Analgésico supera antipsicótico no tratamento de sintomas da demência

Dor da demência

Muitos pacientes com demência atualmente tratados com medicamentos antipsicóticos poderiam se beneficiar mais de tratamentos à base de simples analgésicos, indica um pequeno estudo.

Especialistas britânicos e noruegueses concluíram que remédios para dor diminuíram significativamente sintomas como agitação e comportamento agressivo, comuns em pessoas que sofrem da condição.

Tendo em vista os resultados do trabalho, a Alzheimer's Society - entidade britânica que promove pesquisas sobre várias formas de demência e oferece suporte a pacientes e profissionais - quer que os médicos passem a considerar outros tratamentos para aliviar esse tipo de sintoma em seus pacientes.

Os autores do trabalho acreditam que a descoberta pode ajudar pacientes com demência a conviver melhor com a condição.

O estudo foi publicado no site da revista científica British Medical Journal (BMJ).

Agitação e agressividade

Segundo especialistas, anualmente, na Grã-Bretanha, cerca de 150 mil pacientes com demência que apresentam sintomas como agitação e agressividade são tratados com antipsicóticos.

Esses remédios têm um poderoso efeito sedativo e podem piorar os sintomas de demência, além de aumentar os riscos de derrames e morte.

Mas os pesquisadores do Kings College, em Londres, e da Noruega, suspeitavam de que os sintomas poderiam, em alguns casos, resultar de dor (que os pacientes, por causa de sua condição, teriam dificuldade em expressar).

Eles fizeram um experimento com 352 pacientes com demência grave ou moderada que vivem em lares para idosos na Noruega.

A metade passou a tomar analgésicos junto com as refeições, os outros continuaram a seguir o tratamento convencional.

Analgésico melhor do que antipsicótico

Após oito semanas, o grupo que tomou analgésicos apresentou uma redução de 17% nos sintomas agitação e agressividade. Esse grau de melhora foi superior ao que se poderia esperar de tratamentos à base de antipsicóticos.

Os pesquisadores concluíram que, se a dor do paciente for tratada de forma adequada, os médicos poderão reduzir o uso de drogas antipsicóticas.

O especialista Clive Ballard, diretor de pesquisas da Alzheimer's Society e um dos autores do estudo, disse que as revelações são importantes.

"No momento, a dor é pouco tratada em pessoas com demência porque é muito difícil reconhecê-la", disse.

"Acho que (a descoberta) pode fazer uma grande diferença na vida das pessoas, pode ajudá-las a conviver melhor com a demência".

Ballard ressalta, no entanto, que analgésicos devem ser receitados sob supervisão médica.

Complexidades da demência

A Alzheimer's Society está publicando novas orientações sobre o assunto, sugerindo a médicos que pensem muito antes de receitar antipsicóticos e que procurem receitar analgésicos.

A National Care Association - organização britânica que representa entidades que oferecem serviços a idosos e os usuários desses serviços - disse que o estudo ressalta algumas das complexidades da demência.

"A dor em si já é debilitante, então identificá-la como a causa da agitação e do comportamento agressivo é um grande avanço, que permitirá que cuidemos das pessoas de forma apropriada", disse a presidente da organização, Nadra Ahmed.

Descoberto primeiro adenovírus a saltar entre macacos e humanos

Vírus interespécies

Um novo tipo de vírus, que se espalhou pela colônia de macacos no estado da Califórnia, nos Estados Unidos, em 2009, também atingiu seres humanos.

Este é o primeiro caso identificado de um adenovírus que "salta" de uma espécie para outra e permanece contagiosa depois do salto.

O vírus que atingiu os macacos também infectou um pesquisador que trabalhava com os animais e dois membros de sua família, que não tiveram contato com os macacos.

Direção do contágio

Pesquisadores da Universidade de São Francisco identificaram o vírus na época da infecção entre os macacos.

Agora eles confirmaram que é o mesmo vírus que infectou os três humanos.

Também foi confirmado que o vírus é muito raro tanto entre humanos quanto entre macacos, o que sugere que ele pode ter-se originado em uma terceira espécie animal, ainda não identificada.

A direção na qual se deu o contágio - dos macacos para os humanos, ou dos humanos para os macacos - também continua sendo um mistério.

O fato inédito é que, tendo saltado de uma espécie para outra, ele manteve seu poder infeccioso.

Adenovírus

Os adenovírus infectam naturalmente muitos animais, incluindo humanos, macacos e roedores.

Eles são conhecidos por causar uma grande variedade de doenças em humanos, de sintomas semelhantes aos da gripe à diarreia e pneumonia.

Ao contrário dos coronavírus e dos vírus influenza (dos resfriados e da gripe), não se sabia que os adenovírus se espalham de uma espécie animal para outra.

Fatal para os macacos

O adenovírus, chamado TMAdV (titi monkey adenovirus) infectou um terço dos macacos sauá no Instituto Nacional de Pesquisas em Primatas da Califórnia, em 2009.

Entre os macacos o vírus teve um efeito devastador, com problemas respiratórios que progrediram para pneumonia, matando 19 dos 23 macacos que adoeceram (83%).

Nesse mesmo período, um pesquisador que trabalhava com os macacos e dois membros de sua família que não tiveram contato com os animais tiveram uma infecção respiratória que durou quatro semanas. Todos se recuperaram bem.

VIII CONGRESSO BRASILEIRO DE EPIDEMIOLOGIA

New Contrast Agents Detect Bacterial Infections With High Sensitivity and Specificity

ScienceDaily (July 18, 2011) — A new family of contrast agents that sneak into bacteria disguised as glucose food can detect bacterial infections in animals with high sensitivity and specificity. These agents -- called maltodextrin-based imaging probes -- can also distinguish a bacterial infection from other inflammatory conditions.

Schematic showing the chemical design of maltodextrin-based imaging probes, which have been used to detect bacterial infections in animals with high sensitivity and specificity. The probes are composed of maltohexaose conjugated to a fluorescent dye. They are internalized at a high rate by bacteria through the maltodextrin transport pathway as a glucose source.

"These contrast agents fill the need for probes that can accurately image small numbers of bacteria in vivo and distinguish infections from other pathologies like cancer," said Niren Murthy, an associate professor in the Wallace H. Coulter Department of Biomedical Engineering at Georgia Tech and Emory University. "These probes could ultimately improve the diagnosis and treatment of bacterial infections, which remains a major challenge in medicine."

The imaging probes were described in the July 17, 2011 advance online edition of the journal Nature Materials. The research was sponsored by the National Science Foundation and National Institutes of Health.

Coulter Department postdoctoral fellows Xinghai Ning and Seungjun Lee led the project. University of Georgia Complex Carbohydrate Research Center postdoctoral associate Zhirui Wang; and Georgia State University Department of Biology associate professor Eric Gilbert and student Bryan Subblefield also contributed to the work.

In the United States in 2010, bacterial infections caused 40,000 deaths from sepsis and were the leading cause of limb amputations. A major limitation preventing the effective treatment of bacterial infections is an inability to detect them inside the body with accuracy and sensitivity. To image bacterial infections, probes must first deliver a large quantity of the contrast agent into bacteria.

"Most existing imaging probes target the bacterial cell wall and cannot access the inside of the bacteria, but maltodextrin-based imaging probes target a bacterial ingestion pathway, which allows the contrast agent to reach a high concentration within bacteria," said Murthy.

Maltodextrin-based imaging probes consist of a fluorescent dye linked to maltohexaose, which is a major source of glucose for bacteria. The probes deliver the contrast agent into bacteria through the organism's maltodextrin transporter, which only exists in bacterial cells and not mammalian cells.

"To our knowledge, this represents the first demonstration of a targeting strategy that can deliver millimolar concentrations of an imaging probe within bacteria," noted Murthy.

In experiments using a rat model, the researchers found that the contrast agent accumulated in bacteria-infected tissues, but was efficiently cleared from uninfected tissues. They saw a 42-fold increase in fluorescence intensity between bacterial infected and uninfected tissues. However, the contrast agent did not accumulate in the healthy bacterial microflora located in the intestines. Because systemically administered glucose molecules cannot access the interior of the intestines, the bacteria located there never came into contact with the probe.

They also found that the probes could detect as few as one million viable bacteria cells. Current contrast agents for imaging bacteria require at least 100 million bacteria, according to the researchers.

In another experiment, the researchers found that the maltodextrin-based probes could distinguish between bacterial infections and inflammation with high specificity. Tissues infected with E. coli bacteria exhibited a 17-fold increase in fluorescence intensity when compared with inflamed tissues that were not infected.

Additional laboratory experiments showed that the probes could deliver large quantities of imaging probes to gram-positive and gram-negative bacteria for internalization. Both types of bacteria internalized the maltodextrin-based probes at a rate three orders of magnitude faster than mammalian cells.

"Maltodextrin-based probes show promise for imaging infections in a wide range of tissues, with an ability to detect bacteria in vivo with a sensitivity two orders of magnitude higher than previously reported," said Murthy.

Genetic Basis for Muscle Endurance Discovered in Animal Study

ScienceDaily (July 18, 2011) — Researchers at the Perelman School of Medicine at the University of Pennsylvania have identified a gene for endurance, or more precisely, a negative regulator of it. Not having the gene relates to greater endurance in the knockout mice that were studied. The investigators also showed that the gene is linked to Olympic-level athletes in endurance sports such as swimming compared to athletes in sprint sports such as the 100-meter dash.

Muscles from mice lacking IL‑15R‑alpha and control mice were processed for presence of a mitochondrial marker. The mice lacking IL‑15R‑alpha show a greater number of darkly stained muscle fibers (right), indicating an increase in their mitochondrial content caused by reprogramming due to the lack of IL‑15R‑alpha. 

The study appears online this week in the Journal of Clinical Investigation. The work has implications for improving muscle performance in disease states including metabolic disorders, obesity, and aging.

"We have shown that mice lacking the gene run six times longer than control mice and that the fatigable muscles of the mouse -- the fast muscle in the front of the leg -- have been reprogrammed and are now fatigue-resistant," explains senior author Tejvir S. Khurana, MD, PhD, professor of Physiology and member of the Pennsylvania Muscle Institute. "This has wide ramifications for various aspects of muscle biology ranging from athletics to treating muscle and metabolic diseases."

The gene codes for a protein called Interleukin-15 receptor-alpha (IL-15R-alpha), which acts alone or in conjunction with the IL-15 protein. IL-15R-alpha is important in the immune response, but it also has other functions. IL-15 and IL-15R-alpha have been implicated in muscle physiology, but the exact role in muscle function has not been defined.

"We found a previously unrecognized role for IL-15R-alpha in defining muscle function, and manipulation of this gene has the potential to improve muscle performance in disease states including metabolic disorders, obesity, and aging." says lead author Emidio E. Pistilli, PhD, who was a postdoctoral researcher at Penn and is now an assistant professor in the Division of Exercise Physiology at the West Virginia School of Medicine.

Slow Vs. Fast

Slow muscles are used for endurance and fast muscles are used for speed. The champion fast muscles are the muscles moving the eye, but they are also fatigue-resistant, the only muscles like this.

In the IL-15R-alpha knockout mouse used in this study, fast muscles behave like slow muscles. These mice ran 6.3 times greater distances and had greater ambulatory activity than controls. Their fast muscles displayed fatigue-resistance and slower contractions compared to fast muscles in control mice.

They also showed that the loss of IL-15R-alpha induces a shift in how energy is burned in fast muscles, substantially increasing fatigue resistance and exercise capacity.

The molecular signature of the muscles in the knockout mice included a greater number of active transcription factors, which indicates more muscle fibers with more mitochondria, and the machinery to better process calcium since this chemical drives muscle contraction. Mitochondria are the energy storehouses of the cell.

Morphologically, the fast muscles had a greater number of muscle fibers, smaller fiber areas, and a greater number of nuclei per fiber. The alterations of physiological properties and increased resistance to fatigue in the fast muscles are consistent with a shift towards a slower, more oxidative muscle type in the knockout mice.

The study also found significant associations between the gene and elite endurance athletes and hence supports the possibility that these athletes had a genetic predisposition or advantage.

From these two lines of evidence, the researchers concluded that IL-15R-alpha plays a role in defining the function of fast skeletal muscles.

Importantly, the study demonstrates that muscles can be reprogrammed to perform much better at endurance sports and hence IL-15R-alpha manipulation is of great importance from an athletic doping standpoint as currently it is neither tested for nor do methods exist to detect its misuse by athletes. The investigators are working toward this.

This research identifies a "druggable target" that allows possible reprogramming of muscle function by increasing genes, proteins and pathways typically expressed in slow or fatigue-resistant muscle, similar to adaptations seen after endurance exercise. It is widely accepted that these types of adaptations would be beneficial or protect against obesity, diabetes and aging and may help ameliorate pathology in myopathies such as muscular dystrophy. Hence, say the researchers, the identification of this pathway should facilitate better understanding of these diseases and aid in the development of rational therapies drugs for these disorders.

From a translational research point of view the team will test the role IL-15R-alpha plays in obesity, diabetes, aging, and muscle diseases, as well as develop methods to harness the therapeutic potential of it for patients.

The research was funded by the National Institute of Arthritis and Musculoskelatal and Skin Diseases; the National Eye Institute; the National Institute on Aging; and the VA Puget Sound Health Care System.

In addition to Khurana and Pistilli, co-authors were from the Institute for Neuroscience and Muscle Research, The Children's Hospital at Westmead, Sydney, New South Wales, Australia; the Australian Institute of Sport, Canberra, Australia; Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle; Division of Gerontology and Geriatric Medicine, Department of Medicine, University of Washington, Seattle; and the Division of Endocrinology, Diabetes, and Metabolism, Penn.

Massive Enzyme Footballs Control Sugar Metabolism

ScienceDaily (July 18, 2011) — Neutron scattering has revealed how massive enzyme complexes inside cells might determine whether sugar is burnt for energy or stored as fat. The findings promise to improve understanding of diabetes and a range of metabolic diseases. Scientists using neutron scattering at the Institut Laue-Langevin (ILL) have shown how pyruvate dehydrogenase complexes (PDCs) could control the rate of sugar metabolism by actively changing their own composition.

Images 1-4 show the different arrangements of enzymes E2 (structural - green) and E3BP (metabolising - red) within the PDC structure. The PDC molecules can exist in any of these forms within the cell depending on the rate of metabolism required. Image 1, with the highest proportion of the E3BP enzyme, would promote the highest rate of metabolism and could play a key role in bringing blood sugar levels down to normal rates following a meal.

The research is published in theBiochemical Journal.

PDCs are found within all cell types from bacteria to mammals and are known to help regulate the level of sugar in the blood to meet the continuously changing metabolic demands of the body. The complexes have a unique, football-shaped central scaffold, forming a hollow ball with 12 open pentagonal faces. They are composed of 60 subunits made up of two related proteins. The first is a scaffolding enzyme that acts as the structural heart of the complex, whilst the second has binding role with a third enzyme (attached to the outside of the central football) to generate rapid metabolism. Whilst the structure of the complex is well understood, the exact composition was undetermined. Most previous purification studies had suggested a ratio of 48 scaffold enzyme units to 12 binding units.

The team at the ILL synthesised human PDC in bacteria and identified the location of the two enzymes through low angle neutron scattering. This revealed a new, unexpected ratio of 40:20 in favour of the scaffold enzyme. However experiments on PDCs from cow heart cells confirmed the expected figure of 48:12. With further mathematical modelling the team have shown that their synthesised PDC could vary its composition, with any ratio from 60:0 to 40:20 possible. This flexibility may explain why the PDC complex is so quick to react to changes in blood sugar levels, says Dr Phil Callow, an instrument scientist at ILL. "Our models show how the structural organisation of PDC could be fine-tuned through changes in its overall composition to promote maximal metabolic efficiency." These findings could provide vital information for future treatments of diseases caused by unusual blood sugar levels such as diabetes and those directly related to mutations in the PDC such as Biliary cirrhosis, a progressive form of liver inflammation.

Professor Gordon Lindsay, University of Glasgow: "Using neutron scattering at ILL, we have shown the potential of these football structures to vary their composition to allow the most efficient utilisation of sugars by the body and enables precise control of sugar breakdown. The next step is to see if this occurs naturally across different tissues of the body and in different living organisms."

Andrew Harrison, ILL's Director for Science: "ILL has a proud history carrying out fundamental research that underpins medical breakthroughs and potential new treatments. The PDC complexes studied by Dr Callow and his colleagues are too large for most other techniques. By using neutrons and the wide range of instruments available at ILL, they have given the medical world a new perspective on diseases that affect millions of people across the world."

Monitoring Cellular Interactions at Nano-Scale in More Detail Than Ever Before

ScienceDaily (July 18, 2011) — Using nanotechnology to engineer sensors onto the surface of cells, researchers at Brigham and Women's Hospital (BWH) have developed a platform technology for monitoring single-cell interactions in real-time. This innovation addresses needs in both science and medicine by providing the ability to further understand complex cell biology, track transplanted cells, and develop effective therapeutics. These findings are published in the July 17 issue of Nature Nanotechnology.

Using nanotechnology to engineer sensors onto the surface of cells, researchers at Brigham and Women's Hospital (BWH) have developed a platform technology for monitoring single-cell interactions in real-time. Sensing the niche - Cells carrying sensors monitor the cellular nano-environment in real-time.

"We can now monitor how individual cells talk to one another in real-time with unprecedented spatial and temporal resolution," says Jeffrey Karp, senior study author, and co-director of the Center for Regenerative Therapeutics (ReGen Rx) at BWH. "This allows us to understand signaling between cells and interactions with drugs in great detail that should have broad implications for basic science and drug discovery",.

The cell-signaling sensors researchers currently use are limited to measuring the activity in the bulk environment that a group of cells are in. In this study, researchers used nanotechnology to anchor a sensor to the membrane of individual cells, allowing them to monitor soluble signals within the cellular nanoenvironment. Given that cells are directly labeled with sensors permits application to transplanted cells or tissues.

"Once this is refined as a tool, and used to study drug interactions with cells on a regular basis, there is potential that it may be used for personalized medicine in the future," said Weian Zhao, lead author of the study, also of the Center for Regenerative Therapeutics (ReGen Rx) at BWH. Karp adds, "We may one day be able to test a drug's influence on cell-cell interactions before deciding on the appropriate therapeutic for each person."

The researchers are also especially excited by preliminary data that demonstrates the potential to use this engineering approach to track and monitor the environment surrounding transplanted cells, in real time, which was never before possible. This would be useful for developing a deeper understanding of signaling events that define a site of inflammation for example or the stem cell niche, which may have implications for treatment of many diseases.

"This new study takes a significant step toward the goal to eavesdrop in real-time and at high spatial resolution on communications between cells in their native environment, with far-reaching implications for the development of new drugs and diagnostics" said Ulrich von Andrian, the Mallinckrodt Professor of Immunopathology at Harvard Medical School who was not involved in this study.

This work was funded by the National Institutes of Health and the American Heart Association.

Scientists Grow Brain Cells from Skin: Cancer Cells and Stem Cells Share Same Origin, Research Shows

ScienceDaily (July 18, 2011) — Oncogenes are generally thought to be genes that, when mutated, change healthy cells into cancerous tumor cells. Scientists at the Keck School of Medicine of the University of Southern California (USC) have proven that those genes also can change normal cells into stem-like cells, paving the way to a safer and more practical approach to treating diseases like multiple sclerosis and cancer with stem cell therapy.

"The reality may be more complicated than people think," said Jiang F. Zhong, Ph.D., assistant professor of pathology at the Keck School. "What is a stem cell gene? What is a cancer gene? It may be the same thing."

Zhong and colleagues at the Children's Hospital of Orange County (CHOC) in California and Good Samaritan Hospital Medical Center in New York successfully converted human skin cells into brain cells by suppressing the expression of p53, a protein encoded by a widely studied oncogene. This suggests that p53 mutation helps determine cell fate -- good or bad -- rather than only the outcome of cancer.

The study is slated to appear in the online edition of Proceedings of the National Academy of Sciences, a peer-reviewed scientific journal, the week of July 18, 2011.

"When you turn off p53, people think the cell becomes cancerous because we tend to focus on the bad thing," Zhong said. "Actually, the cell becomes more plastic and could do good things, too. Let's say the cell is like a person who loses his job (the restriction of p53). He could become a criminal or he could find another job and have a positive effect on society. What pushes him one way or the other, we don't know because the environment is very complicated."

Stem cells can divide and differentiate into different types of cells in the body. In humans, embryonic stem cells differentiate into three families, or germ layers, of cells. The reasons why and how certain stem cells differentiate into particular layers are not clearly understood. However, from those layers, tissues and organs develop. The endoderm, for example, leads to formation of the stomach, colon and lungs, while the mesoderm forms blood, bone and heart tissue. In its study, Zhong's team examined human skin cells, which are related to brain and neural cells from the ectoderm.

When p53 was suppressed, the skin cells developed into cells that looked exactly like human embryonic stem cells. But, unlike other human-made stem cells that are "pluripotent" and can become any other cells in the body, these cells differentiated only into cells from the same germ layer, ectoderm.

"IPSCs [induced pluripotent stem cells] can turn into anything, so they are hard to control," Zhong said. "Our cells are staying within the ectoderm lineage."

Zhong said he expects that suppressing other oncogenes in other families of cells would have the same effect, which could have critical significance for stem cell therapy. Future research should focus on determining which genes to manipulate, Zhong said.

This study was supported by the CHOC Children's Foundation, CHOC Neuroscience Institute, Austin Ford Tribute Fund, W. M. Keck Foundation, National Institutes of Health and National Science Foundation.