss underlying the development of heart failure after cardiac injury.[40]

Initially, the observed improvements were attributed to a transdifferentiation of BM-MSCs into cardiomyocyte-like cells.[28] Given the apparent inadequacy of unmodified stem cells for heart tissue regeneration, a more promising modern technique involves treating these cells to create cardiac progenitor cells before implantation to the injured area.[41]

The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient must be made for successful transplantation treatments, but matches are uncommon, even between first-degree relatives. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments.[citation needed]

Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells.[42] Further research into this technique should have potential benefits to gene therapy, blood transfusion, and topical medicine.

In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice[43] and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that the tooth regeneration technology can be used to grow live teeth in human patients.

In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks.[44] It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells could be a choice for the replacement of missing teeth in the future.[45][46]

Research is ongoing in different fields, alligators which are polyphyodonts grow up to 50 times a successional tooth (a small replacement tooth) under each mature functional tooth for replacement once a year.[47]

Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.[48]

Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restore vision.[49] The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty patients using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.[50]

In April 2005, doctors in the UK transplanted corneal stem cells from an organ donor to the cornea of Deborah Catlyn, a woman who was blinded in one eye when acid was thrown in her eye at a nightclub. The cornea, which is the transparent window of the eye, is a particularly suitable site for transplants. In fact, the first successful human transplant was a cornea transplant. The absence of blood vessels within the cornea makes this area a relatively easy target for transplantation. The majority of corneal transplants carried out today are due to a degenerative disease called keratoconus.

The University Hospital of New Jersey reports that the success rate for growth of new cells from transplanted stem cells varies from 25 percent to 70 percent.[51]

In 2014, researchers demonstrated that stem cells collected as biopsies from donor human corneas can prevent scar formation without provoking a rejection response in mice with corneal damage.[52]

In January 2012, The Lancet published a paper by Steven Schwartz, at UCLA's Jules Stein Eye Institute, reporting two women who had gone legally blind from macular degeneration had dramatic improvements in their vision after retinal injections of human embryonic stem cells.[53]

In June 2015, the Stem Cell Ophthalmology Treatment Study (SCOTS), the largest adult stem cell study in ophthalmology ( http://www.clinicaltrials.gov NCT # 01920867) published initial results on a patient with optic nerve disease who improved from 20/2000 to 20/40 following treatment with bone marrow derived stem cells.[54]

Diabetes patients lose the function of insulin-producing beta cells within the pancreas.[55] In recent experiments, scientists have been able to coax embryonic stem cell to turn into beta cells in the lab. In theory if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient.[56]

Human embryonic stem cells may be grown in cell culture and stimulated to form insulin-producing cells that can be transplanted into the patient.

However, clinical success is highly dependent on the development of the following procedures:[11]

Clinical case reports in the treatment orthopaedic conditions have been reported. To date, the focus in the literature for musculoskeletal care appears to be on mesenchymal stem cells. Centeno et al. have published MRI evidence of increased cartilage and meniscus volume in individual human subjects.[57][58] The results of trials that include a large number of subjects, are yet to be published. However, a published safety study conducted in a group of 227 patients over a 3-4-year period shows adequate safety and minimal complications associated with mesenchymal cell transplantation.[59]

Wakitani has also published a small case series of nine defects in five knees involving surgical transplantation of mesenchymal stem cells with coverage of the treated chondral defects.[60]

Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells.[61] A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation.[61] Researchers are still investigating different aspects of the "soil" tissue that are conducive to regeneration.[61]

Culture of human embryonic stem cells in mitotically inactivated porcine ovarian fibroblasts (POF) causes differentiation into germ cells (precursor cells of oocytes and spermatozoa), as evidenced by gene expression analysis.[62]

Human embryonic stem cells have been stimulated to form Spermatozoon-like cells, yet still slightly damaged or malformed.[63] It could potentially treat azoospermia.

In 2012, oogonial stem cells were isolated from adult mouse and human ovaries and demonstrated to be capable of forming mature oocytes.[64] These cells have the potential to treat infertility.

Destruction of the immune system by the HIV is driven by the loss of CD4+ T cells in the peripheral blood and lymphoid tissues. Viral entry into CD4+ cells is mediated by the interaction with a cellular chemokine receptor, the most common of which are CCR5 and CXCR4. Because subsequent viral replication requires cellular gene expression processes, activated CD4+ cells are the primary targets of productive HIV infection.[65] Recently scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).[66]

On 23 January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the initiation of the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on patients with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions".[67] In 2013 biotechnology and regenerative medicine company BioTime (NYSEMKT:BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.[68]

Scientists have reported that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth(fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in invitro culture before these are administered for clinical trials or experimental therapies, re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various clinical trials on MSCs have failed which used cryopreserved product immediately post thaw as compared to those clinical trials which used fresh MSCs.[69]

There is widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections.[110] There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.

Stem-cell research and treatment was practiced in the People's Republic of China. The Ministry of Health of the People's Republic of China has permitted the use of stem-cell therapy for conditions beyond those approved of in Western countries. The Western World has scrutinized China for its failed attempts to meet international documentation standards of these trials and procedures.[111]

State-funded companies based in the Shenzhen Hi-Tech Industrial Zone treat the symptoms of numerous disorders with adult stem-cell therapy. Development companies are currently focused on the treatment of neurodegenerative and cardiovascular disorders. The most radical successes of Chinese adult stem cell therapy have been in treating the brain. These therapies administer stem cells directly to the brain of patients with cerebral palsy, Alzheimer's, and brain injuries.[citation needed]

Since 2008 many universities, centers and doctors tried a diversity of methods; in Lebanon proliferation for stem cell therapy, in-vivo and in-vitro techniques were used, Thus this country is considered the launching place of the Regentime[112] procedure. http://www.researchgate.net/publication/281712114_Treatment_of_Long_Standing_Multiple_Sclerosis_with_Regentime_Stem_Cell_Technique The regenerative medicine also took place in Jordan and Egypt.[citation needed]

Stem-cell treatment is currently being practiced at a clinical level in Mexico. An International Health Department Permit (COFEPRIS) is required. Authorized centers are found in Tijuana, Guadalajara and Cancun. Currently undergoing the approval process is Los Cabos. This permit allows the use of stem cell.[citation needed]

In 2005, South Korean scientists claimed to have generated stem cells that were tailored to match the recipient. Each of the 11 new stem cell lines was developed using somatic cell nuclear transfer (SCNT) technology. The resultant cells were thought to match the genetic material of the recipient, thus suggesting minimal to no cell rejection.[113]

As of 2013, Thailand still considers Hematopoietic stem cell transplants as experimental. Kampon Sriwatanakul began with a clinical trial in October 2013 with 20 patients. 10 are going to receive stem-cell therapy for Type-2 diabetes and the other 10 will receive stem-cell therapy for emphysema. Chotinantakul's research is on Hematopoietic cells and their role for the hematopoietic system function in homeostasis and immune response.[114]

Today, Ukraine is permitted to perform clinical trials of stem-cell treatments (Order of the MH of Ukraine 630 "About carrying out clinical trials of stem cells", 2008) for the treatment of these pathologies: pancreatic necrosis, cirrhosis, hepatitis, burn disease, diabetes, multiple sclerosis, critical lower limb ischemia. The first medical institution granted the right to conduct clinical trials became the "Institute of Cell Therapy"(Kiev).

Other countries where doctors did stem cells research, trials, manipulation, storage, therapy: Brazil, Cyprus, Germany, Italy, Israel, Japan, Pakistan, Philippines, Russia, Switzerland, Turkey, United Kingdom, India, and many others.

Read the rest here:
Stem-cell therapy - Wikipedia, the free encyclopedia

Recommendation and review posted by Bethany Smith

Stem Cell 100 is formulated to rejuvenate your body and slow the aging process to help you feel and function more like a young person. This can help you feel better, look younger and improve your health. Most of the cells in your body lose function with age. Everyone has special cells called adult stem cells which are needed to rejuvenate damaged and old tissues, but adult stem cells themselves are also aging. Until now there was not much you could do about it. Stem Cell 100 rejuvenates adult stem cells and their micro-environments. Stem Cell 100+ is a more advanced and faster acting version of Stem Cell 100.

Developed by experts in the anti-aging field, patent-pending Stem Cell 100 is the only supplement proven to double maximum lifespan of an animal model. No other product or therapy including caloric restriction even comes close.

SK of Santa Fe, NM

I have been using Stem Cell 100 for about one year. Initially I noticed a boost in energy level, which now remains steady-hence not noticed I have experienced no adverse effects from taking this product. I heartily recommend Stem Cell 100 and plan to continue on it.

Leslie

Stem Cell 100 has made a noticeable difference in me, including turning my gray hair back to its original color, which supposedly is impossible. The reversal of the gray hair to original color began a couple of months after starting the pill. After about 10 months, the gray hair is mostly gone. At the current rate of improvement, I expect my hair to completely be back to its original color within 1 to 2 months. I think my beard will take longer, but it was the first to gray. Also, my skin became smoother and younger looking. The skin and hair rely heavily on stem cells, and they seem to benefit strongly from this product. I'm so excited about telling people my results because there is nothing that can reverse the graying of hair. It will give me evidence that this supplement thing is really powerful. Unfortunately, I don't have before and after pictures because I didn't read any claims that the product would affect hair color. I would just say that I'm a person who totally believes that it does me no good to imagine things or interpret tings in a way favorable to what I want to believe. When I'm convinced enough to make a statement, you can count on it.

Joey of San Diego, CA

I am a 48 year old working woman. A friend of mine introduced me to Stem Cell 100. After taking Stem Cell 100 for about 4 months my anxiety level has really been diminished. Its a great supplement and I would recommend it to everyone!

Paul of San Diego, CA

I am an active 61 year old man in excellent health, but had experienced a serious drop in my energy level at the time I enrolled in a 4-month trial of Stem Cell 100. Within a month, my energy increased noticeably and I began to take to my physical activities (running, cycling) with a renewed enthusiasm and intensity level. My mood began to elevate steadily, and soon I had even lost those few stubborn pounds that had eluded me for years. I am very enthusiastic about Stem Cell 100. I look forward to continuing with the new, improved formulation, and would not hesitate to recommend it.

Mike, Texas

After taking the Stem Cell 100 for the last month my sinuses have also cleared, unplugging my ears for the first time since mid September.

Willie, California

As I was sprinting this morning around 6:00am I noticed that I was not hurting anymore! I have been having sore knees, ankles, hamstrings and back for the last couple of years. I usually just ran through it, but I noticed since I have been taking the Stem Cell 100 capsules for about 45 days now, those nagging pains are gone away!

Tom, Australia

Only after about 2-3 weeks of taking Stem Cell 100 my eye sight returned back to a level where I did not need glasses to work on my computer monitors. My eyes had always been good but had started to deteriorate about a year ago where 50% of the time I had to wear my glasses. I was shocked to find the improvement so quick. I found I was less stressed. No other changes to lifestyle yet a measureable difference. My fingers would sometimes get stiff in the mornings after long days on the keyboard. This stiffness disappeared. Some of my hair is getting darker. I have a full body of hair that had virtually all turned grey but I noticed that some of my hair was starting regrow brown - my original colour. I had some age spots in my left leg that are disappearing. Generally, I feel great.

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Harness the Power of Your Own Stem Cells

Millions of people suffer from chronic conditions of aging and disease. Based on international scientific studies in many academic and industry laboratories, there is new hope that many of the conditions afflicting mankind can some day be cured or greatly improved using stem cell regenerative medicine. Stem Cell 100 offers a way to receive some of the benefits of stem cell therapy today by improving the activity and effectiveness of your own adult stem cells.

Stem Cell 100 Helps to Support:

The statements above have not been reviewed by the FDA. Stem Cell 100 is not a preventive or treatment for any disease.

Help Rejuvenate Your Body by Boosting Your Own Stem Cells

As a child, we are protected from the ravages of aging and can rapidly recover from injury or illness because of the ability of the young regenerative stem cells of children have a superior ability to repair and regenerate most damaged tissues. As we age, our stem cell populations become depleted and/or slowly lose their capacity to repair. Moreover, the micro-environment (i.e. niches) around stem cells becomes less nurturing with age, so cell turnover and repair are further reduced. This natural progression occurs so slowly that we are barely aware of it, but we start to notice the body changes in our 20s, 30s, 40s, and especially after 50 years of age. Stem Cell 100 helps adults regain their youthful regenerative potential by stabilizing stem cell function.

Stem Cell 100 works differently than other stem cell products on the market

You may have seen a number of products that are advertised as stimulating or enhancing the number of stem cells. Each person only has a limited number of stem cells so using them up faster may not be a good strategy. Stem Cell 100 is about improving the effectiveness and longevity of your stem cells as well as preserving the stem cell micro-environment. That should be the goal of any effective stem cell therapy and is what Stem Cell 100 is designed to do and what other stem cell products cannot do.

Stem Cell 100 Extends Drosophila (Fruit Fly) Lifespan

In extensive laboratory testing Stem Cell 100 greatly extended both the average and maximum lifespan of Drosophila fruit flies. The study (see Charts below) included three cages of Drosophila fruit flies that were treated with Stem Cell 100 (Cages T1 to T3) and three cages which were untreated controls (Cages C1 to C3). Each cage started with 500 fruit flies including 250 males and 250 females. The experiment showed that median lifespan more than doubled with a 123% increase. While fruit flies are not people they are more like us than you might think. Drosophila have a heart and circulatory system, and the most common cause of death is heart failure. Like humans and other mammals (e.g. mice), it is difficult to increase their lifespan significantly. These observed results outperform every lifespan enhancing treatment ever tested - including experiments using genetic modification and dietary restriction.

The longest living fruit fly receiving Stem Cell 100 lived 89 days compared to the longest living untreated control which lived 48 days. It is possible that the single longest living fruit fly lived longer for other reasons such as genetic mutation, however, there were many others that lived almost as long so it was not just an aberation. The oldest 5% of the treated fruit flies lived 77% longer than the oldest 5% of the control group. It is also important that the study showed an improved ability of the fruit flies to survive stress and illness at all ages not just during old age. Even after the first few days of the study there were already more of the Stem Cell 100 treated fruit flies alive that survived youth than the control group of untreated fruit flies. For additional information about the study please go to our Longevity page.

Supplement Facts

Stem Cell 100 is a Patent-Pending Life Code Nutraceutical. All Life Code products are nutraceutical grade and provide the best of science along with the balance of nature.

All Life Code products are nutraceutical grade and provide the best of science along with the balance of nature.

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Stem Cell 100 Plus+ is a more powerful and faster acting version of Stem Cell 100.

Click label to enlarge

Serving Size: One type O capsule

Servings Per Container: 60 Capsules

Recommended Use: Typical usage of Stem Cell 100 is two capsules per day, preferably at meal times. While both capsules can be taken at the same time, it is preferable to separate the two capsules by at least 4 hours. Since Stem Cell 100 is a potent formulation, do not take more than three capsules per day. One capsule per day may be sufficient for those below 110 pounds.

Recommended Users: Anyone from ages 22 and up could benefit from Stem Cell 100. Those in their 20s and 30s will like the boost in endurance during sports or exercise, while older users will notice better energy and general health with the potential for some weight loss.

Active Ingredients in Stem Cell 100: There are ten herbal components that make up the patent-pending combination in Stem Cell 100. The herbal components are highly extracted natural herbs that are standardized for active components that promote adult stem cells and lower inflammation:

1) Polysaccharides, flavonoids, and astragalosides extracted from Astragalus membranaceus, which has many positive effects on stem cells and the cardiovascular and immune systems.

2) Proprietary natural bilberry flavonoids and other compounds from a stabilized nutraceutical grade medicinal Vaccinium extract. Activate metabolic PPARS and helps produce healthy levels of cholesterol and silent inflammation. Also has anti-fungal and anti-viral activity.

3) Flavonoids and oligo-proanthocyanidins (OPCs) extracted from Pine Bark, which greatly reduce oxidative stress, DNA damage, and inflammation.

4) L-Theanine, which is a natural amino acid from Camellia sinesis that reduces mental stress and inflammation while improving cognition and protecting brain cells from ischemic or toxic injury.

5) Pterocarpus Marsupium, which contains two stable resveratrol analogs which promote stem cells, lower inflammation, and stabilized metabolism.

6) Polygonum Multiflorium stem stem is a popular Chinese herbal tonic that fights premature aging and promotes youthfulness. Polygonum is reported to enhance fertility by improving sperm count in men and egg vitality in women. Polygonum is also widely used in Asia to strengthen muscle and is thus used by many athletes as an essential tonic for providing strength and stamina to the body. Modern research has supported Polygonum multiflorium stem in that animal studies have proven that it can extend lifespan and improve the quality of life. Polygonum appears to protect the liver and brain against damage, perhaps by improving immune and cardiovascular health. The stem sections of Polygonum multiflorium are also calming to the nervous system and promote sounder sleep. Life Code uses a proprietary Polygonum multiflorium stem extract.

7) Schisandra Berry is used by many Chinese women to preserve their youthful beauty. For thousands of years, Schisandra has been prized as an antiaging tonic that increases stamina and mental clarity, while fighting stress and fatigue. In Chinese traditional medicine, Schisandra berry has been used for liver disorders and to enhance resistance to infection and promote skin health and better sleep. Schisandra berry is classified as an adaptogen, which can stimulate the central nervous system, increase brain efficiency, improve reflexes, and enhance endurance. Modern research indicates that Schisandra berry extracts have a protective effect on the liver and promote immunity. A double-blind human trial suggested that Schisandra berry may help patients with viral hepatitis, which is very prevalent in China. Recent work indicates that the liver is protected by the enhanced production of glutathione peroxidase, which helps detoxify the liver. Life Code uses a proprietary Schisandra berry extract.

8) Fo-Ti Root (aka He-Shou-Wu) is one of the most widely used Chinese herbal medicines to restore blood, kidney, liver, and cardiovascular health. Fo-Ti is claimed to have powerful rejuvenating effects on the brain, endocrine glands, the immune system, and sexual vigor. Legend has it that Professor Li Chung Yun took daily doses of Fo-Ti to live to be 256 and is said to have outlived 23 wives and spawned 11 generations of descendents before his death in 1933. While it is unlikely that he really lived to such an old age there is scientific support for Fo-Ti as beneficial for health and longevity. Like the Indian Keno bark, Fo-ti contains resveratrol analogs and likely acts by various mechanism, which includes liver detoxification and protection of skin from UVB radiation. Life CodeTM uses a proprietary Fo-Ti root extract.

9 ) Camellia sinensis has many bioactive polyphenols including the potent epigallocatechin-3-gallate (EGCG). A 2006 Japanese study published in the Journal of the American Medical Association reports that adults aged 40 to 79 years of age who drank an average of 5 or more cups of tea per day had a significantly lower risk of dying from all causes (23% lower for females and 12% lower for males). The study tracked more than 40,000 adults for up to 11 years and found dramatically lower rates of cardiovascular disease and strokes in those drinking 5 or more cups of tea. Many studies have found that adults drinking 3 or more cups of tea per day have significantly less cancer. Other studies have found that green tea helps protect against age-related cognitive decline, kidney disease, periodontal disease, and type 2 diabetes. Green tea also promotes visceral fat loss and higher endurance levels. Summarizing all of the thousands of studies on tea and tea polyphenols that have been published, it can be concluded that tea polyphenols preserve health and youth. This conclusion is backed up by gene studies showing that tea polyphenols decrease insulin-like growth factor-1 (IGF-1), which is a highly conserved genetic pathway that has been strongly linked to aging in yeast, worms, mice, and humans. If everyone could drink 4 to 5 cups of green tea each day, they could enjoy these important health benefits, but for most people drinking that much green tea can disturb their sleep patterns. Life Code uses a nutraceutical grade green tea extract that has 98% polyphenols and 50% ESCG that provides the polyphenol and ESCG equivalent of 4 to 5 cups of green tea with only 2% of the caffeine. Thus, most or all of the benefits of green tea are provided without concerns about disturbing sleep.

10) Drynaria Rhizome is used extensively in traditional Chinese medicine as an effective herb for healing bones, ligaments, tendons, and lower back problems. Eastern martial art practitioners have used Drynaria for thousands of years to help in recovering from sprains, bruises, and stress fractures. Drynaria has also helped in many cases of bleeding gums and tinnitus (ringing in the ears). The active components of Drynaria protect bone forming cells by enhancing calcium absorption and other mechanisms. Drynaria is also reported to act as a kidney tonic and to promote hair growth and wound healing. Life Code uses a proprietary Drynaria rhizome extract.

Active Ingredients in Stem Cell 100+ There are 11 herbal extracts in Stem Cell 100+ along with two nutraceutical grade vitamins Methyl Folate (5-MTHF) and Methyl B12 that are bioavailable vitamin supplements that are highly potent but rarely found. The highly extracted natural herbs are standardized for active components that promote adult stem cells and lower inflammation and have been tested as a synergistic herbal formulation with the proper dosage of each component:

1) Polysaccharides, flavonoids, and astragalosides extracted from Astragalus membranaceus, which has many positive effects on stem cells and the cardiovascular and immune systems. Astragalus has been used for thousands of years in Traditional Chinese Medicine (TCM) to promote cardiovascular and immune health. Astragalus is also known as a primary stimulator of Qi (Life Force). Life Code uses a high quality proprietary TCM extract that tested highest in our longevity experiments.

2) Proprietary natural bilberry flavonoids and other compounds from a stabilized nutraceutical grade medicinal Vaccinium extract. Activate metabolic PPARS and helps produce healthy levels of cholesterol and silent inflammation. Also has anti-fungal and anti-viral activity.

3) Flavonoids and oligo-proanthocyanidins (OPCs) extracted from Pine Bark, which promote the vascular system and reduce oxidative stress, DNA damage, and inflammation.

4) L-Theanine, which is a natural amino acid from Camellia sinesis that reduces mental stress and inflammation while improving cognition and protecting brain cells from ischemic or toxic injury. Life Code tested supplement with Mass Spec to verify high purity.

5) Genistein, which is an isoflavone phytoestrogen, activates telomerase, metabolic PPARs, autophagy (cell waste disposal), and smooth muscles. It also inhibits DNA methylation and the carbohydrate transporter GLUT1. Life Code tested supplement with Mass Spec to verify high purity.

6) Harataki Extract (aka Terminalia chebula) contains rejuvenating tannin flavonoids that have doubled human cell longevity in culture while maintaining telomere length. In Traditional Indian Medicine, Harataki has been used to treat skin disorders and heart disease, among many other uses.

7) Two stable resveratrol analogs from extracts of Pterocarpus Marsupium, which promote stem cells, less silent inflammation, and better metabolism. Life Code uses a highly purified proprietary source that is only available to Indian doctors. Life Code does not recommend taking resveratrol supplements or synthetic analogs, as these supplements are inherently unstable.

8) He-Shou-Wu is one of the most widely used Chinese herbal medicines to restore blood, kidney, liver, and cardiovascular health. He-Shou-Wu is claimed to have powerful rejuvenating effects on the brain, endocrine glands, the immune system, and sexual vigor. Legend has it that Professor Li Chung Yun took daily doses to live to 256 years and is said to have outlived 23 wives and spawned 11 generations of descendants before his death in 1933. While it is unlikely that he really lived to such an old age, there is scientific support for He-Shou-Wu as beneficial for health and longevity. Life Code uses a proprietary TCM He-Shou-Wu root extract.

9) Schisandra Berry is used by many Chinese women to preserve their youthful beauty. For thousands of years, Schisandra has been prized as an antiaging tonic that increases stamina and mental clarity, while fighting stress and fatigue. In TCM, Schisandra berry has been used for liver disorders and to enhance resistance to infection and promote skin health and better sleep. Schisandra berry is classified as an adaptogen, which can stimulate the central nervous system, increase brain efficiency, improve reflexes, and enhance endurance. Life Code uses a proprietary TCM extract.

10) Drynaria Rhizome is used extensively in TCM as an effective herb for healing bones, ligaments, tendons, and lower back problems. Eastern martial art practitioners have used Drynaria for thousands of years to help in recovering from sprains, bruises, and stress fractures. The active components of Drynaria protect bone forming cells by enhancing calcium absorption and other mechanisms. Drynaria is also reported to act as a kidney tonic and to promote hair growth and wound healing. Life Code uses a proprietary TCM Drynaria rhizome extract.

11) BioPerine is a proprietary brand of peperine extracted from black pepper. BioPerine has been shown to enhance bioavailability of herbal extracts. Piperine has been shown in rats to have cognitive enhancing effects and to help control silent inflammation.

Safety: The extracts in Stem Cell 100 and Stem Cell 100+ are nutraceutical grade and have been individually tested in both animals and humans without significant safety issues. Those with pre-existing conditions of diabetes or hypertension should coordinate this product with your doctor, as lower blood glucose or reduced blood pressure can result from taking the recommended dose of this product.

Warnings: may lower glucose and/or blood pressure in some individuals. The supplement is not recommended for pregnant, lactating, or hypoglycemic individuals.

References

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2. Xu, C.J., et al., [Effect of astragalus polysaccharides on the proliferation and ultrastructure of dog bone marrow stem cells induced into osteoblasts in vitro]. Hua Xi Kou Qiang Yi Xue Za Zhi, 2007. 25(5): p. 432-6.

3. Xu, C.J., et al., [Effects of astragalus polysaccharides-chitosan/polylactic acid scaffolds and bone marrow stem cells on repairing supra-alveolar periodontal defects in dogs]. Zhong Nan Da Xue Xue Bao Yi Xue Ban, 2006. 31(4): p. 512-7.

4. Zhu, X. and B. Zhu, [Effect of Astragalus membranaceus injection on megakaryocyte hematopoiesis in anemic mice]. Hua Xi Yi Ke Da Xue Xue Bao, 2001. 32(4): p. 590-2.

5. Qiu, L.H., X.J. Xie, and B.Q. Zhang, Astragaloside IV improves homocysteine-induced acute phase endothelial dysfunction via antioxidation. Biol Pharm Bull, 2010. 33(4): p. 641-6.

6. Araghi-Niknam, M., et al., Pine bark extract reduces platelet aggregation. Integr Med, 2000. 2(2): p. 73-77.

7. Rohdewald, P., A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther, 2002. 40(4): p. 158-68.

8. Koch, R., Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Phytother Res, 2002. 16 Suppl 1: p. S1-5.

9. Rimando, A.M., et al., Pterostilbene, a new agonist for the peroxisome proliferator-activated receptor alpha-isoform, lowers plasma lipoproteins and cholesterol in hypercholesterolemic hamsters. J Agric Food Chem, 2005. 53(9): p. 3403-7.

10. Manickam, M., et al., Antihyperglycemic activity of phenolics from Pterocarpus marsupium. J Nat Prod, 1997. 60(6): p. 609-10.

11. Grover, J.K., V. Vats, and S.S. Yadav, Pterocarpus marsupium extract (Vijayasar) prevented the alteration in metabolic patterns induced in the normal rat by feeding an adequate diet containing fructose as sole carbohydrate. Diabetes Obes Metab, 2005. 7(4): p. 414-20.

12. Mao, X.Q., et al., Astragalus polysaccharide reduces hepatic endoplasmic reticulum stress and restores glucose homeostasis in a diabetic KKAy mouse model. Acta Pharmacol Sin, 2007. 28(12): p. 1947-56.

13. Schafer, A. and P. Hogger, Oligomeric procyanidins of French maritime pine bark extract (Pycnogenol) effectively inhibit alpha-glucosidase. Diabetes Res Clin Pract, 2007. 77(1): p. 41-6.

14. Kwak, C.J., et al., Antihypertensive effect of French maritime pine bark extract (Flavangenol): possible involvement of endothelial nitric oxide-dependent vasorelaxation. J Hypertens, 2009. 27(1): p. 92-101.

15. Xue, B., et al., Effect of total flavonoid fraction of Astragalus complanatus R.Brown on angiotensin II-induced portal-vein contraction in hypertensive rats. Phytomedicine, 2008.

16. Mizuno, C.S., et al., Design, synthesis, biological evaluation and docking studies of pterostilbene analogs inside PPARalpha. Bioorg Med Chem, 2008. 16(7): p. 3800-8.

17. Sato, M., et al., Dietary pine bark extract reduces atherosclerotic lesion development in male ApoE-deficient mice by lowering the serum cholesterol level. Biosci Biotechnol Biochem, 2009. 73(6): p. 1314-7.

18. Kimura, Y. and M. Sumiyoshi, French Maritime Pine Bark (Pinus maritima Lam.) Extract (Flavangenol) Prevents Chronic UVB Radiation-induced Skin Damage and Carcinogenesis in Melanin-possessing Hairless Mice. Photochem Photobiol, 2010.

19. Pavlou, P., et al., In-vivo data on the influence of tobacco smoke and UV light on murine skin. Toxicol Ind Health, 2009. 25(4-5): p. 231-9.

20. Ni, Z., Y. Mu, and O. Gulati, Treatment of melasma with Pycnogenol. Phytother Res, 2002. 16(6): p. 567-71.

21. Bito, T., et al., Pine bark extract pycnogenol downregulates IFN-gamma-induced adhesion of T cells to human keratinocytes by inhibiting inducible ICAM-1 expression. Free Radic Biol Med, 2000. 28(2): p. 219-27.

22. Rihn, B., et al., From ancient remedies to modern therapeutics: pine bark uses in skin disorders revisited. Phytother Res, 2001. 15(1): p. 76-8.

23. Saliou, C., et al., Solar ultraviolet-induced erythema in human skin and nuclear factor-kappa-B-dependent gene expression in keratinocytes are modulated by a French maritime pine bark extract. Free Radic Biol Med, 2001. 30(2): p. 154-60.

24. Van Wijk, E.P., R. Van Wijk, and S. Bosman, Using ultra-weak photon emission to determine the effect of oligomeric proanthocyanidins on oxidative stress of human skin. J Photochem Photobiol B, 2010. 98(3): p. 199-206.

25. Haskell, C.F., et al., The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol, 2008. 77(2): p. 113-22.

26. Owen, G.N., et al., The combined effects of L-theanine and caffeine on cognitive performance and mood. Nutr Neurosci, 2008. 11(4): p. 193-8.

27. Yamada, T., et al., Effects of theanine, a unique amino acid in tea leaves, on memory in a rat behavioral test. Biosci Biotechnol Biochem, 2008. 72(5): p. 1356-9.

28. Jia, R.Z., et al., [Neuroprotective effects of Astragulus membranaceus on hypoxia-ischemia brain damage in neonatal rat hippocampus]. Zhongguo Zhong Yao Za Zhi, 2003. 28(12): p. 1174-7.

29. Nathan, P.J., et al., The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother, 2006. 6(2): p. 21-30.

30. Nobre, A.C., A. Rao, and G.N. Owen, L-theanine, a natural constituent in tea, and its effect on mental state. Asia Pac J Clin Nutr, 2008. 17 Suppl 1: p. 167-8.

31. Murakami, S., et al., Effects of oral supplementation with cystine and theanine on the immune function of athletes in endurance exercise: randomized, double-blind, placebo-controlled trial. Biosci Biotechnol Biochem, 2009. 73(4): p. 817-21.

32. Kawada, S., et al., Cystine and theanine supplementation restores high-intensity resistance exercise-induced attenuation of natural killer cell activity in well-trained men. J Strength Cond Res, 2010. 24(3): p. 846-51.

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Recommendation and review posted by sam

Human chorionic gonadotropin (hCG) is a hormone produced by the embryo after implantation.[1][2] The presence of hCG is detected in some pregnancy tests (HCG pregnancy strip tests). Some cancerous tumors produce this hormone; therefore, elevated levels measured when the patient is not pregnant can lead to a cancer diagnosis and, if high enough, paraneoplastic syndromes. However, it is not known whether this production is a contributing cause or an effect of carcinogenesis. The pituitary analog of hCG, known as luteinizing hormone (LH), is produced in the pituitary gland of males and females of all ages.[1][3]

Regarding endogenous forms of hCG, there are various ways to categorize and measure them, including total hCG, C-terminal peptide total hCG, intact hCG, free -subunit hCG, -core fragment hCG, hyperglycosylated hCG, nicked hCG, alpha hCG, and pituitary hCG. Regarding pharmaceutical preparations of hCG from animal or synthetic sources, there are many gonadotropin preparations, some of which are medically justified and others of which are of a quack nature. As of December 6, 2011[update], the United States FDA has prohibited the sale of "homeopathic" and over-the-counter hCG diet products and declared them fraudulent and illegal.[4][5][6]

Human chorionic gonadotropin is a glycoprotein composed of 237 amino acids with a molecular mass of 25.7 kDa.[7]

It is heterodimeric, with an (alpha) subunit identical to that of luteinizing hormone (LH), follicle-stimulating hormone (FSH), thyroid-stimulating hormone (TSH), and (beta) subunit that is unique to hCG.

The two subunits create a small hydrophobic core surrounded by a high surface area-to-volume ratio: 2.8 times that of a sphere. The vast majority of the outer amino acids are hydrophilic.[7]

Human chorionic gonadotropin interacts with the LHCG receptor of the ovary and promotes the maintenance of the corpus luteum during the beginning of pregnancy. This allows the corpus luteum to secrete the hormone progesterone during the first trimester. Progesterone enriches the uterus with a thick lining of blood vessels and capillaries so that it can sustain the growing fetus[citation needed].

Due to its highly negative charge, hCG may repel the immune cells of the mother, protecting the fetus during the first trimester[citation needed]. It has also been hypothesized that hCG may be a placental link for the development of local maternal immunotolerance[citation needed]. For example, hCG-treated endometrial cells induce an increase in T cell apoptosis (dissolution of T cells). These results suggest that hCG may be a link in the development of peritrophoblastic immune tolerance, and may facilitate the trophoblast invasion, which is known to expedite fetal development in the endometrium.[10] It has also been suggested that hCG levels are linked to the severity of morning sickness or Hyperemesis gravidarum in pregnant women.[11]

Because of its similarity to LH, hCG can also be used clinically to induce ovulation in the ovaries as well as testosterone production in the testes. As the most abundant biological source is women who are presently pregnant, some organizations collect urine from pregnant women to extract hCG for use in fertility treatment.[12][13]

Human chorionic gonadotropin also plays a role in cellular differentiation/proliferation and may activate apoptosis.[14]

Naturally, it is produced in the human placenta by the syncytiotrophoblast.

Like other gonadotropins, it can be extracted from the urine of pregnant women or produced from cultures of genetically modified cells using recombinant DNA technology.

In Pregnyl, Follutein, Profasi, Choragon and Novarel, it is extracted from the urine of pregnant women. In Ovidrel, it is produced with recombinant DNA technology.[15]

Regarding endogenous forms of hCG, there are various ways to categorize and measure them, including total hCG, C-terminal peptide total hCG, intact hCG, free -subunit hCG, -core fragment hCG, hyperglycosylated hCG, nicked hCG, alpha hCG, and pituitary hCG.

Regarding pharmaceutical preparations of hCG from animal or synthetic sources, there are many gonadotropin preparations, some of which are medically justified and others of which are of a quack nature.

Blood or urine tests measure hCG. These can be pregnancy tests. hCG-positive indicates an implanted blastocyst and mammalian embryogenesis. These can be done to diagnose and monitor germ cell tumors and gestational trophoblastic diseases.

Concentrations are commonly reported in thousandth international units per milliliter (mIU/ml). The international unit of hCG was originally established in 1938 and has been redefined in 1964 and in 1980.[16] At the present time, 1 international unit is equal to approximately 2.351012 moles,[17] or about 6108 grams.[18]

Most tests employ a monoclonal antibody, which is specific to the -subunit of hCG (-hCG). This procedure is employed to ensure that tests do not make false positives by confusing hCG with LH and FSH. (The latter two are always present at varying levels in the body, whereas the presence of hCG almost always indicates pregnancy.)

Many hCG immunoassays are based on the sandwich principle, which uses antibodies to hCG labeled with an enzyme or a conventional or luminescent dye. Pregnancy urine dipstick tests are based on the lateral flow technique.

The following is a list of serum hCG levels. (LMP is the last menstrual period dated from the first day of your last period.) The levels grow exponentially after conception and implantation.

The ability to quantitate the hCG level is useful in the monitoring germ cell and trophoblastic tumors, follow-up care after miscarriage, and in diagnosis of and follow-up care after treatment of ectopic pregnancy. The lack of a visible fetus on vaginal ultrasound after the hCG levels have reached 1500 mIU/ml is strongly indicative of an ectopic pregnancy.[21] Still, even an hCG over 2000 IU/l does not necessarily exclude the presence of a viable intrauterine pregnancy in such cases.[22]

As pregnancy tests, quantitative blood tests and the most sensitive urine tests usually detect hCG between 6 and 12 days after ovulation.[23] However, it must be taken into account that total hCG levels may vary in a very wide range within the first 4 weeks of gestation, leading to false results during this period.[24] A rise of 35% over 48 hours is proposed as the minimal rise consistent with a viable intrauterine pregnancy.[22]

Gestational trophoblastic disease like hydatidiform moles ("molar pregnancy") or choriocarcinoma may produce high levels of hCG (due to the presence of syncytialtrophoblasts- part of the villi that make up the placenta) despite the absence of an embryo. This, as well as several other conditions, can lead to elevated hCG readings in the absence of pregnancy.

hCG levels are also a component of the triple test, a screening test for certain fetal chromosomal abnormalities/birth defects.

A study of 32 normal pregnancies came to the result a gestational sac of 13mm was detected at a mean hCG level of 1150 UI/l (range 800-1500), a yolk sac was detected at a mean level of 6000 UI/l (range 4500-7500) and fetal heartbeat was visible at a mean hCG level of 10,000 UI/l (range 8650-12,200).[25]

Human chorionic gonadotropin can be used as a tumor marker,[26] as its subunit is secreted by some cancers including seminoma, choriocarcinoma, germ cell tumors, hydatidiform mole formation, teratoma with elements of choriocarcinoma, and islet cell tumor. For this reason a positive result in males can be a test for testicular cancer. The normal range for men is between 0-5 mIU/mL. Combined with alpha-fetoprotein, -HCG is an excellent tumor marker for the monitoring of germ cell tumors.[citation needed]

Human chorionic gonadotropin is extensively used parenterally for final maturation induction in lieu of luteinizing hormone. In the presence of one or more mature ovarian follicles, ovulation can be triggered by the administration of HCG. As ovulation will happen between 38 and 40 hours after a single HCG injection,[27] procedures can be scheduled to take advantage of this time sequence,[28] such as intrauterine insemination or sexual intercourse. Also, patients that undergo IVF, in general, receive HCG to trigger the ovulation process, but have an oocyte retrieval performed at about 34 to 36 hours after injection by, a few hours before the eggs actually would be released from the ovary.

As HCG supports the corpus luteum, administration of HCG is used in certain circumstances to enhance the production of progesterone.

In the male, HCG injections are used to stimulate the Leydig cells to synthesize testosterone. The intratesticular testosterone is necessary for spermatogenesis from the sertoli cells. Typical uses for HCG in men include hypogonadism and fertility treatment.

Several vaccines against human chorionic gonadotropin (hCG) for the prevention of pregnancy are currently in clinical trials.[29]

In the case of female patients who want to be treated with HCG Pregnyl:[30] a) Since infertile female patients who undergo medically assisted reproduction (especially those who need in vitro fertilization), are known to often be suffering from tubal abnormalities, after a treatment with this drug they might experience many more ectopic pregnancies. This is why early ultrasound confirmation at the beginning of a pregnancy (to see whether the pregnancy is intrauterine or not) is crucial. - Pregnancies that have occurred after a treatment with this medicine are submitted to a higher risk of multiplets. - Female patients who have thrombosis, severe obesity or thrombophilia should not be prescribed this medicine as they have a higher risk of arterial or venous thromboembolic events after or during a treatment with HCG Pregnyl. b)Female patients who have been treated with this medicine are usually more prone to pregnancy losses.

In the case of male patients: A prolonged treatment with HCG Pregnyl is known to regularly lead to increased production of androgen. Therefore: Patients who are suffering from overt or latent cardiac failure, hypertension, renal dysfunction, migraines or epilepsy might not be allowed to start using this medicine or may require a lower dose of HCG Pregnyl. Also this medicine should be used with extreme caution in the treatment of prepubescent teenagers in order to reduce the risk of precocious sexual development or premature epiphyseal closure. This type of patients' skeletal maturation should be closely and regularly monitored.

Both male and female patients who have the following medical conditions must not start a treatment with HCG Pregnyl: (1) Hypersensitivity to this medicine or to any of its main ingredients. (2) Known or possible androgen-dependent tumors for example male breast carcinoma or prostatic carcinoma.

In the world of performance-enhancing drugs, HCG is increasingly used in combination with various anabolic androgenic steroid (AAS) cycles. As a result, HCG is included in some sports' illegal drug lists.

When exogenous AAS are put into the male body, natural negative-feedback loops cause the body to shut down its own production of testosterone via shutdown of the hypothalamic-pituitary-gonadal axis (HPGA). This causes testicular atrophy, among other things. HCG is commonly used during and after steroid cycles to maintain and restore testicular size as well as normal testosterone production.[31]

High levels of AASs, that mimic the body's natural testosterone, trigger the hypothalamus to shut down its production of gonadotropin-releasing hormone (GnRH) from the hypothalamus. Without GnRH, the pituitary gland stops releasing luteinizing hormone (LH). LH normally travels from the pituitary via the blood stream to the testes, where it triggers the production and release of testosterone. Without LH, the testes shut down their production of testosterone.[32] In males, HCG helps restore and maintain testosterone production in the testes by mimicking LH and triggering the production and release of testosterone.

If HCG is used for too long and in too high a dose, the resulting rise in natural testosterone would eventually inhibit its own production via negative feedback on the hypothalamus and pituitary gland.[citation needed]

Professional athletes who have tested positive for HCG have been temporarily banned from their sport, including a 50-game ban from MLB for Manny Ramirez in 2009[33] and a 4-game ban from the NFL for Brian Cushing for a positive urine test for HCG.Mixed Martial Arts fighter Dennis Siver was fined $19,800 and suspended 9 months for being tested positive after his bout at UFC 168.[35]

British endocrinologist Albert T. W. Simeons proposed HCG as an adjunct to an ultra-low-calorie weight-loss diet (fewer than 500 calories).[36] Simeons, while studying pregnant women in India on a calorie-deficient diet, and "fat boys" with pituitary problems (Frlich's syndrome) treated with low-dose HCG, observed that both lost fat rather than lean (muscle) tissue.[36] He reasoned that HCG must be programming the hypothalamus to do this in the former cases in order to protect the developing fetus by promoting mobilization and consumption of abnormal, excessive adipose deposits. Simeons in 1954 published a book entitled Pounds and Inches, designed to combat obesity. Simeons, practicing at Salvator Mundi International Hospital in Rome, Italy, recommended low-dose daily HCG injections (125IU) in combination with a customized ultra-low-calorie (500 cal/day, high-protein, low-carbohydrate/fat) diet, which was supposed to result in a loss of adipose tissue without loss of lean tissue.[36]

Simeons' results were not reproduced by other researchers and in 1976 in response to complaints the FDA required Simeons and others to include the following disclaimer on all advertisements:[37]

These weight reduction treatments include the injection of HCG, a drug which has not been approved by the Food and Drug Administration as safe and effective in the treatment of obesity or weight control. There is no substantial evidence that HCG increases weight loss beyond that resulting from caloric restriction, that it causes a more attractive or "normal" distribution of fat, or that it decreases the hunger and discomfort associated with calorie-restrictive diets.

1976 FDA-mandated disclaimer for HCG diet advertisements

There was a resurgence of interest in the "HCG diet" following promotion by Kevin Trudeau who was later banned from making HCG diet weight-loss claims by the U.S. Federal Trade Commission and eventually jailed over such claims.[38]

While not specifically cited here, review studies refuting the HCG diet have been published in the Journal of the American Medical Association and the American Journal of Clinical Nutrition,[39] concluded that HCG is not more effective as a weight-loss aid than dietary restriction alone.[40]

A meta analysis found that studies supporting HCG for weight loss were of poor methodological quality and concluded that "there is no scientific evidence that HCG is effective in the treatment of obesity; it does not bring about weight-loss or fat-redistribution, nor does it reduce hunger or induce a feeling of well-being".[41]

There is no scientific evidence that HCG is effective in the treatment of obesity. The meta-analysis found insufficient evidence supporting the claims that HCG is effective in altering fat-distribution, hunger reduction or in inducing a feeling of well-being. The authors stated the use of HCG should be regarded as an inappropriate therapy for weight reduction In the authors opinion, Pharmacists and physicians should be alert on the use of HCG for Simeons therapy. The results of this meta-analysis support a firm standpoint against this improper indication. Restraints on physicians practicing this therapy can be based on our findings.

According to the American Society of Bariatric Physicians, no new clinical trials have been published since the definitive 1995 meta-analysis.[42]

The scientific consensus is that any weight loss reported by individuals on an "HCG diet" may be attributed entirely to the fact that such diets prescribe calorie intake of between 500 and 1,000 calories per day, substantially below recommended levels for an adult, to the point that this may risk health effects associated with malnutrition.[43]

Controversy about, and shortages[44] of, injected HCG for weight loss have led to substantial Internet promotion of "homeopathic HCG" for weight control. The ingredients in these products are often obscure, but if prepared from true HCG via homeopathic dilution, they contain either no HCG at all or only trace amounts. Moreover, it is highly unlikely that oral HCG is bioavailable due to the fact that digestive protease enzymes and hepatic metabolism renders peptide-based molecules (such as insulin and human growth hormone) biologically inert. HCG can likely only enter the bloodstream through injection.

The United States Food and Drug Administration has stated that over-the-counter products containing HCG are fraudulent and ineffective for weight loss. They are also not protected as homeopathic drugs and have been deemed illegal substances.[45][46] HCG itself is classified as a prescription drug in the United States and it has not been approved for over-the-counter sales by the FDA as a weight loss product or for any other purposes, and therefore neither HCG in its pure form nor any preparations containing HCG may be sold legally in the country except by prescription.[4] In December 2011, FDA and FTC started to take actions to pull unapproved HCG products from the market.[4] In the aftermath, some suppliers started to switch to "hormone-free" versions of their weight loss products, where the hormone is replaced with an unproven mixture of free amino acids[47] or where radionics is used to transfer the "energy" to the final product.

In order to induce a stronger immune response, some versions of human chorionic gonadotropin based anti-fertility vaccines were designed as conjugates of the subunit of HCG covalently linked to tetanus toxoid.[29][48] It has been alleged that a non-conguated tetanus vaccine used in developing countries is laced with a human chorionic gonadotropin based anti-fertility drug[49] and is distributed as a means of mass sterilization.[50] This charge has been vigorously denied by the World Health Organization (WHO) and UNICEF.[51] Others have argued that a hCG laced vaccine could not be used for sterilization since the effects of the anti-fertility vaccines are reversible (requiring booster doses to maintain immunity) and a non-conjugated vaccine is likely to be ineffective.[52][53] Finally, independent testing of the tetanus vaccine by Kenyas health authorities has revealed no traces of the human chorionic gonadotropin hormone.[54]

PDB gallery

1hcn: STRUCTURE OF HUMAN CHORIONIC GONADOTROPIN AT 2.6 ANGSTROMS RESOLUTION FROM MAD ANALYSIS OF THE SELENOMETHIONYL PROTEIN

1hrp: CRYSTAL STRUCTURE OF HUMAN CHORIONIC GONADOTROPIN

1qfw: TERNARY COMPLEX OF HUMAN CHORIONIC GONADOTROPIN WITH FV ANTI ALPHA SUBUNIT AND FV ANTI BETA SUBUNIT

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Rev Urol. 2004; 6(Suppl 6): S3S8.

Auxilium Pharmaceuticals, Inc., Norristown, PA

Hypogonadism can be of hypothalamic-pituitary origin or of testicular origin, or a combination of both, which is increasingly common in the aging male population. In the postpubertal male, testosterone replacement therapy can be used to treat the signs and symptoms of low testosterone, which include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, loss of muscle mass and strength, and some regression of secondary sexual characteristics. Before initiation of testosterone replacement therapy, an examination of the prostate and assessment of prostate symptoms should be performed, and both the hematocrit and lipid profile should be measured. Absolute contraindications to testosterone replacement therapy are prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation.

Key words: Hypogonadism, Testosterone replacement therapy, Serum hormone-binding globulin, Luteinizing hormone, Follicle-stimulating hormone

Hypogonadism is a lack of testosterone in male patients and can be of central (hypothalamic or pituitary) or testicular origin, or a combination of both. Hypogonadism in male patients with testicular failure due to genetic disorders (eg, Klinefelters syndrome), orchitis, trauma, radiation, chemotherapy, or undescended testes, is known as hypergonadotropic hypogonadism or primary hypogonadism. Hypogonadism in male patients with gonadotropin deficiency or dysfunction as a result of disease or damage to the hypothalamic-pituitary axis is known as hypogonadotropic hypogonadism, central hypogonadism, or secondary hypogonadism. This might be due to Kallmanns syndrome, tumor, trauma, radiation, sarcoidosis, or tuberculosis. In addition, men older than 50 years might have low testosterone levels with functional abnormalities at multiple levels of the hypothalamic-pituitary-testicular axis.1,2,3

The prevalence of hypogonadism has increased in recent years. It has been reported that 12%, 19%, 28%, and 49% of men greater than 50, 60, 70, or 80 years of age, respectively, fit the criteria of hypogonadism.4

During puberty, testosterone is required for the development of male secondary sexual characteristics, stimulation of sexual behavior and function, and initiation of sperm production.5,6 In adult males, testosterone is involved in maintaining muscle mass and strength, fat distribution, bone mass, red blood cell production, male hair pattern, libido and potency, and spermatogenesis.13,5,6

In men, the major gonadal steroid hormone is testosterone. Testosterone circulates in 3 major forms: unbound, or free, testosterone; tightly bound testosterone, which is bound to sex hormone-binding globulin (SHBG); and weakly bound testosterone, which is bound to albumin. Only free and weakly bound testosterone is bioavailable or able to bind to the androgen receptor.2,3

In males, serum testosterone levels show a circadian variation, with the highest levels in the morning and lowest levels in the late afternoon. In young men, the variation in testosterone levels is approximately 35%. Although the normal range for serum testosterone might vary between different laboratories, the normal range for early morning total testosterone in healthy adult males is approximately 300 ng/dL to 1000 ng/dL.7,8

To determine whether a patient is testosterone deficient, a clinician must consider clinical signs and symptoms in conjunction with laboratory values. The initial clinical picture will vary depending on the age of the patient at the onset of the disorder.

In the normal male, the start of puberty is apparent by enlargement of the testes and the appearance of pubic hair, followed by the appearance of auxiliary and facial hair. At puberty there is also increased penile length and the onset of spermatogenesis. If signs of puberty are not evident in boys by 14 years of age, a workup for delayed puberty is warranted.

In the prepubertal age group, hypogonadism might be either primary hypogonadism or secondary hypogonadism. To differentiate primary from secondary hypogonadism, early morning luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels must be obtained. Because LH and FSH are secreted during the early morning at the beginning of puberty, it is necessary to measure these hormones in the early morning (8:0010:00 AM). Primary hypogonadism is associated with low levels of testosterone and high-normal to high levels of LH and FSH. Secondary hypogonadism is associated with low levels of testosterone and normal to low levels of LH and FSH.5,6

The signs and symptoms of low testosterone in postpubertal adult males can be more difficult to diagnose and might include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, loss of muscle mass and strength, and some regression of secondary sexual characteristics.13 At the initial visit, the first objective is to distinguish between primary gonadal failure, in which low testosterone is accompanied by increased FSH and increased LH, and hypothalamic-pituitary disorders (secondary hypogonadism), with low testosterone and low to normal FSH and LH levels.

Initial laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone, prolactin, FSH, and LH levels. For the diagnosis of primary hypogonadism, FSH measurement is particularly important because FSH has a longer half life, is more sensitive, and demonstrates less variability than LH.2,3

The aging male patient can present with signs and symptoms of low testosterone, including loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.13 At the initial visit, laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone. In elderly men, testosterone levels decrease between 15% and 20% over the course of 24 hours.8

Total testosterone levels might be normal with hypogonadism if the SHBG levels are increased.79 Levels of SHBG increase with age, causing a decrease in bioavailable testosterone.9 If testosterone levels are low-normal but the clinical symptoms and signs indicate hypogonadism, measurement of serum total testosterone levels should be repeated and an SHBG level should be determined. With the total testosterone and SHBG levels, a bioavailable testosterone value can be calculated. A bioavailable testosterone calculator is available at http://www.issam.ch/freetesto.htm.

It is usually not necessary to determine FSH or LH levels in the aging male.

It is well accepted that testosterone levels should be measured in the early morning, when they are at their peak level. However, in community practice the choice of which testosterone parameter to measure is still debatable.

Total testosterone assay is widely available and inexpensive to perform. Although the ranges and methods vary, physicians can consult their local laboratories for the applicable values in their clinical practice. Total testosterone values, however, must be interpreted carefully in the aging male because SHBG levels might be elevated. If the total testosterone level is normal in the aging male presenting signs of hypogonadism, the clinician can measure free testosterone or measure SHBG and calculate bioavailable testosterone.9

Free testosterone can be measured by equilibrium dialysis or ultrafiltration, which are difficult to perform and largely unavailable but reliable. In contrast, the radioimmunoassay for free testosterone is widely available but unreliable. Because total testosterone and SHBG assays are readily available and cheap, calculating bioavailable testosterone might be a good compromise. Whichever method is chosen, if the early morning testosterone level is at or below the lower limit of normal for the individual laboratory, then a repeat measurement of the early morning testosterone level should be performed to confirm the result. Because testosterone is secreted in a pulsatile fashion, it is important to obtain 2 early morning testosterone levels.

In selected patients, FSH, LH, and prolactin can be measured. If the FSH and LH levels are raised, this suggests a primary testicular cause, and if levels are low or normal, a hypothalamic or pituitary cause should be considered. A raised prolactin level suggests that further investigation of the pituitary gland should be undertaken.1,2

The clinical signs and symptoms of hypogonadism will vary depending on whether the patient presents before or after puberty. Depending on the age of the patient, the degree of pubertal development is important for establishing the differential diagnosis.

Boys aged 14 years or older should be suspected of being hypogonadal if on examination they have underdeveloped testes, lack of penile enlargement, and absence of pubic, auxiliary, and facial hair.

In patients with primary hypogonadism, history might reveal the cause for primary testicular failure, such as familial autoimmune disease, physical trauma to the testes, or trauma to the testes caused by radiation, chemotherapy, or infection.

A karyotype should be obtained to diagnose chromosomal abnormalities, such as Klinefelters syndrome, and a physical examination will reveal small or absent testes resulting from anorchia, Noonans syndrome, or other testicular disorders.

Hypothalamic or pituitary deficiency might be transitory or permanent. Transient secondary hypogonadism might be related to malnutrition or stress states and can be diagnosed by physical examination and evaluation of the patients growth chart. If permanent hypothalamic or pituitary hormone deficiency is suspected, serum levels of pituitary hormones and magnetic resonance imaging of the brain and pituitary should be obtained to screen for hypothalamic or pituitary disease.

If both physical examination and serum chemistry tests are normal, then by exclusion a diagnosis of constitutional pubertal delay must be considered.

To establish a diagnosis of hypogonadism, it is important to take a careful history to determine whether there have been major medical problems, toxic exposure, concomitant drug therapy that might cause hypogonadism, or fertility problems.

Low libido, impotence, fatigue, impaired concentration, and sexual dysfunction are important clinical problems that might not be raised by the patient in the clinic. Therefore, these symptoms need to be asked about specifically if hypogonadism is suspected.13

Formal assessment of intellectual changes, mood, and cognitive changes can be performed. Changes in lean body mass will be apparent from the medical history and examination, as will changes in hair, skin, and fat distribution. Decreases in bone mineral density might be apparent from a history of recent fractures but can only be confirmed by dual energy x-ray absorptiometry (DEXA).1

Physical examination should include testicular examination, including size and consistency. The distribution and amount of body hair should also be noted. Penile size is not affected by postpubertal testosterone deficiency. An assessment of the prostate by digital rectal examination (DRE) should be performed and a prostate-specific antigen (PSA) value obtained.3

To establish a diagnosis of hypogonadism in the aging male, it is important to assess the patient carefully for signs and symptoms. Low libido, impotence, fatigue, impaired concentration, and sexual dysfunction are important clinical problems that might not be raised by the patient in the clinic, especially by an aging patient. Therefore, as with the younger postpubertal patient, these symptoms need to be asked about specifically if hypogonadism is suspected.1,2 As with the postpubertal patient (see previous section), changes in intellectual functioning; mood; lean body mass; and hair, skin, and fat distribution should all be assessed, and DEXA can be used to confirm decreases in bone mineral density.1

In older patients, an important part of the physical examination includes an assessment of the prostate by DRE and PSA assay. In addition, an assessment of prostate-related symptoms should be undertaken. The presence of gynecomastia or carcinoma of the breast are important physical findings.

In cases of primary and permanent secondary hypogonadism diagnosed in the prepubertal male, life long testosterone treatment is needed. The usual treatment is initiation of therapy with small doses of testosterone (50100 mg IM) every 3 to 4 weeks at the appropriate psychosocial stage in development. When a final adult height is thought to have been obtained, the adult dose of testosterone replacement is inaugurated.

In the postpubertal period, once the diagnosis of testosterone deficiency has been made, replacement therapy should be considered in light of the clinical signs and symptoms in conjunction with the laboratory values. The objective of testosterone replacement therapy is to normalize serum testosterone and maintain the level within the eugonadal state. In addition, treatment objectives might include improving sexual dysfunction, intellectual capacity, depression, and lethargy; maintaining bone mineral density and possibly reducing fracture risk; increasing muscle mass and strength; and enhancing the quality of life.13,9

Although the normal range for serum testosterone might vary between different laboratories, the normal range for early morning testosterone in male adults is approximately 300 ng/dL to 1000 ng/dL.7 An early morning total serum testosterone level of less than 300 ng/dL clearly indicates hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy. A healthy male adult patient with a serum testosterone level greater than 400 ng/dL is unlikely to be testosterone deficient, and therefore clinical judgment should be exercised if he has symptoms suggestive of testosterone deficiency.

There are some absolute contraindications to testosterone replacement therapy. These include prostate cancer, which must be assessed by history and clinical examination. If on DRE the prostate is enlarged or if the PSA level is greater than 4.0 ng/mL, biopsy of the prostate should be undertaken to confirm a diagnosis of prostate cancer or benign prostatic hyperplasia (BPH).3

An existing or prior history of breast cancer is also an absolute contraindication to testosterone replacement therapy. Testosterone therapy is known to increase the hematocrit, and therefore a pre-existing hematocrit of 55% or greater is an absolute contraindication to replacement therapy.

Sensitivity to any of the ingredients in the testosterone formulation would also be an absolute contraindication. Relative contraindications include an increased hematocrit, untreated sleep apnea, severe obstructive symptoms of BPH, and advanced congestive cardiac failure.2,3

The goal of replacement therapy is to maintain testosterone in the normal physiological range; therefore, a combination of clinical and biochemical measures should be monitored 6 to 12 weeks after initiating therapy. In most cases, an early morning serum total testosterone level is adequate to determine whether dosage adjustment is necessary. However, patients receiving injections of testosterone enanthate or cypionate every 2 weeks will require an earlier measurement of serum testosterone at 1 to 2 weeks after commencement of therapy.3

Examination of the prostate should be performed routinely, although the exact frequency after initiation of testosterone replacement is still debatable. Digital rectal examination of the prostate and PSA assay should be performed before initiation of therapy, along with an assessment of prostate-related symptoms. In elderly men, a DRE and PSA assay should be performed at 3 and 6 months after commencing testosterone therapy and then annually thereafter.3 A high PSA level should be further evaluated with a highly specific PSA assay, if available. A patient should be referred to a urologist if his PSA level increases over time or if he has a PSA level greater than 4.0 ng/mL.3

It is known that testosterone stimulates bone marrow production of erythrocytes, which might result in an increased hematocrit in some men, and therefore this should be checked at the same time as the PSA level.2,3

Lipid disturbances in testosterone-treated male patients are generally not a problem because the ratio of high-density lipoprotein to total cholesterol usually remains constant. An initial lipid profile should be performed before therapy, and a follow-up profile should be obtained after 6 to 12 months of therapy and annually thereafter.3

Hypogonadism can be of hypothalamic-pituitary origin or of testicular origin, or a combination of both, which is increasingly common in the aging male population. It can be easily diagnosed with measurement of the early morning serum total testosterone level, which should be repeated if the value is low. Follicle-stimulating hormone, LH, and prolactin might also need to be measured. If the clinical signs and symptoms suggest hypogonadism but the serum testosterone level is near normal, then assay of serum testosterone should be repeated in conjunction with SHBG because serum testosterone might be normal in the presence of hypogonadism if the SHBG level is raised, which commonly occurs in elderly male patients.

Before initiation of testosterone replacement therapy, an examination of the prostate, including DRE, PSA assay, and assessment of prostate symptoms should be undertaken, and both the hematocrit and lipid profile should be measured. There are few absolute contraindications to testosterone replacement therapy other than prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation. Monitoring of the prostate (assessed with DRE and PSA assay) and hematocrit and lipid profile should be repeated during testosterone replacement therapy.

The benefits of testosterone replacement therapy may include restoring metabolic parameters to the eugonadal state; improving psychosexual function and intellectual capacity, including depression and lethargy; maintaining bone mineral density and reducing bone fractures; improving muscle mass and strength; and enhancing quality of life.

Hypogonadism is a lack of testosterone in male patients and can be of central (hypothalamic or pituitary) or testicular origin, or a combination of both.

Boys ages 14 years or older should be suspected of being hypogonadal if on examination they have underdeveloped testes, a lack of penile enlargement, and an absence of pubic, auxiliary, and facial hair.

In pre- and postpubertal male patients, primary hypogonadism is associated with low levels of testosterone and high-normal to high levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH); secondary hypogonadism is associated with low levels of testosterone and normal to low levels of LH and FSH.

In the aging male patient, signs and symptoms of hypogonadism can include loss of libido, erectile dysfunction, diminished intellectual capacity, depression, lethargy, osteoporosis, and loss of muscle mass and strength.

For aging men, laboratory testing should include early morning (8:0010:00 AM) measurement of serum testosterone; levels less than 300 ng/dL clearly indicate hypogonadism, and under most circumstances benefit will be derived from testosterone replacement therapy.

Before initiation of testosterone replacement therapy, an examination of the prostate and assessment of prostate symptoms should be performed, and both the hematocrit and lipid profile should be measured.

There are few absolute contraindications to testosterone replacement therapy other than prostate or breast cancer, a hematocrit of 55% or greater, or sensitivity to the testosterone formulation.

1. AACE Hypogonadism Task Force. Endocr Pract. 2002;8:439456.

5. Griffin JE, Wilson JD. Endocrinology & Metabolism. 15th Ed. Vol. 335. New York, NY: McGraw Hill; 2001. Disorders of the testes. Harrisons principles of internal medicine; pp. 21432154.

6. Beers MH, Berkow R, editors. The Merck Manual of Diagnosis and Therapy. 17th ed. New York, NY: John Wiley & Sons; 1999.

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Diagnosis of Hypogonadism: Clinical Assessments and ...

Recommendation and review posted by simmons

Some types of cancer run in certain families, but most cancers are not clearly linked to the genes we inherit from our parents. Gene changes that start in a single cell over the course of a person's life cause most cancers. In this section you can learn more about the complex links between genes and cancer.

Cancer is such a common disease that it is no surprise that many families have at least a few members who have had cancer. Sometimes, certain types of cancer seem to run in some families. But only a small portion of all cancers are inherited. This document focuses on those cancers.

Advances in genetics and molecular biology have improved our knowledge of the inner workings of cells, the basic building blocks of the body. Here we review how cells can change during a persons life to become cancer, how certain types of changes can build on inherited gene changes to speed up the development of cancer, and how this information can help us better prevent and treat cancer.

Genetic testing can be useful for people with certain types of cancer that seem to run in their families, but these tests aren't recommended for everyone. Here we offer basic information to help you understand what genetic testing is and how it is used in cancer.

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Genetics and Cancer | American Cancer Society

Recommendation and review posted by sam

The directory of Innovative Doctors and Health Practitioners is a worldwide listing of anti-aging doctors and other medical professionals who practice or have expressed interest in all aspects of preventive medicine (such as heart attack and stroke prevention), hormone replacement therapy, nutrition and dietary supplements, and other areas of alternative and complementary medicine. Invariably, they welcome individuals who choose to be involved in their own health care.

Provided to you by Extension, the directory of Innovative Doctors and Health Practitioners facilitates the location of anti-aging doctors and health practitioners who are open to alternatives to allopathic medicine. Conveniently organized geographically, the listing can be used to find a doctor by areaa handy feature for those who are traveling or are simply seeking out anti-aging doctors or health practitioners at home. The directory of Innovative Doctors and Health Practitioners is especially useful for those on a life extension program that includes the use of dietary supplements and hormones, as the listed physicians and health practitioners would likely be more suited to evaluate such a program than more conventional doctors.

While prevention, nutrition and longevity are important to the physicians and health practitioners listed, each of them has their own approach to health and wellness. So be sure to clarify the reason for your visit, as well as your goals in seeking out such treatment when scheduling your appointment.

ALABAMA ALASKA AMERICAN SAMOA ARIZONA ARKANSAS ARMED FORCES AMERICAS ARMED FORCES EUROPE ARMED FORCES PACIFIC CALIFORNIA COLORADO CONNECTICUT DELAWARE DISTRICT OF COLUMBIA FLORIDA GEORGIA GUAM HAWAII IDAHO ILLINOIS INDIANA IOWA KANSAS KENTUCKY LOUISIANA MAINE MARSHALL ISLANDS MARYLAND MASSACHUSETTS MICHIGAN MICRONESIA FED STATES MINNESOTA MISSISSIPPI MISSOURI MONTANA NEBRASKA NEVADA NEW HAMPSHIRE NEW JERSEY NEW MEXICO NEW SOUTH WALES NEW YORK NORTH CAROLINA NORTH DAKOTA NORTHERN MARIANA ISLANDS OHIO OKLAHOMA OREGON PALAU PENNSYLVANIA PLEASE SELECT PUERTO RICO RHODE ISLAND SOUTH AUSTRALIA SOUTH CAROLINA SOUTH DAKOTA TASMANIA TENNESSEE TEXAS UTAH VERMONT VICTORIA VIRGIN ISLANDS VIRGINIA WASHINGTON WEST VIRGINIA WISCONSIN WYOMING

DISCLAIMER: Inclusion in the directory of Innovative Doctors and Health and Wellness Practitioners does not constitute endorsement by Life Extension, nor are these physicians or other health practitioners affiliated with Life Extension. All physicians and health practitioners who appear on this list do so on the sole basis of their own expression of interest in the fields of health and wellness, longevity, or preventive medicine. Life Extension has not verified the competence, professional credentials, business practices or validity of the expressed interests of these physicians and health practitioners. Life Extension makes no recommendation of any physician or health practitioner on this list and makes no suggestion that any such physician or health practitioner will cure or prevent any disease, reduce anyone's rate of aging or extend anyone's life. Those consulting a physician or other health practitioner on this list should approach the consultation exactly as they would with any other unknown physician or health practitioner. Listings are periodically updated. However, physicians and health practitioners are not obligated to notify Life Extension should they relocate or retire. Life Extension relies in great part on feedback, which determines the continued eligibility of the physicians and health practitioners listed. Please contact Life Extension if you have any comments concerning any of the physicians or other health practitioners on this list.

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Recommendation and review posted by Bethany Smith

RATIONALE:

Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis.

To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects.

Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4 1.7%, P=0.0002) and decreased scar mass (-47.5 8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93 0.07), whereas revascularized (0.5 0.21) and nontreated segments (-0.07 0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments).

Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications.

http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

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Autologous mesenchymal stem cells produce concordant ...

Recommendation and review posted by simmons

Myotonic dystrophy type 1 (DM1) is caused by expanded Cytosine-Thymine-Guanine (CTG) repeats in the 3'-untranslated region (3' UTR) of the Dystrophia myotonica protein kinase (DMPK) gene, for which there is no effective therapy. The objective of this study is to develop genome therapy in human DM1 induced pluripotent stem (iPS) cells to eliminate mutant transcripts and reverse the phenotypes for developing autologous stem cell therapy. The general approach involves targeted insertion of polyA signals (PASs) upstream of DMPK CTG repeats, which will lead to premature termination of transcription and elimination of toxic mutant transcripts. Insertion of PASs was mediated by homologous recombination triggered by site-specific transcription activator-like effector nuclease (TALEN)-induced double-strand break. We found genome-treated DM1 iPS cells continue to maintain pluripotency. The insertion of PASs led to elimination of mutant transcripts and complete disappearance of nuclear RNA foci and reversal of aberrant splicing in linear-differentiated neural stem cells, cardiomyocytes, and teratoma tissues. In conclusion, genome therapy by insertion of PASs upstream of the expanded DMPK CTG repeats prevented the production of toxic mutant transcripts and reversal of phenotypes in DM1 iPS cells and their progeny. These genetically-treated iPS cells will have broad clinical application in developing autologous stem cell therapy for DM1.Molecular Therapy (2016); doi:10.1038/mt.2016.97.

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Genome Therapy of Myotonic Dystrophy Type 1 iPS Cells for ...

Recommendation and review posted by Bethany Smith