Folate and vitamin B12 reduce disabling schizophrenia symptoms in some patients

Contact: Kristen Stanton kstanton3@partners.org 617-643-3907 Massachusetts General Hospital

Adding supplements to antipsychotic medication alleviated negative symptoms in patients with specific gene variants

Adding the dietary supplements folate and vitamin B12 to treatment with antipsychotic medication improved a core symptom component of schizophrenia in a study of more than 100 patients. The study focused on negative symptoms of schizophrenia – which include apathy, social withdrawal, and a lack of emotional expressiveness. While the level of improvement across all participants was modest, results were more significant in individuals carrying specific variants in genes involved with folate metabolism. The report from a team based at Massachusetts General Hospital (MGH) will appear in the journal JAMA Psychiatry (formerly Archives of General Psychiatry) and has been issued online.

“The symptoms of schizophrenia are complex, and antipsychotic medications provide no relief for some of the most disabling parts of the illness. These include negative symptoms, which can be particularly devastating,” says Joshua Roffman, MD, MMSc, of the MGH Department of Psychiatry, corresponding author of the JAMA Psychiatry paper. “Our finding that folate plus vitamin B12 supplementation can improve negative symptoms opens a new potential avenue for treatment of schizophrenia. Because treatment effects differed based on which genetic variants were present in each participant, the results also support a personalized medical approach to treating schizophrenia.”

An essential nutrient, folate (or folic acid) is required for the synthesis of DNA and neurotransmitters and plays a role in the control of gene expression. Adequate folate intake during pregnancy can reduce the risk of birth defects – in particular neural tube defects – and studies have suggested that folate deficiency during pregnancy significantly increases the risk of schizophrenia among offspring. Earlier research by members of the MGH-based team associated low blood folate levels with more severe negative symptoms among patients with schizophrenia.

The current study was designed specifically to investigate whether supplementation with folate and B12 – which can magnify the effects of folate – reduced negative symptoms of schizophrenia. A 2011 pilot study found symptom improvement only among patients carrying a variant in a folate-pathway gene called MTHFR that reduced the gene’s activity. To get a clearer picture of folate’s effect on negative symptoms, the current study enrolled 140 patients with schizophrenia at community mental health centers in Boston, Rochester, N.Y., and Grand Rapids, Mich.

Participants were all taking antipsychotic medications – which have been shown to alleviate positive symptoms, such as hallucinations and delusions, but not negative symptoms – and were randomized to receive daily doses of either folate and vitamin B12 or a placebo for 16 weeks. Every two weeks their medical and psychiatric status was evaluated, using standard symptom assessment tools along with measurements of blood levels of folate and homocysteine, an amino acid that tends to rise when folate levels drop. Nutritional information was compiled to account for differences in dietary intake of the nutrients. Participants’ blood samples were analyzed to determine the variants they carried of MTHFR and three other folate-pathway genes previously associated with the severity of negative symptoms of schizophrenia.

Among all 140 participants in the study protocol, those receiving folate and vitamin B12 showed improvement in negative symptoms, but the degree of improvement was not statistically significant compared with the placebo group. But when the analysis accounted for the variants in the genes of interest, intake of the two nutrients did provide significant improvement in negative symptoms, chiefly reflecting the effects of specific variants in MTHFR and in a gene called FOLH1. Variants in the other two genes studied did not appear to have an effect on treatment outcome.

While a low-functioning variant in FOLH1 had been associated with more severe negative symptoms in previous research, in this study it was the high-functioning FOLH1 variant that predicted a better treatment outcome. Measurement of participants’ blood folate levels throughout the study provided an explanation for this unexpected finding. Those with the low-functioning FOLH1 variant started the trial with substantially lower folate levels, suggesting a problem with folate absorption. Although supplementation enabled their blood folate levels to eventually catch up with those of participants with the high-functioning variant, it was probably too late to produce symptom improvement during the 16-week trial period.

“For participants who did show a benefit, it took the full 16 weeks of treatment for that benefit to appear,” Roffman explains. “While we don’t know why this is the case, changes in gene expression – which take time – are a likely explanation. Folate plays a critical role in DNA methylation, which regulates gene expression, so it’s plausible that its effects on negative symptoms act through gene expression changes. Participants with the low-functioning FOLH1 variant might eventually show a benefit of folate supplementation if treated for a longer period of time, but that needs to be investigated in future studies.”

He adds that, while the benefits of supplementation for the overall group were modest, the lack of effective treatment for negative symptoms and the safety of folate and vitamin B12 supplementation support the need for larger-scale trials. In addition, the impact of genotype on this study’s results suggests the need to investigate the role of folate pathway variants in conditions such as dementia and cardiovascular disease, in which low folate appears to increase risk but supplementation trials have had inconclusive results.

“We are now conducting a clinical trial of 1-methylfolate, which bypasses some of these folate-pathway enzymes and might have greater efficiency among individuals with low-functioning variants,” explains Roffman, an assistant professor of Psychiatry at Harvard Medical School. “Understanding more about the basic neural mechanisms of folate in patients with schizophrenia could help us generate more targeted and effective interventions to reduce and possibly even prevent symptoms.”

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The senior author of the JAMA Psychiatry report is Donald Goff, MD, formerly of MGH Psychiatry and now at the Nathan Kline Institute and New York University School of Medicine. Additional co-authors are Gail Galendez, Lisa Raeke, Noah Silverstein, Jordan Smoller, MD, ScD, and Michelle Hill, MD, MGH Psychiatry; Eric Macklin, PhD, MGH Biostatistics Center; Steven Lamberti, MD, University of Rochester Medical Center; and Eric Achtyes, MD, MS, Michigan State University College of Human Medicine. The study was supported primarily by National Institute of Mental Health grant R01MH070831.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $775 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2012, MGH moved into the number one spot on the 2012-13 U.S. News & World Report list of “America’s Best Hospitals.”

Common food dye may hold promise in treating spinal cord injury: stops the cascade of molecular events that cause secondary damage to the spinal cord

2009 study posted for filing

Contact: Mark Michaud
mark_michaud@urmc.rochester.edu
585-273-4790
University of Rochester Medical Center

A common food additive that gives M&Ms and Gatorade their blue tint may offer promise for preventing the additional – and serious – secondary damage that immediately follows a traumatic injury to the spinal cord. In an article published online today in the Proceedings of the National Academy of Sciences, researchers report that the compound Brilliant Blue G (BBG) stops the cascade of molecular events that cause secondary damage to the spinal cord in the hours following a spinal cord injury, an injury known to expand the injured area in the spinal cord and permanently worsen the paralysis for patients.

This research builds on landmark laboratory findings first reported five years ago by researchers at the University of Rochester Medical Center. In the August 2004 cover story of Nature Medicine, scientists detailed how ATP, the vital energy source that keeps our body’s cells alive, quickly pours into the area surrounding a spinal cord injury shortly after it occurs, and paradoxically kills off what are otherwise healthy and uninjured cells.

This surprising discovery marked a milestone in establishing how secondary injury occurs in spinal cord patients. It also laid out a potential way to stop secondary spinal injury, by using oxidized ATP, a compound known to block ATP’s effects. Rats with damaged spinal cords who received an injection of oxidized ATP were shown to recover much of their limb function, to the point of being able to walk again, ambulating effectively if not gracefully.

Now, scientists detail the clearing of yet another hurdle in moving this research closer from bench to bedside by successfully identifying a compound that could be administered systemically to achieve the same benefit. Previously, the team needed to inject a compound directly into the injured spinal cord area to achieve its results.

“While we achieved great results when oxidized ATP was injected directly into the spinal cord, this method would not be practical for use with spinal cord-injured patients,” said lead researcher Maiken Nedergaard, M.D., D.M.Sc., professor of Neurosurgery and director of the Center for Translational Neuromedicine at the University of Rochester Medical Center. “First, no one wants to put a needle into a spinal cord that has just been severely injured, so we knew we needed to find another way to quickly deliver an agent that would stop ATP from killing healthy motor neurons. Second, the compound we initially used, oxidized ATP, cannot be injected into the bloodstream because of its dangerous side effects.”

Nedergaard cautions that while this body of work offers a promising new way of treating spinal cord injury, it is still years away from possible application in patients. In addition, any potential treatments would only be helpful to people who have just suffered a spinal cord injury, not for patients whose injury is more than a day old. Just as clot-busting agents can help patients who have had a stroke or heart attack who get to an emergency room within a few hours, so a compound that could stem the damage from ATP might help patients who have had a spinal cord injury and are treated immediately.

Too Much of a Good Thing

While ATP is usually considered to be helpful to our bodies – after all, it’s the main source of energy for all of our body’s cells – Nedergaard was the first to uncover its darker side in the spinal cord. Immediately after a spinal cord injury occurs, ATP surges to the damaged area, at levels hundreds of times higher than normal. It is this glut of ATP that over-stimulates neurons and causes them to die from metabolic stress.

Neurons in the spinal cord are so susceptible to ATP because of a molecule known as “the death receptor.” Scientists know that the receptor – called P2X7 – plays a role in regulating the deaths of immune cells such as macrophages, but in 2004, Nedergaard’s team discovered that P2X7 also is carried in abundance by neurons in the spinal cord. P2X7 allows ATP to latch onto motor neurons and send them the flood of signals that cause their deaths, worsening the spinal cord injury and resulting paralysis.

So the team set its sights on finding a compound that not only would prevent ATP from attaching to P2X7, but could be delivered intravenously. In a fluke, Nedergaard discovered that BBG, a known P2X7R antagonist, is both structurally and functionally equivalent to the commonly used FD&C blue dye No. 1. Approved by the Food and Drug Administration as a food additive in 1982, more than 1 million pounds of this dye are consumed yearly in the U.S.; each day, the average American ingests 16 mgs. of FD&C blue dye No. 1.

“Because BBG is so similar to this commonly used blue food dye, we felt that if it had the same potency in stopping the secondary injury as oxidized ATP, but with none of its side effects, then it might be great potential treatment for cord injury,” Nedergaard said.

The team was not disappointed. An intravenous injection of BBG proved to significantly reduce secondary injury in spinal cord-injured rats, who improved to the point of being able to walk, though with a limp. Rats that had not received the BBG solution never regained the ability to walk. There was one side effect: Rats who were injected with BBG temporarily had a blue tinge to their skin.

Nedergaard’s long-time collaborator on this and other projects, chair of the University of Rochester Department of Neurology Steven Goldman, M.D., Ph.D., adds, “We have no effective treatment now for patients who have an acute spinal cord injury. Our hope is that this work will lead to a practical, safe agent that can be given to patients shortly after injury, for the purpose of decreasing the secondary damage that we have to otherwise expect.”

Nedergaard and Goldman believe that further laboratory testing will be needed to test the safety of BBG and related agents before human clinical trials could begin. Nonetheless, the investigators are optimistic that with sufficient study, strategies like this could yield new treatments for acute spinal cord injuries within the next several years.

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Other authors from the University of Rochester Medical Center include Weiguo Peng, Maria L. Cotrina, Xiaoning Han, Hongmei Yu, Lane Bekar, Livnat Blum, Takahiro Takano, and Guo-Feng Tia.

The research was supported by the New York State Spinal Cord Injury program, the Miriam and Sheldon Adelson Medical Research Foundation, and grants from the National Institutes of Health.

Dioxins in Food Chain Linked to Breastfeeding Ills

2009 study posted for filing

Exposure to dioxins during pregnancy harms the cells in rapidly-changing breast tissue, which may explain why some women have trouble breastfeeding or don’t produce enough milk, according to a University of Rochester Medical Center study.

Researchers believe their findings, although only demonstrated in mice at this point, begin to address an area of health that impacts millions of women but has received little attention in the laboratory, said corresponding author B. Paige Lawrence, Ph.D., associate professor of Environmental Medicine and of Microbiology and Immunology at URMC.

“Estimates are that three to six million mothers worldwide are either unable to initiate breastfeeding or are unable to produce enough milk to nourish their infants,” Lawrence said. “But the cause of this problem is unclear, though it has been suggested that environmental contaminants might play a role. We showed definitively that a known and abundant pollutant has an adverse effect on the way mammary glands develop during pregnancy.”

Dioxins are generated mostly by the incineration of municipal and medical waste, especially certain plastics. Most people are exposed through diet. Dioxins get into the food supply when air emissions settle on farm fields and where livestock graze. Fish also ingest dioxins and related pollutants from contaminated waters. When humans take in dioxin – most often through meat, dairy products, fish and shellfish – the toxin settles in fatty tissues; natural elimination takes place very slowly. The typical human exposure is a daily low dose, which has been linked to possible impairment of the immune system and developing organs.

In 2004 Lawrence’s laboratory made the novel discovery that dioxin impairs the normal development of mammary glands during pregnancy. However, the underlying mechanisms were unclear, as was the extent of injury and whether exposure during certain stages of pregnancy had more or less of an impact on milk production.

This week, in an online report in Toxicological Sciences, researchers showed that dioxin has a profound effect on breast tissue by causing mammary cells to stop their natural cycle of proliferation as early as six days into pregnancy, and lasting through mid-pregnancy. In tissue samples from mice, exposure to dioxin caused a 50-percent decrease in new epithelial cells. This is important, Lawrence said, because mammary glands have a high rate of cell proliferation, especially during early to mid-pregnancy when the most rapid development of the mammary gland occurs.

Researchers also found that dioxin altered the induction of milk-producing genes, which occurs around the ninth day of pregnancy, and decreased the number of ductal branches and mature lobules in the mammary tissue.

The timing of dioxin exposure also seemed to be significant, the study noted. For example, when exposure occurs very early in pregnancy but not later, lab experiments showed that sometimes the mammary glands can partially recover from the cellular injury. However, although it is important to understand timing of exposure for research purposes, it is irrelevant for humans, who cannot really control their exposure to dioxins, Lawrence said.

“Our goal is not to find a safe window of exposure for humans, but to better understand how dioxins affect our health,” she said. “The best thing people who are concerned about this can do is think about what you eat and where your food comes from. We’re not suggesting that we all become vegans — but we hope this study raises awareness about how our food sources can increase the burden of pollutants in the body. Unfortunately, we have very little control over this, except perhaps through the legislative process.”

Much of Lawrence’s research focuses on a transcription factor known as aryl hydrocarbon receptor, or AhR.When pollutants enter the body they bind to AhR, which then turns on certain genes responsible for detoxification. By using dioxin to activate AhR, researchers have learned that dioxin impairs the ability to fight off infection. The link between dioxin and the immune system is still being studied, but meanwhile researchers looked further at the mammary tissue after observing coincidentally that cells involved in milk production were sustaining so much damage that rodents could not nourish their offspring.

The next step is to understand what controls the differentiation process. An important question to answer, Lawrence said, is whether the toxic harm is occurring directly in the breast, or if it occurs throughout the entire body but has a unique manifestation in the fatty mammary tissue.

The URMC research group is also studying a possible connection between dioxin and breast cancer.Their hypothesis is that dioxin exposure in some people might cancel the general protection that pregnancy has on breast tissue against breast cancer.

The research was supported by grants from the National Institutes of Health and the URMC Environmental Health Sciences Center, as well as the Art BeCAUSE Foundation of Boston, which funds breast-cancer related research.

New study proves that pain is not a symptom of arthritis, pain causes arthritis

2008 study posted for filing

Contact: Greg Williams
Greg_Williams@urmc.rochester.edu
585-273-1757
University of Rochester Medical Center

New treatments will seek to interrupt ‘crosstalk’ between joints and the spinal cord

Pain is more than a symptom of osteoarthritis, it is an inherent and damaging part of the disease itself, according to a study published today in journal Arthritis and Rheumatism. More specifically, the study revealed that pain signals originating in arthritic joints, and the biochemical processing of those signals as they reach the spinal cord, worsen and expand arthritis. In addition, researchers found that nerve pathways carrying pain signals transfer inflammation from arthritic joints to the spine and back again, causing disease at both ends.

Technically, pain is a patient’s conscious realization of discomfort. Before that can happen, however, information must be carried along nerve cell pathways from say an injured knee to the pain processing centers in dorsal horns of the spinal cord, a process called nociception. The current study provides strong evidence that two-way, nociceptive “crosstalk” may first enable joint arthritis to transmit inflammation into the spinal cord and brain, and then to spread through the central nervous system (CNS) from one joint to another.

Furthermore, if joint arthritis can cause neuro-inflammation, it could have a role in conditions like Alzheimer’s disease, dementia and multiple sclerosis. Armed with the results, researchers have identified likely drug targets that could interfere with key inflammatory receptors on sensory nerve cells as a new way to treat osteoarthritis (OA), which destroys joint cartilage in 21 million Americans. The most common form of arthritis, OA eventually brings deformity and severe pain as patients loose the protective cushion between bones in weight-bearing joints like knees and hips.

“Until relatively recently, osteoarthritis was believed to be due solely to wear and tear, and inevitable part of aging,” said Stephanos Kyrkanides, D.D.S., Ph.D., associate professor of Dentistry at the University of Rochester Medical Center. “Recent studies have revealed, however, that specific biochemical changes contribute to the disease, changes that might be reversed by precision-designed drugs. Our study provides the first solid proof that some of those changes are related to pain processing, and suggests the mechanisms behind the effect,” said Kyrkanides, whose work on genetics in dentistry led to broader applications. The common ground between arthritis and dentistry: the jaw joint is a common site of arthritic pain.

Study Details

Past studies have shown that specific nerve pathways along which pain signals travel repeatedly become more sensitive to pain signals with each use. This may be a part of ancient survival skill (if that hurt once, don’t do it again). Secondly, pain has long been associated with inflammation (swelling and fever).

In fact, past research has shown that the same chemicals that cause inflammation also cause the sensation of pain and hyper-sensitivity to pain if injected. Kyrkanides’ work centers around one such pro-inflammatory, signaling chemical called Interleukin 1-beta (IL-1β), which helps to ramp up the bodies attack on an infection.

Specifically, Kyrkanides’ team genetically engineered a mouse where they could turn up on command the production of IL-1β in the jaw joint, a common site of arthritis. Experiments showed for the first time that turning up IL-1β in a peripheral joint caused higher levels of IL-1β to be produced in the dorsal horns of the spinal cord as well.

Using a second, even more elaborately engineered mouse model, the team also demonstrated for the first time that creating higher levels of IL-1β in cells called astrocytes in the spinal cord caused more osteoarthritic symptoms in joints. Past studies had shown astrocytes, non-nerve cells (glia) in the central nervous system that provide support for the spinal cord and brain, also serve as the immune cells of CNS organs. Among other things, they release cytokines like IL-1β to fight disease when triggered. The same cytokines released from CNS glia may also be released from neurons in joints, possibly explaining how crosstalk carries pain, inflammation and hyper-sensitivity back and forth.

In both mouse models, experimental techniques that shut down IL-1β signaling reversed the crosstalk effects. Specifically, researchers used a molecule, IL-1RA, known to inhibit the ability of IL-1β to link up with its receptors on nerve cells. Existing drugs (e.g. Kineret® (anakinra), made by Amgen and indicated for rheumatoid arthritis) act like IL-1RA to block the ability IL-1β to send a pain signal through its specific nerve cell receptor, and Kyrkanides’ group is exploring a new use for them as osteoarthritis treatment.

The implications of this process go further, however, because the cells surrounding sensory nerve cell pathways too can be affected by crosstalk. If 10 astrocytes secrete IL-1β in response to a pain impulse, Kyrkanides said, perhaps 1,000 adjacent cells will be affected, greatly expanding the field of inflammation. Spinal cord astrocytes are surrounded by sensory nerve cells that connect to other areas of the periphery, further expanding the effect. According to Kyrkanides’ model, increased inflammation by in the central nervous system can then send signals back down the nerve pathways to the joints, causing the release of inflammatory factors there.

Among the proposed, inflammatory factors is calcitonin gene related peptide (CGRP). The team observed higher levels calcitonin-gene related peptide (CGRP) production in primary sensory fibers in the same regions where IL-1β levels rose, and the release of IL-1β by sensory neurons may cause the release of CGRP in joints. Past studies in Kyrkanides reveal that CGRP can also cause cartilage-producing cells (chondrocytes) to mature too quickly and die, a hallmark of osteoarthritis.

Joining Kyrkanides in the publication from the University of Rochester School of Medicine and Dentistry were co-authors M. Kerry O’Banion, M.D., Ph.D., Ross Tallents, D.D.S., J. Edward Puzas, Ph.D. and Sabine M. Brouxhon, M.D. Paolo Fiorentino was a student contributor and Jennie Miller was involved as Kyrkanides’ technical associate. Maria Piancino, led a collaborative effort at the University of Torino, Italy. This work was supported in part by grants from the National Institutes of Health.

“Our study results confirm that joints can export inflammation in the form of higher IL-1β along sensory nerve pathways to the spinal cord, and that higher IL-1β inflammation in the spinal cord is sufficient in itself to create osteoarthritis in peripheral joints,” Kyrkanides said. “We believe this to be a vitally important process contributing to orthopaedic and neurological diseases in which inflammation is a factor.”

Nutrient in Eggs and Meat May Influence Gene Expression from Infancy to Adulthood: Choline

 

 

Implications for Wide Range of Disorders – Hypertension to Mental Health Problems

 

September 20, 2012

 

Just as women are advised to get plenty of folic acid around the time of conception and throughout early pregnancy, new research suggests another very similar nutrient may one day deserve a spot on the obstetrician’s list of recommendations.

 

Consuming greater amounts of choline – a nutrient found in eggs and meat – during pregnancy may lower an infant’s vulnerability to stress-related illnesses, such as mental health disturbances, and chronic conditions, like hypertension, later in life.

 

In an early study in The FASEB Journal, nutrition scientists and obstetricians at Cornell University and the University of Rochester Medical Center found that higher-than-normal amounts of choline in the diet during pregnancy changed epigenetic markers – modifications on our DNA that tell our genes to switch on or off, to go gangbusters or keep a low profile – in the fetus. While epigenetic markers don’t change our genes, they make a permanent imprint by dictating their fate: If a gene is not expressed – turned on – it’s as if it didn’t exist.

 

The finding became particularly exciting when researchers discovered that the affected markers were those that regulated the hypothalamic-pituitary-adrenal or HPA axis, which controls virtually all hormone activity in the body, including the production of the hormone cortisol that reflects our response to stress and regulates our metabolism, among other things.

 

More choline in the mother’s diet led to a more stable HPA axis and consequently less cortisol in the fetus. As with many aspects of our health, stability is a very good thing: Past research has shown that early exposure to high levels of cortisol, often a result of a mother’s anxiety or depression, can increase a baby’s lifelong risk of stress-related and metabolic disorders.

 

“The study is important because it shows that a relatively simple nutrient can have significant effects in prenatal life, and that these effects likely continue to have a long-lasting influence on adult life,” said Eva K. Pressman, M.D., study author and director of the high-risk pregnancy program at the University of Rochester Medical Center. “While our results won’t change practice at this point, the idea that maternal choline intake could essentially change fetal genetic expression into adulthood is quite novel.”

 

Pressman, who advises pregnant women every day, says choline isn’t something people think a lot about because it is already present in many things we eat and there is usually no concern of choline deficiency. Though much more research has focused on folate – functionally very similar to choline and used to decrease the risk of neural tube defects like spina bifida – a few very compelling studies sparked her interest, including animal studies on the role of choline in mitigating fetal alcohol syndrome and changing outcomes in Down syndrome.

 

A long-time collaborator with researchers at Cornell, Pressman joined a team led by Marie Caudill, Ph.D., R.D., professor in the Division of Nutritional Sciences at Cornell, in studying 26 pregnant women in their third trimester who were assigned to take 480 mg of choline per day, an amount slightly above the standard recommendation of 450 mg per day, or about double that amount, 930 mg per day. The choline was derived from the diet and from supplements and was consumed up until delivery.

 

The team found that higher maternal choline intake led to a greater amount of DNA methylation, a process in which methyl groups – one carbon atom linked to three hydrogen atoms – are added to our DNA. Choline is one of a handful of nutrients that provides methyl groups for this process. The addition of a single methyl group is all it takes to change an individual’s epigenome.

 

Measurements of cord blood and samples from the placenta showed that increased choline, via the addition of methyl groups, altered epigenetic markers that govern cortisol-regulating genes. Higher choline lessened the expression of these genes, leading to 33 percent lower cortisol in the blood of babies whose mom’s consumed 930 mg per day.

 

Study authors say the findings raise the exciting possibility that choline may be used therapeutically in cases where excess maternal stress from anxiety, depression or other prenatal conditions might make the fetal HPA axis more reactive and more likely to release greater-than-expected amounts of cortisol.

 

While more research is needed, Caudill says that her message to pregnant women would be to consume a diet that includes choline rich foods such as eggs, lean meat, beans and cruciferous vegetables like broccoli. For women who limit their consumption of animal products, which are richer sources of choline than plant foods, she adds that supplemental choline may be warranted as choline is generally absent in prenatal vitamin supplements.

 

“One day we might prescribe choline in the same way we prescribe folate to all pregnant women,” notes Pressman, the James R. Woods Professor in the Department of Obstetrics and Gynecology. “It is cheap and has virtually no side effects at the doses provided in this study. In the future, we could use choline to do even more good than we are doing right now.”

 

In addition to Pressman and Caudill, several scientists and clinicians from the Division of Nutritional Science and the Statistical Consulting Unit at Cornell and the Cayuga Medical Center in Ithaca, N. Y., participated in the research. The study was funded by the Egg Nutrition Center, the National Cattlemen’s Beef Association, the Nebraska Beef Council, the U.S. Department of Agriculture and the President’s Council of Cornell Women. The funding sources had no role in the study design, interpretation of the data, or publication of the results.

 

 

 

For Media Inquiries:

Emily Boynton

(585) 273-1757

Email Emily Boynton

 

Statins have unexpected effect on pool of powerful brain cells : Reduces Glial progenitor cells

Re-post 34th HRR 2008

Contact: Tom Rickey
tom_rickey@urmc.rochester.edu
585-275-7954
University of Rochester Medical Center

Cholesterol-lowering drugs known as statins have a profound effect on an elite group of cells important to brain health as we age, scientists at the University of Rochester Medical Center have found. The new findings shed light on a long-debated potential role for statins in the area of dementia.

Neuroscientists found that statins, one of the most widely prescribed classes of medication ever used, have an unexpected effect on brain cells. Researchers looked at the effects of statins on glial progenitor cells, which help the brain stay healthy by serving as a crucial reservoir of cells that the brain can customize depending on its needs. The team found that the compounds spur the cells, which are very similar to stem cells, to shed their flexibility and become one particular type of cell.

The new findings come at a time of increasing awareness among neurologists and cardiologists of the possible effects of statins on the brain. Several studies have set out to show that statins provide some protection against dementia, but the evidence has been inconclusive at best. Meanwhile, there is some debate among physicians about whether statins might actually boost the risk of dementia. The new research published in the July issue of the journal Glia by Steven Goldman, M.D., Ph.D., and first author Fraser Sim, Ph.D., provides direct evidence for an effect of statins on brain cells.

“There has been a great deal of discussion about a link between statins and dementia, but evidence either way has been scant,” said Goldman, a neurologist who led the team. “This new data provides a basis for further exploration.

“These findings were made through experiments done in cell culture using human brain cells and exposing them to doses of statins used widely in patients. But this research was not done in people. There are a great number of questions that need to be explored further before anyone considers changing the way statins are used,” Goldman added.

Goldman’s team is recognized as a leader identifying and directing the molecular signals that direct the development of stem cells and their daughter cells, known as progenitor cells. In this study, Sim ran a genomic screen to see which genes are more active in these cells compared to other brain cells. Sim and Goldman found several related to cholesterol, including the enzyme HMG-CoA reductase, which is central to making cholesterol and is the main target of statins.

“It was quite surprising that the cholesterol-signaling pathways are so active in these cells,” Goldman said. “Since such signaling is blocked with compounds used literally by millions of patients every day, we decided to take a closer look.”

The team measured the effects of two widely used statins, simvastatin and pravastatin, on glial progenitor cells, which can become either astrocytes or oligodendrocytes. The team looked at progenitor cells from 16 patients who had brain tissue removed during surgery to treat epilepsy, tumors, or vascular problems.

Scientists found that both compounds, when used at doses that mimic those that patients take, spur glial progenitor cells to develop into oligodendrocytes. For example, in one experiment, they found about five times as many oligodendrocytes in cultures of human progenitor cells exposed to pravastatin compared to cultures not exposed to the substance. Similarly, they found that the number of progenitor cells was just about one-sixth the level in cultures exposed to simvastatin compared to cultures not exposed to the compound.

To understand the process, think of a baseball team raising a group of great young prospects. They run fast, they throw hard, they hit well. Most teams will tailor their players to the positions the team needs – a few pitchers, for instance, and several batters. Any team that suddenly found itself with all pitchers or all hitters would be ill prepared to compete.

The Rochester team discovered that statins essentially push most of the raw talent in one direction.

Scientists don’t really know the long-term effects of such a shift. Physicians are looking at statins as a possible treatment for multiple sclerosis, where the myelin coating that covers nerve cells in the central nervous system is damaged. Myelin is produced by oligodendrocytes – so spurring the development of oligodendrocytes might provide one way to reduce or repair the damage seen in M.S.

But the body maintains a pool of uncommitted glial progenitor cells for a reason. The body normally turns to that reservoir of cells when it needs to repair damage from a variety of causes, such as an infection, hemorrhage, a serious blow to the head, or inflammation within the brain, such as in patients with multiple sclerosis. No one knows the consequences if such cells weren’t available when needed, though increased cognitive impairment might be one possibility.

“These are the cells ready to respond if you have a region of the brain that is damaged due to trauma, or lack of blood flow like a mini-stroke,” said Sim, assistant professor of Neurology. “Researchers need to look very carefully at what happens if these cells have been depleted prematurely.”

Glial progenitor cells are distributed throughout the brain and, according to Sim, make up about 3 percent of our brain cells. While true stem cells that can become any type of cell are very rare in the brain, their progeny, progenitor cells, are much more plentiful. They are slightly more specialized than stem cells but can still develop into different cell types.

The work may be relevant to drugs commonly used by diabetics as well. That’s because the team discovered that a signaling molecule called PPAR gamma is central to the effect of statins on glial progenitor cells. When PPAR gamma was blocked, the statins no longer had the effect. Since PPAR gamma is the main target of diabetes medications such as Avandia and Actos, which trigger the molecule, Goldman said it’s likely that those medications have the same effect on progenitor cells. He also noted that many patients are on both diabetes drugs and statins, which could increase the effect.

“Our results suggest the need for awareness of the possible toxicities accruing to long-term statin use, and identify one such potential toxicity, the premature differentiation and attendant long-term depletion of oligodendrocyte progenitor cells of the adult brain,” conclude the authors in their Glia paper.

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Besides Sim and Goldman, other authors include medical student Jennifer Lang, technical associate Tracy Ali, Cornell scientist Neeta Roy, and neurosurgeons Edward Vates, M.D., and Webster Pilcher, M.D. The National Institute of Neurological Disorders and Stroke and the National Multiple Sclerosis Society funded the work

Researchers detail chemotherapy’s damage to the brain” Chemotherapy drugs used to treat a wide range of cancers were more toxic to healthy brain cells than the cancer cells they were intended to treat

Re-post from 2008: This is not the watered down Chemo brain article released 5 Sep 2012..4 years later

contact: Mark Michaud
mark_michaud@urmc.rochester.edu
585-273-4790
University of Rochester Medical Center

A commonly used chemotherapy drug causes healthy brain cells to die off long after treatment has ended and may be one of the underlying biological causes of the cognitive side effects – or “chemo brain” – that many cancer patients experience. That is the conclusion of a study published today in the Journal of Biology.

A team of researchers at the University of Rochester Medical Center (URMC) and Harvard Medical School have linked the widely used chemotherapy drug 5-fluorouracil (5-FU) to a progressing collapse of populations of stem cells and their progeny in the central nervous system.

“This study is the first model of a delayed degeneration syndrome that involves a global disruption of the myelin-forming cells that are essential for normal neuronal function,” said Mark Noble, Ph.D., director of the University of Rochester Stem Cell and Regenerative Medicine Institute and senior author of the study. “Because of our growing knowledge of stem cells and their biology, we can now begin to understand and define the molecular mechanisms behind the cognitive difficulties that linger and worsen in a significant number of cancer patients.”

Cancer patients have long complained of neurological side effects such as short-term memory loss and, in extreme cases, seizures, vision loss, and even dementia. Until very recently, these cognitive side effects were often dismissed as the byproduct of fatigue, depression, and anxiety related to cancer diagnosis and treatment. Now a growing body of evidence has documented the scope of these conditions, collectively referred to as chemo brain. And while it is increasingly acknowledged by the scientific community that many chemotherapy agents may have a negative impact on brain function in a subset of cancer patients, the precise mechanisms that underlie this dysfunction have not been identified.

Virtually all cancer survivors experience short-term memory loss and difficulty concentrating during and shortly after treatment. A study two years ago by researchers with the James P. Wilmot Cancer Center at the University of Rochester showed that upwards of 82% of breast cancer patients reported that they suffer from some form of cognitive impairment.

While these effects tend to wear off over time, a subset of patients, particularly those who have been administered high doses of chemotherapy, begin to experience these cognitive side effects months or longer after treatment has ceased and the drugs have long since departed their systems. For example, a recent study estimates that somewhere between 15 and 20 percent of the nation’s 2.4 million female breast cancer survivors have lingering cognitive problems years after treatment. Another study showed that 50 percent of women had not recovered their previous level of cognitive function one year after treatment.

Two years ago, Noble and his team showed that three common chemotherapy drugs used to treat a wide range of cancers were more toxic to healthy brain cells than the cancer cells they were intended to treat. While these experiments were among the first to establish a biological basis for the acute onset of chemo brain, they did not explain the lingering impact that many patients experience.

The scientists conducted a similar series of experiments in which they exposed both individual cell populations and mice to doses of 5-fluorouracil (5-FU) in amounts comparable to those used in cancer patients. 5-FU is among a class of drugs called antimetabolites that block cell division and has been used in cancer treatment for more than 40 years. The drug, which is often administered in a “cocktail” with other chemotherapy drugs, is currently used to treat breast, ovarian, stomach, colon, pancreatic and other forms of cancer.

The researchers discovered that months after exposure, specific populations of cells in the central nervous – oligodendrocytes and dividing precursor cells from which they are generated – underwent such extensive damage that, after 6 months, these cells had all but disappeared in the mice.

Oligodendrocytes play an important role in the central nervous system and are responsible for producing myelin, the fatty substance that, like insulation on electrical wires, coats nerve cells and enables signals between cells to be transmitted rapidly and efficiently. The myelin membranes are constantly being turned over, and without a healthy population of oligodendrocytes, the membranes cannot be renewed and eventually break down, resulting in a disruption of normal impulse transmission between nerve cells.

These findings parallel observations in studies of cancer survivors with cognitive difficulties. MRI scans of these patients’ brains revealed a condition similar to leukoencephalopathy. This demyelination – or the loss of white matter – can be associated with multiple neurological problems.

“It is clear that, in some patients, chemotherapy appears to trigger a degenerative condition in the central nervous system,” said Noble. “Because these treatments will clearly remain the standard of care for many years to come, it is critical that we understand their precise impact on the central nervous system, and then use this knowledge as the basis for discovering means of preventing such side effects.”

Noble points out that not all cancer patients experience these cognitive difficulties, and determining why some patients are more vulnerable may be an important step in developing new ways to prevent these side effects. Because of this study, researchers now have a model which, for the first time, allows scientists to begin to examine this condition in a systematic manner.

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Other investigators participating in the study include Ruolan Han, Ph.D., Yin M. Yang, M.D., Anne Luebke, Ph.D., Margot Mayer-Proschel, Ph.D., all with URMC, and Joerg Dietrich, M.D., Ph.D., formerly with URMC and now with Harvard Medical School. The study was funded by the National Institutes of Neurological Disorders and Stroke, the Komen Foundation for the Cure, and the Wilmot Cancer Center

Local Outbreak Highlights New Source of Infection – Tattoo Ink

In Rochester, a Tale of Tainted Tattoos

September 06, 2012

The New England Journal of Medicine ©2012

If you end up with a rash on a new tattoo, you should probably think twice before brushing it off as an allergic reaction or a normal part of the healing process.

A recent study in the New England Journal of Medicine documents 19 cases in the Rochester, N.Y., area – the largest ever reported – of tattoos infected with a type of bacteria often found in tap water. Evidence points to a premixed gray ink, the type used in currently popular portrait or photography tattoos, as the culprit.

Mary Gail Mercurio, M.D., a dermatologist at the University of Rochester Medical Center, saw 18 of the 19 individuals infected. She says some people with tattoos have allergies or experience other dermatologic complications, but it’s not common. “I’ve seen people with tattoo-related issues over the years, but never this many: The volume of patients impacted makes this a real public health concern.

“Patients and doctors need to have a certain level of suspicion when they see a rash developing in a tattoo. Many of the patients I saw thought their skin was just irritated and the issue would go away during the healing process. In actuality, they had an infection that needed to be treated with an antibiotic; it wasn’t going to go away easily on its own.”

The investigation of the outbreak, which was also highlighted in the U.S. Centers for Disease Control and Prevention’s Morbidity and Mortality Weekly Report, started with a previously healthy 20-year-old man who had a history of multiple tattoos in the past without any issues. In October 2011, he received a new tattoo on his arm and subsequently developed a persistent, inflamed rash in that area. After learning of his case, the Monroe County Department of Public Health explored the issue and identified 18 other individuals who developed similar rashes after getting tattoos at the same parlor, from the same artist.

Tests conducted at the Medical Center revealed that a specific type of bacteria, Mycobacterium chelonae, was in the patients’ skin and led to the red, itchy bumps in their tattoos. Further testing found that a premixed gray ink, which the local artist had bought from a manufacturer in Arizona, contained the same bacteria and likely transmitted it to the skin.

Robert F. Betts, M.D., a long-time infectious disease expert at the Medical Center who treated almost all of the patients, confirmed that the infection was only in the areas tattooed with the gray ink. Also called gray wash, it is used to achieve shading and a three-dimensional quality in tattoos.

According to the local tattoo artist, the manufacturer diluted black ink with distilled water to create a gray color. “This organism, M. chelonae, is found in some water supplies,” said Betts. “What probably happened is that the water used to dilute the ink introduced the bacteria into it and the trauma associated with getting the tattoo compromised the circulation to that area of the skin, allowing the organism to enter into the skin and grow.”

Betts says that this species of bacteria grows best at around 86 °F, a little bit below normal body temperature, which is approximately 98.6 °F. The skin is cooler than the rest of the body, which may explain why the bacteria flourished in the tattooed areas.

Following the investigation, the CDC issued a nationwide alert about the outbreak and the manufacturer voluntarily recalled the ink. Betts evaluated and treated 16 of the 19 patients with standard antibiotics – azithromycin and doxycycline – and everyone improved, although at different speeds based on the extent of the infection.

Both Betts and Mercurio believe that tattoo-associated infections are probably more common than we think and that physicians should think about infectious causes if patients aren’t responding to topical or other dermatologic treatments that would typically dispel any sort of allergic reaction to a tattoo.

In addition to Betts and Mercurio, Glynis A. Scott, M.D., Matthew A. Lewis, M.D., and Mark H. Goldgeier, M.D., from the Medical Center contributed to the research. Byron S. Kennedy, M.D., Ph.D., from the Monroe County Department of Public Health was the lead author of the New England Journal of Medicine study. Physicians and scientists from the New York State Department of Health, the CDC and the FDA participated in the research as well.

For Media Inquiries:                       Emily Boynton                         (585) 273-1757 Email Emily Boynton

Daisies lead scientists down path to new leukemia drug – DMAPT can kill both dormant cells and cells that are busy dividing

Contact: Leslie Orr Leslie_Orr@urmc.rochester.edu 585-275-5774 University of Rochester Medical Center

OCT 2007

Rochester team develops compound to attack cancer stem cells

A new, easily ingested form of a compound that has already shown it can attack the roots of leukemia in laboratory studies is moving into human clinical trials, according to a new article by University of Rochester investigators in the journal, Blood.

The Rochester team has been leading the investigation of this promising therapy on the deadly blood cancer for nearly five years. And to bring it from a laboratory concept to patient studies in that time is very fast progress in the drug development world, said Craig T. Jordan, Ph.D., senior author of the Blood article and director of Translational Research for Hematologic Malignancies at the James P. Wilmot Cancer Center, at the University of Rochester Medical Center.

Clinical trials are expected to begin in England by the end of 2007. Investigators expect to initially enroll about a dozen adult volunteers who’ve been diagnosed with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) or other types of blood or lymph cancers, Jordan said.

Under development is dimethylamino-parthenolide (DMAPT), a form of parthenolide (PTL) that is derived from a daisy-like plant known as feverfew or bachelor’s button. DMAPT is a water-soluble agent that scientists believe will selectively target leukemia at the stem-cell level, where the malignancy is born. This is significant because standard chemotherapy does not strike deep enough to kill cancer at the roots, thus resulting in relapses. Even the most progressive new therapies, such as Gleevec, are effective only to a degree because they do not reach the root of the cancer.

DMAPT appears to be unique. It’s mechanism of action is to boost the cancer cell’s reactive oxygen species – which is like pushing the stress level of the cell over the edge – to the point where the cell can no long protect itself and dies, said Monica L. Guzman, Ph.D., the lead researcher on the DMAPT project and a senior instructor at the University of Rochester Medical Center.

Leukemia is different from most cancers and particularly hard to eradicate because leukemia stem cells lie dormant. Standard cancer treatments are designed to seek out actively dividing cells. But in studies so far, DMAPT can kill both dormant cells and cells that are busy dividing, Guzman said

Rochester investigators looked at whether DMAPT could eliminate leukemia in donated human cells, and in mice and dogs. In all cases, DMAPT induced rapid death of AML stem and progenitor cells, without harming healthy blood cells.

DMAPT also has shown potential as a treatment for breast and prostate cancer, melanoma, and multiple myeloma, Guzman said, although those studies have only been conducted in cell cultures to date.

“Once we begin seeing evidence from the clinical trials, it will give us more insight into the pharmacological properties of DMAPT and it will be easier to figure out its potential for other cancers,” Guzman said.

In addition to the studies of DMAPT, Guzman and Jordan also reported in the same issue of Blood on another new type of leukemia drug known as TDZD-8.  Although this agent is at a much earlier stage of development, it also shows the ability to kill leukemia stem cells and may some day lead to better forms of treatment.

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The National Cancer Institute RAID program (Rapid Access to Interventional Development) is funding the fast-track research into DMAPT at the University of Rochester. RAID attempts to push promising new therapeutics into the marketplace more quickly. Additional funding came from the Leukemia and Lymphoma Society and the U.S. Department of Defense. Co-authors and partners include chemists at the University of Kentucky, who contributed to developing the analog form of parthenolide

Reposted For Filing….

Vaccine tied to ‘superbug’ ear infection – Old Prevnar 2007 Historical Only

*Requested Repost From 2007 – Info is Historical

 

A vaccine that has dramatically curbed pneumonia and other serious illnesses in children is also having an unfortunate effect: promoting new superbugs that cause ear infections

On Monday, doctors reported discovering the first such germ that is resistant to all drugs approved to treat childhood ear infections. Nine toddlers in Rochester, N.Y., have had the bug and researchers say it may be turning up elsewhere, too.

Wyeth anticipated this and is testing a second-generation vaccine. But it is at least two years from reaching the market, and the new strains could become a public health problem in the meantime if they spread hard-to-treat infections through day care centers and schools.

It is a strain of strep bacteria not included in the pneumococcal vaccine, Wyeth’s Prevnar, which came on the market in 2000. It is recommended for children under age 2.

Prevnar, however, is losing its punch because strains not covered by the vaccine are filling the biological niche that the vaccine strains used to occupy, and they are causing disease.

One strain in particular, called 19A, is big trouble. A new subtype of it caused ear infections in the nine Rochester children, ages 6 months to 18 months, that were resistant to all pediatric medications, said Dr. Michael Pichichero, a microbiologist at the University of Rochester Medical Center.

The children had been unsuccessfully treated with two or more antibiotics, including high-dose amoxicillin and multiple shots of another drug. Many needed surgery to place ear tubes to drain the infection, and some recovered only after treatment with a newer, powerful antibiotic whose safety in children has not been established.

–Scientists from a drug company and two labs analyzed more than 21,000 bacterial samples from around the nation and found 19A increasing. Among children 2 and under, the portion of samples that were this strain rose to 15 percent in 2005-2006, from 4 percent in the previous three years.

–A British lab tracking respiratory infections in U.S. kids found that the 19A strain accounted for 40 percent of drug-resistant cases.

–University of Iowa researchers found 19A accounted for 35 percent of penicillin-resistant infections in 2004-05, compared with less than 2 percent the year before the new vaccine came out.

Purple periwinkles battle inflammatory diseases ( COPD Treatment Breakthrough )

Repost from 2010…Breakthrough treatment completely ignored

Natural supplement boasts excellent safety

A widely and safely used plant extract acts as a novel anti-inflammatory agent that may one day be used for the treatment of chronic obstructive pulmonary disease, or COPD, as well as other inflammatory conditions. There is an urgent need for new therapies for the treatment of chronic inflammatory diseases, such as COPD, otitis media (ear infection), and atherosclerosis (chronic inflammation in the walls of arteries), because the most effective and commonly used agents – steroids – often cause serious side effects, such as liver damage, which prevent long-term use. 

In a study published today in the Proceedings of the National Academy of Sciences, researchers at the University of Rochester Medical Center were the first to find that vinpocetine, a natural product derived from the periwinkle plant, acts as a potent anti-inflammatory agent when tested in a mouse model of lung inflammation, as well as several other types of human cells.  Results of the study show that vinpocetine greatly reduces inflammation, and, unlike steroids, does not cause severe side effects.

“What is extremely exciting and promising about these findings is vinpocetine’s excellent safety profile,” said Chen Yan, Ph.D., associate professor within the Aab Cardiovascular Research Institute at the Medical Center and a senior author of the study. “Previously, most drugs tested in this area have failed, not because of a lack of efficacy, but because of safety issues. We’re very encouraged by these results and believe vinpocetine has great potential for the treatment of COPD and other inflammatory diseases.”

Vinpocetine is a well-known natural product that was originally discovered nearly 30 years ago and is currently used as a dietary supplement for the prevention and treatment of cognitive disorders, such as stroke and memory loss, in Europe, Japan and China. The therapy has no evidence of toxicity or noticeable side effects in human patients. Scientists at the University of Rochester hope to reposition this compound as an anti-inflammatory agent for the treatment of COPD, and potentially other inflammatory conditions, such as asthma, otitis media, rheumatoid arthritis, atherosclerosis and psoriasis in the future.

While steroids successfully combat inflammation, patients often pay a high price when it comes to side effects. Steroids can cause liver damage, and can also suppress the immune system, increasing the likelihood of infections. With such a high risk profile, steroids are usually only used for a short period of time, which is problematic when treating chronic diseases.

In managing chronic conditions such as COPD, it is crucial to have a therapy that can be used safely over the long term,” said Jian-Dong Li, M.D., Ph.D., professor in the Department of Microbiology and Immunology at the University of Rochester Medical Center and a senior author of the study. “There is a great need for a drug like vinpocetine, because patients currently have no good options when it comes to long-term care.” 

Vinpocetine decreases inflammation by targeting the activity of a specific enzyme, known as IKK. IKK is responsible for regulating inflammation, and does so through the activation of a key protein, nuclear-factor kappaB (NF-κB).  By directly inhibiting IKK, vinpocetine is able to switch off NF-κB, which normally produces pro-inflammatory molecules that cause inflammation. Halting the activity of NF-κB ultimately reduces inflammation.

“Inflammation is a hallmark of a wide range of human diseases, so there is great potential for vinpocetine to be used for several indications,” said Bradford C. Berk, M.D., Ph.D., CEO of the University of Rochester Medical Center and co-author of the study. “Given vinpocetine’s efficacy and solid safety profile, we believe there is great potential to bring this drug to market.”

Repositioning a therapy – taking a known compound that has been used safely in humans and testing it for a new application – can be an effective way to bring new therapies to market more quickly than starting the discovery process from scratch.

Inflammatory diseases are a major cause of illness worldwide. For example, chronic obstructive pulmonary disease is the fourth leading cause of death in the United States. In people with COPD, airflow is blocked due to chronic bronchitis or emphysema, making it increasingly difficult to breathe. Most COPD is caused by long-term smoking, although genetics may play a role as well. Approximately 13.5 million people in the United States are diagnosed with COPD each year, and in 2004 the annual cost of the disease was $37.2 billion.