Yesterday, Stem Cell Reports published must read paper, which describes manufacturing of GMP-grade iPS cell line for potential clinical use. We saw a few very similar paper titles in in the past, but this one is special. Here is why:

We didnt want Lonza to own the process, even though they helped develop it, Rao said, speaking on his own behalf. We wanted the government to be able to provide the process to people, so they could modify it or have access to the process at a reasonable cost. That was one reason why the government funded this All the basic processes will be free.

I have few general consideration about this protocol and few technical. Lets start from general: Since, Im as US taxpayer also funded this study, Id like to have an option for process tech transfer to my facility. If not Lonza, who is owner of this process? Can I get a license and do the same thing in-house? The process largerly developed on Lonzas reagents and platforms (such as nucleofection). Also, proprietary reagent and process were mentioned in the paper. Id be ok to buy Lonzas reagents for this wonderful process, but what if Id like alternative to reduce the cost? Also, in GMP must be back-up supplier for every reagent and material. Who is back-up for Lonza?

Now, some technical considerations:

Overall, I was enjoying reading this paper. Id highly recommend this protocol to every cell product developer, irrespective to type of your cells!

Tagged as: clinical protocols, donor eligibility, drug master file, GMP, iPS, iPS cell bank, manufacturing, master cell bank, protocol, QC

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A protocol for manufacturing of GMP-compliant iPS cell lines

Recommendation and review posted by Bethany Smith

Expert: Kristiann Dougherty, PhD - 9/22/2007

I can answer questions related to Mendelian inheritance, heredity, population genetics, genetic diseases, molecular biology techniques, transcription/translation, mitosis, meiosis. Please don't ask for predictions about what (or whom) your unborn baby will look like. I can't see the future, and in most cases, I am unable to provide a satisfactory answer, just a range of possiblities. That being said, I will attempt to answer questions related to children already born.

Conducted research in the field for about 12 years. Also am a Biology professor so I teach most of these subjects on a regular basis. Familiar with many examples to use as illustations.

Organizations Natl Association of Biology Teachers

Publications Journal Biological Chemistry Proceedings of the National Academy of Science (PNAS) Cancer Research

Education/Credentials BS in Biology, with concentration in Genetics - Purdue University PhD in Molecular Biology and Human Genetics - Johns Hopkins University

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Genetics / Does the male or female carrier the gene for twins.

Recommendation and review posted by Bethany Smith

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Hypogonadism occurs when the body's sex glands produce little or no hormones. In men, these glands (gonads) are the testes. In women, these glands are the ovaries.

Gonadal deficiency

The cause of hypogonadism can be primary or central. In primary hypogonadism, the ovaries or testes themselves do not function properly. Causes of primary hypogonadism include:

The most common genetic disorders that cause primary hypogonadism are

If you already have other autoimmune disorders you may be at higher risk of autoimmune damage to the gonads. These can include disorders that affect the liver and adrenal and thyroid glands as well as type 1 diabetes.

In central hypogonadism, the centers in the brain that control the gonads (hypothalamus and pituitary) do not function properly. Causes of central hypogonadism include:

A genetic cause of central hypogonadism is Kallmann syndrome. Many people with this condition also have a decreased sense of smell.

Girls who have hypogonadism will not begin menstruating. Hypogonadism can affect their breast development and height. If hypogonadism occurs after puberty, symptoms in women include:

In boys, hypogonadism affects muscle, beard, genital and voice development. It also leads to growth problems. In men the symptoms are:

If a pituitary or other brain tumor is present (central hypogonadism), there may be:

The most common tumors affecting the pituitary are craniopharyngioma in children and prolactinoma adenomas in adults.

You may need to have tests to check:

Other tests may include:

Sometimes imaging tests are needed, such as a

You may need to take hormone-based medicines. Estrogen and progesterone are used for girls and women. The medicines comes come in the form of a pill or skin patch. Testosterone is used for boys and men. The medicine can be given as a skin patch, skin gel, a solution applied to the armpit, a patch applied to the upper gum, or by injection.

For women who have not had their uterus removed, combination treatment with estrogen and progesterone may decrease the chance of developing endometrial cancer. Women with hypogonadism who have low sex drive may also be prescribed low-dose testosterone.

In some women, injections or pills can be used to stimulate ovulation. Injections of pituitary hormone may be used to help men produce sperm. Other people may need surgery and radiation therapy.

Many forms of hypogonadism are treatable and have a good outlook.

In women, hypogonadism may cause

Some women with hypogonadism take estrogen therapy, especially those who have early menopause. But long-term used of hormone therapy can increase the risk of breast cancer, blood clots and heart disease. Women should talk with their health care provider about the risks and benefits of hormone replacement therapy with your doctor.

In men, hypogonadism results in loss of sex drive and may cause:

Men normally have lower testosterone as they age. However, the decline in hormone levels is not as dramatic as it is in women.

Talk to your health care provider if you notice:

Both men and women should call their provider if they have headaches or vision problems.

Maintain normal body weight and healthy eating habits may help in some cases. Other causes may not be preventable.

Ali O, Donohoue PA. Hypofunction of the testes. In: Kliegman RM, Stanton BF, St. Geme JW III , et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 577.

Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in adult men with androgen deficiency syndromes: An Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab. 2010;95:2536-59. PMID: 20525905 http://www.ncbi.nlm.nih.gov/pubmed/20525905

Kansra AR, Donohoue PA. Hypofunction of the ovaries. In: Kliegman RM, Stanton BF, St. Geme JW III, et al., eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia, PA: Elsevier Saunders; 2011:chap 580.

Swerdloff RS, Wang C. The testis and male sexual function. In: Goldman L, Schafer AI. Goldman's Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2012:chap 242.

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Hypogonadism | University of Maryland Medical Center

Recommendation and review posted by Bethany Smith

The Y chromosome is one of two sex chromosomes (allosomes) in mammals, including humans, and many other animals. The other is the X chromosome. Y is the sex-determining chromosome in many species, since it is the presence or absence of Y that determines the male or female sex of offspring produced in sexual reproduction. In mammals, the Y chromosome contains the gene SRY, which triggers testis development. The DNA in the human Y chromosome is composed of about 59 million base pairs.[2] The Y chromosome is passed only from father to son. With a 30% difference between humans and chimpanzees, the Y chromosome is one of the fastest evolving parts of the human genome.[3] To date, over 200 Y-linked genes have been identified.[4] All Y-linked genes are expressed and (apart from duplicated genes) hemizygous (present on only one chromosome) except in the cases of aneuploidy such as XYY syndrome or XXYY syndrome. (See Y linkage.)

The Y chromosome was identified as a sex-determining chromosome by Nettie Stevens at Bryn Mawr College in 1905 during a study of the mealworm Tenebrio molitor. Edmund Beecher Wilson independently discovered the same mechanisms the same year. Stevens proposed that chromosomes always existed in pairs and that the Y chromosome was the pair of the X chromosome discovered in 1890 by Hermann Henking. She realized that the previous idea of Clarence Erwin McClung, that the X chromosome determines sex, was wrong and that sex determination is, in fact, due to the presence or absence of the Y chromosome. Stevens named the chromosome "Y" simply to follow on from Henking's "X" alphabetically.[5][6]

The idea that the Y chromosome was named after its similarity in appearance to the letter "Y" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well-defined shape during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during mitosis, has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape.[7]

Most mammals have only one pair of sex chromosomes in each cell. Males have one Y chromosome and one X chromosome, while females have two X chromosomes. In mammals, the Y chromosome contains a gene, SRY, which triggers embryonic development as a male. The Y chromosomes of humans and other mammals also contain other genes needed for normal sperm production.

There are exceptions, however. For example, the platypus relies on an XY sex-determination system based on five pairs of chromosomes.[8] Platypus sex chromosomes in fact appear to bear a much stronger homology (similarity) with the avian Z chromosome,[9] and the SRY gene so central to sex-determination in most other mammals is apparently not involved in platypus sex-determination.[10] Among humans, some men have two Xs and a Y ("XXY", see Klinefelter syndrome), or one X and two Ys (see XYY syndrome), and some women have three Xs or a single X instead of a double X ("X0", see Turner syndrome). There are other exceptions in which SRY is damaged (leading to an XY female), or copied to the X (leading to an XX male). For related phenomena, see Androgen insensitivity syndrome and Intersex.

Many ectothermic vertebrates have no sex chromosomes. If they have different sexes, sex is determined environmentally rather than genetically. For some of them, especially reptiles, sex depends on the incubation temperature; others are hermaphroditic (meaning they contain both male and female gametes in the same individual).

The X and Y chromosomes are thought to have evolved from a pair of identical chromosomes,[11][12] termed autosomes, when an ancestral mammal developed an allelic variation, a so-called 'sex locus' simply possessing this allele caused the organism to be male.[13] The chromosome with this allele became the Y chromosome, while the other member of the pair became the X chromosome. Over time, genes which were beneficial for males and harmful to (or had no effect on) females either developed on the Y chromosome, or were acquired through the process of translocation.[14]

Until recently, the X and Y chromosomes were thought to have diverged around 300 million years ago. However, research published in 2010,[15] and particularly research published in 2008 documenting the sequencing of the platypus genome,[9] has suggested that the XY sex-determination system would not have been present more than 166 million years ago, at the split of the monotremes from other mammals.[10] This re-estimation of the age of the therian XY system is based on the finding that sequences that are on the X chromosomes of marsupials and eutherian mammals are present on the autosomes of platypus and birds.[10] The older estimate was based on erroneous reports that the platypus X chromosomes contained these sequences.[8][16]

Recombination between the X and Y chromosomes proved harmfulit resulted in males without necessary genes formerly found on the Y chromosome, and females with unnecessary or even harmful genes previously only found on the Y chromosome. As a result, genes beneficial to males accumulated near the sex-determining genes, and recombination in this region was suppressed in order to preserve this male specific region.[13] Over time, the Y chromosome changed in such a way as to inhibit the areas around the sex determining genes from recombining at all with the X chromosome. As a result of this process, 95% of the human Y chromosome is unable to recombine. Only the tips of the Y and X chromosomes recombine. The tips of the Y chromosome that could recombine with the X chromosome are referred to as the pseudoautosomal region. The rest of the Y chromosome is passed on to the next generation intact. It is because of this disregard for the rules that the Y chromosome is such a superb tool for investigating recent human evolution from a male perspective.

By one estimate, the human Y chromosome has lost 1,393 of its 1,438 original genes over the course of its existence, and linear extrapolation of this 1,393-gene loss over 300 million years gives a rate of genetic loss of 4.6 genes per million years.[17] Continued loss of genes at the 4.6 genes per million year rate would result in a Y chromosome with no functional genes that is the Y chromosome would lose complete function within the next 10 million years, or half that time with the current age estimate of 160 million years.[13][18] Comparative genomic analysis reveals that many mammalian species are experiencing a similar loss of function in their heterozygous sex chromosome. Degeneration may simply be the fate of all non-recombining sex chromosomes, due to three common evolutionary forces: high mutation rate, inefficient selection, and genetic drift.[13]

However, comparisons of the human and chimpanzee Y chromosomes (first published in 2005) show that the human Y chromosome has not lost any genes since the divergence of humans and chimpanzees between 67 million years ago,[19] and a scientific report in 2012 stated that only one gene had been lost since humans diverged from the rhesus macaque 25 million years ago.[20] These facts provide direct evidence that the linear extrapolation model is flawed and suggest that the current human Y chromosome is either no longer shrinking or is shrinking at a much slower rate than the 4.6 genes per million years estimated by the linear extrapolation model.

The human Y chromosome is particularly exposed to high mutation rates due to the environment in which it is housed. The Y chromosome is passed exclusively through sperm, which undergo multiple cell divisions during gametogenesis. Each cellular division provides further opportunity to accumulate base pair mutations. Additionally, sperm are stored in the highly oxidative environment of the testis, which encourages further mutation. These two conditions combined put the Y chromosome at a greater risk of mutation than the rest of the genome.[13] The increased mutation risk for the Y chromosome is reported by Graves as a factor 4.8.[13] However, her original reference obtains this number for the relative mutation rates in male and female germ lines for the lineage leading to humans.[21]

Without the ability to recombine during meiosis, the Y chromosome is unable to expose individual alleles to natural selection. Deleterious alleles are allowed to "hitchhike" with beneficial neighbors, thus propagating maladapted alleles in to the next generation. Conversely, advantageous alleles may be selected against if they are surrounded by harmful alleles (background selection). Due to this inability to sort through its gene content, the Y chromosome is particularly prone to the accumulation of "junk" DNA. Massive accumulations of retrotransposable elements are scattered throughout the Y.[13] The random insertion of DNA segments often disrupts encoded gene sequences and renders them nonfunctional. However, the Y chromosome has no way of weeding out these "jumping genes". Without the ability to isolate alleles, selection cannot effectively act upon them.

A clear, quantitative indication of this inefficiency is the entropy rate of the Y chromosome. Whereas all other chromosomes in the human genome have entropy rates of 1.51.9 bits per nucleotide (compared to the theoretical maximum of exactly 2 for no redundancy), the Y chromosome's entropy rate is only 0.84.[22] This means the Y chromosome has a much lower information content relative to its overall length; it is more redundant.

Even if a well adapted Y chromosome manages to maintain genetic activity by avoiding mutation accumulation, there is no guarantee it will be passed down to the next generation. The population size of the Y chromosome is inherently limited to 1/4 that of autosomes: diploid organisms contain two copies of autosomal chromosomes while only half the population contains 1 Y chromosome. Thus, genetic drift is an exceptionally strong force acting upon the Y chromosome. Through sheer random assortment, an adult male may never pass on his Y chromosome if he only has female offspring. Thus, although a male may have a well adapted Y chromosome free of excessive mutation, it may never make it in to the next gene pool.[13] The repeat random loss of well-adapted Y chromosomes, coupled with the tendency of the Y chromosome to evolve to have more deleterious mutations rather than less for reasons described above, contributes to the species-wide degeneration of Y chromosomes through Muller's ratchet.[23]

As it has been already mentioned, the Y chromosome is unable to recombine during meiosis like the other human chromosomes; however, in 2003, researchers from MIT discovered a process which may slow down the process of degradation. They found that human Y chromosome is able to "recombine" with itself, using palindrome base pair sequences.[24] Such a "recombination" is called gene conversion.

In the case of the Y chromosomes, the palindromes are not noncoding DNA; these strings of bases contain functioning genes important for male fertility. Most of the sequence pairs are greater than 99.97% identical. The extensive use of gene conversion may play a role in the ability of the Y chromosome to edit out genetic mistakes and maintain the integrity of the relatively few genes it carries. In other words, since the Y chromosome is single, it has duplicates of its genes on itself instead of having a second, homologous, chromosome. When errors occur, it can use other parts of itself as a template to correct them.

Findings were confirmed by comparing similar regions of the Y chromosome in humans to the Y chromosomes of chimpanzees, bonobos and gorillas. The comparison demonstrated that the same phenomenon of gene conversion appeared to be at work more than 5 million years ago, when humans and the non-human primates diverged from each other.

In the terminal stages of the degeneration of the Y chromosome, other chromosomes increasingly take over genes and functions formerly associated with it. Finally, the Y chromosome disappears entirely, and a new sex-determining system arises.[13] Several species of rodent in the sister families Muridae and Cricetidae have reached these stages,[25][26] in the following ways:

Outside of the rodent family, the black muntjac, Muntiacus crinifrons, evolved new X and Y chromosomes through fusions of the ancestral sex chromosomes and autosomes.[32]

Fisher's principle outlines why almost all species using sexual reproduction have a sex ratio of 1:1, meaning that 50% of offspring will receive a Y chromosome, and 50% will not. W.D. Hamilton gave the following basic explanation in his 1967 paper on "Extraordinary sex ratios",[33] given the condition that males and females cost equal amounts to produce:

In humans, the Y chromosome spans about 58 million base pairs (the building blocks of DNA) and represents approximately 1% of the total DNA in a male cell.[34] The human Y chromosome contains over 200 genes, at least 72 of which code for proteins.[2] Traits that are inherited via the Y chromosome are called holandric traits (although biologists will usually just say 'Y-linked').

Some cells, especially in older men and smokers, lack a Y-chromosome. It has been found that men with a higher percentage of hematopoietic stem cells in blood lacking the Y-chromosome (and perhaps a higher percentage of other cells lacking it) have a higher risk of certain cancers and have a shorter life expectancy. Men with "loss of Y" (which was defined as no Y in at least 18% of their hematopoietic cells) have been found to die 5.5 years earlier on average than others. This has been interpreted as a sign that the Y-chromosome plays a role going beyond sex determination and reproduction[35] (although the loss of Y may be an effect rather than a cause). And yet women, who have no Y-chromosome, have lower rates of cancer. Male smokers have between 1.5 and 2 times the risk of non-respiratory cancers as female smokers.[36][37]

The human Y chromosome is normally unable to recombine with the X chromosome, except for small pieces of pseudoautosomal regions at the telomeres (which comprise about 5% of the chromosome's length). These regions are relics of ancient homology between the X and Y chromosomes. The bulk of the Y chromosome, which does not recombine, is called the "NRY" or non-recombining region of the Y chromosome.[38] It is the SNPs (single-nucleotide polymorphism) in this region that are used to trace direct paternal ancestral lines.

Not including pseudoautosomal genes, genes include:

Y-Chromosome-linked diseases can be of more common types, or very rare ones. Yet, the rare ones still have importance in understanding the function of the Y-chromosome in the normal case.

No vital genes reside only on the Y chromosome, since roughly half of humans (females) do not have a Y chromosome. The only well-defined human disease linked to a defect on the Y chromosome is defective testicular development (due to deletion or deleterious mutation of SRY). However, having two X chromosomes and one Y chromosome has similar effects. On the other hand, having Y chromosome polysomy has other effects than masculinization.

Y chromosome microdeletion (YCM) is a family of genetic disorders caused by missing genes in the Y chromosome. Many affected men exhibit no symptoms and lead normal lives. However, YCM is also known to be present in a significant number of men with reduced fertility or reduced sperm count.

This results in the person presenting a female phenotype (i.e., is born with female-like genitalia) even though that person possesses an XY karyotype. The lack of the second X results in infertility. In other words, viewed from the opposite direction, the person goes through defeminization but fails to complete masculinization.

The cause can be seen as an incomplete Y chromosome: the usual karyotype in these cases is 44X, plus a fragment of Y. This usually results in defective testicular development, such that the infant may or may not have fully formed male genitalia internally or externally. The full range of ambiguity of structure may occur, especially if mosaicism is present. When the Y fragment is minimal and nonfunctional, the child is usually a girl with the features of Turner syndrome or mixed gonadal dysgenesis.

Klinefelter syndrome (47, XXY) is not an aneuploidy of the Y chromosome, but a condition of having an extra X chromosome, which usually results in defective postnatal testicular function. The mechanism is not fully understood; the extra X does not seem to be due to direct interference with expression of Y genes.

47,XYY syndrome (simply known as XYY syndrome) is caused by the presence of a single extra copy of the Y chromosome in each of a male's cells. 47, XYY males have one X chromosome and two Y chromosomes, for a total of 47 chromosomes per cell. Researchers have found that an extra copy of the Y chromosome is associated with increased stature and an increased incidence of learning problems in some boys and men, but the effects are variable, often minimal, and the vast majority do not know their karyotype. When chromosome surveys were done in the mid-1960s in British secure hospitals for the developmentally disabled, a higher than expected number of patients were found to have an extra Y chromosome. The patients were mischaracterized as aggressive and criminal, so that for a while an extra Y chromosome was believed to predispose a boy to antisocial behavior (and was dubbed the 'criminal karyotype'). Subsequently, in 1968 in Scotland the only ever comprehensive nationwide chromosome survey of prisons found no over-representation of 47,XYY men, and later studies found 47,XYY boys and men had the same rate of criminal convictions as 46,XY boys and men of equal intelligence. Thus, the "criminal karyotype" concept is inaccurate and obsolete.[citation needed]

The following Y chromosome-linked diseases are rare, but notable because of their elucidating of the nature of the Y chromosome.

Greater degrees of Y chromosome polysomy (having more than one extra copy of the Y chromosome in every cell, e.g., XYYY) are rare. The extra genetic material in these cases can lead to skeletal abnormalities, decreased IQ, and delayed development, but the severity features of these conditions are variable.

XX male syndrome occurs when there has been a recombination in the formation of the male gametes, causing the SRY-portion of the Y chromosome to move to the X chromosome. When such an X chromosome contributes to the child, the development will lead to a male, because of the SRY gene.

In human genetic genealogy (the application of genetics to traditional genealogy), use of the information contained in the Y chromosome is of particular interest because, unlike other chromosomes, the Y chromosome is passed exclusively from father to son, on the patrilineal line. Mitochondrial DNA, maternally inherited to both sons and daughters, is used in an analogous way to trace the matrilineal line.

Research is currently investigating whether male-pattern neural development is a direct consequence of Y chromosome-related gene expression or an indirect result of Y chromosome-related androgenic hormone production.[39]

The presence of male chromosomes in fetal cells in the blood circulation of women was discovered in 1974.[40] In 1996, it was found that male fetal progenitor cells could persist postpartum in the maternal blood stream for as long as 27 years.[41]

A 2004 study at the Fred Hutchinson Cancer Research Center, Seattle investigated the origin of male chromosomes found in the peripheral blood of women who had not had male progeny. A total of 120 subjects (women who had never had sons) were investigated and it was found that 21% of them had male DNA. The subjects were categorised into four groups based on their case histories:[42]

The study noted that 10% of the women had never been pregnant before, raising the question where the Y Chromosomes in their blood could have come from? The study suggests that possible reasons for occurrence of male chromosome microchimerism could be one of the following:[42]

A 2012 study, at the same institute, has detected cells with the Y chromosome in multiple areas of the brains of dead women.[43]

Many groups of organisms in addition to mammals have Y chromosomes, but these Y chromosomes do not share common ancestry with mammalian Y chromosomes. Such groups include Drosophila, some other insects, some fish, some reptiles, and some plants. In Drosophila melanogaster, the Y chromosome does not trigger male development. Instead, sex is determined by the number of X chromosomes. The D. melanogaster Y chromosome does contain genes necessary for male fertility. So XXY D. melanogaster are female, and D. melanogaster with a single X (X0), are male but sterile. There are some species of Drosophila in which X0 males are both viable and fertile.

Other organisms have mirror image sex chromosomes: the female is "XY" and the male is "XX", but by convention biologists call a "female Y" a W chromosome and the other a Z chromosome. For example, female birds, snakes, and butterflies have ZW sex chromosomes, and males have ZZ sex chromosomes.

There are some species, such as the Japanese rice fish, where the Y chromosome is not inverted and can still swap genes with the X. Because the Y does not have male-specific genes and can interact with the X, XX males can be formed as well as XY and YY females.[44]

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Y chromosome - Wikipedia, the free encyclopedia

Recommendation and review posted by simmons

Researchers at the University of California, Berkeley, in collaboration with scientists at the Gladstone Institutes, have developed a template for growing beating cardiac tissue from stem cells, creating a system that could serve as a model for early heart development and a drug-screening tool to make pregnancies safer.

In experiments to be published Tuesday, July 14, in the journal Nature Communications, the researchers used biochemical and biophysical cues to prompt stem cells to differentiate and self-organize into micron-scale cardiac tissue, including microchambers.

"We believe it is the first example illustrating the process of a developing human heart chamber in vitro," said Kevin Healy, a UC Berkeley professor of bioengineering, who is co-senior author of the study with Dr. Bruce Conklin, a senior investigator at the Gladstone Institute of Cardiovascular Disease and a professor of medical genetics and cellular and molecular pharmacology at UC San Francisco. "This technology could help us quickly screen for drugs likely to generate cardiac birth defects, and guide decisions about which drugs are dangerous during pregnancy."

Screening for drug toxicity

To test the potential of the system as a drug-screening tool, the researchers exposed the differentiating cells to thalidomide, a drug known to cause severe birth defects. They found that at normal therapeutic doses, the drug led to abnormal development of microchambers, including decreased size, problems with muscle contraction and lower beat rates compared with heart tissue that had not been exposed to thalidomide.

"We chose drug cardiac developmental toxicity screening to demonstrate a clinically relevant application of the cardiac microchambers," said Conklin. "Each year, as many as 280,000 pregnant women are exposed to drugs with evidence of potential fetal risk. The most commonly reported birth defects involve the heart, and the potential for generating cardiac defects is of utmost concern in determining drug safety during pregnancy."

The new milestone comes nearly four months after Healy and other UC Berkeley researchers publicly debuted a system of beating human heart cells on a chip that could be used to screen for drug toxicity. However, that heart-on-a-chip device used pre-differentiated cardiac cells to mimic adult-like tissue structure.

In this new study, the scientists mimicked human tissue formation by starting with stem cells genetically reprogrammed from adult skin tissue to form small chambers with beating human heart cells. Conklin's lab at Gladstone, an independent, nonprofit life science research organization affiliated with UC San Francisco, supplied these human induced pluripotent stem cells for this study.

The undifferentiated stem cells were then placed onto a circular-patterned surface that served to physically regulate cell differentiation and growth.

Location, location, location

By the end of two weeks, the cells that began on a two-dimensional surface environment started taking on a 3D structure as a pulsating microchamber. Moreover, the cells had self-organized based upon whether they were positioned along the perimeter or in the middle of the colony.

Compared with cells in the center, cells along the edge experienced greater mechanical stress and tension, and appeared more like fibroblasts, which form the collagen of connective tissue. The center cells, in contrast, developed into cardiac muscle cells. Such spatial organization was observed as soon as the differentiation started. Center cells lost the expression of octamer-binding transcription factor 4 (OCT4) and epithelial cadherin (E-cadherin) faster than perimeter cells, which are critical to the development of heart tissue.

"This spatial differentiation happens in biology naturally, but we demonstrated this process in vitro," said study lead author Zhen Ma, a UC Berkeley postdoctoral researcher in bioengineering. "The confined geometric pattern provided biochemical and biophysical cues that directed cardiac differentiation and the formation of a beating microchamber."

Could eventually replace animal models

Modeling early heart development is difficult to achieve in a petri dish and tissue culture plates, the study authors said. This area of study has typically involved the dissection of animals at different stages of development to study the formation of organs, and how that process can go wrong.

"The fact that we used patient-derived human pluripotent stem cells in our work represents a sea change in the field," said Healy. "Previous studies of cardiac microtissues primarily used harvested rat cardiomyocytes, which is an imperfect model for human disease."

The researchers pointed out that while this study focused on heart tissue, there is great potential for use of this technology to study other organ development.

"Our focus here has been on early heart development, but the basic principles of patterning of human pluripotent stem cells, and subsequently differentiating them, can be readily expanded into a broad range of tissues for understanding embryogenesis and tissue morphogenesis," said Healy.

The National Institutes of Health and a Siebel Postdoctoral Fellowship helped support this research.

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Growing beating cardiac tissue from stem cells: New model ...

Recommendation and review posted by Bethany Smith

Ok. Bits of this film are a little grim, but its worth it. Well, go on then!

Amazing right? And yes, its real! I have to admit I double-checked the date when my friend forwarded me the National Geographic link, but April first it was not. Researchers at the University of Pittsburgs McGowan Institute for Regenerative Medicine have made the skin cell spray gun a very real, very effective treatment for burn victims.

So how does it work? At its core, this treatment relies on the unique properties of stem cells, so thats where Ill begin. Stem cells

Stem cells have fascinated biologists for years. They are unique amongst all other cells of the body in two ways; their capacity for self-renewal, and their ability to give rise to many different cell types.

Embryonic stem cells, which frequently (and controversially) make the news, are derived from a developing fetus. They are the ultimate in stem cell-iness because they have the potential to direct the development of an entire organism. This means that they contain all the information need to make muscles, nerves, eyes etc. And naturally this pluripotency (from the Latin pluri meaning many, and potency or potential) seemed like a fantastic quality for biologist to understand. Not only were there fundamental developmental principles to be learned, the medical applications were endless. However, glaring ethical issues arose regarding the taking of a life to save a life (that I wont get into here) that have resulted in the stringent regulation of embryonic stem cell research.

And so researchers turned to adult stem cells. While adult stem cells are not as versatile as embryonic stem cells, they do have the potential to direct the development of certain cell lineages. For example hematopoietic stem cells, which reside in your bone marrow, can divide asymmetrically into all the different cells of your blood. Similarly, all the different layers of your skin have ancestral skin stem cells.

Research into embryonic stem cells resulted in the identification of certain genes that were expressed in, and required by, stem cells. In 2006, a Japanese group generated the first induced pluripotent stem cells. Since then much work has gone into understanding the potential of these induced stem cells. However due to genetic manipulation and lack of correct genomic imprinting (small chemical modifications in our DNA that are laid down in the egg), induced pluripotent stem cells have the unfortunate ability to become cancerous. As detailed in a recent paper in Cell however, while these cells are not yet ready for the clinic, this should not prevent them from being used in a laboratory setting. Stem cells as a treatment

Bone marrow transplantation was the first example of a stem cell therapy. In 1959 the French surgeon Georges Math treated six nuclear power plant workers who had been so severely irradiated that their hematopoietic stem cell populations had been destroyed. The procedure has since been used with great success in the treatment of leukemia.

As with all transplants, the potential of the host rejecting the donor tissue exists. This rejection occurs because of subtle cellular differences between each and every one of us. Our immune system recognizes these differences as foreign, much as it would any other pathogenic invader, and mounts a formidable defense. With the development of tissue typing procedures and administration of immunosuppressive drugs, transplant rejection has significantly decreased.

By far the best way of avoiding rejection, however, is to transplant the recipients own tissue. In certain procedures, such as small areas of skin grafting, such auto-grafting is a viable option. But in others, such as in the case of organ transplantation, it is not. And this is where stem cells can sweep in and save the day.

Tissues in dishes

We have long had the capacity to grow cells in vitro (which literally means within a glass). Bacterial cells grow happily in test tubes when provided with simple nutrients and an incubator, as do yeast cells. Mammalian cells are a little more difficult to deal with, but again we have been culturing them in the lab for over a hundred years. All they require is a container to grow in that protects them from infection, liquid media containing essential amino acids and other nutrients, and a warm humid chamber in which to grow.

I am however talking about growing one type of cell at a time. Growing an organized tissue presents a far greater challenge. Not only do the cells have to grow and divide, they have to interact with one another and take on specialized roles within the tissue. Normally in our bodies external forces and small molecules send signals between cells that direct this process. Culturing a tissue in vitro requires a significant understanding of how the tissue forms, and an ability to isolate the stem cells from which the tissue is derived.

In the case of transplantation, the stem cells can be derived from the patient who will receive the cultured tissue, thus removing the chance of complications arising due to donor incompatibility. As you saw in the video, skin grafts have been performed in this way for quite some time, but with variable success.

The skin gun

And this is of course where the genius of the skin gun, and its inventor Joerg C. Gerlach, comes in; it bypasses the need for the in vitro tissue culturing. Skin stem cells that had been destroyed in the burn are replaced, and then the tissue is allowed to heal. As in the case of tissue culture in a lab, these cells require a sterile and nutrient rich environment to thrive. After the initial spraying, the wound is covered with a dressing that contains a synthetic circulatory system that brings nutrients to the infant skin and removes any toxins and waste products.

The speed and effectiveness of this treatment is out of this world. The guy in the video didnt even have a scar after his treatment. Perhaps the spray gun as a means of stem cell delivery is unique to skin regeneration, but there are a couple of features that should be transferable to other transplants, particularly the ability to enrich a patients own stem cells and re-apply them to damaged tissue. This will likely be advanced from burgeoning knowledge on where adult stem cells reside in our body, in so-called stem cell niches. With skin stem cell therapy now a reality, what will be next? Will we be able to re-grow more complex organs such as kidneys? Or will we be able to harvest healthy stem cells from a niche before a disease such as leukemia becomes debilitating? What do you think?

Bock, C., Kiskinis, E., Verstappen, G., Gu, H., Boulting, G., Smith, Z., Ziller, M., Croft, G., Amoroso, M., & Oakley, D. (2011). Reference Maps of Human ES and iPS Cell Variation Enable High-Throughput Characterization of Pluripotent Cell Lines Cell, 144 (3), 439-452 DOI: 10.1016/j.cell.2010.12.032

Hi Peter,

Thanks for the links. I should probably have pointed out in my article that this idea is not totally novel. The Australian plastic surgeon Dr. Fiona Wood has been using a similar technique for close to a decade. She has since started a company, http://www.avitamedical.com/index.php?ob=1&id=37. The technique was used extensively to treat burn victims of the Bali bombings in 2002. The recent development of the stem cell gun has basically increased the efficiency of the system, reduced damage caused to the stem cells during spraying, and made the technique more user friendly in a hospital setting.

However, I searched and searched and there is no Nature paper, which honestly baffled me too.

I was happy to see in that link that a clinical trial is in the works. Hopefully from that some concrete data can be collected as to the precise efficacy of the cell spray system, as well as a peer-reviewed article on the subject. It seems to me that burn experts are divided on the merit or value of the treatment. In my opinion the only way a consensus can be reached is through a thorough, scientific and transparent trial. But should the therapy prove itself in that setting, I think it is a fantastic advancement in the therapeutic use of adult stem cells.

Would this work on a aged skin, skin damaged other than fire, frostbite, gangrene, cancer, etc?

What about those sunbathers with leathery type of skin?

Thanks

Ha I like your idea about the leathery sun-worshipers! I think stem cell therapy like this has potential for aiding wound healing, ie where large amounts of skin have had to be removed. But I do not think it could help adult skin thats already present. Youd have to remove the whole leathery mess and start againa new era of cosmetic surgery?

See the rest here:
Spray on some stem cells and grow your own skin! | Katie PhD

Recommendation and review posted by Bethany Smith

Over the past two decades or so, we've learned a lot about how the pituitary gland develops. Today, that ever-evolving knowledge helps us better serve our patients and their families.

Laurie Cohen, MD, director, Neuroendocrinology Program

You may have never heard of hypopituitarism until your child was diagnosed with it. Hypopituitarism occurs when the anterior (front) lobe of the pituitary gland loses its ability to make hormones. The resulting symptoms depend on which hormones are no longer being produced by the gland.

The good news is that treating the underlying condition thats causing your childs hypopituitarism often leads to a full recovery.

How Childrens Hospital Boston approaches hypopituitarism

At Childrens, you can rest assured knowing that your child will be cared for by knowledgeable physicians whove devoted their careers to understanding this condition. We treat children with hypopituitarism in our General Endocrinology Programa multidisciplinary program dedicated to the treatment of children with a wide range of endocrinological disorders. For these children, our dedicated team of doctors, nurses and other caregivers offer hope for a healthier future.

Ranked #1 in Endocrinology In 2015, Boston Children's Hospital was ranked #1 in Endocrinology by U.S. News & World Report.

Read more here:
Hypopituitarism | Boston Children's Hospital

Recommendation and review posted by Bethany Smith

Highlights

We present a strategy to optimize cardiac differentiation in suspension for hiPSCs.

The matrix-free suspension platform integrates hPSC expansion and differentiation.

Cardiac production in suspension achieves >90% purity with 1L spinner flasks.

The production process in suspension is defined, scalable, and GMP compliant.

To meet the need of a large quantity of hPSC-derived cardiomyocytes (CM) for pre-clinical and clinical studies, a robust and scalable differentiation system for CM production is essential. With a human pluripotent stem cells (hPSC) aggregate suspension culture system we established previously, we developed a matrix-free, scalable, and GMP-compliant process for directing hPSC differentiation to CM in suspension culture by modulating Wnt pathways with small molecules. By optimizing critical process parameters including: cell aggregate size, small molecule concentrations, induction timing, and agitation rate, we were able to consistently differentiate hPSCs to >90% CM purity with an average yield of 1.5 to 2109 CM/L at scales up to 1L spinner flasks. CM generated from the suspension culture displayed typical genetic, morphological, and electrophysiological cardiac cell characteristics. This suspension culture system allows seamless transition from hPSC expansion to CM differentiation in a continuous suspension culture. It not only provides a cost and labor effective scalable process for large scale CM production, but also provides a bioreactor prototype for automation of cell manufacturing, which will accelerate the advance of hPSC research towards therapeutic applications.

Myocardial infarction and heart failure are leading causes of death worldwide. As the myocardium has a very limited regenerative capacity, endogenous cell regeneration cannot adequately compensate for heart damage caused by myocardial infarction. The concept of cell replacement therapy is an appealing approach to the treatment of these cardiac diseases. HPSCs are an attractive cell source for cell replacement therapies because they can be expanded indefinitely in culture and efficiently differentiated into a variety of cell lineages, including cardiac cells. However, current hPSC expansion and differentiation methods rely on adherent cell culture systems that are challenging to scale up to the levels required to support pre-clinical and clinical studies.

Activin/Nodal/TGF-, BMP, and Wnt signaling play pivotal roles in regulating mesoderm and cardiac specification during embryo development (Arnold and Robertson, 2009, Buckingham et al., 2005, Tam and Loebel, 2007, David et al., 2008, Naito et al., 2006, Ueno et al., 2007andBurridge et al., 2012). Significant progress has been made in the cardiac differentiation process by modulating Activin, BMP, and Wnt pathways, which can efficiently drive differentiation to over 80% purity of CM (Burridge et al., 2014, Kattman et al., 2011, Lian et al., 2012, Yang et al., 2008, Zhang et al., 2012andZhu et al., 2011). Using an adherent cell culture platform, one study revealed that using 2 small Wnt pathway modulators to sequentially activate and then inhibit Wnt signaling at different differentiation stages of the culture is sufficient to drive cardiac differentiation and generate CM with high purity (Lian et al., 2012). In spite of this, adherent culture systems have limited scalability and are not practical to support the anticipated CM requirements of clinical trials. Alternatively, using an embryoid body (EB) differentiation method, a complex cardiac induction procedure involving stage-specific treatments with growth factors and small molecules to modulate Activin/Nodal, BMP, and Wnt pathways has been reported to be effective in cardiac differentiation in a suspension culture system (Kattman et al., 2011andYang et al., 2008). However, the process of generating EBs is inefficient, rendering this method impractical for large scale CM production. An additional limitation of these approaches for scale-up application is that both methods are based on the expansion of the hPSCs in adherent culture and the subsequent CM differentiation process in either adherent culture or as EBs. The labor intensiveness and limited scalability of current processes have been the primary bottle necks to the large scale production of CM for clinical applications of hPSC-derived CM.

Pre-clinical studies suggest that doses of up to one billion CM will be required to achieve therapeutic benefit after transplantation (Chong et al., 2014andLaflamme and Murry, 2005). In order to meet the current CM demand for pre-clinical studies and the anticipated demand for foreseeable clinical studies, development of a robust, scalable and cGMP-compliant differentiation process for the production of both hPSCs and hPSC-derived CM is essential. Suspension cell culture is an attractive platform for large scale manufacture of cell products for its scale-up capacity. Application of a suspension culture platform to support hPSC growth in matrix-free cell aggregates has been well established (Amit et al., 2010, Krawetz et al., 2010, Olmer et al., 2010, Singh et al., 2010, Steiner et al., 2010andChen et al., 2012). We previously also reported the development of a defined, scalable and cGMP-compliant suspension system to culture hPSCs in the form of cell aggregates (Chen et al., 2012). With this suspension culture system, hPSC cultures can be serially passaged and consistently expanded. In the present study we adapted our suspension culture system to establish a robust, scalable and cGMP-compliant process for manufacturing CM. We were able to use hPSC aggregates generated in the suspension culture system directly to produce CM with high efficiency and yield in suspension with various scales of spinner flasks. We optimized various critical process parameters including: small molecule concentration, induction timing and agitation rates for differentiation cultures in spinner flasks with scales up to 1L. In this study, we integrated undifferentiated hPSC expansion and small molecule-induced cardiac differentiation into a scalable suspension culture system using spinner flasks, providing a streamlined and cGMP-compliant process for scale-up CM differentiation and production.

We routinely maintained the hPSCs lines H7 (WA07, WiCell), ESI-017 (BioTime), and a hiPSC line (a gift from Dr. Joseph Wu, Stanford) in the form of cell aggregates in suspension culture as previously described (Chen et al., 2012). Briefly, suspension-adapted hPSCs were seeded as single cells at a density of 2.53105 cells/mL in 125, 500, or 1000mL spinner flasks (Corning) containing culture medium (StemPro hESC SFM, Thermo Fisher Scientific, Life Technologies) with 40ng/mL bFGF (Life Technologies) and 10M Y27632 (EMD Millipore). Stirring rates were adjusted to between 5070rpm depending on the vessel size and hPSC line. Medium was changed every day by demi-depletion with fresh culture medium without Y27632. Cells were dissociated with Accutase (Millipore) into single cells and passaged every 34days when the aggregate size reached approximately 300m. Cell suspension cultures were maintained in 5% CO2 with 95% relative humidity at 37C.

Read the original:
Development of a scalable suspension culture for cardiac ...

Recommendation and review posted by simmons

Hypopituitarism is a rare disorder involving underproduction of hormones by the pituitary gland. The pituitary, deep in the brain, is the most important gland in the bodys endocrine, or hormonal, system.

One of the six hormones produced by the anterior portion of the pituitary is human growth hormone (HGH). In children, HGH deficiency may lead to impaired growth, or dwarfism. Early diagnosis and administration of HGH can correct this hormonal deficiency and result in normal or near-normal height.

Deficiencies in other pituitary hormones produce a wide variety of symptoms; in panhypopituitarism, deficiencies occur in all pituitary hormones. Because pituitary hormones stimulate hormone production in other glands, hypopituitarism may have a snowball effect, resulting in deficiencies of adrenal, thyroid, and sex hormones

Sources:

Johns Hopkins Symptoms and Remedies: The Complete Home Medical Reference

Simeon Margolis, M.D., Ph.D., Medical Editor

Prepared by the Editors of The Johns Hopkins Medical Letter: Health After 50

Updated by Remedy Health Media

Publication Review By: the Editorial Staff at Healthcommunities.com

Published: 16 Nov 2011

Last Modified: 06 Nov 2014

Originally posted here:
What Is Hypopituitarism (Dwarfism)? - Child Growth and ...

Recommendation and review posted by simmons

Bone marrow is the tissue comprising the center of large bones.

It is the place where new blood cells are produced.

Bone marrow contains two types of stem cells: hemopoietic (which can produce blood cells) and stromal (which can produce fat, cartilage and bone).

There are two types of bone marrow: red marrow (also known as myeloid tissue) and yellow marrow.

Red blood cells, platelets and most white blood cells arise in red marrow; some white blood cells develop in yellow marrow.

The color of yellow marrow is due to the much higher number of fat cells.

Both types of bone marrow contain numerous blood vessels and capillaries.

At birth, all bone marrow is red.

With age, more and more of it is converted to the yellow type.

Adults have on average about 2.6kg (5.7lbs) of bone marrow, with about half of it being red.

Red marrow is found mainly in the flat bones such as hip bone, breast bone, skull, ribs, vertebrae and shoulder blades, and in the cancellous ("spongy") material at the proximal ends of the long bones femur and humerus.

Pink Marrow is found in the hollow interior of the middle portion of long bones.

There are several serious diseases involving bone marrow.

In cases of severe blood loss, the body can convert yellow marrow back to red marrow in order to increase blood cell production.

The normal bone marrow architecture can be displaced by malignancies or infections such as tuberculosis, leading to a decrease in the production of blood cells and blood platelets.

In addition, cancers of the hematologic progenitor cells in the bone marrow can arise; these are the leukemias.

Read more:
Bone marrow stem-cells - ScienceDaily

Recommendation and review posted by Bethany Smith

Value Genetics Bull & Female Sale

Saturday March 5, 2016 12:30 p.m. Clinton Livestock Auction, Clinton, OK View Sale Book View Videos

Davis Angus began in 1973 when Bud Davis, Jim's father purchased ten registered Angus cows from Al Rutledge. Jim and wife Debbie, later added cattle from the UT, Allen Greer and Pat O'Brian, and B&L dispersals. The first AI sires were introduced in 1995; Davis Angus chose BR New Design 323 and TC Dividend 963. Through the technological advances of breeding and the use of artificial insemination inspiration developed, a dream that cattle could be produced that had all the desired carcass traits with the show ring appeal. This idea led Davis Angus to produce the cattle you see today. Cattle that have Carcass and Conformation without Compromise.

The 2007 Davis Angus calf crop was very successful with 100% of the steers grading choice, 60% went CAB and prime, producing a 46% yield grade 1 and 2, this allowed Davis Angus to receive a premium of $106.95 per head above the market while costing only $0.78 per pound with corn costing $6.00 per bushel.

Davis Angus was very successful in the show ring with several champions; we encourage you to view our "Hall of Champions" page and view the results!

In the past decade we have become very successful in the show ring as well as winning several carcass competitions.

We encourage you to come visit us at Davis Angus, let us put you in the winner's circle!

Read the rest here:
Davis Angus Foss, Oklahoma

Recommendation and review posted by Bethany Smith

If any of the above pms, menstrual, or menopausal symptoms belong to you, you've come to the right place. We were searching for answers just like you are...and a lot of us discovered that using bio-identical, natural hormones was one of keys to restoring balance and health.

We also found that talking with each other was extremely helpful. Under why we use it you'll find some personal examples of how natural progesterone cream can change your life. In the forum you can talk to other women who have symptoms like yours and find out what works for them.

Natural progesterone cream, for instance, can be an extremely effective remedy for symptoms of PMS, infertility, osteoporosis, and menopause. There are wonderful resources available to help you decide if natural hormone replacment is right for you. We encourage you to explore some of the best resources available. Talk to your health care providers. Get reliable information from non-commercial websites. Talk to other women about what works for them...our new ebook (which is a fantastic resource) and the forum are great places to start. And you can download our free booklet A Woman's Guide to Natural Progesterone.

The more you learn, the better healthcare decisions you can make for yourself.

One more thing. Most sites have a link to their "privacy policy." Here is ours: We will not use your personal details for anything other than processing your order. PERIOD. We absolutely regard this as sacrosanct.

More:
A Natural Progesterone Cream by Resonance Direct

Recommendation and review posted by simmons

What are Stem Cells?

Types of Stem Cells

Why are Stem Cells Important?

Can doctors use stem cells to treat patients?

Pros and Cons of Using Stem Cells

What are Stem Cells?

There are several different types of stem cells produced and maintained in our system throughout life. Depending on the circumstances and life cycle stages, these cells have different properties and functions. There are even stem cells that have been created in the laboratory that can help us learn more about how stem cells differentiate and function. A few key things to remember about stem cells before we venture into more detail:

Stem cells are the foundation cells for every organ and tissue in our bodies. The highly specialized cells that make up these tissues originally came from an initial pool of stem cells formed shortly after fertilization. Throughout our lives, we continue to rely on stem cells to replace injured tissues and cells that are lost every day, such as those in our skin, hair, blood and the lining of our gut.

Source ISSCR

Stem Cell History

Until recently, scientists primarily worked with two kinds of stem cells from animals and humans: embryonic stem cells and non-embryonic "somatic" or "adult" stem cells. Scientists discovered ways to derive embryonic stem cells from early mouse embryos nearly 30 years ago, in 1981. The detailed study of the biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human embryos and grow the cells in the laboratory. These cells are called human embryonic stem cells. The embryos used in these studies were created for reproductive purposes through in vitro fertilization procedures. When they were no longer needed for that purpose, they were donated for research with the informed consent of the donor. In 2006, researchers made another breakthrough by identifying conditions that would allow some specialized adult cells to be "reprogrammed" genetically to assume a stem cell-like state. This new type of stem cell is now known as induced pluripotent stem cells (iPSCs).

Source NIH

Types of Stem Cells

Adult Stem Cells (ASCs):

ASCs are undifferentiated cells found living within specific differentiated tissues in our bodies that can renew themselves or generate new cells that can replenish dead or damaged tissue. You may also see the term somatic stem cell used to refer to adult stem cells. The term somatic refers to non-reproductive cells in the body (eggs or sperm). ASCs are typically scarce in native tissues which have rendered them difficult to study and extract for research purposes.

Resident in most tissues of the human body, discrete populations of ASCs generate cells to replace those that are lost through normal repair, disease, or injury. ASCs are found throughout ones lifetime in tissues such as the umbilical cord, placenta, bone marrow, muscle, brain, fat tissue, skin, gut, etc. The first ASCs were extracted and used for blood production in 1948. This procedure was expanded in 1968 when the first adult bone marrow cells were used in clinical therapies for blood disease.

Studies proving the specificity of developing ASCs are controversial; some showing that ASCs can only generate the cell types of their resident tissue whereas others have shown that ASCs may be able to generate other tissue types than those they reside in. More studies are necessary to confirm the dispute.

Types of Adult Stem Cells

Embryonic Stem Cells (ESCs):

During days 3-5 following fertilization and prior to implantation, the embryo (at this stage, called a blastocyst), contains an inner cell mass that is capable of generating all the specialized tissues that make up the human body. ESCs are derived from the inner cell mass of an embryo that has been fertilized in vitro and donated for research purposes following informed consent. ESCs are not derived from eggs fertilized in a womans body.

These pluripotent stem cells have the potential to become almost any cell type and are only found during the first stages of development. Scientists hope to understand how these cells differentiate during development. As we begin to understand these developmental processes we may be able to apply them to stem cells grown in vitro and potentially regrow cells such as nerve, skin, intestine, liver, etc for transplantation.

Induced Pluripotent Stem Cells (iPSCs)

Induced pluripotent stem cells are stem cells that are created in the laboratory, a happy medium between adult stem cells and embryonic stem cells. iPSCs are created through the introduction of embryonic genes into a somatic cell (a skin cell for example) that cause it to revert back to a stem cell like state. These cells, like ESCs are considered pluripotent Discovered in 2007, this method of genetic reprogramming to create embryonic like cells, is novel and needs many more years of research before use in clinical therapies.

NIH

Why are Stem Cells Important?

Stem cells are important for living organisms for many reasons. In the 3- to 5-day-old embryo, called a blastocyst, the inner cells give rise to the entire body of the organism, including all of the many specialized cell types and organs such as the heart, lung, skin, sperm, eggs and other tissues. In some adult tissues, such as bone marrow, muscle, and brain, discrete populations of adult stem cells generate replacements for cells that are lost through normal wear and tear, injury, or disease.

Given their unique regenerative abilities, stem cells offer new potentials for treating diseases such as diabetes, and heart disease. However, much work remains to be done in the laboratory and the clinic to understand how to use these cells for cell-based therapies to treat disease, which is also referred to as regenerative or reparative medicine.

Laboratory studies of stem cells enable scientists to learn about the cells essential properties and what makes them different from specialized cell types. Scientists are already using stem cells in the laboratory to screen new drugs and to develop model systems to study normal growth and identify the causes of birth defects.

Research on stem cells continues to advance knowledge about how an organism develops from a single cell and how healthy cells replace damaged cells in adult organisms. Stem cell research is one of the most fascinating areas of contemporary biology, but, as with many expanding fields of scientific inquiry, research on stem cells raises scientific questions as rapidly as it generates new discoveries.

Source NIH

Can doctors use stem cells to treat patients?

Some stem cells, such as the adult bone marrow or peripheral blood stem cells, have been used in clinical therapies for over 40 years. Other therapies utilizing stem cells include skin replacement from adult stem cells harvested from hair follicles that have been grown in culture to produce skin grafts. Other clinical trials for neuronal damage/disease have also been conducted using neural stem cells. There were side effects accompanying these studies and further investigation is warranted. Although there is much research to be conducted in the future, these studies give us hope for the future of therapeutics with stem cell research.

Potential Therapies using Stem Cells

Adult Stem Cell Therapies

Bone marrow and peripheral blood stem cell transplants have been utilized for over 40 years as therapy for blood disorders such as leukemia and lymphoma, amongst many others. Scientists have also shown that stem cells reside in most tissues of the body and research continues to learn how to identify, extract, and proliferate these cells for further use in therapy. Scientists hope to yield therapies for diseases such as type I diabetes and repair of heart muscle following heart attack.

Scientists have also shown that there is potential in reprogramming ASCs to cause them to transdifferentiate (turn back into a different cell type than the resident tissue it was replenishing).

Embryonic Stem Cell (ESC) Therapies

There is potential with ESCs to treat certain diseases in the future. Scientists continue to learn how ESCs differentiate and once this method is better understood, the hope is to apply the knowledge to get ESCs to differentiate into the cell of choice that is needed for patient therapy. Diseases that are being targeted with ESC therapy include diabetes, spinal cord injury, muscular dystrophy, heart disease, and vision/hearing loss.

Induced Pluripotent Stem Cell Therapies

Therapies using iPSCs are exciting because somatic cells of the recipient can be reprogrammed to en ESC like state. Then mechanisms to differentiate these cells may be applied to generate the cells in need. This is appealing to clinicians because this avoids the issue of histocompatibility and lifelong immunosuppression, which is needed if transplants use donor stem cells.

iPS cells mimic most ESC properties in that they are pluripotent cells, but do not currently carry the ethical baggage of ESC research and use because iPS cells have not been able to be manipulated to grow the outer layer of an embryonic cell required for the development of the cell into a human being.

Pros and Cons of Using Various Stem Cells

Read the original:
What are Stem Cells? - University of Nebraska Medical Center

Recommendation and review posted by Bethany Smith

What are BRCA1 and BRCA2?

BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of the cells genetic material. When either of these genes is mutated, or altered, such that its protein product either is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

Specific inherited mutations in BRCA1 and BRCA2 increase the risk of female breast and ovarian cancers, and they have been associated with increased risks of several additional types of cancer. Together, BRCA1 and BRCA2 mutations account for about 20 to 25 percent of hereditary breast cancers (1) and about 5 to 10 percent of all breast cancers (2). In addition, mutations in BRCA1 and BRCA2 account for around 15 percent of ovarian cancers overall (3). Breast and ovarian cancers associated with BRCA1 and BRCA2 mutations tend to develop at younger ages than their nonhereditary counterparts.

A harmful BRCA1 or BRCA2 mutation can be inherited from a persons mother or father. Each child of a parent who carries a mutation in one of these genes has a 50 percent chance (or 1 chance in 2) of inheriting the mutation. The effects of mutations in BRCA1 and BRCA2 are seen even when a persons second copy of the gene is normal.

How much does having a BRCA1 or BRCA2 gene mutation increase a womans risk of breast and ovarian cancer?

A womans lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2.

Breast cancer: About 12 percent of women in the general population will develop breast cancer sometime during their lives (4). By contrast, according to the most recent estimates, 55 to 65 percent of women who inherit a harmful BRCA1 mutation and around 45 percent of women who inherit a harmful BRCA2 mutation will develop breast cancer by age 70 years (5, 6).

Ovarian cancer: About 1.3 percent of women in the general population will develop ovarian cancer sometime during their lives (4). By contrast, according to the most recent estimates, 39 percent of women who inherit a harmful BRCA1 mutation (5, 6) and 11 to 17 percent of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by age 70 years (5, 6).

It is important to note that these estimated percentages of lifetime risk are different from those available previously; the estimates have changed as more information has become available, and they may change again with additional research. No long-term general population studies have directly compared cancer risk in women who have and do not have a harmful BRCA1 or BRCA2 mutation.

It is also important to note that other characteristics of a particular woman can make her cancer risk higher or lower than the average risks. These characteristics include her family history ofbreast, ovarian, and, possibly, other cancers; the specific mutation(s) she has inherited; and other risk factors, suchas her reproductivehistory. However, at this time, based on current data, none of these other factors seems to be as strong as the effect of carrying a harmful BRCA1 or BRCA2 mutation.

What other cancers have been linked to mutations in BRCA1 and BRCA2?

Are mutations in BRCA1 and BRCA2 more common in certain racial/ethnic populations than others?

Yes. For example, people of Ashkenazi Jewish descent have a higher prevalence of harmful BRCA1 and BRCA2 mutations than people in the general U.S. population. Other ethnic and geographic populations around the world, such as the Norwegian, Dutch, and Icelandic peoples, also have a higher prevalence of specific harmful BRCA1 and BRCA2 mutations.

In addition, limited data indicate that the prevalence of specific harmful BRCA1 and BRCA2 mutations may vary among individual racial and ethnic groups in the United States, including African Americans, Hispanics, Asian Americans, and non-Hispanic whites (15, 16).

Are genetic tests available to detect BRCA1 and BRCA2 mutations?

Yes. Several different tests are available, including tests that look for a known mutation in one of the genes (i.e., a mutation that has already been identified in another family member) and tests that check for all possible mutations in both genes. DNA (from a blood or saliva sample) is needed for mutation testing. The sample is sent to a laboratory for analysis. It usually takes about a month to get the test results.

Who should consider genetic testing for BRCA1 and BRCA2 mutations?

Because harmful BRCA1 and BRCA2 gene mutations are relatively rare in the general population, most experts agree that mutation testing of individuals who do not have cancer should be performed only when the persons individual or family history suggests the possible presence of a harmful mutation in BRCA1 or BRCA2.

In December 2013, the United States Preventive Services Task Force recommended that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a family history that is associated with an increased risk of a harmful mutation in one of these genes (17).

Several screening tools are now available to help health care providers with this evaluation (17). These tools assess family history factors that are associated with an increased likelihood of having a harmful mutation in BRCA1 or BRCA2, including:

When an individual has a family history that is suggestive of the presence of a BRCA1 or BRCA2 mutation, it may be most informative to first test a family member who has cancer if that person is still alive and willing to be tested. If that person is found to have a harmful BRCA1 or BRCA2 mutation, then other family members may want to consider genetic counseling to learn more about their potential risks and whether genetic testing for mutations in BRCA1 and BRCA2 might be appropriate for them.

If it is not possible to confirm the presence of a harmful BRCA1 or BRCA2 mutation in a family member who has cancer, it is appropriate for both men and women who do not have cancer but have a family medical history that suggests the presence of such a mutation to have genetic counseling for possible testing.

Some individualsfor example, those who were adopted at birthmay not know their family history. In cases where a woman with an unknown family history has an early-onset breast cancer or ovarian cancer or a man with an unknown family history is diagnosed with breast cancer, it may be reasonable for that individual to consider genetic testing for a BRCA1 or BRCA2 mutation. Individuals with an unknown family history who do not have an early-onset cancer or male breast cancer are at very low risk of having a harmful BRCA1 or BRCA2 mutation and are unlikely to benefit from routine genetic testing.

Professional societies do not recommend that children, even those with a family history suggestive of a harmful BRCA1 or BRCA2 mutation, undergo genetic testing for BRCA1 or BRCA2. This is because no risk-reduction strategies exist for children, and children's risks of developing a cancer type associated with a BRCA1 or BRCA2 mutation are extremely low. After children with a family history suggestive of a harmful BRCA1 or BRCA2 mutation become adults, however, they may want to obtain genetic counseling about whether or not to undergoing genetic testing.

Should people considering genetic testing for BRCA1 and BRCA2 mutations talk with a genetic counselor?

Genetic counseling is generally recommended before and after any genetic test for an inherited cancer syndrome. This counseling should be performed by a health care professional who is experienced in cancer genetics. Genetic counseling usually covers many aspects of the testing process, including:

How much does BRCA1 and BRCA2 mutation testing cost?

The Affordable Care Act considers genetic counseling and BRCA1 and BRCA2 mutation testing for individuals at high risk a covered preventive service. People considering BRCA1 and BRCA2 mutation testing may want to confirm their insurance coverage for genetic tests before having the test.

Some of the genetic testing companies that offer testing for BRCA1 and BRCA2 mutations may offer testing at no charge to patients who lack insurance and meet specific financial and medical criteria.

What does a positive BRCA1 or BRCA2 genetic test result mean?

BRCA1 and BRCA2 gene mutation testing can give several possible results: a positive result, a negative result, or an ambiguous or uncertain result.

A positive test result indicates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, therefore, has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when an individual will actually develop cancer. For example, some women who inherit a harmful BRCA1 or BRCA2 mutation will never develop breast or ovarian cancer.

A positive genetic test result may also have important health and social implications for family members, including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that persons relatives:

What does a negative BRCA1 or BRCA2 test result mean?

A negative test result can be more difficult to understand than a positive result because what the result means depends in part on an individuals family history of cancer and whether a BRCA1 or BRCA2 mutation has been identified in a blood relative.

If a close (first- or second-degree) relative of the tested person is known to carry a harmful BRCA1 or BRCA2 mutation, a negative test result is clear: it means that person does not carry the harmful mutation that is responsible for the familial cancer, and thus cannot pass it on to their children. Such a test result is called a true negative. A person with such a test result is currently thought to have the same risk of cancer as someone in the general population.

If the tested person has a family history that suggests the possibility of having a harmful mutation in BRCA1 or BRCA2 but complete gene testing identifies no such mutation in the family, a negative result is less clear. The likelihood that genetic testing will miss a known harmful BRCA1 or BRCA2 mutation is very low, but it could happen. Moreover, scientists continue to discover new BRCA1 and BRCA2 mutations and have not yet identified all potentially harmful ones. Therefore, it is possible that a person in this scenario with a "negative" test result actually has an as-yet unknown harmful BRCA1 or BRCA2 mutation that has not been identified.

It is also possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test used. People considering genetic testing for BRCA1 and BRCA2 mutations may want to discuss these potential uncertainties with a genetic counselor before undergoing testing.

What does an ambiguous or uncertain BRCA1 or BRCA2 test result mean?

Sometimes, a genetic test finds a change in BRCA1 or BRCA2 that has not been previously associated with cancer. This type of test result may be described as ambiguous (often referred to as a genetic variant of uncertain significance) because it isnt known whether this specific gene change affects a persons risk of developing cancer. One study found that 10 percent of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result (18).

As more research is conducted and more people are tested for BRCA1 and BRCA2 mutations, scientists will learn more about these changes and cancer risk. Genetic counseling can help a person understand what an ambiguous change in BRCA1 or BRCA2 may mean in terms of cancer risk. Over time, additional studies of variants of uncertain significance may result in a specific mutation being re-classified as either harmful or clearly not harmful.

How can a person who has a positive test result manage their risk of cancer?

Several options are available for managing cancer risk in individuals who have a known harmful BRCA1 or BRCA2 mutation. These include enhanced screening, prophylactic (risk-reducing) surgery, and chemoprevention.

Enhanced Screening. Some women who test positive for BRCA1 and BRCA2 mutations may choose to start cancer screening at younger ages than the general population or to have more frequent screening. For example, some experts recommend that women who carry a harmful BRCA1 or BRCA2 mutation undergo clinical breast examinations beginning at age 25 to 35 years (19). And some expert groups recommend that women who carry such a mutation have a mammogram every year, beginning at age 25 to 35 years.

Enhanced screening may increase the chance of detecting breast cancer at an early stage, when it may have a better chance of being treated successfully. Women who have a positive test result should ask their health care provider about the possible harms of diagnostic tests that involve radiation (mammograms or x-rays).

Recent studies have shown that MRI may be more sensitive than mammography for women at high risk of breast cancer (20, 21). However, mammography can also identify some breast cancers that are not identified by MRI (22), and MRI may be less specific (i.e., lead to more false-positive results) than mammography. Several organizations, such as the American Cancer Society and the National Comprehensive Cancer Network, now recommend annual screening with mammography and MRI for women who have a high risk of breast cancer.

No effective ovarian cancer screening methods currently exist. Some groups recommend transvaginal ultrasound, blood tests for the antigen CA-125, and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 mutations, but none of these methods appears to detect ovarian tumors at an early enough stage to reduce the risk of dying from ovarian cancer (23). For a screening method to be considered effective, it must have demonstrated reduced mortality from the disease of interest. This standard has not yet been met for ovarian cancer screening.

The benefits of screening for breast and other cancers in men who carry harmful mutations in BRCA1 or BRCA2 is also not known, but some expert groups recommend that men who are known to carry a harmful mutation undergo regular mammography as well as testing for prostate cancer. The value of these screening strategies remains unproven at present.

Prophylactic (Risk-reducing) Surgery. Prophylactic surgery involves removing as much of the "at-risk" tissue as possible. Women may choose to have both breasts removed (bilateral prophylactic mastectomy) to reduce their risk of breast cancer. Surgery to remove a woman's ovaries and fallopian tubes (bilateral prophylactic salpingo-oophorectomy) can help reduce her risk of ovarian cancer. Removing the ovaries also reduces the risk of breast cancer in premenopausal women by eliminating a source of hormones that can fuel the growth of some types of breast cancer.

No evidence is available regarding the effectiveness of bilateral prophylactic mastectomy in reducing breast cancer risk in men with a harmful BRCA1 or BRCA2 mutation or a family history of breast cancer. Therefore, bilateral prophylactic mastectomy for men at high risk of breast cancer is considered an experimental procedure, and insurance companies will not normally cover it.

Prophylactic surgery does not completely guarantee that cancer will not develop because not all at-risk tissue can be removed by these procedures. Some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after prophylactic surgery. Nevertheless, the mortality reduction associated with this surgery is substantial: Research demonstrates that women who underwent bilateral prophylactic salpingo-oophorectomy had a nearly 80 percent reduction in risk of dying from ovarian cancer, a 56 percent reduction in risk of dying from breast cancer (24), and a 77 percent reduction in risk of dying from any cause (25).

Emerging evidence (25) suggests that the amount of protection that removing the ovaries and fallopian tubes provides against the development of breast and ovarian cancer may be similar for carriers of BRCA1 and BRCA2 mutations, in contrast to earlier studies (26).

Chemoprevention. Chemoprevention is the use of drugs, vitamins, or other agents to try to reduce the risk of, or delay the recurrence of, cancer. Although two chemopreventive drugs (tamoxifen and raloxifene) have been approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at increased risk, the role of these drugs in women with harmful BRCA1 or BRCA2 mutations is not yet clear.

Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in BRCA1 and BRCA2 mutation carriers (27), including the risk of cancer in the opposite breast among women previously diagnosed with breast cancer (28, 29). Studies have not examined the effectiveness of raloxifene in BRCA1 and BRCA2 mutation carriers specifically.

Oral contraceptives (birth control pills) are thought to reduce the risk of ovarian cancer by about 50 percent both in the general population and in women with harmful BRCA1 or BRCA2 mutations (30).

What are some of the benefits of genetic testing for breast and ovarian cancer risk?

There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.

The potential benefits of a true negative result include a sense of relief regarding the future risk of cancer, learning that one's children are not at risk of inheriting the family's cancer susceptibility, and the possibility that special checkups, tests, or preventive surgeries may not be needed.

A positive test result may bring relief by resolving uncertainty regarding future cancer risk and may allow people to make informed decisions about their future, including taking steps to reduce their cancer risk. In addition, people who have a positive test result may choose to participate in medical research that could, in the long run, help reduce deaths from hereditary breast and ovarian cancer.

What are some of the possible harms of genetic testing for breast and ovarian cancer risk?

The direct medical harms of genetic testing are minimal, but knowledge of test results may have harmful effects on a persons emotions, social relationships, finances, and medical choices.

People who receive a positive test result may feel anxious, depressed, or angry. They may have difficulty making choices about whether to have preventive surgery or about which surgery to have.

People who receive a negative test result may experience survivor guilt, caused by the knowledge that they likely do not have an increased risk of developing a disease that affects one or more loved ones.

Because genetic testing can reveal information about more than one family member, the emotions caused by test results can create tension within families. Test results can also affect personal life choices, such as decisions about career, marriage, and childbearing.

Violations of privacy and of the confidentiality of genetic test results are additional potential risks. However, the federal Health Insurance Portability and Accountability Act and various state laws protect the privacy of a persons genetic information. Moreover, the federal Genetic Information Nondiscrimination Act, along with many state laws, prohibits discrimination based on genetic information in relation to health insurance and employment, although it does not cover life insurance, disability insurance, or long-term care insurance.

Finally, there is a small chance that test results may not be accurate, leading people to make decisions based on incorrect information. Although inaccurate results are unlikely, people with these concerns should address them during genetic counseling.

What are the implications of having a harmful BRCA1 or BRCA2 mutation for breast and ovarian cancer prognosis and treatment?

A number of studies have investigated possible clinical differences between breast and ovarian cancers that are associated with harmful BRCA1 or BRCA2 mutations and cancers that are not associated with these mutations.

There is some evidence that, over the long term, women who carry these mutations are more likely to develop a second cancer in either the same (ipsilateral) breast or the opposite (contralateral) breast than women who do not carry these mutations. Thus, some women with a harmful BRCA1 or BRCA2 mutation who develop breast cancer in one breast opt for a bilateral mastectomy, even if they would otherwise be candidates for breast-conserving surgery. In fact, because of the increased risk of a second breast cancer among BRCA1 and BRCA2 mutation carriers, some doctors recommend that women with early-onset breast cancer and those whose family history is consistent with a mutation in one of these genes have genetic testing when breast cancer is diagnosed.

Breast cancers in women with a harmful BRCA1 mutation are also more likely to be "triple-negative cancers" (i.e., the breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein), which generally have poorer prognosis than other breast cancers.

Because the products of the BRCA1 and BRCA2 genes are involved in DNA repair, some investigators have suggested that cancer cells with a harmful mutation in either of these genes may be more sensitive to anticancer agents that act by damaging DNA, such as cisplatin. In preclinical studies, drugs called PARP inhibitors, which block the repair of DNA damage, have been found to arrest the growth of cancer cells that have BRCA1 or BRCA2 mutations. These drugs have also shown some activity in cancer patients who carry BRCA1 or BRCA2 mutations, and researchers are continuing to develop and test these drugs.

What research is currently being done to help individuals with harmful BRCA1 or BRCA2 mutations?

Research studies are being conducted to find new and better ways of detecting, treating, and preventing cancer in people who carry mutations in BRCA1 and BRCA2. Additional studies are focused on improving genetic counseling methods and outcomes. Our knowledge in these areas is evolving rapidly.

Information about active clinical trials (research studies with people) for individuals with BRCA1 or BRCA2 mutations is available on NCIs website. The following links will retrieve lists of clinical trials open to individuals with BRCA1 or BRCA2 mutations.

NCIs Cancer Information Service (CIS) can also provide information about clinical trials and help with clinical trial searches.

Do inherited mutations in other genes increase the risk of breast and/or ovarian tumors?

Yes. Although harmful mutations in BRCA1 and BRCA2 are responsible for the disease in nearly half of families with multiple cases of breast cancer and up to 90 percent of families with both breast and ovarian cancer, mutations in a number of other genes have been associated with increased risks of breast and/or ovarian cancers (2, 31). These other genes include several that are associated with the inherited disorders Cowden syndrome, Peutz-Jeghers syndrome, Li-Fraumeni syndrome, and Fanconi anemia, which increase the risk of many cancer types.

Most mutations in these other genes are associated with smaller increases in breast cancer risk than are seen with mutations in BRCA1 and BRCA2. However, researchers recently reported that inherited mutations in the PALB2 gene are associated with a risk of breast cancer nearly as high as that associated with inherited BRCA1 and BRCA2 mutations (32). They estimated that 33 percent of women who inherit a harmful mutation in PALB2 will develop breast cancer by age 70 years. The estimated risk of breast cancer associated with a harmful PALB2 mutation is even higher for women who have a family history of breast cancer: 58 percent of those women will develop breast cancer by age 70 years.

PALB2, like BRCA1 and BRCA2, is a tumor suppressor gene. The PALB2 gene produces a protein that interacts with the proteins produced by the BRCA1 and BRCA2 genes to help repair breaks in DNA. Harmful mutations in PALB2 (also known as FANCN) are associated with increased risks of ovarian, pancreatic, and prostate cancers in addition to an increased risk of breast cancer (13, 33, 34). Mutations in PALB2, when inherited from each parent, can cause a Fanconi anemia subtype, FA-N, that is associated with childhood solid tumors (13, 33, 35).

Although genetic testing for PALB2 mutations is available, expert groups have not yet developed specific guidelines for who should be tested for, or the management of breast cancer risk in individuals with, PALB2 mutations.

Excerpt from:
BRCA1 and BRCA2: Cancer Risk and Genetic Testing

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Since their discovery/invention a little less than a decade ago, induced pluripotent stem (iPS) cells inspired hope to become a powerful tool for drug discovery and development applications. With advances in reprogramming and differentiation technologies, as well as with the recent availability of gene editing approaches, we are finally able to create more complex and phenotypically accurate cellular models based on iPS cell technology. This opens new and exciting opportunities for iPS cell utilization in early discovery, preclinical and translational research. Cambridge Healthtech Institutes inaugural iPS Cell Technology in Drug Discovery and Development conference is designed to bring together experts and bench scientists working with iPS cells and end users of their services, researchers working on finding cures for specific diseases and disorders.

Final Agenda

Day 1 | Day 2 | Speaker Biographies | Download Brochure

Wednesday, June 15

7:00 am Registration and Morning Coffee

8:25 Chairpersons Opening Remarks

8:35 KEYNOTE PRESENTATION: iPS CELL TECHNOLOGY, GENE EDITING AND DISEASE RESEARCH

Rudolf Jaenisch, M.D., Founding Member, Whitehead Institute for Biomedical Research; Professor, Department of Biology, Massachusetts Institute of Technology

The development of the iPS cell technology has revolutionized our ability to study human diseases in defined in vitro cell culture systems. A major problem of using iPS cells for this disease in the dish approach is the choice of control cells because of the unpredictable variability between different iPS / ES cells to differentiate into a given lineage. Recently developed efficient gene editing methods such as the CRISPR/Cas system allow the creation of genetically defined models of monogenic as well as polygenic human disorders.

9:05 iPSC Genome Editing: From Modeling Disease to Novel Therapeutics

Chad Cowan, Ph.D., Associate Professor, Harvard Department of Stem Cell & Regenerative Biology (HSCRB)

Our goal is to understand how naturally occurring human genetic variation protects (or predisposes) some people to cardiovascular and metabolic diseasethe leading cause of death in the worldand to use that information to develop therapies that can protect the entire population from disease.

9:35 Stem Cells and Genome Editing to Enable Drug Discovery

Jeffrey Stock, Ph.D., Principal Scientist, Global R&D Groton Labs, Pfizer

Significant advances have been made in recent years in the isolation/generation and differentiation of human pluripotent stem cells (hPSC). Similarly, powerful tools for in vitro genomic editing are now readily available. When combined, these technologies make it possible to generate physiologically relevant models of human disease to enable drug discovery. In this presentation, we provide some examples of how we have applied these technologies to produce models that are suitable for target validation as well as small molecule screening.

10:05 Grand Opening Coffee Break in the Exhibit Hall with Poster Viewing

10:50 Phenotypic Diversity in a Large Cohort of iPSC-Derived Cardiomyocytes as a Platform for Response Modeling in Drug Development

Ulrich Broeckel, M.D., Professor of Pediatrics, Medicine and Physiology, Pediatrics, Medical College of Wisconsin

We will discuss the underlying concepts of phenotypic variation and the impact of genomic variation on common, complex phenotypes in iPSCs. To demonstrate this, we have established 250 iPSC cell lines from the NHLBI HyperGen study. We will discuss our approach to analyzing disease phenotypes on a molecular level using iPSC-derived cardiomyocytes. Furthermore we will present data, which provides a framework to use the obtained data for the selection of samples for compound screening and drug development.

11:20 Transcriptional and Proteomic Profiling of Human Pluripotent Stem Cell-Derived Motor Neurons: Implications for Familial Amyotrophic Lateral Sclerosis

Joseph Klim, Ph.D., Postdoctoral Scholar, Eggan Lab, Stem Cell and Regenerative Biology Department, Harvard University

We combined pluripotent stem cell technologies with both RNA sequencing and mass spectrometry-based proteomics to map alterations to mRNA and protein levels in motor neurons expressing mutant SOD1. This approach enabled us to study the effects of mutant SOD1 in purified populations of motor neurons using multiple molecular metrics over time. These investigations have afforded an unprecedented glimpse at the biochemical make-up of human stem cell-derived motor neurons and how they change in culture.

11:50 Presentation to be Announced

Yoko Ejiri, Researcher, Microdevice Team, New Business Development Division, Kuraray Co. Ltd.

12:05 Sponsored Presentation (Opportunity Available)

12:20 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:50 Session Break

1:40 Chairpersons Remarks

Vikram Khurana, M.D., Co-Founder and Vice President, Discovery Technologies, Yumanity Therapeutics

1:50 High-Throughput Phenotyping of Human PSC Derived Neurons

Bilada Bilican, Ph.D., Investigator II, Neuroscience, Novartis Institutes for BioMedical Research (NIBR)

We established a fully automated human pluripotent stem cell (PSC) maintenance and excitatory cortical neuronal differentiation platform that enables parallel phenotyping of many different lines at once. This human disease-modeling platform is being integrated into Novartis lead discovery pipeline to identify new targets, molecules, and to elucidate cellular aspects of human neuronal biology.

2:20 Modeling ALS with Patient Specific iPSCs

Shila Mekhoubad, Ph.D., Scientist, Stem Cell Biology Lab, Biogen

Advances in stem cell biology and neuronal differentiations have provided a new platform to study ALS in vitro. Here we will describe our use of induced pluripotent stem cells (iPSCs) from patients with familial ALS to establish new models and tools that can contribute to the development and validation of novel ALS therapeutics.

2:50 Refreshment Break in the Exhibit Hall with Poster Viewing

3:35 Modeling Huntingtons Disease in IPS Cells: Development and Validation of Phenotypes Relevant for Disease

Kimberly B. Kegel-Gleason, Ph.D., Assistant Professor in Neurology, Massachusetts General Hospital & Harvard Medical School

Huntingtons disease (HD) is a neurodegenerative disease caused by a CAG expansion in the HD gene. Using induced pluripotent stem (IPS) cells from controls and HD patients with low and medium CAG repeat expansions, we are developing assays for target validation and drug discovery based on phenotypic changes observed in PI 3-kinase dependent signaling, Rac activation and cell motility in microfluidic channels.

4:05 From Yeast to Patient iPS Cells: A Drug Discovery Pipeline for Neurodegeneration

Vikram Khurana, M.D., Co-Founder and Vice President, Discovery Technologies, Yumanity Therapeutics

Phenotypic screening in neurons and glia derived from patients is now conceivable through unprecedented developments in reprogramming, transdifferentiation, and genome editing. We outline progress in this nascent field, but also consider the formidable hurdles to identifying robust, disease-relevant and screenable cellular phenotypes in patient-derived cells. We illustrate how analysis in the simple bakers yeast cell Saccharaomyces cerevisiae is driving discovery in patient-derived neurons, and how approaches in this model organism can establish a paradigm to guide the development of stem cell-based phenotypic screens.

4:35 Sponsored Presentation (Opportunity Available)

5:05 PANEL DISCUSSION: iPSC-Based Neurodegenerative Disease Modeling

Moderator: Vikram Khurana, M.D., Co-Founder and Vice President, Discovery Technologies, Yumanity Therapeutics

Human neurodegenerative disorders are among the most difficult to study. This panel will discuss existing and future models for major neurodegenerative diseases.

5:35 Welcome Reception in the Exhibit Hall with Poster Viewing

6:45 Close of Day

Day 1 | Day 2 | Speaker Biographies | Download Brochure

Thursday, June 16

7:00 am Registration.

7:30 Interactive Breakout Discussion Groups with Continental Breakfast

This session features various discussion groups that are led by a moderator/s who ensures focused conversations around the key issues listed. Attendees choose to join a specific group and the small, informal setting facilitates sharing of ideas and active networking. Continental breakfast is available for all participants.

Modeling neurodegenerative disorders for drug discovery and development

Moderator: Bilada Bilican, Ph.D., Investigator II, Neuroscience, Novartis Institutes for BioMedical Research (NIBR)

iPS Cell Technology Enabled Organ-on-Chip Models

Moderator: James Hickman, Ph.D., Professor, NanoScience Technology Center, University of Central Florida

Gene Editing in iPS Cells: Technology and Major Applications

Moderator:Joseph Klim Ph.D., Postdoctoral Scholar, Eggan Lab, Stem Cell and Regenerative Biology Department

8:35 Chairpersons Remarks

James J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida

8:45 Utilization of iPSCs in Developing Human-on-a-Chip Systems for Phenotypic Screening Applications

James J. Hickman, Ph.D., Founding Director, NanoScience Technology Center and Professor, Nanoscience Technology, Chemistry, Biomolecular Science, Material Science and Electrical Engineering, University of Central Florida

Our lab is developing multi-organ human-on-a-chip systems for evaluating toxicity and efficacy compounds for drug discovery applications. Validation of the systems has already indicated good agreement with previous literature values, which gauges well for the predictive power of these platforms. Applications for neurodegenerative diseases, metabolic disorders as well as cardiac and muscle deficiencies will be highlighted in the talk.

9:15 Human-Induced Pluripotent Stem Cells Recapitulate Breast Cancer Patients Predilection to Doxorubicin-Induced Cardiotoxicity

Paul W. Burridge, Ph.D., Assistant Professor, Department of Pharmacology, Center for Pharmacogenomics, Northwestern University Feinberg School of Medicine

The ability to predict which patients are likely to experience cardiotoxicity as a result of their chemotherapy represents a powerful clinical tool to attenuate this devastating side-effect. We report our progress towards this aim using the hiPSC cell model, a battery of in vitro assays, and machine learning.

9:45 Utilization of Induced Pluripotent Stem Cells to Understand Tyrosine Kinase Inhibitors (TKIs)-Induced Hepatotoxicity

Qiang Shi, Ph.D., Principal Investigator, Division of Systems Biology, National Center for Toxicological Research (NCTR), U.S. FDA

For cancer patients, the benefits of anti-cancer agents are often countered by hepatotoxicity. The purpose of current study is to predict tyrosine kinase inhibitors (TKIs)-induced toxicity using rat primary hepatocytes and human induced pluripotent stem cell (iPSC) -derived hepatocytes. Multi-parameter cellular endpoints have been used to examine the utilization of iPSC in safety screening. Data on cross-species comparison from rodent to human will be presented.

10:15 Coffee Break in the Exhibit Hall with Poster Viewing

10:55 Chairpersons Remarks

Joseph Klim, Ph.D., Postdoctoral Scholar, Eggan Lab, Stem Cell and Regenerative Biology Department, Harvard University

11:00 KEYNOTE PRESENTATION: STEM CELL PROGRAMMING AND REPROGRAMMING, AND APPLICATIONS OF iPSC TECHNOLOGIES TO MODELING OF THE NEUROMUSCULAR SYSTEM AND THE DISEASES THAT AFFECT IT

Kevin C. Eggan, Ph.D., Harvard Department of Stem Cell and Regenerative Biology, Howard Hughes Medical Institute

While iPSCs have created unprecedented opportunities for drug discovery, there remains uncertainty concerning the path to the clinic for candidate therapeutics discovered with their use. Here we share lessons that we learned, and believe are generalizable to similar efforts, while taking a discovery made using iPSCs into a clinical trial.

11:30 Trans-Amniotic Stem Cell Therapy (TRASCET) for the Treatment of Birth Defects

Dario O. Fauza, M.D., Ph.D., Associate in Surgery, Boston Children's Hospital; Associate Professor, Surgery, Harvard Medical School

Trans-Amniotic Stem Cell Therapy (TRASCET) is a novel therapeutic paradigm for the treatment of birth defects. It is based on the principle of harnessing/enhancing the normal biological role of amniotic fluid-derived mesenchymal stem cells (afMSCs) for therapeutic benefit. The intra-amniotic delivery of afMSCs in large numbers can either elicit the repair, or significantly mitigate the effects associated with major congenital anomalies such as neural tube and abdominal wall defects.

12:00 pm Bridging Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

12:30 Session Break

1:00 Coffee and Dessert in the Exhibit Hall with Poster Viewing

1:45 PLENARY KEYNOTE SESSION

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing

4:15 Close of Conference

Day 1 | Day 2 | Speaker Biographies | Download Brochure

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Advances in iPS Cell Technology for Drug Development ...

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What is hypopituitarism?

Hypopituitarism (also called pituitary insufficiency) is a rare condition in which your pituitary gland doesnt make enough of certain hormones. Your body cant work properly when important glands, such as your thyroid gland and adrenal gland, dont get the hormones they need from your pituitary gland.

The pituitary gland is a pea-sized gland found at the base of your brain. It is called the master gland because it affects the action of many other important glands that produce their own hormones. The pituitary gland affects almost all parts of your body.

Hypopituitarism can develop very slowly, over several months or even over several years.

Hypopituitarism can be caused by

Sometimes, the cause is unknown.

Symptoms can include one or more of the following:

Your doctor will check your hormone levels with blood tests. You may have other tests, such as an MRI of your pituitary gland, to help find the cause of your hypopituitarism.

Treatment usually includes taking the hormones youre missing, sometimes for life. Your doctor also will teach you how to take extra cortisone (a hormone) when you are sick or under stress. If a tumor is causing your hypopituitarism, you might need surgery to remove it and/or possibly radiation treatment. If needed, you can take medicine for infertility.

You will need to get regular check-ups. Its wise to wear medical identification, such as a bracelet or pendant, which provides information about your condition in case of an emergency.

You can expect a normal life span, as long as you regularly take the medications recommended by your doctor.

Read the original here: Hypopituitarism Symptoms and Treatment | Hormone Health

Hypopituitarism is a general term that refers to any under-performance of the pituitary gland. This is a clinical definition used by endocrinologists and is interpreted to mean that one or more functions of the pituitary are deficient. The term may refer to both anterior and posterior pituitary gland failure. Below is a list of the hormones secreted by the pituitary and their functions:

In cases of hypopituitarism, single or multiple hormone deficiencies are present. The deficiencies affect the target organ activity or secretion (the thyroid; the adrenals; or the gonads, which includes both female and male sexual development and function). Causes of hypopituitarism are tumors or lesions of various origins, congenital defects, trauma, radiation, surgery, encephalitis, hemochromatosis, and stroke. In children, the condition results in slowed growth and development and is known as dwarfism. The cause may also be unknown.

Deficient pituitary gland function can result from damage to either the pituitary or the area just above the pituitary, namely the hypothalamus. The hypothalamus contains releasing and inhibitory hormones that control the pituitary. Since these hormones are necessary for normal pituitary function, damage to the hypothalamus can also result in deficient pituitary gland function. Injury to the pituitary can occur from a variety of insults, including damage from an enlarging pituitary tumor, irradiation of the pituitary gland, limited blood supply (as experienced in a stroke), trauma or abnormal iron storage (hemochromatosis). There appears to be a predictable loss of hormonal function with increasing damage. The progression from most vulnerable to least vulnerable is usually as follows:

Additional symptoms that may be associated with this disease:

Men develop testicular suppression with decreased libido, impotence, decreased ejaculate volume, loss of body and facial hair, weakness, fatigue and often anemia. On testing, blood levels of testosterone are low and should be replaced. In the United States, testosterone may be given as a bi-weekly intramuscular injection, in a patch form or as a gel or creme preparation. In some countries, oral preparations of testosterone are available.

Thyroid Stimulation Hormone (TSH) Deficiency Deficiency of thyroid hormone causes a syndrome consisting of decreased energy, increased need to sleep, intolerance of cold (inability to stay warm), dry skin, constipation, muscle aching and decreased mental functions. This variety of symptoms is very uncomfortable and is often the symptom complex that drives patients with pituitary disease to seek medical attention. Replacement therapy consists of a either T4 (thyroxine) and/or T3 (triiodothyronine). The correct dose is determined through experimentation and blood tests.

Adrenal Hormone Deficiency Deficiency of ACTH resulting in cortisol deficiency is the most dangerous and life-threatening of the hormonal deficiency syndromes. With gradual onset of deficiency over days or weeks, symptoms are often vague and may include weight loss, fatigue, weakness, depression, apathy, nausea, vomiting, anorexia and hyperpigmentation. As the deficiency becomes more serious or has a more rapid onset (Addison crisis), symptoms of confusion, stupor, psychosis, abnormal electrolytes (low serum sodium, elevated serum potassium), and vascular collapse (low blood pressure and shock) can occur. Treatment consists of cortisol administration or another similar steroid (like prednisone). For patients with acute adrenal insufficiency, rapid intravenous administration of high dose steroids is essential to reverse the crisis.

Posterior Pituitary Antidiuretic Hormone (ADH) Deficiency Replacement of antidiuretic hormone resolves the symptoms of increased thirst and urination seen in diabetes insipidus. Antidiuretic hormone (ADH) is currently replaced by administration of a synthetic type of ADH either by subcutaneous injection, intranasal spray, or by tablet, usually once or twice a day.

Endocrine substitution therapy is indicated for replacement of hormones for the affected organs. These include corticosteroids, thyroid hormone, sex hormones (testosterone for men and estrogen for women), and growth hormone. Drugs are available to treat associated infertility in men and women.

Growth hormone is only available in injectable form and is usually given 6-7 times per week. Homeopathic GH or IGF has been proven to provide benefits in blinded trials.

Follow this link: Hypopituitarism Symptoms, Diagnosis, Treatment and

What are the symptoms of hypopituitarism?

The symptoms of hypopituitarism depend on the specific hormone that is lacking. For example, patients with reduced ACTH secretion have low cortisol levels, which can result in loss of appetite, weight loss, nausea, vomiting, fatigue, weakness and/or lightheadedness. This condition is called adrenal insufficiency. Patients with reduced TSH secretion have low thyroid hormone levels resulting in a condition called hypothyroidism. Signs and symptoms of hypothyroidism can include weight gain, fatigue, dry skin, constipation, cold intolerance and hair loss. Women of reproductive age with reduced LH and FSH secretion develop amenorrhea (absence of menstrual periods), infertility, and bone loss due to low estrogen levels. Men with low LH and FSH levels develop low testosterone levels, which results in lack of libido (sex drive), erectile dyfunction, infertility, fatigue, body composition abnormalities (loss of muscle mass and an increase in abdominal fat), bone loss, and sometimes, depression. Low growth hormone (GH) in children leads to short stature. In adults, GH deficiency is associated with a diminished quality of life, body composition abnormalities (including a reduction in muscle mass and increase in abdominal fat mass) and low bone density. Women with low prolactin are unable to breastfeed, but there are no known adverse effects of low prolactin in men.

Pituitary Symptoms

Hypopituitarism is caused by damage to the pituitary gland, usually from a tumor, radiation, surgery. Traumatic brain injury and subarachnoid hemorrhages can also cause hypopituitarism. Occasionally inflammation can cause hypopituitarism and sometimes the cause is unclear. Medications can also cause hypopituitarism. For example, high-dose steroid use can lead to adrenal insufficiency and anabolic steroid use can result in low testosterone that lasts beyond the time in which the medication is used and can be permanent.

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The complications of hypopituitarism are due to the specific hormone deficiency. See What are the symptoms of hypopituitarism above. Patient with hypopituitarism not receiving appropriate hormone replacement therapies have an increased risk of mortality.

Research Studies

Youre likely to start by seeing your family doctor or a general practitioner. However, in some cases when you call to set up an appointment, you may be referred immediately to an endocrinologist, a doctor who specializes in endocrine (hormonal) disorders.

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Hypopituitarism (Medical Condition) Symptoms, risk factors and treatments of Hypopituitarism (Medical Condition) Hypopituitarism is the decreased secretion of one or more of the eight hormones normally produced by the pituitary

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Hypopituitarism is the failure of production of one or more hormones from the pituitary gland.

Hypopit; pituitary insufficiency; partial hypopituitarism; panhypopituitarism (pan referring to all pituitary hormones being affected); anterior hypopituitarism.

Hypopituitarism is failure of the pituitary gland to produce one, some, or all of the hormones it normally produces. The pituitary gland has two parts, anterior pituitary and posterior pituitary, and hormone production can be affected in both parts.

Below are listed some of the causes of hypopituitarism:

The signs and symptoms of hypopituitarism depend on which of the pituitary gland hormones are involved, to what extent and for how long. It also depends on whether the hormone deficiencies began as a child or later in adult life. Symptoms can be slow at the start and vague.It is worth understanding the normal function and effects of these hormones in order to understand the signs and symptoms of hypopituitarism. (See the article on pituitary gland.) There may also be additional symptoms due to the underlying cause of the hypopituitarism, such as the effects of pressure from a tumour.

Symptoms can include:

Hypopituitarism is rare. At any given time, between 300 and 455 people in a million may have hypopituitarism. A number of endocrinologists believe that hypopituitarism is quite common after brain injuries. If this belief is confirmed, then hypopituitarism may be significantly more common than previously believed.

Most cases of hypopituitarism are not inherited.However, there are some very rare genetic abnormalities than can cause hypopituitarism.

Blood tests are required to check the level of the hormones which are either produced by the pituitary gland itself or peripheral endocrine glands controlled by the pituitary gland. These blood tests may be one-off samples or the patient may require more detailed testing on a day-unit. These are called dynamic tests and they measure hormone levels before and after stimulation to see if the normal pituitary gland is working properly.They usually last between1 to 4 hours.

If it is suspected that there is a lack of anti-diuretic hormone, the doctor may organise a water deprivation test. The patient will be deprived of water for a period of eight hours under very close supervision with regular blood and urine tests.The test may be extended to a 24 hour period if needed which means an overnight stay in hospital.

See more here: You & Your Hormones | Endocrine conditions | Hypopituitarism

Hypopituitarism is a general term that refers to any under function of the pituitary gland. This is a clinical definition used by endocrinologists and is interpreted to mean that one or more functions of the pituitary are deficient. The term may refer to both anterior and posterior pituitary gland failure.

Deficient pituitary gland function can result from damage to either the pituitary or the area just above the pituitary, the hypothalamus. The hypothalamus contains releasing and inhibitory hormones which control the pituitary. Since these hormones are necessary for normal pituitary function, damage to the hypothalamus can also result in deficient pituitary gland function. Injury to the pituitary can occur from a variety of insults, including damage from an enlarging pituitary tumor, irradiation to the pituitary, pituitary apoplexy, trauma and abnormal iron storage (hemochromatosis). With increasing damage there is a progressive decrease in function. There appears to be a predictable loss of hormonal function with increasing damage. The progression from most vulnerable to least vulnerable is usually as follows: first is growth hormone (GH), next the gonadotropins (LH and FSH which control sexual/reproductive function), followed by TSH (which control thyroid hormone release) and finally the last to be lost is typically ACTH (which controls adrenal function).

Sheehans syndrome is a condition that may occur in a woman who has a severe uterine hemorrhage during childbirth. The resulting severe blood loss causes tissue death in her pituitary gland and leads to hypopituitarism following the birth. For more on this Sheehans syndrome, please visit MedlinePlus on Sheehans Syndrome.

Deficiency of ACTH resulting in cortisol deficiency is the most dangerous and life threatening of the hormonal deficiency syndromes. With gradual onset of deficiency over days or weeks, symptoms are often vague and may include weight loss, fatigue, weakness, depression, apathy, nausea, vomiting, anorexia and hyperpigmentation. As the deficiency becomes more serious or has a more rapid onset, (Addisonian crisis) symptoms may include confusion, stupor, psychosis, abnormal electrolytes (low serum sodium, elevated serum potassium), and vascular collapse (low blood pressure and shock) which can be fatal. Treatment consists of cortisol administration or another similar steroid (like prednisone). For patients with acute adrenal insufficiency (Addisonian crisis), rapid intravenous administration of high dose steroids is essential to reverse the crisis.

Deficiency of thyroid hormone causes a syndrome consisting of decreased energy, increased need to sleep, intolerance of cold (inability to stay warm), dry skin, constipation, muscle aching and decreased mental functions. This constellation of symptoms is very uncomfortable and is often the symptom complex that drives patients with pituitary disease to seek medical attention. Replacement therapy consists of a daily pill called thyroxine (Synthroid, Levothyroxine etc). The correct dose is determined through blood tests.

Women develop ovarian suppression with irregular periods or absence of periods (amenorrhea), infertility, decreased libido, decreased vaginal secretions, breast atrophy, and osteoporosis. Blood levels of estradiol are low. Estrogen should be replaced and can be given orally as Premarin or estrace, or can be given as a patch applied twice weekly. Women taking estrogen also need to take progesterone replacement (unless they have undergone a hysterectomy). Annual pap smears and mammograms are mandatory.

Men develop testicular suppression with decreased libido, impotence, decreased ejaculate volume, loss of body and facial hair, weakness, fatigue and often anemia. On testing, blood levels of testosterone are low and should be replaced. In the United States, testosterone may be given as a bi-weekly intramuscular injection, a patch form, or a gel preparation. In other countries, oral preparations of testosterone are available.

Growth hormone is necessary in children for growth, but also appears necessary in adults to maintain normal body composition (muscle and bone mass). It may also be helpful for maintaining an adequate energy level, optimal cardiovascular status and some mental functions. Symptoms of GH deficiency in adults include fatigue, poor exercise performance and symptoms of social isolation. GH is only available in injectable form and must be given 6-7 times per week.

This problem arises from damage to the pituitary stalk or the posterior pituitary gland. It may occur transiently after transsphenoidal surgery but is rarely permanent. Patients with diabetes insipidus have increased thirst and urination. Replacement of antidiuretic hormone resolves these symptoms. Antidiuretic hormone (ADH) is currently replaced by administration of DDAVP (also called Desmopressin) a synthetic type of ADH. DDAVP can be given by subcutaneous injection, intranasal spray, or by tablet, usually once or twice a day.

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How to Pronounce Hypopituitarism This video shows you how to pronounce Hypopituitarism.

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Over the past two decades or so, weve learned a lot about how the pituitary gland develops. Today, that ever-evolving knowledge helps us better serve our patients and their families.

Laurie Cohen, MD, director, Neuroendocrinology Program

You may have never heard of hypopituitarism until your child was diagnosed with it. Hypopituitarism occurs when the anterior (front) lobe of the pituitary gland loses its ability to make hormones. The resulting symptoms depend on which hormones are no longer being produced by the gland.

The good news is that treating the underlying condition thats causing your childs hypopituitarism often leads to a full recovery.

How Childrens Hospital Boston approaches hypopituitarism

At Childrens, you can rest assured knowing that your child will be cared for by knowledgeable physicians whove devoted their careers to understanding this condition. We treat children with hypopituitarism in our General Endocrinology Programa multidisciplinary program dedicated to the treatment of children with a wide range of endocrinological disorders. For these children, our dedicated team of doctors, nurses and other caregivers offer hope for a healthier future.

Ranked #1 in Endocrinology In 2014, Boston Childrens Hospital was ranked #1 in Endocrinology by U.S. News & World Report.

Reviewed by Laurie Cohen, MD Childrens Hospital Boston, 2010

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Hypopituitarism refers to under-function of the Pituitary Gland. The term refers to both anterior and posterior pituitary gland dysfunction. It may be temporary or permanent. Panhypopituitarism refers to complete loss of all pituitary function. Patients with pan-hypopituitarism should carry a Medic Alert Bracelet at all times to notify health care personnel of this problem in case of an emergency.

There appears to be a predictable loss of hormonal function: the growth hormone (GH), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secreting cells appear most vulnerable while thyroid stimulating (TSH) and adrenocorticotropic hormone (ACTH) secreting cells are less vulnerable. Approximately 50% of patients will have some recovery of pituitary function after surgical removal of a pituitary adenoma. Approximately 45% will have no recovery or change, and 5% will have diminished pituitary function.

Deficiency of Acth and Cortisol

Treatment consists of glucocorticoids (hydrocortisone, dexamethasone or prednisone). For patients with acute adrenal insufficiency (Addisonian crisis), rapid intravenous administration of high dose steroids is essential.

Definciency of TSH and Thyroid Hormone

Treatment with thyroxin (Synthroid) reverses the symptoms and signs over days or weeks and requires careful monitoring of free T4 or total T4 (thyroid function levels).

Deficiency of LH and FSH (Hypogonadotropic Hypogonadism)

Women on estrogen also need progesterone. Men with hypogonadism develop decreased libido, impotence, decreased ejaculate volume, loss of body and facial hair, weakness, fatigue and often anemia. Blood testosterone levels are low and should be replaced as a daily patch or gel or as an injection every 2-3 weeks.

Growth Hormone Deficiency

Antidiuretic Hormone Deficiency (ADH) and Diabetes Insipidus (DI)

Read the original post: Hypopituitarism (Pituitary Gland Failure) | Providence

Home Frequently asked HYPOPITUITARY questions.and their answers

When not on any thyroid meds, you find yourself with a very low TSH lab (the TSH is a pituitary hormone), yet you have a low free T3, plus hypothyroid symptoms, you may have hypopituitarism.

Here are the most frequently asked questions concerning this condition, created by Chris, a hypopituitary patient who has worked with other hypopituitary patients for several years. Please note these are quick general answers so its recommended you do your own research to learn more. You can also join Chriss Hypopituitary Support Group on Yahoo. It is closed to posting, but you can join to access the great deal of information it contains, including over 500 links and 100 files.

1) What is hypopituitarism? 2) What are symptoms of hypopituitarism? 3) What causes hypopituitarism? 4) Is adrenal and/or thyroid treatment different if I am hypopituitary? 5) What labs will detect hypopituitarism? 6) If I cant afford all those labs, can you tell just from TSH? DHEA? 7) Can you detect hypopituitarism from saliva cortisol labs? 8 ) Im already on HC, can I test cortisol or ACTH levels? 9) Is there any test for hypopituitarism once Im already on HC? 10) If one pituitary hormone is low, does that mean all of them are? 11) My Dr or Insurance wont approve further tests what should I do? 12) Should I start treating the sex hormones right away? 13) Is hypopituitarism curable? 14) My doctor says my cortisol doubled during the ACTH stimulation test, so I am ok-is he right? 15) Could I have a pituitary tumor? Should I get an MRI? Is it gonna grow? Will I need an operation? 16) Are there shades of Gray on this? Does someone get sort-of hypo-pit, then then next guys labs even more so, then finally one sets off the buzzer and gets a definitive label of Hypo-Pit? 1) What is hypopituitarism? Hypopituitary is the pituitary gland functioning below where it needs to be, and one or more hormones can be involved. The pituitary is a pea sized gland located at the base of the brain and it runs the adrenals, thyroid, and sex hormones. It also produces growth hormone and stores oxytocin and vasopressin, both of which are made in the hypothalamus. If the pituitary doesnt put out enough TSH, thyroid hormone production can decrease. It the pituitary doesnt produce enough ACTH, cortisol (and DHEA) can decrease. 2) What are the symptoms of hypopituitarism? Because the pituitary may not be sending adequate levels of TSH and or ACTH, you could feel fatigue, weakness, have low blood pressure, feel colder than normal, have a decrease in your appetite, headaches, and depression. Symptoms of hypopit (concerning low TSH, low ACTH, low LH and FSH) are the same as if thyroid-adrenals-gonads are the cause. In most cases you cant tell by symptoms if you may be hypopituitary or not. If you arent getting enough ACTH, you could have symptoms of weight loss and nausea, plus the fatigue, low blood pressure, weakness, and depression. Because of a deficiency of TSH and LH, women could lose their periods, or have problems conceiving. Men could have a decreased libido, erectile dysfunction, and loss of facial hair. If hypopituitary occurs in childhood, the result can be a short stature. Thirst and increased need to urinate can occur is you have an ADH deficiency. (Note: a large body of hypothyroid patients have a low normal TSH without hypopituitarism. Why? Because the man-made TSH lab is often slow to reveal the hypothyroid state. Those with hypopituitarism will often have a TSH at 0.8 and lower for women, and 1.8 and lower for men, with accompanying hypo symptoms. See #5 and 6 below.)

3) What causes hypopituitarism? A common cause of hypopituitarism is head injury. Even a seemingly mild bump to the head can damage the pituitary. A Pituitary tumor can also cause hypopituitary, though perhaps less than 3 percent have this as a cause. Sheehans syndrome is another cause, which is any type of blood loss, and where the pituitary at least partially dies from the lack of blood. Blood loss from childbirth, or an injury can result in Sheehans syndrome. Other causes can be radiation, antibody attack, and environmental. In most cases, it can not be known for sure what the cause is.

4) Is adrenal and/or thyroid treatment different if I am hypopituitary? In treating the adrenals and thyroid caused by low ACTH (secondary AI) and low TSH (secondary hypothyroid), treatment is the same as it is for primary Adrenal Insufficiency and primary hypothyroid. Sex hormone treatment can be different with the use of HCG (almost identical to LH) in secondaries hypogonadism (low LH and FSH production in the pituitary which will cause low sex hormones in men and women), whereas primary hypogonadism involves the gonads being the cause of low sex hormones, LH and FSH will go up. The treatment for primary hypogonadism is the use of testosterone (in men, sometimes along with estrogen blocker) and estrogen, progesterone and even testosterone in women. Some men with primary hypogonadism also use HCG, but is rarely used in women.

5) What labs will detect hypopituitarism? -low TSH (below 1.8 for men, below 0.8 for women) -low ACTH (below 30 for am. Is possible to be secondary with ACTH as high as low 40s) -ACTH stimulation or ITT that doubles cortisol from a low base value. -ITT for GH stim -low GHRH -low TRH -low vasopressin (hypothalamic hormone which is stored in the pituitary) -low renin and low aldosterone -very low or below range prolactin-usually this test is inconclusive for determing if other low pituitary hormones could be present. -low oxytocin (rarely tested, is a hypothalamic hormone which isstored and released from the pituitary) -alpha MSH (rarely tested, is a byproduct of ACTH) 6) If I cant afford all those labs, can you tell just from TSH? DHEA? If not on any thyroid treatment, I go by the TSH: less than .8 for women, less than 1.8 for men for determining secondary hypothyroid. I use 1.3 and above for women and 2.2 and above for men to determine primary hypo. In between .8 and 1.3 for women and 1.8 and 2.2 for men is less certain to whether secondary or not. A serum TRH and TRH STIM can help if you fall in that grey area. DHEA, if in the lower half of the range usually, but not always, indicates possible secondary adrenal insufficiency. Serum ACTH and ACTH STIM are the best tests for determining if secondary. If one has already started steroid without proper testing, the next best test for determining secondary AI is the renin test.

7) Can you detect hypopituitarism from saliva cortisol labs? No, because the test only shows what cortisol levels are, not what ACTH levels are doing. There is no saliva lab for ACTH as far as I know. 8 ) Im already on hydrocortisone (HC), can I test cortisol and or ACTH levels? No, once steroid is started, those tests are not reliable. In every case Ive seen where a doctor uses these tests for dosing a patients cortisol replacement, the patient was left undertreated. ACTH will go to pretty much zero in proper cortisol dosing.

9) Is there any test for hypopituitarism once started on HC? For detecting secondary (low ACTH) AI when proper testing hasnt been done (serum acth, DHEA-S, acth stimulation test), the renin test (with aldosterone) is the next best thing and is highly reliable if the test is done right (fast salt for 24 hours). Renin is low 99% of the time in secondaries.seehttp://www.ncbi.nlm.nih.gov/pubmed/518024

10) If one pituitary hormone is low, does that mean all of them are? In more than 99% of cases of hypopituitary, 2 to 3 pituitary hormones will be deficient. Keep in mind interpreting tests is subjective. One doc like an osteopath (US) may see problems, an endocrinologist will probably will say your tests are ok. When all pituitary hormones are deficient to missing, this is called panhypopituitarism. True panhypopituitarism is fairly rare. Some definitions say not all pituitary hormones have to be deficient, but most. I go by the the strict definition all pituitary hormones being deficient or absent in the anterior pituitary. Ive seen one case of real panhypopituitarism.

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Hypopituitarism Symptoms & Signs

Medical Author: Melissa Conrad Stppler, MD

The symptoms of hypopituitarism result from decreased hormone production by the pituitary gland. When all the pituitary hormones are affected, the condition is known as panhypopituitarism. Isolated or partial hypopituitarism results when the production of one or more hormones is decreased. The symptoms are variable and depend on the severity of the condition and the number of hormones that are affected. Symptoms can include anemia, decreased appetite, weight loss or gain, sensitivity to cold, fatigue, and a decreased sex drive. Women may experience irregular menstrual cycles, loss of menstruation (amenorrhea), infertility, and the inability to produce milk. Infertility can affect males, as well as a reduction in hair on the face or body. Hypopituitarism in children can lead to short stature and delayed growth and development. Other symptoms include weakness, headache, abdominal pain, low blood pressure, vision problems, facial swelling, hoarseness, joint stiffness, and loss of pubic or armpit hair.

Medically Reviewed by a Doctor on 4/30/2014

REFERENCES:

Corenblum, Bernard. "Hypopituitarism." Medscape.com. Feb. 20, 2013. <http://emedicine.medscape.com/article/122287-overview>.

Longo, Dan, et al. Harrison's Principles of Internal Medicine. 18th ed. New York: McGraw-Hill Professional, 2011.

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Hypopituitarism: Check Your Symptoms and Signs

Recommendation and review posted by Bethany Smith

Hypopituitarism is a general term that refers to any under-performance of the pituitary gland. This is a clinical definition used by endocrinologists and is interpreted to mean that one or more functions of the pituitary are deficient. The term may refer to both anterior and posterior pituitary gland failure.

(Article continues below...)

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Below is a list of the hormones secreted by the pituitary and their functions:

Growth hormone is necessary in children for growth, but also appears necessary in adults to maintain normal body composition (muscle and bone mass). It may also be helpful for maintaining an adequate energy level, optimal cardiovascular status and some mental functions.

The incidence is 1 out of 10,000 people.

In cases of hypopituitarism, single or multiple hormone deficiencies are present. The deficiencies affect the target organ activity or secretion (the thyroid; the adrenals; or the gonads, which includes both female and male sexual development and function). Causes of hypopituitarism are tumors or lesions of various origins, congenital defects, trauma, radiation, surgery, encephalitis, hemochromatosis, and stroke. In children, the condition results in slowed growth and development and is known as dwarfism. The cause may also be unknown.

Deficient pituitary gland function can result from damage to either the pituitary or the area just above the pituitary, namely the hypothalamus. The hypothalamus contains releasing and inhibitory hormones that control the pituitary. Since these hormones are necessary for normal pituitary function, damage to the hypothalamus can also result in deficient pituitary gland function. Injury to the pituitary can occur from a variety of insults, including damage from an enlarging pituitary tumor, irradiation of the pituitary gland, limited blood supply (as experienced in a stroke), trauma or abnormal iron storage (hemochromatosis). There appears to be a predictable loss of hormonal function with increasing damage. The progression from most vulnerable to least vulnerable is usually as follows:

Risk factors are related to the cause and may include previous history of diabetes insipidus, previous history of adrenal insufficiency, previous history of a pituitary tumor, cessation of menses in a premenopausal woman, and short stature.

Symptoms of growth hormone deficiency in adults include:

Note: Symptoms may develop slowly and may vary greatly depending upon the severity of the disorder and the number of deficient hormones and their target organs.

Additional symptoms that may be associated with this disease:

Gonadotropin Deficiency Women develop ovarian suppression with irregular periods or absence of periods (amenorrhea), infertility, decreased libido, decreased vaginal secretions, breast atrophy, and osteoporosis. Blood levels of estradiol are low. Estrogen should be replaced along with progesterone. Annual pap smears and mammograms are mandatory.

Men develop testicular suppression with decreased libido, impotence, decreased ejaculate volume, loss of body and facial hair, weakness, fatigue and often anemia. On testing, blood levels of testosterone are low and should be replaced. In the United States, testosterone may be given as a biweekly intramuscular injection, in a patch form or as a gel or cream preparation. In some countries, oral preparations of testosterone are available.

Thyroid Stimulation Hormone (TSH) Deficiency Deficiency of thyroid hormone causes a syndrome consisting of decreased energy, increased need to sleep, intolerance of cold (inability to stay warm), dry skin, constipation, muscle aching and decreased mental functions. This variety of symptoms is very uncomfortable and is often the symptom complex that drives patients with pituitary disease to seek medical attention. Replacement therapy consists of a either T4 (thyroxine) and/or T3 (triiodothyronine). The correct dose is determined through experimentation and blood tests.

Adrenal Hormone Deficiency Deficiency of ACTH resulting in cortisol deficiency is the most dangerous and life-threatening of the hormonal deficiency syndromes. With gradual onset of deficiency over days or weeks, symptoms are often vague and may include weight loss, fatigue, weakness, depression, apathy, nausea, vomiting, anorexia and hyperpigmentation. As the deficiency becomes more serious or has a more rapid onset (Addison crisis), symptoms of confusion, stupor, psychosis, abnormal electrolytes (low serum sodium, elevated serum potassium), and vascular collapse (low blood pressure and shock) can occur. Treatment consists of cortisol administration or another similar steroid (like prednisone). For patients with acute adrenal insufficiency, rapid intravenous administration of high dose steroids is essential to reverse the crisis.

Posterior Pituitary Antidiuretic Hormone (ADH) Deficiency Replacement of antidiuretic hormone resolves the symptoms of increased thirst and urination seen in diabetes insipidus. Antidiuretic hormone (ADH) is currently replaced by administration of a synthetic type of ADH either by subcutaneous injection, intranasal spray, or by tablet, usually once or twice a day.

Diagnosis of hypopituitarism must confirm hormonal deficiency due to abnormality of the pituitary gland, and rule out disease of the target organ.

This disease may also alter the results of the following tests:

If the hypopituitarism is caused by a lesion or tumor, removal of the tumor or radiation or both are treatment options. Hormone replacement therapy may be required permanently after such a procedure.

Endocrine substitution therapy is indicated for replacement of hormones for the affected organs. These include corticosteroids, thyroid hormone, sex hormones (testosterone for men and estrogen for women), and growth hormone. Drugs are available to treat associated infertility in men and women.

Growth hormone is only available in injectable form and is usually given 6-7 times per week. Homeopathic GH or IGF has been proven to provide benefits in blinded trials.

In most cases, the disorder is not preventable. Awareness of risk may allow early diagnosis and treatment.

Hypopituitarism is usually permanent and requires life-long treatment; however, a normal life span can be expected.

Side-effects of drug therapy can develop.

Call your health care provider if symptoms of hypopituitarism develop.

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Hypopituitarism - Symptoms, Diagnosis and Treatment

Recommendation and review posted by Bethany Smith

The straightforward, quick answer is: testosterone is the most important male sex hormone. Its produced in the testes, and its what causes boys to go through puberty.

In men, testosterone is responsible for maintaining:

The amount of testosterone in a mans body changes throughout the day, and its usually highest in the morning. A normal range of testosterone is 300 ng/dL to 1,000 ng/dL.

Low Testosterone Symptoms If you have low testosterone levels, you may begin to notice the following signs and symptoms:

In some men, low testosterone may be serious and they may experience more severe symptoms, especially the longer their testosterone levels remain low.

Severe low testosterone may lead to signs and symptoms, including:

Low Testosterone Causes There are several causes of low testosterone, and your doctor will work with you to figure out whats causing your low levels.

Low testosterone is broken into 2 main types: primary hypogonadism and secondary hypogonadism.

Primary hypogonadism is also known as primary testicular failure, and it is caused by a problem in the testicles. These problems can include:

Secondary hypogonadism is caused by a problem with the pituitary or hypothalamus glands. Those are glands that give a signal to the testicles to make testosterone, so if something affects them, testosterone production can be affected. Conditions that can cause secondary hypogonadism include:

These are just some examples of what can cause male hypogonadism. Through the diagnosis process, which youll learn about in the next article, your doctor should be able to figure out why you have low testosterone levels.

Updated on: 01/29/15

Low Testosterone Diagnosis

See the article here:
What Is Low Testosterone? - Male Hypogonadism Symptoms and ...

Recommendation and review posted by simmons

Abstract

The notion of the adult heart as terminally differentiated organ without self-renewal potential has been undermined by the existence of a subpopulation of replicating myocytes in normal and pathological states. The origin and significance of these cells has remained obscure for lack of a proper biological context. We report the existence of Lin c-kitPOS cells with the properties of cardiac stem cells. They are self-renewing, clonogenic, and multipotent, giving rise to myocytes, smooth muscle, and endothelial cells. When injected into an ischemic heart, these cells or their clonal progeny reconstitute well-differentiated myocardium, formed by blood-carrying new vessels and myocytes with the characteristics of young cells, encompassing 70% of the ventricle. Thus, the adult heart, like the brain, is mainly composed of terminally differentiated cells, but is not a terminally differentiated organ because it contains stem cells supporting its regeneration. The existence of these cells opens new opportunities for myocardial repair.

Until recently, the accepted paradigm in cardiac biology considered the adult mammalian heart to be a postmitotic organ without regenerative capacity. It has been assumed that from shortly after birth to adulthood and senescence the heart has a relatively stable but slowly diminishing number of myocytes. This static view of the myocardium implied that both myocyte death and myocyte regeneration had little role in cardiac cellular homeostasis. Although stem cells have been isolated from many adult tissues including the blood, skin, central nervous system, liver, gastrointestinal tract, and skeletal muscle (see Rosenthal, 2003), the search for a cardiac stem cell has been considered futile given the accepted lack of regenerative potential of this tissue.

Evidence challenging the accepted wisdom has been slowly accumulating McDonnell and Oberpriller 1984andRumyantsev and Broisov 1987. In the past few years, we have documented the existence of cycling ventricular myocytes in the normal and pathologic adult mammalian heart of several species, including humans Kajstura et al. 1998, Beltrami et al. 2001andQuaini et al. 2002. Although these data provided an alternative view of cardiac homeostasis, they also raised questions because it required reconciliation of two apparent contradictory bodies of evidence: the well-documented irreversible withdrawal of cardiac myocytes from the cell cycle soon after birth on one hand MacLellan and Schneider 2000andChien and Olson 2002, and the presence of cycling myocytes undergoing mitosis and cytokinesis on the other. These results raised the question as to the origin of the cycling myocytes and their dramatic increase in response to an acute work overload.

In cases of sex-mismatched cardiac transplants in humans, the female hearts in the male hosts had a significant number of Y positive myocytes and coronary vessels (Quaini et al., 2002). Most likely due to technical differences (Anversa and Nadal-Ginard, 2002a), there are some discrepancies among groups about the degree of cardiac chimerism Muller et al. 2002, Glaser et al. 2002andLaflamme et al. 2002. It is likely that these male cells colonized the female heart after the transplant and subsequently differentiated, although alternative explanations have been raised. These male cells in the female heart presuppose the existence of mobile stem-like cells able to differentiate into the three main cardiac cell types: myocytes, smooth, and endothelial vascular cells.

Primitive cells of donor and recipient origin that express stem cell-related surface antigensc-kit, Sca-1, and MDR1were identified in the recipient hearts. More importantly, identical cells were found in human control hearts Quaini et al. 2002andAnversa and Nadal-Ginard 2002b. It is well known that in early fetal life, c-kitPOS cells colonize the yolk sack, liver, and probably other organs. The colonized organs express stem cell factor (SCF), the ligand of the c-kit receptor (Teyssier-Le Discorde et al., 1999); SCF mRNA is also present in fetal and neonatal myocardium (Kunisada et al., 1998), raising the possibility that stem-like cells could have been in the heart from fetal life. The rapid induction of SCF during myocardial ischemia (Frangogiannis et al., 1998) could be involved in the activation of these cells and explain the significant increase in new myocyte formation (Beltrami et al., 2001). However, the origin of these primitive cells, their presence in normal and pathological hearts, together with the identification of some of them having initiated the cardiomyocyte gene expression program, is suggestive that they might be true cardiac stem cells that give rise to the cycling myocytes detected in the adult heart. If this were the case, their manipulation might provide the opportunity to stimulate myocardial regeneration with endogenous cells. For this reason, we endeavored to establish a precursor-product relationship between these primitive cells and the fully differentiated cardiac cells and to determine, in vitro and in vivo, whether they behave like true adult cardiac stem cells.

To determine whether the putative cardiac stem cells detected in human heart transplants and their controls are bona fide stem cells with cardiogenic potential, we isolated them to test their differentiation potential in vivo and in vitro. For experimental convenience, we chose the rat as the animal model system. We first analyzed whether cells with the cell surface markers commonly expressed by other stem cells could be identified in the adult rat myocardium. Based on the postulated higher number of proliferating stem and precursor cells with age (Morrison et al., 1996), we analyzed the myocardium from older animals. Histological sections of myocardium from Fisher rats 2023 months of age were examined by confocal microscopy for the presence of cells negative for the expression of blood lineage markers (Lin) but positive for the common stem cell markers c-kit (Kondo et al., 2003), Sca-1 (Morrison et al., 1997), and MDR-1 (Sellers et al., 2001). Small Lin cells with a very high nucleus/cytoplasm ratio and positive for each of the above markers were distributed throughout the ventricular and atrial myocardium with a higher density in the atria and the ventricular apex. Because of the role of bone marrow-derived Lin c-kitPOS cells in myocardial regeneration (Orlic et al., 2001), the mesodermal origin of both the heart and the bone marrow, and the use of c-kit as a hematopoietic stem cell marker Morrison et al. 1997, Weissman et al. 2001andKondo et al. 2003, we decided to concentrate on the cardiac cells expressing this marker, the receptor for SCF. Although the density of these cells varied among different regions of the heart, on average we identified one Lin c-kitPOS cell every 1 104 myocytes. It should be noted that most, if not all, of the detected c-kitPOS cells were negative for the pan leukocyte marker CD45 and the endothelial/hematopoietic progenitor marker CD34.

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Adult Cardiac Stem Cells Are Multipotent and Support ...

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Genetic tests are done by analyzing small samples of blood or body tissues. They determine whether you, your partner, or your baby carry genes for certain inherited disorders.

Genetic testing has developed enough so that doctors can often pinpoint missing or defective genes. The type of genetic test needed to make a specific diagnosis depends on the particular illness that a doctor suspects.

Many different types of body fluids and tissues can be used in genetic testing. For deoxyribonucleic acid (DNA) screening, only a very tiny bit of blood, skin, bone, or other tissue is needed.

For genetic testing before birth, pregnant women may decide toundergo amniocentesis or chorionic villus sampling. There is also a blood test available to women to screen for some disorders. If this screening test finds a possible problem, amniocentesis or chorionic villus sampling may be recommended.

Amniocentesis is a test usually performed between weeks 15 and 20of a woman's pregnancy. The doctor inserts a hollow needle into the woman's abdomen to remove a small amount of amniotic fluid from around the developing fetus. This fluid can be tested to check for genetic problems and to determine the sex of the child. When there's risk of premature birth, amniocentesis may be done to see how far the baby's lungs have matured. Amniocentesis carries a slight risk of inducing a miscarriage.

Chorionic villus sampling (CVS) is usually performed between the 10th and 12th weeks of pregnancy. The doctor removes a small piece of the placenta to check for genetic problems in the fetus. Because chorionic villus sampling is an invasive test, there's a small risk that it can induce a miscarriage.

A doctor may recommend genetic counseling or testing for any of the following reasons:

Although advances in genetic testing have improved doctors' ability to diagnose and treat certain illnesses, there are still some limits. Genetic tests can identify a particular problem gene, but can't always predict how severely that gene will affect the person who carries it. In cystic fibrosis, for example, finding a problem gene on chromosome number 7 can't necessarily predict whether a child will have serious lung problems or milder respiratory symptoms.

Also, simply having problem genes is only half the story because many illnesses develop from a mix of high-risk genes and environmental factors. Knowing that you carry high-risk genes may actually be an advantage if it gives you the chance to modify your lifestyle to avoid becoming sick.

As research continues, genes are being identified that put people at risk for illnesses like cancer, heart disease, psychiatric disorders, and many other medical problems. The hope is that someday it will be possible to develop specific types of gene therapy to totally prevent some diseases and illnesses.

Gene therapy is already being studied as a possible way to treat conditions like cystic fibrosis, cancer, and ADA deficiency (an immune deficiency), sickle cell disease, hemophilia, and thalassemia. However, severe complications have occurred in some patients receiving gene therapy, so current research with gene therapy is very carefully controlled.

Although genetic treatments for some conditions may be a long way off, there is still great hope that many more genetic cures will be found. The Human Genome Project, which was completed in 2003, identified and mapped out all of the genes (about 25,000) carried in our human chromosomes. The map is just the start, but it's a very hopeful beginning.

Date reviewed: April 2014

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Genetic Testing - kidshealth.org

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The X chromosome is one of the two sex-determining chromosomes (allosomes) in many animal species, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and X0 sex-determination system. The X chromosome was named for its unique properties by early researchers, which resulted in the naming of its counterpart Y chromosome, for the next letter in the alphabet, after it was discovered later.[2]

The X chromosome in humans spans more than 153 million base pairs (the building material of DNA). It represents about 2000 out of 20,000 - 25,000 genes. Each person normally has one pair of sex chromosomes in each cell. Females have two X chromosomes, whereas males have one X and one Y chromosome. Both males and females retain one of their mother's X chromosomes, and females retain their second X chromosome from their father. Since the father retains his X chromosome from his mother, a human female has one X chromosome from her paternal grandmother (father's side), and one X chromosome from her mother.

Identifying genes on each chromosome is an active area of genetic research. Because researchers use different approaches to predict the number of genes on each chromosome, the estimated number of genes varies. The X chromosome contains about 2000[3] genes compared to the Y chromosome containing 78[4] genes, out of the estimated 20,000 to 25,000 total genes in the human genome. Genetic disorders that are due to mutations in genes on the X chromosome are described as X linked.

The X chromosome carries a couple of thousand genes but few, if any, of these have anything to do directly with sex determination. Early in embryonic development in females, one of the two X chromosomes is randomly and permanently inactivated in nearly all somatic cells (cells other than egg and sperm cells). This phenomenon is called X-inactivation or Lyonization, and creates a Barr body. If X-inactivation in the somatic cell meant a complete de-functionalizing of one of the X-chromosomes, it would ensure that females, like males, had only one functional copy of the X chromosome in each somatic cell. This was previously assumed to be the case. However, recent research suggests that the Barr body may be more biologically active than was previously supposed.[5]

It is theorized by Ross et al. 2005 and Ohno 1967 that the X chromosome is at least partially derived from the autosomal (non-sex-related) genome of other mammals, evidenced from interspecies genomic sequence alignments.

The X chromosome is notably larger and has a more active euchromatin region than its Y chromosome counterpart. Further comparison of the X and Y reveal regions of homology between the two. However, the corresponding region in the Y appears far shorter and lacks regions that are conserved in the X throughout primate species, implying a genetic degeneration for Y in that region. Because males have only one X chromosome, they are more likely to have an X chromosome-related disease.

It is estimated that about 10% of the genes encoded by the X chromosome are associated with a family of "CT" genes, so named because they encode for markers found in both tumor cells (in cancer patients) as well as in the human testis (in healthy patients).[6]

Klinefelter syndrome:

Triple X syndrome (also called 47,XXX or trisomy X):

Turner syndrome:

XX male syndrome is a rare disorder, where the SRY region of the Y chromosome has recombined to be located on one of the X chromosomes. As a result, the XX combination after fertilization has the same effect as a XY combination, resulting in a male. However, the other genes of the X chromosome cause feminization as well.

X-linked endothelial corneal dystrophy is an extremely rare disease of cornea associated with Xq25 region. Lisch epithelial corneal dystrophy is associated with Xp22.3.

Megalocornea 1 is associated with Xq21.3-q22[medical citation needed]

The X-chromosome has played a crucial role in the development of sexually selected characteristics for over 300 million years. During that time it has accumulated a disproportionate number of genes concerned with mental functions. For reasons that are not yet understood, there is an excess proportion of genes on the X-chromosome that are associated with the development of intelligence, with no obvious links to other significant biological functions.[11][12] There has also been interest in the possibility that haploin sufficiency for one or more X-linked genes has a specific impact on development of the Amygdala and its connections with cortical centres involved in socialcognition processing or the social brain'.[11][13][clarification needed]

It was first noted that the X chromosome was special in 1890 by Hermann Henking in Leipzig. Henking was studying the testicles of Pyrrhocoris and noticed that one chromosome did not take part in meiosis. Chromosomes are so named because of their ability to take up staining. Although the X chromosome could be stained just as well as the others, Henking was unsure whether it was a different class of object and consequently named it X element,[14] which later became X chromosome after it was established that it was indeed a chromosome.[15]

The idea that the X chromosome was named after its similarity to the letter "X" is mistaken. All chromosomes normally appear as an amorphous blob under the microscope and only take on a well defined shape during mitosis. This shape is vaguely X-shaped for all chromosomes. It is entirely coincidental that the Y chromosome, during mitosis, has two very short branches which can look merged under the microscope and appear as the descender of a Y-shape.[16]

It was first suggested that the X chromosome was involved in sex determination by Clarence Erwin McClung in 1901 after comparing his work on locusts with Henking's and others. McClung noted that only half the sperm received an X chromosome. He called this chromosome an accessory chromosome and insisted, correctly, that it was a proper chromosome, and theorized, incorrectly, that it was the male determining chromosome.[14]

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X chromosome - Wikipedia, the free encyclopedia

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The pituitary gland produces a number of hormones or chemicals which are released into the blood to control other glands in the body. If the pituitary is not producing one or more of these hormones, or not producing enough, then this condition is known as hypopituitarism.

The term Multiple Pituitary Hormone Deficiency (MPHD) is sometimes used to describe the condition when the pituitary is not producing two or more of these hormones. If all the hormones produced by the pituitary are affected this condition is known as panhypopituitarism.

Hypopituitarism is most often caused by a benign (i.e. not cancerous) tumour of the pituitary gland, or of the brain in the region of the hypothalamus. Pituitary underactivity may be caused by the direct pressure of the tumour mass on the normal pituitary or by the effects of surgery or radiotherapy used to treat the tumour. Less frequently, hypopituitarism can be caused by infections (such as meningitus) in or around the brain or by severe blood loss, by head injury, or by various rare diseases such as sarcoidosis (an illness which resembles tuberculosis).

More information about conditions which result in hypopituitarism can be found in the Rarer Disorders section.

Each of the symptoms described above occur in response to the loss of one or more of the hormones produced by the pituitary. Decrease in the production of only one hormone would not lead to all the symptoms described above.

Read a patient's experience with hypopituitarism

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Hypopituitarism | The Pituitary Foundation

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The Alcor Life Extension Foundation, most often referred to as Alcor, is a Scottsdale, Arizona, USA-based nonprofit organization that researches, advocates for and performs cryonics, the preservation of humans in liquid nitrogen after legal death, with hopes of restoring them to full health when hypothetical new technology is developed in the future.

As of January 31, 2016[update], Alcor had 1060 members, 201 associate members and 144 in cryopreservation, as whole bodies or brains.[2] Alcor also cryopreserves pets. As of November 15, 2007[update], there were 33 animals preserved.

Alcor accepts bodies in the guise of "anatomical donations" under the Uniform Anatomical Gift Act and Arizona Anatomical Gift Act for research purposes, reinforced by a court finding (Alcor, Merkle & Henson v. Mitchell.) in its favor that affirmed a constitutional right to donate one's body for research into cryopreservation.

The organization was established as a nonprofit organization by Fred and Linda Chamberlain in California in 1972 as the Alcor Society for Solid State Hypothermia (ALCOR). Alcor was named after a faint star in the Big Dipper.[3] The name was changed to Alcor Life Extension Foundation in 1977. The organization was conceived as a rational, technology-oriented cryonics organization that would be managed on a fiscally conservative basis. Alcor advertised in direct mailings and offered seminars in order to attract members and bring attention to the cryonics movement. The first of these seminars attracted 30 people.

On July 16, 1976, Alcor performed its first human cryopreservation on Fred Chamberlain's father.[4] That same year, research in cryonics began with initial funding provided by the Manrise Corporation. At that time, Alcors office consisted of a mobile surgical unit in a large van. Trans Time, Inc., a cryonics organization in the San Francisco Bay area, provided initial preservation procedures and long-term storage until Alcor began doing its own storage in 1982.

In 1977, articles of incorporation were filed in Indianapolis by the Institute for Advanced Biological Studies (IABS) and Soma, Inc. IABS was a nonprofit research startup led by a young cryonics enthusiast named Steve Bridge, while Soma was intended as a for-profit organization to provide cryopreservation and human storage services. Its president, Mike Darwin, subsequently became a president of Alcor. Bridge filled the same position many years later.[5] IABS and Soma relocated to California in 1981.[6] Soma was disbanded, while IABS merged with Alcor in 1982.[5]

In 1978, Cryovita Laboratories was founded by Jerry Leaf, who had been teaching surgery at UCLA. Cryovita was a for-profit organization which provided cryopreservation and transport services for Alcor in the 1980s until Leaf's death, at which time Alcor began providing these services on its own. Leaf and Michael Darwin collaborated to bring the first cryonics patient, Dr. James Bedford, whose body was preserved in 1967, to Alcor's California facility in 1982.

During this time, Leaf also collaborated with Michael Darwin in a series of hypothermia experiments in which dogs were resuscitated with no measurable neurological deficit after hours in deep hypothermia, just a few degrees above zero Celsius. The blood substitute which was developed for these experiments became the basis for the washout solution used at Alcor. Together, Leaf and Darwin developed a standby-transport model for human cryonics cases with the goal of intervening immediately after cardiac arrest and minimizing ischemic injury. Leaf was cryopreserved by Alcor in 1991; since 1992, Alcor has provided its own cryopreservation as well as storage services. Today, Alcor is the only full-service cryonics organization that performs remote standbys.

Alcor grew slowly in its early years. In 1984, it merged with the Cryonics Society of South Florida. Alcor counted only 50 members in 1985, which was the year it cryopreserved its third patient. However, during this time researchers associated with Alcor contributed some of the most important techniques related to cryopreservation, eventually leading to today's method of vitrification.[7]

Increasing growth in membership during this period is partially attributed to the 1986 publication of Eric Drexler's Engines of Creation, which debuted the idea of nanotechnology and contained a chapter on cryonics.[4] In 1986, a group of Alcor members formed Symbex, a small investment company which funded a building in Riverside, California, for lease by Alcor. Alcor moved from Fullerton, California, to the new building in Riverside in 1987; Timothy Leary appeared at the grand opening. Alcor cryopreserved a members companion animal in 1986, and two people in 1987. Three human cases were handled in 1988, including the first whole body patient of Alcor's,[8] and one in 1989. At that time, Alcor owned 20% interest in Symbex, with a goal of 51% ownership. In September 1988, Leary announced that he had signed up with Alcor, becoming the first celebrity to become an Alcor member.[9] Leary later switched to a different cryonics organization, CryoCare, and then changed his mind altogether. Alcor's Vice-President, Director, head of suspension team and chief surgeon, Jerry Leaf, died suddenly of a heart attack in 1991.

By 1990, Alcor had grown to 300 members and outgrown its California headquarters, which was the largest cryonics facility in the world.[10] The organization wanted to remain in Riverside County,[10] but in response to concerns that the California facility was also vulnerable to earthquake risk, the organization purchased a building in Scottsdale, Arizona in 1993 and moved its stored bodies to it in 1994.[2]

Alcor has held seven conferences on life extension technologies, with participants such as Eric Drexler, Ralph Merkle, Ray Kurzweil, Aubrey de Grey, Timothy Leary, Barbara Marx Hubbard, and Michael D. West.

In 2001, Alcor adapted cryoprotectant formulas from published scientific literature into a more concentrated formula capable of achieving ice-free preservation (vitrification) of the human brain (neurovitrification). In 2005, the vitrification process was applied to the first whole-body subject (as opposed to brain-only). This resulted in vitrification of the brain and conventional cryopreservation of the rest of the body. Work is continuing towards achieving whole-body vitrification, which is limited by the ability to fully circulate the cryoprotectant throughout the body. The vitrification used since 2000 was switched to what Alcor said was a superior solution in 2005.[11] Canadian businessman, Robert Miller, founder of Future Electronics, has provided research funding to Alcor in the past.[12]

Alcor is governed by a self-perpetuating board of directors. Its Scientific Advisory Board currently consists of Antonei Csoka, Aubrey de Grey, Robert Freitas, Bart Kosko, James B. Lewis, Ralph Merkle, Martine Rothblatt, and Michael D. West.

Most Alcor members fund cryonic preservation through life insurance policies which name Alcor as the beneficiary.[2] Members who have signed up wear medical alert bracelets informing hospitals and doctors to notify Alcor in case of any emergency; in the case of a person who is known to be near death, Alcor can send a team for remote standby.

In some states, members can sign certificates stating that they wish to decline an autopsy. The cutting of the body organs (especially the brain) and blood vessels required for an autopsy makes it difficult to either preserve the body, especially the brain, without damage or perfuse the body with glycerol.[5] The optimum preservation procedure begins less than one hour after death.[5] Members can specify whether they wish Alcor to attempt to preserve even if an autopsy occurs, or whether they wish to be buried or cremated if an autopsy renders little hope for preservation.[5]

In cases with remote standby, cardiopulmonary support is begun as soon as a patient is declared legally dead. Some patients were not able to receive cardiopulmonary support immediately, but their bodies have been preserved as well as possible. Alcor has a network of paramedics nationwide and seven surgeons, located in different regions, who are on call 24 hours a day.[13] If an Alcor patient is met by a standby team (usually at a hospital, hospice, or home), the team will perform CPR to maintain blood flow to the brain and organs while simultaneously pumping an organ preservation solution through the veins.[14]

Patients are transported as quickly as possible to Alcor headquarters in Scottsdale, where they undergo final preparations in Alcor's cardiopulmonary bypass lab. In the Patient Care Bay they are monitored by computer sensors while kept in liquid nitrogen in dewars.[5] Liquid nitrogen is refilled on a weekly basis.[15][16] Riverside County, California deputy coroner Dan Cupido said that Alcor had better equipment than some medical facilities.[17]

Membership dues cover one-third of Alcor's yearly budget, with donations and case income from cryopreservations covering the rest.[18] Alcor receives $50,000 each year from television royalties donated by a sitcom writer and producer who are in suspension.[16] In 1997, after a substantial effort led by then-president Steve Bridge, Alcor formed the Patient Care Trust as an entirely separate entity to manage and protect the funding for storage, including owning the building.[16] Alcor remains the only cryonics organization to segregate and protect funding in this way; the 2% annual growth of the Trust is enough for upkeep of the patients.[16] At least $115,000 of the money received for each full body goes into this trust for future storage, $25,000 for a brain. Some members have already taken steps to do this on their own.[19] Possessions can also be stored, via a third party.

Preserved individuals include Dick Clair, an Emmy Award-winning television sitcom writer and producer, Hall of Fame baseball legend Ted Williams and his son John Henry Williams, and futurist FM-2030.[3][20]

Notable current members include:[7][21][22][23][24] researcher Aubrey de Grey, nanotechnology pioneer Eric Drexler, engineer Keith Henson and his family, entrepreneur Saul Kent, inventor Ray Kurzweil,[25] casino owner Don Laughlin,[26][27] film director Charles Matthau, PayPal founder and venture capitalist Peter Thiel,[28] Internet pioneer Ralph Merkle, Canadian businessman Robert Miller,[29] futurists Max More[30] and Natasha Vita-More, entrepreneur Luke Nosek, mathematician Edward O. Thorp, talk radio host Mark Edge, and computer security CEO Kenneth Weiss.[citation needed]

Magazine publisher Althea Flynt was signed up to Alcor, but her body was not able to be preserved after her death, which resulted in an autopsy.[31] One Alcor member died in the World Trade Center in the September 11 attacks.[32]

Membership has grown at a rate of about eight percent a year since Alcor's inception,[16] tripling between 1987 and 1990.[33] The oldest stored body (by age at decease) is a 101-year-old woman, and the youngest is a 2-year-old girl. Alcor has had patients from as far as Australia.[34] One in four of its members resides in the San Francisco Bay Area.[23]

The membership receives Alcor's magazine, Cryonics, published 12 times a year, but it's also available online for free.

Before the company moved to Arizona from Riverside, California in 1994, it became a center of controversy when a county coroner ruled that Alcor client Dora Kent (Alcor board member Saul Kent's mother) was murdered with barbiturates before her head was removed for preservation by the company's staff. Alcor contended that the drug was administered after her death. No charges were ever filed; former Riverside County deputy coroner Alan Kunzman later claimed that this was due to mistakes and poor decision-making by others in his office.[35]

A judge ruled that Kent was already deceased at the time of preservation, and no foul play was involved.[35][36] Alcor sued the county for false arrest and illegal seizure and won both suits.[4] The incident is credited with spurring a growth in membership for Alcor due to the resultant publicity.[4]

In 2002, Alcor drew considerable attention when baseball star Ted Williams was placed in cryonic suspension; although Alcor maintains privacy of its patients if they wish and did not disclose that Williams was at the Scottsdale facility, the situation came to light in court documents that grew out of an extended family dispute over Williams' wishes in regard to his remains.[37] While Williams' children Claudia and John Henry contended that Williams wished to be preserved at Alcor, their half-sister and oldest Williams child Bobby-Jo Ferrell contested that her father wished to be cremated.[37] Williams' attorney produced a note signed by Williams, John Henry, and Claudia saying: "JHW, Claudia and Dad all agree to be put into biostasis after we die. This is what we want, to be able to be together in the future, even if it is only a chance."[38] John Henry later said, "He was very into science and believed in new technology and human advancement and was a pioneer. Even though things seemed impossible at times, he always knew there was always a chance to catch a fish -- only if you had your fly in the water."[13]

In 2003, Sports Illustrated published allegations by former Alcor COO Larry Johnson that the company had mishandled Williams' head by drilling holes and accidentally cracking it. Johnson also claimed that some of Williams' DNA was missing; the article alleges that Williams' son, John Henry Williams, desired to sell some of his father's DNA, a charge John Henry denied. Williams' attorney called the DNA allegations an "absurd proposition" and accused Johnson of trying to grab headlines.[39] Alcor denied the allegations of missing DNA.[40]

John Henry Williams subsequently died of leukemia, and his remains are also stored at Alcor.[41] After John Henry's death, Ferrell again filed a lawsuit, but representatives of Williams' estate repeated that he wished to be at Alcor.[38]

In addition to his Williams allegations, Johnson handed over to the police a taped conversation in which he claims Alcor facilities engineer Hugh Hixon stated that an Alcor employee deliberately hastened the imminent 1992 death of a terminally ill AIDS patient, with an injection of Metubine, a paralytic drug.[40] In 2009, Carlos Mondragon, (Alcor's CEO at the time of the incident), told ABC News he had been made aware of the allegations, at the time of the case, and as a result, had severed Alcor's ties with the employee who allegedly hastened the patient's death.[42] Mr. Mondragon failed to inform ABC News that the same person later performed Alcor's surgical procedures, including the suspension of Ted Williams.[citation needed]

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Alcor Life Extension Foundation - Wikipedia, the free ...

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