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Week Ending FRIDAY July 3, 2009---------------------------News Archive / Return to News Alerts

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Thawed Embryo Transfer After PGD = Same Pregnancy Rates
Transferring just one embryo at a time to a woman's womb after embryos have undergone preimplantation genetic diagnosis (PGD) and freezing at the blastocyst stage has become a real option after researchers achieved pregnancy rates that were as good as those for blastocysts that had not had a cell removed for PGD before freezing. Their results mean that it will be possible to reduce the number of multiple pregnancies after PGD and the consequent complications associated with these pregnancies.

The research was presented at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam and published online in Europe's leading reproductive medicine journal, Human Reproduction, simultaneously today (Tuesday).

Dr Yacoub Khalaf, director of the assisted conception unit at Guy's and St Thomas' Hospital, London (UK), told the conference: "To the best of our knowledge, our study is the first to provide reassurance that a strategy of elective single embryo transfer in good prognosis patients seeking PGD, backed by an efficient PGD cryopreservation service, can result in pregnancy rates that are comparable to those for non-biopsied embryos that are frozen as part of conventional fertility treatment. These results should empower fertility centres to include PGD cycles for inherited genetic disorders in their efforts to reduce the multiple pregnancy rates after various forms of assisted conception treatment. Given the increasing number of PGD cycles performed each year, the advantage of widespread application of this policy would be considerable."

Until now, fertility specialists have not applied a single embryo transfer policy to PGD for inherited genetic disorders because of concerns about how well biopsied embryos survive after freezing and thawing. "It was thought that the effect of the biopsy might reduce the embryos' tolerance to freezing. This concern was not based on any scientific evidence, only on observations of low survival rates of biopsied frozen embryos," said Dr Khalaf.

From January 2006 to July 2008 Dr Khalaf and his colleagues offered single embryo transfer together with freezing of surplus blastocysts to couples seeking PGD for single inherited genetic disorders such as cystic fibrosis. All the embryos were biopsied for the purposes of PGD on the third day after fertilisation, which is the time that they start to divide. Healthy embryos were cultured in the laboratory for a further two to three days to check that they were capable of reaching the next appropriate stage of development – the blastocyst stage. At this point, 32 couples who had two or more embryos that had successfully reached the blastocyst stage were offered the option of having one transferred to the womb and the rest frozen.

The researchers compared the pregnancy outcomes from a subsequent 32 frozen-thawed PGD cycles in these couples with the pregnancy outcomes from a control group of couples where 191 cycles of conventional IVF/ICSI were carried out using embryos that were frozen and thawed before implantation, but not biopsied at any stage.

They found that the blastocyst survival rate after thawing was similar between the PGD and IVF/ICSI groups (87% versus 88% respectively). There was no significant difference in the implantation and clinical pregnancy rates (35% versus 29% and 34% versus 36% respectively). The overall ongoing pregnancy rate for all frozen cycles (PGD and IVF/ICSI) was 34%, which compares favourably with the UK national average for frozen cycles (currently 18% live birth rate per thaw).

When the same period was compared with the period before the single embryo transfer policy was introduced for PGD couples, the multiple pregnancy rate in the cycles of fresh PGD dropped from 36% to 10% with no reduction in pregnancy rates.

Dr Khalaf said: "This research suggests that responsible clinical decisions do not have to come at the expense of reducing effectiveness of treatment. You can be responsible and maintain the chances of success for your patients by good clinical judgment and using the appropriate techniques.

"For patients, this provides reassurance that a couple's chance of having a healthy child is not reduced by replacing only one blastocyst and freezing the surplus ones. Those frozen blastocysts do have a very good chance of leading to a healthy pregnancy too, and, therefore, patients will not feel pressurised to have more than one embryo replaced (with the increased risk of multiple pregnancies) in order to make use of their biopsied, unaffected embryos for which, otherwise, they might have little use. Now, these frozen blastocysts offer them the chance of an additional healthy pregnancy without having to go through the whole treatment cycle again."


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Preterm Birth & a High Incidence of Brain Malformation
New research out of Wake Forest University School of Medicine provides for the first time a solid scientific answer for the long-standing question of whether there is an association between preterm birth and brain malformations

In a study of more than 1,000 preterm infant autopsies, researchers found that there is a strong association between congenital brain defects and preterm birth, leading investigators to believe that something about the brain malformations may be causing preterm birth and providing a possible study path toward a better understanding of the problem.

The study appears in the June issue of Pediatric Research. It is the first to investigate the risk of being born preterm for infants who have a variety of congenital brain defects.

“The most important thing about this study is that to-date, it is still unknown why there are so many preterm births. This study suggests that one way to look for the causes of preterm birth is to look at those types of brain malformations that have very strong association with preterm birth, and see if there is some sort of difference between those babies and full-term babies – some sort of soluble factor or an increased amount of something in the preterm babies that is not found in other babies,” said William R. Brown, Ph.D., a research associate professor of radiologic sciences and author/investigator for the study.

Funded by the National Institutes of Health, March of Dimes Birth Defects Foundation and the Pratt Family Foundation, Brown’s research on brain malformations and preterm birth grew out of a study of bleeds in the brains of babies, where researchers found that a large percentage of the babies being studied had small, unrecognized types of brain malformations that warranted further investigation.

Previous studies have shown that malformations of other parts of the body are associated with preterm birth. However, though there has been evidence suggesting brain malformations are also associated with preterm birth, it has been difficult to document such an association because brain defects can be hidden within the cranium and may remain undetected until autopsy, whereas malformations of other parts of the body can be determined through birth registries.

For his study, Brown looked at 1,168 autopsy files that contained congenital brain defects as well as information on the gestational age at birth of the subject. For comparison, Brown also looked at published files of over 7,000 infants with “significant birth defects of any kind” and more than 260,000 infants without brain defects. The control cases came from a large registry published by the Metropolitan Atlanta Congenital Defects Program.

In his review, Brown found that, in the autopsy cases with brain defects, the mean gestational age was 36.6 weeks, whereas the data showed a mean gestational age of 39.9 weeks for infants with no defects and a gestation of 38.1 weeks for infants with defects of any kind. “Preterm” birth is defined as 20 to 36 weeks gestation, while “term” birth is defined as 37 to 41 weeks. Only 9.3 percent of babies born without defects were preterm, compared to 21.5 percent of those with defects. In the autopsy cases with brain defects, the rate of preterm birth was even greater at 33.1 percent, showing the strongest association between the two.

Some types of brain defects have a stronger association with preterm birth than others, the study showed. The list itself could possibly offer some clue to the association. Among the malformations studied with the highest rates of preterm birth were hydrocephaly, an abnormal buildup of cerebrospinal fluid (CSF) in the ventricles of the brain (65.2 percent); anencephaly, a defect in the closure of the neural tube during fetal development resulting in the absence of a major portion of the brain, skull, and scalp (57.7 percent); multicystic encephalomalacia, the formation of multiple cystic cavities of various sizes in the cerebral cortex (50.5 percent); and hydranencephaly, a rare condition in which the brain's cerebral hemispheres are absent and replaced by sacs filled with cerebrospinal fluid (38.5 percent).

“There are a lot of preterm births where there are no apparent causes,” Brown said. “I speculate that brain defects or other defects not easily detected could be causing some of them and perhaps we should focus on studying coagulopathy (a tendency to excessive blood coagulation and formation of blood clots) to find what the association is between that and preterm birth.

“The placenta could be a key element,” he added. “In placental conditions such as preclampsia, which is strongly associated with preterm birth, there may be blood clots coming from the placenta, causing brain damage and malformations in the brain and then, perhaps, the malformed fetus induces its own preterm birth or perhaps the coagulopathy causes the preterm birth through some other mechanism. The next step is to look at the brain malformations that have the strongest association with preterm birth and see if it’s possible to identify the factors associated with those malformations that may be causing preterm birth. These are possible new directions to explore.”

Meanwhile, Brown endorses the use of folic acid before and during pregnancy.

“It’s not completely known how it works, but it could be impacting coagulopathy because folic acid is involved with the pathways that are also involved with coagulation,” he said.

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Tamoxifen Stimulates Uterine Cell Growth & Cancer
UCSF researchers have identified a new “feed-forward” pathway linking estrogen receptors in the membrane of the uterus to a process that increases local estrogen levels and promotes cell growth.

The research is significant in helping determine why tamoxifen and other synthetic estrogens are linked to increased rates of endometriosis and uterine cancer, and identifies a pathway that could be targeted in drug therapies for those diseases, researchers say.

Findings are published in the July 1, 2009 issue of “Cancer Research,” the journal of the American Association for Cancer Research. The paper also can be found online at http://cancerres.aacrjournals.org/current.shtml.

The research found that when activated by estrogens, endometrial cells obtained from patients suffering from endometriosis or human uterine cancer cells initiate a previously unknown cascade of signals that leads to cellular replication and further estrogen production, the paper says.

The ensuing cycle leads to abnormal growth of the cells lining the uterus, or endometrium, which occurs in endometriosis and uterine cancer, according to senior author Holly A. Ingraham, PhD, a professor in the UCSF School of Medicine’s Department of Cellular and Molecular Pharmacology.

“It turns out that displaced endometrial cells, such as those used in this study, are estrogen factories,” said Ingraham, who also is affiliated with the UCSF Helen Diller Family Comprehensive Cancer Center and the UCSF Center for Reproductive Sciences. “They pump out estrogen in a feed-forward pathway, so the more estrogen they produce, the more estrogen they’re capable of producing.”

While this pathway was previously unknown, Ingraham said a June 2009 paper led by researchers at the University of New Mexico and published in the journal “Nature Chemical Biology” showed that blocking the GPR30 receptor in this pathway decreases uterine proliferation in a mouse. The two together, she said, validate what researchers now think may be a key area in addressing both uterine cancer and endometriosis.

Uterine cancer is the fourth most common cancer in women, with more than 37,000 women being diagnosed each year in the United States alone, according to data from the Centers for Disease Control.

Endometriosis, in which endometrial cells grow in areas other than the uterus, is the most common gynecological disease and affects more than 5.5 million women in North America, according to the National Institutes of Health. The disease often causes severe pain and can lead to infertility.

Working in collaboration with clinicians at Northwestern University in Chicago, the UCSF team analyzed cells from women with ectopic endometriosis. By studying those patients’ endometrial cells, the team was able to identify an unusual, circular pathway involving these cells, the transmembrane estrogen receptor GPR30 and the nuclear receptor SF-1.

The researchers propose that this pathway increases local concentrations of estrogen and, together with classic estrogen-receptor signaling, control the proliferative effects of these estrogens in promoting endometriosis and endometrial cancers.

The UCSF team used a unique chemical biology approach, making use of a tamoxifen-like compound developed in the laboratory of co-author Thomas Scanlan, PhD, who is affiliated with both the UCSF Department of Pharmaceutical Chemistry and the Department of Chemical Biology at the Oregon Health Sciences University in Portland.

“Tamoxifen and other synthetic estrogens have been known to increase the risk of uterine cancer, but until now, we didn’t know why that was on a cellular level,” Ingraham said. “We think this pathway is going to be an important one in solving that mystery.”


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PCOS: New Causes and Effects on Male Relatives
Researchers have found evidence that chronic disease in either a mother or father can create unfavourable conditions in the womb that are associated with the development of polycystic ovarian syndrome (PCOS) in daughters

In another study, researchers found that brothers of women with PCOS and insulin resistance are themselves at greater risk of developing insulin resistance or diabetes, suggesting that factors associated with the condition can be passed down to sons as well as daughters.

The two studies were presented to the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam heard today (Tuesday).

Associate Professor Michael Davies told a news briefing: "We already know from clinical studies of women with reproductive problems that foetal growth restriction is associated with the development of PCOS symptoms in daughters, and that problems during pregnancy and in the way the mother adapts to the metabolic challenge of pregnancy can indicate the future cardiovascular health of both the mother and the child. What we don't know is whether giving birth to a daughter who later develops PCOS is associated with increased, long term cardiovascular disease risk in the mother. Nor do we know whether conditions underlying chronic disease in the father increases the risk of PCOS in the daughter."

Prof Davies, co-director of the Research Centre for the Early Origins of Health and Disease at the University of Adelaide (Australia), looked at records for all female babies who were born and survived between 1973-1976 at The Queen Elizabeth Hospital in Adelaide. He and his colleagues interviewed the daughters to build up a picture of their health and any history of chronic disease in their parents. So far, 998 (63%) have responded, and Prof Davies reported preliminary data up to mid-1975 to the conference.

Sixty-two daughters (6.2% of the group) had a pre-existing diagnosis of PCOS. Mothers of these women tended to have elevated blood pressure during pregnancy. Daughters were nearly eight times as likely to have PCOS if their mothers had it, and they had a slightly higher risk if their mothers smoked during pregnancy. Mothers were 1.6 times as likely to have high blood pressure in later life if their daughters developed PCOS. If their fathers had heart disease or stroke, the daughters also had a higher risk of PCOS: double and three times the risk respectively. A history of diabetes in either parent was not significant.

Prof Davies said: "These findings suggest a new pathway for the development of PCOS. We think that factors associated with the pre-existence of cardiovascular dysfunction in the mother or the father, and which operate during pregnancy, may create adverse conditions for the foetus, which alter the metabolic profile of offspring, leading to insulin resistance and reproductive consequences, such as PCOS, for daughters. A family history of diabetes is, therefore, not essential to observe an insulin resistance-related disease in offspring."

He said it was still unclear exactly how the cardiovascular risk in the father affected the daughter. "We firstly need to consider the potential role of a common environment; for instance, that families with high levels of obesity (and therefore cardiovascular disease) will also tend to have heavy daughters who are thereby more likely to be affected by PCOS. However, the paternal effect that we saw was independent of the daughter's weight, maternal age, socioeconomic status, maternal smoking, and country of birth, which suggests either a direct genetic effect on the daughter, or an effect of paternal genetic factors that are expressed during pregnancy."

Dr Verena Mattle told the news briefing that her study was the first to show that brothers of women who had PCOS and insulin resistance were themselves more likely to develop insulin resistance or even diabetes or dyslipidaemia (a disruption in the levels of lipids (or fats) in the blood).

"Until now, it was not clear whether the male relatives of women with PCOS were at increased risk for the metabolic disorders associated with PCOS," said Dr Mattle, who is chief resident at the University Clinic of Gynecological Endocrinology and Reproduction Medicine in Innsbruck (Austria).

Dr Mattle and her colleagues conducted oral glucose tolerance tests on 15 brothers of sisters with PCOS and insulin resistance (group 1). They also performed a serum analysis to determine lipid levels. As a control, nine brothers of sisters with PCOS but without insulin resistance were included in the study (group 2).

The researchers found that in the first group eight brothers showed an insulin resistance, one was diagnosed with diabetes and six had a normal glucose tolerance test. All nine affected brothers had a body mass index (BMI) between 19-31 kg/m2 and had elevated cholesterol and triglyceride levels. The six unaffected brothers had a BMI between 23-29, and none had high levels of cholesterol or triglycerides. In the second group, no insulin resistance was diagnosed. BMI was between 18-27 and two brothers had elevated cholesterol levels. Although there was a trend towards higher BMI in the first group, Dr Mattle said there was no statistically significant difference in BMIs between the two groups.

Dr Mattle said: "These results mean that we should pay attention to the health not only of women with PCOS but also to their brothers as they seem to have an increased risk for the medical problems that make up the metabolic syndrome, such as insulin resistance, diabetes and cardiovascular disease. Our findings are also in accordance with the hypothesis that not only is PCOS is a heritable disease, but that factors associated with it, such as insulin resistance, can be passed down to the next generation of either sex."

She said that it could not be the case that the high BMI by itself could have caused the insulin resistance and diabetes in the affected brothers. "There must be a correlation between PCOS and insulin resistance because we could only find brothers with insulin resistance in the group that had sisters with PCOS and insulin resistance, but we couldn't find brothers with insulin resistance in the group that had sisters with PCOS and no insulin resistance. It is known that about 50% of women with PCOS are insulin resistant and also that lean PCOS patients are insulin resistant. The BMI of insulin-resistant and non-resistant brothers were not statistically different."

Dr Mattle and her colleagues are continuing to test brothers of women with PCOS for insulin resistance and lipid levels to collect more data from a larger group. "At this stage we would hesitate to say that a genetic inheritance is definitely playing a role in the increased risk of insulin resistance and other, related conditions in these brothers. We need to explore the possible effect of conditions in the womb and also the role of the environment. However, we think our data strongly support the view that brothers of women with PCOS and insulin resistance may have an increased risk of insulin resistance, diabetes and other, adverse metabolic conditions," she concluded.


THURSDAY July 2, 2009---------------------------News Archive / Return to News Alerts

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Daily Sex Helps Reduce Sperm Damage - Improve Fertility
Daily sex (or ejaculating daily) for seven days improves men's sperm quality by reducing the amount of DNA damage, according to an Australian study presented today (Tuesday) to the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam

Until now there has been no evidence-based consensus amongst fertility specialists as to whether or not men should refrain from sex for a few days before attempting to conceive with their partner, either spontaneously or via assisted reproduction.

Dr David Greening, an obstetrician and gynaecologist with sub specialist training in reproductive endocrinology and infertility at Sydney IVF, Wollongong, Australia, said: "All that we knew was that intercourse on the day of ovulation offered the highest chance of pregnancy, but we did not know what was the best advice for the period leading up to ovulation or egg retrieval for IVF.

"I thought that frequent ejaculation might be a physiological mechanism to improve sperm DNA damage, while maintaining semen levels within the normal, fertile range."

To investigate this hypothesis, Dr Greening studied 118 men who had higher than normal sperm DNA damage as indicated by a DNA Fragmentation Index (DFI). Men who had a more than 15% of their sperm (DFI >15%) damaged were eligible for the trial. At Sydney IVF, sperm DNA damage is defined as less than 15% DFI for excellent quality sperm, 15-24% DFI for good, 25-29% DFI for fair and more than 29% DFI for poor quality; but other laboratories can have slightly different ranges.

The men were instructed to ejaculate daily for seven days, and no other treatment or lifestyle changes were suggested. Before they started, levels of DNA damage ranged between 15% and 98% DFI, with an average 34% DFI when measured after three days' abstinence. When the men's sperm was re-assessed on the seventh day, Dr Greening found that 96 men (81%) had an average 12% decrease in their sperm DNA damage, while 22 men (19%) and an average increase in damage of nearly 10%. The average for the whole group dropped to 26% DFI.

Dr Greening said: "Although the mean average was 26% which is in the 'fair' range for sperm quality, this included 18% of men whose sperm DNA damage increased as well as those whose DNA damage decreased. Amongst the men whose damage decreased, their average dropped by 12% to just under 23% DFI, which puts them in the 'good' range. Also, more men moved into the 'good' range and out of the 'poor' or 'fair' range. These changes were substantial and statistically highly significant.

"In addition, we found that although frequent ejaculation decreased semen volume and sperm concentrations, it did not compromise sperm motility and, in fact, this rose slightly but significantly.

"Further research is required to see whether the improvement in these men's sperm quality translates into better pregnancy rates, but other, previous studies have shown the relationship between sperm DNA damage and pregnancy rates.

"The optimal number of days of ejaculation might be more or less than seven days, but a week appears manageable and favourable. It seems safe to conclude that couples with relatively normal semen parameters should have sex daily for up to a week before the ovulation date. In the context of assisted reproduction, this simple treatment may assist in improving sperm quality and ultimately achieving a pregnancy. In addition, these results may mean that men play a greater role in infertility than previously suspected, and that ejaculatory frequency is important for improving sperm quality, especially as men age and during assisted reproduction cycles."

Dr Greening said he thought the reason why sperm quality improved with frequent ejaculation was because the sperm had a shorter exposure in the testicular ducts and epididymis to reactive oxygen species – very small molecules, high levels of which can damage cells. "The remainder of the men who had an increase in DFI might have a different explanation for their sperm DNA damage," he concluded.


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Fewer Eggs May Mean Higher Risk for Trisomic Pregnancy
Women who have a diminished number of eggs in their ovaries, either because they are older or for some other reason such as ovarian surgery, may be more at risk of a trisomic pregnancy than women with an ovarian reserve within the normal, fertile range


Trisomic pregnancies occur when the embryo has three copies of a chromosome rather than the normal two. The most common trisomy is Down's syndrome or trisomy 21. Most foetuses with other trisomies miscarry, but if they are born alive then they have multiple abnormalities and usually die in childhood.

Dr Maaike Haadsma, a researcher in the departments of obstetrics & gynaecology and genetics at the University Medical Center Groningen (The Netherlands) presented her findings at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam on Tuesday, June 30th.

She said: "The results of my study support a relation between trisomic pregnancy and a decreased quantity of eggs available in the ovaries of women attending fertility clinics for IVF treatment. This finding is independent of the women's age. This suggests that the effect of a mother's age on the risk of trisomy may be explained by the age-related decrease in the numbers of eggs. Younger women may also be at increased risk of trisomic pregnancy if their ovarian reserve is reduced, either because of treatment affecting the ovaries such as surgery, or because of their genetic inheritance."

Dr Haadsma and her colleagues analysed data from a nationwide group of 19,840 women undergoing fertility treatment in The Netherlands from 1983-1995. They identified 28 women who had a trisomic pregnancy after IVF and matched them with a control group of women who had healthy children. They looked at three indications of ovarian reserve: 1) a history of ovarian surgery at the time of IVF treatment (such as the removal of benign ovarian cysts); 2) the number of eggs (oocytes) retrieved during the fertility treatment; 3) menopausal status at the end of the study period.

They found that a history of ovarian surgery increased the risks of trisomic pregnancy more than three-fold; if only four or fewer eggs were retrieved during treatment, this quadrupled the risk of trisomy (conventional IVF aims to retrieve between 8-10 eggs at one time); if there were signs of the menopause at the end of the study period, this increased the risk of a trisomic pregnancy more than five-fold.

"The biological mechanism behind our findings is, as yet, unclear," said Dr Haadsma. "It may be that women use their 'best' eggs first in their fertile life and leave their abnormal ones to the last. Women with fewer eggs would then be at increased risk of trisomic pregnancy. However, more convincing in my opinion, is the hypothesis that the chance that a fertilised, abnormal egg is selected for embryo transfer in IVF is increased in women with reduced ovarian reserve, simply because there are fewer eggs and thus embryos to choose from. The proportion of normal and abnormal embryos may be the same in women with normal and diminished ovarian reserve, but if you only have one or two embryos available (instead of, say, six or eight) the chance that no normal embryo is available is relatively high."

As women get older their supply of eggs decreases. In younger women, the reasons for a diminished ovarian reserve are more complex. "Next to ovarian surgery, other medical interventions, such as chemotherapy or radiotherapy, may cause a decrease in ovarian reserve. However, a woman's ovarian reserve is most likely to be mainly determined by her genes: the number of oocytes a woman is born with and the rate of depletion of her oocyte pool is believed to be heritable. This is reflected in the similar ages at menopause of mothers and daughters. However, exactly which genes are involved remains to be determined," said Dr Haadsma.

She concluded: "Since we studied a relatively small number of women, our results should be interpreted as an indication and not as proof of a relation between ovarian reserve and trisomy risk. We have to confirm our findings in a different IVF cohort first and than determine the exact extent of the increase in trisomy risk. Then the next step would be to study our hypothesis in a fertile group of women, since results from women having IVF cannot be extrapolated to the general population right away. If our findings are indeed confirmed, women with reduced ovarian reserve should be informed about their 'new' trisomy risk. It's perceivable this may influence their choices in prenatal testing."

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Will IVF Work for You? The Answer May Be In Your Blood
For the first time, researchers have been able to identify genetic predictors of the potential success or failure of IVF treatment in blood

Dr. Cathy Allen, from the Rotunda Hospital, Dublin, Ireland, told the 25th annual conference of the European Society of Human Reproduction and Embryology on Wednesday 1 July, that her research would help understand why IVF works for some patients but not for others.

Previous work in this area has looked at gene profiles in such tissues as the uterine lining, but Dr. Allen and her team chose to examine the gene expression patterns in RNA extracted from peripheral (circulating) blood, an easily accessible biological sample. Blood samples were taken at eight different stages during the period around conception and the early stages of the IVF cycle. Five of these samples came from women who achieved clinical pregnancies, three from those who had implantation failure, and three from subfertile women who conceived spontaneously. Analysis showed that 128 genes showed a more than two-fold difference in expression in early clinical pregnancy compared with a non-pregnant state.

The molecular pathways that were most over-represented in this expression were concerned with angiogenesis (the growth of new blood vessels), endothelin signalling (blood vessel constriction), inflammation, oxidative stress (damage to cell structures), vascular endothelial growth factor (signalling processes in blood vessel growth), and pyruvate metabolism (the supply of energy to cells). "All these processes are important in the achievement and maintenance of pregnancy," said Dr. Allen.

"We found that the gene expression profiles in blood of patients at the time of pituitary down-regulation showed interesting patterns of gene clustering. Over 200 genes were differentially expressed in patients who went on to achieve an IVF pregnancy compared with those who did not," she said.

The researchers found that the peripheral blood gene expression 'signature' (also known as the transcriptome) before IVF was predictive of IVF outcome. This finding demonstrates the power of high-dimensional technology in biomarker discovery, and highlights the potential for developing clinically useful tools, they say.

One of the most difficult decisions for patients who have had unsuccessful IVF treatments is whether they should undergo further attempts at IVF, or if there are ways to optimise chances of success. The researchers hope that the results generated by this work will lead to the development of a test to aid in IVF decision-making. They say that their work will help to identity biomarkers that can identify events occurring at implantation, the maintenance of pregnancy and successful or unsuccessful pregnancy outcome.

"IVF technology has advanced tremendously over the past three decades, yet success after IVF remains an unpredictable outcome," said Dr. Allen. "Our work will help understand whether the implantation of embryos is influenced by the constantly changing expression of human genes."

Previous studies in the field of gene-expression have focused on single genes as opposed to genome-wide screening of all the human genes with high density DNA microarrays, as used by Dr. Allen and her team. The advent of tools like microarrays that can simultaneously probe for up to 29,000 genes has radically changed scientific approaches to this type of research. "It's like looking at how a team of players perform together rather than focusing on the individual players," said Dr. Allen.

"We intend to look further at the most significant genes we have identified as being important in this field in order to be able to understand their exact biological role in reproductive function. We hope that our work will lead to the development of a clinically useful tool to help doctors counsel their patients in the difficult decision-making involved in IVF," she said.


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Test Can Detect an Embryo's Genetic & Chromosome Defects
One-step screening for both genetic and chromosomal abnormalities has come a stage closer as scientists announced that an embryo test they have been developing has successfully screened cells taken from spare embryos that were known to have cystic fibrosis

They told a news briefing at the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam on Tuesday, June 30th, that, as a result, they would be able to offer clinical trials to couples seeking fertility treatment later this year.

The researchers based in the USA and the UK have been able to prove that the technique, known as genome-wide karyomapping, was capable of not only detecting diseases caused by a specific gene mutation, in this case cystic fibrosis, but that it was also capable of detecting aneuploidy (an abnormal number of any of the 23 pairs of chromosome) at the same time. This is the first time they have been able to demonstrate that the test can work in cells taken from embryos that have already been diagnosed with the cystic fibrosis gene mutation using conventional preimplantation genetic diagnosis (PGD).

Gary Harton, PGD scientific director of the Genetics & IVF Institute in Fairfax, Virginia (USA) told a news briefing: "Karyomapping is a universal method for analysing the inheritance of genetic defects in the preimplantation embryo without any prior patient or disease specific test development, which often delays patient treatment. For the first time, the inheritance of both single gene defects and chromosomal abnormalities can be detected simultaneously at the single cell level. Unlike other methods, this is achieved entirely by analysing the DNA sequence at over 300,000 locations genome-wide in parents and appropriate family members, often children already affected by a disease, and comparing their sequence with that inherited by the embryo. This can be achieved very rapidly using current microchip technology known as microarray."

With karyomapping it is not necessary to know the exact DNA mutation that is being sought; the scientists just need to take the relevant chunk of DNA from the parent that carries the mutation somewhere along its length, and if it matches a chunk of DNA from the embryo, then they know the embryo has inherited the mutation. As karyomapping involves analysing chromosomes, it also detects the existence of aneuploidy at the same time.

"The range of applications is broad and includes single gene defects, abnormal chromosome number, structural chromosome abnormalities and HLA [human leukocyte antigen] matching in 'saviour sibling' cases," said Mr Harton.

Karyomapping was developed by Professor Alan Handyside of the London Bridge Fertility Gynaecology and Genetics Centre in London (UK), and Mr Harton has been providing samples and DNA information in order to test the method and validate it for use in the clinic.

"The hope is that clinicians will be able to test embryos for specific genetic diseases and know that, with one test, they are transferring chromosomally normal embryos. This will be a step forward from current technology that is mostly limited to choosing one test or the other," explained Prof Handyside.

Karyomapping would also be quicker and cheaper. Currently, developing a PGD test for a single gene defect can take weeks or months, as scientists have to identify the exact patient or disease-specific genetic mutation first before screening for it, which is labour-intensive and costly. By contrast, karyomapping can be carried out without such extended pre-test development; at present, it takes about three days, but Mr Harton and his colleagues believe this could be reduced to 18-24 hours.

In this most recent stage of their research they examined cells from five embryos that had been donated for medical research by a couple who had received successful fertility treatment, including PGD for cystic fibrosis. The embryos had developed to the blastocyst stage, which is about five days after fertilisation. Conventional PGD had already identified which embryos were unaffected, affected or were carriers of the disease. Karyomapping of cells from the donated embryos confirmed these diagnoses, but, in addition, it was able to identify which parent carried the affected chunk of DNA. Karyomapping also revealed two aneuploidies in two embryos, which had not been detected by the earlier PGD.

Mr Harton said: "This demonstrates that karyomapping, following genome-wide analysis of a single cell biopsied from embryos at the blastocyst stage, can provide highly accurate analysis for cystic fibrosis, combined with the detection of chromosomal aneuploidy. Now that vitrification [an improved method of embryo freezing] has improved embryo survival after thawing, it should be possible to vitrify embryos at the blastocyst stage, either before or after biopsy, and analyse the embryos for virtually any genetic disease and screen for aneuploidy of all 23 pairs of chromosomes simultaneously. This approach could make PGD by karyomapping less expensive than conventional single disease PGD because fewer embryos will be biopsied, more embryos will be chromosomally normal following growth to the blastocyst stage, and there is no need to custom develop tests for each disease or couple interested in PGD."

Prof Handyside concluded: "These tests have helped us to learn everything we can before we start to treat actual patients. I am confident that we will be offering a clinical trial to patients using karyomapping some time this year."


WEDNESDAY July 1, 2009---------------------------News Archive / Return to News Alerts

Kohl's

Women More Likely Than Men to Reject Unattractive Babies
Women are more likely than men to reject unattractive-looking babies, according to a study by researchers at Harvard-affiliated McLean Hospital, possibly reflecting an evolutionary-derived need for diverting limited resources towards the nurturing of healthy offspring

The findings also challenge the idea of unconditional maternal love.

"Our study shows how beauty can affect parental attitudes," said Dr. Igor Elman, senior author and Director of the Clinical Psychopathology Laboratory at McLean Hospital. "It shows women are more invested in raising healthy babies and that they are more prone to reject unattractive kids."

The paper, which will be in June 24 issue of the journal PLoS ONE, sought to determine whether aesthetic appearance affects how hard adults are willing to work in order to watch pictures of babies.

Subjects, including 13 healthy men and 14 healthy women, were shown photos of 80 infants, including 50 normal ones and 30 who had abnormal facial features, including such abnormalities such as cleft palates, skin disorders, Down's syndrome and others.

Each photo was set to remain on screen for four seconds, but subjects could extend or shorten the viewing time of each photo by pressing certain computer keys. A second part of the experiment asked the subjects to rate the attractiveness of each infant on a numerical scale.

The study found that men and women expended a similar amount of effort — quantified by the number of key presses made to keep photos up on the screen — to extend the viewing time of the normal babies. At the same time, the attractiveness ratings given by men for these normal babies were significantly lower than those given by the women. However, when it came to the photos of abnormal babies, women made a greater effort to avoid looking at them, compared to men. Still, the women rated abnormal faces as unattractive as did men.

The differences between men and women in motivational effort to extend or shorten the viewing time of abnormal-looking babies "may reflect an evolutionary-derived need for diversion of limited resources to the nurturance of healthy offspring," the paper concludes.

The findings question the concept of unconditional parental love, at least among women. "What our results suggest is that this is determined by facial attractiveness," said Dr. Rinah Yamamoto, first author. "Women may be more sensitized to aesthetic defects and may be more prone to reject unattractive kids. Men do not appear to be as motivated. They didn't expend the same effort."

The study noted that work with abandoned and neglected children firmly link their abnormal appearance to maltreatment by caregivers. One study, done in Israel, found that 70 percent of children abandoned by their parents had a conspicuous flaw in their appearance even though those flaws were not life-threatening nor did they affect the children's intellectual development.

"This may be to some extent because adults are unconsciously motivated to care for infants with healthy facial features, indicating fitness for survival and to exclude the least fit," the paper said.

"The abandonment and neglect data along with our findings may thus challenge the commonly held view of unconditional maternal love and acceptance of the offspring," it said. "If mother's love is not unconditional, what is the condition? The results provide indirect support for . . .the idea that babies' aesthetic appearance has a motivating influence on the adults' caretaking behavior."

The paper suggests that the findings may have clinical implications in terms of predicting potential for abuse and neglect of children.

Elman, who is also an Associate Professor of Psychiatry at Harvard Medical School, said since the study involved small numbers of subjects, it must be replicated in larger follow-up studies. Future studies will also involve brain scans of subjects in order to try and pinpoint how men's and women's brains may be functioning differently while they view the images and make their choices for extending or shortening the time they are looking at the images.

The study, which also involved researchers from the Massachusetts Institute of Technology and the University of Pennsylvania, was funded by grants from the National Institute of Drug Abuse.

McLean Hospital is the largest psychiatric facility of Harvard Medical School, an affiliate of Massachusetts General Hospital and a member of Partners HealthCare. For more information about McLean Hospital, visit www.mclean.harvard.edu.


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Fallopian Tubes Offer New Stem Cell Source
Human tissues normally discarded after surgical procedures could be a rich additional source of stem cells for regenerative medicine


New research from BioMed Central's open access Journal of Translational Medicine shows for the first time that human fallopian tubes are abundant in mesenchymal stem cells which have the potential of becoming a variety of cell types.

It has previously been shown that mesenchymal stem cells obtained from umbilical cords, dental pulp and adipose tissue, which are all biological discards, are able to differentiate into muscle, fat, bone and cartilage cell lineages; therefore, the search for sources to obtain multipotent stem cells from discarded tissues and without ethical problems is of great interest.

Tatiana Jazedje, and the research team from Human Genome Research Centre at the University of São Paulo, directed by Mayana Zatz, with the collaboration of medical doctors from the reproductive area, set out to isolate and assess the differentiation potential of mesenchymal stem cells from discarded human fallopian tubes. In the study, human fallopian tubes were obtained from hysterectomy and other gynecological procedures from fertile women in their reproductive years (range 35-53 years) who had not undergone hormonal treatment for at least three months prior to surgery.

The Brazilian team found that human fallopian tube mesenchymal stem cells could be easily isolated and expanded in vitro, and are able to differentiate into muscle, fat, cartilage and bone cell lines. The cells' chromosome complement showed no abnormalities, suggesting chromosomal stability. Jazedje comments, "In addition to providing an additional potential source for regenerative medicine, these findings might contribute to reproductive science as a whole."

Jazedje concludes, "Moreover, the use of human tissue fragments that are usually discarded in surgical procedures does not pose ethical problems."


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Stress in the Womb Can Last a Lifetime
Researchers from Imperial College London hope to raise families' awareness of the importance of reducing levels of stress and anxiety in expectant mothers. They say that reducing stress during pregnancy could help prevent thousands of children from developing emotional and behavioural problems

Visitors to the Exhibition will have the chance to play a game that shows how a mother's stress can increase the heart rate of her unborn baby. They will also be able to touch a real placenta, encased safely in plastic. The placenta is crucial for fetal development and it usually protects the unborn baby from the stress hormone cortisol. However, when the mother is stressed, the placenta becomes less protective and the mother's cortisol may have an effect on the fetus.

The Imperial researchers' work has shown that maternal stress and anxiety can alter the development of the baby's brain. This in turn can result in a greater risk of emotional problems such as anxiety or depression, behavioural problems such as Attention Deficit Hyperactivity Disorder, and being considerably slower at learning. Some studies have even suggested that it may increase the likelihood of later violent or criminal behaviour. Their findings have suggested that the effects of stress during pregnancy can last many years, including into adolescence.

Professor Vivette Glover, the lead researcher behind the exhibit from the Institute of Reproductive and Developmental Biology at Imperial College London, said: "We all know that if a mother smokes or drinks a lot of alcohol while pregnant it can affect her fetus. Our work has shown that other more subtle factors, such as her emotional state, can also have long-term effects on her child. We hope our exhibit will demonstrate in a fun way why we all need to look after expectant mothers' emotional wellbeing.

"Our research shows that stress due to the mother's relationship with her partner can be particularly damaging. We want fathers visiting our exhibit to see how they can help with the development of their child even before the birth, by helping their partner to stay happy," added Professor Glover.

The researchers say that the stress hormone cortisol may be one way in which the fetus is affected by the mother's anxiety during pregnancy. Usually the placenta protects the unborn baby from the mother's cortisol, by producing an enzyme that breaks the hormone down. When the mother is very stressed, this enzyme works less well and lets her cortisol through the placenta. By studying the amount of cortisol in the amniotic fluid, the Imperial researchers' latest study suggests that the higher the level of cortisol in the womb, the lower the toddler's cognitive development or "baby IQ" at 18 months.

Kieran O'Donnell from the Institute of Reproductive and Developmental Biology at Imperial College London said: "We are very excited to have this opportunity to talk with the public about our work. We think that by promoting awareness of this subject we may be able to benefit many families in the future."

Diapers.com

Who Goes Abroad for Fertility Treatment and Why?
A substantial number of European patients travel to other countries for fertility treatment, both because they think that they will receive better quality care abroad and in order to undergo procedures that are banned in their home country says a study of the subject launched at the 25th annual conference of the European Society of Human Reproduction and Embryology (Monday June 29)

Study co-ordinator Dr. Françoise Shenfield, from University College Hospital, London, UK, said that this was the first hard evidence of considerable fertility patient migration within Europe. "Until now we have only had anecdotal evidence of this phenomenon", she said. "We think that our results will be of considerable value to patients, doctors, and policymakers."

During a one-month period, the ESHRE Task Force analysed data from participating clinics in six European countries: Belgium, the Czech Republic, Denmark, Slovenia, Spain and Switzerland. Clinics were asked to provide questionnaires to patients coming from abroad for treatment. The questionnaires asked about their age, country of residence, reasons for travelling to another country for treatment, which treatment they had received, whether they had received information in their own language, how they had chosen the centre they were attending, and whether they had received reimbursement from their home country's health system. 1230 forms were completed and returned.

"This may not seem to be a very high number", said Dr. Shenfield, "but it reflects only one month of events in a limited number of centres in six countries. The total number of treatment cycles per year can be estimated by extrapolating our monthly data to a year and by assuming that the centres represent no more than half of the centres in each of the countries studied. This leads to an estimate of at least 20 000 to 25 000 cross-border treatment cycles per year in these countries. It is, however, difficult to derive a number of patients from these numbers as patients receive more than one cycle to obtain a pregnancy, the mean number depending on the type of treatment."

Almost two-thirds of the patients surveyed came from four countries, with the largest number coming from Italy (31.8%), followed by Germany (14.4%), the Netherlands (12.1%) and France (8.7%). In total, people from 49 countries crossed borders for fertility treatment.

The main reason for going abroad for fertility was to avoid legal restrictions at home. 80.6% of the German patients surveyed have this as their primary reason, 71.6% of Norwegians, 70.6% of Italians, and 64.5% of French. Difficulties of access to treatment were cited more by patients from the UK (34.0%) than those from other countries.

Age also played an important part in the decision to travel for treatment. The average age across all countries was over 37.5, but German and UK patients tended to have a much higher age profile with 51.1% of Germans being aged over 40 and 63.5% of British. Civil status also varied between countries; overall 69.9% of all women were married and only 6.1% single. But 82% of Italian women were married, while 50% of French women were cohabiting (often in same sex couples), and 43.4% of Swedish women were single.

The majority of respondents were seeking assisted reproduction treatment (ART) only (73%) as opposed to 22.2% intrauterine insemination (IUI), and 4.9% both ART and IUI. These figures also varied between one country and other; there was a majority of IUI treatments for French (53.3%) and Swedish (62.3%) patients, with a majority of ART for most other countries.

Fertility treatment abroad is poorly reimbursed, says Dr. Shenfield. "Only 13.4% of the patients we surveyed received partial reimbursement, and as few as 3.8% were reimbursed totally for their treatment."

The most generous country was The Netherlands, with a partial or total reimbursement of 44.4% and 22.1% of patients. In France, patients could only be reimbursed for overseas treatment where there was a delay at home, and treatment that was illegal at home, for example for single women or homosexual couples, was not reimbursed at all.

"This was a pilot study carried out in a small number of countries, and hence has limitations", said Dr. Shenfield. "However, it confirms information already gathered by patient support groups and reported in the media. For example, Spain and the Czech Republic are popular destinations for oocyte donation; Swedes travel to Denmark for insemination, and French to Belgium.

"It has also enabled us to have concrete proof of the large numbers of Italians who cross borders to obtain treatments which were made illegal under the 2004 legislation, or because by doing so they will receive what they perceive to be better quality treatment. This may mean, for instance, the possibility of embryo freezing", she said.

In another study, Professor Guido Pennings from the University of Ghent, Ghent, Belgium, looked in more detail at the situation in his own country. 16 out of the 18 Belgian reproductive medicine centres which were licensed to handle oocytes and create embryos were surveyed on the nationality of foreign patients coming for treatment between 2000 and 2007, as well as on the type of treatment for which they came.

The researchers found that, since 2006, the flow of foreign patients into Belgium had stabilised at around 2100 patients per year, and that the majority of these were lesbian couples from France seeking sperm donation.

There appeared to be a clear correlation between legal prohibitions in patients' home countries and the numbers who travelled abroad, he said. "The changes in numbers of patients coming from a specific country for a specific treatment and changes in the law in that country are not coincidental.

"In France couples have to be heterosexual, in a stable relationship and of reproductive age in order to have access to assisted reproduction. In addition to the legal reasons, given the geographical closeness of the two countries and the fact that language difficulties are limited, it was not surprising to find French patients made up the largest percentage of those travelling to Belgium (38%). These were followed by patients from the Netherlands (29%), Italy (12%) and Germany (10%)", he said.

Professor Pennings believes that the numbers may be an underestimate. Not only did 2 out of the 18 qualifying centres not reply, but centres which only provided treatments that were less technically demanding, such as hormonal stimulation or artificial insemination, were not included. Additionally, no data were included from countries which provided fewer than five patients per year per centre.

"Although collection of data on the numbers of patients moving from one country to another is a first and important step, future research should include the experiences of patients, the difficulties they experience, the impact of such movements on the national health care systems, and the effects of, for instance, portability of insurance on the numbers", he said. "We will only be able to evaluate the phenomenon properly when we can see the full picture."


TUESDAY June 30, 2009---------------------------News Archive / Return to News Alerts

Kohl's

First Baby is Born After Ovarian Transplant
A new technique for transplanting the ovaries of women who have lost their fertility as a result of cancer treatment was outlined to the 25th annual conference of the European Society of Human Reproduction and Embryology today (Monday 29 June)

Dr. Pascal Piver, manager of the IVF Centre at Limoges University Hospital, Limoges, France, described a new, two-step method of ovarian transplant that has produced excellent results in women whose ovaries have been frozen because of cancer treatment. He said that his team's technique worked to restore ovarian function quickly and already one patient from his clinic had had a baby and another had become pregnant.

"On June 22, a baby girl was born to a mother who had been menopausal for two years as a result of treatment for sickle cell anaemia. After transplanting her own ovarian tissue she started ovulating in four months and became pregnant naturally six months after transplantation. Both mother and baby are doing well", he said.

Dr. Piver and colleagues set out to tackle one of the biggest problems of ovarian transplantation: the low response to stimulation caused by insufficient vascularisation of the transplanted tissue.

"In order for a woman to become pregnant, the ovaries need to be responsive to the action of hormones that cause them to release eggs each month," he explained. "If the blood supply to the ovaries is insufficient, this will not happen, even though the transplant may look as though it has been successful."

To overcome this problem they carried out a two-stage procedure, first grafting small pieces of the frozen ovarian tissue in the ovarian and peritoneal areas three days before the real transplant. The first graft encourages the growth of blood vessels and paves the way for the ovary to become fully functioning in a shorter time scale than would be possible if all the tissue were to be transplanted at the same time.

The researchers have so far utilised this technique with two patients who had been treated for cancer and had their ovaries frozen. In addition to the first patient, treated for sickle cell anaemia, the second patient had been treated for periarteritis nodosa, an inflammation of medium-sized arteries, which become swollen and damaged from attack by rogue immune cells.

"She suffered menopause for eight and a half years before transplantation," said Dr. Piver. "But after transplanting half of the frozen ovary, she recovered spontaneous ovulation in four months. Her right fallopian tube had been destroyed by the ovarian retrieval, and the function of the ovary and hence the chances of pregnancy are limited in time. Hence we decided to collect the highest number of eggs we could, and carry out an IVF procedure on this patient.

"Six months after the operation, we transferred two blastocysts. A total of 22 oocytes were retrieved and produced 16 embryos, which in turn produced seven blastocysts. Unfortunately the first time round this patient developed an ectopic pregnancy, but she is now pregnant again."

The technique was developed by Dr. Piver and his team, he told the conference. "This is the first time that a pregnancy has been obtained after a ten year gap between ovarian cryopreservation and grafting. We believe that it represents a considerable advance on the methods of ovarian transplantation used until now, not least because we are able to obtain large numbers of oocytes. We hope that it will enable more young patients who have been cured of cancer to regain their reproductive health and become pregnant with their own children," he said.


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Female Human Embryos Balance X Chromosomes Before Implanting
Results have implications for in vitro fertilisation and embryonic stem cell research

Amsterdam, The Netherlands: Dutch researchers have found the first evidence that a process of inactivating the X chromosome during embryo development and implantation, which was known to occur in mice but unknown in humans, does, in fact, take place in human female embryos prior to implantation in the womb.

Ms Ilse van den Berg told the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam today (Monday) that her findings may have implications for the laboratory cultures that embryos are grown in before transfer to a woman's womb during fertility treatment, as well as for embryo stem cell research.

Males and females have two sex chromosomes: X and Y. While females have two X chromosomes and no Y chromosome, males have one of each. As the X chromosome is much larger then the Y chromosome, males and females also differ in their numbers of genes and gene expression. To equalise this difference in gene expression, females need to silence one X chromosome in every cell – a process known as X chromosome inactivation (or XCI).

In mice, XCI occurs before embryo implantation when the X chromosome inherited from the father is turned off, while the maternal X chromosome remains turned on. As the cells carry on dividing and reach the blastocyst stage, the cells that will go on to form the placenta continue to have the paternal X chromosome switched off, but it is switched back on in the cells that are going to form the inner cell mass that develops into the foetus.

"It is from these cells that mice embryonic stem cell lines are made; these ES cells have two active X chromosomes and are capable of becoming any kind of cell in the body. As soon as the cells are going to differentiate into any kind of specialised cell, one X chromosome is turned off again, but this time it is a random process and it can be either the maternal or paternal X chromosome that is switched off," explained Ms van den Berg, who is a PhD student at Erasmus Medical Centre (Rotterdam, The Netherlands).

If preimplantation XCI in mice fails for any reason, it results in cell and embryo death.

Due to the difficulties of investigating XCI in human embryos (because of the shortage of embryos available for research), no one knew how XCI worked in humans and, in fact, it was thought that this initial inactivation of the X chromosome before implantation did not happen at all, and that only the random XCI after implantation occurred.

However, Ms van den Berg and her colleagues have now found the first evidence that XCI does occur in pre-implantation embryos, indicating that this mechanism of compensating for gene dosages has remained basically unchanged throughout evolution and is probably the same in all mammals that have their young attached to a placenta in the womb – from mice to humans.

The researchers looked at human embryos that had been donated for scientific research by couples undergoing fertility treatment. They studied them at three stages of their development: after the embryo had divided into eight cells, the morula stage (a solid cluster of approximately 16 cells) and the blastocyst stage (about five days after fertilisation when the embryo's cells have started to differentiate into different cell layers).

They used probes designed for detecting a gene called XIST (X chromosome Inactive Specific Transcript), which is only expressed on an inactive X chromosome and is transcribed (or copied) into RNA. Other probes were used to detect the sex and chromosomal status of each embryo.

Ms van den Berg found that while the male embryos showed hardly any signs of XIST, the female embryos started to show signs of XIST at the eight-cell stage, and the XIST signal grew stronger at the morula and blastocyst stages.

"Our results are the first to show that, contrary to what was previously published, human embryos do inactivate a single X chromosome before implantation. We have shown that major characteristics that are present in mouse pre-implantation embryos are present also in human embryos. This means that dosage compensation is present before implantation and this could have possible implications for in vitro culture such as during IVF treatment. Furthermore, our research shows that X chromosome inactivation in humans is not very different from other placental mammals, suggesting that it has remained basically unchanged throughout evolution," said Ms van den Berg.

"Early failure to perform correct XCI is likely to lead to the demise of the embryo. A recent publication showed that the sex ratio of children born after blastocyst transfer in IVF/ICSI treatments is altered in favour of males. As a result of our finding that XCI occurs at the pre-implantation stage, further research should be able to clarify whether culture conditions in the laboratory influence the growth rate and survival of female embryos and whether this can be improved."

She said that her results also had implications for human embryo stem (ES) cell research. "Human embryonic stem cell lines are derived from blastocysts that, we know now, already have, or still have, a form of XCI. While mouse embryos reactivate the X chromosome in the inner cell mass at the blastocyst stage so that the derived embryonic stem cells are completely undifferentiated, it is not yet known whether this occurs in human embryos. The onset and subsequent steps of XCI in human pre-implantation embryos occur at a later stage than in mouse embryos. Thus, it is possible that reactivation of the X chromosome happens also at a later stage, after the usual time for ES cell derivation. The current human ES cell lines may, therefore, still have the first wave of XCI. Indeed, the majority of human ES cells have XCI features."

This might mean that human embryonic stem cells could behave in a different and possibly unpredictable way to that expected. If they are not fully undifferentiated, then they might be unable to transform completely into the particular tissues that researchers might be trying to create in the laboratory for therapeutic purposes.

"If the current human ES cell lines are in fact isolated too early, before X chromosome reactivation happens in the human blastocyst, then alternative strategies for generating human ES cell lines need to be developed. Obviously, an important step is to investigate exactly when and how reactivation of the X chromosome happens in the human embryo and to use this information in the derivation of new human ES cell lines. We are planning further research to clarify these issues," concluded Ms van den Berg.

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Babies Born From ICSI or IVF Frozen Embryos Do Just As Well
Analysis of the longest running ICSI program in the United States has found reassuring evidence that babies born from frozen embryos fertilised via ICSI (intracytoplasmic sperm injection) do just as well as those born from frozen embryos fertilised via standard IVF treatment

The researchers also compared babies born as a result of cycles in which the women had additional hormone medication with babies born as a result of unmedicated, natural cycles, and, although they found a slightly higher rate of malformations in babies born from medicated cycles, the difference was small – 2.2% versus 0.4%.

Ms Queenie Neri, a research associate at Cornell University (New York, USA) and a member of the team headed by Professor Gianpiero Palermo who pioneered ICSI in 1992, told the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam today (Monday) that she and her colleagues had looked at all births from frozen embryos, conceived via ICSI or IVF, between 1993 and 2007.

Ms Neri identified 720 IVF and 1231 ICSI frozen embryo transfers. The survival rate of the frozen embryos was 74% after IVF and 77.2% after ICSI. The clinical pregnancy rate was 42.8% after IVF and 39.4% after ICSI. These resulted in 84.1% IVF and 89.7% ICSI deliveries. There were 27.8% multiple IVF pregnancies and 21.1% multiple ICSI pregnancies. Outcomes at the time of birth for Apgar scores, gestational ages, birth weights and congenital malformations were similar for both IVF and ICSI singleton babies.

When she grouped the babies according to whether they came from medicated or unmedicated cycles, she found that the clinical pregnancy rate was 42.1% and 39.4% respectively; delivery rates were 86.7% (with 28.7% multiple births) and 87.5% (19.2% multiple births) respectively. Gestational ages and birth weights were similar between the two groups, but the malformation rate was 2.2% from the medicated cycles and 0.4% from the natural cycles.

Ms Neri said: "Freezing embryos as part of fertility treatment has become a fundamental part of assisted reproduction technology. We found no differences in the ability of embryo generated by IVF or ICSI to implant, even after undergoing the stress of cryopreservation. We were unable to confirm a significant benefit of the unmedicated cycle on the neonatal outcome of the cryopreserved embryos; the difference in malformation rates was small.

"The original premise of the study was to identify a difference in neonatal outcome while in the presence or absence of infertility medication, with the assumption that the unmedicated cycles would generate better offspring outcomes. Interestingly, we did not see any clear difference in neonatal outcomes between the medicated and unmedicated groups. From our study, the combination of exposure to cryopreservation and medications or both did not significantly impair offspring outcome."

The malformations ranged from heart defects to defects caused by hereditary factors and sporadic genetic mutations or interactions. However, Ms Neri said: "They were within the spectrum of malformations observed in newborns in the general population."

As there was no statistical difference between the medicated and unmedicated cycles, Ms Neri said that it was not possible to say that medicated cycles were associated with higher rates of malformations, or, if they were, what mechanism might be responsible.

"Our study reported none of the specific abnormalities linked to male factor infertility, medications or other environmental triggers such as extended in vitro culture, which have been reported by other studies," she said.

"When you think about it, the reproductive medical field has created a new sub-population. These children are now reaching puberty and their fertility status still remains to be assessed. Therefore, the continuous monitoring of children generated through artificial conception is of paramount importance," she concluded.


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Less Invasive Genetic Test Improves Pregnancy Rates in Older Women (40 years +)
A new test examining chromosomes in human eggs a few hours after fertilisation can identify those that are capable of forming a healthy baby, a researcher told the 25th annual conference of the European Society of Human Reproduction and Embryology today (Monday 29 June)

Dr. Elpida Fragouli, from the Department of Obstetrics and Gynaecology, University of Oxford, UK, and Reprogenetics UK, said that her team's work had already enabled seven ongoing pregnancies in a group of older women with a history of multiple failed IVF attempts.

"Out of 35 patients who had embryo transfers after the test, we achieved a pregnancy rate of 20%, which is exceptional considering the extremely poor prognosis of the women involved." she said. "This represents a doubling of the usual pregnancy rate for women who fall into this category, which is otherwise, at best, under 10% and, at worst, zero. To date, we have two live births from this group, and all the other women who became pregnant have maintained their pregnancies. The study is continuing, and we believe that we will achieve more pregnancies with the help of this technology in the future."

The scientists used the Comparative Genomic Hybridisation (CGH) technique to count the chromosomes in each egg. Unlike conventional screening strategies, using the fluorescent in situ hybridisation (FISH) method, which allows less than half of the chromosomes of an embryonic cell to be examined, CGH enables the evaluation of the entire chromosome complement. CGH was used to examine the fertilised eggs by looking at polar bodies, tiny cells that are a by-product of egg development. The chromosomes of polar bodies provide an indication of whether the corresponding egg is normal or abnormal; if the polar bodies have the wrong number of chromosomes, so does the egg.

Looking at polar bodies is a less invasive way of obtaining information about the chromosome content of an egg and its resulting embryo than other alternatives, such as day-three biopsy, which take place during conventional screening strategies involving the use of the FISH technique. The removal of the polar bodies does not adversely affect the subsequent development of the embryo. Additionally, the results obtained after CGH analysis of polar bodies are not affected by the presence of chromosomal mosaicism (the presence of two populations of cells with different genotypes) and therefore may be more accurate than conventional methods based upon screening of cells removed from embryos.

The scientists examined 400 fertilised eggs generated by women with a very poor reproductive history and with an average age of 42 who were undergoing IVF because of being unable to conceive or to maintain a pregnancy. They found that more than half of all the eggs produced by these women had chromosomal abnormalities, and therefore the resulting embryos were also chromosomally abnormal. Some of the women had a tendency to produce eggs that were extremely abnormal and carried multiple chromosome errors. This could explain the poor reproductive history of these women, the scientists say.

"But where we could find fertilised eggs free of chromosomal abnormalities, the resulting embryos were also normal and their transfer to the mother led to pregnancies," said Dr. Fragouli. "Results suggest that the use of this technique will improve IVF success rates for poor prognosis patients. It is also likely to achieve a reduction in congenital abnormalities such as Down's syndrome, as well as a reduction in the frequency of spontaneous miscarriage."

The incidence of chromosomal abnormalities in human eggs is closely related to maternal age, and can affect more than 60% of all eggs in women over 40 years of age. Being able to select the right egg can not only lead to more successful IVF, but also enhance the use of single embryo transfer, especially in countries where embryo testing is forbidden and only eggs can be tested. "Being able to examine the first polar body means that this test can be used in countries where embryo testing is forbidden by law," said Dr. Fragouli.

"We are close to applying technical innovations which will make this test even better, faster, and cheaper. We are also going to be using the test in cases where fertility preservation is required, due to cancer, for example," she said.


MONDAY June 29, 2009---------------------------News Archive / Return to News Alerts

Kohl's

Pregnancy Complications Affect Subsequent Pregnancies
Complications in early pregnancy or in previous pregnancies can predict the likelihood of further problems in current or subsequent pregnancies, according to research carried out by an international group of experts

Their findings will help clinicians to predict more easily which women might need greater care and supervision during pregnancy, as well as enabling new research to improve clinical management of such high risk patients. Improving care for pregnant women and their babies is of particular importance in countries such as The Netherlands where perinatal mortality is a cause for concern. The Netherlands has a perinatal mortality rate of 9.8 per 1000 (2006 figures) – the second highest rate in Europe.

Dr Robbert van Oppenraaij told the 25th annual meeting of the European Society of Human Reproduction and Embryology in Amsterdam today (Monday) that he and his colleagues from the UK, Denmark and Spain had reviewed 75 studies carried out between 1980-2008 that looked at the impact of early pregnancy complications.

Dr van Oppenraaij, a medical doctor and PhD student in the Department of Obstetrics and Gynaecology at Erasmus MC University Medical Centre (Rotterdam, The Netherlands), said: "There were several interesting findings. To name two: firstly, we found that after any first trimester complication or event, the risk of preterm or very preterm delivery is increased in the subsequent or ongoing pregnancy; secondly, we found that increased risks of adverse obstetric outcome are, in all cases, related to the severity or recurrence, or both, of the first trimester complication or event. To our knowledge, this is the first comprehensive review in which the impact of more than one first trimester complication on adverse obstetric outcome has been investigated systematically."

The researchers found that a history of one or more miscarriages nearly doubled the risk in an ongoing pregnancy of preterm premature rupture of the membrane that surrounds the baby in the womb, and increased the risk of premature or very premature delivery (earlier than 37 or 34 weeks respectively). Recurrent miscarriages (three or more miscarriages) increased the risk in a subsequent pregnancy of all of these conditions; in addition, it increased the risk of placenta praevia (where the placenta partially or completely blocks the cervix) six-fold and congenital malformations nearly two-fold. If a previous pregnancy had to be terminated for any reason, this increased the risk of premature rupture of the membrane, premature and very premature delivery in subsequent pregnancies.

Dr van Oppenraaij said: "The finding of a six-fold risk of placenta praevia needs to be treated with caution as it came from one, small, retrospective study. More and larger studies are needed to confirm this finding."

If problems were encountered in the first trimester of an ongoing pregnancy, this increased the risk of further complications later on in the same pregnancy. For instance, vaginal bleeding in the first trimester increased the risk of preeclampsia, premature or very premature delivery and more than doubled the risk of low birth weight and very low birth weight. These risks were further increased after detection of an intrauterine haematoma. The survivor in a vanishing twin pregnancy (a twin pregnancy in which one twin miscarries very early in the pregnancy) was at increased risk of premature or very premature delivery, had double the risk of low birth weight, three times the risk of very low birth weight, and more than three times the risk of perinatal death. Extreme early morning sickness (hyperemesis gravidarum) was associated with a three-fold increased risk of premature delivery and a nearly three-fold risk of low birth weight.

Dr van Oppenraaij said: "While it is true that most conditions are difficult to prevent, with improved monitoring in high risk pregnancies it is possible to reduce perinatal or postnatal foetal complications. For example, in pregnancies with increased risk of preterm or very preterm delivery or intrauterine growth restriction, extra ultrasonic measurement of the cervical length and foetal growth can provide a better prediction of pregnancies at risk and better therapeutic care can be given, such as bed rest, corticosteroids and monitoring of the baby's heart beat. Furthermore, by identifying high-risk patients, this could enable new research for improved clinical management.

"Events and complications in early pregnancy are amongst the most common complications in women during their pregnancy and can be extremely distressing for them. For the clinician it is important to interpret the symptoms and to understand not only the short-term consequences, but also the long-term consequences of these early pregnancy complications. This is especially important for reassuring and supporting the couple at a difficult time.

"More large controlled studies, using local National Birth Registries, are needed to confirm our findings. In particular, larger studies concerning the risk of adverse late pregnancy outcome in women presenting with unexplained recurrent miscarriage, intrauterine haematoma and a smaller than expected foetus are needed."


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Single 'Spelling Mistake' In Genetic Code Can Lead To Rare And Untreatable Form Of Ovarian Cancer
Eureka! Vancouver scientists from the Ovarian Cancer Research (OvCaRe) Program at BC Cancer Agency and Vancouver Coastal Health Research Institute have discovered that there appears to be a single spelling mistake in the genetic code of granulosa cell tumours, a rare and often untreatable form of ovarian cancer

This means that out of the three billion nucleotide pairs that make up the genetic code of the tumour, one – the same one in every tumour sample – is incorrect.

The discovery, published online June 10th in the New England Journal of Medicine, marks the beginning of a new era of cancer genomics, where the complete genetic sequence of cancers can be unravelled and the mutations that cause them exposed. For women with granulosa cell tumours it represents the first specific diagnostic tool and clear path to develop much needed treatments for this cancer.

"This is really a two-fold discovery," says Dr. David Hunstman, lead author and genetic pathologist at the BC Cancer Agency and Vancouver General Hospital and associate professor in the Department of Pathology and Laboratory Medicine at the University of British Columbia. "It clearly shows the power of the new generation of DNA sequencing technologies to impact clinical medicine, and for those of us in the area of ovarian cancer research and care, by identifying the singular mutation that causes granulosa cell tumours, we can now more easily identify them and develop news ways to treat them."

In the past when scientists wanted to look at the sequence of a tumour, it was a laborious process, with each gene individually decoded into thousands of nucleotides and all data accumulated and sorted. Most studies could only look at one or at most a few of the 20,000 genes in the human genome whereas the new sequencing technologies allow scientists to look at everything at once. Through a collaboration between OvCaRe and the BC Cancer Agency's Genome Sciences Centre, the research team used "next generation" sequencing machines that are able to decode billions of nucleotides at rapid speed and new computer techniques to quickly assemble the data. "This task would have been unfathomable in terms of both cost and complexity even two years ago," says Dr. Marco Marra, Director of the BC Cancer Agency's Genome Sciences Centre.

The OvCaRe team decoded four tumour samples of the relatively rare granulosa cell tumour, which affects five percent of ovarian cancer patients. Using the new sequencing technology and bioinformatics, they discovered a single nucleotide located in the FOXL2 gene was mutated in every sample. The research team further validated their work by examining a large number of additional tumour samples from across Canada and around the world, and are satisfied they have been able to validate that this mutation is present in almost all granulosa cell tumours and not in unrelated cancers. Most types of cancers, including ovarian cancers, have a broad range of genetic abnormalities. This finding shows that granulosa cell tumours have a characteristic single DNA spelling mistake that can serve as an easy to read identity tag for this cancer type.

"Although it has been suggested that hundreds of any cancer type would have to be sequenced at great depth to make clinically useful discoveries," says Huntsman, "we had hypothesized that knowledge could be gained from much smaller studies if the cancers were carefully selected and represented clinically homogenous diseases. There are many rarer cancer types, like granulosa cell tumours that fit that bill and based upon our success in decoding granulosa cell tumours we are focusing on other rare tumours in what could be described as a guerrilla war on cancer. We hope that these studies will not only help future patients with rare tumours but will also teach us about more common ones as well."

"This cancer is unique," says Dr. Dianne Miller, gynecologic oncologist at BC Cancer Agency and Vancouver General Hospital. "For patients with this tumour type, it means they should all have the same response to the same treatment. And now that we have this pathway, we can look for existing cancer drugs that might work on this particular gene mutation to make the cancer disappear."

The OvCaRe team was able to make this discovery because of the multidisciplinary nature of the group, which crosses two provincial health authorities and is made up of gynaecologists, pathologists, bioinformatics specialists, and oncologists. Further enhancing the team's success is the centralization of patient treatment and record keeping.

"We are excited by this paper," says Dr. Michael Birrer, professor, Department of Medicine, Harvard Medical School and director GYN/Medical Oncology, Medicine, Massachusetts General Hospital. "The ovarian cancer research and care community now has new biologic insights into this poorly understood tumour and a potential therapeutic target. More importantly, this tour de force study reveals the power of genomic approaches to cancer, particularly rare tumours."

Ovarian cancer affects about one in 70 Canadian women. Approximately 2500 new cases are diagnosed each year and the five-year survival rate is only 30 per cent.

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Worldwide Increase in Assisted Reproduction
Assisted reproductive technology (ART) is responsible for an estimated 219,000 to 246,000 babies born each year worldwide according to an international study

The study also finds that the number of ART procedures is growing steadily: in just two years (from 2000 to 2002) ART activity increased by more than 25%.

The study, which is published online today (Thursday 28 May) in Europe’s leading reproductive medicine journal Human Reproduction [1], gives figures and estimates for the year 2002, the most recent year for which world figures are available. A total of 1563 clinics in 53 countries provided data for the report, but data were missing from several other countries, mostly in Asia, Africa, Oceania and the West Indies. The authors estimated that these missing countries probably performed between 10-20% of ART procedures, and they took this into account when they calculated the total number of ART babies born worldwide.

Professor Jacques de Mouzon, a specialist in public health at INSERM (Paris, France), led the International Committee for Monitoring Assisted Reproductive Technology (ICMART) that compiled the report. He said: “This is the eighth world report on ART produced by ICMART since 1989, and is useful because, even if it is imperfect, it gives data that can inform debate and decision-making on issues such as availability and the benefits and risks of this important medical practice. It allows us to make comparisons between countries and regions, and to analyse trends by comparing with previous reports.

“There are several important points to highlight. There has been a constant increase in ART activity: it increased by more than 25% in the two years since the previous report for the year 2000. This is due not only to an increase in the number of countries participating in this report but also to an increase in ART activity in most individual countries.

“However, there are wide variations between countries in the availability and quality of ART. There are several reasons for this, such as fertility rates, women’s age, insurance cover, the national economy, but the most important is certainly inequality in access to healthcare and ART. In Western Europe it is easier for people to access good healthcare, and funding for ART tends to be more generous than in developing countries. This raises the question of developing so called ‘low cost’ ART in low-income countries; it would probably mean lower success rates (the problem would be to define what rates would be acceptable), but greater access to treatment. In addition, treatment is usually more aggressive in developing countries and in all countries where ART is expensive for patients, leading to the consequent problems of multiple births, ovarian hyperstimulation syndrome and the need for foetal reductions.”

Availability of ART varied from two cycles per million inhabitants (Ecuador) to 3688 per million in Israel.

Other key findings from the study include:
1. A large increase in the use of ICSI (intracytoplasmic sperm injection) as opposed to conventional IVF (in vitro fertilisation) worldwide. Since 2000 it increased from 54% to 61% in North America, 46% to 54% in Europe, and in 2002 it had reached 76% in Latin America and more than 92% in the Middle East.
2. Pregnancy and delivery rates have increased for both fresh and frozen embryo cycles despite a decrease in the number of embryos transferred. More than 601,250 ART cycles worldwide resulted in delivery rates after IVF, ICSI and frozen embryo transfer (FET) of 22%, 21% and 15% respectively per aspiration (attempt at egg retrieval). This compares with delivery rates after IVF, ICSI and FET in 2000 of nearly 19%, 20% and 12% respectively.
3. When cycles using fresh embryos were combined with frozen embryo cycles, the cumulative delivery rate per aspiration was 26%.
4. Cumulative delivery rates per aspiration varied among countries, ranging from 14% to 39%. While Tunisia and Libya reported the highest rates at 39%, this represented only a few fertility centres in each country. Therefore, the USA, where reports cover almost all fertility centres in the country, had the highest rate at 37.5%.
5. The transfer of multiple embryos has decreased, leading to a small decline in multiple births. The percentage of four or more embryo transfers decreased from 15.4% in 2000 to 13.7% in 2002. The proportion of twin and triplet pregnancies decreased from 26.5% to 25.7%, and from 2.9% to 2.5% respectively.
6. There has been a 47% increase in the proportion of FET cycles, which is due mainly to the decrease in the number of embryos transferred at one time, with any left over being frozen for future attempts.
Prof de Mouzon said: “It is difficult to explain the reasons behind the increase in ICSI as we have no reason to believe there has been a similar increase in the rise in male infertility, and ICSI has not been demonstrated to improve treatment results for infertility that is not caused by infertile men. It could be because more infertile men are agreeing to seek treatment, that the diagnosis of male infertility is improving, that male infertility per se is increasing (due to exposure to sperm-damaging compounds in the environment), that fertility teams turn to ICSI more rapidly when conventional IVF fails, or that ICSI is still viewed as more efficient, even in the absence of scientific proof, which may be the major factor in Latin America and the Middle East. I suspect the overall explanation is probably a mixture of several of these factors.”

The increased use of frozen embryo cycles was very good news because it improved cumulative pregnancy and delivery rates and helped reduce the number of multiple embryo transfers and multiple births, he said.

“Our report shows that delivery rates per aspiration increased in 2002 even though the average number of embryos transferred was reduced. For example, in Australia where a mean average of 1.8 embryos were transferred, the delivery rate per aspiration was 19.5% for fresh cycles and 29.4% for fresh and frozen cycles together. This should encourage countries to implement embryo transfer policies that reduce the risk of multiple births,” said Prof de Mouzon.

The authors warn that variation in data quality, in addition to differences in practices, legislation, guidelines, culture and religion, means that comparisons between countries “must be done with caution”.



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Like Burrs on Your Clothes, Virus-Size Capsules Stick to Cells Targeting Drug Delivery
It is now possible to engineer tiny containers the size of a virus to deliver drugs and other materials with almost 100 percent efficiency to targeted cells in the bloodstream

According to a new Cornell study, the technique could one day be used to deliver vaccines, drugs or genetic material to treat cancer and blood and immunological disorders. The research is published online at the Web site of the journal Gene Therapy.

"This study greatly extends the range of therapies," said Michael King, Cornell associate professor of biomedical engineering, who co-authored the study with lead author Zhong Huang, a former Cornell research associate who is now an assistant professor at the Shenzhen University School of Medicine in China. "We can introduce just about any drug or genetic material that can be encapsulated, and it is delivered to any circulating cells that are specifically targeted," King added.

The technique involves filling the tiny lipid containers, or nanoscale capsules, with a molecular cargo and coating the capsules with adhesive proteins called selectins that specifically bind to target cells. A shunt coated with the capsules is then inserted between a vein and an artery. Much as burrs attach to clothing, the selectin-coated capsules adhere to targeted cells in the bloodstream. After rolling along the shunt wall, the cells break free from the wall with the capsules still attached and ingest their contents.

The technique mimics a natural immune response that occurs during inflammation, which stimulates cells on blood vessel walls to express selectins, which quickly form adhesive bonds with passing white blood cells. The white blood cells then stick to the selectins and roll along the vessel wall before leaving the bloodstream to fight disease or infection. Selectin proteins may be used to specifically target nucleated (cells with a nucleus) cells in the bloodstream.

The study shows that since only the targeted cells ingest the contents of the nanocapsules, the technique could greatly reduce the adverse side effects caused by some drugs.

In a previous paper, King showed how metastasizing cancer cells circulating in the blood stream can stick to selectin-coated devices containing a second protein that programs cancer cells to self-destruct.

Said King, "We've found a way to disable the function of cancer cells without compromising the immune system," which is a problem with many other therapies directed against metastasis.

The current study demonstrates that genetic material can be delivered to targeted cells to turn off specific genes and interfere with processes that lead to disease. The researchers filled nanocapsules with a small-interfering RNA (siRNA) and targeted them to specific circulating cells. When the targeted cells ingested the capsules, the siRNA turned off a gene that produces an enzyme that contributes to the degradation of cartilage in arthritis.

In a similar manner, the method could be used to target the delivery of chemotherapy drugs, vaccine antigens to white blood cells, specific molecules that mitigate auto-immune disorders and more, King said.















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