Monthly Archives: March 2017

Heart inflammation, or myocarditis, is a disorder usually caused by an infection reaching the heart. Although the condition is rare, it can sometimes lead to dilated cardiomyopathy - a leading cause of heart failure in younger adults. New research helps to explain why this happens in some cases and not others, by examining an immune cell that appears to cause heart failure in mice.

Myocarditis occurs when an infection has reached the heart. During an infection, the body's immune system produces disease-fighting cells - but in heart inflammation, these cells enter the heart and can damage its muscle.

The condition is not often diagnosed; it rarely causes severe symptoms and detecting it requires a heart biopsy - a rather invasive procedure of moderate risk.

In some cases, myocarditis progresses into inflammatory dilated cardiomyopathy (DCMi) - a disorder in which the heart's muscle dilates, weakens, and can no longer properly pump blood. In the United States, DCMi is one of the leading causes of heart failure among younger adults, with a prevalence of between 300 and 400 patients per million U.S. adults.

New research, led by Dr. Daniela Cihakova from the Johns Hopkins University School of Medicine in Baltimore, MD - set out to understand why in some cases the heart heals from the inflammation, while in others it progresses into DCMi.

As the authors of the new paper mention, previous studies have pointed to the role of eosinophils - a specific type of immune cell - in the development of heart disease. As Dr. Cihakova explains, the new research "provide[s] more details about how these immune system cells may lead to deterioration of heart muscle function in mice in a way that lets us draw some parallels to human disease processes."

The findings were published in The Journal of Experimental Medicine.

Dr. Cihakova and colleagues genetically modified a group of mice to have a deficiency of eosinophils. They then induced myocarditis in this group, using a technique called experimental autoimmune myocarditis. In this procedure, mice receive a peptide from their heart muscle cells, which makes the body's immune system attack the heart.

The researchers also induced myocarditis in another group of normal mice, with a healthy level of eosinophils. After 21 days, the scientists measured the inflammation in the hearts of both groups of mice.

They also analyzed the hearts for fibrosis or scar tissue - both signs of dying heart muscles in mammals. Scar tissue is also present in cases of DCMi.

The scientists found similarly acute inflammation in both groups.

However, when the scientists examined the groups for signs of heart failure, they found drastic differences between the eosinophil-deficient group and the normal group.

The mice with normal levels of eosinophils went on to develop heart failure, whereas the mice with eosinophil deficiency displayed no signs of heart malfunction.

The team also found scar tissue in both groups to a similar degree. However, the normal mice had DCMi, while the eosinophil-deficient ones were not affected.

To see if they could replicate their findings, the team designed an additional experiment in which they genetically modified mice to have an excess of an eosinophil-producing protein called IL5.

The IL5-excessive mice developed more inflammation and more scar tissue in the heart's upper chambers (or atria) compared with normal mice.

Mice with excessive IL5 protein also had more heart-infiltrating cells. As much as 60 percent of these cells were eosinophils in the IL5-excessive mice, compared with only 3 percent in the normal mice.

Additionally, the researchers examined the mice's hearts 45 days after the experiment and found severe DCMi in the mice with too much IL5 protein.

Finally, to account for the possibility that it is the IL5 protein and not the eosinophils that drive DCMi development, the team genetically modified eosinophil-deficient mice to have an excess of the protein.

The researchers found no reduction in the heart function of these IL5-excessive, eosinophil-deficient mice, compared with normal mice. This confirms that it is the immune cells, not the protein, that causes DCMi.

In an attempt to understand exactly how eosinophils are responsible for DCMi, the researchers investigated further and managed to isolate a protein called IL4, which is produced by eosinophils.

Using yet another mouse model, Dr. Cihakova and team established that it is indeed the IL4 that facilitates the development of DCMi, and which is triggered by eosinophils.

"The take-home message is that inflammation severity does not necessarily determine long-term disease progression, but specific infiltrating cell types - eosinophils, in this case - do."

Dr. Daniela Cihakova

The study's senior author points out that their study is the first one to investigate the role of eosinophils in the onset of heart inflammation, and in its development from inflammation to DCMi.

Nicola Diny, a Ph.D. student in the Bloomberg School of Public Health and the study's first author, also comments on the findings:

"Our studies show that the presence of eosinophils in the heart makes mice more likely to get DCMi following myocarditis. And if there are a lot of eosinophils, the mice develop even more severe heart failure," Diny says. "It will be important to test if the same is true in patients. That way, we may be able to intervene early and prevent DCMi."

The researchers hope that their study will help to develop IL4-targeting medicines that could one day treat people with myocarditis, thus potentially halting its progression into DCMi.

Learn how marijuana use may temporarily weaken heart muscle.

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Immune cell may turn heart inflammation into heart failure - Medical News Today

The macula is the spot in the center of your eye's retina. When that tissue begins to thin and break down, this is referred to as macular degeneration, a blurring of the sharp central vision necessary for driving, reading and other close-up work. Most people develop this disease as they age.

For the latest study, researchers led by Dr. Michiko Mandai of the laboratory for retinal regeneration at RIKEN Center for Developmental Biology in Japan tested an experimental stem cell treatment on a 77-year-old woman diagnosed with "wet," or neovascular age-related, macular degeneration.

The "wet" form of the disease involves blood vessels positioned underneath the pigment epithelium (a layer of retinal cells) growing through the epithelium and harming the eye's photoreceptor cells. In Japan, wet age-related macular degeneration is the most common form, but in Caucasian populations, only about 10% of people with age-related macular degeneration gets that form.

The "dry" form involves the macula breaking down without growth of blood vessels where they're not supposed to be.

To stop the progress of wet macular degeneration, the researchers performed surgery to transplant a sheet of retinal pigment epithelial cells under the retina in one of the patient's eye.

The transplanted cells had been derived from autologous induced pluripotent stem cells, which are reprogrammed cells. They were created using cells from the connective tissue of the woman's skin.

One year after surgery, the transplanted sheet remained intact, and there was no evidence of lasting adverse effects. Although the patient showed no evidence of improved eyesight, her vision had stabilized.

"This research serves multiple purposes," wrote Peter Karagiannis, a science writer, in an email on behalf of Dr. Shinya Yamanaka, the Nobel Prize-winning co-author of the study and director of the Center for iPS Cell Research and Application at Kyoto University. From the patient's perspective, the study shows that induced pluripotent stem cells can alleviate the problems associated with age-related macular degeneration.

"From a greater medical perspective, however, the bigger impact is that it shows iPS cells can be used as cell therapies," the email said, adding that newly initiated stem cell research applications at the center include Parkinson's disease and thrombocytopenia, a lack of platelets in the blood.

The American story, like the Japanese story, begins with patients slowly losing their sight as a result of macular degeneration -- in this case, three women ages 72 to 88, two of whom had the "dry" form.

Each patient paid $5,000 for the procedure at an unnamed clinic in Florida, the authors noted. Some of the patients, including two of the three women described in the paper, learned of the so-called clinical trial on ClinicalTrials.gov, a registry database run by the US National Library of Medicine. However, the consent form and other written materials did not mention a trial.

The procedure took less than an hour and began with a standard blood draw and the removal of fat cells from each patient's abdomen. To obtain stem cells, the fat tissue was processed with enzymes, while platelet-dense plasma was isolated from the blood. The stem cells were mixed with the plasma and injected into both eyes.

Complications may have been caused by contamination during stem cell preparation, or the stem cells might have changed into myofibroblasts, a type of cell associated with scarring, after injection, the authors wrote.

Before the surgery, the women's vision ranged from 20/30 to 20/200. After treatment and complications, the patients were referred in June 2015 to two university-based ophthalmology practices, including the University of Miami, where lead author Dr. Ajay E. Kuriyan was practicing.

"Many stem-cell clinics are treating patients with little oversight and with no proof of efficacy," Kuriyan and his co-authors wrote in the paper, acknowledging that it is difficult for patients to know whether a stem cell therapy -- or a clinical trial -- is legitimate.

One red flag is that the patients were required to pay for their procedure; another is that both eyes were treated at once, the authors said. Legitimate clinical trials do not require payment, and for any experimental treatment of the eyes, a good doctor would observe how one eye responds before attempting the second eye.

Another problem for unsavvy patients: Listings on ClinicalTrials.gov are not fully scrutinized for scientific soundness, noted the authors.

Today, the clinic is no longer performing these eye injections, the authors said, but it is still seeing patients. In October 2015, months after the procedures had been performed, the Food and Drug Administration released more specific guidelines for stem cell treatments.

Writing on behalf of the FDA in an editorial alongside the paper, Drs. Peter W. Marks, Celia M. Witten and Robert M. Califf say there's an absence of compelling evidence, yet some practitioners argue that stem cells have a unique capacity to restore health because of their ability to differentiate into whatever cell is necessary for repairing a defect. Another argument is that clinical trials are too complex for all except large industrial sponsors.

Despite the shadow cast by some stem cell experiments, the Japanese study earned praise from the scientific community.

Michael P. Yaffe, vice president of scientific programs at the New York Stem Cell Foundation Research Institute, said the RIKEN study was "incredibly thorough, careful and well-documented."

"Many experts in the field of regenerative medicine believe that the treatment of macular degeneration and other retinal diseases will be among the first areas of success in the use of stem cell-derived tissues," said Yaffe, whose foundation was not involved in the RIKEN study.

Yaffe said this optimism stems from preliminary studies using retinal cells derived from stem cells in animals. Scientists are also hopeful because the procedures to generate pure cells of the correct type and surgical techniques necessary for transplantation have already been developed.

"A number of research groups are moving toward developing stem cell-based treatments for age-related macular degeneration and other retinal diseases," Yaffe said.

The National Eye Institute at the National Institutes of Health is planning a similar study using patient-specific pluripotent stem cells, according to Kapil Bharti, a Stadtman Investigator in the Unit on Ocular Stem Cell & Translational Research at the institute. After getting approval to conduct a phase I safety trial, the institute will treat 10 to 12 patients to check safety and tolerability of stem cell-based eye tissue transplants.

"Data from 10 to 12 patients is needed to show that the implanted cells are indeed safe," he said, adding that the trial is likely to begin in 2018.

"While researchers have used embryonic stem cell derived cells to treat age-related macular degeneration, (the RIKEN study) is the first study that used induced pluripotent stem cells," said Bharti, who was not involved in the research.

Both induced pluripotent stem cells and embryonic stem cells can be used to make other kinds of cells of the body, explained Bharti. However, induced pluripotent stem cells can be derived from adult skin or blood cells, rather than from embryos.

"Another big scientific advantage with induced pluripotent stem cells is that they can be made patient-specific (because it's the patient's own cells), reducing the chances of tissue rejection," he said.

P. Michael Iuvone, a professor of ophthalmology and director of vision research at Emory University School of Medicine, also noted the importance of using the patient's own stem cells.

Past studies have used embryonic stem cells to treat age-related macular degeneration, but there were problems related to rejection, when the body refuses to accept a transplant or graft, explained Iuvone, who was not involved in the latest study. In the new RIKEN study, the researchers took the patient's own cells and converted them into retinal cells to avoid these complications.

"The results from the standpoint of the graft taking and surviving without any signs of any kind of toxicity or tumorigenicity are very positive," Iuvone said. "But the weakness is, they only had one patient, and it's very difficult to make any conclusions from one patient."

He noted that the RIKEN researchers planned to work with more patients, but in 2014, the Japanese government passed a law that said regenerative medicine clinical trials could be performed only at medical institutions, not at research institutions such as RIKEN.

Though the experiment was performed on a woman with wet age-related macular degeneration, it also might be useful for "dry" age-related macular degeneration, which is more common in the United States, according to Iuvone.

Currently, there are some effective treatments for age-related macular degeneration.

"The standard of care in most cases is to give injections of drugs that inhibit the growth hormones that is called vascular epithelial growth factor, or VEGF," Iuvone said. "For most people, it at least slows the progression and in some cases actually improves visual acuity."

Laser treatments have also been used but are on the decrease because of side effects. "Given the fact that the VEGF treatments seem to be effective, I think that most clinicians have turned to that," Iuvone said.

Bharti believes the RIKEN study is a major milestone in the field. "We and others are learning from the Japan study," he said.

Susan L. Solomon, CEO of the New York Stem Cell Foundation Research Institute, agrees.

"This study represents a fundamental advance in regenerative medicine, in the use of stem cell-derived tissues and in the treatment of eye disease," she said. However, additional work and many more studies are needed, she said, before a safe and efficacious stem cell-based treatment will be available "to the broad and growing population with retinal disease" -- all of us, growing older.

Originally posted here:
One stem cell treatment stabilizes macular degeneration, another blinds 3 patients - CNN

March 17, 2017 A UT Southwestern study determined that the metabolite uridine helps the body regulate glucose. This graphic depicts how the bodys fat cell-liver-uridine axis works to maintain energy balance. Credit: UT Southwestern Medical Center

How do mammals keep two biologically crucial metabolites in balance during times when they are feeding, sleeping, and fasting? The answer may require rewriting some textbooks.

In a study published today in Science, UT Southwestern Medical Center researchers report that fat cells "have the liver's back," so to speak, to maintain tight regulation of glucose (blood sugar) and uridine, a metabolite the body uses in a range of fundamental processes such as building RNA molecules, properly making proteins, and storing glucose as energy reserves. Their study may have implications for several diseases, including diabetes, cancer, and neurological disorders.

Metabolites are substances produced by a metabolic process, such as glucose generated in the metabolism of complex sugars and starches, or amino acids used in the biosynthesis of proteins.

"Like glucose, every cell in the body needs uridine to stay alive. Glucose is needed for energy, particularly in the brain's neurons. Uridine is a basic building block for a lot of things inside the cell," said Dr. Philipp Scherer, senior author of the study and Director of UT Southwestern's Touchstone Center for Diabetes Research.

"Biology textbooks indicate that the liver produces uridine for the circulatory system," said Dr. Scherer, also Professor of Internal Medicine and Cell Biology. "But what we found is that the liver serves as the primary producer of this metabolite only in the fed state. In the fasted state, the body's fat cells take over the production of uridine."

Basically, this method of uridine production can be viewed as a division of labor. Researchers found that during fasting, the liver is busy producing glucose and so fat cells take over the role of producing uridine for the bloodstream. These findings were replicated in human, mouse, and rat studies.

Although uridine has many roles, this study is the first to report that fat cells produce plasma uridine during fasting and that a fat cell-liver-uridine axis regulates the body's energy balance.

Study lead author Dr. Yingfeng Deng, Assistant Professor of Internal Medicine, found that blood uridine levels go up during fasting and down when feeding. During feeding, the liver reduces uridine levels by secreting uridine into bile, which is transferred to the gallbladder and then sent to the gut, where it helps in the absorption of nutrients.

"It turns out that having uridine in your gut helps you absorb glucose; therefore uridine helps in glucose regulation," Dr. Scherer said.

The uridine in the blood works through the hypothalamus in the brain to affect another tightly regulated system body temperature, Dr. Scherer added. It appears that only uridine made by fat cells reduces body temperature, he said.

Among the study's other key findings:

Blood uridine levels are elevated during fasting and drop rapidly during feeding. Excess uridine is released through the bile.

The liver is the predominant uridine biosynthesis organ, contributing to blood uridine levels in the fed state.

The fat cells dominate uridine biosynthesis and blood levels in the fasted state.

The fasting-induced rise in uridine is linked to a drop in core body temperature driven by a reduction in the metabolic rate.

In dietary studies, the researchers found that prolonged exposure to a high-fat diet blunted the effects of fasting on lowering body temperature, an effect also associated with obesity. Further testing indicated those findings were due to the reduced elevation in uridine in response to fasting, said Dr. Deng, also a member of the Touchstone Diabetes Center.

Future research questions include studying the effects of feeding-induced reductions in uridine levels in organs that rely heavily on uridine from plasma, such as the heart, and whether bariatric surgery affects blood uridine levels.

"Our studies reveal a direct link between temperature regulation and metabolism, indicating that a uridine-centered model of energy balance may pave the way for future studies on uridine balance and how this process is dysregulated in the diabetic state," Dr. Scherer said.

Explore further: Size matters when it comes to keeping blood sugar levels in check

More information: Yingfeng Deng et al. An adipo-biliary-uridine axis that regulates energy homeostasis, Science (2017). DOI: 10.1126/science.aaf5375

How do mammals keep two biologically crucial metabolites in balance during times when they are feeding, sleeping, and fasting? The answer may require rewriting some textbooks.

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Fat cells step in to help liver during fasting - Medical Xpress

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