Fumar maconha pode adiantar o aparecimento da esquizofrenia

Fumar maconha pode adiantar em quase três anos o aparecimento de esquizofrenia e de outros quadros psicóticos.

A conclusão é de uma revisão de 83 estudos científicos já publicados sobre a relação entre o consumo dessa erva e o transtorno.

Pesquisas sobre maconha viram armas no debate sobre legalização

Os resultados, divulgados no periódico médico "Archives of General Psychiatry", dão mais munição a pesquisadores que se opõem à liberação da substância ilícita.

No total, os pesquisadores das universidades de New South Wales, Austrália, e Emory, EUA, avaliaram dados de mais de 22 mil portadores de distúrbios psicóticos _sendo 8.167 deles usuários de maconha.

A doença aparecia em média 2,7 anos (cerca de 32 meses) antes entre quem consumia a erva do que nos membros do grupo-controle.

"Acredito que essa relação seja de causa e consequência, e a maconha tem um papel importante [no aparecimento precoce do transtorno] em certas pessoas", disse à Folha o psiquiatra australiano Matthew Large, um dos autores do estudo.

Uma hipótese é que pessoas com predisposição genética para esquizofrenia são mais suscetíveis à influência da maconha.

Nelas, os quadros psicóticos poderiam ser desencadeados pela alteração na concentração de neurotransmissores como dopamina e serotonina, causada pela droga, o que desregularia o funcionamento cerebral.

"Pessoas com histórico familiar de esquizofrenia devem ser instruídas a jamais usar essa droga. Não dá pra arriscar", diz Hélio Elkis, coordenador do Projeto Esquizofrenia do Hospital das Clínicas de São Paulo.

Segundo o psiquiatra, quanto mais cedo aparece a doença, pior o prognóstico. "Se surge na adolescência, o cérebro não teve tempo de se desenvolver completamente." Isso piora o deficit cognitivo, próprio do transtorno.

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Mas para Marcelo Niel, psiquiatra do Programa de Orientação e Atendimento a Dependentes da Unifesp, deve-se ter cuidado ao fazer a relação direta entre esquizofrenia e uso da cânabis.

"Em alguns pacientes com vulnerabilidade, isso pode acontecer, mas há fatores que devem ser considerados", ressalva.

Niel afirma que, como a esquizofrenia geralmente começa quando os indivíduos são adolescentes ou adultos jovens, pode ser que o consumo da substância esteja mais relacionado a um hábito do grupo social naquela idade do que a uma causalidade.

"E muitos pacientes esquizofrênicos começam a fumar maconha para aliviar os sintomas do estágio inicial da doença, como ansiedade e depressão", diz.

Matthew Large, o autor do estudo, sugere: "Jovens deveriam evitar o uso de maconha ou, mais precisamente, deveriam se conscientizar sobre os seus riscos.

Como informá-los disso já é outra história", completa.

Firefly Glow: Scientists Develop a Hydrogen Peroxide Probe Based on Firefly Luciferin

ScienceDaily (Feb. 11, 2011) — A unique new probe based on luciferase, the enzyme that gives fireflies their glow, enables researchers to monitor hydrogen peroxide levels in mice and thereby track the progression of infectious diseases or cancerous tumors without harming the animals or even having to shave their fur. Developed by researchers with the Lawrence Berkeley National Laboratory (Berkeley Lab) and the University of California (UC) Berkeley, this new bioluminescent probe has already provided the first direct experimental evidence that hydrogen peroxide is continuously made even in a healthy animal.

Bioluminescent signal from firefly luciferase lights up mouse 30 minutes after injection with PCL-1, a probe that can be used to monitor hydrogen peroxide levels without harming the animal. 

"We are reporting the design, synthesis, and in vivo applications of Peroxy Caged Luciferin-1 (PCL-1), a chemoselective bioluminescent probe for the real-time detection of hydrogen peroxide within living animals," says Christopher Chang, a chemist who holds appointments with Berkeley Lab's Chemical Sciences Division and UC Berkeley's Chemistry Department, as well as the Howard Hughes Medical Institute.

Chang is the corresponding author of a paper in the Proceedings of the National Academy of Science (PNAS) that describes this research. Co-authoring with Chang were Genevieve Van de Bittner, Elena Dubikovskaya and Carolyn Bertozzi.

The PCL-1 probe consists of a light-emitting luciferin molecule enclosed inside a molecular cage of boronic acid. The boronic acid selectively reacts with hydrogen peroxide molecules to release the luciferin, triggering a bioluminescent response in the presence of firefly luciferase. For their studies, Chang and his co-authors worked with transgenic mice that carried the firefly luciferase gene.

"The high sensitivity and selectivity of the PCL-1 probe for hydrogen peroxide, combined with the favorable properties of bioluminescence for in vivo imaging, afford a unique technology for monitoring physiological fluctuations in hydrogen peroxide levels in real-time," Chang says. "This offers opportunities to dissect the disparate contributions of hydrogen peroxide to health, aging and disease."

Hydrogen peroxide is nature's disinfectant. Cells produce this small but highly reactive molecule to kill invading pathogens. It also plays a critical role in cellular signaling that is essential to the growth, development and physical well-being of humans and other organisms. However, over-production of hydrogen peroxide in cells is the mark of oxidative stress and inflammation, and has been linked to the onset and advancement of cancer and diabetes, and numerous cardiovascular and neurodegenerative diseases.

Chang and his group have shown that hydrogen peroxide can serve as a highly effective signaling agent for in vivo imaging. To this end, they've developed a series of hydrogen peroxide fluorescent tags for tracking small-molecule oxygen metabolites in living cells, tissue and organisms. With their new PCL-1 probe, they were able to study mice with prostate cancers and monitor fluctuations in the hydrogen peroxide generated by cancerous cells based on the amount of light emitted by the probe.

"The PCL-1 probe enables us to study the chemistry in living animals as cancers and other diseases progress," Chang says. "We can use the probe to look at the same mouse over time to see how see how therapeutics and other treatments affect its physiology, without having to do biopsies or sacrifice the animal. This is a significant advance over previous hydrogen peroxide probes."

In addition to doing no harm to the animal, Chang and his group wanted a probe that could simultaneously detect hydrogen peroxide signals from multiple regions or the entire organism. They also wanted a probe that could detect intracellular signals, and preferred not having to remove fur or skin to detect a signal from a specific tissue of interest. They elected to pursue bioluminescence because of its favorable properties for in vivo imaging.

"The fact that in nature fireflies use the luciferin enzyme to communicate by light inspired us to adapt this same strategy for pre-clinical diagnostics," Chang says. "Bioluminescence from the catalytic transformation of firefly luciferin by the firefly luciferase enzyme exhibits a high efficiency for photon production and a 612 nanometer emission frequency that provides a detectable bioluminescent signal in all organs of a mouse. The PCL-1 probe is small enough to travel through a mouse's body andits red-shifted luminescent reaction with luciferase allows for deep tissue signal penetration with an optical readout."

Chang and his colleagues are now working to improve the sensitivity of the PCL-1 probe. They would also like to refine their methodology to be able to simultaneously examine multiple biomarkers.

This work was supported in part by the National Institute of General Medical Sciences in the National Institutes of Health.

Sugar Residues Regulate Growth and Survival of Nerve Cells

ScienceDaily (Feb. 11, 2011) — Researchers in Bochum have found out that certain sugar residues in the spinal cord regulate the growth and survival of nerve cells which control the movement of muscles. "We hope that our findings can improve regenerative treatment of nerve injuries," explains Prof. Dr. Stefan Wiese from the Molecular Cell Biology study group (Faculty of Biology and Biotechnology).

The motoneurons from the spinal cord were cultivated on various substrates for five days. Nerve cells on substrates with chondroitin sulfate sugar residues (B-D) form longer processes than nerve cells on a substrate without sugar residues (A). 

The researchers report on these sugar residues in the environment of the cells, which is called the extracellular matrix, in the Journal of Neuroscience Research.

The vision of healing nerves

Brain and spinal cord comprise more than just nerve cells. The extracellular matrix, a complex scaffold of proteins with sugar residues, surrounds the cells and influences their well-being. Prof. Wiese's team is interested in the interaction of the matrix with a specific kind of nerve cells, which transmit signals from the brain to muscles (motoneurons). Because injured motoneurons lead to paralysis, clinicians have great interest in being able to influence the growth of these cells. "If we had a medication that could change the extracellular matrix so that it favours the growth and survival of nerve cells, that would be a large step in the treatment of nerve injuries after accidents or also for the treatment of diseases such as Multiple Sclerosis," says Prof. Wiese.

Growing muscle-controlling nerve cells

In cooperation with Prof. Dr. Andreas Faissner (Chair of Cell Morphology & Molecular Neurobiology, Faculty of Biology and Biotechnology), Dr. Alice Klausmeyer from Prof. Wiese's team cultivated motoneurons from the spinal cord of mice on various kinds of extracellular matrix, from which the researchers experimentally removed certain sugar residues (chondroitin sulfates). By comparing the cell cultures with and without sugar residues, they were able to show that the residues control the growth and survival of the motoneurons.

Staining, counting and measuring

To express the growth of the cells in understandable figures, the cell biologists in Bochum measured the longest process of the motoneurons under a microscope and counted the number of processes which the cells had formed. With the help of the processes, the cells communicate and transmit signals across large distances. Some of the chondroitin sulfate sugar residues examined had a positive effect on the length and number of the processes, others had an inhibiting influence. The question of whether the growth of the nerve cells was supported or inhibited also depended on the kind of extracellular matrix with which a certain sugar residue was combined. Furthermore, the researchers stained for an enzyme in the motoneurons which is a marker for cell death. This analysis showed that the chondroitin sulfate sugar residues not only regulate the growth of the motoneurons, but can also lead to survival of these cells.

The experiments performed by Dr. Klausmeyer and her colleagues were supported, amongst other things, by the RUB Rector's Office programme for start-up funding of research projects of the next scientific generation.

Nanoparticles May Enhance Circulating Tumor Cell Detection

ScienceDaily (Feb. 11, 2011) — Tiny gold particles can help doctors detect tumor cells circulating in the blood of patients with head and neck cancer, researchers at Emory and Georgia Tech have found.

Gold-based nanoparticles can detect circulating tumor cells. (Credit: Image courtesy of Emory University)

The detection of circulating tumor cells (CTCs) is an emerging technique that can allow oncologists to monitor patients with cancer for metastasis or to evaluate the progress of their treatment. The gold particles, which are embedded with dyes allowing their detection by laser spectroscopy, could enhance this technique's specificity by reducing the number of false positives.

The results are published online in the journal Cancer Research.

One challenge with detecting CTCs is separating out signals from white blood cells, which are similarly sized as tumor cells and can stick to the same antibodies normally used to identify tumor cells. Commercially available devices trap CTCs using antibody-coated magnetic beads, and technicians must stain the trapped cells with several antibodies to avoid falsely identifying white blood cells as tumor cells.

Emory and Georgia Tech researchers show that polymer-coated and dye-studded gold particles, directly linked to a growth factor peptide rather than an antibody, can detect circulating tumor cells in the blood of patients with head and neck cancer.

"The key technological advance here is our finding that polymer-coated gold nanoparticles that are conjugated with low molecular weight peptides such as EGF are much less sticky than particles conjugated to whole antibodies," says Shuming Nie, PhD, a professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "This effect has led to a major improvement in discriminating tumor cells from non-tumor cells in the blood."

The particles are linked to EGF (epithelial growth factor), whose counterpart EGFR (epithelial growth factor receptor) is over-produced on the surfaces of several types of tumor cells.

Upon laser illumination, the particles display a sharp fingerprint-like pattern that is specific to the dye, because the gold enhances the signal coming from the dyes. This suggests that several types of nanoparticles could be combined to gain more information about the growth characteristics of the tumor cells. In addition, measuring CTC levels may be sensitive enough to distinguish patients with localized disease from those with metastatic disease.

"Nanoparticles could be instrumental in modifying the process so that circulating tumor cells can be detected without separating the tumor cells from normal blood cells," Nie says. "We've demonstrated that one tumor cell out of approximately one to ten million normal cells can be detected this way."

In collaboration with oncologists at Winship Cancer Institute, researchers used nanoparticles to test for CTCs in blood samples from 19 patients with head and neck cancer. Of these patients, 17 had positive signals for CTCs in their blood. The two with low signals were verified to have no circulating cells by a different technique.

"Although the results have not been compared or validated with current CTC detection methods, our 'one-tube' SERS technology could be faster and lower in costs than other detection methods," says Dong Moon Shin, MD, professor of hematology and oncology and otolaryngology, associate director of academic development for Winship Cancer Institute and director of the Winship Cancer Institute Chemoprevention Program. "We need to validate this pilot study by continuing with larger groups of patients and comparing with other tests."

Experimental Agent Better Than Aspirin at Preventing Stroke, Study Suggests

ScienceDaily (Feb. 11, 2011) — A new anti-clotting agent is vastly superior to aspirin at reducing stroke risk (1.6 percent per year versus 3.6 percent per year) in atrial fibrillation (AF) patients unable to take stronger drugs, according to final data reported February 10 at the American Stroke Association's International Stroke Conference 2011. Researchers found the drug also works better in people with a history of stroke or a warning stroke.

Atrial fibrillation is a heartbeat abnormality that can cause blood clots which raise the risk of stroke, particularly in the elderly.

The AVERROES: Apixaban Versus Acetylsalicylic Acid (ASA) to Prevent Strokes trial is a randomized trial of 5,600 AF patients at moderate to high risk of stroke who were not willing or able to take oral vitamin-K antagonists like warfarin, a drug commonly prescribed to prevent blood clots in people with AF. They were treated at 520 medical centers worldwide. A May 2010 interim analysis found evidence that the investigational oral drug apixaban was so much more superior to aspirin that the researchers were advised to end the trial early, said Hans-Christoph Diener, M.D., professor and chairman, Department of Neurology and Stroke Center, University Hospital Essen, Essen, Germany.

In releasing the study's final results, he reported that apixaban was far superior to aspirin at preventing stroke or systemic embolism (blood clot) and was also very safe. The drug blocks factor Xa, a crucial step in blood clot formation, said Diener, co-chair of the study's adjudication committee.

"Apixaban was highly superior to aspirin. We had not anticipated that apixaban would show such a big difference compared with aspirin while showing no significant increase in major bleeds," he said. "Everyone had expected that a more powerful drug like apixaban would be associated with more severe bleeding complications compared to aspirin, but it wasn't."

The study's primary endpoint was the reduction of ischemic stroke (stroke caused by blockages in the brain's circulation), hemorrhagic stroke (stroke due to bleeding in the brain) and systemic embolism (blockages due to blood clots elsewhere in the body), he said. The primary safety endpoint was major bleeding incidents.

Up to 50 percent of all AF patients with moderate or high stroke risk are unsuitable for the most effective class of anti-clotting treatment known as vitamin K antagonists (VKA). That class includes the well-known drug warfarin.

All of the AVERROES patients were unsuitable for VKA therapy, which carries an increased risk of hemorrhage and requires frequent blood testing to monitor its effectiveness. For such patients the only alternate treatment is aspirin, which is just modestly effective, Diener said.

The patients in this study, all over age 50, were at moderate to high risk because they had at least one stroke risk factor in addition to AF, such as being age 75 or older, having high blood pressure, heart failure, diabetes or having a history of stroke or transient ischemic attack (a possible precursor of stroke), he explained.

Patients were randomized to receive either apixaban at 5 milligrams (mg) twice a day (2.5 mg twice a day in selected patients) or between 81 mg and 324 mg of aspirin per day. The study's double-dummy design mandated that patients randomized to receive apixaban took an aspirin-placebo and those randomized to receive aspirin got an apixaban-placebo, he explained.

During an average of 1.1 years of follow up, the researchers found 51 strokes or systemic embolism events in the 2,808 patients taking apixaban compared to 113 strokes and systemic embolic events in the 2,791 patients taking aspirin. That represents an annual rate of 1.6 percent for apixaban vs. 3.6 percent for aspirin, meaning apixaban carries about half the relative risk of stroke or systemic embolism compared to aspirin. Although bleeding events were slightly higher with apixaban, the difference fell short of statistical significance.

The researchers will also report on a subgroup of patients with a history of stroke or transient ischemic attack (TIA), often a precursor to stroke.

"If validated by future studies I think this is the end of aspirin as a drug to prevent stroke in patients with AF," he added.

Diener said the study's major limitation is the limited time period of observation, shortened further by the study's early conclusion. "AF patients need anticoagulation for the rest of their lives and we would have liked to see a much longer duration of the trial," he said.

"By evaluating the use of apixaban as a replacement for aspirin in AF patients who are unsuitable for VKA therapy, the AVERROES study is addressing an important unmet clinical need."

Co-authors are Salim Yusuf M.D., Ph.D.; John Eikelboom, M.D.; Martin O. O'Donnell, M.D.; and Stuart J. Connolly, M.D. Disclosures are on the abstract. Bristol-Myers Squibb and Pfizer funded the study.

Virus, Parasite May Combine to Increase Harm to Humans

ScienceDaily (Feb. 11, 2011) — A parasite and a virus may be teaming up in a way that increases the parasite's ability to harm humans, scientists at the University of Lausanne in Switzerland and Washington University School of Medicine in St. Louis recently reported in Science.

Viral infections appear red in this photo of the parasite Leishmania; the parasites' nuclei are blue. New evidence published in Science this week suggests that these infections may help Leishmania cause more harm when it infects animal and human hosts.

When the parasite Leishmaniainfects a human, immune system cells known as macrophages respond. However, some Leishmaniastrains are infected with a virus that can trigger a severe response in macrophages, allowing the parasite to do more harm in animal infections. In humans, the parasite's viral infection may be why some strains ofLeishmania in Central and South America tend to cause a disfiguring form of disease that erodes the soft tissues around the nose and mouth.

"This is the first reported case of a viral infection in a pathogen of this type leading to increased rather than reduced pathogenicity," says Stephen Beverley, PhD, the Marvin M. Brennecke Professor and head of the Department of Molecular Microbiology at Washington University School of Medicine. "It raises a number of important questions, including whether we can use antiviral strategies to reduce the damage caused by forms ofLeishmania that carry viruses."

Leishmania infection, known as leishmaniasis, affects an estimated 12 million people worldwide. It is mainly spread by sand fly bites and is a major public health problem in the Mediterranean basin, Asia, Africa, the Middle East, Central and South America and a potential hazard to travelers and military personnel. Symptoms include large skin lesions, fever, swelling of the spleen and liver, and, in more serious forms of the disease, disfigurement and death.

The study brought together two different lines of investigation in Europe and the Americas.

Nicolas Fasel, PhD, professor of biology and medicine at the University of Lausanne, and Nancy Saravia, PhD, of the International Center for Medical Training and Investigation in Cali, Columbia, have been studying the causes of mucocutaneous leishmaniasis, a particularly harmful form of the disease that destroys the soft tissues of the nose and mouth. This type of infection is frequently associated withLeishmania Viannia, a subgenus of Leishmania strains prevalent in Central and South America.

In tests in mice and hamsters using parasite strains taken from the wild, Fasel and Saravia showed that only some Vianniastrains spread rapidly and cause high levels of inflammation and damage similar to that seen in mucocutaneous leishmaniasis.

A breakthrough came when researchers realized that the rapid, highly damaging form of infection relied on an immune system sensor protein called TLR3. This protein is found in intracellular vesicles, which are compartments inside macrophages also known to host the parasite.

"Those vesicles are where the rendezvous between host, parasite and virus takes place," Fasel says. "TLR3 normally helps the immune system fight infections, but when we deleted it in mice and repeated the experiment, infections with virus-infected Leishmania were less harmful."

Researchers sorted the Leishmania into viral-infected and non-infected strains and found that the more serious infections in laboratory animals were much more likely to be caused by viral-infected Leishmania.

Beverley's group has been exploring the role of viral infections of Leishmania in the evolution of the RNA interference pathway, which can help fight viruses.

"Surprisingly many Leishmania species have lost the RNAi interference pathway, and one force contributing to this loss could be the successful infection of the parasite by viruses," he says. "This hints at the possibility of an evolutionary trade-off, suggesting that the loss of RNAi could be balanced if the parasite gained some type of advantage when infected by a virus."

To ensure that genetic differences in the wild strains weren't interfering with the results, Lon-Fye Lye, PhD, staff scientist, and Suzanne Hickerson, senior research technician, both of Beverley's lab, supplied lines of genetically identicalLeishmania with and without the virus. As in the prior comparisons, virally-infected Leishmania caused more disease and provoked a stronger response from macrophages.

According to Beverley, the results suggest that some viral infections in Leishmania may be improving the parasite's chances to infect the mammalian host's immune cells. He speculates that this increased pathogenicity may be one evolutionary trade-off that makes losing the RNAi pathway worthwhile for Leishmania and other microbes.

"How the virally increased pathogenicity arises is now a fascinating question in its own right," Beverley says. "It could teach us a great deal about how Leishmania causes a severe form of the disease and potentially offer new opportunities for its cure."

Funding from Swiss National Science Foundation, Foundation Pierre Mercier and the National Institutes of Health supported this research.