Primeira vacina contra esquistossomose terá tecnologia 100% nacional

Para a pesquisadora da Fiocruz e médica Miriam Tendler, a vacina será um investimento social de impacto global 

O Brasil será o primeiro país a desenvolver uma vacina contra a esquistossomose, doença que acomete cerca de 200 milhões de pessoas no mundo, segundo dados da Organização Mundial de Saúde (OMS). A substância, desenvolvida com tecnologia 100% nacional, foi descoberta no início da década de 1990 pela médica e pesquisadora titular da Fundação Oswaldo Cruz (Fiocruz) Miriam Tendler. Desde então, já apresentou resultados positivos em testes com animais – 70% de imunização em camundongos – e, ainda em 2011, será testada em humanos. Além de estar se mostrando eficaz para promover a imunização contra casos de esquistossomose, a vacina também poderá evitar casos de outras doenças causadas por helmintos, como a fasciolose, doença do gado de corte que tem um parasita causador semelhante ao da esquistossomose. O estudo contou com recursos da FAPERJ, por meio do edital Apoio ao Estudo de Doenças Negligenciadas e Reemergentes, além de recursos da Financiadora de Estudos e Projetos (Finep). 

Como em qualquer outra vacina, a técnica consistiu em utilizar um antígeno – substância que estimula a produção de anticorpos – para fortalecer o sistema imunológico do potencial hospedeiro contra o ataque do parasita. No caso, foi a proteína SM-14, obtida pelo grupo de pesquisadores da Fiocruz e colaboradores coordenado por Miriam Tendler, a partir do próprio Schistosoma mansoni, o parasita causador da esquistossomose. Proteína essencial para a sobrevivência do parasita, a Sm-14 é propriedade intelectual da Fiocruz e faz parte de um grupo conhecido como fatty acid-binding proteins (proteínas ligadoras de ácidos graxos). “No início dos anos 1990, a SM-14 foi eleita pela OMS como um dos seis antígenos prioritários para o desenvolvimento da primeira vacina contra a esquistossomose, ao lado de quatro propostas americanas, que não foram para frente, e de uma francesa, que não tem a mesma abrangência que a nossa, pois é restrita à esquistossomose”, conta.

A proteína SM-14: antígeno da vacina pode imunizar contra esquistossomose e fasciolose 

De acordo com a coordenadora do projeto, a versatilidade da utilização do antígeno é o grande diferencial da proposta brasileira. A proteína SM-14 pode servir como base para a produção de vacinas que atuem contra diversas doenças causadas por helmintos. “Estamos na fase final do desenvolvimento de uma vacina anti-helmíntica bivalente, ou seja, capaz de prevenir duas doenças, a esquistossomose, doença humana de grande importância social, e a fasciolose, que acomete rebanhos em todo o mundo”, explica Miriam Tendler. O próximo passo, no entanto, é ampliar ainda mais a abrangência da vacina para torná-la multivalente. “Já temos em vista adaptá-la para que também possa prevenir outras doenças causadas por helmintos, como a hemoncose, que afeta bovinos e ovinos”, completa. 

A possibilidade de abrir o leque, tornando a vacina um produto da indústria veterinária em um futuro próximo, ajudou a impulsionar, indiretamente, o desenvolvimento da substância também para humanos. Uma parceria que envolve o licenciamento da exploração de patentes foi fechada entre a Fiocruz e a indústria brasileira Ourofino Agronegócio. “Estamos às vésperas da realização de testes de segurança da vacina em humanos, que deve durar cinco meses. Depois dessa etapa, será importante que a vacina transponha os limites da academia e seja produzida em escala industrial, para entrar no mercado”, avalia. “Será a primeira vacina desenvolvida com tecnologia totalmente brasileira. Isso dará ao país autonomia para prevenir a esquistossomose, adotando a prevenção como medida prioritária, e não apenas o tratamento. Será uma vitória nacional e um investimento social de impacto global”, conclui Miriam Tendler.

Sobre a esquistossomose e a fasciolose 

Conhecida popularmente como “barriga d’água”, a esquistossomose é considerada uma doença negligenciada, por ser típica de países tropicais em desenvolvimento e não receber atenção adequada da indústria farmacêutica para a produção de ferramentas para a sua erradicação. Ela é transmitida através do contato direto com as larvas do parasita em águas não tratadas. Embora o homem seja seu hospedeiro definitivo, o parasita necessita de caramujos de água doce como hospedeiros intermediários. O planorbídeo, caramujo hospedeiro do Schistossoma mansoni, verme que causa a esquistossomose, habita barragens, rios, lagos e terras irrigadas de qualquer parte do país.

A esquistossomose compromete a saúde em geral e a capacidade de aprendizado, além de provocar diarreia, dores de cabeça, vômitos e sangramento do sistema digestivo. No Brasil, os focos da doença, antes concentrados principalmente nas regiões Nordeste e Centro-Oeste, agora estão em expansão também para outros estados. Segundo a OMS, 747 milhões de pessoas vivem sob o risco da infecção causada pelo parasita Schistosoma mansoni em 56 países das Américas, da África e Ásia. Já a fasciolose hepática é uma das mais importantes doenças que atingem os ruminantes, gerando constantes prejuízos aos produtores rurais de todo o mundo, devido à mortalidade do gado e à redução na produção de carne e leite.

Ômega-3 em excesso eleva risco de câncer de próstata agressivo

Coração e próstata

Um estudo que procurava examinar a associação entre gorduras na dieta e o risco de câncer de próstata concluiu que o que é bom para o coração pode não ser bom para a próstata.

Homens com as maiores porcentagens de ácido docosahexanoico, ou DHA, um ácido graxo ômega-3 redutor de inflamações, comumente encontrado em peixes, têm duas vezes e meia mais risco de desenvolverem câncer de próstata agressivo de alto grau, em comparação com homens com níveis mais baixos de DHA.

Não foi encontrada conexão quando o foco é o câncer de próstata de baixo risco, menos agressivo.

A conclusão é dos pesquisadores do Centro de Estudos do Câncer Fred Hutchinson, nos Estados Unidos, depois de analisarem dados de um estudo nacional envolvendo mais de 3.400 homens.

De cabeça para baixo

Inversamente, homens com maiores índices de ácidos graxos trans no sangue - que estão ligados à inflamação e doenças do coração e abundante em alimentos industrializados que contêm óleos vegetais parcialmente hidrogenados - apresentaram uma redução de 50 por cento no risco de contrair câncer da próstata agressivo.

Por outro lado, nenhuma destas gorduras foi associada com um risco de câncer de próstata de baixo grau, menos severo.

Os pesquisadores também concluíram que os ácidos graxos ômega-6, que são encontrados na maioria dos óleos vegetais e estão ligados à inflamação e às doenças cardíacas, não têm conexão com o risco de câncer de próstata.

"Ficamos surpresos ao ver esses resultados e gastamos muito tempo para garantir que as análises estavam corretas," disse o Dr. Theodore Brasky, coordenador da pesquisa.

"Nossos resultados colocam de cabeça para baixo o que sabemos - ou melhor, o que nós pensamos que sabemos - sobre a dieta, a inflamação e o desenvolvimento do câncer de próstata, e mostra a complexidade de se estudar a associação entre a nutrição e o risco de várias doenças crônicas," diz ele.

Ácidos graxos e câncer de próstata

Os pesquisadores realizaram o estudo porque sabe-se que a inflamação crônica aumenta o risco de vários cânceres, e os ácidos graxos ômega-3, encontrados principalmente no óleo de peixe, têm efeitos anti-inflamatórios.

Em contrapartida, outras gorduras, como o ômega-6, dos óleos vegetais, e as gorduras trans encontrados em fast foods, podem promover a inflamação.

"Queríamos testar a hipótese de que as concentrações dessas gorduras no sangue estariam associadas com o risco de câncer de próstata," disse Brasky. "Nós pensávamos que os ácidos graxos ômega-3 poderiam reduzir e o ômega-6 e os ácidos gordos trans aumentarem o risco de câncer de próstata."

Mas não foi isto o que os dados mostraram - embora um estudo com 3.400 casos seja considerado pequeno para fundamentar qualquer recomendação a respeito, ou mesmo ser considerado conclusivo.

Mais pesquisas

Os mecanismos por trás do impacto do ômega-3 no risco do câncer de próstata de alto grau são desconhecidos.

"Além da inflamação, as gorduras ômega-3 afetam outros processos biológicos. Pode ser que esses mecanismos desempenhem um papel no desenvolvimento de certos cânceres da próstata", disse Brasky. "Esta é certamente uma área que necessita de mais pesquisas."

Cientistas debatem teorias sobre a origem do câncer

Teoria sobre o câncer

Em artigos publicados no exemplar deste mês da revista científica BioEssays, cientistas de renome internacional na área do câncer discutiram suas controvérsias sobre as duas teorias que tentam explicar a origem do câncer.

Os especialistas apresentaram suas defesas e críticas em relação à Teoria da Mutação Somática - a teoria mais aceita hoje na comunidade científica para explicar o câncer - e a ainda debatida Teoria de Campo da Organização dos Tecidos.

Esta é a primeira vez que especialistas se dispõem e têm a oportunidade de discutir abertamente as controvérsias sobre as duas teorias, defendidas por autores de lados opostos do debate.

Mutação Somática versus Organização dos Tecidos

Ana Soto e Carlos Sonnenschein, ambos da Universidade Tufts, nos Estados Unidos, argumentam que a Teoria da Mutação Somática (TMS), que se baseia na acumulação de mutações genéticas nas células, não só não consegue dar uma explicação para os fenômenos observáveis na biologia do câncer, como também é uma teoria essencialmente não testável com as tecnologias atuais.

A Teoria da Organização dos Tecidos (TOT) propõe que o câncer é uma doença clonal, baseada nas células, e assume implicitamente que a imobilidade é o estado padrão das células nos organismos multicelulares.

"A TMS é fortemente apoiada por observações das leucemias, que carregam translocações cromossômicas específicas," defende o Dr. David Vaux, do Instituto de Ciências Moleculares La Trobe, na Austrália, em defesa da TMS.

"Talvez a mais forte validação [da teoria] venha do sucesso do tratamento de certas doenças malignas com drogas que visam diretamente o produto do gene mutante," afirma.

Mudar teorias para alcançar resultados

Obviamente, em uma primeira discussão não poderia haver consenso, e cada pesquisador ressalta os pontos que acredita positivos e negativos em cada teoria.

Também, poucos acreditam, dada a variedade dos cânceres - a rigor, cada câncer pode ser enquadrado como uma doença diferente - que alguma teoria consiga dar conta de todas essas realidades.

O mais provável será o desenvolvimento de teorias para grupos mais parecidos da doença.

Este mesmo processo está ocorrendo no campo do Mal de Alzheimer, onde a falta de resultados encorajadores das pesquisas atuais - o que de resto vem acontecendo com o câncer há décadas - tem ensejado a busca de novas explicações para a doença:

• É hora de uma nova teoria sobre a Doença de Alzheimer

Recentemente, cientistas que estudam a AIDS mudaram a estratégia para procurar por uma vacina contra o HIV, também fundamentados na falta de resultados que as teorias até então utilizadas lhes forneceram.

Debate científico

O artigo agora publicado, questionando as teorias sobre o câncer, representa apenas o começo da discussão: a revista pretende manter um fórum permanente para que os cientistas discutam e troquem informações.

"A ciência avança através da exposição clara dos pontos de vista contrários. Criar um novo fórum para o debate vigoroso, que aborda as bases fundamentais do câncer permitirá que os nossos leitores possam decidir por si mesmos!" afirma David Thomas, editor da BioEssays.

Tomar suplementos alimentares pode ser faca de dois gumes

Comportamento de risco

Você pertence à metade da população que utiliza frequentemente suplementos alimentares com a esperança de que eles lhe façam bem?

Bem, de acordo com um estudo publicado na revista científica Psychological Science, parece haver uma interessante relação assimétrica entre a frequência do uso de suplementos alimentares e o estado de saúde dos indivíduos.

Ou seja, quem toma suplementos alimentares parece acreditar ter ingerido uma licença para assumir comportamentos pouco saudáveis.

"Uma revisão da literatura médica sobre a prevalência do uso de suplementos alimentares, mostra que o uso de suplementos alimentares é crescente, mas não parecia haver uma correlação disto com uma melhora na saúde pública," Wen-Bin Chiou, da Universidade Nacional de Sun Yat-Sen, em Taiwan.

Invulnerabilidade presumida

Foram feitos dois experimentos utilizando um conjunto diversificado de medidas comportamentais para determinar se o uso de suplementos alimentares poderia induzir a comportamentos danosos à saúde.

Os participantes do grupo A ficaram sabendo que iriam tomar um multivitamínico, e os participantes no grupo-controle ouviram que iriam tomar um placebo.

Na verdade, todos os participantes tomaram pílulas de placebo.

Os resultados dos experimentos demonstraram que os participantes que acreditaram que tinham tomado suplementos vitamínicos sentiam-se invulneráveis aos riscos à saúde, o que os levou a se engajar em comportamentos de risco à saúde.

Especificamente, os participantes do grupo que achava que haviam tomado suplementos usar expressaram menos vontade de praticar atividades físicas e mais desejo de se envolver em atividades prazerosas, mas não-saudáveisf.

Maldição da auto-indulgência

O que significa tudo isto?

De acordo com as conclusões do estudo, "as pessoas que usam suplementos alimentares para a proteção da saúde podem pagar um preço oculto, a maldição da auto-indulgência.

Depois de tomar suplementos alimentares no período da manhã, as pessoas devem verificar se sua invulnerabilidade ilusória não foi ativada, restaurando seu comportamento saudável," dizem os pesquisadores.

Simplificando, as pessoas que tomam suplementos alimentares podem ter a falsa ideia de que são invulneráveis a problemas de saúde e podem tomar decisões ruins quando se trata de sua saúde - como a escolha de fast foodem detrimento de uma refeição saudável e orgânica.

Inverting a Standard Experiment Sometimes Produces Different Results

ScienceDaily (Apr. 28, 2011) — Nanoparticles will soon be used as tiny shuttles to deliver genes to cells and drugs to tumors in a more targeted way than was possible in the past. But as the scientists prepare to use the nanoparticles in medicine, concerns have arisen about their potential toxicity. Studies of both the applications of nanoparticles and their toxicity rely on the ability of scientists to quantify the interaction between the nanoparticles and cells, particularly the uptake (ingestion) of nanoparticles by cells.

The experiments in Xia’s lab compared the usual experimental setup (top) to an upside-down setup (bottom). Nanoparticle uptake in the two setups differs only if the ratio of the forces driving sedimentation (S) to those driving diffusion (D) are different. In the situation shown here the upright cells have taken up more nanoparticles than the upside-down ones because there is sedimentation. 

In the standard laboratory tests of the biological activity of nanoparticles, cells are plated on the bottom of a dish and culture medium containing nanoparticles is poured on top of them.

It seems straightforward enough. But recently Washington University in St. Louis scientist Younan Xia started to worry about the in vitro experiments his lab was doing with gold nanoparticles.

What if the cells were upside down, he wondered? Would that make a difference? Would it change their uptake rate?

"People assumed that if they prepared a suspension, the suspension was going to have the same concentration everywhere, including at the surface of the cells," says Xia, PhD, the James M. McKelvey Professor in the Department of Biomedical Engineering.

A battery of experiments in Xia's lab with both the standard and upside-down setups showed that nanoparticles above certain sizes and weights will settle out. So concentrations of the nanoparticles near the cell surfaces are different from those in the bulk solution and cellular uptake rates are higher.

As the scientists conclude in the Nature Nanotechnologyarticle describing the experiments, "Studies on the cellular uptake of nanoparticles that have been conducted with cells in the upright configuration may have given rise to erroneous and misleading data."

Topsies and Turveys

Scientists have felt they could safely assume that the concentration of nanoparticles in the fluid next to the cells, which drives cellular uptake, was the same as the initial concentration of nanoparticles in the medium because the particles are small enough to be easily lofted by Brownian motion, the random motion of the molecules in the liquid.

Gravity, by this accounting, did not override this force for diffusion and the nanoparticles stayed in solution instead of settling out.

"We started to wonder, however, because our nanoparticles are made of gold," Xia says. "Gold is nontoxic but it is also very heavy, so it was conceivable relatively large nanoparticles might settle."

Since it is impossible to measure the exact concentration of gold nanoparticles at the surface of a cell, Xia and coworkers designed a simple experiment to test whether settling changed the concentration there and the cellular uptake.

Xia's lab tested gold nanospheres of three sizes, nanocages of two edge lengths, and nanorods, some with surface coatings that picked up serum proteins in solution and others coated with a chemical that acts as an antifouling agent.

After the cells were incubated in the nanoparticle-bearing medium, the concentration of the nanoparticles in the medium was measured spectroscopically and the number of particles each cell had taken up was calculated from the difference in the concentrations.

In the literature, Xia says, there are reports that the cellular uptake of nanoparticles depends on the nanoparticles' size, shape and surface coating.

His lab's experiments showed that these characteristics are secondary, relevant only insofar as they affect the sedimentation and diffusion velocities of the nanoparticles.

For small, light particles, there was no disparity between the cells in the upright and the upside-down configurations. In the case of larger, heavier particles, however, sedimentation dominated, and the upright cells took in more nanoparticles than the upside-down cells.

"All earlier work may need to be re-evaluated to account for the effects of sedimentation on nanoparticle dosimetry," the authors conclude.

"It's no different from medicines that have to be shaken to suspend a powder in a water. If you don't shake the bottle," Xia says, "you end up under- or overdosing yourself."

Mystery Solved: How Sickle Hemoglobin Protects Against Malaria

ScienceDaily (Apr. 28, 2011) — The latest issue of the journal Cell carries an article that is likely to help solve one of the long-standing mysteries of biomedicine. In a study that challenges currently held views, researchers at the Instituto Gulbenkian de Ciência (IGC), in Portugal, unravel the molecular mechanism whereby sickle cell hemoglobin confers a survival advantage against malaria, the disease caused by Plasmodium infection. These findings, by the research team lead by Miguel P. Soares, open the way to new therapeutic interventions against malaria, a disease that continues to inflict tremendous medical, social and economic burdens to a large proportion of the human population.

These are normal and sickle red blood cells. 

Sickle cell anemia is a blood disease in which red blood cells reveal an abnormal crescent (or sickle) shape when observed under a conventional microscope. It is an inherited disorder -- the first ever to be attributed to a specific genetic modification (mutation), in 1949 by Linus Pauling (two-times Nobel laureate, for Chemistry in 1954, and Peace, in 1962). The cause of sickle cell anemia was attributed unequivocally to a single base substitution in the DNA sequence of the gene encoding the beta chain of hemoglobin, the protein that carries oxygen in red blood cells.

Only those individual that inherit two copies of the sickle mutation (one from their mother and the other from their father) develop sickle cell anemia. If untreated, these individuals have a shorter than normal life expectancy and as such it would be expected that this mutation would be rare in human populations. This is however, far from being the case. Observations made during the mid-20th century and building on Pauling's findings, revealed that the sickle mutation is, in fact, highly, selected in populations from areas of the world were malaria is very frequent, with sometimes 10-40% of the population carrying this mutation.

Individuals carrying just one copy of the sickle mutation (inherited from either the father or mother) were known not to develop sickle cell anemia, leading rather normal lives. However, it was found that these same individuals, said to carry the sickle cell trait, were in fact highly protected against malaria, thus explaining the high prevalence of this mutation in geographical areas where malaria is endemic.

These findings lead to the widespread believe in the medical community that understanding the mechanism whereby sickle cell trait protects against malaria would provide critical insight into developing treatment or a possible cure for this devastating disease, responsible for over a million premature deaths in sub-Saharan Africa. Despite several decades of research, the mechanism underlying this protective effect remained elusive. Until now.

Several studies suggested that, in one way or another, sickle hemoglobin might get in the way of the Plasmodium parasite infecting red blood cells, reducing the number of parasites that actually infect the host and thus conferring some protection against the disease. The IGC team's results challenge this explanation.

In painstakingly detailed work, Ana Ferreira, a post-doctoral researcher in Miguel Soares' laboratory, demonstrated that mice obtained from Prof. Yves Beuzard's laboratory, that had been genetically engineered to produce one copy of sickle hemoglobin similar to sickle cell trait, do not succumb to cerebral malaria, thus reproducing what happens in humans.

When Prof. Ingo Bechman observed the brains of these mice he confirmed that the lesions associated with the development of cerebral malaria where absent, despite the presence of the parasite.

Ana Ferreira went on to show that the protection afforded by sickle hemoglobin in these mice, acts without interfering directly with the parasite's ability to infect the host red blood cells. As Miguel Soares describes it, "sickle hemoglobin makes the host tolerant to the parasite."

Through a series of genetic experiments, Ana Ferreira was able to show that the main player in this protective effect is heme oxygenase-1 (HO-1), an enzyme whose expression is strongly induced by sickle hemoglobin. This enzyme, that produces the gas carbon monoxide, had been previously shown by the laboratory of Miguel Soares to confer protection against cerebral malaria. In the process of dissecting further this mechanism of protection Ana Ferreira demonstrated that when produced in response to sickle hemoglobin the same gas, carbon monoxide, protected the infected host from succumbing to cerebral malaria without interfering with the life cycle of the parasite inside its red blood cells.

Miguel Soares and his team believe that the mechanism they have identified for sickle cell trait may be a general mechanism acting in other red blood cell genetic diseases that are also know to protect against malaria in human populations: "Due to its protective effect against malaria, the sickle mutation may have been naturally selected in sub-Saharan Africa, where malaria is endemic and one of the major causes of death. Similarly, other clinically silent mutations may have been selected throughout evolution, for their ability to provide survival advantage against Plasmodium infection."

This research was carried out the at the IGC in collaboration with the Team of Prof. Yves Beuzard (Université Paris VII et XI, France), an expert in sickle cell anemia, and Prof. Ingo Bechman an expert in neuropathological diseases (Institute of Anatomy, University of Leipzig, Germany). Other IGC researchers involved in this study are Ivo Marguti, Viktória Jeney, Ângelo Chora, Nuno Palha and Sofia Rebelo. This project was funded by Fundação para a Ciência e a Tecnologia (Portugal), GEMI Fund Linde Healthcare and the European Commission's Framework Programme 7.

Indigenous Cases of Leprosy Found in the Southern United States: Human Contamination Through Contact With Armadillos

ScienceDaily (Apr. 28, 2011) — Using advanced DNA analysis and extensive field work, an international research team has confirmed the link between leprosy infection in Americans and direct contact with armadillos. In a joint collaboration between the Global Health Institute at EPFL in Switzerland and Louisiana State University, clear evidence was found that a never-before-seen strain of Mycobacterium leprae has emerged in the Southern United States and that it is transmitted through contact with armadillos carrying the disease. The results will be published on April 28th in the New England Journal of Medicine.

There are only around 150 cases of leprosy in the United States each year. Most of these victims have worked abroad in areas in which leprosy is endemic, making it likely that they may have acquired the disease while outside the US. But, to the alarm of health authorities, a third of all patients infected appear to have contracted the disease locally. The hypothesis that the disease is transmitted though contact with armadillos -- aside from humans, the only other known carriers of the leprosy-causing bacteria -- was confirmed by fine-grained DNA analysis of both armadillo and human samples done at EPFL.

Leprosy bacilli found in armadillos

It has been known since the 1970s that armadillos are potential carriers of the disease, most likely introduced by European immigrants 500 years ago. But the current study shows inter-species contamination and the presence of a unique strain. "There is a very strong association between the geographic location of the presence of this particular strain of M. lepraeand the presence of armadillos in the Southern US," explains Stewart Cole, head of the Global Health Institute in Lausanne and world-leader in the field of genomics of leprosy bacilli. "Our research provides clear DNA evidence that the unique strain found in armadillos is the same as the one in certain humans."

The study included 33 wild armadillos known to have the disease and 50 leprosy patients. The new strain of the bacteria, named 3I, was found in 28 armadillos and in 22 patients who reported no foreign residence. The researchers used genome sequencing to identify the new strain and cross check it with other known strains from Europe, Brazil and Asia, and used genotyping to identify and classify the population infected. It became clear that leprosy patients who never travelled outside the US but lived in areas where infected armadillos are prevalent were infected with the same strain as the armadillos. These findings prompted the researchers to state in the article that "Frequent direct contact with armadillos and cooking and consumption of armadillo meat should be discouraged." The study also suggests that armadillo range expansion should be monitored.

It is not known exactly why armadillos contract and carry leprosy. While their low body temperature (89° F / 32° C) makes them perfect incubators for the bacteria, which grow in temperatures between 86° F and 89° F (30° C to 32° C), there are almost certainly other factors such as immune deficiency that also play a role. Similarly, the bacteria attack the extremities of humans because our core body temperature is too high for a generalized infection, and over 90% of humans who come into direct contact with the disease spontaneously fight it off. "The last thing we want is to induce panic in the population and incite a slaughter of armadillos. The best way to combat further infection is though education and prudence," says Cole.

The stigma of leprosy

José Ramirez, a former migrant worker from Houston who contracted the disease after hunting and eating armadillo meat and took part in the study, has consecrated his life to combating social stigmas. He hopes that the study brings to light the stigma attached to leprosy. "We need to take this opportunity to give leprosy patients a voice and to learn to not use the word 'leper' that has negative connotations around the world, a stigma that should be replaced with an understanding of the disease and its causes." Ramirez, who struggled over five years with the disease before it was properly diagnosed, is now disease-free after receiving antibiotic treatment. Proving what few know to be true -- that leprosy is a bacterial infection that can be cured.

Microsleep: Brain Regions Can Take Short Naps During Wakefulness, Leading to Errors

ScienceDaily (Apr. 28, 2011) — If you've ever lost your keys or stuck the milk in the cupboard and the cereal in the refrigerator, you may have been the victim of a tired brain region that was taking a quick nap.

A photo of rats with objects introduced into their cages to keep them awake. 

Researchers at the University of Wisconsin-Madison have a new explanation. They've found that some nerve cells in a sleep-deprived yet awake brain can briefly go "off line," into a sleep-like state, while the rest of the brain appears awake.

"Even before you feel fatigued, there are signs in the brain that you should stop certain activities that may require alertness," says Dr. Chiara Cirelli, professor of psychiatry at the School of Medicine and Public Health. "Specific groups of neurons may be falling asleep, with negative consequences on performance."

Until now, scientists thought that sleep deprivation generally affected the entire brain. Electroencephalograms (EEGs) show network brain-wave patterns typical of either being asleep or awake.

"We know that when we are sleepy, we make mistakes, our attention wanders and our vigilance goes down," says Cirelli. "We have seen with EEGs that even while we are awake, we can experience shorts periods of 'micro sleep.' "

Periods of micro sleep were thought to be the most likely cause of people falling asleep at the wheel while driving, Cirelli says.

But the new research found that even before that stage, brains are already showing sleep-like activity that impairs them, she says.

As reported in the current issue of Nature, the researchers inserted probes into specific groups of neurons in the brains of freely-behaving rats. After the rats were kept awake for prolonged periods, the probes showed areas of "local sleep" despite the animals' appearance of being awake and active.

"Even when some neurons went off line, the overall EEG measurements of the brain indicated wakefulness in the rats," Cirelli says.

And there were behavioral consequences to the local sleep episodes.

"When we prolonged the awake period, we saw the rats start to make mistakes," Cirelli says.

When animals were challenged to do a tricky task, such as reaching with one paw to get a sugar pellet, they began to drop the pellets or miss in reaching for them, indicating that a few neurons might have gone off line.

"This activity happened in few cells," Cirelli adds. "For instance, out of 20 neurons we monitored in one experiment, 18 stayed awake. From the other two, there were signs of sleep -- brief periods of activity alternating with periods of silence."

The researchers tested only motor tasks, so they concluded from this study that neurons affected by local sleep are in the motor cortex.

Tobacco-Derived Compound Prevents Memory Loss in Alzheimer's Disease Mice

ScienceDaily (Apr. 28, 2011) — Cotinine, a compound derived from tobacco, reduced plaques associated with dementia and prevented memory loss in a mouse model of Alzheimer's disease, a study led by researchers at Bay Pines VA Healthcare System and the University of South Florida found.

The findings are reported online in the Journal of Alzheimer's Disease in advance of print publication.

"We found a compound that protects neurons, prevents the progression of Alzheimer's disease pathology, enhances memory and has been shown to be safe," said Valentina Echeverria, PhD, a scientist at Bay Pines VA Healthcare System and an assistant professor of Molecular Medicine at USF Health. "It looks like cotinine acts on several aspects of Alzheimer's pathology in the mouse model. That, combined with the drug's good safety profile in humans, makes it a very attractive potential therapy for Alzheimer's disease."

While the current drugs for Alzheimer's may help delay the onset of symptoms, none halt or reverse the processes of Alzheimer's disease. In addition, existing drugs may have undesirable side effects.

Some epidemiological studies showed that people who smoke tend to have lower incidences of Parkinson's disease and Alzheimer's disease. Studies have widely attributed this apparently beneficial effect to nicotine, which has been reported to improve memory and reduce Alzheimer's-like plaques in mice. However, nicotine's harmful cardiovascular effects and addictive properties make the compound a less than ideal drug candidate for neurodegenerative diseases.

The Bay Pines VA/USF team decided to look at the effects of cotinine, the major byproduct of nicotine metabolism, in Alzheimer's disease mice. Cotinine is nontoxic and longer lasting than nicotine. Furthermore, its safety has already been demonstrated in human trials evaluating cotinine's potential to relieve tobacco withdrawal symptoms.

The researchers administered cotinine daily for five months to young adult (2-month-old) mice genetically altered to develop memory problems mimicking Alzheimer's disease as they aged. At the end of the five-month study, the Alzheimer's mice treated with cotinine performed better on tasks measuring their working memory and thinking skills than untreated Alzheimer's control mice. Long-term cotinine treatment appeared to provide the Alzheimer's mice complete protection from spatial memory impairment; their performance in this area of testing was identical to that of normal mice without dementia.

The brains of Alzheimer's mice treated with cotinine showed a 26-percent reduction in deposits of amyloid plaques, which are a hallmark of Alzheimer's disease. Cotinine also inhibited the accumulation of the amyloid peptide oligomers -- a predecessor of senile plaques -- in the brains of these mice. Furthermore, the researchers discovered that cotinine stimulated the signaling factor Akt, which promotes the survival of neurons and enhances attention and memory.

Senile plaques likely had not yet formed or were just beginning to accumulate in the brains of the young adult mice when long-term cotinine treatment was started. The researchers suggest that "cotinine may be useful in preventing cognitive deterioration when administered to individuals not yet exhibiting Alzheimer's disease cognitive impairment or those with mild cognitive impairment at early stages of the disease."

The researchers are seeking additional support for a pilot clinical trial to investigate cotinine's effectiveness in preventing progression to Alzheimer's dementia in patients with mild cognitive impairment, Echeverria said.

The VA-USF team is also studying the potential of the tobacco-derived compound to relieve fear-induced anxiety and help blunt traumatic memories in mouse models of post-traumatic stress disorder.

Study co-authors included researchers from the University of Miami, the University of Manchester (UK), Boston College, and Saitama Medical Center and Saitama Medical University (Japan). The study was supported in part by awards from the Florida Department of Health's James and Esther King Biomedical Research Program, the Alzheimer's Association and the Japan Society for the Promotion of Science.

Can Traumatic Memories Be Erased?

ScienceDaily (Apr. 28, 2011) — Could veterans of war, rape victims and other people who have seen horrific crimes someday have the traumatic memories that haunt them weakened in their brains? In a new study, UCLA life scientists report a discovery that may make the reduction of such memories a reality.

Could veterans of war, rape victims and other people who have seen horrific crimes someday have the traumatic memories that haunt them weakened in their brains? In a new study, UCLA life scientists report a discovery that may make the reduction of such memories a reality. "I think we will be able to alter memories someday to reduce the trauma from our brains," said the study's senior author

"I think we will be able to alter memories someday to reduce the trauma from our brains," said the study's senior author, David Glanzman, a UCLA professor of integrative biology and physiology and of neurobiology.

The study appears in the April 27 issue of the Journal of Neuroscience.

Glanzman, a cellular neuroscientist, and his colleagues report that they have eliminated, or at least substantially weakened, a long-term memory in both the marine snail known as Aplysia and neurons in a Petri dish. The researchers say they gaining important insights into the cell biology of long-term memory.

They discovered that the long-term memory for sensitization in the marine snail can be erased by inhibiting the activity of a specific protein kinase -- a class of molecules that modifies proteins by chemically adding to them a phosphate (an inorganic chemical), which changes the proteins' structure and activity. The protein kinase is called PKM (protein kinase M), a member of the class known as protein kinase C (PKC), which is associated with memory.

The research has important potential implications for the treatment of post-traumatic stress disorder, as well as drug addiction, in which memory plays an important role, and perhaps Alzheimer's disease and other long-term memory disorders.

"Almost all the processes that are involved in memory in the snail also have been shown to be involved in memory in the brains of mammals," said Glanzman, who added that the human brain is far too complicated to study directly.

PKM is rare in that while most protein kinases have both a catalytic domain, which is the part of the molecule that does its work, and a regulatory domain, akin to an on-off switch that can be used by other signaling pathways to shut off the activity of the kinase, PKM has only the catalytic domain -- not the regulatory domain.

"This means that once PKM is formed, there is no way to shut it off," said Glanzman, who is a member of UCLA's Brain Research Institute. "Once it is activated, PKM's continual activity maintains a memory until PKM degrades."

Glanzman decided to study PKM in the marine snail, which has simple forms of learning and a simple nervous system, so that he could understand in precise detail how PKM's activity maintains a long-term memory, a process that is not well understood.

Glanzman and his colleagues -- researchers Diancai Cai, lead author of the study; Kaycey Pearce; and Shanping Chen, all of whom work in his laboratory -- studied a simple kind of memory called sensitization. If marine snails are attacked by a predator, the attack heightens their sensitivity to environmental stimuli -- a "fundamental form of learning that is necessary for survival and is very robust in the marine snail," Glanzman said.

"The advantage of Aplysia," he said, "is that we know the neurons that produce this reflex; we know where they are in the nervous system."

The scientists removed the key neurons from the snail's nervous system and put them in a Petri dish, thereby recreating in the dish the two-neuron "circuit" -- a sensory neuron and a motor neuron -- that produces the reflex.

"The point is to reduce the problem so we can study on a fundamental biological level how PKM is maintaining long-term memory," Glanzman said.

They succeeded in erasing a long-term memory, both in the snail itself and in the circuit in the dish. They are the first scientists to show that long-term memory can be erased at a connection between just two neurons.

"We found that if we inhibit PKM in the marine snail, we will erase the memory for long-term sensitization," Glanzman said. "In addition, we can erase the long-term change at a single synapse that underlies long-term memory in the snail."

The scientists administered electric shocks to the snails' tails. Following this training, when the scientists gently touched a snail's siphon (an organ in their mid-section used in respiration), the animal responded with a reflexive contraction that lasted about 50 seconds. A week later, when the scientists touched the siphon, the reflex still lasted 30 seconds or more, rather than just the second or two the reflex normally lasts without the shock training. This constituted a long-term memory.

Then, once the marine snail had formed the long-term memory, the scientists injected an inhibitor of PKM into the snail and 24 hours later touched the siphon; the marine snail responded as though it had never received the tail shocks, with a very brief contraction.

"The long-term memory is gone," Glanzman said.

Life scientists agree that learning is due to changes in the synaptic connections, some of which strengthen and some of which weaken, in the brain. This new research opens the door to learning how the changes in synaptic connections are maintained and what role PKM plays in this memory maintenance. Glanzman and his colleagues are now conducting detailed analyses.

During the long-term memory, new synaptic connections grow between the sensory neuron and the motor neuron. If the scientists inhibit PKM, will those synaptic connections disappear?

"We're going to study that," Glanzman said. "Now we can study the cell biology of how PKM maintains long-term memory. Once we know that, we may be able to alter long-term memories. This has implications for psychiatric disorders that are related to memory. Post-traumatic stress disorder is a hyper-induction of a long-term memory that won't go away."

Targeting specific memories

Is there a way to turn the traumatic memory down?

"This is the first step toward figuring that out," Glanzman said. "Even after we know this, we will still need a way to target the memory. We have captured the memory in the dish, but we also have to know where in the brain the memory is."

Does he think it will become possible to target and weaken specific traumatic memories?

"I do," Glanzman said. "Not in the immediate future, but I think we will be able to go into one's brain, identify the location of the memory of a traumatic experience and try to dampen it down. We can do this in culture, and there is no essential difference between the synapse in culture and the synapse in your brain. We have captured the memory in the dish; now we have to figure out a way to target the memories in human brains. Once we know the neural circuit that contains the memory, then we need a selective way to inhibit the activity of PKM in that circuit."

People have different brain circuits -- collections of neurons and synapses that join neurons -- for different memories, Glanzman believes. Scientists may seek to inhibit PKM in a particular circuit. The goal would be to find the brain circuit that is predominantly associated with a traumatic memory and target PKM in that circuit.

If you boost rather than inhibit PKM activity, might that have a beneficial affect for patients with Alzheimer's disease? Alzheimer's disease appears to initially disrupt the synaptic basis of learning, Glanzman said, and PKM might be involved in that disruption.

Just as scientists are seeking to target and kill cancer cells without damaging healthy cells, Glanzman intends to study whether it is possible to weaken only certain synapses associated with traumatic memories, while leaving other memories intact.

"The brain is the most complicated organ in the body," Glanzman said, noting that the brain has many trillions of synapses. "The research is complex, but this is the way we are going to understand how memories in our brains last a lifetime, or at least part of the way. It will take a lot of research, but I think it will be feasible."

Next steps include studying the relationship between PKM and the synapses and how the structure of synapses changes when PKM is inhibited.

"That is going to tell us how long-term memories are maintained," Glanzman said. "This is the first step. The more we know about how long-term memory is induced in the brain and how our memories are maintained in the brain, the more we are going to be able to treat long-term memory loss."

The experiments are very difficult, and Glanzman praised co-authors Cai, Pearce and Chen as "unbelievably skilled."

For 28 years, Glanzman has studied learning and memory in the marine snail, which is substantially larger than its garden variety counterpart and has approximately 20,000 neurons in its central nervous system; humans have approximately 1 trillion. However, the cellular and molecular processes seem to be very similar between the marine snail and humans.

"The fundamental mechanisms of learning and memory are identical, as far as we can tell," Glanzman said.

Glanzman's research is funded by a Senator Jacob Javits Award in the Neurosciences from the National Institute of Neurological Disorders and Stroke (NINDS) and by the National Institute of Mental Health.

The marine snail processes information about its environment and is capable of learning when an environment is safe and when it is not, learning to escape from predators, and learning to identify food. The marine snail is native to California, living in tidal waters off the coast.

Glanzman is also studying learning at the synaptic level in the zebra fish.

In earlier research, Glanzman's team identified a cellular mechanism in the Aplysia that plays an important role in learning and memory. A protein called the NMDA (N-methyl D-aspartate) receptor enhances the strength of synaptic connections in the nervous system and plays a vital role in memory and in certain kinds of learning in the mammalian brain as well. Glanzman's demonstration that the NMDA receptor plays a critical role in learning in the marine snail was entirely unexpected.

Mutations in Single Gene May Have Shaped Human Cerebral Cortex

ScienceDaily (Apr. 28, 2011) — The size and shape of the human cerebral cortex, an evolutionary marvel responsible for everything from Shakespeare's poetry to the atomic bomb, are largely influenced by mutations in a single gene, according to a team of researchers led by the Yale School of Medicine and three other universities.

An MRI of brain of patient with severe form of microcephaly compared to a control subject. A team of researchers have found that mutations in a single gene may cause large discrepancy in size of the cerebral cortex.

The findings, reported April 28 in theAmerican Journal of Human Genetics, are based on a genetic analysis of in one Turkish family and two Pakistani families with offspring born with the most severe form of microcephaly. The children have brains just 10 percent of normal size. They also lacked the normal cortical architecture that is a hallmark of the human brain. This combination of factors has not been seen in other genes associated with the development of the human brain, the authors note.

The researchers found that mutations in the same gene, centrosomal NDE1, which is involved in cell division, were responsible for the deformity.

"The degree of reduction in the size of the cerebral cortex and the effects on brain morphology suggest this gene plays a key role in the evolution of the human brain," said Murat Gunel, co-senior author of the paper and the Nixdorff-German Professor of Neurosurgery and professor of genetics and neurobiology at Yale.

Scientists from Yale, the University of Cambridge, Harvard and Northwestern universities collaborated on the study with colleagues around the world, including those in Turkey and Saudi Arabia.

"These findings demonstrate how single molecules have influenced the expansion of the human cerebral cortex in the last five million years," Gunel said. "We are now a little closer to understanding just how this miracle happens."

The research was funded by the Yale Program on Neurogenetics, the Yale Center for Human Genetics and Genomics, the National Institutes of Health and the Wellcome-Trust.

Mehmet Bakircioglu of Yale was co-first author of the paper. Other Yale authors on the paper are Tanyeri Barak, Saliha Yilmaz, Okay Caglayan and Kaya Bilguvar.

Electrical Oscillations Found to Be Critical for Storing Spatial Memories in Brain

ScienceDaily (Apr. 28, 2011) — Biologists at UC San Diego have discovered that electrical oscillations in the brain, long thought to play a role in organizing cognitive functions such as memory, are critically important for the brain to store the information that allows us to navigate through our physical environment.

Red dots signal the location of electrical impulses generated within this grid cell, which are needed for the brain to store information about the rat's physical environment.

The scientists report in the April 29 issue of the journal Science that neurons called "grid cells" that create maps of the external environment in one portion of our brain require precisely timed electrical oscillations in order to function properly from another part of the brain that serves as a kind of neural pacemaker.

Their discovery has important implications for understanding the underlying causes of neurological diseases such as Alzheimer's disease and for restoring memory in areas of the brain that are necessary for orientation.

"This work is the first to demonstrate that oscillatory activity has a well-defined function in brain areas that store memories," says Stefan Leutgeb, an assistant professor of biology at UCSD who headed the team of researchers.

Scientists have long known that among the first brain areas to degenerate in Alzheimer's disease, leading to symptoms such as memory loss and disorientation, are the hippocampus and the nearby entorhinal cortex, important structures for the formation of memory. Those two regions of the brain contain three types of neurons that contribute to the formation of spatial memories and the spatial information in episodic memories from our life experiences.

These three types of neurons provide an internal GPS system to the brain. For example, one type of neuron, called "place cells," generates electrical activity only when an animal is at a certain position, while another type, called "head direction cells," acts like a compass. A third class of neurons, called "grid cells," provides grid-like patterns for the brain to store memories of physical dimensions of the external environment. The most striking feature about these cells is that their electrical activity is distributed at equidistant, periodic locations within each cell (shown in the image). Grid cells were discovered by Norwegian scientists in rats in 2005, but in 2010 researchers in London detected groups of cells in human entorhinal cortex that share the same characteristics.

Leutgeb and his team of UCSD biologists -- postdoctoral researcher Julie Koenig, undergraduate student Ashley Linder and Jill Leutgeb, an assistant professor of biology -- were motivated to understand the function of electrical oscillations in the brain, which are routinely measured in clinical settings to diagnose neurological disorders.

Leutgeb's group demonstrated that neurons called grid cells in the entorhinal cortex that create maps of the external environment require precisely timed electrical oscillatory input signals from a neural pacemaker in the subcortex of the brain to function properly.

"Our findings represent a major milestone in understanding memory processing, and they will guide efforts to restore memory function when cells in the entorhinal cortex are damaged," says Stefan Leutgeb.

A group of scientists from Boston University reports related findings in a companion paper in the same April 29th issue of Science.

The UCSD researchers monitored the electrical activity of grid cells in rats that explored a small four-foot by four-foot enclosure. Grid cells, located in the entorhinal cortex just adjacent to the hippocampus, maintain an internal representation of the external environment. This representation is a grid-like map made of repeating equilateral triangles that tile the space in a hexagonal pattern. As an animal navigates through its environment, a given grid cell becomes active when the animal's position coincides with any of the vertices within the grid.

The scientists silenced the oscillatory input by manipulating a small group of pacemaker cells in the brain and observed a significant deterioration of the grid cells' maps of the environment.

Surprisingly, silencing the oscillatory input did not disrupt brain signals that indicate precise location (provided by place cells) and the compass signal (provided by head direction cells).

"It has been thought that the hippocampus is under control of the entorhinal cortex, so there was the assumption that grid cells would have a very large impact on place cells. We are surprised at how the function of place cells is maintained in the face of significant disruption in grid cell function," says Leutgeb.

"This important result shows that, in general, you can eliminate a substantial amount of incoming information to a brain circuit without that brain circuit losing a majority of its functionality," he adds. "The implication of this finding is that restoring memory function does not require that we exactly reassemble damaged neural circuitry, rather we can regain function by preserving or restoring key components."

"Our findings are a major step towards identifying these key components in an effort to preserve memory function in aging individuals and in patients with neurodegenerative diseases," he says.

The research project was supported by grants from the National Science Foundation, the National Institutes of Health, the Ellison Medical Foundation and the Alzheimer's Association.