O poder dos placebos - até 60% dos médicos acreditam em sua eficácia

Receitando placebos

Os psiquiatras canadenses parecem estar mais preparados do que quaisquer outros médicos para reconhecerem os benefícios dos placebos.

Eles podem até se sentir desconfortáveis em falar sobre isso, mas definitivamente estão tirando proveito desses benefícios.

Um estudo realizado pela equipe do Dr. Amiz Raz, da Universidade McGill, mostra que um em cada cinco doutores - médicos e psiquiatras em escolas médicas canadenses - já prescreveram ou administraram placebo para seus pacientes.

E uma proporção ainda maior dos psiquiatras (mais de 35 por cento) relataram prescrever doses subterapêuticas de medicamentos para o tratamento de seus pacientes - ou seja, doses que estão abaixo, por vezes, consideravelmente abaixo, do nível mínimo recomendado.

Placebos entre psiquiatras

E a prescrição dos pseudoplacebos - isto é, tratamentos que, em princípio, são ativos, mas que dificilmente serão eficazes para a patologia a ser tratada, por exemplo, o uso de vitaminas para tratar a insônia crônica - é ainda mais disseminada.

O Dr. Raz e seus colegas sugerem que isso pode estar ocorrendo porque os médicos têm-se mostrado mais dispostos a prescrever materiais bioquimicamente ativos, embora em doses mais baixas do que poderia ser eficaz.

A pesquisa, que também foi concebida para estudar as atitudes dos médicos frente ao uso dos placebos, revelou que a maioria dos psiquiatras entrevistados (mais de 60 por cento) acredita que os placebos podem ter efeitos terapêuticos.

Esta é uma proporção significativamente maior do que a verificada entre médicos de outras especialidades. "Os psiquiatras parecem dar mais valor à influência que os placebos exercem sobre a mente e o corpo", diz Raz.

Apenas 2% dos psiquiatras acreditam que os placebos não têm nenhum benefício clínico.

Expectativas e enganos

O interesse do próprio Dr. Raz em relação aos placebos veio de seu trabalho em três áreas muito diferentes: seus estudos sobre como a fisiologia das pessoas é influenciada por suas expectativas do que está para acontecer, seu trabalho sobre o auto-engano, e seu treinamento como mágico.

Juntas, essas três áreas distintas da experiência de Raz levaram-no a explorar o que continua a ser um terreno incômodo da prática médica para muitos profissionais - o uso de placebos na medicina - justamente por suas ligações com as expectativas e, mais eticamente problemático, o engano.

"Enquanto a maioria dos médicos provavelmente valorize o mérito clínico dos placebos, orientações técnicas e conhecimentos científicos limitados, bem como as considerações éticas, impedem a discussão aberta sobre a melhor maneira de re-introduzir os placebos no meio médico", diz Raz.

"Esta pesquisa fornece um valioso ponto de partida para futuras investigações sobre as atitudes dos médicos [...] e para a utilização dos placebos," conclui.

• Pesquisa redefine o placebo como parte efetiva do tratamento médico

Researchers On the Trail of a Treatment for Cancer of the Immune System

ScienceDaily (Aug. 22, 2011) — Danish researchers from the University of Copenhagen have become the first in the world to regulate a special receptor or bio-antenna that plays a vital part when the Epstein Barr herpes virus infects us and when this infection appears to be mutating into cancer of the immune system. Using a biochemical blueprint and a tiny bio-molecule the Danish researchers have succeeded in blocking the receptor concerned. This will make it possible to adjust and regulate the memory cells of the immune system.

Infection with Epstein Barr means that the B cells, which are the primary memory cells of the immune system, are hi-jacked.

Infection with Epstein Barr means that the B cells, which are the primary memory cells of the immune system, are hi-jacked.

When the virus has penetrated, researchers observe an excess of a special bio-antenna, a receptor known as EB12, suddenly sprouting from the surface of the B cells. But why they do so remains a mystery.

The receptors are a vital component of the way cells communicate with their surroundings via hormones and other bio-molecules, for example, but in a body consisting of millions of cells and transmitters it can be hard to determine the part each molecule plays.

"It is possible that the large numbers of EB12 receptors could actually be the B cells response to the virus and an attempt to combat the infection. Another possibility is that the EB virus reprogrammes the cell for this explosive growth in the number of EB12 receptors. What we know for certain is that more EB12 receptors assist the B cell infected by the EB virus to multiply more rapidly thus spreading the infection faster," says postdoc Tau Benned-Jensen from the Faculty of Health Sciences, University of Copenhagen.

The Epstein Barr virus can cause cancer

No fewer than 95 per cent of us carry the Epstein Barr Herpes virus.

We often encounter it as kids and it is normally harmless. Are we infected later in life EB virus may cause mononucleosis, and it seems to play a part in some forms of cancer, just as HPV affects the risk of cervical cancer. But we have no drugs to combat the Epstein Barr virus, and no vaccines for it.

"Under normal circumstances our immune systems can keep the EB virus infection in a latent state and a truce or stand-off may arise between the immune system and the virus," explains Mette Rosenkilde, professor of pharmacology at the Department of Neuroscience and Pharmacology, University of Copenhagen.

"We cannot dispense with the infection and we carry it all life long, but to most of us it is harmless. For people whose immune systems do not function due to disease or because they are suppressed by drugs in conjunction with organ transplants it is a very different matter. Now the Epstein Barr virus is suddenly free to reproduce so uninhibitedly and dramatically that it may lead to cancer," says Mette Rosenkilde.

The first step on the road to solving the EB12-puzzle

While researchers know that the B cell EB12 receptors play a part when the cell visits the lymph glands, the immune system's Central Station, we have not yet explained the exact role of the receptor.

So the Danish researchers started by mapping the bio-antenna molecule by molecule and then, as the first in the world, they made a blueprint of a tiny molecule they thought could bind to the B cell EB12 receptor.

"When we know what receptors react to, it tells us more about the part they play," Mette Rosenkilde explains, "and our tiny molecule, a ligand, blocks the EB12 receptor, preventing it from doing its job."

"In time this block may be able to help transplant patients. If we can restrain EB virus reproduction when the immune system is being medically suppressed, we may well be able to avoid cancer," Tau Benned-Jensen says.

"On the other hand the EP virus also appears to play a part in other immune diseases such as autoimmune disease, where the ability to adjust the immune system would be beneficial," says Mette Rosenkilde.

And shortly after the Danish researchers published their article on their ligand, the first articles appeared about natural substances in the body, which activate the EB12 receptor and direct the B cell to specific areas in the lymph glands.

"Our molecule can inhibit the activation of the new substances, and the next step in our research will be experiments to identify even more biochemical dials to twiddle and to help us develop new drugs," Tau-Benned says.

The discovery has just been published in the Journal of Biological Chemistry.

Common Cause of All Forms of Amyotrophic Lateral Sclerosis (ALS) Discovered

ScienceDaily (Aug. 22, 2011) — The underlying disease process of amyotrophic lateral sclerosis (ALS and Lou Gehrig's disease), a fatal neurodegenerative disease that paralyzes its victims, has long eluded scientists and prevented development of effective therapies. Scientists weren't even sure all its forms actually converged into a common disease process.

Artist's view. The basis of amyotrophic lateral sclerosis (ALS) is a broken down protein recycling system in the neurons of the spinal cord and the brain.

But a new Northwestern Medicine study for the first time has identified a common cause of all forms of ALS.

The basis of the disorder is a broken down protein recycling system in the neurons of the spinal cord and the brain. Optimal functioning of the neurons relies on efficient recycling of the protein building blocks in the cells. In ALS, that recycling system is broken. The cell can't repair or maintain itself and becomes severely damaged.

The discovery by Northwestern University Feinberg School of Medicine researchers, published in the journal Nature, provides a common target for drug therapy and shows that all types of ALS are, indeed, tributaries, pouring into a common river of cellular incompetence.

"This opens up a whole new field for finding an effective treatment for ALS," said senior author Teepu Siddique, M.D., the Les Turner ALS Foundation/Herbert C. Wenske Professor of the Davee Department of Neurology and Clinical Neurosciences at Northwestern's Feinberg School and a neurologist at Northwestern Memorial Hospital. "We can now test for drugs that would regulate this protein pathway or optimize it, so it functions as it should in a normal state."

The discovery of the breakdown in protein recycling may also have a wider role in other neurodegenerative diseases, specifically the dementias. These include Alzheimer's disease and frontotemporal dementia as well as Parkinson's disease, all of which are characterized by aggregations of proteins, Siddique said. The removal of damaged or misfolded proteins is critical for optimal cell functioning, he noted.

This breakdown occurs in all three forms of ALS: hereditary, which is called familial; ALS that is not hereditary, called sporadic; and ALS that targets the brain, ALS/dementia.

In related research, Feinberg School researchers also discovered a new gene mutation present in familial ALS and ALS/dementia, linking these two forms of the disease.

Siddique has been searching for the causes and underlying mechanism of ALS for more than a quarter century. He said he was initially drawn to it because, "It was one of the most difficult problems in neurology and the most devastating, a disease without any treatment or known cause."

Siddique's efforts first showed in 1989 that molecular genetics techniques were applicable to ALS, then described the first ALS gene locus in 1991, which led to the discovery of SOD1 and engineering of the first genetic animal model for ALS.

ALS affects an estimated 350,000 people worldwide, including children and adults, with about 50 percent of people dying within three years of its onset. In the motor disease, people progressively lose muscle strength until they become paralyzed and can no longer move, speak, swallow and breathe. ALS/dementia targets the frontal and temporal lobes of the brain, affecting patients' judgment, the ability to understand language and to perform basic tasks like planning what to wear or organizing their day.

"These people in the prime of their lives and the peak of their productivity get this devastating illness that kills them," Siddique said. "The people who get ALS/dementia, an even more vicious disease, have a double whammy."

Broken Down Recycling System

Feinberg School scientists found the cause of ALS by discovering a protein, ubiquilin2, whose critical job is to recycle damaged or misfolded proteins in motor and cortical neurons and shuttle them off to be reprocessed.

In people with ALS, Feinberg researchers found ubiquilin2 isn't doing its job. As a result, the damaged proteins and ubiquilin2 loiter and accumulate in the motor neurons in the spinal cord and cortical and hippocampal neurons in the brain. The protein accumulations resemble twisted skeins of yarn -- characteristic of ALS -- and cause the degeneration of the neurons.

Researchers found ubiquilin2 in these skein-like accumulations in the spinal cords of ALS cases and in the brains of ALS/dementia cases.

The scientists also discovered mutations in ubiquilin2 in patients with familial ALS and familial ALS/dementia. But the skein-like accumulations were present in people's brains and spinal cords in all forms of ALS and ALS/dementia, whether or not they had the gene mutation.

"This study provides robust evidence showing a defect in the protein degradation pathway causes neurodegenerative disease," said Han-Xiang Deng, M.D., lead author of the paper and associate professor of neurology at the Feinberg School. "Abnormality in protein degradation has been suspected, but there was little direct evidence before this study." The other lead author is Wenjie Chen, senior research technologist in neurology.

About 90 percent of ALS is sporadic, without any known cause, until this study. The remaining 10 percent is familial. To date, mutations in about 10 genes, several of which were discovered at Northwestern, including SOD1 and ALSIN, account for about 30 percent of classic familial ALS, noted Faisal Fecto, M.D., study co-author and a graduate student in neuroscience at Feinberg.

New Way to Treat Common Hospital-Acquired Infection: Novel Approach May Offer Treatment for Other Bacterial Diseases

ScienceDaily (Aug. 22, 2011) — Researchers at the David Geffen School of Medicine at UCLA and the University of Texas Medical Branch at Galveston have discovered a molecular process by which the body can defend against the effects of Clostridium difficile infection (CDI), pointing the way to a promising new approach for treating an intestinal disease that has become more common, more severe and harder to cure in recent years.

The right image shows abundant S-nitrosylation (green) in human colitis compared with much less found in the left image of a normal colon.

In the U.S., several million people are infected each year, approximately double the incidence of a decade ago, mainly due to the emergence of a new, highly virulent strain of the bacteria that causes CDI.

As a result of the study findings, published in the Aug. 21 online edition of the journal Nature Medicine, the researchers are preparing to launch clinical trials using their discovery as a new CDI therapeutic approach. The team also included researchers from Case Western Reserve University, Tufts University and the Commonwealth Medical College.

CDI is a bacterial infection that can cause diarrhea and more serious intestinal conditions, such as colitis, the inflammation of the colon. In the most severe cases, CDI can be fatal. It is most commonly acquired in hospitals by patients, particularly the elderly, who are being treated with antibiotics for another infection.

Currently, one of two potent antibiotics is used to treat the infection, but up to 20 percent of patients experience a relapse and a return of symptoms within a few weeks.

"We are treating a disease caused by antibiotics with yet another antibiotic, which creates the conditions for re-infection from the same bacteria," said study co-author Dr. Charalabos Pothoulakis, director of UCLA's Inflammatory Bowel Disease Center and a professor of medicine in the division of digestive diseases. "Identification of new treatment modalities to treat this infection would be a major advance."

Clostridium difficile causes diarrhea and colitis by releasing two potent toxins into the gut lumen that bind to intestinal epithelial cells, initiating an inflammatory response. These toxins are released only when the Clostridium difficile bacteria are multiplying. When antibiotics are used to treat another infection, it changes the bacterial landscape in the gut and, in the process, may kill bacteria that under normal conditions would compete with Clostridium difficile for energy. Scientists believe this may be what provides the opportunity forClostridium difficile to grow and release its toxins.

The UCLA and University of Texas researchers found in laboratory studies that upon infection with Clostridium difficile, human cells in the gut are capable of releasing molecules that will neutralize these toxins, rendering them harmless. In animal studies, the researchers showed that using a drug to induce this process, known as protein s-nitrosylation, inhibitedClostridium difficile toxins from destroying intestinal cells. Forthcoming clinical trials will test this approach in humans.

"Our study suggests a novel therapeutic approach for treatingClostridium difficile infection by exploiting a newly discovered defense mechanism that has evolved in humans to inactivate microbial toxins," said Tor C. Savidge, an associate professor in the division of gastroenterology and hepatology at the University of Texas Medical Branch at Galveston and the paper's lead author.

Along with its potential to provide a much-needed new approach to treating CDI, the discovery could be applied to developing new treatments for other forms of diarrhea, as well as non-diarrheal diseases caused by bacteria.

"We already know through gene-sequencing analysis that hundreds of microbial proteins can be regulated by s-nitrosylation," Pothoulakis said. "If we are successful with this approach, we may be able to treat other bacterial diseases in a similar way."

The study was funded by grants from the National Institutes of Health, The Eli and Edythe Broad Medical Foundation, the John S. Dunn Gulf Coast Consortium for Chemical Genomics/Robert A. Welch Collaborative Grant Program, and the Howard Hughes Medical Institute.

Other study authors included Petri Urvil, Numan Oezguen, Ali Kausar, Aproteem Choudhury, Vinay Acharya, Irina Pinchuk, Alfredo G. Torres, Robert D. English, Michael Loeffelholz and Werner Braun from the University of Texas Medical Branch at Galveston; Raj Kumar from the Commonwealth Medical College; Liamfa Shi, Weijia Nie and Hanping Feng from Tufts University; and Bo Herman, Alfred Hausladen and Jonathan S. Stamier from Case Western Reserve University.

Tuning Natural Antimicrobials to Improve Their Effectiveness at Battling Superbugs

ScienceDaily (Aug. 22, 2011) — Ongoing research at the Institute of Food Research, which is strategically funded by BBSRC, is exploring the use of virus-produced proteins that destroy bacterial cells to combat potentially dangerous microbial infections. Bacteriophages produce endolysin proteins that specifically target certain bacteria, and IFR has been studying one that destroys Clostridium difficile, a common and dangerous source of hospital-acquired infections. New research is showing that it is possible to 'tune' these endolysin properties to increase their effectiveness and aid their development as a new weapon in the battle against superbugs.

The truncated endolysin, tagged with Green fluorescent protein, bound to C. difficile.

Clostridium difficile infection (CDI) is a common and growing problem as a cause of infections, especially in hospitals where the characteristics of the bacteria make it difficult to clear. At the moment, antibiotics are used to treat infections, but C. difficile is adept at acquiring resistance, meaning the number of effective antibiotics is ever decreasing.

This has driven the search for new antimicrobials, and at IFR Melinda Mayer and Arjan Narbad have been focussing on bacteriophage endolysins. These are relatively short proteins produced by viruses that specifically target certain species of bacteria and then break open the cell walls. They had previously isolated an endolysin, CD27L, which is active against C. difficile when applied externally, but does not affect a large range of other bacteria. This is important as any potential treatment must not affect the native gut bacteria in patients, whose gut microbiota may already have been disturbed.

However, although CD27L works in the laboratory, its activity would probably not be high enough to cope with the vast numbers of C. difficile cells in a growing population in the harsh gut environment to be used as an effective treatment. This prompted the researchers to look more closely at the endolysin.

Endolysins commonly have two domains, one at each end. One domain is thought to be responsible for the specificity of the endolysin, allowing it to bind specifically to wall molecules unique to the bacterial species. This is what was thought to give the endolysin its specific host range. The other catalytic domain attacks the cell wall, causing lysis.

They produced shortened versions of the endolysin containing only one of these domains. The truncated CD27L containing only the catalytic domain showed a much higher activity against the C. difficile cells. Surprisingly, however, the truncated endolysin was still inactive on a range of other bacteria, even though the domain thought to make it specific had been removed.

Working with colleagues at the European Molecular Biology Laboratory (EMBL) in Hamburg, the structure of the catalytic domain was solved and used to design mutants to investigate what controls the specificity and activity of the endolysins. The researchers propose that the catalytic domain contributes to the specificity of the endolysin.

In the case of CD27L, binding to the cell wall is not a critical part of the activity of the endolysin, and from these results seems to reduce the activity. This fundamental science on the mode of action of endolysins establishes that in the development of valuable novel therapeutics it may be more appropriate to use truncated versions of endolysins.