Apneia causa problemas de pressão alta, mostra estudo

Pela primeira vez, um estudo mostra que pessoas com apneia tem alterações na função dos vasos sanguíneos da mesma forma que aqueles que têm pressão alta.

O problema de reatividade dos vasos, que faz com que eles se fechem mais, aumenta o risco de hipertensão e de problemas cardíacos. A conclusão é de uma pesquisa da Universidade de Birmingham, no Reino Unido, publicada no periódico "Hypertension", da Associação Americana do Coração.

A apneia é o fechamento das vias aéreas superiores que leva a pausas na respiração durante o sono. Estima-se que um terço da população da cidade de São Paulo tenha o problema.

Segundo o vice-presidente da Sociedade Brasileira de Hipertensão, Decio Mion, já se sabia da relação entre hipertensão e apneia ""é comum que hipertensos tenham o problema relacionado ao sono, e vice-versa. Mas essa é a primeira vez que um estudo mostra que pessoas com apneia têm as mesmas alterações da reatividade dos vasos presentes em quem é hipertenso.

SAUDÁVEIS

O estudo procurou por mudanças na função dos vasos sanguíneos em 108 pessoas saudáveis. Aqueles com apneia severa ou moderada e sem pressão alta foram comparados com pacientes hipertensos, mas sem apneia, e com pessoas sem nenhum dos dois problemas. Os pesquisadores analisaram a função dos vasos sanguíneos com exames como o ecocardiograma de contraste (para o coração) e com a injeção de nitroprussiato de sódio, um vasodilatador.

O resultado é que as pessoas com apneia e as que tinham hipertensão (mas sem apneia) mostraram bombeamento de sangue do coração anormal e reatividade alterada da artéria braquial (que passa pelo braço). Ou seja, sob o mesmo estímulo, os vasos dos participantes com apneia e hipertensão reagem diferentemente dos vasos das pessoas saudáveis, fechando-se mais.

Tanto os pacientes hipertensos como os que tinham apneia do sono tiveram melhora na função do miocárdio e da artéria braquial depois de 26 semanas de tratamento com o CPAP (máscara de ar usada durante o sono para tratar a apneia). Mion acredita que os achados do estudo podem ter consequências na terapia para a apneia do sono, mas ainda é cedo para dizer se pacientes com apneia terão de usar os mesmos remédios de pacientes hipertensos.

O nefrologista diz que ainda não dá para saber como essas alterações dos pacientes com apneia se comportarão no futuro, mas é possível que, com o passar do tempo, os vasos fiquem mais endurecidos, aumentando o risco de problemas cardíacos. "Às vezes os pacientes com apneia negligenciam o problema, mas é importante que saibam que eles podem ter os mesmos problemas da pressão alta", afirma ele.

Scientists Solve Mystery of Nerve Disease Genes; Findings May Lead to New Therapies for Charcot-Marie-Tooth Disease and Other Conditions

ScienceDaily (July 12, 2011) — For several years, scientists have been pondering a question about a genetic disease called Charcot-Marie-Tooth (CMT) disease type 2D: how can different types of mutations, spread out across a gene, produce the same condition?

The new Scripps Research study found a common feature of genetic mutations causing Charcot-Marie-Tooth disease (CMT) type 2D. This image shows hotspots on the enzyme GlyRS (gold) opened up by CMT-causing mutations. The other subunit of the GlyRS dimer is shown in ribbon (cyan).

Now, a team of scientists at The Scripps Research Institute may have found the answer. By studying a gene called GARS, which is mutated in individuals with the disease, the team found that all the mutations have one thing in common: they cause the tightly coiled three-dimensional shape of the resulting protein to shift open.

The more open configuration creates a space for other proteins to bind, causing havoc. "That is the basis for potential disease-causing interactions," said Scripps Research Associate Professor Xiang-Lei Yang, senior author of the study, "but also for potential therapeutic intervention." It is possible that scientists could develop drugs to fit into the open area, blocking its access to other proteins.

The findings, appearing in the online issue of Proceedings of the National Academy of Sciences (PNAS) help scientists explain how CMT type 2D occurs. The results may also have implications for other diseases, such as amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.

A Puzzling Disease

Named after the three physicians who first reported the disease in 1886, CMT is the most common inherited neurological disorder, estimated to affect one in 2,500 people. Although it is not fatal, CMT causes progressive weakness and wasting of muscles in the feet, legs, hands, and forearms by striking down the nerves that reach down into these muscles.

There are five different forms of CMT, and each is broken down in various subtypes depending on the gene responsible. CMT type 2D, which is caused by mutations in the GARS gene, is inherited in an autosomal dominant manner -- this means that a person needs to inherit only one faulty copy of the GARS gene from one parent to get the disease.

The GARS gene holds the instructions for producing an enzyme called glycyl-tRNA synthase (GlyRS), which is vital to the process by which amino acids, the building blocks of proteins, are attached to one another during protein synthesis. So far, scientists have found 11 different kinds of mutations in the GARS gene that cause CMT type 2D. Some of the mutations affect the protein-building function of the GlyRS enzyme, but others don't, suggesting that a change in enzyme activity is not what causes CMT.

Thus, scientists have been trying to find a common feature shared by all GlyRS mutants that might explain the disease mechanism.

Structures in Solution

To find this common feature, Yang and colleagues turned to the three-dimensional structure of GlyRS. In 2007, they published the X-ray crystal structure of the wild-type protein and one of the mutants, but the structures were not all that different from each other (PNAS 104:11239-44, 2007).

"When we compared the wild type with the mutant, we did not find dramatic conformational change," said Weiwei He, a Scripps Research graduate student who joined Yang's lab and took on the project around the time of the 2007 paper's publication. "We thought maybe it was because of the crystal packing."

X-ray crystallography requires obtaining high amounts of a protein and packing the protein molecules into crystals that are bombarded with X-rays to determine the positions of all the atoms. This preparation, Yang and He reasoned, may mask any subtle conformation changes in a protein. "That is why we thought to look at the structure in solution, under more physiological conditions," said He.

In collaboration with Hui-Min Zhang, a postdoctoral fellow in the laboratory of Alan Marshall at the National High Magnetic Field Laboratory at Florida State University, Yang and He used a method to obtain the structures of five different GlyRS mutants and the wild-type protein in solution. This method, called hydrogen-deuterium exchange, gives information about which parts of a protein are in touch with a solution -- in other words, which parts lie on the outside rather than being buried deep inside its three-dimensional shape. In collaboration with Min Guo, assistant professor at Scripps Florida, a second method, called small angle X-ray scattering, was used to measure changes in the overall shape of the protein structure in solution.

Together, the results revealed that every GARS mutation studied causes a structural opening in the resulting mutant protein. By superimposing the information obtained from the structures in solution to the high-resolution X-ray crystal structure of the wild-type GlyRS protein, Yang, He, Zhang and colleagues were able to determine that the structural opening maps to a common region of the GlyRS protein in all the mutants.

By becoming more open to potential new partners, the GlyRS mutants may gain a new function that is toxic to nerve cells. That would explain why CMT type 2D is inherited in a dominant fashion.

Exciting Implications

The team is now looking for proteins that might bind to this region and already have leads on several candidates. As exciting as this work is, says He, "this paper is just the start of the story; we have more story coming, and it's getting more and more exciting."

This disease mechanism may also apply to other conditions. "Some proteins may be relatively unstable and can be easily triggered into another conformation by different types of mutations," explained Yang. "This example deals with the GlyRS protein, but the general idea can be applied to many other mutation-induced human diseases."

One example may be ALS. Some inherited forms of ALS are caused in a gene that encodes the enzyme copper-zinc superoxide dismutase (commonly called SOD1). To date, more than 100 different mutations in the SOD1 gene have been linked to inherited ALS.

In addition to He, Zhang, Guo, Marshall, and Yang, Yeeting E. Chong of Scripps Research is a co-author of the paper, "Dispersed disease-causing neomorphic mutations on a single protein promote the same localized conformational opening."

Nervous System Stem Cells Can Replace Themselves, Give Rise to Variety of Cell Types, Even Amplify

ScienceDaily (July 12, 2011) — A Johns Hopkins team has discovered in young adult mice that a lone brain stem cell is capable not only of replacing itself and giving rise to specialized neurons and glia -- important types of brain cells -- but also of taking a wholly unexpected path: generating two new brain stem cells.

A green fluorescent protein-labeled neural stem cell clone contains the mother stem cell with neuronal and astroglial progeny within the mouse brain. 

A report on their study appears June 24 in Cell.

Although it was known that the brain has the capacity to generate both neurons, which send and receive signals, and the glial cells that surround them, it was unclear whether these various cell types came from a single source. In addition to demonstrating that a single radial glia-like (RGL) brain cell is able to generate two very different functional cell types, the Hopkins researchers, by following the fates of single cells over time, found that a single brain stem cell can even produce two stem cells like itself.

"Now we know they don't just maintain their numbers, or go down in number, but that stem cells can amplify," says Hongjun Song, Ph.D., professor of neurology and neuroscience and director of the Stem Cell Program in the Institute for Cell Engineering, the Johns Hopkins University School of Medicine. "If we can somehow cash in on this newly discovered property of stem cells in the brain, and find ways to intervene so they divide more, then we might actually increase their numbers instead of losing them over time, which is what normally happens, perhaps due to aging or diseases."

The researchers' findings hinged on a decision to single out and follow lone, radial glia-like cells, instead of labeling and monitoring entire stem cell populations in the mouse brain. They took this approach because they suspected radial glia-like cells were essentially stem cells, having been shown in previous studies to give rise to neurons.

Using mice genetically modified with special genes that color-code cells for easy labeling and tracking, the Hopkins team injected a very small amount of a chemical into about 50 mouse brains to induce extremely limited cell labeling.

"It's a simple idea that forced us to confront a lot of complex technical issues," Song says. "With so many millions of cells in the relatively large mouse brain, labeling a single stem cell and then chasing its family history was like finding a needle in a haystack."

The scientists developed computer programs and devised a new imaging technique that allowed them to examine stained slices of the mouse brain and, ultimately, follow single, randomly chosen radial glia-like stem cells over time. The method allowed them to track down all the new cells derived from a single original stem cell.

"We reconstituted single stem cells' family trees to look at the progeny they gave rise to," says Guo-li Ming, associate professor of neurology and neuroscience and a member of the Neuroregeneration Program in the Institute for Cell Engineering. "We discovered that single cells in an intact animal nervous system absolutely do exhibit stem-cell properties; they are capable of both replicating themselves and producing different types of differentiated neural progeny."

The team followed the fates of all the marked radial glia-like stem cells for at least a month or two, and examined some a full year later to discover that even over the long term, the "mother" cell was still generating itself as well as different kinds of progeny.

In addition, the researchers investigated how these RGLs were activated on a molecular level, focusing, in particular, on the regulatory role of an autism-associated gene called PTEN. Conventional wisdom was that deleting this gene led to an increase in stem-cell activation. However, the scientists demonstrated that was a transient effect in the mouse brains, and that, ultimately, PTEN deletion leads to stem-cell depletion.

Support for this research came from the National Institutes of Health, the Brain and Behavior Research Foundation, and the Maryland Stem Cell Research Foundation.

Authors of the paper, in addition to Hongjun Song and Guo-li Ming, are Michael A. Bonaguidi, Michael A. Wheeler, Jason S. Shapiro and Gerald. J. Sun, all of Johns Hopkins.

Malaria Parasites Use Camouflage to Trick Immune Defences of Pregnant Women

ScienceDaily (July 12, 2011) — Researchers from Rigshospitalet -- Copenhagen University Hospital -- and the University of Copenhagen have discovered why malaria parasites are able to hide from the immune defences of expectant mothers, allowing the parasite to attack the placenta. The discovery is an important part of the efforts researchers are making to understand this frequently fatal disease and to develop a vaccine.

Staff member at CMP. Photo: Lars Hviid"We have found one likely explanation for the length of time it takes for the expectant mother's immune defences to discover the infection in the placenta," says Lea Barfod, MSc, who is working with Professor Lars Hviid at the Centre for Medical Parasitology, University of Copenhagen.

"The parasites are able to assume a camouflage that prevents their recognition by the immune system antibodies which would otherwise combat them. So although the immune system has all the weapons it needs to fight the infection of the placenta, these weapons are ineffectual simply because the enemy is hard to spot. Ironically the camouflage also consists of antibodies, but of a type that does not help to fight infection."

The malaria parasite at war with the immune system

One human being in twelve is infected with malaria. That means 500 million people are carrying the tiny parasite, and it kills a million of them a year. The disease costs so many lives because the parasite constantly outmanoeuvres the human immune system. It starts by hiding in the red blood cells. The immune system does not bother with these as the spleen usually filters defective blood cells.

To avoid this filter, the parasite ejects a protein hook which attaches to the inner wall of the blood vessel, and even if the immune system antibodies destroy one such hook, the parasite has more than sixty in its arsenal. One of them has evolved specially to attach to the placenta. While the war is being waged the parasite propagates and infects more and more red blood cells, which are normally used for transporting nutrients and oxygen around the body.

Fighting from house to house

"In an advanced version of hide-and-seek the parasites keep looking for new ways of preventing the antibodies from recognising them. It is a kind of urban guerrilla war in which the fighting is conducted from house to house," says Lars Hviid.

"One example is the ability of the parasites to hide in the placenta. The first time an African woman conceives her placenta provides a new opportunity for the parasite to hide: a new house, so to speak, and in a way that prevents discovery by the immune system. It takes time for the immune defences to react to the new threat, and meanwhile the camouflaged parasite harms the woman and her unborn child."

The researchers are now going to study whether the malaria parasite also uses its camouflage at other stages of an infection.

"Perhaps it is not only the parasites in the placenta that are capable of hiding like this," Lars Hviid says.

"It takes the body a surprisingly long time to develop protection from Malaria, and perhaps the trick we have just discovered is part of the explanation. It is important for us to find out if this is the case in order to help us to understand malaria in general, but also to help us in our efforts to develop a vaccination. We have plenty of work to be going on with," Lars Hviid concludes.

Lea Barfod and Lars Hviid's discovery has just been published in the Proceedings of the National Academy of Sciences.

Biomarker for Autism Discovered

ScienceDaily (July 12, 2011) — Siblings of people with autism show a similar pattern of brain activity to that seen in people with autism when looking at emotional facial expressions. Researchers at the University of Cambridge identified the reduced activity in a part of the brain associated with empathy and argue it may be a 'biomarker' for a familial risk of autism.

Researchers have identified the reduced activity in a part of the brain associated with empathy and argue it may be a 'biomarker' for a familial risk of autism. 

Dr Michael Spencer, who led the study from the University's Autism Research Centre, said: "The findings provide a springboard to investigate what specific genes are associated with this biomarker. The brain's response to facial emotion could be a fundamental building block in causing autism and its associated difficulties."

The Medical Research Council funded study is published on the 12th of July, in the journalTranslational Psychiatry.

Previous research has found that people with autism often struggle to read people's emotions and that their brains process emotional facial expressions differently to people without autism. However, this is the first time scientists have found siblings of individuals with autism have a similar reduction in brain activity when viewing others' emotions.

In one of the largest functional MRI (fMRI) studies of autism ever conducted, the researchers studied 40 families who had both a teenager with autism and a sibling without autism. Additionally, they recruited 40 teenagers with no family history of autism. The 120 participants were given fMRI scans while viewing a series of photographs of faces which were either neutral or expressing an emotion such as happiness. By comparing the brain's activity when viewing a happy verses a neutral face, the scientists were able to observe the areas within the brain that respond to this emotion.

Despite the fact that the siblings of those with autism did not have a diagnosis of autism or Asperger syndrome, they had decreased activity in various areas of the brain (including those associated with empathy, understanding others' emotions and processing information from faces) compared to those with no family history of autism. The scans of those with autism revealed that the same areas of the brain as their siblings were also underactive, but to a greater degree. (These brain regions included the temporal poles, the superior temporal sulcus, the superior frontal gyrus, the dorsomedial prefrontal cortex and the fusiform face area.)

Because the siblings without autism and the controls differed only in terms of the siblings having a family history of autism, the brain activity differences can be attributed to the same genes that give the sibling their genetic risk for autism.

Explaining why only one of the siblings might develop autism when both have the same biomarker, Dr Spencer said: "It is likely that in the sibling who develops autism additional as yet unknown steps -- such as further genetic, brain structure or function differences -- take place to cause autism."

It is known that in a family where one child already has autism, the chances of a subsequent child developing autism are at least 20 times higher than in the general population. The reason for the enhanced risk, and the reason why two siblings can be so differently affected, are key unresolved questions in the field of autism research, and Dr Spencer's group's findings begin to shed light on these fundamental questions.

Professor Chris Kennard, chairman of the Medical Research Council funding board for the research, said: "This is the first time that a brain response to different human facial emotions has been shown to have similarities in people with autism and their unaffected brothers and sisters. Innovative research like this improves our fundamental understanding of how autism is passed through generations affecting some and not others. This is an important contribution to the Medical Research Council's strategy to use sophisticated techniques to uncover underpinning brain processes, to understand predispositions for disease, and to target treatments to the subtypes of complex disorders such as autism."