U.S. must remove the handcuffs from stem-cell researchers

By Dianne Feinstein

July 19, 2005
Source: The Mercury News

Seven years after publicly announcing his battle with Parkinson's disease, Michael J. Fox still draws a crowd. These days it's not for a Hollywood premiere, but to encourage Congress and the president to expand federal funding for embryonic stem-cell research.

Last week, Fox was in Washington representing the millions of Americans who are suffering from devastating and catastrophic diseases and can't understand why our government isn't making a major commitment to fund and encourage this promising research.

I can't quite understand it either. Embryonic stem-cell research is the bright new frontier of medicine. It offers the potential to conquer Parkinson's, diabetes, spinal cord injuries, Alzheimer's and cancer. Our nation should be mobilizing toward this great goal.

But the policy set out by President Bush in August 2001 hamstrings scientists and creates new hurdles for researchers. President Bush's policy originally identified and provided federal funding for 78 stem-cell lines that were already in existence. Today we know that only 22 are available. All 22 are contaminated by mouse feeder cells, and none can be used for research in humans.

The House of Representatives has approved legislation to expand federal funding for embryonic stem-cell research. New lines would be created from embryos that would otherwise be discarded from in vitro fertilization clinics.

The Senate stands ready to pass the same legislation by a large majority and send it to the president.

However, barriers to passage remain. Opponents of this legislation are trying to muddy the waters with alternatives and amendments designed to prevent embryonic stem-cell research from going forward. And President Bush has threatened to veto this legislation.

No matter what happens in Congress, embryonic stem-cell research will go forward.

Researchers in other countries are overcoming hurdles and achieving breakthroughs on stem-cell research almost every day. South Korea has announced that its scientists have crated 11 human stem-cell lines that are genetically identical to 11 patients with spinal cord injuries and juvenile diabetes ranging in age from 2 to 56.

Other countries are not far behind: Research is also moving forward in Australia, India, the United Kingdom, Canada and China. And American scientists have left the United States to work on their research in these countries.

In the United States, four states have provided their own funding for embryonic cell research. Just last week, Illinois Gov. Rod Blagojevich signed an executive order to distribute $10 million in grants. California voters approved a $3 billion bond measure to provide funding over the next 10 years. Connecticut has provided $100 million over the next 10 years. And the New Jersey Senate has approved $150 million.

Nevertheless, there needs to be an effective federal stem-cell policy to provide consistent framework for funding and strict ethical standards.

So I'm calling on all Americans to create a drumbeat of support for embryonic stem-cell research. Call your senators. Write the president. Tell him the time has come for the federal government to equip our researchers with the tools they need to find cures.

President John Kennedy in 1961 set out a great goal before our nation -- to put a man on the moon by the end of the decade. And we reached that goal -- as a result of American ingenuity, persistence and drive.

The same could be true with embryonic stem-cell research. We can find new cures and treatments in the next decade. But we will not reach this goal if we handcuff our researchers and scientists.

DIANNE FEINSTEIN represents California in the U.S. Senate. She wrote this article for the Mercury News.

Stem Cell 'Alternatives' Fog the Debate

By Paul Berg, George Q. Daley and Lawrence S.B. Goldstein

Source: Washington Post, A21

The Senate is on the threshold of a momentous decision: whether to expand research on human embryonic stem cells. In casting their votes, senators must decide whether to support the judgment of a large, bipartisan House majority (and an overwhelming majority of scientists and the public) or to further delay vital medical research.

Given the general agreement that such research has the potential to relieve the misery and suffering of millions, we find it troubling that opponents of this legislation (H.R. 810 or S. 471) are trying to divert the debate about the merits of expanding this research by promoting dubious approaches to obtaining stem cells that even their supporters concede are scientifically and ethically problematic. What is so bizarre about this effort is that there is no need for the administration and its congressional followers to seek authorization to pursue these proposed "new" approaches for obtaining stem cells. Research on these proposed alternatives is already legal and can be funded by existing mechanisms.

We want to be very clear: The most successful demonstrated method for creating the most versatile type of stem cells capable of becoming many types of mature human cells is to derive them from human embryos -- at present, excess embryos created at in vitro fertilization clinics and freely donated for research by couples who choose not to have them destroyed as medical waste.

While some of the proposed alternatives being suggested may have some promise, they are unproven. Some, in fact, are ethically questionable when performed with human tissues. One idea is to derive stem cells from embryos that have stopped developing and are thought to be "biologically dead." Beyond the fact that scientists haven't developed a reliable method for determining an embryo's "death," there is no scientific evidence that stem cells derived from these embryos would have the required properties or be safe for human therapies.

Another set of proposals focuses on attempts to reprogram adult cells to revert to an early, undifferentiated, stem cell-like stage of development. This is an important, though highly speculative and ambitious, goal. Indeed, it is a goal that developmental scientists are already seriously investigating today, but with many uncertainties about whether and how it can be made practical. Still another proposal is to separate a single cell from a live embryo while attempting to preserve the embryo's potential to initiate a pregnancy and normal birth. This proposal is not only speculative but poses ethical concerns as to possible damage that might be inflicted on the embryo.

In a July 12 op-ed in The Post, Leon R. Kass, chairman of the President's Council on Bioethics, wrote: "It may be that some opponents of embryo research are using these worthy proposals for . . . a political purpose." We agree: It is likely that some opponents are pursuing a political purpose in their public embrace of these proposals. We also agree that federal funding for these and many other proposed options, including adult stem cell research, should continue to be provided.

But it needs to be understood that most of the proposed alternatives are not restricted by a presidential executive order, although they may run afoul of other federal restrictions on research with human embryos. Interested scientists need only write a grant proposal and pass the scientific peer review process for technical merit to secure funding for the research. It is the president's executive order of Aug. 9, 2001, that is impeding research progress in bringing potential stem cell therapies to the clinic. That is why legislation to lift the federal limits on research with human embryonic stem cells should be passed.

We urge Congress to deal with this matter on its scientific merits without raising a laundry list of other speculative scientific approaches that serve only to confuse the issue. The treatment of otherwise intractable diseases can become a reality if we expand the number and quality of the stem cells that American scientists have to work with.

Paul Berg is emeritus professor in cancer research at Stanford University. George Q. Daley is an associate professor at Harvard Medical School and associate director of the stem cell program at Children's Hospital in Boston. Lawrence S.B. Goldstein is a professor of cellular and molecular medicine at the University of California at San Diego School of Medicine and an investigator at the Howard Hughes Medical Institute.

Bedtime rituals that forge warm memories

Susan Newman, PhD

Most of us feel as if the entire day flies by without a moment to catch our breaths. Although parents usually follow a bedtime ritual with their young children, it, too, is often cut short or rushed. But reserving that time and making it sacred reaps both immediate and long-term rewards for you and your child.

The rituals below allow you to learn what your child is thinking and build a bond and intimacy difficult to develop during the hectic day. If your child doesn't catch on at first, be patient. Try again the next night and soon one or two of these will become a cozy, welcomed routine.

Remember when...
Tell stories of funny things your child did when she was a baby, too young to remember. Children delight in being the central focus of stories and what is unique to one child separates him from his siblings and helps to define him. Children love repetition so it's unlikely you'll be at a loss for ideas.

Relate silly or memorable things that happened on family vacations or during family get-togethers. Some undoubtedly will become family lore like the visit we had from a squirrel that ran across the dining room floor during Thanksgiving dinner and the human chase that followed. Years later, the children, now teens and young adults, ask if we're inviting a guest squirrel to dinner this year.

Best and worst part of your day
Within this bedtime ritual parents have time to praise the good things a child reports as well as help her with decision-making and problem solving related to bad things she may have encountered -- a toy broken by a friend, a lost sweater, or the demise of a goldfish. If you start this ritual when children are young, they are more likely to express their feelings and be willing to ask for your help you when they are older and bedtime rituals are a thing of the past.

When I grow up I want to be...
A preschooler will want to be a rabbit, a giraffe, or a clown one night, a firefighter or police officer the next. Ask you child what she would do if she were a monkey, for example, and discover her fantasies. With older children you have the chance to explore and explain endless career possibilities. Every night will be an eye-opening peak into your child's mind.

Once upon a time...
Make up a story with parent offering the first line and making your child the hero or heroine, always. Be sure to include his friends in the story. Run the story over several nights or begin a new one each night.

Magic carpet
With fanfare and a flourish lay a small blanket over the bed then tuck it in just so. You can use one of your child's baby blankets or his favorite small quilt. Say, "We're on the magic carpet. Where are we going tonight?:" If your child doesn't have any ideas, suggest a visit to Aunt Betty or a trip to Arizona. Talk about what you might see and do wherever you "go" each night.

In riding the magic carpet you can present a larger world to a child, talk about the weather, the vegetation, the art, the culture, the activities found in the area your child chooses. If he decides to take a Magic Carpet ride to visit a relative, you have a chance to let him know what is special about that relative and in that way keep distant relatives close.


Be thankful
Tell me two or three things you are thankful for today.

Parents may want to start: I'm thankful for the extra time your teacher spent with you and for your help clearing the table. Younger children might be thankful for the dog, a visit from Grandma, two turns on the slide, but as children get older their comments will be more sophisticated. "Things to be thankful for" fosters gratitude and appreciation in children.

Kelley as a little bear
Create a family song to a familiar tune that includes your child's name or family members near and far to sing at bedtime. Here's a start to the tune of "Mary had a Little Lamb:"

Kelley has a little bear, little bear, little bear,
Kelley had a little bear, it's fur is brown as dirt.

She carries Spark to bed each night,
To bed each night, to bed each night.
Everywhere that Kelley went, Kelley went, Kelley went,
Spark was sure to go.
She carries him to bed each night,
To bed each night, to bed each night, that's not against the rules.

Spark makes Kelley laugh and play,
Laugh and play, laugh and play...

Animal tuck-ins
Spread a small blanket the end of your child's bed and let him tuck in Barnekee, Spot and Bandit saying "good night, sleep tight" in turn to each special stuffed animal. You then say, "your turn, I love you" and tuck in your child with an extra long hug.

Goodnight, Grandma
A ritual offering the chance to keep relatives and the important people in your child's life prominent. Beyond grandma and grandpa, include cousins, aunts and uncles, best friends and favored teachers or instructors. Include those special stuffed animals, too, if your child asks. On successive nights, you can ask your child if she would like to add someone -- a baby cousin, a new friend, perhaps?

Nite, nite
At the end of the day top off your rituals with a designer kiss. Two pecks on the forehead, one on the nose and one on the head, for example, underscores how special your child is to you.

Think of bedtime exchanges as warm deposits in your child's memory bank. Anyone of these rituals starts a tradition your child will undoubtedly pass along to his or her children.

Kids Need More Sleep

HEALTH NEWS — It's a problem we tend to associate with adults, but sleep apnea and insomnia can affect children, as well. And just as it is for adults, the side effects can be harmful and dangerous in children.

About one to three percent of children not only snore, but also suffer from breathing problems during their sleep. When snoring is accompanied by gasps or pauses in breathing, the child may have oobstructive sleep apnea (OSAS), according to a report by the National Sleep Foundation.

The National Sleep Foundation says, in children, the most common physical problem associated with sleep apnea is large tonsils. Young children's tonsils are quite large in comparison to the throat, peaking at five to seven years of age. Swollen tonsils can block the airway, making it difficult to breathe and could signify apnea.

Undiagnosed and untreated sleep apnea may contribute to daytime sleepiness and behavioral problems including difficulties at school.

If untreated obstructed sleep apnea can cause a whole host of problems such as heart disease, irregular blood pressure and reduced levels of oxygen in the blood.

A recently published study found that taking the tonsils and adenoids out significantly improved the breathing and oxygen levels in the majority in children.

The only other treatment for kids with sleep apnea is to wear a C-Pap mask, which can be uncomfortable. Children who had surgery had less soar throats and difficult swallowing.

Recent Developments on the Genetics of Alcohol Use

Although researchers know that alcohol-use behavior and disorders are significantly genetic in nature, identification of the specific genes that contribute to an individual's susceptibility for alcohol dependence has been difficult. Many investigators have begun to examine alcohol dependence in relation to its component parts – called phenotypes – to better understand the genetic bases of alcohol use and dependence. Proceedings of a symposium on the genetics of alcohol-related phenotypes at the Congress for the International Society for Biomedical Research on Alcoholism in Mannheim, Germany in October 2004 are published in the July issue of Alcoholism: Clinical & Experimental Research.

"The discoveries we discussed help to narrow the search for those genes that increase a person's vulnerability for developing alcohol dependence and its physical consequences," said Victor Hesselbrock, professor of psychiatry at the University of Connecticut School of Medicine and corresponding author for the proceedings. "Clinically, there are several different types of alcoholism, each with a somewhat different etiology and sometimes a different response to treatment and eventual outcome. Further, there is a variable pattern of physical consequences found among different populations of alcoholics. The current findings provide some clues for understanding the biological bases of these differences."

Some of the key proceedings were:

- Polymorphisms of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase-2 (ALDH2) may explain individual differences in the concentration and elimination of alcohol and acetaldehyde in the blood after heavy drinking, and may also help to explain alcohol-related organ damage.

"When alcohol is consumed, there are two primary enzymes responsible for its metabolism: ADH and ALDH," explained Hesselbrock. "ADH is responsible for the initial metabolism of alcohol into acetaldehyde, and ALDH is responsible for metabolizing acetaldehyde into acetate and water." If acetaldehyde, a volatile and toxic compound, is not quickly converted and then eliminated from the body, it can cause considerable damage to the human body.

"Both enzymes are under genetic control, which determines ADH's ability to metabolize alcohol and ALDH's ability to metabolize acetaldehyde," said Hesselbrock. "Further, there is considerable individual variation in the expression of both ADH and ALDH. Long story short, if a person is not able to rapidly metabolize acetaldehyde, different organ systems are exposed to higher levels of acetaldehyde for extended periods of time. According to these findings, it is this extended exposure to acetaldehyde that is thought to be responsible for organ damage resulting from chronic alcohol use."

- Several chromosomal regions – particularly an area of chromosome two – were linked to suicidal behavior, conduct disorder symptoms, and alcohol dependence. This suggests a "sharing" of genes for several different, but often related, types of behavior.

"Suicidal behavior, childhood problem behaviors, and alcohol dependence are all considered to be 'externalizing behaviors,' that is, behaviors an individual expresses outwardly towards others," said Hesselbrock. "Contrarily, internalizing behaviors are behaviors that are directed inward and include depression and anxiety. For some time, scientists have thought that specific genes may be responsible for influencing specific behaviors. While this is true for certain biological traits and some medical diseases, more recent studies are indicating that many genes influence a variety of behaviors."

Hesselbrock said that individuals with alcohol dependence often display a variety of conduct disorder problems and suicidal behaviors. "In other words, this study indicates that at least some of the genes that increase a person's vulnerability for developing alcohol dependence may also contribute to their susceptibility for conduct disorder and suicidal behavior," he said.

- Serotonin (5-HT) appears to be a key neurotransmitter in antisocial alcoholism and related phenotypes. More specifically, the 5-HT 1B G 861 C polymorphism appears to play a role in antisocial behavior and alcohol dependence.

"Serotonin is a chemical produced in the brain that has been shown to be related to many types of normal and abnormal behavior," explained Hesselbrock. "Aggressiveness, depression, drug use, migraine headache, pain sensitivity, and sleep disorders are examples of clinical conditions that are influenced by altered brain serotonin function. However, there are several different families of serotonin receptors in the brain, and variations in serotonin affect different receptor systems producing different clinical outcomes."

While previous human and animal studies have shown that serotonin is responsible for both aggressive behavior and increased alcohol consumption, said Hesselbrock, this study has demonstrated that the 5-HT 1B G 861 C gene – which controls one family of serotonin receptors, the 5HT1B group – occurs more frequently among antisocial alcoholics than non-antisocial alcoholics. "Although not definitive," he said, "this finding does indicate that the 5HT1B G 861 gene is associated with the development of antisocial alcoholism."

Collectively speaking, said Hesselbrock, "these findings highlight the importance of the clinical phenotype for elucidating susceptibility genes. While chronic drinking is common to all persons with alcohol dependence, there is considerable variation in other aspects of the clinical phenotype. These findings help to narrow the search for those genes that contribute to alcohol dependence, suggesting also that some genetic contribution may be phenotype specific."

Teen girls have healthier stress response than boys

By Charnicia E. Huggins

NEW YORK (Reuters Health) - Adolescent girls may be better protected against the effects of stress than teenage boys, according to a team of Georgia researchers. In a study of teenagers' responses to mental stress, they found that girls did not exhibit the same increase in blood pressure as did their male peers.

"Very few studies have reported a teenager's response to prolonged mental stress," Dr. Gaston Kapuku, of the Medical College of Georgia said in a statement. "Our findings indicate that females are protected against the effects of stress as demonstrated by their ability to maintain lower blood pressure."

The findings were presented Sunday during this year's meeting of the International Society on Hypertension in Blacks (ISHIB), held in Puerto Rico.

For the study, 190 African-American and European-American teenagers, aged 16 to 18 years, with normal blood pressures spent 60 minutes playing a competitive video game. The researchers measured the teenagers' blood pressure and heart rates at 15-minute intervals during the two-hour rest period before they began the stress activity -- i.e., playing the video game -- as well as during the game, analyzing the change that occurred between the two periods.

Based on heart rate alone, teenage boys and girls appear to react similarly to mental stress, the results indicate. Girls had a slightly higher heart rate than did their male counterparts, but both groups seemed to be equally stimulated by the game.

Changes in systolic blood pressure -- i.e., the upper reading, pressure when the heart contracts -- varied between the sexes, however, with teenage girls exhibiting smaller changes in blood pressure than did teenage boys.

"Girls have some kind of protection in terms of blood pressure response," Kapuku told Reuters Health. He added that "people who react with high blood pressure are prone to develop more cardiovascular disease."

White girls had even smaller changes in blood pressure than did black girls, the study findings show. The reason for this "puzzle" is unknown, Kapuku said, although it might be related to differences in hormones or a number of other pathways that influence stress reactions.

Other research has also pointed to the existence of ethnic and sex differences in cardiovascular disease. Heart failure, for example, has been found to be more prevalent among women in comparison to men. Further, blacks are known to have a higher incidence of premature heart attack, high blood pressure and other factors that put them at risk for cardiovascular disease.

The new findings suggest there is "already a difference in childhood," in such risk factors, Kapuku said.

In light of these findings, Kapuku advises that patients, especially those with heart disease, determine their doctor's knowledge of ethnic and sex differences by asking if they will receive the same treatment or if they are expected to respond to treatment in the same way as patients of the opposite sex or a different ethnicity.

In so doing, he said, they can have a "better chance of better care."



© Reuters 2005. All Rights Reserved.

Teen pregnancy effort focuses on guys

St. Clair County rate is higher than statewide average

BY ALIANA RAMOS

News-Democrat


Wise Guys, a teen pregnancy prevention program that focuses on male youths, will be coming to the metro-east this fall.

The program is available because of an $80,000 grant the state awarded to the St. Clair County Health Department in June for teen pregnancy-prevention programs.

"In general, men have been left out of prevention efforts," said Paula Brodie, the health department's director of community programs. "What we want to do specifically with Wise Guys is to focus on young men. They have a responsibility as well as young ladies to prevent pregnancy."

The latest figures from the Illinois Department of Public Health show that although the rate of teen births is decreasing, the percentage of teen births in St. Clair county is 4 percent higher than the percentage of teen births in Illinois.

In 2003, 9.7 percent of births in Illinois were to teen mothers, while in St. Clair County the rate was 13.7 percent.

"This is a new approach," Brodie said. "We have to begin to work with young men and the partners of the young women we work with."

Brodie said the Southern Illinois Healthcare Foundation has been subcontracted to offer the Wise Guys program for to community centers, religious organizations and schools beginning in September for boys ages 11 to 17. The plan is to present the program to 200-300 males in the first year.

The Wise Guys curriculum includes a variety of topics including: personal and family values; communication; sexuality; dating violence; abstinence and contraceptives; sexually transmitted diseases; goal-setting and decision-making.

According to Wise Guys literature, the program also includes a parental involvement component which aims to train parents of young males in communication techniques, teaching self-responsibilty and giving human sexuality information.

One of the activities that is part of the curriculum is having each of the boys rank a list of 15 personal values in order of importance. The values include: "making it on my own," "living by my religion," "being good in sports" and "preparing for my future."

In 1995, Wise Guys was recognized by the Adolescent Pregnancy Prevention Coalition of North Carolina as the "Best Practice Model" and was an award winner for the National Campaign to Prevent Teen Pregnancy in 2003.

Whitney Steele of the health department said any money left over from the grant will be used for revising the department's Baby Think It Over program and adding parental involvement workshops.

The Baby Think It over program involves 2 to 3 days with a simulated infant and a week of classes that focus on youth development. Steele said the program will not include contraceptives but will center on decision-making, self-esteem, responsibility and personal power.

Advances in Pharmacogenomics Reduce Side Effects and Save Lives

By Arline Kaplan
Psychiatric Times



When a 9-year-old diagnosed with attention-deficit/hyperactivity disorder, obsessive-compulsive disorder and Tourette's disorder died, the medical examiner attributed the cause of death to fluoxetine (Prozac) toxicity (Sallee et al., 2000). Genetic testing of autopsy tissue confirmed the presence of a gene defect at the cytochrome P450 (CYP) 2D6 locus, which resulted in poor fluoxetine metabolism. In another case, a woman spent 10 years trying different treatments for her depression, but with each new antidepressant, she experienced excruciating headaches or other intolerable adverse effects until she was switched to a drug that did not need the CYP 2D6 enzyme to function (Lerner, 2004).


Psychiatrists and other physicians have long known that patients vary considerably in their responses to psychotropic medications, with some requiring much higher or lower doses than average and others failing to respond at all. Many factors, including diet, drug-drug interactions, gender, age, overall health, hepatic disease and genetic variations, can affect the availability of a drug in the body. Now, technology, clinical research and government policy are converging to create what has been called "personalized medicine." Advances in DNA testing combined with clinical studies are helping clinicians identify the best drug or dosing strategy for a particular patient.


Recently, the U.S. Food and Drug Administration cleared for marketing the first laboratory test system that allows physicians to consider unique genetic information from patients in selecting medications and doses for psychiatric disorders, among other medical conditions. The new test, the AmpliChip Cytochrome P450 Genotyping Test made by Roche Molecular Systems, Inc., was cleared for use with the Affymetrix GeneChip Microarray Instrumentation System, manufactured by Affymetrix, Inc. A microarray is similar to a computer microchip, but instead of tiny circuits, the chip contains millions of tiny DNA molecules. The test is performed using DNA extracted from a patient's blood. A person's DNA sequence is determined based on the sequence of the probe molecule to which the DNA is most similar.


Last December, the FDA cleared the AmpliChip CYP450 Test for CYP 2D6 and two weeks later cleared the test for CYP 2C19. The complete test kit and instrument system, a company spokesperson told Psychiatric Times, are being made available to reference laboratories and high complexity labs. The AmpliChip CYP450 Test was launched in Europe in fall 2004.


The test checks for the 31 polymorphisms (naturally occurring variations in DNA sequence) and mutations, including gene deletions and duplications, on a single chip (29 polymorphisms and mutations for the 2D6 gene and two polymorphisms for the 2C19 gene). The CYP 2D6 and CYP 2C19 enzymes play a role in the metabolism of about 25% of all prescription drugs. The polymorphisms influence how an individual metabolizes antidepressants, antipsychotics and other psychotropic medications. For example, by recognizing common DNA polymorphisms in the CYP 2D6 or CYP 2C19 genes, DNA chips can determine if an individual is a poor metabolizer who would be at increased risk for experiencing adverse drug reactions or toxicities or an ultrarapid metabolizer who would be at increase risk of being a nonresponder (Table).


Genotyping for CYP 450 drug-metabolizing enzyme DNA sequence variants can be accomplished using a variety of test formats. Several companies are offering testing services either for research studies or for patient management (Technology Evaluation Center, Blue Cross and Blue Shield Association, 2004). Some new pharmacogenetic technologies include GE Healthcare's CodeLink Human P450 SNP Bioarray that genotypes 110 single nucleotide polymorphisms (SNPs) with nine P450 genes, including 2C9, 2C19, 2D6 and 3A4; Jurilab Ltd.'s Drug Met Genotyping Test, a microarray that profiles patients for the presence of SNPs in eight different enzymes, chosen according to their importance in drug metabolism; and Tm Bioscience Corp.'s Tag-It Mutation Detection Kits for the CYP 2D6, CYP 2C9 and CYP 2C19 genes to identify the presence or absence of 26 mutations that can be associated with adverse drug reactions. Some companies providing clinical diagnostics include Seryx-Signature Genetics, Genelex, Esoterix and Quest Diagnostics.


Clinical Studies


In tandem with the advancing technology have come studies looking at the clinical utility of pharmacogenomic genotyping. De Leon and colleagues (2005) found that the CYP 2D6 poor-metabolizer phenotype may be associated with adverse drug reactions to risperidone (Risperdal) and discontinuation, while the CYP 3A5 and P-glycoprotein exon 21 and 26 genotypes were not significantly associated with risperidone response.


Adult inpatients and outpatients from psychiatric facilities in central Kentucky were recruited from July 2000 to March 2003. There were 325 patients who were stabilized on risperidone therapy (73 of whom were having moderate-to-marked adverse drug reactions [ADRs] such as resting tremor, stiffness, hypersalivation and sedation), and there were 212 patients who had discontinued risperidone (81 because of adverse drug reactions and 131 for other reasons). Genetic tests were performed by allele-specific polymerase chain reaction (PCR) and by the AmpliChip CYP450 microarray system for up to 34 separate CYP 2D6 alleles. Polymorphism within CYP 3A5 and the drug transporter P-glycoprotein, thought to be capable of influencing risperidone pharmacokinetics, were also evaluated. The study investigators wanted to determine whether the CYP 2D6 phenotype would prove useful in predicting which patients discontinue risperidone therapy in a real clinical setting. They noted:


If genetic testing is to be introduced as a standard clinical tool, it is important to determine if it can provide meaningful information for clinicians in the uncontrolled, 'noisy' clinical environment where psychiatrists use different doses, prescribe co-medications and often make experience-based decisions that vary from patient to patient.



The authors found that among those still taking the drug, the CYP 2D6 poor-metabolizer phenotype increased the odds of having moderate adverse drug reactions by 3:1. Additionally, the univariate analysis suggested that the CYP 2D6 poor-metabolizer phenotype increased the odds of having risperidone discontinued due to ADRs by 3:0.


"Clinical confounders did not explain the CYP2D6 poor metabolizer phenotype association with moderate-to-marked ADRs or with risperidone discontinuation due to ADRs," the authors wrote. "In fact, the OR [odds ratio] increased from 3.0 to 6.0 for the CYP2D6 poor metabolizer phenotype when confounders were considered among patients who discontinued risperidone due to ADRs."


Not every participant who had CYP 2D6 poor metabolizer phenotype had problems while taking risperidone, the authors added. Low doses of risperidone appear to offer CYP 2D6 poor metabolizers some protection from developing ADRs.


The lead author, Jose de Leon, M.D., is associate professor of psychiatry at the University of Kentucky and medical director of the Mental Health Research Center at Eastern State Hospital. His pharmacogenetic laboratory and research activities are possible due to the support from the Bluegrass Regional Mental Health and Mental Retardation board, which manages Eastern State Hospital. He told PT that he and his colleagues are now engaged in a study funded by Roche Molecular Systems looking at the association of CYP 2D6 genotype with psychiatric treatment outcomes. Part of the study will explore the cost-effectiveness of such testing.


"From the point of view of the patient, these tests are beneficial. If I am a poor metabolizer or my son is a poor metabolizer of CYP 2D6, I want to know. In general, when we do these tests on the patients, the families are very grateful, because for the first time we can provide them with an explanation as to why patients have had problems for so many years. But when you go to a hospital or medical center and tell the administrator that you want the hospital to buy a machine to do this testing, the first question he or she is going to ask is, 'Is it cost-effective?'" de Leon said.


The purpose of the new study is to do testing on 3,000 to 4,000 patients and determine if the DNA tests can be used in clinical practice and whether appropriately matching patients to the drug and dosage can save money over the long term.


"Patients who don't have CYP 2D6, or who have too much, usually don't do well on typical doses of medications. Their doctors have to try several times until they find the right dosage or the right medication," he added.


De Leon already has DNA samples from some 2,500 patients. The study will be much broader than the risperidone study and will look at other antipsychotics and antidepressants metabolized by CYP 2D6. He is also conducting a study funded by the National Alliance for Research on Schizophrenia and Depression to explore the association between genetic variants and selective serotonin reuptake inhibitors toxicity.


"We are going to be looking at genetic variations in the serotonin system (serotonin receptors and serotonin transporters) in brain," he said. "What we are going to be doing is seeing if any variations also have anything to do with the side effects of SSRIs."


The University of California at Los Angeles' (UCLA) Pharmacogenetics and Pharmacogenomics group is carrying out a prospective, phenotype-to-genotype study, known as the Pharmacogenetics of Antidepressant Treatment Response in Mexican-Americans (PATRIMA), involving fluoxetine and desipramine (Norpramine). Another study on the effects of genetic factors on citalopram (Celexa) treatment response in African-Americans and whites is being conducted at Cedars-Sinai Medical Center, Harbor-UCLA Medical Center and UCLA-King/Drew Hospital.


Possibly one of the largest studies in Europe is a multicenter, integrated project focusing on functional genomics of depression and pharmacogenomics of antidepressant treatment (GENDEP). The 7.5 million euro project, funded by the European Union under its Sixth Research and Development Framework Programme, seeks to find a way to use information about patients' genes to help physicians decide which antidepressant treatment will work best with the least side effects. Peter McGuffin, Ph.D., and Katherine Aitchison, Ph.D., both of the Social, Genetic and Developmental Psychiatry Centre at King's College Institute of Psychiatry in London, are leading a team of scientists and clinicians from 10 countries.


In the patient-based part of the project, 1,000 patients with depression will be randomly assigned to one of two antidepressant treatments (the SSRI escitalopram [Lexapro] or the tricyclic antidepressant nortriptyline [Pamelor, Aventyl]). Recruitment for the three-year project began in September of 2004. The clinical progress of the participants and any development of any side effects will be monitored during a six-month follow-up period. The team will then compare how the patients responded to their assigned treatment with information about their genetic makeup being determined by a single blood sample.


The project also provides long-term access to well-characterized samples from specialist groups across Europe and to the platform to identify new targets for drug discovery and for early diagnosis of disease. The team will carry out basic research using cells grown in the laboratory and rodent models to learn more about how antidepressants work at the cellular level and how they affect the nervous system.


Additionally, project funders stipulated that there be a corollary study of the ethical, legal and social implications of pharmacogenetics, examining such issues as informed consent, confidentiality, data handling, findings dissemination, intellectual property, commercialization and attitudes toward tailoring drugs to a person's DNA.


"One third of individuals treated with antidepressants will fail to show an adequate clinical response or will suffer intolerable adverse events," explained McGuffin in the GENDEP proposal. "The resultant delay in effective treatment may contribute to chronicity of illness, and consequent morbidity with resultant burden of disease to society, while the experience of adverse effects may lead to poor compliance with future treatments. There is, therefore, an urgent need to improve our understanding of the aetiology of depression and the efficacy and tolerability of antidepressants."


A spokesperson for Roche Molecular Systems said that their company is providing its DNA testing materials for the GENDEP study and also to Aitchison, who is studying the impact of CYP 2D6 genotyping on reduction of side effects in patients taking TCAs. In the United States, the Roche spokesperson said the company is fully funding a study on the CYP 2D6 genotyping and atomoxetine (Straterra), a selective norepinephrine reuptake inhibitor. The labeling for atomoxetine, which is a CYP 2D6-metabolized drug, includes a discussion of poor metabolizers.


In several countries in Europe, psychiatrists are using CYP 2D6 testing in their clinical practice, de Leon said. In the United States, he knows of two places: the Pharmacogenetics Diagnostic Laboratory at the University of Louisville School of Medicine and the Mayo Medical Laboratories.


"We have been using clinical genotyping of the 2D6 cytochrome gene since February 2003. The test for the 2C19 gene became available in 2004," said David Mrazek, M.D., chairperson of Mayo Clinic's department of psychiatry and psychology and director of Mayo Clinic's Genomic Expression and Neuropsychiatric Evaluation Unit. He explained to PT that psychiatrists from all over the country having been sending in samples for testing over the past year to the Mayo Medical Laboratories. The testing is particularly helpful if the patient has a history of problematic reactions to medications. The purposes of the test, Mrazek added, are to identify poor metabolizers who are at high risk for side effects, ultrarapid metabolizers who do not respond to normal doses of some medications because these medications are metabolized too quickly, and intermediate metabolizers who will usually require a lower dose of the relevant medications.


The University of Louisville lab also works with physicians, clinics and hospitals. Costs of pharmacogenetic testing are about $200 to $500 for each test. The CYP 2D6 (single enzyme) test, for example, is approximately $250.


Federal Initiatives


On the federal level, several initiatives are underway to support the development of pharmacogenetics. The Pharmacogenetics Research Network (PGRN) is a nationwide collaboration of scientists established in 2000 and funded by the National Institutes of Health to study the effect of genes on people's responses to a variety of medications, including antidepressants and drugs for heart disease and asthma. One aspect of the PGRN is PharmGKB, a publicly available Internet research tool developed by Stanford University. The PharmGKB database is a central repository for genetic and clinical information about people who have participated in research studies at various medical centers in the network, as well as genomic, molecular and cellular phenotype data submitted by the scientific community.


Last November, the U.S. Department of Health and Human Services (HHS) launched a Family History Initiative to encourage all Americans to learn about their families' health histories. As an assist, HHS released a free computer program that organizes important health data into a printout that can be taken to a physician to help determine whether a patient is at higher risk for disease. The printout can also be placed in a patient's medical record. Called "My Family Health Portrait," the tool can be downloaded at .


"Family history can be a window into a person's genome," said Francis S. Collins, M.D., Ph.D., director of the National Human Genome Research Institute. He told the press, "In the future, tests resulting from the Human Genome Project will make it possible to identify the glitches we all carry in our genes, glitches that increase our susceptibility to common illnesses. Until then, tracking illnesses from one generation of a family to the next can help doctors infer the illnesses for which we are at risk, and thus enable them to create personalized disease-prevention plans."


Last February, the U.S. Senate approved S. 306, a bill introduced by Sen. Olympia Snow (R-Maine) to prohibit discrimination on the basis of genetic information with respect to health insurance and employment, by a vote of 98-0. The bill amends current employment and medical legislation to prevent genetic information from being used to discriminate against individuals. It prohibits the use of genetic information (including results of genetic tests and family history of disease) by employers in employment decisions and by health insurers and health plans in making enrollment determinations and setting insurance premiums. President George W. Bush and Collins have indicated their support for the bill.


In March, Rep. Judy Biggert (R-Ill.) introduced H.R. 1227 in the House, a bill identical to S. 306. The bill has been sent to three different committees: the House Committee on Ways and Means, House Committee on Energy and Commerce, and House Committee on Education and the Workforce, each of which has jurisdiction over separate sections of the bill. Each committee is likely to hold hearings on it and mark up relevant sections, according to Melissa Guido, Biggert's press secretary.


"We have high hopes for the bill's passage, because of the high number of cosponsors [76], administration support and its early introduction into the 109th Congress so it is on the radar of the House leadership," Guido said.


While efforts are being made to ease the way in gathering genetic information on psychiatric disorders, psychiatrists prominent in the field talk of new responsibilities and the need for education.


Paul Appelbaum, M.D. (2004), warned that as knowledge grows regarding the genetic bases of psychiatric disorders, a variety of ethical issues will need to be confronted. Among these issues are pressures for screening of children and adults, particularly potential adoptees, and family members at risk for major psychiatric disorders, as well as the impact of knowing one's genetic makeup on one's sense of self.


"Many of our training programs fail to educate residents in even the basics of psychiatric genetics, and few practicing psychiatrists stay current with this rapidly developing area," Appelbaum wrote. "The development of residency-based curricula and continuing education programs would be a first step toward the literacy that will be essential in developing policy in the future."


References


Appelbaum PS (2004), Ethical issues in psychiatric genetics. J Psychiatr Pract 10(6):343-351.


de Leon J, Susce MT, Pan RM et al. (2005), The CYP2D6 poor metabolizer phenotype may be associated with risperidone adverse drug reactions and discontinuation. J Clin Psychiatry 66(1):15-27.


Lerner M (2004), The right drug? Ask your DNA. Star Tribune. Nov. 28.


Sallee FR, DeVane CL, Ferrell RE (2000), Fluoxetine-related death in a child with cytochrome P-450 2D6 genetic deficiency. J Child Adolesc Psychopharmacol 10(1):27-34.


Technology Evaluation Center, Blue Cross and Blue Shield Association (2004), Special report: genotyping for cytochrome P450 polymorphism to determine drug-metabolizer status. Chicago: Blue Cross and Blue Shield Association. Available at: www.bcbs.com tec/vol19/19_09.html. Accessed April 20, 2005.


http://www.psychiatrictimes.com

Low-dose Oral Contraceptives May Increase Risk For Heart Attack Or Stroke

RICHMOND, Va. -- Women using low-dose oral contraceptives are at an increased risk for a heart attack or stroke while taking the pill -- however the risk disappears after discontinuation, according to a Virginia Commonwealth University study published in the July issue of the Journal of Clinical Endocrinology and Metabolism.


The findings could have further significance for those women taking low-dose oral contraceptives who already are at increased risk for such events because of polycystic ovary syndrome, or metabolic disorder, according to John Nestler, M.D., professor and chair of the Division of Endocrinology and Metabolism in the VCU School of Medicine.

In the study, researchers reported that the overall estimated risk of cardiovascular events -- both heart attack and stroke -- among current low-dose oral contraceptive users was doubled compared to non-users.

The findings are based on a meta-analysis of peer-reviewed literature. The researchers examined several separate-but-similar experiments that were designed to assess the risk of cardiovascular disease associated with the current use of low-dose oral contraceptives in the population-at-large. The analysis included studies published between January 1980 and October 2002.

"The study suggests that women in general are at an increased risk of having a cardiovascular event while taking even these third-generation, low-dose, birth control pills," said Nestler.

"Prolonged exposure to low-dose oral contraceptives in a population at higher risk may significantly increase the incidence of cardiovascular outcomes and prompt consideration of alternative therapeutic or contraceptive interventions," he wrote.

"A number of women with metabolic syndrome or polycystic ovary syndrome already are at increased risk for heart attack, and a majority of women with PCOS are treated with low-dose oral contraceptives for a prolonged period of time," he said. "An insulin-sensitizing drug might confer better general health benefits than the oral contraceptive."

"For example, insulin-sensitizing drugs have been shown to decrease progression to Type 2 diabetes, and there is evidence suggesting that they also may lower the risk of cardiovascular disease and have beneficial effects on cardiovascular risk factors," he said.

PCOS is a condition that can affect a woman's menstrual cycle, fertility, hormones, insulin production, heart, blood vessels and appearance.

"Despite the doubling of risk associated with the pill, the absolute risk for a cardiovascular event in an individual woman taking the pill is low -- Women using the pill are not going to automatically have a heart attack," said Nestler. "However, our findings do raise the issue of whether oral contraceptives are optimal therapy for certain groups of women who are at baseline risk or who are taking the pill for a longer time, such as women with PCOS."

According to Nestler, previous epidemiological studies have shown an increased risk of cardiovascular events associated with oral contraceptives in women with hypertension, migraines, or who smoke.

Nestler collaborated with Jean-Patrice Baillargeon, M.D., from the Universit-- de Sherbrooke in Canada, and Paulina A. Essah, M.D., of VCU's Division of General Internal Medicine. The research was supported by a grant from the National Institutes of Health and the Fond de Recherche en Sant-- du Qu--bec.

Studies Show More Women Contract AIDS Than Men

By Carol Pearson
Washington

Leaders of the top industrialized countries are set to discuss the global threat of AIDS, a virus that is spreading faster than the efforts to stop it. A recent report shows that more women than men are contracting the AIDS virus.


Dr. Thomas Quinn has spent a quarter of a century researching HIV, the virus that causes AIDS. He works at the Johns Hopkins University Medical School in Baltimore, Maryland, where lab technicians handle the live AIDS virus. In June, Dr. Quinn published a study that shows an alarming trend.

"If you look at the scope of health problems in women across the world, the number one infectious disease problem, without a doubt, is HIV/AIDS."



Dr. Quinn's research shows that in sub-Saharan Africa, 60 percent of the 28 million people with HIV disease are female.

In the Caribbean, women account for half of those living with the virus, and women account for one-third of those with HIV in Latin America.

Dr. Quinn states, "It has spread so rapidly over the last 25 years to a point where it now outnumbers the number of cases of men in the developing world."

Women have a higher risk of contracting AIDS because of their biology and social status. Young women are especially more vulnerable to contracting the virus through tears in the vagina.

In many countries, women are unable to demand that their partners or husbands wear condoms. In some societies, men are allowed multiple sex partners and then spread the infection to their wives.

Dr. Quinn also added, "All of those sociological parameters added to the biological susceptibility make for a huge opportunity for an epidemic of HIV in women."

In the United States, data from the Centers for Disease Control show most of the new infections are among African-American and Hispanic women. Half of the 1.1 million Americans infected with the AIDS virus are African-American.

It's a statistic that alarms Terje Anderson, who is the Director the National Association of People with AIDS, a non-profit organization. " Considering that African-Americans are only 13 percent of the U.S. population, that is so disproportionate it concerns us greatly."

Both Mr. Anderson and Dr. Quinn point to AIDS education and treatment as the answer. Mr. Anderson says it has to be tailored for each specific cultural group. Dr. Quinn says that women need strategies to empower them in negotiating safer sex.

But funding is also an issue. The United Nations warns much more money is needed to fight the global epidemic.

Mr. Anderson says that's true in the United States as well, where AIDS clinics cannot keep up with the demand for treatment and some are cutting back on services.

City life stresses develop insomnia, which results in post-insomnia depression

It is generally believed that a glass of red wine or a shot of whiskey is an efficacious remedy for insomnia

Millions of men, women and children suffer from insomnia, tossing and turning in their beds every night. Numerous people have to go to work and spend "the worst day ever" there, dreaming about the end of the horrible working day.

Insomnia, or sleep disorder, is one of the indications of poor health. Modern life is full of stresses: it is extremely hard to find an absolutely happy and healthy individual in crowds of poor beings exhausted with chronic fatigue, lack of fresh air and simple physical movement.

Healthy and uninterrupted sleep is as important for humans as air, water and food. Almost 50 percent of the Earth's population has to deal with sleep disorders nowadays. There is a list of over 90 diseases, which disrupt the process of sleeping and eventually results in serious physical and psychological consequences. The list includes depression, chronic fatigue syndrome, stresses, and so on and so forth. Insomnia can often be exacerbated with other diseases that a person may suffer from. The stresses that cause insomnia are closely connected with the stresses, which occur afterwards, because of insomnia.

Statistics says that 50 percent of adults suffer from one of numerous sleep disorders. Thirteen percent of those people experience severe health problems because of insufficient sleep. Unfortunately, the majority of people do not discuss their sleep problems with doctors in spite of the fact that consequences can be extremely dangerous to health.

The obvious effect of insomnia - fatigue - has already been reputed as the reason, which causes about one-third of most horrible car accidents. About 50 percent of lethal outcomes on the roads occur because of drivers' fault: many of them suffer from insomnia, but disregard the problem, considering it as something absolutely unimportant, and fall asleep while driving as a result.

It is generally believed that a glass of red wine or a shot of whiskey is an efficacious remedy for insomnia. Alcohol may cause drowsiness indeed, although people may wake up at night all of a sudden and thus be deprived of uninterrupted sleep. It goes without saying that such a "medical treatment" may result in alcoholic addiction. To crown it all, alcohol excites appetite: eating too much food before going to bed may complicate the breathing process, not to mention the fact that the digestive system is forced to work at the time, when it needs to relax. It is noteworthy that an empty rumbling stomach can also become the reason of a sleepless night. The last food intake during the day is supposed to be made not later than two hours before going to bed, doctors recommend.

Some people say that they feel better if they smoke a cigarette, take a shower or have a cup of tea or coffee before sleeping. Caffeine or nicotine, however, exert a stimulating effect on human receptors. Similarly, the exhilarating effect of a shower may ruin the normal physical relaxation of the human body at night.

Others believe that sports relieve stress best and make a human being sleep like a log. Physical training, which is supposed to be a mandatory constituent of everyone's daily schedules, is to be excluded at least three hours before bedtime. Specialists do not recommend doing any physical exercises in the evening, because physical activity does not further relaxation.

The following recommendations may help you experience the pleasure of healthy sleep, wake up with a smile on your face and say "good morning" even to strangers. Try to stick to certain sleeping hours when you go to bed at night and wake up in the morning, even on weekends, developing the so-called daily biological clock for the body. A comfortable bed, mattress, pillow and bed linen are extremely important too. If it is possible, try to take walk to breathe fresh air before bed. Try to get rid of sources of noise in your bedroom. The temperature around 20 degrees above zero Centigrade is considered the best temperature for healthy sleeping. When in bed, try to avoid thinking about tomorrow: draw up your plans after work, on your way home. There should be no TV or radio sets placed in your bedroom.

If all of the above-listed and other recommendations do not help at all, one should
think of other methods of medical help trying to avoid the depression crisis. Russian medics treat insomnia patients with the help of Aura-009 electromagnetic therapy apparatus. The equipment is quite effective in the treatment of not only sleep disorders, but also in cases of chronic fatigue, stresses and depression inherent to big cities.

Children with autism respond favorably to the antipsychotic Risperidone

A study found children with autism characterized by tantrums, aggression, and/or self-injury respond favorably to the antipsychotic drug Risperidone ( Risperdal ) for up to six months.

Research, sponsored by the National Institute of Mental Health ( NIMH ), found the medication not only decreased aggression but also reduced repetitive behaviors and increased social interaction – all with limited side effects. The two-part study also found discontinuation after six months prompted rapid return of disruptive and aggressive behavior in most cases.

Atypical antipsychotic medications such as Risperidone are of interest to doctors who treat children with autism because studies show the newer medications benefit adults with schizophrenia with fewer neurological side effects than older options.

“A variety of treatments, including medication, are used to manage aggressive behaviors in autistic children, but controlled medication trials are limited,” said James McCracken, lead author and at the Semel Institute for Neuroscience and Human Behavior at UCLA. “ Our findings support adding Risperidone to the small arsenal of intermediate-term medication options for the tens of thousands of children with autism who display aggressive and destructive behaviors.

“ The response to Risperidone ranks among the most positive ever observed in children with autism for a drug treatment,” said McCracken, director of the Division of Child and Adolescent Psychiatry at the David Geffen School of Medicine at UCLA.

Autism is a chronic condition that appears in early childhood. Core symptoms include impaired social interaction, delayed language development and restricted patterns of behavior. The disorder affects as many as 20 in 10,000 children. Although the causes of autism are unknown, scientific evidence point to abnormalities in brain development and a strong genetic component.
In addition to core symptoms, children with autism frequently exhibit serious behavior disturbances in response to routine environmental demands. For these disturbances, behavior therapy and medications are the two main forms of treatment.

In the multi-site study, researchers randomly assigned 101 subjects – 82 boys and 19 girls – ages 5 to 17 to receive either placebo or Risperidone.
Subjects who improved substantially after eight weeks continued treatment for up to six months. Researchers observed a small sample of subjects at the end of the study during the withdrawal of the medication.

Previously, the largest extended studies of medication for autism with Haloperidol, an older antipsychotic, showed the drug to be modestly effective but accompanied by neurological and other side effects.

Past research into the effect of Risperidone on children with autism found the medication effective for short-term treatment of aggressive behaviors related to autism in children. Side effects to Risperidone are usually well-tolerated, with some complaints of weight gain.

Source: University of California, Los Angeles ( UCLA ), 2005

Rare syndrome attacks mobility

Young boy battles Guillian- Barré Syndrome

By Rachel E. Sheeley
Staff writer


This spring, 4-year-old Brandon Pickering complained that his leg hurt and that he didn't want to walk.

His family merely thought his leg had gone to sleep. However, within a few days, Brandon was nearly paralyzed by a rare illness, Guillian-Barré Syndrome.

After spending a month in Indianapolis hospitals, Brandon is getting back on his feet at home in Richmond with the aid of therapy at Reid Hospital.

"Things are going pretty good. Brandon is walking without a walker now," said his mother, Mara Pickering. "He only uses the walker when he has to go a long distance. He still uses a wheelchair when there's lots of walking involved.

"We've come a long way," Mara said.

It's certainly different from mid-March when one night, Brandon got up to go the bathroom and fell.

"His legs were like rubber," Mara remembers.

Not knowing the problem, she took Brandon to the doctor on March 14. He fell three times walking into the doctor's office. Doctors first thought he had the flu and sent him home.

That Brandon had Guillian-Barré Syndrome would not be apparent for several more days.

The syndrome's rarity often makes it difficult to diagnose. It develops in one or two children or adults among 100,000 each year -- less than a few dozen cases annually in Indiana.

In Guillian-Barré , the body's immune system attacks part of the peripheral nervous system.

Early symptoms are tingling in the extremities, as if the leg or foot is asleep; weakness, numbness, pain and paralysis. The paralysis is ascending, starting at the lowest part of the body -- legs, feet -- and moving up, said Dr. Bhwan Garg, an Indiana Univeristy School of Medicine professor of neurology.

Children, Garg said, may complain of aches and pains, and may appear clumsy or uncoordinated. Those symptoms don't give a physician a clear-cut diagnosis.

"Most often diagnosis is based on clinical symptoms," Garg said.

Garg said the syndrome reaches its peak within about two weeks.

The day after Brandon saw his physician, he couldn't walk around the living room without falling, Mara said.

This time, they went to the emergency room. After a series of tests, doctors recommended that Brandon see a pediatric neurologist. He was rushed by ambulance to Riley Hospital for Children in Indianapolis.

Tests and examinations there didn't provide an immediate diagnosis. Cancer was even mentioned.

"By then, he couldn't walk. He had trouble rolling over," Mara said. "We started praying."

Four days later, the paralysis had set in, helping solidify the diagnosis. "He was like a baby. Basically, he was an infant," Mara said.

Doctors treat the immune system's reaction to reverse the attacking antibodies and cleanse the blood, Garg said. Brandon's intensive immunoglobulin treatment, with intravenous injections of proteins, lasted five days.

"The earlier you can intravene, the better the outcome," Garg said. "It keeps getting better and better."

The cause of Guillian-Barré Syndrome is unknown, but it often occurs after a respiratory or gastrointestinal viral infection. Within a few weeks of when he became ill, Brandon had inflamed, swollen tonsils and strep throat, his mother said. He was supposed to have his tonsils removed March 31.

With the syndrome's progression stopped, Brandon was transferred to Methodist Hospital for extensive rehabilitation therapy.

"The weaker you are at the maximum point, the longer it takes to recover," Garg said. "You just have to keep working at it. It's very nice to see children that are so weak get better."

Dr. Jennifer Crocker is the pediatric physical medicine and rehabilitation specialist and an attending physican at Riley and Methodist hospitals who worked with Brandon.

When she met him, he was complaining of leg pain, muscle weakness and refusing to walk.

"We really focused on getting him stronger... getting him to regain his confidence," Crocker said. "We used pretty much all of our team on Brandon."

That includes a neuropsychologist, nurses, and occupational, physical and music therapy.

"We involved the family so much. His family was really interacting and had a really positive outlook," Crocker said. "That made him gain so much."

"We have to get him to play games a lot to get him to do the therapy and take his medicine," Mara said.

As a reward after each successful therapy session at Methodist, Brandon was able go for a ride on the elevated monorail, or people mover, connecting the Clarian hospitals in Indianapolis.

His mother made the ride with a gleeful Brandon almost daily, but she disliked every minute.

"I'm not real good on heights and rides," Mara said.

Brandon, Crocker said, was a pretty typical case to treat.

The syndrome disrupts the sheath around the nerves, Crocker said. The sheath is similar to the insulation around a telephone cable. When that insulation, or sheath, is damaged, it makes the transmission slower.

"Nerves grow back at about a milimenter a day. It takes a long time to go back into the legs," Crocker said.

"I anticipate he'll recover very well. It takes a long time," Crocker said. "Only half of the people that contract Guillian-Barré have residual neurological deficits to the point that it's a disability."

Crocker said that developments in rehabilitation have turned recoveries like Brandon's into a more definitive process.

After three weeks of rehabilitation under Crocker's supervision, Brandon came home April 15. Since then, he has been involved in a regimen of physical, occupational and speech therapy at Reid Hospital.

The first time Mara watched Brandon stand in physical therapy was emotional.

"It did bring tears to my eyes -- I just bawled," Mara said.

"The littlest thing he does, it's like a brand new baby. It's just amazing."

In a recent physical therapy session, Brandon took tentative steps on the heavily padded floor mat before plopping down with a giggle.

However, pulling his knees to his chest and stretching his legs made him complain.

And a few minutes later, he was back in good humor, squealing and swinging in a hammock style seat that is blue like Superman's cape.

"We've just put everything in God's hands," she said. "He is getting stronger and he is getting better. It's just going to be a long process -- a long road for him of a lot of work.

http://www.pal-item.com/

Tryptophan Safe For Insomnia

L-tryptophan is one of the eight essential amino acids, one of the building blocks of protein. It is precursor to serotonin, which is a brain chemical that elevates mood.

It is a little known but useful prescription for insomnia, including the sleep disorders of fibromyalgia, chronic fatigue syndrome, grief reactions, PMS and menopause. It can also be used as part of a treatment program for migraines, chronic pain and even the tremors of Parkinson’s disease. In one small French study, of 20 people with severe trembling uncontrolled by the usual drugs, 11 had the tremors controlled by 10 grams of tryptophan daily.

Effective treatment for depression
Tryptophan can be used in treating depression, either by itself or in combination with antidepressant drugs like Prozac where it counters the insomnia side effect and prevents the need for increasing the dosage.

Dr. Anthony Levitt, Assistant Professor of Psychiatry and Nutritional Sciences at University of Toronto, refers to evidence, including his own research, that shows that 55 to 60% of depressed patients who fail to respond to initial treatment with two commonly prescribed types of antidepressants improve with the addition of tryptophan.

“L-tryptophan combines the sleep-inducing activity with a nearly innocuous side effect profile.” says Levitt.

Tryptophan and women's health
Dr. Susan Steinburg, Assistant Professor of Psychiatry at McGill University in Montreal recently completed a controlled double blind study comparing 40 women using 2,000 mg of tryptophan three times a day (from day 14 through to the first three days of the period) for PMS compared to 40 who did not take tryptophan. The study, published in Biological Psychiatry in 1999, showed that tryptophan provided significant relief of symptoms of depression, irritability and mood swings. Women who were particularly helped by tryptophan were those that at baseline had marital problems, or an increased number of negative life events.

Is is safe?
Some doctors are still nervous about prescribing tryptophan. In November 1989, the FDA recalled all tryptophan from the health food stores due to a serious illness and fatalities induced by one contaminated batch of tryptophan. One Japanese company that was using genetically engineered bacteria to produce the tryptophan manufactured all of the contaminated tryptophan.

Biologist Dr. John Fagan says this is one of the best examples of genetic engineering giving rise to unanticipated allergens and toxins. He cites a 1990 study published in Science magazine that confirmed that the tryptophan produced by the bacteria were contaminated by a “novel amino acid” not present in tryptophan produced by other methods.

For unknown reasons L-tryptophan was never allowed back in the market in the United States. Some cynics have suggested that this paved the way for the domination of the depression market by Prozac and its cousins.

Currently in Canada, one company, ICN Canada, manufactures all prescription tryptophan. This company’s product has never been associated with any problem. The cost is about $1.00 per 1,000 mg tablet and is covered by some drug plans. The usual dosage of tryptophan for insomnia ranges from 500 mg to 4,000 mg taken one hour before bedtime.

Dosages and availability
It is best not to take tryptophan with protein, which competes with tryptophan for absorption, but it can be taken with a carbohydrate snack. Vitamin B6 and magnesium enhance the effect of tryptophan. Tryptophan can also be combined with the B vitamin, niacinamide, for chronic pain or depression. M.I.T. researcher Dr. Judith Wurtman, author of The Serotonin Solution, found that a high carbohydrate diet increased the production of serotonin and helped get tryptophan to the brain.

Tryptophan should not be taken by people who have hepatitis or other liver disease or by pregnant women.

In the US, tryptophan is available by prescription from compounding pharmacists. An alternative to tryptophan known as 5-hydroxy-tryptophan or 5-HTP (50 mg of 5-hydroxy-tryptophan equals 500 mg tryptophan) is available without a prescription. In the body, tryptophan is converted to 5-HTP and ultimately to serotonin. Well-known naturopathic doctor and educator Dr. Michael Murray has written a book on the many uses of 5-HTP called The Natural Way to Overcome Depression, Obesity and Insomnia (Bantam, 1998).

TIP: Tryptophan is a safe alternative for insomnia of all kinds. Many drug plans will cover this very useful supplement if a doctor prescribes it.


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Fat: it’s a family affair

by Dr Thomas Stuttaford

Many people inherit a tendency to high cholesterol, but because they lead a healthy lifestyle, they don’t know they’re at risk



ONE OF THE JOYS of visiting France is that there is still enough traditional farming to fashion the countryside. The villages have farms with small dairy herds and the cream from them would make the simplest sauce a dish for a Napoleon, or any other emperor.
Doctors may be one of the few groups who object to the cream and rich cheeses, but when it comes to foie gras the attacks come from two directions, with medicine and the animal rights organisations uniting in their disapproval. But while French food is famously good and notoriously rich, surprisingly their statistics for cardiovascular disease are no worse than ours.



The usual patient who has cholesterol problems — with or without a slightly raised triglyceride level — likes an English breakfast of bacon, bangers and eggs, doesn’t spare the cream, wouldn’t eat toast unless it was well buttered, and can’t resist fish and chips. They are overweight with a girth of more than 40 inches if a man, or 35 if a woman.

If the blood sugar is already rather higher than usual, they may well need to take a statin. If they don’t respond to diet and more exercise they will certainly need statin therapy. If they don’t respond to this — ie, acquiring a normal, or slightly lower than normal, cholesterol and low-density lipoprotein (LDL) level — their doctor might like to consider prescribing Inegy. This is a combination of a statin, simvastatin (originally marketed as Zocor) with Ezetrol (ezetimibe). The Ezetrol component of Inegy boosts the effect of the statin so that smaller doses of statin can be used.

Inegy is available with either 20mg, 40mg or 80mg of simvastatin. It is taken in the evening unless the patient suffers from insomnia. Inegy is useful for those whose cholesterol levels are not being adequately controlled even when taking the more effective statins such as Lipitor or Crestor. Studies have shown that up to 50 per cent of people who are taking statins to treat a high cholesterol or triglyceride level are not achieving the recommended levels.

Dr Clive Weston, a consultant cardiologist in Swansea, speaking in London recently, said: “These patients are taking their statin pills and may feel reassured by this. However, they may still have an elevated risk from complications of heart disease and are missing out on the best treatment available.”

The tendency for someone to develop abnormal blood levels of cholesterol often has a genetic component. Their abnormal levels — raised overall cholesterol blood levels, too much LDL cholesterol (the dangerous form of cholesterol), or too much triglyceride — may owe as much to their genetic inheritance as it does to their diet and lack of exercise.

If genetic tendency is combined with a poor diet and slothful lifestyle (even, perhaps, smoking too) the patient is in for trouble.

As well as the problems caused for the many families in which there is a tendency for high blood fat levels, there are other families in which there is a more obvious pattern of inheritance.

There are 120,000 of these patients in the UK, but they may discover that they have a dangerously raised cholesterol only when they have problems with their coronary arteries— such as angina or a heart attack — or their high cholesterol levels are detected with a routine test. The difficulty in diagnosis is because they are often apparently and outwardly healthy, have a restrained diet and half an hour’s brisk exercise a day. Unfortunately, they also have one or two relatives with cardiovascular disease, or history of a raised cholesterol.

These 120,000 people are said to suffer from familial hyperlipidaemia. The genetic pattern of the many different types of familial hyperlipidaema is complex and their classification confusing.

In some of these families there are specific diagnostic signs as well as a family history of raised cholesterol. These include fatty deposits around the orbits (eye sockets), an early arcus (white rim around the edge of the iris of the eye), or fatty infiltration of some of the tendons.

In one rare form of familial high cholesterol levels, homozygous hypercholesterolaemia, the raised cholesterol levels start in childhood and the affected children may suffer heart attacks, or other cardiovascular problems, while still in their teens or early twenties. In the other forms of familial hypercholesterolaemia, the raised cholesterol may be associated with a raised triglyceride fat level, or it may be only the triglyceride fat level that is high. Triglyceride is a very low density lipoprotein (VLDL).

When someone has a high level of triglyceride in their blood they are not only likely to suffer from heart and other cardiovascular problems, but pancreatitis and occasionally the blocking of the vein leading from the eye, and hence blindness.

Anyone with an obvious familial hypercholesterolaemia will certainly need to go straight on to statins, followed, if they don’t respond, by Inegy. As with all anti-cholesterol treatment the dose may have to be increased slowly until the desired effect is achieved.

Anyone with a raised cholesterol shouldn’t allow it to destroy their equanimity. They shouldn’t even think of cancelling their holiday in France. However, they should rectify their cholesterol levels, by taking advantage of modern medicines and be wary of foie gras and similar fatty delicacies.



http://www.timesonline.co.uk/

Melatonin Helps you

Just when you’re looking forward to a calm and restful night of sleep, insomnia hits. You toss and turn, you try different sleeping positions, you get up for a bit and the next thing you know, the alarm is ringing and its time to get up. Insomnia is one of many sleeping disorders that affect the general population. Wouldn’t it be nice if there was a supplement that could treat a large number of sleeping disorders?

Melatonin to the rescue
Melatonin is a hormone that is naturally produced by the pineal gland in the brain. It is often referred to as the sleep hormone. Melatonin has been shown to facilitate sleep, significantly shorten the time needed to go to sleep, reduce the number of night awakenings, and improve sleep quality. When taken orally, melatonin has been shown to improve the symptoms of various sleep disorders—here are just a few.

Melatonin and insomnia
Melatonin has been shown to be most beneficial in improving sleep quality in the elderly. Studies have shown that elderly patients taking melatonin saw improvements in their symptoms of insomnia. Studies have also shown that melatonin improves sleep quality in adults and in children. Melatonin also seems to improve secondary insomnia related to depression, schizophrenia, Alzheimer's disease, hospitalization and "ICU syndrome," referring to sleep disturbances while in the intensive care unit.

Melatonin and jet lag
Taking melatonin appears to reduce symptoms of jet lag. A study investigated the efficacy of oral melatonin in alleviating jet lag in flight crews after a series of international flights. Fifty-two international cabin crew members were studied. The researchers observed a significantly faster recovery of energy and alertness and concluded that melatonin showed may have potential benefits for international aircrew.

Melatonin and circadian rhythm disorders
The body is regulated by over 100 built-in clocks that create the circadian rhythm. Some people develop circadian rhythm disorders, where their sleep-wake cycle does not correspond to the normal day and night routine. Studies have shown that taking melatonin helps improve circadian rhythm sleep disorders in children and adults.

Sleep tips
Taking melatonin is not the only step you can take to improve your sleeping condition. Visit the Truestar Sleep Tips for suggestions on how to optimize your sleep. Better yet, complete the Truestar Sleep Profile for your own personalized sleep program.

May your night be restful.

Cholesterol and genes

Why does it seem like some people can eat all the ice cream they want without increasing their cholesterol or gaining much weight, while others with high cholesterol have to watch their diets like a hawk? Because no matter what their lifestyle, people's genes play an overriding role in their cholesterol response.

So says a new study by researchers at the Department of Energy's Lawrence Berkeley National Laboratory and the Children's Hospital Oakland Research Institute (CHORI), conducted by Paul Williams of Berkeley Lab's Life Sciences Division in collaboration with Robin Rawlings and Patricia Blanche of CHORI and Ronald M. Krauss of CHORI and Berkeley Lab's Genomics Division. They report their findings in the July 8, 2005, issue of the American Journal of Clinical Nutrition.

The investigators analyzed how "bad" cholesterol (low-density lipoprotein, or LDL, cholesterol) responded to diets that were either high or low in fat in 28 pairs of identical male twins - one twin a vigorous exerciser, the other a comparative couch potato.

"Although identical twins share exactly the same genes, we chose these twins because they had very different lifestyles," says Williams. "One member of each pair was a regular long-distance runner, someone we contacted through Runner's World magazine or at races around the country. His brother clocked 40 kilometers a week less, at least, if he exercised at all."

For six weeks the twins ate either a high-fat diet (40 percent of its calories from fat) or a low-fat diet (only 20 percent of its calories from fat); then the pairs switched diets for another six weeks. After each six-week period the twins' blood cholesterol levels were tested.

The researchers were interested in learning if blood cholesterol changes due to the different diets would be the same or different in each pair of genetically identical twins, even though their lifestyles were very different. A correlation of zero between the two would mean that their responses to the diets had no relation to each other, while a correlation of 1.0 would mean that their responses were identical.

The researchers found an astounding 0.7 correlation in responses to the change in diet, an incredibly strong similarity in the way each pair of twins responded - even though the responses themselves among different pairs of twins differed considerably.

"If one of the twins could eat a high-fat diet without increasing his bad cholesterol, then so could his brother," says Williams. "But if one of the twins' LDL cholesterol shot up when they went on the high-fat diet, his brother's did too."

The correlations showed that the twins had very similar changes in LDL cholesterol because they had the same genes. Some twins had one or more genes that made them very sensitive to the amount of fat in their diets. Other twins had genes that made them insensitive to dietary fat, no matter how much they exercised.

"Our experiment shows how important our genes are," says Williams. "Some people have to be careful about their diets, while others have much more freedom in their dietary choices."

He adds, "This type of experiment allows us to test whether genes are important without having to identify the specific genes involved." Although several specific genes have been associated with cholesterol changes in response to changes in diet, these cannot account for the large correlations seen in this study. Williams hopes his findings will inspire additional research to identify the specific genes involved.

"Concordant lipoprotein and weight responses to dietary fat change in identical twins with divergent exercise levels," by Paul T. Williams, Patricia J. Blanche, Robin Rawlings, and Ronald M. Krauss, appears in the July 8, 2005, issue of the American Journal of Clinical Nutrition. The work was supported by Dairy Management Incorporated, with additional support from the National Institutes of Health.

Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California. Visit our website at
http://www.lbl.gov.

http://www.medicalnewstoday.com/

Genes not diet determine cholesterol level

LOUISE GRAY


LUCKY people can eat all the fatty foods they want without increasing their cholesterol while the less fortunate have to watch their diets like a hawk to avoid risk of heart disease, according to a new study.

Researchers analysed how 28 pairs of identical twins - one an avid exerciser and one a "couch potato" - reacted to six weeks of a high-fat diet followed by a low-fat diet for the same period of time. After each period the twins' blood cholesterol levels were tested.


The researchers at Berkeley National Laboratory found a strong similarity in the way each pair of twins responded despite their different lifestyles - showing that genetic makeup rather than diet determines cholesterol response.

Researcher Paul William said: "Our experiment shows how important our genes are. Some people have to be careful about their diets, while others have more freedom."

But Dr Andrew Rankin, a consultant cardiologist at Glasgow University, said people who think they are the "lucky ones" should still watch their cholesterol levels with care.

He added: "If everybody lowered their cholesterol just a little bit we would lower the number of heart attacks."

Genes not diet determine cholesterol level

LOUISE GRAY


LUCKY people can eat all the fatty foods they want without increasing their cholesterol while the less fortunate have to watch their diets like a hawk to avoid risk of heart disease, according to a new study.

Researchers analysed how 28 pairs of identical twins - one an avid exerciser and one a "couch potato" - reacted to six weeks of a high-fat diet followed by a low-fat diet for the same period of time. After each period the twins' blood cholesterol levels were tested.


The researchers at Berkeley National Laboratory found a strong similarity in the way each pair of twins responded despite their different lifestyles - showing that genetic makeup rather than diet determines cholesterol response.

Researcher Paul William said: "Our experiment shows how important our genes are. Some people have to be careful about their diets, while others have more freedom."

But Dr Andrew Rankin, a consultant cardiologist at Glasgow University, said people who think they are the "lucky ones" should still watch their cholesterol levels with care.

He added: "If everybody lowered their cholesterol just a little bit we would lower the number of heart attacks."

Should Diabetes Be Considered a Coronary Heart Disease Risk Equivalent?

Results From 25 Years of Follow-Up in the Renfrew and Paisley Survey

OBJECTIVE - The purpose of our study was to confirm or refute the view that diabetes be regarded as a coronary heart disease (CHD) risk equivalent and to lest for sex differences in mortality.

RESEARCH DESIGN AND METHODS - This was a prospective cohort study of 7,052 men and 8,354 women aged 45-64 years from Renfrew and Paisley, Scotland, who were first screened in 1972-1976 and followed for 25 years. All-cause mortality was calculated as death per 1,000 person-years. A Cox proportional hazards model was used to adjust survival for age, smoking habit, blood pressure, serum cholesterol, BMI, and social class.

RESULTS - There were 192 deaths in 228 subjects with diabetes and 2,016 deaths in 3,076 subjects with CHD. The highest mortality was in the group with both diabetes and CHD (100.2 deaths/1,000 person- years in men, 93.6 in women) and the lowest in the group with neither (29.2 deaths/1,000 person-years in men, 19.4 in women). Men and women with diabetes only and CHD only formed an intermediate risk group. The adjusted hazard ratio (HR) for CHD mortality in men with diabetes only compared with men with CHD only was 1.17 (95% CI 0.78-1.74; P = 0.56). Corresponding HR for women was 1.97 (1.27- 3.08; P = 0.003).

CONCLUSIONS - Diabetes without previous CHD carries a lifetime risk of vascular death as high as that for CHD alone. Women may be at particular risk. Our data support the view that cardiovascular risk factors in diabetes should be treated as aggressively as in people with CHD.

Diabetes Care 28:1588-1593, 2005

Abbreviations: CHD, coronary heart disease.

Diabetes is associated with an increased risk of cardiovascular morbidity and mortality (1,2), but the magnitude of that risk is disputed. In a Finnish study, Haffner et al. (3) showed that individuals with diabetes but without prior myocardial infarction have as high a risk for fatal cardiovascular events as people without diabetes who have survived a myocardial infarction. This was followed by a U.K. study showing that people with type 2 diabetes were at lower risk of death from all causes and cardiovascular causes and of hospital admission for myocardial infarction than patients with established coronary heart disease (CHD) (4).

Two recent statin trials that included substantial numbers of patients with type 2 diabetes and cardiovascular risk factors showed significant reduction in a composite end point comprising fatal and nonfatal CHD and stroke (5,6), whereas two trials did not show a reduction (7,8). The purpose of our study was to examine long-term CHD and other vascular mortality associated with having diabetes only, CHD only, both, or neither in a population survey of >15,000 middle-aged men and women who were followed for 25 years. Specifically, we wished to confirm or refute the view that diabetes be considered a CHD risk equivalent and to test for possible sex differences in outcome.

RESEARCH DESIGN AND METHODS- The Renfrew and Paisley Survey is a longitudinal study of 7,052 men and 8,354 women aged 45-64 years screened between 1972 and 1976. The survey was preceded by a census that identified all residents aged 45-64 years in Renfrew and Paisley, an industrial conurbation in the west of Scotland. In all, 79% of eligible subjects in Renfrew and 78% in Paisley accepted a postal invitation to take part in the study (9,10).

All participants in the Renfrew/ Paisley Survey signed a confidentiality statement at initial screening agreeing that they would allow members of the research team to access their future medical records. After the establishment of the Argyll & Clyde Health Board local research ethics committee in the 1990s, an application was submitted and approved, ascertaining that this current practice was acceptable.

We divided our cohort into four groups based on their clinical status at the screening examination. These were diabetes with CHD (n = 77), diabetes only (n = 151), CHD only (n = 3,015), and neither diabetes nor CHD (n = 10,796). The diagnosis of diabetes was self- reported in 190 subjects. Random blood glucose measured in 4,702 subjects was ≥1.1 mmol/l in 38 additional patients, for a total of 228 people with diabetes (1.5%). We were unable to distinguish type 1 from type 2 diabetes or to determine the duration of diabetes before the screening examination; however, it is highly likely given the age range of our subjects that most had type 2 diabetes (11). Subjects were considered to have CHD if they responded positively to the Rose Angina Questionnaire (12), had severe chest pain lasting >30 min, or one or more of the following Minnesota codes on a six-lead electrocardiogram: 1.1-1.3, 4.1-4.4, 5.1-5.3, or 7.1 (13). A total of 3,092 (20.1%) subjects fulfilled these criteria.

Table 1-Baseline characteristics by presence or absence of diabetes and CHD

The following risk factors for cardiovascular disease were documented. Smoking habit was classified by mean number of cigarettes smoked per day using the following categories: never smoked, pipe or cigar smoker only, 1-14 per day, 15-24 per day, ≥25 per day, and ex-smoker of ≥5 years. We classified social class as I-V based on occupation at the time of screening (14). Participants were asked their usual occupation and, if retired, their last full-time occupation. Women were given their own occupation, except for housewives who received the code for their husband's or father's occupation. Clinical measurements included blood pressure and BMI, derived from height and weight measurements. Plasma cholesterol was measured in a nonfasting sample.

Records kept by the Registrar General in Edinburgh ensured notification of a subject's death (provided it occurred in the U.K.) together with the cause of death according to ICD-9. Less than 1% of patients were known to have emigrated during the course of the study. We considered three mutually exclusive groups of causes of death: CHD (ICD-9 codes 410-414), other vascular deaths comprising deaths from stroke (ICD-9 430-438) and other vascular causes (ICD-9 390-459), and all nonvascular deaths (all other ICD-9 codes). Mortality data were censored at 25 years of follow-up for each participant.

We had complete information on 6,452 men and 7,587 women; therefore, a total of 14,039 participants were included in our analyses. These were performed using SPSS for Windows, version 11 (Chicago, IL). Comparisons of the baseline characteristics for our cohort were by χ^sup 2^ test, Student's t test, and ANOVA. Mortality in our four groups of patients was calculated as deaths per 1,000 person-years of follow-up. Overall survival was compared using Kaplan-Meier plots. Comparison of CHD and all-cause mortality was undertaken using the Cox proportional hazards model after adjustments for age, smoking habit, blood pressure, serum cholesterol, BMI, and social class. Subjects with CHD only were the referent group. Tests for proportionality in the Cox model gave a nonsignificant result (men P = 0.13; women P = 0.08), indicating that the proportional assumption was met.

RESULTS- Baseline clinical characteristics for men and women in each of the four groups are shown in Table 1. In all, 112 men and 116 women had diabetes. The average age of men and women with diabetes only and CHD only was 55-56 years. Men with diabetes only were less likely to be current smokers (P < 0.001) than subjects with CHD only. The other differences in risk profiles in these two subgroups were small and not statistically significant.

In all, 4,267 (60%) of the men and 3,746 (45%) of the women died during the 25 years of follow-up. There were 192 (84%) deaths in 228 subjects with diabetes and 2,016 (65%) deaths in 3,092 subjects with CHD. The highest mortality was in the group with both diabetes and CHD (37 of 38 or 100.2 deaths/1,000 person-years in men; 37 of 39 or 93.6 deaths/1,000 person-years in women). The lowest mortality was in the group with neither diabetes nor CHD (29.2 deaths/1,000 person- years in men, 19.4 deaths/1,000 person-years in women).

Men and women with diabetes only and with CHD only formed an intermediate risk group. Men with diabetes only had marginally higher mortality than men with CHD only (54.0 vs. 50.5 deaths per 1,000 person-years), whereas women with diabetes only appeared to have a considerably higher risk of vascular death than women with CHD only (46.7 vs. 29.2 deaths per 1,000 person-years) (Fig. 1). Similar trends were observed for each group of causes of death. Specifically, men with diabetes only had marginally higher CHD and other vascular mortality than men with CHD only, whereas women with diabetes only had higher CHD and other vascular mortality than women with CHD only (Fig. 1).

Overall survival over the course of 25 years is shown in Fig. 2. This confirms the similarity in outcome between men with diabetes only and men with CHD only (log-rank χ^sup 2^ = 0.19, P = 0.664) as well as the difference in outcome between women with diabetes only and women with CHD only (log-rank χ^sup 2^ = 8.54, P = 0.004). Survival was least in men and women with both diabetes and CHD and greatest in those with neither (Fig. 2\).

Figure 1-CHD, other vascular, nonvascular, and all-cause mortality in deaths per 1,000 patient-years for men and women with both diabetes and CHD, diabetes only, CHD only, and neither.

The similarity in men and the difference in women persisted after adjustments for age, smoking, hypertension, serum cholesterol, BMI, and social class (Table 2). Adjusted hazard ratios (HRs) for CHD and all-cause mortality in men with diabetes only compared with men with CHD only were 1.17 (95% CI 0.78-1.74; P = 0.450) and 1.20 (0.92- 1.56; P = 0.172), respectively. Corresponding HRs for women were 1.97 (1.27-3.08; P = 0.003) for CHD mortality and 1.80 (1.37-2.35; P < 0.001) for all-cause mortality. Table 2 also shows HRs for the other covariates in the Cox model. Increasing age, cigarette smoking, hypertension, and hyperlipidemia were all associated with CHD mortality. There were trends toward increased CHD mortality with increasing BMI, but these did not achieve statistical significance. Low social class predicted CHD mortality in women but not men. Increasing age, cigarette smoking, hypertension, and low social class were each associated with all-cause mortality in both sexes. Hyperlipidemia did not predict all-cause mortality in men or women, whereas BMI ≥35.0 kg/m^sup 2^ did (Table 2).

Figure 2-Kaplan-Meier plot showing 25-year survival in men and women with both diabetes and CHD, diabetes only, CHD only, and neither. For comparison between all four groups, χ^sup 2^ = 316.8 with P < 0.001 in men and χ^sup 2^ = 253.73 with P < 0.001 in women. For comparison between CHD only and diabetes only, χ^sup 2^ = 0.19 with P = 0.664 in men and χ^sup 2^ = 8.54 with P = 0.004 in women.

Table 2-HRs for CHD and all-cause mortality in men and women

CONCLUSIONS- The main find ing of our study is that, after adjusting for known cardiovascular risk factors, middle-aged men and women with diabetes but no clinical evidence of CHD experience a lifetime vascular risk that is at least as high as (and for women, possibly higher than) that for subjects of similar age who have CHD but no diabetes. In this respect our data reinforce those of Haffner et al. (3) in their study of Finnish men and women. These authors compared the risk of fatal CHD in 890 subjects with type 2 diabetes without prior myocardial infarction and 69 with prior myocardial infarction but no diabetes and found an HR of 1.2 (95% CI 0.6-2.4). When comparing the two studies, however, one should note that Haffner et al. (3) followed their subjects for 7 years rather than 25 years, had only eight deaths in their patients with CHD but no diabetes, and were therefore unable to examine outcome in men and women separately.

Not all authors have reached the same conclusions. Although all recognize that type 2 diabetes is associated with high vascular and all-cause mortality, the belief that diabetes is a CHD risk equivalent is not supported as strongly as we expected, given the views and recommendations of the guideline writers. The Haffner study (3) and an analysis of registry data of patients hospitalized for unstable angina and non-Q-wave myocardial infarction in six different countries (15) both showed that people with diabetes but no previous cardiovascular disease had the same event rates as people with previous vascular disease only. By contrast, the cross- sectional and cohort studies from Tayside (4), the U.S. Physicians Health Study (16), the U.S. Nurses' Health Study (17), and an analysis of data from the Multiple Risk Factor Intervention Trial (MRFIT) (18) all concluded that patients with diabetes only carry lower vascular risks than those with CHD only. So why are there discrepancies in the results?

The studies differ in several respects including age range, sex, criteria for diagnosis of diabetes and CHD, and duration of diabetes. None of these seems likely to account for the discrepancies in results in our view, except for the duration of diabetes, which varied substantially. Studies comparing incident and prevalent cases of diabetes showed higher mortality risks for prevalent diabetes, presumably by virtue of their longer duration of follow-up (3,17). Hu et al. (17) explored this possibility further and were able to show a linear relationship between duration of diabetes and risk. Diabetes duration of <5 years carried a lesser risk of fatal CHD than previous myocardial infarction. Risks were equivalent after 10 years of diabetes and began to exceed those of previous myocardial infarction after 15 years of diabetes. Although we do not know when subjects in the Renfrew and Paisley Survey first developed their diabetes, the 25-year follow-up guaranteed a long duration of diabetes and may therefore be the main reason why our results support the view that diabetes is a CHD risk equivalent.

Studies such as ours have strengths and limitations. We do not know if there were differences between respondents and nonrespondents because we did not have permission to track the nonrespondents, although we believe that a 79% response rate means that subjects in the Renfrew and Paisley Survey were likely to have been representative of the general population from which they were drawn. The inclusion of both sexes, the long duration of follow-up, and the large number of deaths are also strengths, as is the adjustment for the effects on outcome of six possible confounding variables including age, smoking habit, blood pressure, cholesterol, BMI, and social class.

Set against these strengths are a number of limitations. The diagnosis of diabetes was for the most part based on the response to the question, "Do you have or have you ever had diabetes?" Self- reporting of medical conditions such as diabetes is considered to be reliable (19), and other studies we reviewed also based their analyses on self-reported illness (16,17). We did not include any new cases of diabetes or CHD after screening. This is not so much a limitation as an acknowledgment that our findings reflect the risks associated with prevalent rather than incident diabetes. We were unable to distinguish type 1 from type 2 diabetes but suspect, given the age range of our cohort, that the majority had type 2 diabetes.

Of greater potential concern is that we may have overestimated the risk of diabetes and underestimated the risk of CHD. Self- reporting might exaggerate the risks of diabetes by excluding milder cases. However, the prevalence of diabetes at recruitment (1972- 1976) in the subgroup of subjects who had a random glucose measurement (74 of 4,702 or 1.5%) was not dissimilar from the self- reported prevalence of diabetes (190 of 14,039 or 1.3%). At the time of data collection, the random glucose cutoff for diagnosis of diabetes was generally accepted to be 14 mmol/l. A single random glucose of >11.1 mmol/l (the cutoff point used to extend the diabetes population in our analysis) does not on its own fully validate a diagnosis of diabetes but may be associated with a higher CHD risk than abnormal fasting glucose levels (20). The prevalence of type 2 diabetes has since increased to ~3% (21) as a result of increasing levels of obesity; however, this should not alter the ability of a diagnosis of diabetes made 25 years prior to predict outcome.

We may in addition also have underestimated the risk of CHD, particularly in women, by relying on the Rose Angina Questionnaire. It is well known that a higher proportion of women with a typical history of angina do not have CHD (22). Even if we did underestimate CHD risk, however, it is unlikely that we did so to the extent that the CHD death rate in women with CHD only (9.8/1,000 person-years) would then have exceeded that in women with diabetes only (16.9/ 1,000 person-years).

In conclusion, although there remain some differences in the detail, U.S. (23,24), European (25), and U.K. (26,27) guidelines now all recommend that type 2 diabetes be considered a CHD risk equivalent and that people with diabetes should be treated as if they already have vascular disease. The move to more aggressive therapies is supported by the results of the Heart Protection Study (5) and the Collaborative Atorvastatin Diabetes Study (6), which provide clear evidence of benefit from cholesterol lowering drug therapy in patients with diabetes only and no evidence of vascular disease. Two other statin trials containing subgroups of patients with type 2 diabetes failed to show benefit, although the Anglo Scandinavian Cardiac Outcomes Trial simply was not powered to do so (8) and the difference in serum cholesterol between treated and usual care groups in the Antihypertensive and Lipid Eowering Treatment to Prevent Heart Attack Trial was likely to have been insufficient for a difference in outcome to emerge (7). Our study shows that middle-aged men and women with diabetes but no clinical evidence of CHD experience a lifetime vascular risk that is at least as high as (and for women, possibly higher than) that for subjects of similar age who have CHD but no diabetes. These data support the view that patients with type 2 diabetes who have not yet had a myocardial infarction or developed angina should be given the same advice and treatment as is currently recommended for patients with overt vascular disease to prevent vascular events.

Acknowledgments - We thank Dr. Jim Lawrence for his helpful comments during the preparation of this report and Josephine Campbell and Anne Bray for typing the manuscript.

A table elsewhere in this issue shows conventional and Systme International (SI) units and conversion factors for many substances.

2005 by the American Diabetes Association.

Ibuprofen risks similar to those of Vioxx, says Canadian panel of experts

Controversial drug Vioxx is as risky as the common painkiller Ibuprofen, a panel of expert panel set up by Health Canada has said. The former was pulled off the counters in Canada and the United States after its role in increasing cardiac risk in regular users was revealed.

Vioxx, a Cox 2 inhibitor, belongs to a group of drugs called non-steroidal anti-inflammatory drugs (NSAID). Drugs like Bextra and Celebrax, belonging to the same group, were also pulled off along with Vioxx.

“The increased risk of cardiovascular disease caused by Cox-2 selective inhibitors seems similar to the increased risk associated with most NSAIDs,” a report released by the 13-member panel said, after going through data compiled by University of Oxford of 138 trials involving 144,296 patients, and ruling that NSAIDs carry the risk of health ailments like high blood pressure, inflammation and kidney disorders.

Developed in the 1990s, Cox-2 inhibitors became popular for providing pain relief without adverse effects on the stomach. They are especially popular among those suffering from arthritis.
Advocating the return of the drugs to the market, the panel said that the package of these NSAIDs should sport warning labels making the users aware about the health risk of taking these drugs, thus leaving the final decision to the users. Panel chairman Andreas Laupacis, the chief executive of the Institute for Clinical Evaluative Sciences in Toronto, added, “It’s a judgment call. There’s no drug that I know of that’s beneficial that doesn’t have some harms as well.” In the report, the panel added, “Health Canada should consider that ibuprofen only be sold after discussion with a pharmacist, and must ensure that the risks of cardiovascular events are prominently displayed in materials that individuals receive at the time they purchase the drug.”

Even though the panel lobbied for the return of Vioxx and Celebrax, it rated Bextra as the most dangerous and was in favor of a complete ban on the drug.

Responding to the panel’s findings, Canada health minister Ujjal Dosanjh said, “Health Canada supports the direction of the panel’s recommendations. I am not only impressed by the quality of the report, but also by the fact that the panel has made important suggestions that will further advance our plans for making important health and safety information more accessible.” He announced various initiatives following the panel’s findings, including those like directing NSAID manufacturers to provide updated patient safety information, conducting further analysis on ibuprofen and establishing standards for the risk and benefit information that must be included in product labeling of NSAIDs. “Health Canada’s initiatives will not stop there. The public can rest assured that Health Canada will continue to act in the best interests of protecting the health of Canadians. Health Canada will also follow up on other recommendations made by the panel,” Dosanjh added.

WOMEN'S HEALTH STUDY FINDS VITAMIN E DOES NOT PROTECT WOMEN FROM HEART ATTACK, STROKE, OR CANCER

Vitamin E supplements do not protect healthy women against heart attacks and stroke, according to new results from the Women's Health Study, a long-term clinical trial of the effect of vitamin E and aspirin on both the prevention of cardiovascular disease and of cancer.

The vitamin E results of the Women's Health Study are published in the July 6 issue of the "Journal of the American Medical Association". In addition to the cardiovascular disease findings, the study authors report that there was no effect of vitamin E on total cancer or on the most common cancers in women -- breast, lung, and colon cancers. The Women's Health Study was funded by the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute of the National Institutes of Health.

"This landmark trial has given women and their physicians important health information. We can now say that despite their initial promise, vitamin E supplements do not prevent heart attack and stroke. Instead, women should focus on well proven means of heart disease prevention, including leading a healthy lifestyle and controlling risk factors such as high blood pressure and high cholesterol," said NHLBI Director Elizabeth G. Nabel, M.D.

The Women's Health Study was conducted between 1992 and 2004. The participants were 39,876 healthy women age 45 years and older who were randomly assigned to receive 600 IU of Vitamin E or placebo and low-dose aspirin or placebo on alternate days. The participants were followed for an average of 10.1 years. The aspirin results published last March found no benefit of aspirin (100 mg every other day) in preventing first heart attacks or death from cardiovascular causes in women but did find a reduced risk of stroke overall, as well as reduced risk of both stroke and heart attack in women aged 65 and older.

In recent years, there has been a great deal of public and scientific interest in the potential of antioxidant vitamins like vitamin E to reduce the risk of cardiovascular disease. Laboratory and animal research suggested that vitamin E might prevent the accumulation of fatty deposits inside arteries, which would reduce the chance of clogged and blocked arteries. Other large observational studies have also suggested that people who eat foods high in vitamin E or take supplements have a lower risk of coronary heart disease. Although several clinical trials conducted prior to the Women's Health study found little cardiovascular benefit from vitamin E, these trials were shorter and primarily studied individuals with cardiovascular disease or CVD risk factors. The intent of the Women's Health Study was to provide a long-term look at the effects of vitamin E supplementation among healthy women.

Participants in the Women's Health Study were monitored for major cardiovascular "events" -- a combination of nonfatal heart attack, nonfatal stroke, or cardiovascular death. By the end of the study, participants in the vitamin E group had 482 such events compared to 517 in the placebo group. However, this difference was not statistically different.

For the individual cardiovascular events, the study findings were:

-- Non fatal heart attacks: 184 in the vitamin E group versus 181 in the placebo group - not a statistically significant difference.

-- Non fatal strokes: 220 in the vitamin E group versus 222 in the placebo group - not statistically significant.

Study investigators also found no significant effect of vitamin E on total deaths (deaths from all causes). By the end of the study, there were 636 deaths in the vitamin E group compared to 615 in the placebo group.

Although total deaths were unaffected by vitamin E, there was a significant 24 percent reduction in cardiovascular deaths among all women taking the vitamin (106 deaths in the vitamin E group versus 140 in the placebo group). In another positive finding, women 65 and older taking vitamin E had a 26 percent decrease in heart attacks and cardiovascular deaths, but not strokes.

"These intriguing findings deserve further study. But they were not part of the primary aim of the study -- to look at the effect of vitamin E on overall cardiovascular disease, which includes heart attack, stroke, and cardiovascular death. Additionally, previous studies of vitamin E in patients with heart disease have not shown any benefit for cardiovascular deaths. At present, we cannot recommend vitamin E for prevention against cardiovascular disease or cancer," said lead investigator I-Min Lee, MBBS, ScD of Brigham and Women's Hospital.

The study finding of a decrease in major cardiovascular events among women age 65 years and older is relatively unique, added Dr. Lee. "Almost all previous trials have not reported findings by age. If other current trials provide age-related results, these additional data will help clarify the Women's Health Study results of benefit among the women aged 65 years and older," she said.

Overall, the results were not affected by a study participant's menopausal status, use of hormone therapy, body mass index, alcohol intake, or physical activity. The study found no significant side effects among women taking vitamin E except for an increase in nosebleeds, which was likely due to chance, as there was no increase in risk of other types of bleeding, including hemorrhagic stroke.

According to the 1999-2000 National Health and Nutrition Examination Survey, an estimated 13.5 percent of women in the U.S. take vitamin E supplements, although it is not known how many are taking the vitamin to prevent heart disease and stroke.

NHLBI's Dr. Nabel encouraged women to learn more about proven ways to prevent heart disease, the number one killer of women. "The Heart Truth" (www.hearttruth.gov), NHLBI's program to increase women's awareness of the dangers of heart disease, offers resources and information on leading a healthy lifestyle.

NHLBI is part of the National Institutes of Health (NIH).

SCIENTISTS DISCOVER HOW NIPAH VIRUS ENTERS CELLS

Working independently, two research teams funded by the National Institute
of Allergy and Infectious Diseases (NIAID), part of the National Institutes
of Health (NIH), have identified how Nipah and Hendra viruses, closely
related viruses first identified in the mid-1990s, gain entry into human and
animal cells.

Nipah and Hendra are emerging viruses that cause serious respiratory and
neurological disease. People can get these deadly viruses from animals.
Beginning in 1994, public health officials have recognized disease outbreaks
in Malaysia, Singapore, Bangladesh and Australia.

Both viruses use a protein essential to embryonic development to enter cells
and begin their often-fatal attack, report researchers at the University of
California, Los Angeles (UCLA) and the Uniformed Services University of the
Health Sciences (USUHS) in Bethesda, Maryland.

The UCLA team, headed by Benhur Lee, M.D., describes its findings in a
"Nature" paper posted online on July 6. The report by the USUHS researchers,
led by Christopher Broder, Ph.D., is appearing online the week of July 4 in
the "Proceedings of the National Academy of Sciences".

The first reported outbreak of Nipah virus occurred in 1998-1999 in
Malaysia, sickening 265 people and killing 105, according to the World
Health Organization. This outbreak, which in this case spread from pigs to
humans, was contained by culling more than a million pigs. Hendra virus, so
far less of a threat to human health, was first identified in 1994 in
Australia when it spread from horses to humans.

"In addition to our concern about Nipah and Hendra viruses as emerging
global health and economic threats, we worry about their potential use as
bioterror agents," says Anthony S. Fauci, M.D., director of NIAID. "This
work, funded through our biodefense research program, is a major step
towards developing countermeasures to prevent and treat Nipah and Hendra
infection."

Using different methods, both teams identified a specific cell surface
receptor, Ephrin-B2, as the doorway used by Nipah and Hendra viruses to get
inside cells. This receptor is found on cells in the central nervous system
and those lining blood vessels. It is crucial for the normal development of
the nervous system and the growth of blood vessels in human and other animal
embryos. Ephrin-B2 is found in humans, horses, pigs, bats and other mammals,
which explains the unusually broad range of species susceptible to Nipah and
Hendra virus infection.

Dr. Broder and his colleagues collaborated with researchers at the National
Cancer Institute, also part of the NIH, and the Australian Animal Health
Laboratory. The team narrowed the search for the Nipah/Hendra receptor by
first sifting through the genetic sequences of 55,000 possible receptors
using microarray technology as a molecular "sieve."

The scientists compared microarray signals from the 55,000 genetic sequences
in one set of Nipah virus-resistant human cells with microarray signals from
three sets of human cells that the virus can infect. This enabled the
research team to narrow the possible number of receptor proteins to 120 by
identifying those present in the virus-susceptible cells but absent in the
virus-resistant cells. They winnowed the possibilities further -- to just 21
-- by selecting only those candidate receptors within the molecular weight
range they expected. They selected 10 expressed at high levels in the
susceptible cell lines and inserted them, one by one, into the cells that
resisted Nipah virus to identify the receptor. When they inserted the gene
for Ephrin-B2, the previously Nipah-resistant cells admitted the virus.

The UCLA team, with collaborators at the University of Pennsylvania, took a
different approach, using tools of advanced molecular biology as well as
old-fashioned detective work to identify the Ephrin-B2 receptor. They knew
the receptor would be abundant among the type of cells Nipah virus attacks,
that is, nerve cells and cells lining blood vessels.

To identify the human cell receptor, they created a bait: the Nipah protein
that docks to that unknown receptor was attached to part of a human
antibody, like a worm on a fishing hook. When they placed this bait onto
cells susceptible to Nipah virus infection, it attached to a protein on the
cell surface. When placed on Nipah-resistant cells, however, the antibody
did not attach to the cells. The scientists used an instrument that sorts
molecules by weight to identify that Ephrin-B2 was the cell receptor protein
that bound to the antibody/Nipah protein "fishing pole" they had made.

They wanted to confirm their findings, but since they did not have access to
a high-level biosafety laboratory as Dr. Broder's team did, the UCLA
researchers engineered a harmless virus with Nipah virus proteins embedded
in its coat. The UCLA team found that this artificial construct could infect
cells vulnerable to Nipah virus but was unable to infect Nipah
virus-resistant cells. They also showed that this engineered virus could
infect nerve cells and cells lining blood vessels using Ephrin-B2 as the
receptor, in the same way as actual Nipah virus would infect these cells.

Knowing the identity of the Nipah and Hendra receptor will not only help in
developing vaccines and treatments, but also promises to lead to better
understanding of how the viruses cause disease in people and a variety of
animals, the researchers say.

NIAID is a component of the National Institutes of Health, an agency of the
U.S. Department of Health and Human Services. NIAID supports basic and
applied research to prevent, diagnose and treat infectious diseases such as
HIV/AIDS and other sexually transmitted infections, influenza, tuberculosis,
malaria and illness from potential agents of bioterrorism. NIAID also
supports research on transplantation and immune-related illnesses, including
autoimmune disorders, asthma and allergies.

News releases, fact sheets and other NIAID-related materials are available
on the NIAID Web site at http://www.niaid.nih.gov.

The National Institutes of Health (NIH) - The Nation's Medical Research
Agency - is comprised of 27 Institutes and Centers and is a component of the
U. S. Department of Health and Human Services. It is the primary Federal
agency for conducting and supporting basic, clinical, and translational
medical research, and investigates the causes, treatments, and cures for
both common and rare diseases. For more information about NIH and its
programs, visit www.nih.gov.

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References: MI Bonaparte et al. Ephrin-B2 ligand is a functional receptor
for Hendra virus and Nipah virus. "Proceedings of the National Academy of
Sciences" vol 102 (2005) doi:10.1073/pnas/0504887102.

OA Negrete et al. Ephrin B2 is the entry receptor for Nipah virus, an
emergent deadly paramyxovirus. "Nature" (2005) doi: 10.1038/nature03838.
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