A common nutritional supplement may be part of the magic in improving the survival rates of babies born with heart defects, researchers report.

Carnitine, a compound that helps transport fat inside the cell powerhouse where it can be used for energy production, is currently used for purposes ranging from weight loss to chest pain.

New research shows it appears to normalize the blood vessel dysfunction that can accompany congenital heart defects and linger even after corrective surgery, said Dr. Stephen M. Black, cell and molecular physiologist at the Vascular Biology Center at the Medical College of Georgia at Georgia Regents University.

"My hope is this is going to have a major, major impact on survival of babies," Black said. About half the babies born with heart defects have excessive, continuous high pressure on their lungs from misdirected blood flow. Early surgery can prevent full-blown pulmonary vascular disease, but scientists are finding more subtle disruptions in the signaling inside blood vessels walls that can be problematic - even deadly - up to 72 hours after surgery.

The good news is the changes are reversible and that carnitine speeds recovery and can even prevent the damage in a lamb model of these human heart defects, according to studies published in the journal Pediatric Research.

Normally, most blood flow bypasses the lungs in utero when the placenta provides blood and oxygen for the baby. Baby's first breaths naturally expand the lungs and blood vessels, activating a process inside the lining of vessels that enables them to accommodate the initial blood surge, then reduce pressure quickly, dramatically and permanently.

This natural transition doesn't occur when heart defects misdirect blood flow. "It's kind of like a chronic fetal-to-newborn transition," said Black, the study's corresponding author. Lungs get pounded with about three times the normal flow and, even when surgeries are done as early as possible to repair the defect, correct blood flow and protect the lungs, the 20 percent death rates from acute pulmonary hypertension have remained unchanged for a decade. "That's 1 in 5 kid (with this condition)," Black said.


Left unchecked, the barrage thickens blood vessels, making them unresponsive, much like those of an elderly individual who has lived for years with uncontrolled high blood pressure. The comparatively brief periods of pounding these babies experience impairs the ability of the endothelial cells, which line blood vessels, to produce nitric oxide, a major dilator of blood vessels.

The shear force disrupts carnitine homeostasis, weakens the mitochondria (the cell powerhouse) and impairs nitric oxide production. To make bad matters worse, the precursor to nitric oxide instead makes more peroxynitrite, prompting endothelial cells to grow and thickening blood vessels. Black was also corresponding author of a recent study in the Journal of Biological Chemistry that showed peroxynitrite does this by turning on the cell survival protein kinase Akt1.

The new study indicates that even without fixing the heart defect, high daily doses of carnitine in the first four weeks of life can prevent endothelial dysfunction. In fact, the laboratory lambs' ability to make nitric oxide is preserved even without the benefit of heart surgery and the responses to the chemical activity that enables blood vessel dilation is normalized, Black said.
Source:

Medical College of Georgia at Georgia Regents University

Taking enough omega-3 fatty acid supplements to change the balance of oils in the diet could slow a key biological process linked to aging, new research suggests.

The study showed that most overweight but healthy middle-aged and older adults who took omega-3 supplements for four months altered a ratio of their fatty acid consumption in a way that helped preserve tiny segments of DNA in their white blood cells.

These segments, called telomeres, are known to shorten over time in many types of cells as a consequence of aging. In the study, lengthening of telomeres in immune system cells was more prevalent in people who substantially improved the ratio of omega-3s to other fatty acids in their diet.

Omega-3 supplementation also reduced oxidative stress, caused by excessive free radicals in the blood, by about 15 percent compared to effects seen in the placebo group.

"The telomere finding is provocative in that it suggests the possibility that a nutritional supplement might actually make a difference in aging," said Jan Kiecolt-Glaser, professor of psychiatry and psychology at Ohio State and lead author of the study.

In another recent publication from this study, Kiecolt-Glaser and colleagues reported that omega-3 fatty acid supplements lowered inflammation in this same group of adults.

"Inflammation in particular is at the heart of so many health problems. Anything that reduces inflammation has a lot of potentially good spinoffs among older adults," she said.

Study participants took either 2.5 grams or 1.25 grams of active omega-3 polyunsaturated fatty acids, which are considered "good fats" that, when consumed in proper quantities, are associated with a variety of health benefits. Participants on the placebo took pills containing a mix of oils representing a typical American's daily intake.

The researchers say this combination of effects suggests that omega-3 supplements could represent a rare single nutritional intervention that has potential to lower the risk for a host of diseases associated with aging, such as coronary heart disease, Type 2 diabetes, arthritis and Alzheimer's disease.

The study is published online and scheduled for later print publication in the journal Brain, Behavior, and Immunity.

Participants received either the placebo or one of the two different doses of omega-3 fatty acids. The supplements were calibrated to contain a ratio of the two cold-water fish oil fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), of seven to one. Previous research has suggested that EPA has more anti-inflammatory properties than DHA.

In the case of fatty acids, omega-3 supplementation alone doesn't tell the whole story of how this dietary change can affect health, explained Martha Belury, professor of human nutrition at Ohio State and a co-author of the study. Also important is the ratio of omega-6 fatty acids to omega-3 fatty acids that are present in a person's blood.

Omega-6 fatty acids come from vegetable oils, and since the 1960s, research has suggested that these oils, too, can help protect the cardiovascular system. However, the typical American diet tends to be heavy on omega-6 fatty acids and comparatively low in omega-3s that are naturally found in cold-water fish such as salmon and tuna. While the ratio of omega-6 to omega-3 fatty acids averages about 15-to-1, researchers tend to agree that for maximum benefit, this ratio should be lowered to 4-to-1, or even 2-to-1.


The long chains - or bigger molecules - that make up EPA and DHA fatty acids are believed to be the secret to their effectiveness, Belury said.

Both groups of participants who took omega-3 supplements showed, on average, lengthening of telomeres compared to overall telomere effects in the placebo group, but the relationship could have been attributed to chance. However, when the researchers analyzed the participants' omega-6 to omega-3 ratio in relationship to telomere lengthening, a lower ratio was clearly associated with lengthened telomeres.

"The idea we were looking at with the ratio of omega-6 to omega-3 fatty acids was an increase in the denominator to make the ratio smaller. In the United States, we need to focus on the omega-3 part because we don't get enough of those," Belury said.

The researchers also measured levels of compounds called F2-isoprostanes to determine levels of oxidative stress, which is linked to a number of conditions that include heart disease and neurodegenerative disorders. Both omega-3 groups together showed an average overall 15 percent reduction in oxidative stress compared to effects seen in the placebo group.

When the scientists revisited their earlier inflammation findings, they also found that decreases in an inflammatory marker in the blood called interleukin-6 (IL-6) were associated with telomere lengthening. In their earlier paper on omega-3s and inflammation, they reported that omega-3 supplements lowered IL-6 by 10 to 12 percent, depending on the dose. By comparison, those taking a placebo saw an overall 36 percent increase in IL-6 by the end of the study.

"This finding strongly suggests that inflammation is what's driving the changes in the telomeres," Kiecolt-Glaser said.

Telomeres are a hot topic in science, and their tendency to shorten is associated with such age-related problems as heart disease and early mortality. These short fragments of DNA act as caps at the end of chromosomes, and can be likened to the protective plastic at the end of a shoelace.

"If that plastic comes off, the shoelace unravels and it doesn't work anymore," said study co-author Ron Glaser, professor of molecular virology, immunology and medical genetics and director of the Institute for Behavioral Medicine Research (IBMR) at Ohio State. "In the same way, every time a cell divides, it loses a little bit of its DNA at the ends, and over time, that can cause significant problems."

Kiecolt-Glaser noted that this population was disease-free and reported very little stress. The study included 106 adults, average age 51 years, who were either overweight or obese and lived sedentary lives. The researchers excluded people taking medications to control mood, cholesterol and blood pressure as well as vegetarians, patients with diabetes, smokers, those routinely taking fish oil, people who got more than two hours of vigorous exercise each week and those whose body mass index was either below 22.5 or above 40.

"People who are less healthy than this group, and especially those who experience chronic stress, may gain even more benefits from omega-3 supplementation," she said.
Source: Brain, Behavior, and Immunity

Arginine therapy may be a safe and inexpensive treatment for acute pain episodes in patients with sickle cell disease, according to results of a recent clinical study. The study was the first randomized placebo-controlled study to demonstrate benefits of arginine therapy in children with sickle cell disease hospitalized for severe pain.

Sickle cell disease is an inherited condition in which the body makes red blood cells containing abnormal hemoglobin, the protein that carries oxygen from the lungs to other cells in the body. This abnormal hemoglobin (hemoglobin S) causes red blood cells to distort into a sickle, or crescent shape that often blocks blood flow in small blood vessels, leading to pain and organ damage.

An acute deficiency of nitric oxide in sickled red blood cells contributes to the episodes of blocked vessels and pain. Since the amino acid arginine is a building block of nitric oxide, researchers hypothesized that arginine could be a beneficial treatment for pain related to sickle cell disease.

Previous research found that a single dose of arginine given to sickle cell patients with acute pain episodes resulted in a significant dose-dependent increase in plasma nitric oxide.

Building on that knowledge, the current research study was a randomized, double blind clinical trial of 38 children with sickle cell disease hospitalized for 56 episodes of pain. The research team discovered a 54 percent reduction in the use of pain medication and significantly lower pain scores at hospital discharge in those treated with arginine over those receiving placebo.


The results were published in the journal Haematologica. First author was Claudia R. Morris, MD, assistant professor of pediatrics at Emory University School of Medicine. She conducted the study while in her previous position at Children's Hospital and Research Center in Oakland, CA, with senior author Elliott P. Vichinsky, MD.

"Episodes of pain due to vaso-occlusion are the leading cause of hospital admission and emergency room visits and are associated with increased mortality, yet there is no effective therapy targeting the underlying cause," says Morris. "Treatment consists only of symptom relief with pain medicines and hydration. There is an urgent need for new therapies for acute sickle cell pain, and a greater than 50 percent reduction in use of pain medication was a remarkable finding."

The study found no problems with safety in the use of arginine therapy. Although the treatment did not result in a significantly shorter length of stay in the hospital, the researchers believe delivering the study drug as early as possible in the emergency department or clinic may have a greater impact on length of stay, since many patients received their first dose of medication more than 24 hours after presenting at the hospital.

A large, multi-center trial is warranted in order to confirm these observations and test the effects of delivering the therapy sooner, they note in the published paper.
Source:

Emory Health Sciences

A study will be published on March 21, 2009 in World Journal of Gastroenterology addresses the question.

A research group in King Saud University, Kingdom of Saudi Arabia investigated, for the first time, the role of carnitine, a naturally occurring compound that is synthesized mainly in the liver, during the development of hepatocarcinogenesis. Authors of the study reported that carnitine deficiency is a risk factor and should be viewed as a mechanism in hepatic carcinogenesis, and that long-term L-carnitine supplementation prevents the development of liver cancer. Therefore, carnitine supplementation alone or in combination with other natural chemopreventive compounds could be used to prevent, slow or reverse the occurrence of liver cancer.

Chemoprevention is defined as the use of naturally occurring and/or synthetic compounds in cancer therapy in which the occurrence of cancer can be entirely prevented, slowed or reversed. L-carnitine is a naturally occurring compound which is primarily located in mitochondria and possesses potential protective effects against many mitochondrial toxic agents. It is derived from two sources; endogenous synthesis, in the liver and kidney, and from exogenous dietary sources such as red meat and dairy products. L-carnitine is an essential cofactor for the translocation of long chain fatty acids from the cytoplasmic compartment into mitochondria, where beta-oxidation enzymes are located for ATP production. Despite the liver being the main organ responsible for endogenous synthesis of L-carnitine, we were unable to find any studies investigating the role of long-term endogenous carnitine depletion and/or carnitine deficiency during induction of hepatic carcinogenesis.

The research team by Professor Sayed-Ahmed from College of Pharmacy, King Saud University used an experimental model of hepatocarcinogenesis under conditions of carnitine depletion and carnitine supplementation.


In the carnitine-depleted rat model, there were a progressive increase in the activities of liver enzymes as well as massive degenerative changes and evidence of pre-neoplastic lesions in liver tissues including clusters of hepatocytes with atypia and an increased proliferative rate, diffuse bridging fibrosis and nodule formation, bile ducts with marked reactive atypia showing nuclear enlargement, high nuclear/cytoplasmic ratio and prominent nucleoli. Interestingly, L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes compared to normal values, as well as normal liver histology with unremarkable central vein and no evidence of pre-neoplastic lesions in liver tissues.

Due to the fact that liver cancer is one of the major health problems in the world and a large sector of patients seek medical attention at a relatively late stage which increases the cost of treatment, King Saud University granted Prof. Sayed-Ahmed and his colleagues a research project with the following specific aims: (1) to understand the possible molecular mechanisms whereby carnitine deficiency provokes hepatic carcinogenesis. (2) to understand the relationship between hepatic cancer and its resistance to cancer chemotherapy, and (3) to gain knowledge on the possible mechanisms by which carnitine supplementation alone or in combination with other natural chemopreventive compounds could be used to prevent, slow or reverse the occurrence of liver cancer.
Source:

http://www.wjgnet.com/

More than 371 million people worldwide suffer from diabetes, of whom 90% are affected by lifestyle-related diabetes mellitus type 2 (type 2 diabetes).

In new experiments, researchers from the University of Copenhagen working in collaboration with a research group at the University of Cincinnati, USA, have demonstrated that the amino acid arginine improves glucose metabolism significantly in both lean (insulin-sensitive) and obese (insulin-resistant) mice.

"In fact, the amino acid is just as effective as several well-established drugs for type 2 diabetics," says postdoc Christoffer Clemmensen. He has conducted the new experiments based at Faculty of Health and Medical Sciences, University of Copenhagen. He is currently conducting research at the Institute for Diabetes and Obesity at Helmholtz Zentrum M-nchen, the German Research Centre for Environmental Health in Munich.

To test the effect of the amino acid arginine, researchers subjected lean and obese animal models to a so-called glucose tolerance test, which measures the body's ability to remove glucose from the blood over time.

"We have demonstrated that both lean and fat laboratory mice benefit considerably from arginine supplements. In fact, we improved glucose metabolism by as much as 40% in both groups. We can also see that arginine increases the body's production of glucagon-like peptide-1 (GLP-1), an intestinal hormone which plays an important role in regulating appetite and glucose metabolism, and which is therefore used in numerous drugs for treating type 2 diabetes," says Christoffer Clemmensen, and continues:

"You cannot, of course, cure diabetes by eating unlimited quantities of arginine-rich almonds and hazelnuts. However, our findings indicate that diet-based interventions with arginine-containing foods can have a positive effect on how the body processes the food we eat."


The research findings were recently published in the American scientific journal Endocrinology under the heading Oral l-arginine Stimulates GLP-1 Secretion to Improve Glucose Tolerance in Male Mice.

Hormone plays key role

Researchers have known for many years that the amino acid arginine is important for the body's ability to secrete insulin. However, the latest findings show that it is an indirect process. The process is actually controlled by arginine's ability to secrete the intestinal hormone GLP-1, which subsequently affects insulin secretion.

"Mice without GLP-1 receptors are not affected to the same extent by arginine. There is no perceptible improvement in glucose metabolism or insulin secretion, confirming our hypothesis of a close biological connection between GLP-1 and arginine," says Christoffer Clemmensen, who conducted the biological experiments in the USA using a special animal model where the receptor for GLP-1 is genetically inactivated.

The new findings provide optimism for better and more targeted drugs for treating type 2 diabetes; the outlook is long-term, but promising.

"This exciting result has raised several new questions which we want to investigate. Can other amino acids do what arginine does? Which intestinal mechanisms 'measure' arginine and lead to the release of GLP-1? Finally, there is the more long-term perspective - the question of whether the findings can be transferred from mice to humans and be used to design drugs that will benefit diabetes patients," says Professor Hans Br-uner-Osborne, who is continuing work on the project in the research group at the Department of Drug Design and Pharmacology at the University of Copenhagen.
Source:

University of Copenhagen