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Recipients of Hepatitis C Kidneys Disease-free After A Year of Posttransplant

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In a small study, doctors at Johns Hopkins have successfully transplanted 10 hepatitis C-infected kidneys into patients without hepatitis C and prevented the patients from becoming infected by hepatitis C. The success of these transplants could mean more organs being available for the nearly 100,000 people in the U.S. currently waiting for a kidney transplant.

“Right now, most of the usable organs from donors with hepatitis C are discarded because there are very few hepatitis C-positive recipients on the waiting list,” says Niraj Desai, M.D., an assistant professor of surgery at Johns Hopkins University School of Medicine and senior author of the new paper, published in Annals of Internal Medicine.

“Figuring out how to use these kidneys is a way to do more transplants and save more lives.”

Until recently, treating hepatitis C was difficult; treatment regiments often included weekly injections, led to serious side effects that not all patients could tolerate and didn’t cure all cases of the viral infection. That meant that organs — including kidneys — from hepatitis C-positive people were considered too high-risk to transplant into patients without the virus.

Around 500 hepatitis C-positive kidneys are discarded from organ donors in the U.S. every year, Desai says. And hundreds more may never make it to a recipient because some organ procurement organizations don’t procure the kidneys in the first place due to the lack of a suitable recipient.

In the past seven years, however, a handful of new direct-acting antivirals have hit the market; the drugs cure more than 95 percent of all hepatitis C cases and carry few side effects. Desai and his colleagues thought it was time to try taking advantage of the new drugs to pave the way for using hepatitis C-positive kidneys for transplants.

“In this era of organ shortages, it’s difficult to watch good organs get discarded,” says Christine Durand, M.D., an assistant professor of medicine at Johns Hopkins University School of Medicine.

“This was a great opportunity to take a neglected public health resource and put it to good use.”

Desai, Durand and their colleagues approached patients over age 50 who were awaiting kidney transplants, had no previous transplants and no available living donors, and were negative for hepatitis C as well as HIV and hepatitis B. Ten patients agreed to receive hepatitis C-positive kidneys. Their average age was 71 and they had been on the transplant waiting list an average of four months. All donor kidneys were recovered from donors aged 13 through 50, tested positive for hepatitis C and showed no evidence of kidney disease. The donors’ blood was tested for strain and quantity of hepatitis C virus.

Each recipient received a dose of grazoprevir/elbasvir, an oral combination pill, while they were waiting to go into the operating room for their transplant. Each recipient then continued taking a daily pill of grazoprevir/elbasvir for 12 weeks after transplantation. Three patients also took a daily dose of sofosbuvir due to the strain of hepatitis found in their donor organ.

In five of the kidney recipients, there was never any hepatitis C RNA detected in their blood. In the other patients, low levels of the virus were detected shortly after transplant but then became undetectable within days or a week. No recipients ever developed any clinical signs of chronic hepatitis C infection. In addition, the kidneys themselves functioned well. At the time of the study’s publication, all patients are at least a year out from their transplant and doing well, says Desai.

“This was an overwhelmingly positive study,” adds Durand.

The researchers would next like to see their results replicated in a larger, multicenter trial. They say if the success of the transplants continues, it could pave the way for other hepatitis C-positive organs, including hearts and livers, to be transplanted as well.

“We’re always trying to expand what we consider acceptable for an organ donor,” says Durand.

Due to the opioid epidemic and deaths from drug overdoses — many of which occur in hepatitis C-positive individuals — there are an increasing number of hepatitis C-positive organs available. Being able to use these organs for transplants could mean many hundreds of lives saved each year.

“These 10 kidneys we used are 10 kidneys that would not have been transplanted outside of this study,” says Desai.

“They would have been discarded.”

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Paternal Transmission Of Epigenetic Memory Via Sperm

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Studies of human populations and animal models suggest that a father’s experiences such as diet or environmental stress can influence the health and development of his descendants. How these effects are transmitted across generations, however, remains mysterious.

Susan Strome’s lab at UC Santa Cruz has been making steady progress in unraveling the mechanisms behind this phenomenon, using a tiny roundworm called Caenorhabditis elegans to show how marks on chromosomes that affect gene expression, called “epigenetic” marks, can be transmitted from parents to offspring. Her team’s most recent paper, published October 17 in Nature Communications, focuses on transmission of epigenetic marks by C. elegans sperm.

In addition to documenting the transmission of epigenetic memory by sperm, the new study shows that the epigenetic information delivered by sperm to the embryo is both necessary and sufficient to guide proper development of germ cells in the offspring (germ cells give rise to eggs and sperm).

“We decided to look at C. elegans because it is such a good model for asking epigenetic questions using powerful genetic approaches,” said Strome, a distinguished professor of molecular, cell, and developmental biology.

Epigenetic changes do not alter the DNA sequences of genes, but instead involve chemical modifications to either the DNA itself or the histone proteins with which DNA is packaged in the chromosomes. These modifications influence gene expression, turning genes on or off in different cells and at different stages of development. The idea that epigenetic modifications can cause changes in gene expression that are transmitted from one generation to the next, known as “transgenerational epigenetic inheritance,” is now the focus of intense scientific investigation.

For many years, it was thought that sperm do not retain any histone packaging and therefore could not transmit histone-based epigenetic information to offspring. Recent studies, however, have shown that about 10 percent of histone packaging is retained in both human and mouse sperm.

“Furthermore, where the chromosomes retain histone packaging of DNA is in developmentally important regions, so those findings raised awareness of the possibility that sperm may transmit important epigenetic information to embryos,” Strome said.

When her lab looked at C. elegans sperm, they found the sperm genome fully retains histone packaging. Other researchers had found the same is true for another commonly studied organism, the zebrafish.

“Like zebrafish, worms represent an extreme form of histone retention by sperm, which makes them a great system to see if this packaging really matters,” Strome said.

Her lab focused on a particular epigenetic mark (designated H3K27me3) that has been well established as a mark of repressed gene expression in a wide range of organisms. The researchers found that removing this mark from sperm chromosomes causes the majority of the offspring to be sterile. Having established that the mark is important, they wanted to see if it is sufficient to guide normal germline development.

The researchers addressed this by analyzing a mutant worm in which the chromosomes from sperm and egg are separated in the first cell division after fertilization, so that one cell of the embryo inherits only sperm chromosomes and the other cell inherits only egg chromosomes (normally, each cell of an embryo inherits chromosomes from both egg and sperm). This unusual chromosome segregation pattern allowed the researchers to generate worms whose germ line inherited only sperm chromosomes and therefore only sperm epigenetic marks. Those worms turned out to be fertile and to have normal gene expression patterns.

“These findings show that the DNA packaging in sperm is important, because offspring that did not inherit normal sperm epigenetic marks were sterile, and it is sufficient for normal germline development,” Strome said.

While the study shows that epigenetic information transmitted by sperm is important for normal development, it does not directly address how the life experience of a father can affect the health of his descendants. Strome’s lab is investigating this question with experiments in which worms are treated with alcohol or starved before reproducing.

“The goal is to analyze how the chromatin packaging changes in the parent,” she said.

“Whatever gets passed on to the offspring has to go through the germ cells. We want to know which cells experience the environmental factors, how they transmit that information to the germ cells, what changes in the germ cells, and how that impacts the offspring.”

By demonstrating the importance of epigenetic information carried by sperm, the current study establishes that if the environment experienced by the father changes the epigenetics of sperm chromosomes, it could affect the offspring.

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Father’s Nicotine Use Can Cause Cognitive Problems In Children And Grandchildren

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A father’s exposure to nicotine may cause cognitive deficits in his children and even grandchildren, according to a study in mice publishing on October 16 in the open-access journal PLOS Biology by Pradeep Bhide of Florida State University in Tallahassee and colleagues. The effect, which was not caused by direct secondhand exposure, may be due to epigenetic changes in key genes in the father’s sperm.

Exposure of mothers to nicotine and other components of cigarette smoke is recognized as a significant risk factor for behavioral disorders, including attention deficit hyperactivity disorder, (or ADHD) in multiple generations of descendants. Whether the same applies to fathers has been less clear, in part because in human studies it has been difficult to separate genetic factors (such as a genetic predisposition to ADHD) from environmental factors, such as direct exposure to cigarette smoke.

To overcome this difficulty, Deirdre McCarthy, Pradeep Bhide and colleagues exposed male mice to low-dose nicotine in their drinking water during the stage of life in which the mice produce sperm. They then bred these mice with females that had never been exposed to nicotine. While the fathers were behaviorally normal, both sexes of offspring displayed hyperactivity, attention deficit, and cognitive inflexibility. When female (but not male) mice from this generation were bred with nicotine-naïve mates, male offspring displayed fewer, but still significant, deficits in cognitive flexibility. Analysis of spermatozoa from the original nicotine-exposed males indicated that promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning, suggesting that these modifications likely contributed to the cognitive deficits in the descendants.

Nicotine and cigarette smoke have been previously shown to cause widespread epigenetic changes, Bhide said.

“The fact that men smoke more than women makes the effects in males especially important from a public health perspective. Our findings underscore the need for more research on the effects of smoking by the father, rather than just the mother, on the health of their children.”

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Nutrition Has A Greater Impact On Bone Strength Than Exercise

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ANN ARBOR—One question that scientists and fitness experts alike would love to answer is whether exercise or nutrition has a bigger positive impact on bone strength. University of Michigan researchers looked at mineral supplementation and exercise in mice, and found surprising results–nutrition has a greater impact on bone mass and strength than exercise. Further, even after the exercise training stopped, the mice retained bone strength gains as long as they ate a mineral-supplemented diet.

“The longer-term mineral-supplemented diet leads to not only increases in bone mass and strength, but the ability to maintain those increases even after detraining,” said David Kohn, a U-M professor in the schools of dentistry and engineering.

“This was done in mice, but if you think about the progression to humans, diet is easier for someone to carry on as they get older and stop exercising, rather than the continuation of exercise itself.”

The second important finding is that the diet alone has beneficial effects on bone, even without exercising. This surprised Kohn, who expected exercise with a normal diet to fuel greater gains in bone strength, but that wasn’t the case.

“The data suggests the long-term consumption of the mineral-supplemented diet could be beneficial in preventing the loss of bone and strength with age, even if you don’t do exercise training,” he said.

Combining the two amplifies the effect.

Most other studies look at effects of increasing dietary calcium, Kohn said. The U-M study increased calcium and phosphorous, and found benefits to increasing both.

This isn’t to suggest that people run out and buy calcium and phosphorus supplements, Kohn said. The findings don’t translate directly from mice to humans, but they do give researchers a conceptual place to start.

It’s known that humans achieve peak bone mass in their early 20s, and after that it declines. The question becomes how to maximize the amount of bone when young, so that when declines do begin, people start from a better position, Kohn said.

In addition to testing bone mass and strength, Kohn and colleagues performed a full battery of mechanical assessments on the bone, which is important because the amount of bone doesn’t always scale with or predict the mechanical quality of the tissue.

They tested the mice after eight weeks of training and supplemented diet or normal diet, and then after eight weeks of detraining.

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