Friday, October 31, 2008

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Scientific American Magazine - October 28, 2008

25 Years Later: Can HIV Be Cured?
Eliminating HIV from the body would require flushing the virus out of its hiding places and preventing those reservoirs from being refilled. A tall order but perhaps not impossible

By Mario Stevenson

In contrast to the failed attempts at developing a vaccine against HIV, efforts to provide drug therapies stand as a great success. More than 25 agents have been approved thus far, and the right combinations can suppress replication of the virus, often keeping blood levels so low as to be undetectable by standard tests.

These powerful drug cocktails, collectively termed highly active antiretroviral therapy, or HAART, have prolonged life and health in countless infected individuals. Yet vexingly, today’s treatments cannot actually cure the infection. If for any reason therapy is interrupted, the virus rapidly rebounds.

Figuring out how HIV manages to hang around in the company of these potent drugs is one of the most important tasks currently facing researchers. Over the past decade investigators have gleaned key insights into this mystery. The answers, we hope, will ultimately reveal whether complete eradication of the virus in a patient is feasible.

Understanding the nature of HIV’s hiding places, or reservoirs, and what it will take to eradicate them requires some insight into how HIV typically behaves in the body. Like all viruses, HIV needs to get into the body’s cells to replicate.

There the invader exploits the cells’ machinery to make copies of its own genome and to translate viral genes into proteins. It thus generates new viral copies, called virions, which spread to other cells. But unlike most human viruses, HIV actually inserts its genome into that of the cell.

Every time the cell reproduces, the viral genes get copied and passed down to the daughter cells, thereby ensuring that the virus persists for as long as the cell and its progeny survive in the body.

The immune system typically manages to eliminate viruses by knocking out infected cells. It identifies such cells readily by the bits of viral proteins, or antigens, they display on their surface to flag the presence of interlopers within.

In the case of HIV, the immune system has a hard time eradicating infected cells on its own in part because the virus attacks components of the immune system itself. The body does manage for a while to counterattack, generating healthy new immune cells able to recognize the virus and other infectious agents. In untreated individuals, however, the virus gains the upper hand over time, leading to AIDS.

Today’s powerful drug combinations protect the immune system because they suppress HIV replication and limit the spread of virus to new cells. In theory, these treatments should permit the still healthy parts of the immune system to clear out any remaining infected cells and cure the disease. So why is the drug-protected immune system failing to do that job?

Keeping a Low Profile

A big component of the answer appears to be the persistence of cells that are genetically able to make new virions but that do not produce any and thus do not inform the immune system of their presence.

As David I. Watkins notes in “The Vaccine Search Goes On,” starting on page 69, HIV preferentially infects immune cells called helper T lymphocytes, which mostly reside in the lymph nodes and connective tissue of the gastrointestinal tract but also occupy other lymph nodes and circulate in the blood.

In the course of fighting most kinds of viral infections, the bulk of helper T cells involved in the fight die off when they are no longer needed. A subset, however, survives as long-lived memory T cells, ready to multiply and call in the reserves when they encounter signs of reinfection.

It is these memory T cells that appear to produce the most virus in HIV-infected patients. As they prepare to divide to fight remembered pathogens, they both duplicate their own DNA and proteins and churn out new HIV virions. Most of the infected memory cells die from the virus itself or the immune attack against them, but some return to a dormant state.

At that point, HIV exists only as viral DNA sitting quietly in the cells’ genome. This viral DNA does not get copied and does not give rise to viral proteins, so no protein bits get displayed on the surface. Consequently, anti-HIV drugs have no effect on the cells, and the immune system remains blind to them.

This understanding has been informed by studies published in 1997. Teams led independently by Robert F. Siliciano of Johns Hopkins University, Anthony S. Fauci of the National Institutes of Health and Douglas D. Richman of the University of California, San Diego, found that inactive T lymphocytes isolated from HIV-infected individuals do not manufacture HIV.

When those cells were roused, however, the previously dormant virus began replicating anew. HIV is not the only virus to exhibit such latency. An array of viruses can enter into similarly quiet states. In fact, some, such as the herpesviruses, make proteins that actually encourage the virus to become latent.

Estimates based on the life span of memory T cells suggest it would take in excess of five decades for the reservoir of cells infected with latent HIV to naturally die out.

Researchers are also beginning to comprehend that it is not only latent helper T cells that bring HIV back after therapy stops. It seems that despite the absence of virus in the blood, some helper T cells and other cells keep on making new virus at a low level even when therapy seems to be working beautifully.

This activity falls under the radar of tests, because the virus either hides successfully in the cells or, when released, stays trapped in tissues and does not find its way into the blood.

In the past year, for instance, research has revealed that helper T lymphocytes in the gut get depleted within weeks of the individual contracting HIV and even before the virus is detected in the blood.

It is therefore possible that during treatment the virus can continue to replicate in tissues such as those of the gut—activity that could go unnoticed for quite some time until the virus spills over into the blood.

Another Unwitting Accomplice

Most AIDS research has focused on helper T cells because they circulate in the blood, which can easily be drawn for study. Recently, however, investigators have come to realize that other immune cells infected by HIV—macrophages and dendritic cells—may also contribute to resurgence of the virus after HIV therapy is halted or after the virus becomes resistant to it.

Less is known about macrophages and den­dritic cells because they are located strictly in tissues, but recent findings suggest that drug therapy may not totally stop HIV reproduction in these cells. The level may be too low to result in the virus reaching the blood in detectable amounts.

It may, however, be high enough to reach nearby T lymphocytes and to continually restock the reservoir of dormant infected memory T cells. Also, some infected macrophages seem to evade being killed by the virus inside them or by other components of the immune system. Macrophages, then, may sit ready to pump up replication when drug therapy stops.

In 2001, for instance, Malcolm A. Martin of the NIH and his colleagues reported that although monkeys infected with simian immunodeficiency virus (SIV)—a close relative of HIV—lost most of their helper T lymphocytes within a few weeks of being infected, copious quantities of virus were still being produced.

Mac­rophages, it turned out, were generating the virus. Subsequent treatment of the monkeys with a drug that inhibits viral replication—and thus prevents infection of new cells—failed to significantly lower the amount of virus in the animals’ blood. This finding meant that the macrophages were not dying in the process of spewing out new copies of the virus.

HIV also seems to replicate somewhat differently in macrophages as compared with T cells—in a way that may be additionally advantageous to the virus. Whereas in T cells the virus components assemble close to, and subsequently detach from, the cell surface, in macrophages some viral particles appear to be deposited into compartments within the cells called vacuoles.

Eventually the vacuoles may migrate up to the cell surface to release the stored virus particles. The packing of the virus into walled-off compartments might help HIV dodge immune detection by preventing the display of antigens on the cell surface that tip the immune system off to the presence of an intruder.

Finally, studies suggest that higher drug concentrations are needed to suppress viral replication in macrophages than in T cells. Exactly why this should be the case is uncertain. Yet we do know that some cellular proteins whose normal function is to excrete biological substances from the cell can interfere with drug therapy by hindering the uptake and retention of drugs.

Perhaps, then, in macrophages these cellular proteins are particularly active and so prevent the drugs from being efficiently retained inside the cells. The same thing may occur in dendritic cells, although so far very little is known about how these cells respond to HIV.

Anatomical Refuges
It is not only the inherent properties of helper T cells and macrophages that allow HIV to persist in the face of intensive therapy. Certain of these cells also sit in anatomical compartments that may shelter them from various drugs or immune defenses, or both. Ridding the body of HIV would necessitate reaching it in those places.

The central nervous system (CNS) is one such compartment. Researchers have long known that the CNS is susceptible to HIV infection. The neurological problems that arise in late-stage AIDS stem largely from the production of neurotoxins released from infected macrophages in the brain.

To enter the brain, any molecule or cell must cross the blood-brain barrier, essentially a selectively permeable membrane that regulates the traffic of cells and other substances from the blood to the CNS. Macrophages that become infected with HIV in the tissues outside the CNS can apparently cross the blood-brain barrier and settle down in the CNS, where the virus may go on to infect specialized mac­rophages known as microglia, which reside permanently within the CNS.

Evidence suggests that infection of cells in the CNS would afford the virus some degree of protection from drugs because certain of them—notably protease inhibitors important to the proper processing of new viral proteins—do not efficiently cross the blood-brain barrier.

Further, most other circulating immune cells stay out of the brain. No one knows whether infected cells in the brain can send HIV out to other parts of the body, but if the virus-infected macrophages can cross the blood-brain barrier into the CNS, they can probably filter back out as well.

Other sites that seem difficult for some drugs to penetrate include the walls of the gastrointestinal tract and the genital tract. Semen often contains HIV RNA even in people whose blood seems to be clear of the virus.

New Plans of Attack

At a minimum, thoroughly clearing HIV from an infected individual would require removal of all latently infected T cells.

One way that researchers are currently exploring to address the latent reservoirs is treating patients with compounds that stimulate dormant infected T lymphocytes to divide, in the hopes that the cells will make virus and thus become vulnerable to antiretroviral therapy.

A couple of limited human trials have tested this approach using drugs previously approved to treat other conditions. They have yielded mixed results, however.

The ideal agents would tickle the T cells enough to rekindle the production of the viral proteins that get displayed on the cell surface but not so much as to trigger the cells to make new copies of the virus.

To that end, researchers are currently exploring the potential of drugs that would induce the synthesis of HIV proteins by altering the organization of chromatin (complexes of DNA and protein that compose chromosomes) in dormant infected T cells. Yet even these so-called chromatin remodelers would be of limited use if they worked only in T cells and the virus were also present in macrophages.

A second prong of attack for clearing HIV from the body would involve blocking all viral replication, so that HIV disappears not only from the blood but from all tissues and from all cell types that harbor it.

Drugs currently in use typically interfere with one of two enzymes: reverse transcriptase, which converts the virus’s genetic material from RNA to DNA for insertion into the cellular genome, or protease, which helps nascent viral particles to mature. Within weeks after a person starts standard therapy, the level of virus in the individual’s blood drops to undetectable levels.

The slope of decay is fairly consistent from patient to patient, which researchers have taken to mean that the therapies thoroughly forestall viral replication. Yet recent studies have shown that intensifying existing drug regimens with raltegravir, a new drug that targets a viral enzyme not hit by earlier agents (the viral integrase enzyme, which stitches HIV DNA into the cells’ own DNA), actually accelerates the viral decay.

This success suggests that infected cells can probably be hit faster and more effectively than is now the case. If that surmise is correct, the work also implies that intensifying HIV therapy even further might limit the size of the original latent reservoir, block its later restocking and—dare we hope—lower replication so much that the immune system really can wipe out any virus-making reservoirs left over when latent infected memory cells are eliminated.

In the past year several new drugs that interfere with previously untargeted steps in viral replication have entered into clinical trials. In addition to the integrase inhibitor, another drug blocks infection by interfering with the ability of the virus to attach to a molecular receptor known as CCR5 that sits on the cell surface.

Research also suggests that certain cellular proteins may be good therapeutic targets. Whereas HIV commandeers some of these proteins to aid its replication (CCR5, for example), it is now apparent that other cellular proteins—or cellular restrictions, as they are termed—actually antagonize viral replication.

Six years ago Michael H. Malim of King’s College London and his research group identified the first of these cellular restrictions, called A3G. This protein is abundant in macrophages and in lymphocytes.

Unfortunately, the virus has evolved a countermeasure to A3G: it makes a protein called Vif that induces the degradation of A3G. The good news is that both A3G and the viral Vif protein represent promising targets for therapy. Drugs that inhibit Vif or otherwise protect A3G from degradation would theoretically render human cells resistant to HIV infection.

Just this year Paul D. Bieniasz of the Aaron Diamond AIDS Research Center in New York City and John C. Guatelli of U.C.S.D. and their teams independently identified a second cellular restriction, named tetherin, that prevents the release of new copies of the virus from infected cells.

The virus has evolved a defense against tetherin, too—in this case, the viral Vpu protein. Drugs that stymie Vpu could prevent HIV from spreading to new cells.

Basic research will probably continue to reveal novel therapeutic targets, which could lead to the development of new antiviral agents that hit HIV in multiple ways. If we can design drugs that complement and intensify the effects of existing therapies, we may finally be able to deplete the all-important latent reservoir and eradicate the virus.

To that end, larger studies exploring the impact of long-term therapy in­tensification on the virus are currently under way, with results expected within the next two years. Those findings should tell us whether the eradication of HIV from an infected in­dividual is a realistic goal. We wait with great anticipation.

Note: This article was originally printed with the title, "Can HIV Be Cured?".

Further Reading
25 Years Later: The AIDS Vaccine Search Goes On
Hope and the Fight against HIV
Special Report: HIV--25 Years Later
Science of Snacks: Thinking Makes You Hungry

On the Web
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Medical Mystery: Only One Person Has Survived Rabies without Vaccine--But How?
Deadly by the Dozen: 12 Diseases Climate Change May Worsen

Reseach confirms wearing red boosts attraction to men

Global7 the new Millennial Renaissance Vision for the Globe

Our Passion is to reach our individual and collective potential-always!

Dear Patriotic global scientists:

Re: the majic is with the colour red! says recent reseaarch

It is interesting our choices are influenced by our vision and color, especially when it relates to men.

Vison and colour has been a very important part of our emotional characteristics for centuries. For the first time, research is shown men like women who dress red at their dates.

What colour is attractive to women? Do women pay more attention to sound rather than colour? What is common for both sexes, colour, sound and shapes, touch and temperature?

More reserach is needed to complement these initial findings. Here is the BBC story for us to think through.

Dr B Jesus (Globalbelai)
~*~*~*~*~*~*~*~*~*~*~*~*~*~Listen up, ladies: If you're looking to score, break out that red dress.

Men were more eager to bed women wearing red than those decked out in other colors, according to five studies involving 149 men and 32 women published today in the Journal of Personality and Social Psychology. The men also judged those women as more attractive than those sans red duds.

"I'm not going to let my 16-year-old daughter wear red, let's put it that way," says study author Andrew Elliot, a professor of psychology at the University of Rochester. "I do think a female who's interested in a male and going on a date ought to pull that red shirt out of the closet, because most likely it will make her more attractive to him."

There are two explanations for the phenomenon, says Elliot, a visiting professor at the University of Munich this semester. Society's emphasis on red on Valentine's Day as well as in sexy red lingerie may have taught men to link the color with romance, he says. There may also be an evolutionary explanation, based on humans' close genetic relationship with primates: Male primates tend to be especially attracted to female primates who show their red hindquarters, made rosy by increased blood flow when they're most fertile.

The men in the study were asked to rate their level of sexual interest on a scale of one to nine (one signifying zero interest and nine representing the strongest) in the women in photos they were shown. They were also asked to grade the women's attractiveness using the same scale. The desirability score was about 1.5 points higher and their attractiveness rating 1.2 points higher for women in red than for those in gray, green or blue.

Women surveyed didn’t rate their red-clad sisters as being any more attractive than those sporting garb in other hues, and neither they nor the guys found the ladies in red to appear any more likable, nicer or smarter than those in other colors. That suggests that red has a very specific color association with sexual behavior, Elliot says.

Women are likely to show a similar level of increased attraction to men in red in follow-up research he’s doing now, Elliot adds.

"The hypothesis is that you're going to see the same thing for females rating males, but through a different process," he says. "Females are more attracted to dominant, higher-status males. Red is a dominant cue in the wild when it's shown on a male. So human females who see red on a male will view him as more dominant, and that will lead her to be more attracted to him."

One caveat: The findings may be colored by certain situations. Elliot's previous research found that people who literally saw red immediately before a writing task performed worse—possibly because of our negative association with teachers' red pens used to point out errors.

(Image by iStockphoto)


Wearing red 'boosts attraction'
Women who don a little red dress before going out with a man may find their date more attentive and generous, according to scientists.

The University of Rochester study, published in a psychology journal, supports other evidence linking the colour to attractiveness.

Men said they would spend more money on a woman pictured in red, compared with the same woman wearing a blue shirt.

Experts say that red signals ovulation or attractiveness in other species.

It's fascinating to find that something as ubiquitous as colour can be having an effect on our behaviour without our awareness
Professor Andrew Elliot
University of Rochester

The colour has traditionally been linked with romantic and sexual matters, from red hearts on Valentine's Day, to red-light districts.

The researchers say that their study is clear evidence that the colour red makes men feel more amorous - even if this is only on a subconscious level.

Their volunteers were told they had $100, shown the picture of their "date", then asked how much of that money they were prepared to spend.

On average, wearing red meant a more expensive night out, and in general, a higher rating of attractiveness.

When the pictures were shown to other women, there were no wardrobe-dependent differences in attractiveness ratings.

Monkey business

Professor Andrew Elliot, who led the research, published in the Journal of Personality and Social Psychology, said: "It's fascinating to find that something as ubiquitous as colour can be having an effect on our behaviour without our awareness."

Dr Jo Setchell, an anthropologist from Durham University, said that, as the colour of blood, red was the easiest signal for an animal to produce externally, and had become a handy method of advertising fertility.

"For example, a lot of female monkeys have bright red sexual swellings, which show that they are around the time of ovulation.

"There has been controversy over whether, in female humans, ovulation is advertised or not, although there is some evidence that behaviour, such as going out, changes around that time.

"But wearing red could give you an advantage."

Story from BBC NEWS:

Published: 2008/10/28 08:19:06 GMT


Sunday, October 12, 2008

Noble Laurates vision about hiv pandemics

Global7 the new Millennial Renaissance Vision for the Glob
News - October 6, 2008

AIDS in 1988

In their first collaborative article 20 years ago, 2008 Nobel Prize winner Luc Montagnier, along with Robert Gallo, co-investigators who discovered HIV, introduced a Scientific American single-topic issue on AIDS. They recounted the breakthrough and offered prospects for vaccine, for therapy and for the epidemic
By Robert C. Gallo ad Luc Montagnier

Editor's Note: Luc Montagnier shared the 2008 Nobel Prize in Medicine or Physiology, awarded on October 6. The new Nobel laureate co-authored this article, originally published in the October 1988 issue of Scientific American. We are making it available here due to its historical significance.

As recently as a decade ago it was widely believed that infectious disease was no longer much of a threat in the developed world. The remaining challenges to public health there, it was thought, stemmed from noninfectious conditions such as cancer, heart disease and degenerative diseases. That confidence was shattered in the early 1980's by the advent of AIDS.

Here was a devastating disease caused by a class of infectious agents--retroviruses--that had first been found in human beings only a few years before. In spite of the startling nature of the epidemic, science responded quickly. In the two years from mid-1982 to mid-1984 the outlines of the epidemic were clarified, a new virus-the human immunodeficiency virus (HN)-was isolated and shown to cause the disease, a blood test was formulated and the virus's targets in the body were established.

Following that initial burst, progress has been steady, albeit slower. Yet in some respects the virus has outpaced science. No cure or vaccine is yet available, and the epidemic continues to spread; disease-causing retroviruses will be among the human population for a long time.

In view of that prospect, it is essential to ask where we stand in relation to AIDS in 1988. How was HN discovered and linked to AIDS? How does the virus cause its devastation? What are the chances that AIDS will spread rapidly outside the known high-risk groups? What are the prospects for a vaccine? For therapy? How can the epidemic most effectively be fought? Those are some of the questions this article and this issue of Scientific American have set out to answer.

Like other viruses, retroviruses cannot replicate- without taking over the biosynthetic apparatus of a cell and exploiting it for their own ends. What is unique about retroviruses is their capacity to reverse the ordinary flow of genetic information--from DNA to RNA to proteins (which are the cell's structural and functional molecules).

The genetic material of a retrovirus is RNA In addition, the retrovirus carries an enzyme called reverse transcriptase, which can use the viral RNA as a template for making DNA The viral DNA can integrate itself into the genome (the complement of genetic information) of the host. Having made itself at home among the host's genes, the viral DNA remains latent until it is activated to make new virus particles. The latent DNA can also initiate the process that leads to tumor formation.

Retroviruses and their cancer causing potential are not new to science. At the beginning of this century several investigators identified transmissible agents in animals that were capable of causing leukemias (cancers of blood cells) as well as solid-tissue tumors. In the succeeding decades retroviruses were identified in many animal species. Yet the life cycle of retroviruses remained obscure until 1970, when Howard M. Temin of the University of Wisconsin at Madison and (independently) David Baltimore of the Massachusetts Institute of Technology discovered reverse transcriptase, confirming Temin's hypothesis that the retroviral life cycle includes an intermediate DNA form, which Temin had called the provirus. The details of viral replication quickly fell into place.

In spite of such discoveries, by the mid-1970's no infectious retroviruses had been found in human beings, and many investigators firmly believed no human retrovirus would ever be found. Their skepticism had several grounds. Many excellent scientists had tried and failed to find such a virus.

Moreover, most animal retroviruses had been fairly easy to find, because they replicated in large quantities, and the new virus particles were readily observed in the electron microscope; no such phenomenon had been found in human beings. In spite of this skepticism, by 1980 a prolonged team effort led by one of us (Gallo) paid off in the isolation of the first human retrovirus: human T-lymphotropic virus type I (HTLV-I).

HTLV-I infects T lymphocytes, white blood cells that have a central role in the immune response. The virus causes a rare, highly malignant cancer called adult T-cell leukemia (ATL) that is endemic in parts of Japan, Africa and the Caribbean but is spreading to other regions as well.

Two years after the discovery of HlLV-I the same group isolated its close relative, HTLVII. HTLV-II probably causes some cases of a disease called hairy-cell leukemia as well as T-cell leukemias and lymphomas of a more chronic type than those linked to HTLV-I. The two viruses. however. share some crucial features. They are spread by blood. by sexual intercourse and from mother to child. Both cause disease after a long latency. and both infect T lymphocytes. When AIDS was first recognized. these properties took on great additional significance.

The first AIDS cases were diagnosed in 1981 among young homosexual men in the U.S. Although the syndrome was puzzling. it soon became clear that all its victims suffered from a depletion of a specific subset of T cells- T4 cells and that as a result they fell prey to pathogens that would easily be controlled by a healthy immune system. A variety of hypotheses were advanced to explain AIDS. including breakdown of the victims' immune systems following repeated exposure to foreign proteins or even to sperm-during homosexual intercourse. It seemed more plausible. however. to explain a new syndrome by the appearance of a new infectious agent.

To one of us (Gallo) the likeliest agent was a retrovirus. It had already been shown that the AIDS pathogen. like HTLV-I. could be transmitted by sexual intercourse and by blood. Furthermore. Max Essex of the Harvard School of Public Health had shown that a retrovirus of cats called feline leukemia virus (FeLV) could cause either cancer or immune suppression.

Since in most species the infectious retroviruses are closely related. it seemed plausible that the same was true in human beings. Hence the initial hypothesis was that the cause of AIDS was a close relative of HTLV-I. That hypothesis. as it turned out. was wrong. Nonetheless, it was fruitful because it stimulated the search that led to the correct solution.

The retrovirus hypothesis for the origin of AIDS reached the other one of us in France in the following way. Almost as soon as AIDS was first diagnosed. a working group on the syndrome had been formed by a circle of young clinicians and researchers in France. One member of the group.

Jacques Leibowitch of the Raymond Poincare Hospital in Paris. had had some contact with Gallo's team and carried the HTLV hypothesis back to France. The members of the French group wanted to test that hypothesis. and they had the biological materials to do so because the group included clinicians with patients afflicted by AIDS or pre-AIDS. What they lacked, however, was the collaboration of virologists experienced in work with retroviruses.

The French author of this article and his colleagues Francoise Barre-Sinoussi and Jean-Claude Chermann at the Pasteur Institute fitted that description. They were engaged in several lines of work on cancer and interferon including attempts to find retroviruses in patients with cancer particularly in cultures of lymphocytes.

A member of the working group, Willy Rozenbaum of the Salpetriere Hospital, asked whether they were interested in analyzing tissues from a patient with lymphadenopathy. or swollen glands. (Lymphadenopathy can be an early sign of the process that culminates in AIDS.

Such a patient was chosen because finding a virus early in the disease seemed more meaningful than finding one later. when AIDS patients were infected with many opportunistic agents.) The answer was yes, and in January, 1983, a specimen from the swollen lymph node of a young homosexual arrived at Montagnier's laboratory.

The specimen was minced. put into tissue culture and analyzed for reverse transcriptase. After two weeks of culture. reverse-transcriptase activity was detected in the culture medium. A retrovirus was present. But which one? The first possibility that had to be tested was whether the virus was one of the known HTLVs. or perhaps a close relative of them.

That possibility was tested using specific HTLV-I reagents supplied by Gallo. The virus did not react significantly with the HTLV-I reagents; a similar result was later obtained with HTLV-Il reagents. A strenuous effort was begun to characterize the new agent.

Among the first results of that effort was the finding that the new virus (which was named lymphadenopathy associated virus. or LAV) grew in T4 cells but not in related cells called T8; that finding was made by David Klatzmann and Jean-Claude Gluckman of the Salpetriere Hospital in collaboration with the Pasteur group.

It was shown that the virus could kill T4 cells or inhibit their growth. Electron micrographs of the new virus were different from those of HTLV-I and resembled those of a retrovirus of horses. A viral protein called P25 (or P24) that is not present in HTLV-I was identified. In collaboration with virologists from the Claude Bernard Hospital a blood test for lAY antibodies was formulated.

Several examples of lAY or lAV-like viruses were isolated from homosexual men, hemophiliacs and central Africans. Early results of applying the blood test were suggestive but not fully conclusive. lAV antibodies were found in a large fraction of lymphadenopathy patients but in only a minority of AIDS patients. Yet the proportion increased as the sensitivity of the test improved. By October, 1983, it had reached 40 percent. At that point one of us (Montagnier) was convinced lAV was the best candidate for the cause of AIDS.

To the other one of us the evidence did not seem so clear. For one thing, results had been obtained (by Gallo and Essex) indicating that some AIDS patients are infected with HTLV-I or a variant of that virus. It is now known that those results stemmed partly from the fact that among people infected with HIV are some who are also infected with the HTLV's. Moreover, only a minority albeit a substantial one-of AIDS patients had shown serological evidence of lAY infection.

In addition, when it was first isolated, lAY could not be grown in large amounts in continuous cell lines. Without large quantities of virus it was difficult to prepare specific lAY reagents that could be used to show that all people with AIDS or pre-AIDS were infected by the same type of virus.

Therefore on the American side much effort was concentrated on growing the pathogen from the blood of AIDS patients in mass, continuous culture. By the end of 1983 that task had been accomplished by the Gallo team: several cell lines had been identified that could support the growth of the new agent.

The first reagents for specifically typing this virus were rapidly made. Employing those reagents, it was shown that 48 isolates obtained beginning in early 1983 from AIDS patients and people in risk groups were all the same type of virus, which was called HTLV-III on the American side.

A blood test was formulated and used to show that HTLV-III was present in almost all people with AIDS, in a variable proportion of people at risk of the disease (including people who had received blood contaminated by the virus but had no other risk factors) and in no healthy heterosexuals. The cause of AIDS had been conclusively established.

These results confirmed and extended the ones from France. lAV and HTLV-III were soon shown to be the same virus. Before long an international commission had changed its name to HIV, to eliminate confusion caused by two names for the same entity and to acknowledge that the virus does indeed cause AIDS. Thus contributions from our laboratories in roughly equal proportions-had demonstrated that the cause of AIDS is a new human retrovirus.

That HIV is the cause of AIDS is by now firmly established. The evidence for causation includes the fact that HIV is a new pathogen, fulfilling the original postulate of "new disease, new agent." In addition, although the original tests found evidence of HIV infection in only a fraction of people with AIDS, newer and more sensitive methods make it possible to find such evidence in almost every individual with AIDS or pre-AIDS.

Studies of blood-transfusion recipients indicate that people exposed to HIV who have no other risk factors develop AIDS. The epidemiological evidence shows that in every country studied so far AIDS has appeared only after HIV. What is more, HIV infects and kills the very T4 cells that are depleted in AIDS. Although the causative role of HIV in AIDS has been questioned, to us it seems clear that the cause of AIDS is as well established as that of any other human disease.

Soon after the causation was established, a series of findings began to fill in the scientific picture of HIV. In a remarkably short time the genetic material of the virus was cloned and sequenced (in our laboratories and several others).

The genetic complexity of HIV began to emerge when a gene called TAT was discovered by William A Haseltine of the Dana-Farber Cancer Institute, Flossie Wong-Staal of the National Cancer Institute and their collaborators. Such complexity is significant because it underlies the capacity of HIV to remain latent for a long period, . then undergo a burst of replication, a pattern that may hold the key to the pathology of AIDS.

There were other significant early findings. One of us (Gallo), with his colleagues Mikulas Popovic and Suzanne Gartner, showed that HIV could infect not only the T4 cell but also another type of white blood cell, the macrophage. The same one of us, working with his colleagues Beatrice H. Hahn, George M. Shaw and Wong-Staal, found HIV in brain tissues. It seems possible that the macrophage, which can cross the blood-brain barrier, may bring virus into the brain, explaining the central-nervous-system pathology seen in many AIDS patients.

How the virus infects both T4 cells and macro phages became clear when Robin A Weiss of the Chester Beatty Laboratories and, independently, Klatzmann and the Pasteur group showed that HN enters its target cells by interacting with the molecule called CD4. CD4 has a significant role in the immune function of T4 lymphocytes and also serves as a marker for that group of cells. The early work by the British and French teams showed that HN infects cells by binding to CD4. Hence only cells bearing that marker can be infected. (Although CD4 is the marker for the T4 cells, it is also found in smaller numbers on some macrophages, allowing them to be infected.)

Several additional findings rounded out the early discoveries. The potential of the epidemic to spread beyond the original risk groups was shown when Robert R. Redfield and one of us (Gallo) demonstrated that HIV can be transmitted during heterosexual intercourse. Members of the Gallo team also showed that the genetic makeup of the virus is highly variable from strain to strain, a fact that may complicate the attempt to formulate an AIDS vaccine.

After the rapid initial advance the pace slowed somewhat and began to approximate that of a more mature area of research. Yet the continuing work was not without surprises. In October, 1985, one of us (Montagnier) was engaged in analyzing blood samples brought to his laboratory by a visiting investigator from Portugal. Many of the samples were from people who had lived in Guinea-Bissau, a former Portuguese colony in West Africa. Among them were some people who had been diagnosed by Portuguese clinicians and investigators as having AIDS in spite of the fact that their blood showed no sign of HN infection.

One sample, in fact, was negative for HN using the most sophisticated techniques available at the time. Yet workers in the laboratory were able to isolate a virus from the patient's blood. DNA "probes" (short pieces of DNA from the HIV genome) were then prepared. If the new virus were closely related to the original AIDS agent, those probes would bind to its genetic material. As it turned out, there was little binding, and it became clear that the new isolate was not simply a strain of the original AIDS virus but a new virus designated HN-2. Soon a second example was isolated by workers at the Claude Bernard Hospital; many others followed.

In evolutionary terms HIV-2 is clearly related to HIV-1, the virus responsible for the main AIDS epidemic. The two viruses are similar in their overall structure and both can cause AIDS, although the pathogenic potential of HN-2 is not as well established as that of the first AIDS virus. HN-2 is found mainly in West Africa, whereas HN-1 is concentrated in central Africa and other regions of the world. The finding of HIV-2 suggests that other undiscovered HIVs may exist, filling out a spectrum of related pathogens.

The isolation of HN-2 immediately raises the question of the evolutionary origins of these viruses. Although the answer to that question has not been found, some hints have been provided by the discovery in other primate species of related viruses called simian immunodeficiency viruses (SN's). The first such virus, found in the macaque monkey, is designated SN macaque. Isolated and characterized by Ronald C. Desrosiers and his co-workers at the New England Regional Primate Research Center in collaboration with Essex and his colleague Phyllis Kanki, SN macaque has been shown to be closely related to HIV-2, raising the possibility that HIV-2 may have come into human beings relatively recently from another primate species.

No such close simian relative has been found for HN-1 (although the right group of primates may not yet have been studied in sufficient detail). Hence the origin of HN-1 remains more mysterious than the origin of its relative HN-2. It is likely, however, that HN-1 has been in human beings for some time. One of us (Gallo), with Temin, has used the divergence among HN strains and the virus's probable rate of mutation to estimate how long the virus has infected people. It was tentatively concluded that HN has infected human beings for more than 20 years but less than 100, an estimate compatible with those by other workers and with our knowledge of the epidemic.

Where was HN hiding all those years, and why are we only now experiencing an epidemic? Both of us think the answer is that the virus has been present in small, isolated groups in central Africa or elsewhere for many years. In such groups the spread of HN might have been quite limited and the groups themselves may have had little contact with the outside world. As a result the virus could have been contained for decades.

That pattern may have been altered when the way of life in central Africa began to change. People migrating from remote areas to urban centers no doubt brought HN with them. Sexual mores in the city were different from what they had been in the village, and blood transfusions were commoner. Consequently HN may have spread freely. Once a pool of infected people had been established, transport networks and the generalized exchange of blood products would have carried it to every corner of the world. What had been remote and rare became global and common.

What weapons are available against this scourge? Perhaps the best weapon is knowledge. One key form of knowledge is a deeper understanding of HN, its life cycle and the mechanisms by which it causes disease. Although HN kills T4 cells directly, it has become clear that the direct killing of those cells is not sufficient to explain the depletion seen in AIDS. Indirect mechanisms must also be at work. What are they?

Many possibilities have been suggested. Infection by HIV can cause infected and uninfected cells to fuse into giant cells called syncytia, which are not functional. Autoimmune responses, in which the immune system attacks the body's own tissues, may also be at work. What is more, HIV infected cells may send out protein signals that weaken or destroy other cells of the immune system. In addition HN is fragile, and as the virus particle leaves its host cell, a molecule called gp120 frequently falls off the virus's outer coat. As Dani P. Bolognesi of the Duke University Medical Center and his co-workers have shown, gp120 can bind to the CD4 molecules of uninfected cells. When that complex is recognized by the immune system, cells thus marked may be destroyed.

That list does not exhaust the possibilities. One of us (Montagnier) is exploring the possibility that the binding of the virus to its target cells triggers the release of enzymes called proteases. Proteases digest proteins, and if they were released in abnormal quantities, they might weaken white blood cells and shorten their lives. The various proposed mechanisms are not exclusive, and several may operate at once. Yet one is probably central, and some of the most significant work on AIDS is that of distinguishing the central mechanism from the peripheral ones that accompany it.

Although it is clear that a large enough dose of the right strain of HN can cause AIDS on its own, cofactors can clearly influence the progression of the disease. People whose immune systems are weakened before HN infection may progress toward AIDS more quickly than others; stimulation of the immune system in response to later infections may also hasten disease progression.

Interaction with other pathogens may also increase the likelihood that AIDS will develop. Specifically, a herpes virus called human B-cell lymphotropic virus (HBLV) or human herpes virus 6 (HHV-6) that was discovered in the laboratory of one of us (Gallo) can interact with HN in a way that may increase the severity of HN infection. Ordinarily HHV-6 is easily controlled by the immune system. In a person whose immune system is impaired by HN, however, HHV-6 may replicate more freely, becoming a threat to health. In addition, although one of the main hosts of HHV-6 is a white blood cell called the B cell, the virus , can also infect T4 lymphocytes. If the T cell is simultaneously infected by HN, HHV-6 can activate the latent AIDS virus, further impairing the immune system and worsening the cycle.

Clearly, in spite of rapid progress there are many gaps in our understanding of HN and AIDS. Should we panic? The answer is no, for several reasons. The most obvious is that panic does no good. The second reason is that it now seems unlikely HIV infection will spread as rapidly outside the original high-risk groups in the industrial countries as it has within them. A third reason is that this disease is not beyond the curative power of science. Although current knowledge is imperfect, it is sufficient to provide confidence that effective therapies and a vaccine will be developed.

The possibilities for therapy are particularly impressive. In the first phase of the search for AIDS therapies it was necessary to exploit any drug that seemed to provide even a remote chance of combating HIV infection. A variety of compounds formulated for other purposes were taken off the shelf and tested. Most were of little value, but one (AZT), originally formulated as an anticancer drug, turned out to be the first effective anti-AIDS agent. More recently, an experimental regimen in which AZT is alternated with the related compound known as dideoxycytidine offers even greater promise.

Bringing AZT into clinical use was a significant accomplishment, because it gave hope that AIDS would not remain incurable forever. As a form of therapy, however, AZT is not perfect and will probably be supplanted by less toxic agents formulated on the basis of what is known about the HIV life cycle. One promising agent is CD4, the molecule that serves as the viral receptor. Early tests show that soluble CD4 can bind to the virus and prevent it from infecting new cells. Many other drugs are in trials; one of them, perhaps combined with compounds that bolster the immune system, may provide therapy for HIV infection.

In assessing the progress that has been made toward achieving fully effective AIDS therapy, it must be kept in mind that this work has two facets. In addition to combating a complex and evasive pathogen, it must pioneer entirely new areas of medicine.

The reason is that there are few effective treatments for viral diseases-and almost none for retroviruses. There are various reasons for this, among them the fact that viruses (unlike bacteria, for which effective therapies exist) always appropriate the biosynthetic apparatus of the host cell. As a result drugs effective against viruses tend to damage mammalian cells. Yet we are confident that the dual goals of pioneering science and clinical effectiveness will be met.

What is true of therapy is also true of vaccines: an AIDS vaccine will be a pioneering scientific achievement. Since the HIV genome has the capacity to integrate into the chromosomes of the host cell, little serious consideration has been given to using preparations containing the whole virus as a vaccine. An AIDS vaccine must consist of subunits, or parts, of the virus in the right combination. Yet experience with subunit vaccines is slight. Indeed, so far only a few subunit vaccines have proved practical. Much work is under way to find the combination of HIV subunits that will yield the greatest protective response. As in the case of therapy, we believe there will be a practical vaccine against HIV.

Perhaps an even more persuasive reason for hope is that even without a vaccine or a cure, what is already known could bring the epidemic under control. The blood supply has already been largely secured by the presence of a blood test. Moreover, the modes of transmission of HIV-blood, sexual intercourse and from mother to child-are firmly established. Hence any individual can drastically reduce his or her risk of infection. If such knowledge were applied everywhere, there would be a sharp leveling off in the spread of HIV infection, as there has been in some groups in the developed world. The lesson here is that there is a need for education about HIV infection--in clear, explicit language and as early as possible.

Yet there are parts of the epidemic where education alone is not sufficient, and it is in those areas that humanity will be tested. Users of intra· venous drugs, for example, are notoriously resistant to educational campaigns alone. It seems clear that the effort to control AIDS must be aimed in part at eradicating the conditions that give rise to drug addiction. Those conditions are in turn linked to social and economic patterns. Eliminating the disease may entail eliminating some of the social differentials that form the substratum of drug abuse.

It is also the case that in some areas of the developing world education alone will not stem the epidemic. Education is necessary, but it must be accompanied by other measures. In central Africa--the part of the world most beleaguered by AIDs--there are few facilities for blood testing and few technicians trained to perform tests. Furthermore, the blood tests used in the U.S. and Western Europe are too expensive to be helpful. As a result the virus is still being spread by contaminated blood, long after that form of transmission has been practically eliminated in the industrial countries.

To help change this situation the World AIDS Foundation has made improving the situation in central Africa its highest priority. The foundation (along with its parent, the Franco-American AIDS Foundation) was formed as part of the agreement that resolved a lawsuit between France and the U.S. over the AIDS blood test. The parent foundation receives 80 percent of the royalties from the French and American blood tests; the World AIDS Foundation in turn receives 25 percent of that. Much thought has been given to how to allocate the funds, and the first project (carried out in conjunction with the World Health Organization) will be realized in several African countries. It will include training technicians to perform blood tests, establishing one HIV-free blood center and increasing public education about HIV transmission.

Efforts such as this one, coupling public and private funds and energies, will be essential to stopping AIDS. As we stated above, both of us are certain that science will ultimately find a cure and a vaccine for AIDS. But not tomorrow. The AIDS virus (and other human retroviruses) will be with us for a long time. During that time no intelligent person can expect the necessary solutions to come solely from authorities such as scientists, governments or corporations. All of us must accept responsibilities: to learn how HIV is spread, to reduce risky behavior, to raise our voices against acceptance of the drug culture and to avoid stigmatizing victims of the disease. If we can accept such responsibilities, the worst element of nightmare will have been removed from the AIDS epidemic.

Further Reading
Molecular Machines That Control Genes
The Environmental Dangers of Backyard Fire Pits
Mooove Over Cows?--Soy Milk May Be a Healthier Alternative
Too Good to Be True?: Fat That Keeps You Thin

What is deep-vein thrombosis (DVT)?
BPA study: Plastic chemical is unhealthy for children and other living things
From Wine to New Drugs: A Novel Way to Reduce Damage from Heart Attacks
What Happens to Particle Accelerators After They Are Shut Down?

Wednesday, October 08, 2008

Metabolic Syndrome: Diabetes, Dislipemia, Hypertensionand obesity (HODD)

Global7 the new Millennial Renaissance Vision for the Globe

Metabolic Syndrome as a Cardiovascular Disease Risk Factor: Patients Evaluated in Primary Care

Abstract and Background

To estimate the prevalence of metabolic syndrome (MS) in a population receiving attention in primary care centers (PCC) we selected a random cohort of ostensibly normal subjects from the registers of 5 basic-health area (BHA) PCC.

Diagnosis of MS was with the WHO, NCEP and IDF criteria. Variables recorded were: socio-demographic data, CVD risk factors including lipids, obesity, diabetes, blood pressure and smoking habit and a glucose tolerance test outcome. Of the 720 individuals selected (age 60.3 ± 11.5 years), 431 were female, 352 hypertensive, 142 diabetic, 233 pre-diabetic, 285 obese, 209 dyslipemic and 106 smokers. CVD risk according to the Framingham and REGICOR calculation was 13.8 ± 10% and 8.8 ± 9.8%, respectively.

Using the WHO, NCEP and IDF criteria, MS was diagnosed in 166, 210 and 252 subjects, respectively and the relative risk of CVD complications in MS subjects was 2.56. Logistic regression analysis indicated that the MS components (WHO set), the MS components (IDF set) and the female gender had an increased odds ratio for CVD of 3.48 (95CI%: 2.26–5.37), 2.28 (95%CI: 1.84–4.90) and 2.26 (95%CI: 1.48–3.47), respectively. We conclude that MS and concomitant CVD risk is high in ostensibly normal population attending primary care clinics, and this would necessarily impinge on resource allocation in primary care.


The metabolic syndrome (MS) was first described in 1998 by Reaven as "syndrome X". Although previously alluded-to by several authors (Kylin, Marañón and others) and termed a multi-metabolic syndrome or insulin resistance, it represented a known risk factor in the development of cardiovascular disease events and was associated with accelerated atherosclerosis.[1]

From the classical description by Reaven,[2] a common nexus was established: insulin resistance/hyperinsulinemia. Surprisingly, this author did not include obesity in the definition.

Later, other authors included the concept of alterations in fat, disorders of glucose, dyslipemias and hypertension. Recently, a growing interest has developed and MS has been receiving attention not only in hospital-based medicine but also in primary care (PC); albeit in the latter case the number of studies has been considerably lower.

Since epidemiological studies suggest that > 25% of the general population will gradually develop insulin resistance[3] it would appear that this pathology will be diagnosed and treated increasingly within the ambit of PC[4-6] and, as such, has become included in the list of priorities of various public health-care authorities.

Apart from the difficulty in identifying its components, there is the added the lack of consensus diagnostic criteria. The initial criteria were those of the WHO in 1998[7] and subsequently those of the NCEP-ATP III in 2001 which identified clinical types and simplified their management.[8]

Other criteria of note are those of EGIR (European Group for the study of Insulin Resistance) based on European populations and were the first that defined prevalences in and around Spain. Subsequently, the American Association of Clinical Endocrinologists (AACE) developed their criteria in 2003 and, finally, the International Diabetes Federation (IDF) in 2005 issued its consensus document.[9]

Irrespective of the criteria used, the certainty is that MS is very prevalent[10-12] and the initial studies in the USA recognize MS as a principal problem of health with developed countries, and with elevated social and economic consequences.

Reaven recognized some features frequently associated with MS (syndrome of polycystic ovaries, endothelial alteration and non-alcoholic hepatic steatosis)[13].

Of note is that the very existence of MS as a disease entity has been placed in doubt[14] such that the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommended that patients are not to be labeled as MS. However, the IDF has published new criteria for MS adapted to different ethnic groups, among which is the European population.[15]

The relationship between MS and cardiovascular disease has been well documented in the biomedical literature.[16-21]

References in PC in Spain are available,[22-28] and seems to highlight a high-risk population in our country, i.e. hypertension of 47.8% in some samples. In another investigation, the prevalence of MS was calculated as 50.6% overall in patients who had hypertension, dyslipemia, diabetes or a combination of these 3 elements.

As such, MS constitutes a multi-pathology frequently encountered in PC consulting rooms and its high prevalence would indicate the need for alertness in identifying the syndrome and to treatment its components in order to minimize the risk of subsequent cardiovascular disease.

1) To determine the prevalence of MS in the population receiving attention in PC.

2) To indentify factors or components of MS that independently influence the cardiovascular disease prognosis related to MS.

3) To analyse the impact of each component on the appearance of cardiovascular disease events.


a) Design
Prospective, multi-centered cohort study to observe the appearance of cardiovascular disease events. There were 2 cohorts: patients with the diagnosis of MS and those subjects without MS. Follow-up was for 2 years.

b) Study Population
Patients who were attending 5 Basic Health-care Areas (BHA) in Catalonia, Spain; 4 in the urban city of Reus and the 5th located in the rural area of Deltebre. The catchment area of the PC centers has a total of approximately 72,000 individuals. The selection for the present study was patients of both genders aged above 45 years, and who had attended the clinical center at least once in the previous 3 years.

Using the Computerized System for Patient Care (CSPC) we selected a random list of individuals to reflect the distributions of the total of those subjects registered and assigned by the Governmental Health-service Authority to the different PC centers. Under the National Health Service provisions in Catalonia, all citizens are entitled to free-at-the-point-of-access medical attention which, under most circumstances, is the local PC center. The selected subjects were contacted and informed of the study and their written consent to participation was solicited.

The objectives of the study were explained and, as an inducement, a thorough medical check-up and follow-up was offered. The tests included blood constituent analyses and a 75 g glucose tolerance test (except for known diabetics).

All the blood samples were analyzed in the same hospital clinical laboratory which has international quality standard ceditation (ISO9002). Standard clinical history was taken and included information on pharmacological and non-pharmacological drugs used, advice on tobacco habit and on diet, and information with respect to MS diagnosis as well as any other possible illnesses.

The exclusion criterion was that of having suffered any cardiovascular disease complication prior to recruitment to the present study. This item was evaluated from the clinical notes by 2 different members of the investigation team and, in case, of non-concordance, the opinion of a 3rd member was sought.

c) Study Period
From 30th June 2004 to 30th June 2006.

d) Information sources

We designed multi-parameter data collection forms on which the clinical history data were recorded at the initial interview as well as from the archived data recorded at each of the participating BHA centers.

The items included; date of registration at the center, family and personal history, cardiovascular disease risk factors (hypertension, diabetes mellitus, dyslipemia, obesity), dietary and/or pharmacological treatments, blood constituent measurements, presence of vascular complications. The cardiovascular risk was calculated according to the 2 methods; the Framingham equation,[29] and the REGICOR formula[30] (a calibration of Framingham algorhitm adapted for Spain) for each individual participant.

e) Definition of Variables

Age, gender, weight, height, body mass index (BMI), concentrations of plasma triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol, uric acid, baseline insulinemia, baseline glycemia, glycemia at 2 h post-glucose load, fibrinogen, leukocyte count, glycated hemoglobin, waist-hip ratio, abdominal circumference, blood pressure, family history of cardiovascular disease and of diabetes, smoking habit, alcohol consumption, dietary and/or pharmacological treatment, presence of vascular complication as well as the date when these complications had been diagnosed.

f) Definition of MS Criteria and Cardiovascular Diseases
The criteria defining MS according to the NCEP-ATPIII require a combination of at least 3 of the 5 following criteria:

Abdominal circumference ≥ 102 cm in males or ≥ 88 cm in females.

HDL cholesterol < 1.03 mmol/mL (< 40 mg/dL) [males] or < 1.3 mmol/mL (< 50 mg/dL) [females].

Triglycerides ≥ 1.7 mmol/mL (≥ 150 mg/dL).

Blood pressure ≥ 130/85 mmHg or the patient receiving hypotensive treatment.

Baseline glycemia > 6.1 mmol/mL (> 110 mg/dL).

Additionally, IDF criteria are the same precedent with the only differences of:

Abdominal circumference is, for European people, ≥ 94 cm in males or ≥ 80 cm in females.

Fasting glycemia > 5.55 mmol/l (> 100 mg/dL).
According to the WHO criteria, an individual is considered to have MS if:

Glucose intolerance/diabetes/IFG and/or insulin resistance (determined with functional laboratory tests) plus:

Two or more of the following criteria:

Hypertension (or its treatment).

Hypertriglyceridemia of > 1.7 mmol/mL (> 150 mg/dL) or LDL < 0.9 mmol/mL (< 35 mg/dL) [males] and < 1.0 mmol/mL (< 39 mg/dL) [females].

BMI > 30 or WHI (waist-hip index) > 0.9 [males] or > 0.85 [females].

Microalbuminuria (> 20 μg/min) or urinary albumin:creatinine ratio > 30 mg/g.

The patients who fulfilled the NCEP criteria for MS were entered into the study under as the MS cohort. The cohort defined as non-MS was composed of those patients that did not fulfill the NCEP criteria.

Cardiovascular disease complications were defined as ICD-9 codes corresponding to:

Coronary heart disease: clinical history of ischemic heart disease (myocardial infarction, angina) and/or cardiac insufficiency, complementary assessments (ECG, stress test, scans...) (Codes 411 to 416).

Cerebrovascular disease; clinical history suggestive of transitory ischemic attack/cerebrovascular accident and/or image tests that show such evidence (Codes 430 to 438).

Peripheral vascular disease: intermittent claudication, absence of peripheral pulse or demonstrated by Doppler (ankle-brachial index < 0.9). (Codes 250.7, 443).

Diabetic retinopathy: findings in the fundus of the eye compatible with the disease (Code 362).

Nephropathy: microalbuminuria > 30 mg/24 h.

Diabetic neuropathy: employing the Diabetic Neuropathy Symptom (DNS) scale that varies between 0–4 points, with neuropathy defined as a score of ≥ 1 point. Further corroboration with a pathology assessment using 10G-Semmes-Weinstein monofilament in one of more of the 6 plane areas evaluated.

Also considered as a complication are those deaths related to cardiovascular disease e.g. myocardial infarction that causes death.

g) Determination of Sample Size

With an α risk of 0.05 for a precision of ± 3% in a two-tailed test of difference in proportions of MS estimated as 17%, the requirement for a random population sample was 738 subjects; assuming the target population to be 36,600 individuals (36.6% of the total population defined). The loss rate was estimated at 20% (Programa Granmo version 5.2, Institut Municipal d'Investigació Mèdica de Barcelona).[31]

h) Program of Analysis

Epidemiological assessment: Possible associations between different variables or components of MS, with an increase in risk of having cardiovascular disease pathology.

Statistical analyses: the data obtained were analyzed using SPSS program (version 12.0) working with a confidence level of 95% and considering differences as being statistically significant at p < 0.05.

Initially, a descriptive analysis was performed of the variables, and subsequent stepwise multivariate analyses were performed in order to determine the relative importance of the different risk factors as cause of the cardiovascular event.

In the multivariate analyses, the dependent variable was the number of events and the independent variables were the dichotomized risk factors (hypertension, dyslipemia, diabetes, obesity).

Also included was the dichotomized (presence/absence) variable of MS diagnosed on the WHO, NCEP and IDF criteria. The results are presented adjusted for age and gender, with respect to the variables that were significant in the model as well as the coefficients or the b-exponential that explain the percentage prediction of each variable considered in the analyses.

Of the 750 subjects selected, 30 were excluded due to having had previous cardiovascular disease events. Of the 720 subjects followed-up, there were 29 (4%) losses: 8 cardiovascular disease deaths, 7 deaths from non-cardiovascular disease, 7 had moved out of the local area and 7 were lost to follow-up. Figure 1 describes flow of the study.

Figure 1.
Flow chart of the study: Prospective, multi-centered cohort study to evaluate the cardiovascular disease event associated with metabolic syndrome in a randomly selected study sample.

The overall mean age was 60.3 ± 11.5 years and 431 were female (59.9%). The risk factors were: hypertension in 352 (48.9%), diabetes type 2 in 142 (19.7%), pre-diabetes in 233 (32.4%), obesity in 285 (39.6%), dyslipemia in 209 (29%), and 106 (14.7%) were smokers. The mean BMI was 29.1 ± 5.2 kg/m2. The mean cardiovascular risk index (according to the Framingham score) was 13.8 ± 10% and, according to the REGICOR tables, was 8.8 ± 9.8%; both projected to 10 years.

With respect to MS, the study detected 166 subjects (23.1%; 95%CI: 20.0–26.3) who fulfilled the MS diagnostic criteria according to the WHO, and 210 (29.2%, 95%CI: 26.9–32.6) according to the NCEP-ATPIII criteria; 141 individuals fulfilled both definitions. 252 subjects (35.0%; 95%CI: 31.5–38.6) fulfilled IDF criteria; of them 210 fulfilled the NCEP criteria too. The kappa (κ) index of concordance between the first two sets of criteria defining MS was 0.66 (p < 0.001) and between the second two sets was 0.87 (p < 0.001).

Table 1 summarizes the information on the principal characteristics of the study sample segregated into two groups; without MS according to the NCEP criteria and those with MS according to the same criteria.

Cardiovascular disease complications appeared in 113 (15.7%) subjects during the follow-up of 2 years. Overall, there were 142 different complications: 35 (4.9%) were peripheral vascular disease, 30 (4.2) coronary artery disease, 29 (45) nephrotic syndrome, 24 (3.3%) cerebrovascular disease, 18 (2.5%) classified as having retinopathy and 6 (0.8%) developed neuropathy.

Segregated by cohort, the group with MS suffered 15 coronary complications, 12 cerebrovascular, 18 peripheral artery disease, 11 retinopathies, 25 nephropathies and 5 neuropathies. Conversely, in the group without MS, the complications were 15 coronary disease, 12 cerebrovascular, 17 peripheral vascular disease, 7 retinopathies, 4 nephropathies and 1 neuropathy.

Forward stepwise multiple logistic regression analyses of the factors that influenced the appearance of the cardiovascular disease events are summarized in Table 2 and from which it is of note that each MS classification carries a different weight for different complications. As observed in the multivariate analyses ( Table 2 ) the WHO criteria are better predictive of cardiovascular disease event than those of the IDF.

This is evident when the complications are considered globally (OR = 3.48) as well as individually (i.e. cases of coronary artery disease, vascular disease and nephropathy). Conversely, the NCEP criteria predict the cerebrovascular, arteriopathy, nephropathy and neuropathy complication. IDF criteria predict the globally complications, as well as coronary, retinopathy and nephropathy.

The χ2 analysis of the number of components of MS (NCEP criteria) indicated significant differences (p < 0.001) between the subjects with 0, 1 or 2 components (absence of MS) and those that had 3, 4 or 5 (presence of MS). The prevalence of events was 10.78% in subjects free of MS and 27.61% in subjects suffering from MS (OR = 2.56).

The differences were, as well, significant with the χ2 test (p < 0.001) between individuals who did, and did not, fulfill the criteria using the WHO criteria. The prevalence of CVD events was 10.8% in the group without MS and 31.9% in the group with MS (OR = 2.95).

The rate of cardiovascular disease events during the first 2 years of follow-up was 98.6 events/1,000 patient-years.

In Figure 2 describes the increasing number of events per 1,000 inhabitants/year segregated with respect to the number of MS components (NCEP criteria).

Figure 2.
Cardiovascular disease (CVD) events segregated with respect to number of components of metabolic syndrome (MS); NCEP criteria.

Figure 3 depicts the progressively increasing numbers of events in relation to the number of MS components (WHO criteria).

Figure 3.
Cardiovascular disease (CVD) events segregated with respect to number of components of metabolic syndrome (MS): WHO criteria; * = alterations in glucose metabolism not included in the components.

Figure 4 describes the number of events in relation to the number of MS components (IDF criteria).

Figure 4.
Cardiovascular disease (CVD) events segregated with respect to number of components of metabolic syndrome (MS); IDF criteria.

In a sub-analysis of the patients without diabetes (n = 578) we observed that 93 had NCEP criteria for MS and, by the end of the follow-up period, these cases developed 16 (17.2%) complications. Conversely, in the subgroup of 485 subjects without MS or diabetes, there were a total of 43 (8.9%) cardiovascular disease complications.

Considering the diabetic patients alone (n = 142), 97 fulfilled the NCEP criteria for MS and, at 2 years of follow-up, there were 62 (63.9%) CVD complications compared to 21 in the 45 (46.6%) diabetic individuals without MS.

In primary care, the prevalence observed of MS is high and close to the values described in the worldwide literature, representing a problem of health at the developed countries.

After adjusting for age and gender, the analyses performed suggest that MS by WHO and IDF criteria are better predictive of cardiovascular disease events (as independent factor) than those of the NCEP (as well the complications are considered globally as well as individually).

Individually, WHO criteria predicts better coronary artery disease, vascular disease and nephropathy; NCEP criteria the stroke, arteriopathy, nephropathy and neuropathy; and finally the IDF set predict globally complications, as well as coronary, retinopathy and nephropathy.

Of note is that there is a high prevalence of type 2 diabetes and of pre-diabetes in our sample. This is because a glucose tolerance test was performed in all study subjects (except those with known diabetes); the objective being to discount previously-unidentified alterations of carbohydrate metabolism.

This criterion provides added value to the study since the prevalence identified is closer to the reality. The total of diabetes and pre-diabetes was > 50% of the study sample and which is of considerable note for the future disease development.

The principal difficulty in the diagnosis of MS is the criteria used. We followed the criteria of the NCEP-ATPIII which are more clinically-based than those of the previous WHO criteria of 1998. However, we performed the calculation based on the latest methodology as well.

We did not apply other diagnostic methods such as those of the EGIR nor the AACE because the recommended tests were tests are required laboratory facilities that are beyond our reach (and that of most PC centers) such as analyses demonstrating insulin resistance.

The concordance between the WHO and NCEP criteria (kappa index of 0.66) and between the NCEP and IDF criteria (kappa index of 0.87) provides weight to our procedures and indicates that, in usual-care clinical practice it is not important which set of criteria are used to assess MS but more importantly to be aware of MS and to detect its components.

With respect rest to other methodological aspects, primary health care provision is distributed according to the risk factor status of the individual. The first clinical consultation would detect some aspects such as obesity and hypertension and which require prompt action (confirmation of diagnosis, dietary advice, life-style modifications) all of which are standard in our type of clinical practice.

In the present study the added benefit for our general population (and of other similar populations) is that of screening. We were able to detect pathologies which we were not aware of (e.g. identification of subject with hyperglycemia or hypertension) and to detect previously-unknown risk factors for CVD.

Further, we were able to provide advice on life-style modifications, such as anti-smoking, diets, exercise and body-weight control for what is an ostensibly healthy population.

Further, the identification of patients with MS creates an overall "attitude" for the individual in question such that the idea is developed that the preoccupation should not be towards only certain risk factors but, more importantly, all components that have an impact of future CVD.

However, we need to reiterate that we did not conduct an intervention study. Indeed, the measures we employed are standard in PC practice.

The association of MS with cardiovascular disease observed in the present study (OR = 2.56) is comparable with an epidemiological study conducted in the USA using a questionnaire on health (NHANES III) and in which an odds ratio of 2 was calculated not only for myocardial infarction but also for cerebrovascular disease (stroke) in both genders, and independently of age and ethnicity.[33]

The prevalence in the USA now is slighty higher comparing data with newest NHANES from 1999–2000, increasing up to 27.0%.[34] Considering all the criteria set available nowadays, all of them are capable to predict cardiovascular disease, in differents degrees.[35] For example, stroke was predicted, in a 14-year follow-up in Finland, better by WHO and NCEP set than other criteria used.[36]

The global prevalences in another European studies are closer: in Italy, finding a 16.2% but in youngest population[37]; in Greece in a nationwide survey, reaching a 23.6%[38] and in Great Britain finding a 29.8% (in women, with highest mean age).[39] In Germany was lowest by NCEP definition (19.8%) but highest using the IDF definition (32.7%).[40]

So, the prevalence is increasing with each newly published definition of the MS and clearly associated with age and gender, as these studies shows.

Figure 2 shows that the CVD complications had been more numerous in the sub-group of subjects who had 3 components of MS, compared to those who had 4 or 5.

This can be explained by the small numbers of complications in the sub-groups. Figure 3 shows that the patients who fulfilled 5 criteria on the WHO scale (the maximum) had a rate of events that was almost triple that of other sub-groups.

The explanation in this case is that, apart from being relatively few in absolute numbers, the WHO criteria requires microalbuminuria as part of the MS diagnosis, and which is a known independent risk factor for cardiovascular disease. Figure 4 shows CVD complications similar to the Figure 2.

We believe, as well, that the better predictor of cardiovascular disease achieved by the WHO criteria over those of the NCEP ( Table 2 ) needs to take microalbuminuria into account. The WHO criteria achieve a better prediction in overall CVD events (coronary, nephropathy).

Conversely, the NCEP criteria is associated with a better prediction of stroke and arteriopathy. And finally, IDF criteria is a good predictor of retinopathy, nephropathy, coronary disease and all events globally.

With respect to concordance between criteria used (kappa index of 0.66 between WHO and NCEP; and 0.87 between NCEP and IDF) we propose that the clinical effort should be applied to identifying the patients with high risk, irrespective of the choice of criteria used.

Undoubtedly, age and diabetes per se adds an important cardiovascular disease risk in all cases. Indeed, we need to highlight that in this sub-group, the MS modulates the risk such that those diabetic subjects with MS suffer more complications (63.9% vs. 46.6%) than those diabetic subjects without MS. Conversely, in the sub-analyses which excluded the patients with diabetes, and not taking the presence of diabetes into the definition of MS, the prediction of cardiovascular disease events was greater globally when MS was present (17.2% vs. 8.9%).

In conclusion, we believe that MS diagnosis is simple and easy clinical tool to assess potential cardiovascular risk and, as such, can identify those patients who can benefit most from the prioritization of health-care resources, and we conclude that MS and concomitant CVD risk is high in ostensibly normal population attending primary care clinics.

Table 1. Clinical and Metabolic Characteristics of the Subjects as A Function of the Diagnosis of MS Based on the NCEP-ATPIII Criteria

Table 2. Logistic Regression of Component Factors in Cardiovascular Disease Risk, Adjusted for Age and Gender

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The authors thank the Catalan Health Institute [Institut Català de la Salut] (Reus-Tarragona Directorate) for their constant support of our research efforts. We are indebted to the Tarragona-Reus PC laboratories for their expertise in the blood chemistry analyses and the doctors of the PC centers for help in the collection of the clinical histories.

We thank the IDIAP Jordi Gol (Institut d'Investigació en Atenció Primària Jordi Gol) for financial support in the preparation of the manuscript.

We acknowledge the members of the Reus Group for the study of Diabetes and Metabolic Syndrome, the effort in this study.

Authors' Contributions

JC, FM, BC, JP, JB and RS participated in the design of the study. BC conceived of the study, and participated in its coordination. JP performed the statistical analysis. JC, FM, JL, YO, TB, DM, IS-O, AD-M, JF, MG-V, MB, RS, AU, JM, JB and JS included the patients. FB, JV, JS, JH, IP, VR, JB and JS revised the clinical outcomes. All authors read and approved the final manuscript.

Members of the Reus group for the study of diabetes and metabolic syndrome:

Joan-Josep Cabré-Vila (coordinator), Marta Baldrich-Justel, Francesc Barrio-Torrell, Josep Basora-Gallisà, Teresa Basora-Gallisà, Jordi Bladé-Creixenti, Bernardo Costa-Pinel, Jordi Daniel-Díez, Angel Donado-Mazarrón, Joan-Lluís Frigola-Marcet, Ma Teresa García-Vidal, Josep Ma Hernández-Anguera, Josep-Lluís Llor-Vilà, Josep-Ma de-Magriñà, Francisco Martín-Luján, Dolors Montañés-Boncompte, Yolanda Ortega-Vila, Irene Pascual-Palacios, Josep-Lluís Piñol-Moreso, Vanesa Revuelta-Garrido, Josep-Ma Sabaté-Fiestras, Ramon Sagarra-Álamo, Isabel Sánchez-Oro, Judit Saumell-Boronat, Rosa Solà-Alberich, Ana Urbaneja-Díez, Jesús Vizcaíno-Marín.

Funding Information

The study was funded, in part, by the Catalan Society for Family and Community Medicine (IV Convocation) [IV Ayuda de Investigación de la Sociedad Catalana de Medicina Familiar y Comunitaria] and by grants to JC from the Fundación Jordi Gol i Gurina; Institut Català de la Salut.

Reprint Address

Corresponding author* - Email: Joan-Josep Cabré* - ; Francisco Martín - ; Bernardo Costa - ; Josep L Piñol - ; Josep L Llor - ; Yolanda Ortega - ; Josep Basora - ; Marta Baldrich - ; Rosa Solà - ; Jordi Daniel - ; Josep Ma Hernández - ; Judit Saumell - ; Jordi Bladé - ; Ramon Sagarra - ; Teresa Basora - ; Dolors Montañés - ; Joan L Frigola - ; Angel Donado-Mazarrón - ; Maria Teresa García-Vidal - ; Isabel Sánchez- Oro - ; Josep M de Magriñà - ; Ana Urbaneja - ; Francisco Barrio - ; Jesús Vizcaíno - ; Josep M Sabaté - ; Irene Pascual - ; Vanesa Revuelta -

Joan-Josep Cabré,1 Francisco Martín,1 Bernardo Costa,2 Josep L Piñol,6 Josep L Llor,3 Yolanda Ortega,4 Josep Basora,6 Marta Baldrich,1 Rosa Solà,7 Jordi Daniel,6 Josep Ma Hernández,1 Judit Saumell,4 Jordi Bladé,6 Ramon Sagarra,1 Teresa Basora,6 Dolors Montañés,1 Joan L Frigola,1 Angel Donado-Mazarrón,2 Maria Teresa García-Vidal,4 Isabel Sánchez-Oro,2 Josep M de Magriñà,4 Ana Urbaneja,5 Francisco Barrio,2 Jesús Vizcaíno,1 Josep M Sabaté,1 Irene Pascual,1 and Vanesa Revuelta1

1ABS Reus-1, Camí de Riudoms, 53–55, 43202 Reus, Spain
2ABS Reus-2, Camí de Riudoms 53–55, 43202 Reus, Spain
3ABS Deltebre, Avinguda Esportiva, 164, 43580 Deltebre, Spain
4ABS Reus-4, General Moragues 52, 43201 Reus, Spain
5ABS Reus-3, General Moragues 52, 43201 Reus, Spain
6Reus-Altebrat Primary Care Service, Spain
7Medicine Faculty, Rovira i Virgili University, Sant Llorenç 11, 43202 Reus, Spain

Green Fluorescent Proetein and Brainbow Experiment wins the nobel prize for Chemistry 2008

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1 Japanese, 2 Americans win Nobel chemistry prize By KARL RITTER and MATT MOORE, Associated Press Writers
13 minutes ago

Two Americans and a U.S.-based Japanese scientist won the Nobel Prize in chemistry on Wednesday for discovering and developing a glowing jellyfish protein that revolutionized the ability to study disease and normal development in living organisms.

Japan's Osamu Shimomura and Americans Martin Chalfie and Roger Tsien shared the prize for their work on green fluorescent protein, or GFP, the Royal Swedish Academy of Sciences said.

Researchers worldwide now use GFP to track such processes as the development of brain cells, the growth of tumors and the spread of cancer cells. It has let them study nerve cell damage from Alzheimer's disease and see how insulin-producing beta cells arise in the pancreas of a growing embryo, for example.

The academy compared the impact of GFP on science to the invention of the microscope. For the past decade, the academy said, the protein has been "a guiding star for biochemists, biologists, medical scientists and other researchers."

When exposed to ultraviolet light, the protein glows green. So it can act as a tracer to expose the movements of other, invisible proteins it is attached to as they go about their business. It can also be used to mark particular cells in a tissue and show when and where particular genes turn on and off.

Tsien developed GFP-like proteins that produced a variety of colors so that multiple proteins or cells can be followed simultaneously.

"In one spectacular experiment, researchers succeeded in tagging different nerve cells in the brain of a mouse with a kaleidoscope of colors," the Nobel citation said. The experiment was called the "brainbow."

Shimomura and a colleague found GFP in material they extracted from about 10,000 jellyfish they had recovered off the coast of the state of Washington. They reported in 1962 that it glowed bright green under ultraviolet light.

Some 30 years later, Chalfie showed that the GFP gene could make individual nerve cells in a tiny worm glow bright green. Tsien later extended the scientific palette to a variety of colors.

"This is a technology that has literally transformed medical research," said Dr. John Frangioni, an associate professor of medicine and radiology at Harvard Medical School. "For the first time, scientists could study both genes and proteins in living cells and in living animals."

Shimomura, 80, works at the Marine Biological Laboratory in Woods Hole, Mass., and the Boston University Medical School.

Chalfie, 61, is a professor at Columbia University in New York, while Tsien, 56, is a professor at the University of California, San Diego.

The trio will split the 10 million kronor (US$1.4 million) award.

Chalfie said he slept through the Nobel committee's phone calls early Wednesday and only found out about the prize when he checked the Nobel Web site to see who had won.

"It's not something out of the blue, but you never know when it's going to come or if it's going to come so it's always a big surprise when it actually happens," Chalfie said in New York.

Speaking to reporters by telephone from California, Tsien said he was surprised to receive the award.

"There had been some rumors, but from sources whose reliability was questionable," he said.

In a news release issued by his university, Tsien said he had set his sights on imaging and treating cancer.

"I've always wanted to do something clinically relevant in my career, if possible, and cancer is the ultimate challenge," he said.

Gunnar von Heijne, the chairman of the chemistry prize committee, demonstrated the award-winning research to reporters by shining ultraviolet light on a tube with E. coli bacteria containing GFP. The tube glowed in a green fluorescent light.

Von Heijne said that kind of experiment "gets scientists' hearts beating three times faster than normal."

The winners of the Nobel Prizes in medicine and physics were presented earlier this week. The prizes for literature, peace and economics are due to be announced Thursday, Friday and Monday.

The awards include the money, a diploma and an invitation to the prize ceremonies in Stockholm and Oslo on Dec. 10, the anniversary of prize founder Alfred Nobel's death in 1896.

Last year's chemistry award went to Gerhard Ertl of Germany for studies of chemical reactions on solid surfaces, which are key to understanding such questions as why the ozone layer is thinning.


Associated Press writer Malcolm Ritter and Online Video Reporter Ted Shaffrey in New York, and Louise Nordstrom in Stockholm contributed to this report.