“Our brains are very well designed,” says Dr. Douglas Tweed, physiology professor at U of T and senior author on a paper in the March 6 issue of Nature. “The brain takes in raw data from its surroundings through sensors and interprets it, rejecting interpretations that it considers unlikely. The brain gauges the probabilities of things in real life and uses these estimates to guide our perceptions. But sometimes we can be fooled by bizarre things.

“This shouldn’t be seen as a flaw in the system, however,” Tweed argues. “This is the way the brain works. Sensors are always flawed; they simply do not provide enough information for us to reconstruct our world. The brain must use prior knowledge to interpret our surroundings and we found that it seems to do this optimally.”

This research project, led by U of T post-doctoral fellow Matthias Niemeier, uses a theory presented in the 1800s by Hermann von Helmholtz, a German physiologist. Helmholtz, who stated that perception is a matter of unconscious inference, suggested that all of our senses are imperfect and those signals sent to the brain are flawed. With this flawed data, the brain is forced to guess – based on its sensor readings – what is happening in the environment. With small or unexpected changes it often guesses wrong, which is why people can be fooled by optical illusions or sleight of hand, Tweed explains. He and Niemeier conducted the research with Professor Douglas Crawford of York University.

The researchers tested whether the brain’s perception processes are working optimally given the flawed data it receives. They programmed a computer-simulated brain to make optimal use of sensor data and prior knowledge, giving it realistic vision and quick eye movements (also known as saccades). The researchers then measured how well it perceived events in its simulated world.

The team compared these findings with those of human subjects. Subjects’ heads were immobilized and a device shaped like a contact lens inserted into their eye to measure its motion and relay information back to a computer. Using a large screen, researchers conducted two experiments that tested participants’ perceptions of distance and degree of change, using a white dot that “jumped” on the screen. They found that small jumps were invisible to participants; larger ones were seen but individuals underestimated how far the dot jumped.

“What we found was that, in simple situations, the simulated computer brain perceived things the same way and made the same kinds of errors that human brains do, even when we programmed the computer to function optimally,” says Niemeier.

“When small changes occurred during a saccade, these changes were either ignored or downplayed by both the computer and the test subjects. So we concluded that the optimal solution when it comes to perceiving the outside environment is to ignore some changes.”

The brain knows what can and cannot realistically occur based on probability and prior knowledge, say the researchers. Eyes have quite a narrow field of high-resolution vision, something in the area of two degrees, Niemeier explains. To obtain a complete picture, a person’s eyes are constantly making quick movements. These saccades – about 100,000 a day – scan our surroundings and take about 30 milliseconds each. The brain knows that an event is unlikely to happen in 30 milliseconds and either ignores or downplays small changes (also known as saccadic suppression of displacement). Only when a change is large enough does the brain notice, he says.

“The brain makes the best possible use of the flawed data it gets from sensors like the eyes or ears, piecing together bits of information until a final picture is obtained, much like the process involved in solving a jigsaw puzzle,” adds Tweed. “The sensors react even to unlikely or unexpected events but the brain disregards some of these signals to form one coherent picture. The brain is always compromising.”

The research was supported by the Canadian Institutes of Health Research and the Canada Research Chairs program.

The research was published online in the articles-in-press section of the American Thoracic Society’s American Journal of Respiratory and Critical Care Medicine.

Burnout is believed to be a psychological response to chronic stress. It can lead to emotional instability, feelings of failure and low production or an urge to leave the job.

"Avoiding and understanding burnout is especially important now, given the projected shortage of ICU caregivers, in addition to the intensity and costliness of training these specialized professionals," noted Paolo Merlani, MD, attending physician at the University Hospital of Geneva.

To evaluate risk of burnout among different individual in different settings, the researchers used a self-administered questionnaire that captured demographic data, personal characteristics, subjective stress and risk of burnout. They evaluated more than 3,000 individuals in 72 Swiss ICUs. In addition to individual characteristics, they analyzed center-level factors (e.g., proportion of female caregivers among nurses and physicians) and patient-related factors.

In addition to the finding that a higher proportion of female nurses reduced overall risk of burnout, the researchers found more gender-related differences. While female caregivers were more likely to say that they experienced stress, they were more resistant to burnout than their male colleagues.

"This could be due to a methodological bias," said Dr. Merlani. "Indeed, female caregivers may have found it easier to admit their distress than did males….Men may be less inclined to express their distress."

Interestingly, the researchers also found that stress was not always associated with burnout. "One explanation may be that that being burned out may lessen the resistance to stress and therefore may contribute to a vicious cycle where the role of each factor might be confounding," wrote Dr. Merlani.

Of all the professions examined, nurse-assistants were at highest risk for burnout. "Since the participation to end-of-life and post-mortem care is known in the literature to increase the psychological burden and the risk of burnout and since these caregivers are usually less numerous in ICUs, the unavoidable consequence is that they are more frequently confronted to these difficult situations than others. This could be one of the causes of the increased risk of burnout in nurse-assistants," said Dr. Merlani.

Finally, Dr. Merlani and colleagues found that among women caregivers, those who were young, single and without children were at the highest risk for burnout.

"Our study could open a new frontier concerning burnout in ICUs, highlighting the importance of the team composition," said Dr. Merlani. "Of course, our results should be confirmed in a prospective multicenter, multinational study. Whether the results can be exported to other medical settings where team-working is pivotal remains for the moment an interesting question to be investigated."

"In the meanwhile," he continued, "ICU heads should ascertain that personnel at higher risk would be especially taken care of, and that resources should be provided to afford psychological support and promote a team culture. This could finally also increase the number of women staying in ICUs, thereby reducing the overall risk of burnout."

The team, led by Dr Chris Cardwell and Dr Chris Patterson, examined 20 published studies from 16 countries including around 10,000 children with Type 1 diabetes and over a million control children.

They found a 20 per cent increase in the risk of children born by Caesarean section developing the disease. The increase could not be explained by factors such as birth weight, the age of the mother, order of birth, gestational diabetes and whether the baby was breast-fed or not, all factors associated with childhood diabetes in previous studies.

Dr Cardwell, from the School of Medicine, Dentistry and Biomedical Sciences, said: "This study revealed a consistent 20 per cent increase in the risk of Type 1 diabetes. It is important to stress that the reason for this is still not understood. It is possible that children born by Caesarean section differ from other children with respect to some unknown characteristic which consequently increases their risk of diabetes, but it is also possible that Caesarean section itself is responsible.

“Type 1 diabetes occurs when the immune system destroys the insulin producing cells in the pancreas, and one theory suggests that being born by Caesarean section may affect the development of the immune system because babies are first exposed to bacteria originating from the hospital environment rather than to maternal bacteria.”

Dr Chris Patterson said: “The study findings are interesting, but unless a biological mechanism is established it would be unwise to read too much into this association between Caesarean section delivery and diabetes.

“Fortunately figures from the Northern Ireland Type 1 diabetes register indicate that only around two per 1,000 children will develop diabetes by their 15th birthday so a 20 per cent increase is on quite a low baseline risk.”

Diabetes is a serious condition that, if not managed, can lead to fatal complications including heart disease, stroke, kidney failure and amputations. There are 2.3 million people in the UK diagnosed with diabetes and 250,000 with Type 1 diabetes. In Northern Ireland over 62,000 people have diabetes, 6,000 of them with Type 1 diabetes.

Around one in four babies in Northern Ireland are delivered by Caesarean section, which is significantly higher that the World Health Organisation’s recommended rate of 15 per cent.

Iain Foster, Director of Diabetes UK Northern Ireland, said: "Not all women have the choice of whether to have a Caesarean section or not, but those who do may wish to take this risk into consideration before choosing to give birth this way.

"We already know that genetics and childhood infections play a vital role in the development of Type 1 diabetes in children, but the findings of this study indicate that the way a baby is delivered could affect how likely it is to develop this condition later in life. Diabetes UK Northern Ireland would welcome more research in this area."

“This research provides important new evidence that the risk of developing a maladaptive pattern of alcohol consumption is influenced by genetically determined neurobiological differences that exert their effects during young adulthood,” says Ting-Kai Li, M.D., director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA).

NIAAA clinical investigators Paolo B. DePetrillo, M.D., and Research Fellow Aryeh I. Herman B.A., along with researchers from George Washington University in Washington, D.C., conducted the study of 262 male and female college students and analyzed data from the largest homogenous group: 204 male and female Caucasian college students aged 17 to 23 years. To assess the frequency and patterns of alcohol consumption, the scientists asked all the students a set of questions, for example, how many times in the past two weeks they had engaged in binge drinking (five or more drinks for men and four or more drinks for women on one occasion).

The research team also analyzed each student’s genotype with a focus on the 5-HTT gene, which is involved in recycling the chemical serotonin after it is secreted into the synapse of a cell. The researchers determined which students had long or short versions of this so-called serotonin transporter gene.

Everyone inherits two copies of each gene, one from each parent. There are two normal variations, or polymorphisms, of the serotonin transporter gene, labeled the long and the short variants. Most people are heterozygous, that is, they have one copy of each variant, but about 30 percent of the Caucasian population are homozygous (carry duplicate copies) of either the long or the short version. This percentage varies depending on the ethnic background of the individual.

The researchers found that the students who carried two copies of the short version of 5-HTT were more likely to report troublesome drinking patterns. Dr. DePetrillo says, “Our findings reveal a significant association of the serotonin transporter promoter polymorphism with increased alcohol consumption behavior in the students that we studied. Taken together with other research, this finding suggests that genetically mediated differences in serotonergic response play an important role in mediating patterns of alcohol intake.” The students with two copies of the short form of the gene engaged more frequently in binge drinking, drank more often to get drunk, and consumed more alcoholic drinks per occasion than did students with the other genotypes.

Another difference the researchers observed was that students with at least one copy of the long variant of the 5-HTT gene tended to consume a smaller number of drinks at a sitting, even though they went out to drink as often as the other students.

Why should the presence of the shorter gene variant make such a difference? The authors speculate that, because individuals who are homozygous for the short version are known to be at risk for higher levels of anxiety, they may use alcohol to reduce tension. Further studies are needed to understand the influence of the serotonin transporter gene on drinking behavior, with special attention given to replication in other ethnic groups.

The article “Serotonin transporter promoter polymorphism and differences in alcohol consumption behavior in a college student population” is published as a Rapid Communication at alcalc.oupjournals/. The study will appear in the September printed issue of Alcohol and Alcoholism (Volume 38, Number 5).

Additional information about genetic and other areas of NIAAA research is available from the NIAAA Press Office and at niaaa.nih.

The National Institute on Alcohol Abuse and Alcoholism, a component of the National Institutes of Health, U.S. Department of Health and Human Services, conducts and supports approximately 90 percent of U.S. research on the causes, consequences, prevention, and treatment of alcohol abuse, alcoholism, and alcohol problems and disseminates research findings to science, practitioner, policy making and general audiences.

The process, created in the laboratory of Rick A. Wetsel, Ph.D., a professor of molecular medicine at the IMM, is described in this week’s edition of the Proceedings of the National Academy of Sciences (PNAS). Research scientist Dachun Wang, M.D., is lead author of the article, “A pure population of lung alveolar epithelial type II cells derived from human embryonic stem cells.”

“We have developed a reliable molecular procedure which facilitates, via genetic selection, the differentiation of human embryonic stem cells into an essentially pure population of lung epithelial cells,” said Wetsel, noting the procedure also can be used to create other types of highly-specialized cells.

Scientists at the IMM used the in vitro method to create lung epithelial cells known as alveolar epithelial type II. The cells were derived from a human embryonic stem cell line approved by the National Institutes of Health (NIH).

The method involves the use of protein markers under the control of cell-specific promoters to convert undifferentiated human embryonic stem cells into highly-specialized cells. The human embryonic stem cells were cultured on specially coated dishes and transfected with a lung epithelial gene regulator of a drug selection gene.

“It is a general technology for developing select cells from human embryonic stem cells,” said C. Thomas Caskey, M.D., the IMM’s chief operating officer, director and CEO-elect. “The technology has allowed us to develop a platform that could potentially be useful in the development of spinal cord cells, heart cells, nerve cells and others.”

James T. Willerson, M.D., president of the UT Health Science Center at Houston, said " I believe this is an important development by the Wetsel laboratory at the IMM. I look forward to seeing its transitional impact."

Alveolar epithelial type II cells are called “the stem cells of the lungs” because of their versatility and many important functions. They produce proteins including surfactant that inflates lungs. They also make other cells lining the inner lung. “They regulate lung fluids and oxygen levels,” Wetsel said.

The cells are part of the tiny air sacs lining the lower airways known as alveoli. Tissue thin, they transfer oxygen into the blood and remove carbon dioxide. If the walls of the hundreds of millions of alveolus in a pair of lungs could be spread out and placed side by side, they would cover the floor of a classroom.

According to Wetsel, transplantable alveolar epithelial type II cells can be explored as treatments for pulmonary genetic diseases, acquired lung disease, as well as lung trauma caused by car accidents, gunshot wounds and sports injuries. “These are the cells that can potentially be used for regenerative lung repair,” he said.

Hereditary lung disorders most likely to benefit from transplantation of alveolar epithelial type II cells include respiratory distress syndrome of the newborn, alpha-1 related emphysema and cystic fibrosis, Wetsel believes. “All three of these diseases are caused by single gene defects and therefore have been logical candidates for gene therapy,” Wetsel said.

Respiratory distress syndrome of the newborn, a condition affecting premature infants less than 37 weeks of age, may be caused by a genetic mutation triggering a surfactant shortage. Likewise, alpha-1 related emphysema, a condition affecting 100,000 Americans, results from an inherited deficiency of alpha-1 antitrypsin. Further, cystic fibrosis is the second most common childhood onset inherited disorder in the United States.

Transplantable alveolar epithelial type II cells may also one day be helpful in the treatment of other lung diseases including chronic obstructive pulmonary disease (COPD), the fourth leading cause of death in the United States, claiming the lives of 122,283 Americans in 2003, and asthma, Wetsel said.

Still years away from their use in regenerative medicine, Wetsel said the next step involves research trials with mice.

Other IMM investigators participating in the study included David L. Haviland, Ph.D., assistant professor in the Center for Immunology and Autoimmune Diseases, and Eva Zsigmond, Ph.D., assistant professor and associate director of the IMM’s Laboratory for Developmental Biology.

Funding for the study of the NIH-approved human embryonic stem cell line was provided by Houston philanthropists Clive and Nancy Runnells.

Dr. Shuming Nie, PhD, professor in the Coulter Department of Biomedical Engineering at Emory University and the Georgia Institute of Technology and director of cancer nanotechnology at Emory’s Winship Cancer Institute, highlights recent research in at the 225th National Meeting of the American Chemical Society on March 27.

“We believe biomedical nanotechnology will soon produce major advances in molecular diagnostics, therapeutics, molecular biology and bioengineering,” Dr. Nie says. “Already, scientists have begun to develop functional nanoparticles that are linked to biological molecules such as peptides, proteins and DNA.”

Nanoparticles assume special properties by virtue of their miniature size that distinguish them from larger particles, including changes in color as they grow smaller and smaller. Because of their compact structure, nanoparticles emit light and can act as a fluorescent tag. This makes them highly suitable as contrast agents for magnetic resonance imaging (MRI), in positron emission tomography (PET) for molecular imaging in patients, or as fluorescent tracers in optical microscopy. Nanoparticles also have advantages over conventional dyes: they fade less quickly, they are less toxic to cells and they can be used in combination to create almost an infinite number of colors.

Although nanoparticles are similar in size to biomolecules such as proteins and DNA, human-made nanoparticles can be engineered to have specific or multiple functions. Bioconjugated quantum dots, consisting of different sized dots embedded in tiny beads made of polymer material, can be finely tuned to a myriad of different colors that can tag a multitude of different proteins or genetic sequences in a process called “multiplexing.”

By chemically binding the quantum dots to particular genes and proteins, scientists including Dr. Nie are developing molecular nanoprobes to rapidly analyze biopsy tissue from cancer patients, to monitor the effectiveness of drug therapy, as scaffolding in tissue engineering, and as “smart bombs” to deliver controlled amounts of drugs into genetically classified tumor cells.

Now a team led by McMaster University hematologist Dr. Catherine Hayward has discovered the genetic cause of Quebec Platelet Disorder (QPD). They have gone on to develop a genetic test for the condition — a major advance in diagnosing this serious and unusual bleeding problem. Their research appears in the journal Blood.

The condition is called a platelet disorder because it transforms platelets (blood cells that control bleeding) from clot formers into clot busters.

It is called QPD because careful detective work has traced all individuals with this condition back to one Quebec family. In parts of Canada, about one out of 150,000 persons have QPD and the new genetic test is expected to uncover many more.

Hayward, a professor of both the departments of medicine and pathology and molecular medicine in the Michael G. DeGroote School of Medicine, calls the discovery of the genetic cause of QPD a "milestone" in her career.

Because the genetic cause of most bleeding disorders continues to be a mystery, "it’s satisfying to know that our team tackled the genetic cause of a really fascinating genetic disorder and have an answer," she said. "And, it’s not the answer anybody expected, which makes it even more interesting."

QPD is an autosomal dominant bleeding disorder, which means a person only needs to receive the abnormal gene from one parent to inherit the disease. The research team discovered that QPD is caused by a mutation involving an extra copy of the gene PLAU, the urokinase plasminogen activator (uPA) gene that causes overproduction of an enzyme that accelerates blood clot breakdown and this turns platelets into clot busters.

This is "novel," Hayward said, "as QPD is the very first bleeding disorder attributed to having an extra copy of a gene, rather than a defective copy. QPD is also the first bleeding problem attributed to a mutation in the uPA gene."

"The types of mutation that causes some bleeding problems are mistakes that are likely to happen again, and typically, they cause a protein to become defective or deficient," said Hayward. "Now that we know the mutation, we can focus on solving why there is tremendous uPA overproduction in QPD platelets, which will give us fundamental, new insights on how the uPA gene is controlled."

The work is already having a positive impact on the lives of many people. A recent newborn of the family most impacted by the condition was able to have a test immediately to discover whether he had the condition.

"The family needed to know whether this child would need life-long monitoring, and treatments to counteract their clot busting platelets, as having a definite yes or no answer early is key to proper treatment," said Hayward.

Hayward’s group at McMaster worked with a Canadian team of investigators including Andrew Paterson at the Hospital for Sick Children in Toronto, and Georges Rivard at the University of Montreal.

Hayward and Rivard believe that the known cases they have studied over the last decade are "the tip of the iceberg" and that the true prevalence of QPD has been underestimated because, until the genetic test became available, there was no way to routinely test bleeders for this condition.

"Diagnosis is important as drugs for other platelet problems and transfusions just don’t work for the QPD clot busting problem," said Hayward.

The research was supported funds from the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation of Ontario and Bayer Canada. Federal funding was also provided by Hayward’s Canada Research Chair in Molecular Hemostasis and Paterson’s Canada Research Chair on the Genetics of Complex Diseases.

The European Infliximab for Psoriasis Efficacy and Safety Study
(EXPRESS) was a placebo-controlled trial on 378 patients with moderate
to severe psoriasis, to test the efficacy and safety of the drug. The
findings, published in the 15 October issue of The Lancet, show that
80% of patients achieved at least a 75% improvement in symptoms after
ten weeks treatment with the drug, as opposed to just 3% of those
receiving a placebo.

Psoriasis is a chronic condition which results when skin cells
over-produce and accumulate on the surface of the skin, producing red,
scaly ‘plaques’ which may itch and bleed. It is thought to be genetic
in origin and is a consequence of an abnormal inflammatory response in
the skin. Around 2% of the population suffer from the disease, with
about 30% of cases considered moderate to severe, but until now
treatment options have been limited.

Infliximab blocks the activity of ‘tumour necrosis factor
alpha’ (TNF-alpha), a protein involved in inflammation, and the vast
majority of the trial subjects treated with the drug achieved
clinically-significant levels of skin clearance. Nearly 60% experienced
at least a 90% improvement in symptoms — or near-complete skin
clearance — after ten weeks, versus 1% receiving the placebo, whilst
26% achieved complete skin clearance (versus 0% receiving the placebo).
The improvements continued throughout the 50-week study.

Professor Christopher Griffiths, the University academic
leading the trial from the Dermatology Centre at Hope Hospital,
Salford, said: “These results indicate that Infliximab is a very
effective therapy among the newer biological treatments for psoriasis.
As a dermatologist, I am very encouraged by the data, which show that
patients with moderate to severe psoriasis can rapidly achieve skin
clearance and that these results can be maintained.”

Patients receiving Infliximab also experienced a good response
in nail psoriasis, which is present in 20 — 50% of psoriasis patients
and often thought of as a treatment-resistant disease. By week 24 of
the trial, those receiving the drug were experiencing a 56% average
decrease in this condition, and again this response was maintained
throughout the trial.

“Physicians’ assessments of the patients’ conditions backed up
our findings,” confirmed Professor Griffiths, “with 83% of those
receiving the drug assessed as having minimal or cleared symptoms by
week 10 of the trial as opposed to just 4% of those receiving the
placebo.”

In a study of 72 habitual coffee drinkers, the researchers found that subjects produced more adrenaline and noradrenalin and had higher blood pressure on days when they drank caffeine compared with days they abstained. The two stress hormones are vital to helping the body react quickly in times of danger or stress, but they can damage the heart over a lifetime of heightened production, said James Lane, associate research professor of psychiatry at Duke.

Lane prepared results of his study, funded by the National Heart, Lung and Blood Institute, for presentation Thursday to a meeting of the 1999 Society of Behavioral Medicine.

"Moderate caffeine consumption makes a person react like he or she is having a very stressful day," Lane said in an interview before the meeting. "If you combine the effects of real stress with the artificial boost in stress hormones that comes from caffeine, then you have compounded the effects considerably."

During the two-week study, the subjects experienced, on average, a 32 percent increase in adrenalin and a 14 percent increase in noradrenaline on days when they consumed caffeine. Their blood pressure rose an average of 3 points.

Lane's study builds on smaller ones in which he found that caffeine boosted blood pressure, heart rate and stress hormones in subjects who drank 4 to 5 cups of caffeine per day. In the current study, Lane replicated those findings and added to them by showing that subjects' blood pressures and stress hormone levels stayed elevated until bedtime, even though they last consumed caffeine between noon and 1 p.m.

Occasional surges of stress hormones temporarily raise heart rate, blood pressure and mental acuity – long enough to accomplish the task at hand. But an excess of stress hormones has been shown to compromise health in a variety of ways, from damaging blood vessels to weakening the immune system.

In addition, even the small boost in blood pressure seen in this study – an average of 3 points during the day and evening – can have clinical significance, Lane said. A review of nine major studies of blood pressure and heart-disease risk showed that a 5-point difference in diastolic blood-pressure – the lower number used to assess health risk – was associated with at least a 34 percent increase in stroke and a 21 percent increase in the incidence of coronary heart disease

While researchers have long known that caffeine can boost stress hormones and blood pressure, Lane said most studies have been conducted in a laboratory setting under tightly controlled circumstances where a single dose of caffeine is compared to none in a short time span. Lane said his body of research is unique because it measures blood pressure, heart rate and stress hormone levels at timed intervals during normal working conditions, while subjects are exposed to a range of moods and activities.

"You can measure how caffeine affects people in the laboratory, but that doesn't tell you what effects the drug has in the real world when people are exposed to normal stressors and activities," he said.

In the current study, Lane also studied the effects of caffeine on women taking oral contraceptives, since previous research suggested that this population might be more responsive to the negative effects of caffeine. But Lane found no such effect. In fact, women taking oral contraceptives showed slightly less of a stress response to caffeine than a control group of women.

Lane's next study will measure the effects of eliminating caffeine from the diets of people with high blood pressure. The goal is to see if stopping caffeine use can be a useful therapy in reducing hypertension, along with diet, exercise and salt reduction.

The study results could lead to widespread changes in treatment for HIV patients, particularly those diagnosed at an advanced stage, experts say.

"Even in San Francisco, one of the first epicenters of HIV in the United States, we still find that many people present late in the course of their illness with an opportunistic infection," said Mitch Katz, MD, San Francisco’s director of health, who was not involved in the study. "This study shows that it is life-saving to treat those persons with antiretroviral drugs while they are still in the hospital. The results of this study will change practices throughout the world."

Some 60,000 to 70,000 newly HIV-infected individuals are identified every year in the United States, according to recently revised figures from the federal Centers for Disease Control and Prevention. A growing number of these patients, particularly minorities, youth, injection-drug users and those in poor rural areas, are being diagnosed late in the disease process when they’ve already developed life-threatening conditions, said Andrew Zolopa, MD, associate professor of infectious diseases and geographic medicine at Stanford and first author of the study. When these patients come for treatment of these complications, doctors are often reluctant to give them anti-AIDS drugs at the same time, fearing the two therapies could interfere with one another.

"A lot of people wait, thinking, ‘Let’s get the patient out of acute crisis, and then we’ll deal with the underlying HIV infection later,’" said Zolopa. "But that answer is wrong. If we’re more aggressive with HIV drugs, we can reduce AIDS-related complications and death by 50 percent. It’s a substantial clinical benefit."

The study was conducted by the AIDS Clinical Trials Group, the world’s largest clinical trial organization. Results will be published May 18 in the online journal PLoS-ONE.

William Powderly, MD, dean of medicine at the University College Dublin School of Medicine, said the study addresses one of the last, longstanding unknowns in the management of AIDS.

"Clinicians have long grappled with the question of whether or not early treatment with antiviral drugs will help people who come to the hospital with advanced infections, such as pneumonia," said Powderly, the study’s senior author. "The answer is clearly yes. Early antiviral treatment for HIV improves the clinical outcome, including the likelihood of surviving in the next few months. It probably does so by improving the immune system and therefore adds to the ability to resist these infections."

The study findings, presented in abstract form at an earlier scientific meeting, are already starting to change clinical practices. The International AIDS Society, the CDC and the British AIDS Society all have adopted guidelines that recommend that early antiretroviral treatment be considered in patients with an opportunistic infection, Zolopa noted.

The study involved 262 patients at 39 sites across the United States, from Puerto Rico to Seattle. An additional 20 patients were enrolled in a hospital in Johannesburg, South Africa. Eighty-five percent of the patients were men whose median age was 28. They were an ethnically diverse group: 37 percent were black, 36 percent Hispanic, 23 percent white and 5 percent Asian.

The patients all had one or more opportunistic infection, with the most common ones being pneumocystis jirovecii pneumonia, cryptococcal meningitis and serious bacterial infections. Patients with tuberculosis were excluded from the study because it was unclear what the optimal antiviral treatment was for these patients, Zolopa said.

The patients, who were enrolled between May 2003 and August 2006, were separated into two groups: those who got antiretroviral treatment early and those for whom this treatment was delayed until their opportunistic infections had been dealt with. The patients were all offered antiretroviral drugs free of charge. The drugs for the study were supplied by Abbott Laboratories (lopinavir/ritonavir), Gilead Sciences (tenofovir and emtricitabine) and Bristol-Myers Squibb (stavudine).

The patients in the early intervention arm of the study were treated with ARVs within an average of 12 days, while those in the deferred group received the treatment within an average of 45 days after the start of treatment for the opportunistic infection. Among the patients treated early, there were 20 (14.2 percent) who died or developed another significant AIDS-related complication. That compared with 34 patients (24.1 percent) in the deferred group who died or suffered a new complication.

In addition, the patients in the early treatment group saw a much swifter recovery of their immune systems. The early group patients saw their T-cell counts, a measure of the immune cells destroyed by the AIDS virus, increase to more than 100 within four weeks. In the deferred treatment group, it took 12 weeks for the patients’ T cells to reach that same level, the researchers reported.

"I was quite impressed at how rapidly these T cells could rise in these patients," Zolopa said. "By starting ARVs early you can effectively reduce the window of vulnerability where another AIDS-related complication could develop."

Zolopa said there was no difference between the two sets of patients in their adherence to their prescribed regimens. One concern in treating patients with ARVs soon after being diagnosed with AIDS is that they might not stick to their treatments and could then develop drug resistance. But adherence did not prove to be an issue, he noted.

"Starting the therapies early didn’t scare people off," he said.

According to Zolopa, the study results probably provide some guidance for patients in developing countries, though each country would have to determine its own strategy for initiating ARVs in patients with advanced AIDS.

"These results do have important implications across the globe," he said.

Although the study did not include patients with tuberculosis, the most common AIDS-related complication among patients in sub-Saharan Africa, early ARV treatment has been shown in other, more recent studies to be of value in those patients with TB, Powderly said.

Zolopa said implementing the study findings could entail some logistical challenges, as hospitals will have to develop interdisciplinary teams, including pulmonary specialists, emergency physicians, pharmacists and others, in coordinating early treatment for these critically ill patients as they come into the system.

Other researchers in the study are Janet Andersen, ScD, and Lauren Komarow, both with Harvard School of Public Health; Ian Sanne, MD, of the South African College of Physicians; Alejandro Sanchez, MD, of the USC Keck School of Medicine; Evelyn Hogg with Social & Scientific Systems, Inc.; and Carol Suckow with the Frontier Science and Technology Research Foundation.

The study was funded by the National Institutes of Health through the Division of AIDS.