Clioquinol Inhibits Action Of The CLK1 Aging Gene, May Alleviate Alzheimer’s

Recent animal studies have shown that clioquinol – an 80-year old drug once used to treat diarrhea and other gastrointestinal disorders – can reverse the progression of Alzheimer’s, Parkinson’s and Huntington’s diseases. Scientists, however, had a variety of theories to attempt to explain how a single compound could have such similar effects on three unrelated neurodegenerative disorders.

Researchers at McGill University have discovered a dramatic possible new answer: According to Dr. Siegfried Hekimi and colleagues at McGill’s Department of Biology, clioquinol acts directly on a protein called CLK-1, often informally called “clock-1,” and might slow down the aging process. The advance online edition of their study was published in Oct. 2008 in the Journal of Biological Chemistry.

“Clioquinol is a very powerful inhibitor of clock-1,” explained Hekimi, McGill’s Strathcona Chair of Zoology and Robert Archibald & Catherine Louise Campbell Chair in Developmental Biology. “Because clock-1 affects longevity in invertebrates and mice, and because we’re talking about three age-dependent neurodegenerative diseases, we hypothesize that clioquinol affects them by slowing down the rate of aging.”

Once commonly prescribed in Europe and Asia for gastrointestinal problems like diarrhea and shigella, clioquinol was withdrawn from the market after being blamed for a devastating outbreak of subacute myelo-optic neuropathy (SMON) in Japan in the 1960s. However, because no rigorous scientific study was conducted at the time, and because clioquinol was used safely by millions before and after the Japanese outbreak, some researchers think its connection to SMON has yet to be proven.

The exact mechanism of how clioquinol inhibits CLK-1 is still under investigation, Hekimi said. “One possibility is that metals are involved as clioquinol is a metal chelator,” he explained. Chelation is a type of binding to metal ions and is often used to treat heavy metal poisoning.

Hekimi is optimistic but cautious when asked whether clioquinol could eventually become an anti-aging treatment.

“The drug affects a gene which when inhibited can slow down aging,” he said. “The implication is that we can change the rate of aging. This might be why clioquinol is able to work on this diversity of diseases that are all age-dependent.”

However, he admits to being concerned about how people may interpret his results.

“The danger is that you can buy a kilogram of this compound at a chemical wholesaler, but we don’t want people to start experimenting on themselves. Clioquinol can be a very toxic substance if abused, and far more research is required.”

###

ABOUT McGILL UNIVERSITY

McGill University, founded in Montreal, Que., in 1821, is Canada’s leading post-secondary institution. It has two campuses, 11 faculties, 10 professional schools, 300 programs of study and more than 33,000 students. McGill attracts students from more than 160 countries around the world. Almost half of McGill students claim a first language other than English – including 6,000 francophones – with more than 6,200 international students making up almost 20 per cent of the student body.

Source: Mark Shainblum

McGill University

Women With Pedometers Step Up Exercise Levels

Women with pedometers and a goal of 10,000 steps per day walked more than those whose goal was a brisk, 30-minute walk,
according to new research published in the April issue of Medicine & Science in Sports & Exercise®, the official journal of
the American College of Sports Medicine (ACSM). The study outcomes contribute to a widespread effort to promote fitness with
the use of step-counting devices to increase physical activity.

The study followed 58 women who were physically inactive before the study, averaging fewer than 7,000 steps a day.
Participants were divided into two groups:

- A “30-minute group” instructed to take a brisk, 30-minute walk on most, preferably all, days of the week

- A “10K group” instructed to walk 10,000 steps per day

All participants wore sealed pedometers that recorded the steps taken each day. To establish baseline levels of activity,
steps were measured for 14 days. During the four-week experiment, the 10K group also wore pedometers that were not sealed,
allowing participants to track their steps throughout the day. Thirty-minute walkers kept activity logs recording when the
pedometer was put on and taken off each day, along with their timed walking bouts. Those in the 10K group logged when the
pedometer was put on and taken off, as well as total steps accumulated each day. They also had the option to record which
physical activities they performed to reach the goal of 10,000 steps per day.

Results:

– Over the four-week intervention, the 30-minute group accumulated an average of 8,270 steps per day and the 10K group
averaged 10,149 steps per day.

– On days when they met their target, the 10K group averaged 11,775 steps compared with 9,505 for the 30-minute group.

– On days when they did not meet their target, 10K walkers still averaged significantly more activity than the 30-minute
group (7,780 and 5,597 steps, respectively.)

– Compared with their baseline step count before the four-week experiment, the 10K group averaged significantly more steps
even on days when they did not meet their goal of 10,000 steps. Step counts for participants in the 30-minute group were
about the same as their baseline levels on nonattainment days.

“Pedometers are quite popular now, and with good reason,” said lead researcher Dixie L. Thompson, Ph.D., FACSM. “Our study
shows that they can provide an incentive for people to increase their activity levels. Study participants who monitored their
daily steps with pedometers tended to walk more every day, even when they were below their goal of 10,000 steps per day. For
many individuals, walking is the preferred way to reach ACSM’s recommended level of physical activity, which contributes
directly to better fitness and health. In a society where poor diet and physical inactivity contribute to nearly 400,000
deaths a year, increasing our level of physical activity has a very beneficial effect on public health.”

The American College of Sports Medicine is the largest sports medicine and exercise science organization in the world. More
than 20,000 international, national, and regional members are dedicated to advancing and integrating scientific research to
provide educational and practical applications of exercise science and sports medicine.

NOTE: Medicine & Science in Sports & Exercise® is the official journal of the American College of Sports Medicine, and is
available from Lippincott Williams & Wilkins at 1-800-638-6423. For a complete copy of the research paper (Vol. 37, No. 4,
pages 676-683) or to speak with a leading sports medicine expert on the topic, contact the Department of Communications and
Public Information at 317-637-9200 ext. 127 or 117. Visit ACSM online at acsm.

The conclusions outlined in this news release are those of the researchers only, and should not be construed as an official
statement of the American College of Sports Medicine.

Contact:
Christa Dickey
cdickeyacsm
Dan Henkel
dhenkelacsm

American College of Sports
Medicine

Exercise And Mediterranean-Style Diet Could Be Linked To Lower Risk Of Alzheimer’s

A new observational study from the US suggests that exercise combined with a Mediterranean-style diet is linked with a lower risk for
Alzheimer’s disease and the researchers said the findings were strong enough to justify setting up controlled trials to investigate the link more robustly
and see if there are any other factors that might have an affect on Alzheimer’s risk.

The study was conducted by researchers at the Columbia University Medical Center, New York, New York and was published online on 12 August in
the Journal of the American Medical Association (JAMA). The lead author is Dr Nikos Scarmeas, associate professor of clinical neurology in
the Department of Neurology, in the Sergievsky Center and in the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at the
Center.

Although previous studies have looked at links between diet or physical activity and risk of Alzheimer’s disease (AD), this is the first to look at their
combined effect.

“Often times people who exercise also follow a healthy diet and vice versa,” said Scarmeas.

“We wanted to tease out which of these two behaviors may be associated with lower risk for AD, or if the combination of the two is associated with
decreased risk even further,” he added.

For the study, Scarmeas and colleagues used data on 1,880 elderly residents of average age 77 who were part of a multi-ethnic community living in
Northern Manhattan. None of the participants had dementia at the start of the study.

In interviews that took place at the start of the study, the participants answered questions about their diet and level of physical activity.

For physical activity, the participants were asked to say how much vigorous (eg jogging), moderate (eg hiking or cycling), and light (eg golfing or
gardening) they had undertaken in the two weeks prior to the interview.

For diet, they were asked about their food and drink consumption over the previous 12 months. The questions covered nine food categories, the sum
of which gave a single score for how close the diet was to a Mediterranean-style one.

A Mediterranean-style diet typically comprises a high intake of fish, vegetables, legumes (eg peas, lentils and beans), fruits, cereals and
monounsaturated fatty acids, together with a relatively low intake of dairy foods, meats and saturated fats, and a moderate level of alcohol
consumption.

After this, the participants underwent standardized neurological and neuropsychological tests about every 18 months from 1992 to 2006. The
researchers then looked for patterns between diet, exercise and diagnosed cases of Alzheimer’s.

The results showed that:

A total of 282 incident cases of Alzheimer’s disease were diagnosed during a mean follow up of 5.4 years.
Compared with the participants who were least physically active, the most physically active had a 33 per cent reduction in risk of developing
Alzheimer’s disease.
Compared with those who adhered the least, the participants who adhered the most to a Mediterranean-style diet had a 40 per cent reduction in
risk.
Participants reporting the highest level of exercise and whose diet was closest to the Mediterranean-style showed a 60 percent reduction in risk of
developing Alzheimer’s disease compared to those who did not exercise and did not follow a Mediterranean-style diet.

The authors concluded that:

“In this study, both higher Mediterranean-type diet adherence and higher physical activity were independently associated with reduced risk for
AD.”

Scarmeas said it seemed that the more they did in terms of both diet and exercise, the lower their risk of develop Alzheimer’s.

But he also said that even a low level of physical activity seemed to have a protective effect.

Scarmeas said the study is important because:

“It shows that people may be able to alter their risk of developing Alzheimer’s by modifying their lifestyles through diet and exercise.”

But he went on to caution that this was an observational, epidemiological study, and not a randomized controlled trial. The data came from self
reports, the participants were not randomly assigned to different diet and exercise groups, and there was not control group as there would be in a
clinical trial.

“We know that some part of Alzheimer’s is related to genetic changes and as time goes on we discover more and more of these changes. But it is also
possible that non-genetic changes, including lifestyle and behavior, may also be affecting our brain health and our risk of developing brain diseases,
like Alzheimer’s, maybe in combination with our genetic predisposition,” said Scarmeas.

“We need to understand and learn more about the exact biological mechanisms that may connect physical activity and diet with the biological changes
of Alzheimer’s disease,” he urged.

However, he also said that there are now lots of studies linking healthy diet and exercise with various health benefits and prevention of disease, and
given that this study and several others also suggest these benefits could extent to brain health, it would not be unreasonable to emphasize to patients
and healthy people that lifestyle, and not just genes, impact health, including brain health.

Scarmeas is also a co-author of another French study in the same issue of JAMA that found a link between higher adherence to Mediterranean
-type diet and slower rates of cognitive decline but not with lower risk of Alzheimer’s. However, Scarmeas suggests the absence of a link with lower
Alzheimer’s risk was most likely due to the limitations of the study design, such as the small numbers of participants who developed Alzheimer’s and
the fact it examined a Mediterranean population.

Other related articles

What Is The Mediterranean Diet?

“Physical Activity, Diet, and Risk of Alzheimer Disease.”
Nikolaos Scarmeas; Jose A. Luchsinger; Nicole Schupf; Adam M. Brickman; Stephanie Cosentino; Ming X. Tang; Yaakov Stern.
JAMA. 2009;302(6):627-637.
Published online 12 August 2009.

Additional source: Columbia University Medical Center.

: Catharine Paddock, PhD

Stem Cell “fusion” Occurs In Tumors, OHSU Study Says

An Oregon Health & Science University study is adding credence to an increasingly popular theory that fusion is what bonds stem cells with bone marrow cells to regenerate organ tissue.

Scientists in the OHSU School of Medicine found that transplanted cells derived from adult bone marrow can fuse with intestinal stem cells of both normal and diseased tissue comprising the cellular lining of intestinal walls, known as the epithelium. The findings, reported recently in the Proceedings of the National Academy of Sciences, point to the integral role of bone marrow-derived cells in not only regeneration of damaged tissue, but also disease progression.

“It’s the first observation that there’s fusion at the level of stem cells,” said the study’s corresponding author, Melissa Wong, Ph.D., assistant professor of dermatology, and cell and developmental biology. “Second, we’re seeing cell fusion in tumors and we believe that this concept is an underappreciated mechanism for promoting tumor growth. Our findings have implications on how tissues regenerate and how, in the process of this regeneration, cells may become prone to future problems. ”

Although the tumor in her study did not “initiate” tumors or become malignant, Wong believes the fusion process is one explanation for how tumors acquire genetic instability and have the potential to give rise to malignant cancer.

One promising result could be in better understanding the careful balance between rapid and effective regeneration after tissue injury, and minimizing the risk of cancer. This balance can be examined in mouse models of inflammatory bowel disease, where, like humans, epithelial damage and chronic tissue repair occurs.

“Ten percent of patients with inflammatory bowel disease go on to get colorectal cancer,” Wong said. “We think that the bone marrow cells aid in repair of the epithelium, but the cell fusion hybrids that remain are generally unstable. Fusion may be an underlying molecular explanation of why these cells might be more susceptible to cancer development.”

In the PNAS study, Wong and her colleagues transplanted bone marrow cells from female mice into a male mouse model of intestinal cancer. The donor-derived cells were readily detected in the intestinal tumors of the male mice.

To show that the transplanted donor cells fused with the tumor cells, the scientists detected proteins or markers from both the female donor and male recipient cells in tumors. The only way both donor and recipient markers could be present in a single cell, or colocalized, would be if the two cells fused.

One test to prove cell fusion involved looking for the presence of Y chromosomes, or male-characteristic DNA, within the female donor cells marked with a green fluorescent protein. About 60 percent of the epithelial cells were positive for both donor and recipient cell markers. A second test confirmed colocalization using a confocal microscope, which can scan a single cell layer of intestinal cells for the presence of both the green fluorescent protein, indicating female donor cells, and an enzyme from the male recipient cells

Wong said, “Our paper is unique because it’s the first example that cell fusion occurs in the epithelial compartment of a tumor.”

Other OHSU studies in recent years are giving weight to the fusion theory. A series of discoveries since 2000 by study co-author Markus Grompe, M.D., professor of molecular and medical genetics, and pediatrics, OHSU School of Medicine, and director of OHSU’s Oregon Stem Cell Center, showed that blood-forming stem cells derived from bone marrow, called hematopoietic stem cells, cure liver disease in mice through cell fusion rather than transdifferentiation of the transplanted stem cells.

Wong acknowledges fusion is still a new concept. But it’s gaining popularity as a way of explaining the molecular mechanisms that may be at work in regenerating rapidly turning over damaged tissue, or may even be implicated in disease progression.

“The intestinal lining is the protective barrier between your body and the outside environment. Therefore, it sees all of the offensive contaminants that you ingest, from the beer you drink to the charbroiled hamburger you eat, that can induce mutations in the cells. The gut protects itself by rapidly turning over its epithelial cells. Plus, when there is damage to the surface lining, it is critical that regeneration and reestablishment of the barrier occurs rapidly. We think that cell fusion with bone marrow cells is the body’s way of jump-starting that regeneration of the epithelium,” she said.

###

The study was funded by the National Institutes of Health. Other authors in the OHSU School of Medicine were Adnan Rizvi, M.D., surgical resident in dermatology; John Swain, research assistant in dermatology; Paige Davies, Ph.D., postdoctoral fellow of dermatology; Alexis Bailey, research assistant in medicine (endocrinology, diabetes and clinical nutrition); Adria Decker, graduate research assistant in molecular and medical genetics; Holger Willenbring, M.D., former postdoctoral fellow of molecular and medical genetics; and William Fleming, M.D., Ph.D., associate professor of medicine (hematology and medical oncology) and cell and developmental biology.

To access all OHSU new releases, visit ohsu.edu/news/.

Contact: Jonathan Modie
Oregon Health and Science University

BounceU Says: Don’t Let The Winter Break Be A Break From Your Kids’ Physical Activity

New toys. DVDs. Desserts. Days off from school. All of these elements are a recipe for a lethargic winter break. BounceU is encouraging all parents to keep their kids regularly active and off the couch.

Brent Schmick, president of BounceU says regular physical activity can affect weight, muscular strength, aerobic fitness, bone density, blood pressure, anxiety, stress and self-esteem.

According to the Centers for Disease Control, USDA and the National Institute of Health standards, school-age children need at least 60 minutes of physical activity each day and shouldn’t stay stationary for more than two hours at a time.

“It’s really important that time off school doesn’t mean time off physical exercise or activity. In addition, the best way to get your kids moving is to lead by example. Kids whose parents are physically active are more likely to adopt the same type of lifestyle,” Schmick said. “To put it in perspective, a minute of bouncing up and down can burn about three calories – as many as are in one regular M&M candy.”

Schmick suggests a leisurely family stroll, a game of hoops, sledding, swimming or yoga to help move and play together – all of which will make a huge impact in one’s health.

There are four pieces of advice Schmick offers to parents:

- Encouragement: Encourage your kids to be active. Suggest activities. Cheer for them. Praise their efforts.

- Involvement: Go to the games. Join the team boosters. Show them it matters to you.

- Facilitation: Make sure they have access to facilities and/or programs. Don’t count on your kids getting the activity they need at school alone.

- Role Modeling. Walk to work. Run your errands on a bicycle. Stretch regularly. What you do is what they learn.

BounceU locations have expanded their hours for open bounce sessions, family bounce and morning preschool playdates during the winter break. Residents are encouraged to contact them to make reservations.

bounceu

Novocell Presents Phase I/II Data On Safety And Response To Encapsulated Islets At The American Diabetes Association’s 66th Annual Scientific Session

Novocell, Inc., a stem cell
engineering company, presented preliminary data from its phase I/II
proof-of-principle clinical trial for encapsulated primary human islet
allografts in a late-breaking poster presentation today at the American
Diabetes Association’s 66th Scientific Session.

The poster entitled “Encapsulated Human Islet Allografts — Phase I/II
Clinical Trial” described safety and efficacy results following
subcutaneous implants of encapsulated human islet allografts into patients
with Type I diabetes of long standing duration. The first two partially
implanted patients are showing early evidence of encapsulated islet
function. The recipients are not showing evidence of encapsulated islet
destruction by autoimmune reactions or allograft rejection to date. The
patients only received transient low dose cyclosporine (50-100 ng/ml 12hr
trough) and do not receive cyclosporine long term or any other form of
immunosuppression.

“Patients are free of any safety concerns or adverse events to date,”
commented David Scharp, M.D., Chief Medical Officer. “We hope to see
additional efficacy as these recipients receive increasing doses of
encapsulated islets.”

The single site study is being conducted in San Antonio, Texas, with
Co-Principal Investigators, Sherwyn Schwartz, MD, Director of the Diabetes
and Glandular Disease Center and Paraic Mulgrew, MD, of the Transplant
Institute at the Christus Santa Rosa Hospital. The study is partially
funded by the Juvenile Diabetes Research Foundation.

Novocell believes its proof of principle study is important to
demonstrate the safety and efficacy of the encapsulation technology that
can be used with the unlimited source of insulin-producing cells developed
from stem cells to treat patients with diabetes.

Toward this goal, Chief Scientific Officer Emmanuel Baetge, Ph.D. will
discuss engineering stem cells into definitive endoderm, the gatekeeper
cells that are required to produce unlimited quantities of human islet
cells, in a symposium entitled “First Steps in Making Beta-Cells from Stem
Cells” on Tuesday, June 13th from 8 a.m. to 10 a.m. at this same meeting.
Dr. Baetge’s work in this area was published in Nature Biotechnology in
December of 2005 and reviewed in the New England Journal of Medicine in
February 2006. He will also address the importance of the endoderm in the
creation of insulin-producing islet cells.

The combination of stem cell engineering and cell encapsulation
addresses the two primary issues currently limiting islet implant therapy
for the treatment of diabetes: chronic immunosuppression and islet cell
supply. Novocell is currently engineering stem cell derived endoderm for
the production of insulin-producing islet cells as a solution to the
limited islet supply for implantation in people with diabetes.

About Novocell, Inc.

Novocell, Inc. is a stem cell engineering company with research
operations in Irvine and San Diego, Calif. and Athens, Ga., dedicated to
creating, delivering and commercializing cell and drug therapies for
diabetes and other chronic diseases. Novocell is the first company to
efficiently engineer human embryonic stem cells into definitive endoderm,
the gatekeeper cells that are required for the production of
endoderm-derived tissues such as lung, liver, pancreas, intestine, and
thymus. Novocell has three primary technologies: stem cell-derived endoderm
cells, encapsulation and drug discovery. The company was founded in 1999
and merged with CyThera and BresaGen in 2004. For more information, visit
novocell.

Novocell, Inc.

novocell

Report reveals urgent need to improve physical health of people with Schizophrenia

People with schizophrenia often die prematurely. However researchers from the University of Glasgow, Scotland, and NHS
Greater Glasgow assert that much of the excess mortality of schizophrenia is preventable through lifestyle changes and the
treatment of common diseases.

Schizophrenia, its treatment and the lifestyle of sufferers contribute to high rates of illness and mortality. Sufferers
often have poorer diets, lower rates of physical activity and smoke more than the general population. Such lifestyle
‘choices’ predispose them to poor physical health and diseases.

Schizophrenia is a disabling mental illness where disordered thinking disturbs an individual’s ability to function normally
in society. It affects around one in 100 people across Europe. 10-13% of people with schizophrenia commit suicide but most of
the excess mortality in schizophrenia is from natural causes.

Cardio-vascular risk factors in people with schizophrenia are a consequence of the illness itself, related behaviours,
lifestyle and treatments. It is important that mental health and primary care services appreciate the risks they face and how
the illness contributes to premature death.

Excessive body weight increases the risk of ill health, and is the biggest risk factor for type 2 diabetes caused by
antipsychotics. Sufferers are also predisposed to hypertension, heart disease, stroke, osteoarthritis, respiratory problems
and some cancers.

Research has shown that people with schizophrenia are more obese than the non-schizophrenic population. Weight loss
interventions for people with schizophrenia should start with regular and frequent weight monitoring and address exercise,
and lifestyle advice. Switching of antipsychotic medication to one with less-tendency for weight gain and the use of specific
anti-obesity drugs could also help combat obesity in patients.

However, in Glasgow much work is already underway to tackle poor physical health amongst people with schizophrenia. The
integrated schizophrenia care pathway provides a structured route to ensure that physical as well as mental health needs of
patients are addressed; GPs and mental health staff are working together to improve physical health; and support is available
from grassroots projects where people can have their mental and physical health needs assessed at local mental health
resource centres across the city.

Dr Moira Connolly, report author and Consultant Psychiatrist, NHS Greater Glasgow, said: “It’s important that sufferers get
the right type of support from medical and social services. The potential for improving the overall health of this group of
people is only starting to be addressed. However in Glasgow there is already a lot of good work underway to tackle the
problems of poor physical health – such as services which give advice on healthy lifestyles as well as mental health support
and treatment; and much closer working between primary care and mental health professionals to identify physical health
issues.

“Improving physical health is critical to improving the quality of life for people with schizophrenia. The challenge is to
ensure that the physical health of patients with schizophrenia is given the priority it deserves, helping them to face their
future with the lowest possible illness and mortality odds stacked against them.”

People with schizophrenia may fail to recognise the early signs of physical ill health or choose to avoid contact with health
services. The traditional routes to obtaining health care may prove too complex for someone who is chronically distressed by
symptoms or lacking in the motivation required to make and attend an appointment. Guidelines for clinicians and integrated
working across mental health, primary care and social care services could help improve access to health care for people with
schizophrenia.

The researchers also assert that the evaluation of new therapies should include assessments of long-term risk to physical
health in addition to psychiatric effects.

For more information contact: Dr Moira Connolly, Tel: 0141 211 3616 or Jenny Murray, Press Officer, University of Glasgow,
Tel: 0141 330 8593

Reference URL
gla.ac:443/newsdesk/pressreleases/stories.cfm?PRID=3368

SOURCE: alphagalileo

Immunosuppressive Drugs Combo Led To Less Organ Rejection, Better Kidney Health After Transplant

For the thousands of patients who receive kidney transplants in the United States each year, preventing organ rejection without compromising other aspects of health requires a delicate balance of medications. Immunosuppresive drugs that protect transplanted organs can also cause serious side effects, including compromising patients’ immunity to infection, cancer, and other threats. Finding the best combination and dosage of drugs has often proved difficult for physicians.

A new multi-year study has now shown that using tacrolimus (TAC) and mycophenolate mofetil (MMF) in combination provided the best long-term benefits and the least amount of side effects after a kidney transplant. The results, which come from the longest randomized study to date that has analyzed transplant drugs, provide valuable guidance to physicians who care for for kidney transplant patients. The study, conducted by Giselle Guerra, MD, and colleagues at the University of Miami, appears in an upcoming issue of the Journal of the American Society Nephrology (JASN), a publication of the American Society of Nephrology.

To compare therapies, Dr. Guerra studied 150 kidney transplant recipients who received one of three common immunosuppressive treatment regimens: tacrolimus + MMF, tacrolimus + sirolimus, or cyclosporine + sirolimus. Tacrolimus and cyclosporine are in a class of drugs called calcineurin inhibitors; they can prevent early organ rejection but can be toxic to the kidneys. Sirolimus and MMF do not damage the kidneys. Patients often receive low doses of calcineurin inhibitors plus sirolimus or MMF in order to gain the most benefit without serious risk to their kidneys. All patients in the study also received another immunosuppressive drug called daclizumab shortly after transplantation, as well as steroids long term; they were followed for an average of eight years after transplantation.

Among the major findings:
Survival of transplanted organs was similar in all groups of patients.
Significantly fewer patients treated with tacrolimus + MMF (12%) experienced acute rejection, compared to those treated with tacrolimus + sirolimus (30%) or cyclosporine + sirolimus (28%).
Patients taking tacrolimus + MMF also had better kidney function during the first 36 months.
Patients taking tacrolimus + MMF or cyclosporine + sirolimus were less likely to die with a functioning transplant (12% and 4% respectively), compared to those treated with tacrolimus + sirolimus (26%).
Patients who took sirolimus were more likely to develop viral infections, discontinue treatment, and need cholesterol-lowering medications, compared to patients who were not taking sirolimus.

Taken together, these results suggest that transplant patients do better over the long term with tacrolimus + MMF than with either tacrolimus + sirolimus or cyclosporine + sirolimus. “We have been able to prove that the use of low-dose tacrolimus and MMF is safe and provides excellent outcomes over time to renal transplant patients,” said Dr. Guerra.

Notes:

Study co-authors include Gaetano Ciancio, MD, Jeffrey Gaynor, PhD, Alberto Zarak, Randolph Brown, Lois Hanson, DO, Junichiro Sageshima, MD, David Roth, MD, Linda Chen, MD, Warren Kupin, MD, Lissett Tueros, Phillip Ruiz, MD, PhD, Alan Livingstone, MD, and George Burke III, MD (University of Miami).

Disclosures: The authors of this manuscript have conflicts of interest to disclose as described by the Journal of the American Society of Nephrology. Astellas Pharma US, Inc. provided partial salary support (with a grant of $75,000) for the completion of this study to the Kidney and Kidney/Pancreas Transplant Program at the University of Miami. Representatives of Astellas had no direct involvement in this study, and none of the co-authors have any financial interest in Astellas.

Melatonin’s effect on nocturnal blood pressure

Contact: Carole Bullock
carole.bullockheart
214-706-1279
American Heart Association

DALLAS, TX, USA – Melatonin, a naturally occurring hormone found in the body might one day be an addition to traditional high blood pressure treatments, according to a report in today’s rapid access issue of Hypertension: Journal of the American Heart Association.

Lead author Frank A.J.L. Scheer, Ph.D., a neuroscientist at Brigham and Women’s Hospital and at Harvard Medical School’s division of sleep medicine, said that melatonin’s effect on blood pressure might be due to its ability to help regulate the body’s biological clock.

‘It has been reported that people with high blood pressure often have suppressed nighttime melatonin levels,’ Scheer said. ‘We have recently found that people with high blood pressure have actual anatomical disturbances of their biological clocks. This finding might open the door for a new approach for treating hypertension.’

Scheer and colleagues conducted the study at the Netherlands Institute for Brain Research in Amsterdam. They evaluated melatonin’s effect after a single dose versus after a longer regimen.

For three weeks, researchers gave 16 men with untreated essential hypertension (high blood pressure with no known cause) either placebo or 2.5 mg oral melatonin one hour before they went to sleep. They compared the effect of the three-week course to taking melatonin only on one day.

The researchers found that patients taking repeated melatonin had lower nighttime systolic blood pressure (the top number in a blood pressure reading) by 6 millimeters of mercury (mm Hg) and diastolic blood pressure (bottom number) by 4 mm Hg.

The single dose of melatonin had no effect on blood pressure. Patients taking melatonin also reported improved sleep, but Scheer said that effect was unrelated to blood pressure reduction in this study.

While this small study suggests the biological clock might be a mechanism involved in the blood pressure reduction, Scheer and colleagues don’t exclude that improved sleep over a long time might help reduce blood pressure as well.

Dan Jones, M.D., an American Heart Association spokesperson and high blood pressure expert, added a word of caution about the study findings: ‘This report showing a blood pressure-lowering effect of melatonin use is of interest primarily at a theoretical or research level. Larger studies certainly would be needed prior to recommending this approach to patients with high blood pressure.’

‘Patients with high blood pressure should consult their own health care provider for specific advice, but no one should begin melatonin therapy for blood pressure management for the time being,’ added Jones, who is dean of the University of Mississippi Medical Center School of Medicine in Jackson, Miss.

Scheer agreed. ‘This is just a start. Large-scale studies need to be done, as well as studies of potential interactions between melatonin and traditional antihypertensive treatments.’

Co-authors are Gert A. Van Montfrans, Eus J.W. van Someren, Gideon Mairuhu and Ruud M. Buijs.

ADDITIONAL CONTACT INFORMATION: For journal copies only, please call: 214-706-1396

For other information, call:
Carole Bullock: 214-706-1279
Maggie Francis: 214-706-1397

Popular Statin Reduces Recurrent Stroke Risk

In people who have experienced a stroke, but who have no known history of coronary heart disease, beginning regular treatment with the cholesterol-lowering drug atorvastatin soon after the stroke can reduce the risk of recurrent stroke by 16 percent, according to a five-year study led by an international team that includes a researcher at Duke University Medical Center.

The results of the study, called the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, appear in the August, 2006, issue of the New England Journal of Medicine. The study was funded by Pfizer, the manufacturer of atorvastatin.

“This is the first study to demonstrate that treatment with a statin, a type of cholesterol-lowering drug, can reduce the risk of strokes in patients who have had a recent stroke or a transient ischemic attack and who have no known history of coronary heart disease,” said Larry B. Goldstein, M.D., director of the Duke Stroke Center and a member of the SPARCL steering committee.

A transient ischemic attack is similar to a stroke, but is of shorter duration and severity. Often referred to as a ministroke, it is considered a warning sign or prelude for stroke.

“These results will have a major effect on how people are treated following a stroke,” Goldstein said. “The findings are very important for physicians and patients because they show that the addition of this drug to other treatments further reduces the risk of another stroke, which is a pretty big step in improving what we can do for stroke patients.”

Previous studies, Goldstein said, have demonstrated that atorvastatin and other drugs within the class of medications called statins could reduce risk of stroke in patients who have a history of coronary disease. Coronary heart disease is a narrowing of the small blood vessels that supply blood to the heart, usually due to a build-up of cholesterol. It is a leading cause of death for Americans, he added.

The study results showed that atorvastatin — sold as Lipitor — in addition to reducing recurrent stroke risk, can also reduce stroke patients’ risk of heart attack and other major coronary events by 35 percent; their risk of cardiovascular events such as unstable angina by 42 percent; and their need for coronary revascularization procedures, such as coronary artery bypass grafting or cardiac catheterization, by 45 percent, compared to treatment with an inactive placebo.

In the trial, the researchers enrolled 4,731 patients at 205 study sites in Africa, Australia, Europe, the Middle East, and North and South America. All of the patients had experienced either a stroke or a transient ischemic attack within six months of their enrollment. The patients averaged 63 years of age; 60 percent were male and 40 percent female. Patients were monitored for an average of five years following enrollment.

At the time of their enrollment, roughly 66 percent of the patients had experienced an ischemic stroke, which occurs when the blood supply to a part of the brain is suddenly blocked; 2 percent had experienced a hemorrhagic stroke, which occurs due to a leaking blood vessel in the brain; and 30 percent had experienced a transient ischemic attack.

Ninety-four percent of the patients enrolled were already being treated with aspirin or medications that reduce clotting of the blood, and 69 percent of the patients, most of whom had high blood pressure, were receiving treatment with blood-pressure lowering medications. Those treatments were continued during the patients’ participation in the SPARCL study.

The researchers randomly assigned patients to receive either 80 milligrams per day of atorvastatin or an inactive placebo. The study was double-blinded, meaning that neither the researchers nor the patients knew in advance which patients were receiving the active medication.

The study found that atorvastatin, compared with the placebo, reduced the risk of fatal and nonfatal strokes by 16 percent.

This overall reduction in the risk of stroke was present despite a small increase in the number of patients having one of the types of stroke, hemorrhagic stroke. Due to the small number of people recruited into the SPARCL trial with a previous hemorrhagic stroke, the researchers said that it is not possible to reach any meaningful conclusions regarding their risks and benefits with atorvastatin treatment.

The researchers suggest that the drug appears to exercise its overall protective effect by lowering the levels of low-density lipoprotein (LDL) cholesterol — popularly known as “bad” cholesterol — in patients’ blood. High levels of LDL cholesterol in the blood are known to increase the risk of coronary heart disease, a risk factor for stroke as well as heart attack.

Patients who received atorvastatin had an average LDL cholesterol level of 73 milligrams per deciliter of blood, compared with an average of 129 milligrams per deciliter for patients on placebo, the researchers said.

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The SPARCL study, including the work of the steering committee, was supported by Pfizer. Goldstein also has consulted for Pfizer and other manufacturers of statin medications.

Other members of the SPARCL steering committee, who also were co-authors of the report, include Pierre Amarenco of Denis Diderot University, Paris, France; Julien Bogousslavsky of University of Lausanne, Switzerland; Alfred S. Callahan III of Neurologic Consultants, P.C., Nashville, Tenn.; Michael Hennerici of Universitat Heidelberg, Mannheim, Germany; Henrik Sillesen of University of Copenhagen, Denmark; Justin Zivin of the University of California at San Diego; and K. Michael A. Welch of the Rosalind Franklin University of Medicine and Science, Chicago, who chaired the steering committee. Other co-authors, who are not members of the steering committee, include Amy E. Rudolph, Lisa Simunovic and Michael Szarek, all of Pfizer.

Contact: Tracey Koepke
Duke University Medical Center