CNN.com, May 5, 2010, by Miriam Falco  –  Scientists appear to have broken another barrier in stem cell research by creating a better research model to study human illnesses – a pig – actually 34 pigs.

It’s an important advance for research because pigs are much more like humans than other lab animals are.

The scientists did not clone the pigs – instead they adapted a procedure used in mice and human stem cell researchand were able to grow a specific kind of cell, induced pluripotent stem cells, or IPS cells.

Pluripotent stem cells have the ability to turn into any cell in the body. IPS cells were first developed about five years ago by Shinya Yamanaka, who used four genes to coax a regular mouse cell into acting like an embryo. Creating stem cells with this method is less controversial than harvesting them from an embryo, which destroys the fertilized egg in the process.

According to Dr. Steve Stice, director of the University of Georgia Regenerative Bioscience Center, his team took a bone marrow cell from a pig and injected six new genes, which caused it turn into an embryo-like cell.  Pluripotent stem cells were harvested from this embryo-like cell and injected in another pig embryo. 

The first piglets carrying these new stem cells were born September 3, 2009. 

So far human embryonic stem cell research has not actually found its way into the human body.  Most of the research is still in mice.  But mice aren’t the best animal models to get more accurate data on how a treatment may affect a person.  For example, mice hearts beat four times faster than a human heart and mice don’t get atherosclerosis (clogged arteries) – but pigs do.  That’s why pigs are much better animal models says Stice. “Physiologically, pigs are much closer to a human,” he says.

The researchers also found that unlike mouse embryonic stem cells, which can turn into cancer cells, none of the pigs developed any signs of tumors.

But it has been very difficult to harvest embryonic pluripotent stem cells from pigs. Stice credits his research assistant Franklin West with finding a way to make the existing IPS technology work in pigs.  

Now researchers hope to find many different applications for these new pig stem cells and the pigs they can produce.  They are already working with scientists at Emory University to develop insulin-producing pancreatic islet cells, which might be transplanted into people with diabetes.

Stice thinks this new method can also be used to genetically engineer healthier livestock for other tissue transplants and food consumption. He suggests these stem cells may someday be used to make “artificial bacon,” which would eliminate the need to slaughter pigs.

The research will be published in the online journal “Stem Cell and Development.”

Dopaminergic neurons derived from human embryonic stem cells – Human embryonic stem cells differentiated into dopaminergic neurons after being exposed to a mix of synthetic compounds. Red indicates the protein beta-tubulin III, which is found in the dopaminergic neurons that degenerate in Parkinson’s disease. Blue indicates nuclei. This work could lead to more efficient ways of generating dopaminergic neurons to study the origins and possible treatments for Parkinson’s disease.

This photo was taken by Andrei Kochegarov in the lab of Michael Pirrung at the University of California, Riverside.

GoogleNews.com, May 5, 2010, by Clive Cookson  –  Regenerative medicine has immense potential for renewing failing or damaged tissues throughout the body, from the skin on the surface to organs deep inside. But the most exciting prospect is for regeneration of the brain and nervous system, both because the unmet medical need is so great and because the science is so challenging.

There are two complementary approaches to neural regeneration. The more traditional one is cell therapy – putting new neurons – nerve cells – or their progenitor cells into the brain or nervous system.

The first transplants of foetal neurons into Parkinson’s disease patients took place in the 1980s – with mixed results – and today several companies are on the brink of clinical trials of therapies based on stem cells.

They include: ReNeuron of the UK, which is about to test neural stem cells in stroke patients; and Geron, from California, which plans to treat acute spinal injury with nerve cells derived from human embryonic stem cells.

The other possibility is to stimulate the latent power of some human neurons to regenerate themselves. Scientists have long known that neuro­genesis takes place in more primitive organisms, including some fish and amphibians, but one of the dogmas of 20th century neuroscience – that adult humans do not make new brain cells – was only overturned in the late 1990s.

The discovery then of adult neurogenesis at the Salk Institute in California has inspired a great wave of research, as scientists and biotechnology companies look for ways to increase the low natural level of brain cell generation, without risking the cancer that might accompany unnatural neural growth.

“Very little is known still about human neurogenesis, because it is difficult to look at the growth of neurons in the living human brain,” says Mike Modo of the Institute of Psychiatry in London. “But in postmortems of stroke victims, there is clear evidence of neurogenesis after the stroke.”

Sygnis Pharma, a German biotechnology company, wants to achieve this effect with a protein called “granulocyte colony stimulating factor” or G-CSF, produced naturally in the brain after a stroke – apparently acting both to reduce cell death in the acute phase and to stimulate subsequent regeneration of blood vessels and neurons.

After successful animal tests, Sygnis is undertaking a clinical trial to assess the efficacy of its G-CSF treatment – which the company calls AX200. About 350 stroke patients are taking part in the double-blinded trial; half will receive an infusion of AX200 and the other half a placebo saline solution.

Results are expected in the middle of next year.

A Swedish company, Neuro­Nova, is following a similar approach with two neuro-stimulating proteins – both in early clinical trials. One is a formulation of “platelet-derived growth factor” (PDGF) to treat Parkinson’s disease; the other contains “vascular endothelial growth factor” (VEGF) for amyotrophic lateral sclerosis (known in the US as Lou Gehrig’s disease), the most common form of motor neuron disease.

A third neurogenesis company, BrainCells of San Diego, is taking a different tack. It is pursuing the discovery made in 2003 by one of its founders, René Hen of Columbia University, that antidepressant drugs achieve some of their effects by stimulating the growth of neurons in the hippocampus, a brain area involved in learning and memory.

In contrast to Sygnis and Neuro­Nova, whose early work is focusing on proteins that might help people with serious or acute brain disease, BrainCells is concentrating initially on “small molecule” chemicals that people can take as pills or capsules, with a screening programme that has looked at hundreds of potential drugs to find the ones that best trigger the proliferation of new neurons in cell cultures.

Two of its drugs are already giving promising results in clinical trials with patients suffering from severe depression and anxiety, who do not respond to existing antidepressants.

In terms of results, there may not be much practical difference between the two approaches to brain repair – transplanting neurons and stimulating the brain’s intrinsic growth potential – because animal experiments suggest that cell transplants are particularly good at stimulating neurogenesis. This is because the very presence of newly transplanted cells seems to help the brain repair itself, by activating its own “endogenous” stem cells and growth factors.

Mr Modo says that in cases of serious brain injury or disease, a third component may be necessary for effective treatment. Shrinkage and neuronal death often leave a hole in the brain, which transplanted and regenerated cells cannot fill on their own.

A potential solution then is to add a scaffold, made from biocompatible materials and laden with neurostimulating factors, which can guide and support the cells as they grow.

Neural regeneration may be a young field, with much still to prove, but it is one of the fastest growing and most exciting in the whole of bioscience.

IPS cells can develop into cells of various body parts, such as muscle, neural tissues and cartilage

TimesOnline.co.uk, May 5, 2010, by Mark Henderson  –  Powerful stem cells made by reprogramming adult tissue could reduce the need for animal testing of new drugs, according to a scientific pioneer of the technology.

Jamie Thomson, of the University of Wisconsin, told The Times that “in-vitro trials” based on so-called induced pluripotent stem (IPS) cells would refine pharmaceutical development so that fewer animal experiments would be required.

The cells were already being used as a source of human tissue for testing candidate drugs for safety and effectiveness, he said. As a result, fewer unworkable drugs would advance to animal studies, and some animal tests may become unnecessary.

“If what we are doing is successful it will dramatically reduce animal testing, and maybe towards the end of our lifespan actually eliminate it for some things,” Professor Thomson said. “I think we will have much better models for these things.”

IPS cells, which were created in 2007 by teams led by Professor Thomson and Professor Shinya Yamanaka, of Kyoto University in Japan, are made by manipulating adult skin tissue to give it versatile properties of embryonic stem (ES) cells.

These master cells can be grown into any type of tissue, offering a limitless source of specialised cells for use in research. There is hope that they may eventually be used to produce cell therapies for Parkinson’s disease, diabetes and paralysis. As IPS cells are made without destroying embryos, their use is ethically acceptable.

Cellular Dynamics, a company founded by Professor Thomson, is already using IPS cells to grow heart cells for pharmaceutical companies to use in the development of cardiac drugs.

Next year Cellular Dynamics will produce heart cells using IPS cells taken from people with particular ethnic backgrounds or genetic traits. Any candidate drugs that have damaging side-effects on cells with a particular genetic profile or on cells from people from certain ethnic groups could then be withdrawn, averting the failure of an expensive full-patient trial.

As much of this toxicity testing is currently performed in animals, there is great potential for reducing the number of animal experiments.

Human tissue grown from IPS cells may even provide a better laboratory model than animals, Professor Thomson said. “I trained as a veterinary pathologist, and the correlation [between results in animal and human trials] is not that great at the end of the day,” he said.

Professor Thomson said that the chief value of IPS cells would be as laboratory models for studying disease and testing drugs, rather than cell replacement. While it may prove possible to grow patient-specific spare-part tissue, which would not risk immune rejection, the costs are high.

“This gives us access to the basic building blocks of the human body,” he said. “We’ll learn a tremendous amount about the human body, and that will profoundly change human medicine.”

The master key

— Stem cells are master cells from which all types of human tissue are ultimately derived

— Induced pluripotent stem (IPS) cells, pictured, are made by genetically modifying skin cells. This turns them into an embryo-like state, allowing them to develop into any type of tissue.

— IPS cells are acceptable to some opponents of embryo research, and as they are grown from skin they can carry genetic characteristics.

— Adult stem cells are less powerful than IPS or embryonic stem cells, as they have already started to “specialise”. They can be used to make only a narrower range of tissue.

GoogleNews.com, May 5, 2010  –  Cancer researchers at Princess Margaret Hospital (PMH) have discovered that the ovarian hormone progesterone plays a pivotal role in altering breast stem cells, a finding that has important implications for breast cancer risk.

The findings, published online today in Nature, are significant because reproductive history is among the strongest risk factors for breast cancer, says principal investigator Rama Khokha, a molecular biologist at Ontario Cancer Institute and the Campbell Family Cancer Research Institute, PMH. Other major known risk factors are age, genetics and breast density.

“Our study shows how and when hormones affect breast stem cells during the natural reproductive cycle. There are well accepted links between ovarian hormones and breast cancer, and there is mounting evidence that stem cells are seeds for breast cancer. We now show a direct connection between hormones and breast stem cells. ”

Lead author Purna Joshi adds: “Our research demonstrates that when progesterone peaks during the second half of the menstrual cycle, it starts a cross-talk between stem cells and neighbouring cells that propels normal breast stem cells to expand in number, and may trigger an environment where cancer can begin.”

Until now, breast stem cells were thought to be generally inactive in the adult female breast, says Dr. Khokha, whose speciality is modelling human cancer in the laboratory. In this study, the research team replicated the human natural reproductive cycle in mice to determine the impact of hormones on breast stem cells.

How hormones change these stem cells opens a new pathway to understanding the cell growth that begins breast cancer, and, with further research, will open new ways of targeting stem cells.

“It is the first evidence, to our knowledge, for progesterone-driven dynamic shifts in the mammary stem cell pool. This activation provides an opportunity to start the process of cell transformation leading to breast cancer.”

GoogleNews.com, May 5, 2010, by Anne Harding  –  A daily dose of electricity delivered to a specific part of the brain can lift depression, new research confirms, even for people who’ve already tried multiple antidepressants to no avail.

While there’s evidence that this technique, known as transcranial magnetic stimulation (TMS), helps depressed people get better-and the US Food and Drug Administration has approved TMS for this purpose-many skeptics have questioned whether it really works, notes Dr. Mark S. George of the Medical University of South Carolina in Charleston, the lead author of the new study.

The biggest issue with studies so far, he explained, has been that it’s tough to fake the sound and sensation of the real device in order to run a gold standard clinical trial in which some people get the treatment, and others get a sham treatment, no one knowing which.

But George and his team say they’ve solved that problem by developing a dummy device that clicks in a similar way to the real thing and causes a person’s eye muscles to twitch, just like real a TMS device.

In the May issue of the Archives of General Psychiatry, George and his colleagues report the results of their 190-patient study, the most rigorous investigation of TMS for depression so far. The researchers randomly assigned participants to receive 37.5 minutes of TMS delivered to a part of the brain region that plays a role in emotion, or 37.5 minutes of sham TMS, once a day for three weeks.

After three weeks, 14 percent of patients in the real TMS group had recovered from their depression, compared to 5 percent of the sham TMS group; people who had the real treatment were four times as likely to get better as those who got the fake treatment.

Based on the results, George and his team say, it would be necessary to treat 12 depressed patients with TMS in order to have one patient recover.

Eighty-eight percent of the study participants completed the first phase of the trial. Patients in both groups were equally likely to report side effects, which included headache, discomfort at the TMS site, and eye twitching.

In a second phase of the study, all patients were given the real TMS treatment. Thirty percent of the patients in the second phase recovered from depression.

How long the treatment should last is not yet clear. “It’s very muddy now exactly how long we need to treat patients,” George said. “It looks as if from this trial you at least need to try three weeks and maybe even six weeks before you would give up.”

Patients who got better were prescribed venlafaxine – marketed as Effexor — and a small dose of lithium, noted George, a combination that’s been shown to help people stay well after their depression has remitted. George said he and his colleagues would like to study whether giving people TMS intermittently instead of putting them on antidepressants would produce equally durable effects.

TMS works by producing an electrical current that can pass through the skull and into the target area of the brain. George said he believes the approach works by “resetting” electrical activity and restoring normal mood regulation.

Something similar is likely happening, he added, with electroconvulsive therapy (ECT), or what is sometimes referred to as “electroshock treatment.” Sixty to 70 percent of depressed people who undergo ECT, in which electrodes placed on the front of the brain induce a convulsion while the patient is anesthetized, will recover.

George said he hopes that by better understanding where TMS should be delivered and by figuring out the best dose and duration of treatment, success rates closer to those of ECT might be achieved. “I’m optimistic that it’s pointing us in a path of understanding how to interact with the brain in a non-invasive way to get people well.”

The study has been published in the May issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

SOURCE: Archives of General Psychiatry, May 2010.

Transcranial Magnetic Stimulation provides positive results with few side effects

Belmont, MA – McLean Hospital, the largest psychiatric affiliate of Harvard Medical School, now offers a new, non-invasive treatment for moderate and severe depression called transcranial magnetic stimulation (TMS), the hospital announced today. The procedure is being provided as part of a new Psychiatric Neurotherapeutics Program (PNP) at McLean that includes electroconvulsive therapy (ECT), a clinical service offered to hospital patients for decades.

TMS, approved by the U.S. Food and Drug Administration (FDA) in 2008 after more than 10 years of clinical investigation, is a form of neuromodulation that stimulates nerve cells in an area of the brain linked to depression, by delivering highly focused MRI-strength magnetic pulses. The first McLean patient to use TMS was treated in late September, according to Stephen Seiner, MD, director of McLean’s ECT Service and the new director of the PNP.

TMS is primarily for people who have not experienced relief from depression through the use of antidepressant medications. “It is best used for people who don’t tolerate medicines well or who have not done well with medications and are not candidates for ECT,” explains Seiner. While TMS does not seem to be as effective as ECT in treating depression, he added, the procedure is easier to tolerate.

Patients undergo treatment five days a week for four to six weeks. Each treatment lasts 37 minutes and requires no anesthesia. Side effects are mild and may include headache or scalp discomfort. TMS has not been found to affect memory or cognition, which, which makes it a particularly attractive option.

According to Oscar Morales, MD, director of the TMS Service and associate director of PNP, during a TMS treatment, a patient sits in a comfortable reclining chair while a magnetic coil is gently placed on one side of his or her scalp. The magnetic fields penetrate approximately two to three centimeters beneath the coil directly into the brain to produce electrical currents.

“These currents activate cells within the brain that are thought to release neurotransmitters, which play a role in mood regulation,” explains Morales. “Since depression is believed to be caused by an imbalance of chemicals in the brain, TMS helps restore balance and relieve the symptoms of depression.”

According to Morales, who helped conduct clinical trials of TMS at Columbia University, more than 10,000 procedures were safely performed before TMS was approved by the FDA.

“TMS has been shown to be an extremely safe treatment for depression, with far fewer side effects than antidepressant medications,” said Morales. “It is exciting to add this new tool to the list of treatment options that we can offer to our patients at McLean.”

McLean Hospital is the largest psychiatric facility of Harvard Medical School, an affiliate of Massachusetts General Hospital and a member of Partners HealthCare. For more information about McLean Hospital, visit www.mclean.harvard.edu.

Transcranial Magnetic Stimulation (TMS)

Oscar G. Morales, M.D.
Director, Transcranial Magnetic Stimulation (TMS) Service
Associate Director, Psychiatric Neurotherapeutics Program (PNP)

Stephen J. Seiner, MD
Director, Psychiatric Neurotherapeutics Program (PNP)
Director, Electroconvulsive Therapy (ECT) Service

Paula Bolton, RN/NP/MS
Nurse Director, Psychiatric Neurotherapeutics Program (PNP)

The Psychiatric Neurotherapeutics Program (PNP) at McLean Hospital specializes in the neuromodulatory and neurostimulatory treatment of psychiatric disorders. It offers transcranial magnetic stimulation (TMS), a new and promising method for treating severe depression, as well as electroconvulsive therapy (ECT), a highly effective conventional intervention for chronic depression, mania, catatonia and schizophrenia. TMS and ECT are the first in a line of clinical services to be offered through the program.

With components in clinical care, research and education, the PNP is dedicated to improving the quality of life for individuals with a broad range of psychiatric illnesses.

Its collaborative team approach is aimed at maximizing the effectiveness of psychotherapy, medication management and psychosocial treatments already offered at McLean with emerging techniques, technologies and interventions.

What is Transcranial Magnetic Stimulation

Transcranial Magnetic Stimulation (TMS) is a non-invasive treatment for adults with major depression that uses magnetic stimulation of the brain to help control mood.  The procedure was approved by the Food and Drug Administration in October 2008 after more than ten years of clinical investigation in patients who failed to achieve satisfactory improvement from one course of pharmacotherapy (medication).  For this reason, TMS is particularly helpful for people who have not experienced significant relief from antidepressant medications or have difficulty with their side effects.

How does TMS work?

TMS uses focused magnetic impulses to non-invasively stimulate the brain in the pre-frontal cortex (the region of the brain associated with mood regulation).  During a TMS treatment, a clinician gently places a magnetic coil against one side of a patient’s scalp.

The magnetic impulses are generated by an electric coil that is positioned on the head above the left prefrontal cortex.  The magnetic fields penetrate approximately two to three centimeters beneath the coil directly into the brain to produce electrical currents. These currents activate cells within the brain that are thought to release neurotransmitters, which play a role in mood regulation.  Since depression is believed to be caused by an imbalance of chemicals in the brain, TMS helps restore balance and relieve the symptoms of depression.

The Advantages of TMS

TMS is non-invasive and requires no anesthesia or sedation. The procedure typically lasts an hour during which time patients are awake and alert. Because no medications are administered, there are no systemic effects or cognitive (memory and ability to concentrate) after-effects, therefore patients can return immediately to regular activity.

Treatment

Patients typically receive 20 – 30 treatments over four to six weeks (five times per week). There may also be a taper phase.  The course of treatment will vary according to each individual.  An initial assessment will determine the appropriate dose of the magnetic pulse and the exact area of the brain the coil should target. As the treatment progresses,
 the clinician will conduct periodic re-evaluations of the dose level and coil placement.

During a treatment session the patient sits in a comfortable reclining chair similar to that found  in a dentist’s office.  A headset is applied to deliver the magnetic stimulation.  Ear plugs are also provided to decrease the loud clicks associated with each magnetic pulse and the patient is given the option of watching TV.  During the treatment the patient is monitored continuously to ensure correct positioning and comfort level.

Are There Risks and Side Effects with TMS?

More than 10,000 treatments were safely performed during clinical trials. Patient reported no side effects like those associated with antidepressant medication (weight gain, dry mouth, drowsiness, etc.), no seizures and no cognitive side effects (memory loss, ability to concentrate). Scalp discomfort during the procedure is the most common side effect.

TMS should not be used for patients with implanted metallic devices that include metal plates in the skull or aneurysm coils, clips or stents.  Special precautions are recommended for individuals with implants such as pacemakers and implantable cardioverter defibrillators.

Is TMS covered by insurance?

Both private (indemnity and managed care plans) and public (Medicare and Medicaid) insurers are determining eligibility for TMS on an individual basis.  However until TMS is accepted more widely as a medically necessary treatment insurance coverage will most likely not be authorized. Patients should work directly with their insurers to receive approval for TMS. Once coverage has been determined, patients can work with a Patient Account representative to arrange payment schedules and to obtain assistance in applying for reimbursement or out-of-pocket expenses from their insurers.

Contact

For further information or a referral for consultation, please call 617-855-2355 begin_of_the_skype_highlighting              617-855-2355      end_of_the_skype_highlighting or email tmsmclean@partners.org.

About McLean Hospital

U.S. News & World Report ranked McLean Hospital first among all freestanding psychiatric hospitals. McLean Hospital is the largest psychiatric facility of Harvard Medical School, an affiliate of the Massachusetts General Hospital and a member of Partners HealthCare.

Massage may help lift depression  2010-05-05

NEW YORK — Massage therapy may help relieve symptoms of depression, a new review of the medical literature hints. The authors of the review, however, acknowledge difficulties with research on the effects of massage, including the fact that it’s impossible to…

By Stuart Fox

Thinking Cap A paddle on the top of the head delivers the electromagnetic pulse to prime the neurons for learning courtesy of Lara Boyd, University of British Columbia

I was always told that learning a skill like juggling or playing an instrument requires three things: practice, practice and practice. Now, researchers have found a way to shorten the path to new motor skills to practice, practice and magnetic brain stimulation.

As detailed in a new study in the journal BMC Neuroscience, direct electromagnetic stimulation of the brain speeds up the fixation of simple motor skills. And while this system won’t help a healthy person jump from chop sticks to Rachmaninoff in a weekend, it can speed up the rate at which stroke victims recover basic motor function.

“If you practice a motor skill of any sort, you’re exciting a set of neurons,” said Lara Boyd, a professor at the University of British Columbia and the lead author of the paper. “We’re warming the neurons up. We’re preparing the brain to learn.”

And to prepare the neurons to learn, Boyd stimulates them with very targeted magnetic fields. The fields instigate activity in the target neurons, giving those neurons a running start for forming new connections to other neurons.

According to Boyd, the magnetic stimulation targets a region of the brain called the premotor cortex. The premotor cortex is the middle management of motor control. It figures out the plan, and leaves different parts of the brain to tell the muscles to execute that plan. Because it is higher up in the brain hierarchy, the premotor cortex is central to the fixation of motor memory, and an important redoubt for motor skills when a stroke takes out the neurons farther downstream.

In the study, Boyd found that for 30 minutes after magnetic brain stimulation, test subjects learned to trace a pattern on a computer significantly faster than their non-stimulated counterparts.

And while that’s not enough to convince me to put my head next to the microwave before I practice the piano, the evidence is striking enough to convince Boyd both that the technique has promise for victims of brain damage and that she should start trying this technique on other areas of the brain.

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