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Gene Therapy For Cancer Treatment – Doctor answers on …

From a medical standpoint, “genetic” refers to the potential heritability of various medical conditions. While some conditions are inevitable (at some point in one’s life) as a consequence of simple genetic heritability (eg huntington’s disease), a large number of medical conditions (including all behaviorial health disorders) are the expressed final pathway of a complex interplay of factors. …Read more

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Genetic Testing Report – genome.gov

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

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

September 1997

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

ACKNOWLEDGEMENTS

EXECUTIVE SUMMARY

ENSURING THE SAFETY AND EFFECTIVENESS OF NEW GENETIC TESTS

ENSURING THE QUALITY OF LABORATORIES PERFORMING GENETIC TESTS

IMPROVING PROVIDERS’ UNDERSTANDINGS OF GENETIC TESTING

GENETIC TESTING FOR RARE INHERITED DISORDERS

Chapter 1: INTRODUCTION

Chapter 2: ENSURING THE SAFETY AND EFFECTIVENESS OF NEW

Chapter 3: ENSURING THE QUALITY OF LABORATORIES PERFORMING GENETIC TESTS

Chapter 4: IMPROVING PROVIDERS’ UNDERSTANDINGS OF GENETIC TESTING

Chapter 5: GENETIC TESTING FOR RARE INHERITED DISORDERS

Chapter 6: SUMMARY AND CONCLUSIONS

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

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

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

Appendix 4: Informational Materials about Genetic Tests

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

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

GLOSSARY

Top of page

Last Reviewed: October 1, 2012

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What Is Genetic Testing — Information About Genetic Testing

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

Types of genetic tests include:

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

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

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

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

Sources:

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

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

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

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What Is Genetic Testing — Information About Genetic Testing

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Regenerative medicine IPS Cell Therapy IPS Cell Therapy

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

21 October 2014

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

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

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

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

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

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

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

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Regenerative medicine IPS Cell Therapy IPS Cell Therapy

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Jewish Genetics, Part 1: Jewish Populations (Ashkenazim …

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

Excerpts from page 16222:

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

Excerpts from page 16223:

“The higher diversity in the AJ population was paralleled by a lower inbreeding coefficient, F, indicating the AJ population is more outbred than Europeans, not inbred, as has long been assumed (P

Excerpts from pages 16223-16224:

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

Excerpts from page 16224:

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

Excerpts from page 16226:

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

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

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

Razib Khan. “Genetics and the Jews.” Discover Magazine – Gene Expression (June 6, 2010).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

“Evrei i kurdi – brat’ya po genam.” MIGnews.com (Media International Group)

Max Gross. “‘A Certain People’: Study Confirms Deep Similarities Among Jews.” Forward (August 16, 2002): B11. Excerpts:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

“Jews and Arabs are ‘genetic brothers’.” BBC News (May 10, 2000). Excerpts:

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

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

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

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

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

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

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

Excerpts from page 882:

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

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

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

Razib Khan. “Genetics and the Jews (it’s still complicated.)” Discover Magazine – Gene Expression (June 10, 2010). Excerpts:

Excerpts from the body of the article:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Donald Macintyre. “3.5 million Ashkenazi Jews ‘traced to four female ancestors’.” The Independent (January 14, 2006).

“‘Four mothers’ for Europe’s Jews.” BBC News (January 13, 2006). Excerpts:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Jewish Genetics, Part 1: Jewish Populations (Ashkenazim …

Recommendation and review posted by simmons

Hypopituitarism – Hormonal and Metabolic Disorders – Merck …

By Ian M. Chapman, MBBS, PhD

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

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

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

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

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

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

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

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

DELATESTRYL

PARLODEL

CRINONE

CORTEF, SOLU-CORTEF

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

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

See more here:
Hypopituitarism – Hormonal and Metabolic Disorders – Merck …

Recommendation and review posted by simmons

Stem Cell Serums Visibly Renew Skin / Lifeline Skin Care Blog

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

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

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

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

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

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

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Stem Cell Serums Visibly Renew Skin / Lifeline Skin Care Blog

Recommendation and review posted by Bethany Smith

Stem Cell Niches for Skin Regeneration

Int J Biomater. 2012; 2012: 926059.

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

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

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

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

Academic Editor: Kadriye Tuzlakoglu

Received 2012 Jan 15; Accepted 2012 Apr 8.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Originally posted here:
Stem Cell Niches for Skin Regeneration

Recommendation and review posted by sam

anti-aging stem cells – innovative treatments for skin …

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

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

Expected benefits of stem cells technology for regenerative skin care:

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

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

Our Stem Cell Applications:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[ pH: 5.00 ]

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

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

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

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

[ pH: 4.7 ]

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

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

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

[ pH: 6.00 ]

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

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

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

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

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

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

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

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

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

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

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

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

[ pH: 5.00 ]

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

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

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

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

[ pH: 5.75 ]

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

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

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

[ pH: 5.50 ]

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

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

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

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

[ pH: 6.25 ]

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

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

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

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

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

[ pH: 5.5 ]

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

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

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

[ pH: 5.75 ]

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

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

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

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

[ pH: 6.25 ]

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

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

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

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

[ pH: 6.25 ]

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

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

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

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

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

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

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

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

[ pH: 4.5 ]

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

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

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

[ pH: 7.0 ]

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

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

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

[ pH: 3.00 ]

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

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

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anti-aging stem cells – innovative treatments for skin …

Recommendation and review posted by Bethany Smith

Skin – Wikipedia, the free encyclopedia

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

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

Mammalian skin is composed of two primary layers:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Skin performs the following functions:

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

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

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

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

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

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

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Skin – Wikipedia, the free encyclopedia

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Gene Therapy

Gene Therapy- An Overview

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

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

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

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Gene Therapy

Recommendation and review posted by sam

Scientist Explains the Genetics of Male Pattern Baldness

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

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

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

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

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

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

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

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

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

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

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

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Scientist Explains the Genetics of Male Pattern Baldness

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San Antonio Natural Hormone Therapy Clinic | Bio-Identical …

Bio-Identical

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

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

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

Exclusive Interview

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San Antonio Natural Hormone Therapy Clinic | Bio-Identical …

Recommendation and review posted by Bethany Smith

Bone marrow mesenchymal stem cells stimulate cardiac stem …

RATIONALE:

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

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

Female Yorkshire pigs (n=31) underwent experimental myocardial infarction (MI), and 3 days later, received transendocardial injections of allogeneic male bone marrow-derived MSCs, MSC concentrated conditioned medium (CCM), or placebo (Plasmalyte). A no-injection control group was also studied. MSCs engrafted and differentiated into cardiomyocytes and vascular structures. In addition, endogenous c-kit(+) CSCs increased 20-fold in MSC-treated animals versus controls (P

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

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Bone marrow mesenchymal stem cells stimulate cardiac stem …

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stem cells – Cosmetic Ingredient Dictionary: Cosmetics Cop …

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

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

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

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

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

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stem cells – Cosmetic Ingredient Dictionary: Cosmetics Cop …

Recommendation and review posted by simmons

Transgender hormone therapy Clinic

Educational Materials

Youth: Special Considerations

Transgender Terminology

Resources

Trans Affirming Therapists

Driver’s License

Social Security

Passport

Peer Support Group: Being Me

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

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

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

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

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

Google+

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Transgender hormone therapy Clinic

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What is a Stem Cell Transplant (Bone Marrow Transplant …

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

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

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

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

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

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

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

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

Allogeneic transplantation. Doctors call this an ALLO transplant.

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

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

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

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

Ablative, which uses high-dose chemotherapy

Reduced intensity, which uses milder doses of chemotherapy

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

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

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

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

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

Who can care for you during treatment

How long you will be away from work and family responsibilities

If your insurance pays for the transplant

Who can take you to transplant appointments

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

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

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

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

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

Time: 1 to 2 weeks

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

Time: 5 to 10 days

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

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

Where its done: Clinic or hospital.

Time: approximately 2 weeks

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

Time: Varies based on how the stem cells are collected

Where its done: Clinic or hospital

Time: 5 to 7 days

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

Time: 1 day

Where its done: Clinic or hospital.

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

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

Time: Varies

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

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

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

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

Infection from low numbers of white cells, which fight infections

Bleeding from low numbers of platelets, which stop bleeding

Tiredness from low numbers of red cells, which carry oxygen

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

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

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

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

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

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

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

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

How will we know if the transplant works?

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

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

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

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

Bone Marrow Aspiration and Biopsy

Making Decisions About Cancer Treatment

Donating Blood and Platelets

Donating Umbilical Cord Blood

Explore BMT

Be the Match: National Marrow Donor Program

Blood & Marrow Transplant Information Network

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

National Bone Marrow Transplant Link

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

Recommendation and review posted by simmons

The Endocrine Clinic | Singapore Hormone Specialists

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

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

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

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

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

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The Endocrine Clinic | Singapore Hormone Specialists

Recommendation and review posted by Bethany Smith

Bone marrow mesenchymal stem cells: biological properties …

Mesenchymal stem cells (MSCs) are multipotent adult stem cells that are present in practically all tissues as a specialized population of mural cells/pericytes that lie on the abluminal side of blood vessels. Originally identified within the bone marrow (BM) stroma, not only do they provide microenvironmental support for hematopoietic stem cells (HSCs), but can also differentiate into various mesodermal lineages. MSCs can easily be isolated from the BM and subsequently expand in vitro and in addition they exhibit intriguing immunomodulatory properties, thereby emerging as attractive candidates for various therapeutic applications. This review addresses the concept of BM MSCs via a hematologist’s point of view. In this context it discusses the stem cell properties that have been attributed to BM MSCs, as compared to those of the prototypic hematopoietic stem cell model and then gives a brief overview of the in vitro and vivo features of the former, emphasizing on their immunoregulatory properties and their hematopoiesis-supporting role. In addition, the qualitative and quantitative characteristics of BM MSCs within the context of a defective microenvironment, such as the one characterizing Myelodysplastic Syndromes are described and the potential involvement of these cells in the pathophysiology of the disease is discussed. Finally, emerging clinical applications of BM MSCs in the field of hematopoietic stem cell transplantation are reviewed and potential hazards from MSC use are outlined.

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Bone marrow mesenchymal stem cells: biological properties …

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Genetics – X Linked Problems – The Biology Corner

Name:_____________________________________

**In fruit flies, eye color is a sex linked trait. Red is dominant to white.**

1. What are the sexes and eye colors of flies with the following genotypes?

X R X r _________ X R Y __________ X r X r __________

X R X R ____________ X r Y ____________

2. What are the genotypes of these flies:

white eyed, male ____________ red eyed female (heterozygous) ________

white eyed, female ___________ red eyed, male ___________

3. Show the cross of a white eyed female X r X r with a red-eyed male X R Y .

4. Show a cross between a pure red eyed female and a white eyed male. What are the genotypes of the parents:

___________ and _______________

How many are:

white eyed, male ____ white eyed, female ____ red eyed, male ____ red eyed, female ____

5. Show the cross of a red eyed female (heterozygous) and a red eyed male.

What are the genotypes of the parents?

___________ & ________________

How many are:

white eyed, male ____ white eyed, female ____ red eyed, male ____ red eyed, female ____

Math: What if in the above cross, 100 males were produced and 200 females. How many total red-eyed flies would there be? ________

6. In humans, hemophilia is a sex linked trait. Females can be normal, carriers, or have the disease. Males will either have the disease or not (but they wont ever be carriers)

X h Y= male, hemophiliac

Show the cross of a man who has hemophilia with a woman who is a carrier.

What is the probability that their children will have the disease? __________

7. A woman who is a carrier marries a normal man. Show the cross. What is the probability that their children will have hemophilia? What sex will a child in the family with hemophilia be?

8. A woman who has hemophilia marries a normal man. How many of their children will have hemophilia, and what is their sex?

9. In cats, the gene for calico (multicolored) cats is codominant. Females that receive a B and an R gene have black and oRange splotches on white coats. Males can only be black or orange, but never calico.

Heres what a calico females genotype would look like: X B X R

Show the cross of a female calico cat with a black male?

What percentage of the kittens will be black and male? _________ What percentage of the kittens will be calico and male? _________ What percentage of the kittens will be calico and female? _________

10. Show the cross of a female black cat, with a male orange cat.

What percentage of the kittens will be calico and female? _____What color will all the male cats be? ______

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Genetics – X Linked Problems – The Biology Corner

Recommendation and review posted by Bethany Smith

Scientists Turn Skin Cells Into Heart and Brain Cells …

Neurons created from chemically induced neural stem cells. The cells were created from skin cells that were reprogrammed into neural stem cells using a cocktail of only nine chemicals. This is the first time cellular reprogramming has been accomplished without adding external genes to the cells. (credit: Mingliang Zhang, PhD, Gladstone Institutes)

Scientists at the Gladstone Institutes have used chemicals to transform skin cells into heart cells and brain cells, instead of adding external genes making this accomplishment a breakthrough, according to the scientists.

The research lays the groundwork for one day being able to regenerate lost or damaged cells directly with pharmaceutical drugs a more efficient and reliable method to reprogram cells and one that avoids medical concerns surrounding genetic engineering.

Instead, in two studies published in an open-access paper in Scienceand in Cell Stem Cell, the team of scientists at the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone used chemical cocktails to gradually coax skin cells to change into organ-specific stem-cell-like cells and ultimately into heart or brain cells.

This method brings us closer to being able to generate new cells at the site of injury in patients, said Gladstone senior investigatorSheng Ding, PhD, the senior author on both studies. Our hope is to one day treat diseases like heart failure or Parkinsons disease with drugs that help the heart and brain regenerate damaged areas from their own existing tissue cells. This process is much closer to the natural regeneration that happens in animals like newts and salamanders, which has long fascinated us.

Chemically Repaired Hearts

A human heart cell that was chemically reprogrammed from a human skin cell (credit: Nan Cao/Gladstone Institutes)

Transplanted adult heart cells do not survive or integrate properly into the heart and few stem cells can be coaxed into becoming heart cells.

Instead, in theSciencestudy, the researchers used a cocktail of nine chemicals to change human skin cells into beating heart cells. By trial and error, they found the best combination of chemicals to begin the process by changing the cells into a state resembling multipotent stem cells (cells that can turn into many different types of cells in a particular organ). A second cocktail of chemicals and growth factors then helped transition the cells to become heart muscle cells.

With this method, more than 97% of the cells began beating, a characteristic of fully developed, healthy heart cells. The cells also responded appropriately to hormones, and molecularly, they resembled heart muscle cells, not skin cells. Whats more, when the cells were transplanted into a mouse heart early in the process, they developed into healthy-looking heart muscle cells within the organ.

The ultimate goal in treating heart failure is a robust, reliable way for the heart to create new muscle cells, said Srivastava, co-senior author on the Science paper. Reprogramming a patients own cells could provide the safest and most efficient way to regenerate dying or diseased heart muscle.

Rejuvenating the brain withneural stem cell-like cells

In the second study, authored by Gladstone postdoctoral scholar Mingliang Zhang, PhD, and published inCell Stem Cell, the scientists created neural stem-cell-like cells from mouse skin cells using a similar approach.

The chemical cocktail again consisted of nine molecules, some of which overlapped with those used in the first study. Over ten days, the cocktail changed the identity of the cells, until all of the skin-cell genes were turned off and the genes of the neural stem-cell-like cells were gradually turned on.

When transplanted into mice, theneural stem-cell-like cells spontaneously developed into the three basic types of brain cells: neurons, oligodendrocytes, and astrocytes. The neuralstem-cell-like cells were also able to self-replicate, making them ideal for treating neurodegenerative diseases or brain injury.

With their improved safety, these neural stem-cell-like cells could one day be used for cell replacement therapy in neurodegenerative diseases like Parkinsons disease and Alzheimers disease, according to co-senior authorYadong Huang, MD, PhD, a senior investigator at Gladstone. In the future, we could even imagine treating patients with a drug cocktail that acts on the brain or spinal cord, rejuvenating cells in the brain in real time.

Gladstone Institutes | Chemically Reprogrammed Beating Heart Cell

Abstract ofConversion of human fibroblasts into functional cardiomyocytes by small molecules

Reprogramming somatic fibroblasts into alternative lineages would provide a promising source of cells for regenerative therapy. However, transdifferentiating human cells to specific homogeneous, functional cell types is challenging. Here we show that cardiomyocyte-like cells can be generated by treating human fibroblasts with a combination of nine compounds (9C). The chemically induced cardiomyocyte-like cells (ciCMs) uniformly contracted and resembled human cardiomyocytes in their transcriptome, epigenetic, and electrophysiological properties. 9C treatment of human fibroblasts resulted in a more open-chromatin conformation at key heart developmental genes, enabling their promoters/enhancers to bind effectors of major cardiogenic signals. When transplanted into infarcted mouse hearts, 9C-treated fibroblasts were efficiently converted to ciCMs. This pharmacological approach for lineage-specific reprogramming may have many important therapeutic implications after further optimization to generate mature cardiac cells.

Abstract ofPharmacological Reprogramming of Fibroblasts into Neural Stem Cells by Signaling-Directed Transcriptional Activation

Cellular reprogramming using chemically defined conditions, without genetic manipulation, is a promising approach for generating clinically relevant cell types for regenerative medicine and drug discovery. However, small-molecule approaches for inducing lineage-specific stem cells from somatic cells across lineage boundaries have been challenging. Here, we report highly efficient reprogramming of mouse fibroblasts into induced neural stem cell-like cells (ciNSLCs) using a cocktail of nine components (M9). The resulting ciNSLCs closely resemble primary neural stem cells molecularly and functionally. Transcriptome analysis revealed that M9 induces a gradual and specific conversion of fibroblasts toward a neural fate. During reprogramming specific transcription factors such as Elk1 and Gli2 that are downstream of M9-induced signaling pathways bind and activate endogenous master neural genes to specify neural identity. Our study provides an effective chemical approach for generating neural stem cells from mouse fibroblasts and reveals mechanistic insights into underlying reprogramming processes.

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Scientists Turn Skin Cells Into Heart and Brain Cells …

Recommendation and review posted by Bethany Smith

The Benefits of Using Growth Factors from Human Stem Cells …

Submitted by Lifeline Skin Care on Wed, 2013-05-15 00:00

Biologists are working diligently to find ways to repair diseased tissues or spinal cord injuries with stem cells. Scientists dont have all of those answers yet, but heres what they have figured out: how to repair skin aging with stem cells. Front and center of all of that attention is Lifeline Skin Carethe first anti-aging skin care brand based on human, non-embryonic stem cells.

Human stem cells have the remarkable ability to develop into many different cell types in the bodylungs, liver, hair, skin, etc. But as we get older, the role of stem cells changesand stem cells become the chief repair mechanism for tissue that has become aged, injured or damaged. Adult stem cells remain dormant until they detect cellular damage; then they work to repair or replace the damaged cell. Its this ability that makes stem cells of great interest in repairing skin aging.

The nutrient-rich growth factors, peptides and proteins that are contained in the stem cells are the workhorses for skin repair. The growth factors are responsible for cellular growth, proliferation and repair. They play an important role in maintaining healthy skin structure and function. They help repair wounds; they help promote the formation of collagen; they help regenerate new, healthy tissue. The result: reduced hyperpigmentation, enhanced elasticity, and reduced fine lines and wrinkles.

The genes that are most important to the health and appearance of the skin are Elastin, Collagen, Epidermal Growth Factors, Keratinocyte Growth Factors and Fibroblast Growth Factors.

Laboratory studies showed how exposure to Lifeline creams can increase the expression level of key proteins:

Collagen is the most important protein and provides structure and firmness to the skin. Lifelines stem cell extract increased collagen 42%-55%.

Elastin is responsible for load-bearing and elasticity. Its crucial for keeping skin smooth, supple, firm and tight. The key ingredient in Lifelines stem cell extract increased elastin 46%.

Epidermal growth factors (EGF) stimulate cells to divide. Its natural for skin cells to continue to divide, but with age this process slows. Epidermal growth factors help speed up the renewal process, speeding the production of new, healthy skin cells. The stem cell growth factors contained in Lifelines stem cell extract increased EGF a remarkable 436%.

Keratinocyte growth factors (KGF) help repair injured skin by stimulating cellular proliferation.The stem cell growth factors contained in Lifelines stem cell extract increased KGF 58%.

Fibroblast growth factors (FGF) help repair damaged tissue and promote wound healing. They also play an important role in repairing post-procedural skin damage. The growth factors contained in Lifelines stem cell extract increased FGF 200%.

Lifeline Skin Care serums contain human stem cell growth factors which are taken from human, non-embryonic stem cells. It is this mixture that regulates collagen, elastin and cell proliferation, making the skin cells healthier, stronger and younger-looking.

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The Benefits of Using Growth Factors from Human Stem Cells …

Recommendation and review posted by Bethany Smith

Hypogonadism Symptoms, Diagnosis, Treatments and Causes …

Hypogonadism: Introduction

Hypogonadism: Medical term for a defect of the reproductive system that results in lack of function of the gonads (ovaries or testes). More detailed information about the symptoms, causes, and treatments of Hypogonadism is available below.

Read more about symptoms of Hypogonadism

Home medical testing related to Hypogonadism:

Read more about complications of Hypogonadism.

See full list of 99 causes of Hypogonadism

More information about causes of Hypogonadism:

Research the causes of these diseases that are similar to, or related to, Hypogonadism:

Commonly undiagnosed diseases in related medical categories:

Misdiagnosed weight-related causes of infertility: A woman’s weight status can affect her level of fertility. Although obesity or overweight can in themselves reduce fertility, there are…read more

Read more about Misdiagnosis and Hypogonadism

Research related physicians and medical specialists:

Other doctor, physician and specialist research services:

Rare types of diseases and disorders in related medical categories:

More Hypogonadism animations & videos

Visit our research pages for current research about Hypogonadism treatments.

The US based website ClinicalTrials.gov lists information on both federally and privately supported clinical trials using human volunteers.

Some of the clinical trials listed on ClinicalTrials.gov for Hypogonadism include:

See full list of 55 Clinical Trials for Hypogonadism

Types of Hypogonadism

Related forums and medical stories:

Read about other experiences, ask a question about Hypogonadism, or answer someone else’s question, on our message boards:

Condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development. – (Source – Diseases Database)

Incompetence of the gonads (especially in the male with low testosterone); results in deficient development of secondary sex characteristics and (in prepubertal males) a body with long legs and a short trunk – (Source – WordNet 2.1)

Hypogonadism is listed as a “rare disease” by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). This means that Hypogonadism, or a subtype of Hypogonadism, affects less than 200,000 people in the US population. Source – National Institutes of Health (NIH)

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Hypogonadism Symptoms, Diagnosis, Treatments and Causes …

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DNA repair Wikipedia, the free encyclopedia IPS Cell …

DNA damage resulting in multiple broken chromosomes

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as UV light and radiation can cause DNA damage, resulting in as many as 1 million individual molecular lesions per cell per day.[1] Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cells ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cells genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur, including double-strand breaks and DNA crosslinkages (interstrand crosslinks or ICLs).[2][3]

The rate of DNA repair is dependent on many factors, including the cell type, the age of the cell, and the extracellular environment. A cell that has accumulated a large amount of DNA damage, or one that no longer effectively repairs damage incurred to its DNA, can enter one of three possible states:

The DNA repair ability of a cell is vital to the integrity of its genome and thus to the normal functionality of that organism. Many genes that were initially shown to influence life span have turned out to be involved in DNA damage repair and protection.[4]

The 2015 Nobel Prize in Chemistry was awarded to Tomas Lindahl, Paul Modrich, and Aziz Sancar for their work on the molecular mechanisms of DNA repair processes.[5][6]

DNA damage, due to environmental factors and normal metabolic processes inside the cell, occurs at a rate of 10,000 to 1,000,000 molecular lesions per cell per day.[1] While this constitutes only 0.000165% of the human genomes approximately 6 billion bases (3 billion base pairs), unrepaired lesions in critical genes (such as tumor suppressor genes) can impede a cells ability to carry out its function and appreciably increase the likelihood of tumor formation and contribute to tumour heterogeneity.

The vast majority of DNA damage affects the primary structure of the double helix; that is, the bases themselves are chemically modified. These modifications can in turn disrupt the molecules regular helical structure by introducing non-native chemical bonds or bulky adducts that do not fit in the standard double helix. Unlike proteins and RNA, DNA usually lacks tertiary structure and therefore damage or disturbance does not occur at that level. DNA is, however, supercoiled and wound around packaging proteins called histones (in eukaryotes), and both superstructures are vulnerable to the effects of DNA damage.

DNA damage can be subdivided into two main types:

The replication of damaged DNA before cell division can lead to the incorporation of wrong bases opposite damaged ones. Daughter cells that inherit these wrong bases carry mutations from which the original DNA sequence is unrecoverable (except in the rare case of a back mutation, for example, through gene conversion).

There are several types of damage to DNA due to endogenous cellular processes:

Damage caused by exogenous agents comes in many forms. Some examples are:

UV damage, alkylation/methylation, X-ray damage and oxidative damage are examples of induced damage. Spontaneous damage can include the loss of a base, deamination, sugar ring puckering and tautomeric shift.

In human cells, and eukaryotic cells in general, DNA is found in two cellular locations inside the nucleus and inside the mitochondria. Nuclear DNA (nDNA) exists as chromatin during non-replicative stages of the cell cycle and is condensed into aggregate structures known as chromosomes during cell division. In either state the DNA is highly compacted and wound up around bead-like proteins called histones. Whenever a cell needs to express the genetic information encoded in its nDNA the required chromosomal region is unravelled, genes located therein are expressed, and then the region is condensed back to its resting conformation. Mitochondrial DNA (mtDNA) is located inside mitochondria organelles, exists in multiple copies, and is also tightly associated with a number of proteins to form a complex known as the nucleoid. Inside mitochondria, reactive oxygen species (ROS), or free radicals, byproducts of the constant production of adenosine triphosphate (ATP) via oxidative phosphorylation, create a highly oxidative environment that is known to damage mtDNA. A critical enzyme in counteracting the toxicity of these species is superoxide dismutase, which is present in both the mitochondria and cytoplasm of eukaryotic cells.

Senescence, an irreversible process in which the cell no longer divides, is a protective response to the shortening of the chromosome ends. The telomeres are long regions of repetitive noncoding DNA that cap chromosomes and undergo partial degradation each time a cell undergoes division (see Hayflick limit).[10] In contrast, quiescence is a reversible state of cellular dormancy that is unrelated to genome damage (see cell cycle). Senescence in cells may serve as a functional alternative to apoptosis in cases where the physical presence of a cell for spatial reasons is required by the organism,[11] which serves as a last resort mechanism to prevent a cell with damaged DNA from replicating inappropriately in the absence of pro-growth cellular signaling. Unregulated cell division can lead to the formation of a tumor (see cancer), which is potentially lethal to an organism. Therefore, the induction of senescence and apoptosis is considered to be part of a strategy of protection against cancer.[12]

It is important to distinguish between DNA damage and mutation, the two major types of error in DNA. DNA damages and mutation are fundamentally different. Damages are physical abnormalities in the DNA, such as single- and double-strand breaks, 8-hydroxydeoxyguanosine residues, and polycyclic aromatic hydrocarbon adducts. DNA damages can be recognized by enzymes, and, thus, they can be correctly repaired if redundant information, such as the undamaged sequence in the complementary DNA strand or in a homologous chromosome, is available for copying. If a cell retains DNA damage, transcription of a gene can be prevented, and, thus, translation into a protein will also be blocked. Replication may also be blocked or the cell may die.

In contrast to DNA damage, a mutation is a change in the base sequence of the DNA. A mutation cannot be recognized by enzymes once the base change is present in both DNA strands, and, thus, a mutation cannot be repaired. At the cellular level, mutations can cause alterations in protein function and regulation. Mutations are replicated when the cell replicates. In a population of cells, mutant cells will increase or decrease in frequency according to the effects of the mutation on the ability of the cell to survive and reproduce. Although distinctly different from each other, DNA damages and mutations are related because DNA damages often cause errors of DNA synthesis during replication or repair; these errors are a major source of mutation.

Given these properties of DNA damage and mutation, it can be seen that DNA damages are a special problem in non-dividing or slowly dividing cells, where unrepaired damages will tend to accumulate over time. On the other hand, in rapidly dividing cells, unrepaired DNA damages that do not kill the cell by blocking replication will tend to cause replication errors and thus mutation. The great majority of mutations that are not neutral in their effect are deleterious to a cells survival. Thus, in a population of cells composing a tissue with replicating cells, mutant cells will tend to be lost. However, infrequent mutations that provide a survival advantage will tend to clonally expand at the expense of neighboring cells in the tissue. This advantage to the cell is disadvantageous to the whole organism, because such mutant cells can give rise to cancer. Thus, DNA damages in frequently dividing cells, because they give rise to mutations, are a prominent cause of cancer. In contrast, DNA damages in infrequently dividing cells are likely a prominent cause of aging.[13]

Single-strand and double-strand DNA damage

Cells cannot function if DNA damage corrupts the integrity and accessibility of essential information in the genome (but cells remain superficially functional when non-essential genes are missing or damaged). Depending on the type of damage inflicted on the DNAs double helical structure, a variety of repair strategies have evolved to restore lost information. If possible, cells use the unmodified complementary strand of the DNA or the sister chromatid as a template to recover the original information. Without access to a template, cells use an error-prone recovery mechanism known as translesion synthesis as a last resort.

Damage to DNA alters the spatial configuration of the helix, and such alterations can be detected by the cell. Once damage is localized, specific DNA repair molecules bind at or near the site of damage, inducing other molecules to bind and form a complex that enables the actual repair to take place.

Cells are known to eliminate three types of damage to their DNA by chemically reversing it. These mechanisms do not require a template, since the types of damage they counteract can occur in only one of the four bases. Such direct reversal mechanisms are specific to the type of damage incurred and do not involve breakage of the phosphodiester backbone. The formation of pyrimidine dimers upon irradiation with UV light results in an abnormal covalent bond between adjacent pyrimidine bases. The photoreactivation process directly reverses this damage by the action of the enzyme photolyase, whose activation is obligately dependent on energy absorbed from blue/UV light (300500nm wavelength) to promote catalysis.[14] Photolyase, an old enzyme present in bacteria, fungi, and most animals no longer functions in humans,[15] who instead use nucleotide excision repair to repair damage from UV irradiation. Another type of damage, methylation of guanine bases, is directly reversed by the protein methyl guanine methyl transferase (MGMT), the bacterial equivalent of which is called ogt. This is an expensive process because each MGMT molecule can be used only once; that is, the reaction is stoichiometric rather than catalytic.[16] A generalized response to methylating agents in bacteria is known as the adaptive response and confers a level of resistance to alkylating agents upon sustained exposure by upregulation of alkylation repair enzymes.[17] The third type of DNA damage reversed by cells is certain methylation of the bases cytosine and adenine.

When only one of the two strands of a double helix has a defect, the other strand can be used as a template to guide the correction of the damaged strand. In order to repair damage to one of the two paired molecules of DNA, there exist a number of excision repair mechanisms that remove the damaged nucleotide and replace it with an undamaged nucleotide complementary to that found in the undamaged DNA strand.[16]

Double-strand breaks, in which both strands in the double helix are severed, are particularly hazardous to the cell because they can lead to genome rearrangements. Three mechanisms exist to repair double-strand breaks (DSBs): non-homologous end joining (NHEJ), microhomology-mediated end joining (MMEJ), and homologous recombination.[16] PVN Acharya noted that double-strand breaks and a cross-linkage joining both strands at the same point is irreparable because neither strand can then serve as a template for repair. The cell will die in the next mitosis or in some rare instances, mutate.[2][3]

In NHEJ, DNA Ligase IV, a specialized DNA ligase that forms a complex with the cofactor XRCC4, directly joins the two ends.[21] To guide accurate repair, NHEJ relies on short homologous sequences called microhomologies present on the single-stranded tails of the DNA ends to be joined. If these overhangs are compatible, repair is usually accurate.[22][23][24][25] NHEJ can also introduce mutations during repair. Loss of damaged nucleotides at the break site can lead to deletions, and joining of nonmatching termini forms insertions or translocations. NHEJ is especially important before the cell has replicated its DNA, since there is no template available for repair by homologous recombination. There are backup NHEJ pathways in higher eukaryotes.[26] Besides its role as a genome caretaker, NHEJ is required for joining hairpin-capped double-strand breaks induced during V(D)J recombination, the process that generates diversity in B-cell and T-cell receptors in the vertebrate immune system.[27]

MMEJ starts with short-range end resection by MRE11 nuclease on either side of a double-strand break to reveal microhomology regions.[28] In further steps,[29] PARP1 is required and may be an early step in MMEJ. There is pairing of microhomology regions followed by recruitment of flap structure-specific endonuclease 1 (FEN1) to remove overhanging flaps. This is followed by recruitment of XRCC1LIG3 to the site for ligating the DNA ends, leading to an intact DNA.

DNA double strand breaks in mammalian cells are primarily repaired by homologous recombination (HR) and non-homologous end joining (NHEJ).[30] In an in vitro system, MMEJ occurred in mammalian cells at the levels of 1020% of HR when both HR and NHEJ mechanisms were also available.[28] MMEJ is always accompanied by a deletion, so that MMEJ is a mutagenic pathway for DNA repair.[31]

Homologous recombination requires the presence of an identical or nearly identical sequence to be used as a template for repair of the break. The enzymatic machinery responsible for this repair process is nearly identical to the machinery responsible for chromosomal crossover during meiosis. This pathway allows a damaged chromosome to be repaired using a sister chromatid (available in G2 after DNA replication) or a homologous chromosome as a template. DSBs caused by the replication machinery attempting to synthesize across a single-strand break or unrepaired lesion cause collapse of the replication fork and are typically repaired by recombination.

Topoisomerases introduce both single- and double-strand breaks in the course of changing the DNAs state of supercoiling, which is especially common in regions near an open replication fork. Such breaks are not considered DNA damage because they are a natural intermediate in the topoisomerase biochemical mechanism and are immediately repaired by the enzymes that created them.

A team of French researchers bombarded Deinococcus radiodurans to study the mechanism of double-strand break DNA repair in that bacterium. At least two copies of the genome, with random DNA breaks, can form DNA fragments through annealing. Partially overlapping fragments are then used for synthesis of homologous regions through a moving D-loop that can continue extension until they find complementary partner strands. In the final step there is crossover by means of RecA-dependent homologous recombination.[32]

Translesion synthesis (TLS) is a DNA damage tolerance process that allows the DNA replication machinery to replicate past DNA lesions such as thymine dimers or AP sites.[33] It involves switching out regular DNA polymerases for specialized translesion polymerases (i.e. DNA polymerase IV or V, from the Y Polymerase family), often with larger active sites that can facilitate the insertion of bases opposite damaged nucleotides. The polymerase switching is thought to be mediated by, among other factors, the post-translational modification of the replication processivity factor PCNA. Translesion synthesis polymerases often have low fidelity (high propensity to insert wrong bases) on undamaged templates relative to regular polymerases. However, many are extremely efficient at inserting correct bases opposite specific types of damage. For example, Pol mediates error-free bypass of lesions induced by UV irradiation, whereas Pol introduces mutations at these sites. Pol is known to add the first adenine across the T^T photodimer using Watson-Crick base pairing and the second adenine will be added in its syn conformation using Hoogsteen base pairing. From a cellular perspective, risking the introduction of point mutations during translesion synthesis may be preferable to resorting to more drastic mechanisms of DNA repair, which may cause gross chromosomal aberrations or cell death. In short, the process involves specialized polymerases either bypassing or repairing lesions at locations of stalled DNA replication. For example, Human DNA polymerase eta can bypass complex DNA lesions like guanine-thymine intra-strand crosslink, G[8,5-Me]T, although can cause targeted and semi-targeted mutations.[34] Paromita Raychaudhury and Ashis Basu[35] studied the toxicity and mutagenesis of the same lesion in Escherichia coli by replicating a G[8,5-Me]T-modified plasmid in E. coli with specific DNA polymerase knockouts. Viability was very low in a strain lacking pol II, pol IV, and pol V, the three SOS-inducible DNA polymerases, indicating that translesion synthesis is conducted primarily by these specialized DNA polymerases. A bypass platform is provided to these polymerases by Proliferating cell nuclear antigen (PCNA). Under normal circumstances, PCNA bound to polymerases replicates the DNA. At a site of lesion, PCNA is ubiquitinated, or modified, by the RAD6/RAD18 proteins to provide a platform for the specialized polymerases to bypass the lesion and resume DNA replication.[36][37] After translesion synthesis, extension is required. This extension can be carried out by a replicative polymerase if the TLS is error-free, as in the case of Pol , yet if TLS results in a mismatch, a specialized polymerase is needed to extend it; Pol . Pol is unique in that it can extend terminal mismatches, whereas more processive polymerases cannot. So when a lesion is encountered, the replication fork will stall, PCNA will switch from a processive polymerase to a TLS polymerase such as Pol to fix the lesion, then PCNA may switch to Pol to extend the mismatch, and last PCNA will switch to the processive polymerase to continue replication.

Cells exposed to ionizing radiation, ultraviolet light or chemicals are prone to acquire multiple sites of bulky DNA lesions and double-strand breaks. Moreover, DNA damaging agents can damage other biomolecules such as proteins, carbohydrates, lipids, and RNA. The accumulation of damage, to be specific, double-strand breaks or adducts stalling the replication forks, are among known stimulation signals for a global response to DNA damage.[38] The global response to damage is an act directed toward the cells own preservation and triggers multiple pathways of macromolecular repair, lesion bypass, tolerance, or apoptosis. The common features of global response are induction of multiple genes, cell cycle arrest, and inhibition of cell division.

After DNA damage, cell cycle checkpoints are activated. Checkpoint activation pauses the cell cycle and gives the cell time to repair the damage before continuing to divide. DNA damage checkpoints occur at the G1/S and G2/M boundaries. An intra-S checkpoint also exists. Checkpoint activation is controlled by two master kinases, ATM and ATR. ATM responds to DNA double-strand breaks and disruptions in chromatin structure,[39] whereas ATR primarily responds to stalled replication forks. These kinases phosphorylate downstream targets in a signal transduction cascade, eventually leading to cell cycle arrest. A class of checkpoint mediator proteins including BRCA1, MDC1, and 53BP1 has also been identified.[40] These proteins seem to be required for transmitting the checkpoint activation signal to downstream proteins.

DNA damage checkpoint is a signal transduction pathway that blocks cell cycle progression in G1, G2 and metaphase and slows down the rate of S phase progression when DNA is damaged. It leads to a pause in cell cycle allowing the cell time to repair the damage before continuing to divide.

Checkpoint Proteins can be separated into four groups: phosphatidylinositol 3-kinase (PI3K)-like protein kinase, proliferating cell nuclear antigen (PCNA)-like group, two serine/threonine(S/T) kinases and their adaptors. Central to all DNA damage induced checkpoints responses is a pair of large protein kinases belonging to the first group of PI3K-like protein kinases-the ATM (Ataxia telangiectasia mutated) and ATR (Ataxia- and Rad-related) kinases, whose sequence and functions have been well conserved in evolution. All DNA damage response requires either ATM or ATR because they have the ability to bind to the chromosomes at the site of DNA damage, together with accessory proteins that are platforms on which DNA damage response components and DNA repair complexes can be assembled.

An important downstream target of ATM and ATR is p53, as it is required for inducing apoptosis following DNA damage.[41] The cyclin-dependent kinase inhibitor p21 is induced by both p53-dependent and p53-independent mechanisms and can arrest the cell cycle at the G1/S and G2/M checkpoints by deactivating cyclin/cyclin-dependent kinase complexes.[42]

The SOS response is the changes in gene expression in Escherichia coli and other bacteria in response to extensive DNA damage. The prokaryotic SOS system is regulated by two key proteins: LexA and RecA. The LexA homodimer is a transcriptional repressor that binds to operator sequences commonly referred to as SOS boxes. In Escherichia coli it is known that LexA regulates transcription of approximately 48 genes including the lexA and recA genes.[43] The SOS response is known to be widespread in the Bacteria domain, but it is mostly absent in some bacterial phyla, like the Spirochetes.[44] The most common cellular signals activating the SOS response are regions of single-stranded DNA (ssDNA), arising from stalled replication forks or double-strand breaks, which are processed by DNA helicase to separate the two DNA strands.[38] In the initiation step, RecA protein binds to ssDNA in an ATP hydrolysis driven reaction creating RecAssDNA filaments. RecAssDNA filaments activate LexA autoprotease activity, which ultimately leads to cleavage of LexA dimer and subsequent LexA degradation. The loss of LexA repressor induces transcription of the SOS genes and allows for further signal induction, inhibition of cell division and an increase in levels of proteins responsible for damage processing.

In Escherichia coli, SOS boxes are 20-nucleotide long sequences near promoters with palindromic structure and a high degree of sequence conservation. In other classes and phyla, the sequence of SOS boxes varies considerably, with different length and composition, but it is always highly conserved and one of the strongest short signals in the genome.[44] The high information content of SOS boxes permits differential binding of LexA to different promoters and allows for timing of the SOS response. The lesion repair genes are induced at the beginning of SOS response. The error-prone translesion polymerases, for example, UmuCD2 (also called DNA polymerase V), are induced later on as a last resort.[45] Once the DNA damage is repaired or bypassed using polymerases or through recombination, the amount of single-stranded DNA in cells is decreased, lowering the amounts of RecA filaments decreases cleavage activity of LexA homodimer, which then binds to the SOS boxes near promoters and restores normal gene expression.

Eukaryotic cells exposed to DNA damaging agents also activate important defensive pathways by inducing multiple proteins involved in DNA repair, cell cycle checkpoint control, protein trafficking and degradation. Such genome wide transcriptional response is very complex and tightly regulated, thus allowing coordinated global response to damage. Exposure of yeast Saccharomyces cerevisiae to DNA damaging agents results in overlapping but distinct transcriptional profiles. Similarities to environmental shock response indicates that a general global stress response pathway exist at the level of transcriptional activation. In contrast, different human cell types respond to damage differently indicating an absence of a common global response. The probable explanation for this difference between yeast and human cells may be in the heterogeneity of mammalian cells. In an animal different types of cells are distributed among different organs that have evolved different sensitivities to DNA damage.[46]

In general global response to DNA damage involves expression of multiple genes responsible for postreplication repair, homologous recombination, nucleotide excision repair, DNA damage checkpoint, global transcriptional activation, genes controlling mRNA decay, and many others. A large amount of damage to a cell leaves it with an important decision: undergo apoptosis and die, or survive at the cost of living with a modified genome. An increase in tolerance to damage can lead to an increased rate of survival that will allow a greater accumulation of mutations. Yeast Rev1 and human polymerase are members of [Y family translesion DNA polymerases present during global response to DNA damage and are responsible for enhanced mutagenesis during a global response to DNA damage in eukaryotes.[38]

DNA repair rate is an important determinant of cell pathology

Experimental animals with genetic deficiencies in DNA repair often show decreased life span and increased cancer incidence.[13] For example, mice deficient in the dominant NHEJ pathway and in telomere maintenance mechanisms get lymphoma and infections more often, and, as a consequence, have shorter lifespans than wild-type mice.[47] In similar manner, mice deficient in a key repair and transcription protein that unwinds DNA helices have premature onset of aging-related diseases and consequent shortening of lifespan.[48] However, not every DNA repair deficiency creates exactly the predicted effects; mice deficient in the NER pathway exhibited shortened life span without correspondingly higher rates of mutation.[49]

If the rate of DNA damage exceeds the capacity of the cell to repair it, the accumulation of errors can overwhelm the cell and result in early senescence, apoptosis, or cancer. Inherited diseases associated with faulty DNA repair functioning result in premature aging,[13] increased sensitivity to carcinogens, and correspondingly increased cancer risk (see below). On the other hand, organisms with enhanced DNA repair systems, such as Deinococcus radiodurans, the most radiation-resistant known organism, exhibit remarkable resistance to the double-strand break-inducing effects of radioactivity, likely due to enhanced efficiency of DNA repair and especially NHEJ.[50]

Most life span influencing genes affect the rate of DNA damage

A number of individual genes have been identified as influencing variations in life span within a population of organisms. The effects of these genes is strongly dependent on the environment, in particular, on the organisms diet. Caloric restriction reproducibly results in extended lifespan in a variety of organisms, likely via nutrient sensing pathways and decreased metabolic rate. The molecular mechanisms by which such restriction results in lengthened lifespan are as yet unclear (see[51] for some discussion); however, the behavior of many genes known to be involved in DNA repair is altered under conditions of caloric restriction.

For example, increasing the gene dosage of the gene SIR-2, which regulates DNA packaging in the nematode worm Caenorhabditis elegans, can significantly extend lifespan.[52] The mammalian homolog of SIR-2 is known to induce downstream DNA repair factors involved in NHEJ, an activity that is especially promoted under conditions of caloric restriction.[53] Caloric restriction has been closely linked to the rate of base excision repair in the nuclear DNA of rodents,[54] although similar effects have not been observed in mitochondrial DNA.[55]

It is interesting to note that the C. elegans gene AGE-1, an upstream effector of DNA repair pathways, confers dramatically extended life span under free-feeding conditions but leads to a decrease in reproductive fitness under conditions of caloric restriction.[56] This observation supports the pleiotropy theory of the biological origins of aging, which suggests that genes conferring a large survival advantage early in life will be selected for even if they carry a corresponding disadvantage late in life.

Defects in the NER mechanism are responsible for several genetic disorders, including:

Mental retardation often accompanies the latter two disorders, suggesting increased vulnerability of developmental neurons.

Other DNA repair disorders include:

All of the above diseases are often called segmental progerias (accelerated aging diseases) because their victims appear elderly and suffer from aging-related diseases at an abnormally young age, while not manifesting all the symptoms of old age.

Other diseases associated with reduced DNA repair function include Fanconi anemia, hereditary breast cancer and hereditary colon cancer.

Because of inherent limitations in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer.[57][58] There are at least 34 Inherited human DNA repair gene mutations that increase cancer risk. Many of these mutations cause DNA repair to be less effective than normal. In particular, Hereditary nonpolyposis colorectal cancer (HNPCC) is strongly associated with specific mutations in the DNA mismatch repair pathway. BRCA1 and BRCA2, two famous genes whose mutations confer a hugely increased risk of breast cancer on carriers, are both associated with a large number of DNA repair pathways, especially NHEJ and homologous recombination.

Cancer therapy procedures such as chemotherapy and radiotherapy work by overwhelming the capacity of the cell to repair DNA damage, resulting in cell death. Cells that are most rapidly dividing most typically cancer cells are preferentially affected. The side-effect is that other non-cancerous but rapidly dividing cells such as progenitor cells in the gut, skin, and hematopoietic system are also affected. Modern cancer treatments attempt to localize the DNA damage to cells and tissues only associated with cancer, either by physical means (concentrating the therapeutic agent in the region of the tumor) or by biochemical means (exploiting a feature unique to cancer cells in the body).

Classically, cancer has been viewed as a set of diseases that are driven by progressive genetic abnormalities that include mutations in tumour-suppressor genes and oncogenes, and chromosomal aberrations. However, it has become apparent that cancer is also driven by epigenetic alterations.[59]

Epigenetic alterations refer to functionally relevant modifications to the genome that do not involve a change in the nucleotide sequence. Examples of such modifications are changes in DNA methylation (hypermethylation and hypomethylation) and histone modification,[60] changes in chromosomal architecture (caused by inappropriate expression of proteins such as HMGA2 or HMGA1)[61] and changes caused by microRNAs. Each of these epigenetic alterations serves to regulate gene expression without altering the underlying DNA sequence. These changes usually remain through cell divisions, last for multiple cell generations, and can be considered to be epimutations (equivalent to mutations).

While large numbers of epigenetic alterations are found in cancers, the epigenetic alterations in DNA repair genes, causing reduced expression of DNA repair proteins, appear to be particularly important. Such alterations are thought to occur early in progression to cancer and to be a likely cause of the genetic instability characteristic of cancers.[62][63][64][65]

Reduced expression of DNA repair genes causes deficient DNA repair. When DNA repair is deficient DNA damages remain in cells at a higher than usual level and these excess damages cause increased frequencies of mutation or epimutation. Mutation rates increase substantially in cells defective in DNA mismatch repair[66][67] or in homologous recombinational repair (HRR).[68] Chromosomal rearrangements and aneuploidy also increase in HRR defective cells.[69]

Higher levels of DNA damage not only cause increased mutation, but also cause increased epimutation. During repair of DNA double strand breaks, or repair of other DNA damages, incompletely cleared sites of repair can cause epigenetic gene silencing.[70][71]

Deficient expression of DNA repair proteins due to an inherited mutation can cause increased risk of cancer. Individuals with an inherited impairment in any of 34 DNA repair genes (see article DNA repair-deficiency disorder) have an increased risk of cancer, with some defects causing up to a 100% lifetime chance of cancer (e.g. p53 mutations).[72] However, such germline mutations (which cause highly penetrant cancer syndromes) are the cause of only about 1 percent of cancers.[73]

Deficiencies in DNA repair enzymes are occasionally caused by a newly arising somatic mutation in a DNA repair gene, but are much more frequently caused by epigenetic alterations that reduce or silence expression of DNA repair genes. For example, when 113 colorectal cancers were examined in sequence, only four had a missense mutation in the DNA repair gene MGMT, while the majority had reduced MGMT expression due to methylation of the MGMT promoter region (an epigenetic alteration).[74] Five different studies found that between 40% and 90% of colorectal cancers have reduced MGMT expression due to methylation of the MGMT promoter region.[75][76][77][78][79]

Similarly, out of 119 cases of mismatch repair-deficient colorectal cancers that lacked DNA repair gene PMS2 expression, PMS2 was deficient in 6 due to mutations in the PMS2 gene, while in 103 cases PMS2 expression was deficient because its pairing partner MLH1 was repressed due to promoter methylation (PMS2 protein is unstable in the absence of MLH1).[80] In the other 10 cases, loss of PMS2 expression was likely due to epigenetic overexpression of the microRNA, miR-155, which down-regulates MLH1.[81]

In further examples (tabulated in Cancer epigenetics), epigenetic defects were found at frequencies of between 13%-100% for the DNA repair genes BRCA1, WRN, FANCB, FANCF, MGMT, MLH1, MSH2, MSH4, ERCC1, XPF, NEIL1 and ATM. These epigenetic defects occurred in various cancers (e.g. breast, ovarian, colorectal and head and neck). Two or three deficiencies in the expression of ERCC1, XPF or PMS2 occur simultaneously in the majority of the 49 colon cancers evaluated by Facista et al.[82]

The chart in this section shows some frequent DNA damaging agents, examples of DNA lesions they cause, and the pathways that deal with these DNA damages. At least 169 enzymes are either directly employed in DNA repair or influence DNA repair processes.[83] Of these, 83 are directly employed in the 5 types of DNA repair processes illustrated in the chart. The more well studied genes central to these repair processes are also shown in the chart. As indicated by the DNA repair genes shown in red, many of the genes in these repair pathways are regulated by epigenetic mechanisms, and these are frequently reduced or silent in various cancers (marked by an asterisk). Two review articles,[65][84] and two broad experimental survey articles[85][86] document most of these epigenetic DNA repair deficiencies.

It appears that epigenetic repression of DNA repair genes in accurate DNA repair pathways are central to carcinogenesis. However microhomology-mediated end joining (MMEJ) is an additional error-prone repair pathway for double-strand breaks. In MMEJ repair of a double-strand break, an homology of 5 25 complementary base pairs on both strands is identified and used as a basis to align the strands, but with mismatched ends. MMEJ removes extra nucleotides (flaps) where strands are joined, then ligates the strands to create an intact DNA double helix. MMEJ always involves at least a small deletion, so that it is a mutagenic pathway.[30]FEN1, the flap endonuclease in MMEJ, is epigenetically increased by promoter hypomethylation and is over-expressed in the majority of cancers of the breast,[87] prostate,[88] stomach,[89][90] neuroblastomas,[91] pancreatic,[92] and lung.[93] Other genes in the MMEJ pathway are also over-expressed in a number of cancers (see MMEJ for summary), and are shown in cyan (blue) in the chart in this section.

The basic processes of DNA repair are highly conserved among both prokaryotes and eukaryotes and even among bacteriophage (viruses that infect bacteria); however, more complex organisms with more complex genomes have correspondingly more complex repair mechanisms.[94] The ability of a large number of protein structural motifs to catalyze relevant chemical reactions has played a significant role in the elaboration of repair mechanisms during evolution. For an extremely detailed review of hypotheses relating to the evolution of DNA repair, see.[95]

The fossil record indicates that single-cell life began to proliferate on the planet at some point during the Precambrian period, although exactly when recognizably modern life first emerged is unclear. Nucleic acids became the sole and universal means of encoding genetic information, requiring DNA repair mechanisms that in their basic form have been inherited by all extant life forms from their common ancestor. The emergence of Earths oxygen-rich atmosphere (known as the oxygen catastrophe) due to photosynthetic organisms, as well as the presence of potentially damaging free radicals in the cell due to oxidative phosphorylation, necessitated the evolution of DNA repair mechanisms that act specifically to counter the types of damage induced by oxidative stress.

On some occasions, DNA damage is not repaired, or is repaired by an error-prone mechanism that results in a change from the original sequence. When this occurs, mutations may propagate into the genomes of the cells progeny. Should such an event occur in a germ line cell that will eventually produce a gamete, the mutation has the potential to be passed on to the organisms offspring. The rate of evolution in a particular species (or, in a particular gene) is a function of the rate of mutation. As a consequence, the rate and accuracy of DNA repair mechanisms have an influence over the process of evolutionary change.[96] Since the normal adaptation of populations of organisms to changing circumstances (for instance the adaptation of the beaks of a population of finches to the changing presence of hard seeds or insects) proceeds by gene regulation and the recombination and selection of gene variations alleles and not by passing on irreparable DNA damages to the offspring,[97] DNA damage protection and repair does not influence the rate of adaptation by gene regulation and by recombination and selection of alleles. On the other hand, DNA damage repair and protection does influence the rate of accumulation of irreparable, advantageous, code expanding, inheritable mutations, and slows down the evolutionary mechanism for expansion of the genome of organisms with new functionalities. The tension between evolvability and mutation repair and protection needs further investigation.

A technology named clustered regularly interspaced short palindromic repeat shortened to CRISPR-Cas9 was discovered in 2012. The new technology allows anyone with molecular biology training to alter the genes of any species with precision.[98]

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Genetics and Inheritance – National Fragile X Foundation

What Are Chromosomes?

Our bodies are made up of about 60 trillion cells. Each one of those cells manufactures proteins. The kinds of proteins any given cell makes determine its particular characteristics, which in turn create the characteristics of the entire body.

The instructions for making these proteins are stored in chemicals or molecules called DNA, which is organized into chromosomes. Chromosomes are found in the center, or nucleus, of all of our cells, including the eggs and sperm.

Female Chromosomes

Male Chromosomes

Chromosomes are passed down from generation to generation through the egg and sperm. Typically, we all have 46 chromosomes in our cells, two of which are sex chromosomes. In females, these are two Xs; in males they are an X and a Y.

Genes are sections of DNA that are passed from generation to generation and perform one function. If we think of DNA as letters in the alphabet, the genes are words and the chromosome is a full sentence. All 46 chromosomes then make up the whole book.

There are many genes on each chromosome; we all have tens of thousands of genes that instruct our bodies on how to develop.

Genes are given names to identify them and the gene responsible for fragile X syndrome is called FMR1. The FMR1 Gene is on the X chromosome.

The FMR1 gene appears in four forms that are defined by the number of repeats of a pattern of DNA called CGG repeats.

Individuals with less than 45 CGG repeats have a normal FMR1 gene. Those with 45-54 CGG repeats have what is called an intermediate or grey zone allele, which does not cause any of the known fragile X associated disorders.

Individuals with 55-200 CGG repeats have a premutation, which means they carry an unstable mutation of the gene that can expand in future generations and thus cause fragile X syndrome in their children or grandchildren. Individuals with a premutation can also develop FXTAS or FXPOI themselves.

Individuals with over 200 CGG repeats have a full mutation of the FMR1 gene, which causes fragile X syndrome.

The full mutation causes the FMR1 gene to shut down or methylate in one region. Normally, the FMR1 gene produces an important protein called FMRP. When the gene is turned off, the individual does not make this protein. The lack of this specific protein is what causes fragile X syndrome.

Fragile X-associated Disorders are a group of conditions called trinucleotide repeat disorders. A common feature of these conditions is that the gene can change sizes over generations, becoming more unstable, and thus the conditions may occur more frequently or severely in subsequent generations. These conditions are often caused by a gene change that begins with a premutation and then expands to a full mutation in subsequent generations.

Approximately 1 in 151 females and 1 in 468 males carry the FMR1 premutation. They are thus carriers of the premutation.

Premutations are defined as having 55-200 CGG repeats and can occur in both males and females. When a father passes the premutation on to his daughters, it usually does not expand to a full mutation. A man never passes the fragile X gene to his sons, since he passes only his Y chromosome to them, which does not contain a fragile X gene.

A female with the FMR1 premutation will often pass on a larger version of the mutation to her children (more on this point below). She also has a 50 percent chance of passing on her normal X chromosome in each pregnancy, since usually only one of her X chromosomes has the FMR1 mutation.

The chance of the premutation expanding to a full mutation is related to the size of the mothers premutation. The larger the mothers CGG repeat number, the higher the chance that it will expand to a full mutation if it is passed on.

Typically, the premutation has no immediate and observable impact on a persons appearance or health. However, some females with a premutation will experience fragile X-associated primary ovarian insufficiency (FXPOI), which causes infertility, irregular or missed menstrual cycles, and/or early menopause.

Additionally, some older adults with a premutation may develop a neurological condition called FXTAS, (fragile X-associated tremor/ataxia syndrome), an adult onset neurodegenerative disorder.

FXTAS and FXPOI are part of the family of conditions called Fragile X-associated Disorders.

A full mutation is defined as having over 200 CGG repeats and causes that indicate the presence of fragile X syndrome in males and some females. Most full mutation expansions have some degree of Methylation (the process which turns off the gene). Males with a full mutation will have Fragile X Syndrome, though with varying degrees of severity

About 65-70 percent of females with a full mutation exhibit some difficulties with cognitive, learning, behavioral, or social functioning, and may also have some of the physical features of FXS (such as large ears or a long face). The remaining 30-35 percent are at risk to develop mental health issues such as anxiety or depression, or they may have no observable effects of the full mutation.

Fragile X in an X-linked condition, which means that the gene is on the X chromosome.

Since a woman has two X chromosomes a woman with a premutation or full mutation has a 50% chance of passing on the X with the mutation in each pregnancy, and a 50% chance of passing on her normal X.

If she has a premutation, and it is passed on (to either males or females), it can remain a premutation or it can expand to a full mutation. If she has a full mutation and it is passed on (to either males or females), it will remain a full mutation.

Because males have only one X chromosome, fathers who carry the premutation will pass it on to all their daughters and none of their sons (they pass their Y chromosome on to their sons). There have been no reports of premutations that are passed from a father to his daughter expanding to a full mutation. This appears to only occur when passed from a mother to her children.

In many X-linked conditions only males who inherit the abnormal gene are affected. Fragile X syndrome is one of the X-linked conditions that can also affect females.

Additionally, in other X-linked conditions all males who carry the abnormal form of the gene are affected. In fragile X syndrome, unaffected males can carry the gene in the premutation form while themselves having no symptoms of the condition.

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