Monday, March 22, 2010

Santa Clara Valley Medical begins study on traumatic brain injuries

Starting this month, someone rushed to Santa Clara Valley Medical Center with a traumatic brain injury may get a shot of a sex hormone.
The hospital is joining Stanford, San Francisco General and about a dozen hospitals across the country to test if progesterone, a hormone pregnant women produce in abundance, can stop the brain from wreaking self-destruction after an accident.

Neuroscientists say the trial is the most promising in decades to find a drug that can treat traumatic brain injury, or TBI, which afflicts 1 million to 2 million Americans each year. Researchers say the illness has been chronically underfunded and understudied, but is now stepping into the limelight as the signature illness of the wars in Iraq and Afghanistan.

Currently, no drug exists to stop the brain from swelling a few hours after a blow to the head, commonly from a car crash, an accidental fall, or in Iraq, a blast from an improvised explosive. Swelling causes bystanding brain cells to die and under extreme pressure, the brain can leak out of the base of the skull, killing the patient. Progesterone may halt the brain from bulging and protect brain cells around the injury.

Few drugs have shown promise to treat TBI. For the past three decades, "all of the clinical trials have failed," said Geoffrey Manley, chief of neurosurgery at San Francisco General Hospital. Two studies were halted when the drugs made patients worse. But in a 100-person trial at an Atlanta hospital between 2001 and 2005, TBI patients given progesterone were more than twice as likely to survive than those given a placebo. Patients with a moderate brain injury were more likely to recover if given progesterone. And progesterone, which occurs naturally in both men and women and is packaged in birth-control pills, has well-understood and limited side effects.

In the next five years, 1,140 patients will be enrolled in the study.

The progesterone must be administered within four hours, about the time it takes a blow to the head to begin perverting the brain's chemistry. Since brain injured patients are likely unconscious when rushed to the hospital and can't give consent, the study has an FDA exception to enroll a patient if a medical proxy can't be found.

The war in Iraq has done more than anything else to elevate traumatic brain injuries to the public consciousness, according to neurosurgeon Dr. Roland Torres at Santa Clara Valley Medical, who oversees about a thousand TBI cases each year. "All of a sudden, there was an incredible amount of money to do studies on brain injury," Torres said. Nearly US$400 million in research grants for TBI were awarded by the Department of Defense, Veteran's Affairs, and Health and Human Services between 2003 and 2008, which doctors say is a dramatic increase from the 1990's. "It was sort of a blessing in disguise," Torres says.

If this trial shows progesterone is effective in treating TBI, soldiers will add injectable progesterone to their medical kits, and paramedics could give it at the site of a car wreck.

Torres believes one reason TBI has been underfunded is that nurses and doctors often see brain injured patients go in wheelchairs to nursing homes, but rarely get to see the patients who recover and return to school or work.

Sex on the brain: 'Doublesex' gene key to determining fruit fly gender

The brains of males and females, and how they use them, may be far more different then previously thought, at least in the fruit fly Drosophila melanogaster, according to research funded by the Wellcome Trust.
In a paper published today in the journal Nature Neuroscience, researchers from the University of Glasgow and the University of Oxford, have shown that the gene known as 'doublesex' (dsx), which determines the shape and structure of the male and female body in the fruit fly, also sculpts the architecture of their brain and nervous system, resulting in sex-specific behaviours.

The courtship behaviour of the fruit fly has long been used to study the relationship between genes and behaviour: it is innate, manifesting in a series of stereotypical behaviours largely performed by the male. The male chases an initially unreceptive female, and 'woos' her through tapping and licking and using wing vibration to generate a 'courtship' song. If successful, the female will slow and present a receptive posture, which allows copulation to occur.

For some time now, the gene 'fruitless' (fru), which is specific to the adult male fruit fly, was thought to be the key to male behaviour and the development of male specific neural circuitry of flies.

However, the researchers have shown that fru does not explain the complete repertoire of male behaviours in the fly: female flies in which the fru gene has been activated demonstrate some, but not all, of the characteristics usually associated with courtship behaviour in males. The researchers have also shown that dsx plays an important role in shaping the neural circuitry involved in this behaviour.

"The dogma was that dsx made fruit flies look the way they did and fru made them behave the way they did," explains Dr Stephen Goodwin from the University of Oxford, who led the research. "We now know that this is not true. dsx and fru act together to form the neuronal networks - the wiring - for sexual behaviour."
fru has so far been found only in insects; dsx, however, is found throughout the animal kingdom, where it plays a fundamental role in sex determination, and so is of particular interest to researchers.

Using a transgenic tool generated in his lab, Dr Goodwin and colleagues were able to map dsx throughout the fly's development using a fluorescent protein marker that illuminates areas where DSX is active. This highlighted profound differences in neural architecture between the sexes. In males, the researchers were able to show that dsx complements fru activity to create a 'shared' male-specific neural circuit; in females (where fru is inactive), dsx forms a female-specific circuit.

Importantly the researchers were able to manipulate these cells, impinging their ability to function, and show that these circuits are responsible for behaviours unique to the individual sexes.

"It has been suggested that there are only minor trivial differences between the neural circuits that underlie behaviour in males and females," explains Dr Goodwin. "We have shown that in fact there is quite a bit of difference in the number of neurons and how these neurons connect, or 'talk', to each other. These differences can have big consequences on the structure and function of the nervous system."

In addition, while dsx was known to establish the gender of the adult fly, the pattern of dsx activity in the adult was unknown. Dr Goodwin and colleagues have shown that this pattern is not ubiquitous, but rather is restricted in a specific and telling manner.

Some tissues, such as blood cells, may not require a defined gender in order to function. However, others such as the 'fat body', which in the adult fly functions in part to produce hormones, and the oenocytes, which produce sex-specific pheromones, require a specified sexual identity. It was unsurprising to Dr Goodwin and colleagues to find dsx expressed in these tissues in both males and females, as they would be key to establishing a normal sexual physiological state.

"Determining gender in a fruit fly seems to be about adding different splashes of ''colour' here or there," he says. "It's not like the canvas, meaning the nervous system, needs to be all blue or pink, just a little bit of blue over here or a little bit of pink over there. Not all cells need to know what sex they are, but those that do need to know will be ones that are important for sex-specific behaviours."

The research performed by Dr Goodwin and colleagues allows greater insight into how a male and female nervous systems may be established and how this may then coordinate the sex-specific physiology needed to create the complete, integrated adult sexual state.
More information: Rideout, E. et al. Control of Sexual Differentiation and Behavior by the doublesex gene in Drosophila melanogaster. Nature Neuroscience, e-pub 21 March 2010.

Scientists rethink chronic pain

London - Barriers to understanding pain are starting to fall and scientists and drug firms say a fresh approach is producing potential new drugs to hit where it hurts.

Millions of people across the world suffer chronic pain - such as nerve, joint or muscle pain that lasts weeks, months or years - and many fail to get adequate relief, partly because doctors have a relatively scant grasp of what causes it.

But new imaging techniques, a recognition that the brain's responses are central to pain and a growing realisation of pain's cost to society, mean the scientific community is now pushing for it to be redefined as a disease in its own right.

As pain moves status from symptom to disease, interest among some of the biggest drug firms is picking up.

All in the mind
Pfizer, the world's mightiest drug maker, has a large pain research team working on a portfolio of drugs, some of which are generating excitement in the field.

"The science has moved on considerably," Martin Mackay, Pfizer's head of research and development, told Reuters.

He said new technologies allow more objective measuring of pain, adding: "Our knowledge of targets and human genetics has taken a real step forward in the last few years."

Science is shifting attitudes too.

Irene Tracey of the Pain Imaging Neuroscience Group at Oxford University published a study last year which reviewed 10 years of imaging research and found chronic pain is linked to functional, structural and chemical changes in the brain.

So, pain is very much in the mind, and the brain's responses to it are key to what it feels like and how long it goes on.

Old medicine
"Pain doesn't exist until the brain gets hold of it. And one of the things brain imaging has been very good at is taking away some of the myths and cultural biases against pain," she said at a meeting of experts in London earlier this month.

"Chronic pain fits the definition of a disease," she said.

Pain, however, can be a tricky condition to medicate, as the numbers of sufferers show, and not all drug makers are convinced it is a profitable area. Britain's GlaxoSmithKline said last month it was cutting research in the field.

Many pain killers around today, from products like aspirin or paracetamol to opiates used for cancer pain, rely on mechanisms of action exploited since Egyptian times or were found as side effects of drugs developed for other things.
When it hurts
The sheer size of the problem shows the need for more effective drugs. Pain hurts, in more ways than one.

In Britain alone, it affects about 7.8 million people, about 13% of the population, and a 2002/03 survey by a group called Pain in Europe estimated that as many as one in five Europeans suffers chronic pain.

Studies show that around 22% of people with chronic pain become depressed and 25% go on to lose their jobs.

Pain is estimated to cost more than €200bn a year in Europe and $150bn in the US.

"It has huge ramifications, not only for the person themselves but also for society as a whole," said Beverly Collett, a consultant in pain medicine at the University Hospital of Leicester in central England.

In recognition of this, the EU's Innovative Medicines Initiative gave some of its first grants to pain researchers to work with pharmaceutical firms to try to speed up the process of finding new drugs.

The pain pipeline
Steve McMahon, director of the London Pain Consortium, said his group and several others in Europe were now working with about 10 major drug companies to push the field forward.
Among the most promising drug prospects is tanezumab from Pfizer, which McMahon says is "the first drug in a long time to have originated from basic science identifying the biological problem and suggesting a therapy".
Pfizer's MacKay is naturally upbeat about the experimental medicine - an antibody currently in late-stage trials for osteoarthritis caused by wear and tear of the joints. He named it among the firm's top picks for "blockbuster potential".

McMahon hopes it will be the first of many.
Another potential from Pfizer is a drug based on work by British scientists who identified a genetic mutation several years ago that prevents those who have it from feeling pain.

In the genes
The gene clue was found in a Pakistani boy - and members of three related families - who had become a local celebrity as a street performer, stunning crowds by plunging knives through his arms and walking on burning coals.

The experimental drug seeks to mimic the gene mutation and block a sodium channel which normally produces nerve impulses that convey pain signals to the brain.

"This is the way that pain (research) is going to go now, where you have very strong human genetic evidence and you're able to mount really large campaigns against tough targets and then take them through to the clinic," MacKay said.

For Tracey, scientific progress will only keep its momentum if society agrees pain is something scientists should fight.

"You can still hear it in the language, with expressions like 'no pain no gain'," she said. "These are real barriers that we have to get over in society if we're really going to accept that we should be treating pain and putting more money into it."