Wednesday, May 24, 2006

Male Infertility & Spinal Cord Injury

Fertility in Men with Spinal Cord Injury; New Insights

In the United States, 80% of new injuries occur to males. 62% are 16-35 years old. Although reproductive function in women with SCI is generally normal, infertility is a major complication of SCI in men. 90% cannot father children via sexual intercourse.

Dr Bracket highlighted the fact that there are well established and effective treatment for both erectile dysfunction and ejaculatory dysfunction. Although, electroejaculation (EEJ) and vibratory stimulation (PVS) has demonstrated efficacy in the retrieval of sperm which is sufficient for intrauterine or even intravaginal insemination, Dr Bracket presented data demonstrating that nearly 2/3 of physicians recommend the utilization of testicular sperm acquisition techniques and in vitro fertilization and intracytolplasmic sperm injection for SCI patients. A review carried out by Dr Brackett indicated that 70% of all electroejaculation and 90% of PVS antegrade trials had sufficient sperm recovery for IUI. Most providers who do not offer electroejaculation or vibratory stimulation do so because of the lack of access to specialized equipment. Dr Bracket advocated that physician attempt to acquire ejaculated sperm using EEJ and PVS and utilized these specimens for IUI in the management of patients with SCI.

Editorial comment:
It is important to recognize that ejaculated sperm can and should be utilized when possible. Providers should ideally not utilize IVF and ICSI when less expensive and effective alternatives are available. However, the utilization of testicular sperm acquisition and IVF appears to be more widely available and will allow men with SCI to achieve parenthood.

By Harris M. Nagler, MD
Society for the Study of Male Reproduction by Harris Nagler
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Monday, May 15, 2006

Factor Isolated that Regenerates Nerve Fibers

Factor Isolated That Regenerates Nerve Fibers; Previously Unknown Molecule Spurs Regeneration in Optic Nerve

Researchers at Children's Hospital Boston have discovered a naturally occurring growth factor that stimulates regeneration of injured nerve fibers (axons) in the central nervous system. Under normal conditions, most axons in the mature central nervous system (which consists of the brain, spinal cord and eye) cannot regrow after injury. The previously unrecognized growth factor, called oncomodulin, is described in the May 14 online edition of Nature Neuroscience.

Neuroscientists Yuqin Yin, MD, PhD, and Larry Benowitz, PhD, who are also on the faculty of Harvard Medical School, did their studies in the optic nerve, which connects nerve cells in the eye's retina to the brain's visual centers, and is often used as a model in studying axon regeneration.

When oncomodulin was added to retinal nerve cells in a Petri dish, with known growth-promoting factors already present, axon growth nearly doubled. No other growth factor was as potent. In live rats with optic-nerve injury, oncomodulin released from tiny sustained-release capsules increased nerve regeneration 5- to 7-fold when given along with a drug that helps cells respond to oncomodulin. Yin, Benowitz and colleagues also showed that oncomodulin switches on a variety of genes associated with axon growth.

Benowitz, the study's senior investigator, believes oncomodulin could someday prove useful in reversing optic-nerve damage caused by glaucoma, tumors or traumatic injury. In addition, the lab has shown that oncomodulin works on at least one other type of nerve cell, and now plans to test whether it also works on the types of brain cells that would be relevant to treating conditions like stroke and spinal cord injury.

The current study builds on work Benowitz, Yin and colleagues published a few years ago. Studying the optic nerve, they found - quite by accident - that an injury to the eye activated axon growth: it caused an inflammatory reaction that stimulated immune cells known as macrophages to move into the eye.

"To make this finding clinically useful, we wanted to understand what was triggering the growth, so we could achieve nerve regeneration without causing an injury," Benowitz says.

Working in Benowitz's lab, Yin took a closer look and found that the macrophages secreted an essential but as-yet unidentified protein. Further studies revealed it to be oncomodulin, a little-known molecule first observed in association with cancer cells.

"Out of the blue, we found a molecule that causes more nerve regeneration than anything else ever studied," Benowitz says. "We expect this to spur further research into what else oncomodulin is doing in the nervous system and elsewhere."

For oncomodulin to work, it must be given along with an agent that raises cell levels of cyclic AMP, a "messenger" that initiates various cellular reactions. Increased cyclic AMP levels are needed to make the oncomodulin receptor available on the cell surface.

A two-pronged approach

Benowitz also notes that there is another side to the nerve-regeneration problem: overcoming agents that act as natural inhibitors of axon growth. These inhibitors are the subject of intense study by several labs, including that of Zhigang He, PhD, at Children's Hospital Boston.

In a study published in 2004, Benowitz and postdoctoral fellow Dietmar Fischer, PhD, collaborated with He to combine both approaches - overcoming inhibition and activating the growth state (by injuring the lens of the eye) - and achieved dramatic optic-nerve regeneration. Now that Benowitz has isolated oncomodulin, he believes even greater regeneration is possible by combining it with agents that counteract growth inhibitors.

"We're in the midst of an exciting era of research in nerve regeneration," Benowitz says. "There are a lot of promising leads in the area of blocking molecules that inhibit regeneration. But to get really strong regeneration, you also have to activate nerve cells' intrinsic growth state."
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Wednesday, May 03, 2006

Female Spinal Cord Patients w/ Amenorrhea May Still Conceive Children

Some Female Spinal Cord Patients With Amenorrhea May Still Conceive Children: Presented at AACE

Many women who sustain permanent spinal cord injury and develop resulting transitory amenorrhea may still be able to conceive children, according to a poster presented here at the annual meeting of the American Association of Clinical Endocrinologists (AACE).

Amenorrhea has been proven to be stress-related, but women return to normal sexual function after transitory amenorrhea," said Ghasa Mahmood, MD, endocrinology fellow, Martin Luther King/Charles Drew University Medical Center, Los Angeles, California, United States, in a presentation on April 27th.

Of 128 women who sustained a spinal cord injury, 53 immediately developed amenorrhea, or a cessation of menstrual flow. Of those, 3 went into menopause, Mahmood said. The study was a retrospective analysis of patients in a cardiovascular risk study. All of the women who went into menopause were over 40 years of age at the time, she said.

"Of the remaining 50 women, we had 10 pregnancies," Dr. Mahmood said, calling the study the largest to date in the field. The median period of transitory amenorrhea was 7.96 months, she said. "But even if the patient gets amenorrhea for 15 months, not 6 months, she can still get pregnant, because the duration of amenorrhea is not statistically significant."

Also bearing no apparent relation to the likelihood of pregnancy in the study was the level of a patient's injury. Spinal trauma experience by the patients included cervical, thoracic, and lumbar spinal trauma. "All of these were permanent injuries, resulting in irreversible paralysis," Dr. Mahmood emphasized.

"The only thing that our data suggested to be a relevant factor was the patient's age at the time of the trauma," Dr. Mahmood said. "The mean age was 21 among women who later got pregnant, and 28 among the women who didn't."

Among the 10 women who conceived, 4 elected to terminate the pregnancy, while at least half of the remaining 6 gave birth via Caesarean section, according to the poster.

Dr. Mahmood said he intends to investigate the relationship between spinal cord trauma and amenorrhea.

"We're going to go back and check the levels of prolactin, luteinizing hormone (LH), and follicle stimulating hormone (FSH), as well as the estrogen and progesterone levels among those patients," she said, noting that traumatic injuries can affect the hypothalamus or the pituitary stalk, possibly resulting in amenorrhea.

"Another reason for the amenorrhea may be the drugs these patients take to control spasms which result from the injury," Mahmood said.

By John Otrompke
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Lowering body temp shows promise for trauma treatment

Twenty years ago, W. Dalton Dietrich and his colleagues had a problem: the rats in their laboratory experienced the same kind of stroke but had dramatically different outcomes.

''We were perplexed,'' Dietrich says.

To try to figure out what was going on, they started measuring the temperature of the rats' brains. The results were shocking.

Rats whose brains were just a few degrees cooler than normal fared far better than others. Outcomes for those whose brains were a few degrees warmer than normal were, in Dietrich's words, ``really, really, really bad.''

That discovery inspired new interest in an old idea that had lost favor: using hypothermia to help patients who have suffered grave harm to the heart, brain or spinal cord. Now research is moving out of the laboratory and into the clinic. Some studies have shown no benefit from inducing hypothermia, but others have shown great promise.

Doctors are using a wide range of techniques for cooling -- from simple ice packs to high-tech machines that run cold fluid through the veins. Specific treatments vary, but patients are typically cooled until their body temperature is in the low 90s (98.6 is normal), and kept that way for 12 to 48 hours. Treatment must be started early -- usually within hours of the injury or cardiovascular event.

Last year, following the publication of two major studies, the American Heart Association recommended inducing hypothermia in some patients after cardiac arrest. Doctors at Jackson Memorial Hospital plan to adopt the recommendations in the coming months, said Dr. Kathy Schrank, who runs the hospital's emergency department.

In other studies, doctors are cooling oxygen-deprived newborns as well as adults who have suffered strokes, heart attacks and traumatic brain injuries.

At the Miami Project to Cure Paralysis, where Dietrich is now scientific director, researchers are trying to understand exactly how temperature variations affect cell behavior. And Dr. Barth Green, the Miami Project's co-founder, is inducing hypothermia in some of the most gravely injured spinal cord patients in the minutes or hours after they arrive at the trauma center.

''It's a wonderful opportunity for us, for the first time ever, to protect the spinal cord after injury,'' Green says.

Manny Gomez, a policeman who fell from his horse in January, was the first South Florida spinal cord trauma patient to be treated with hypothermia. Doctors lowered his body temperature by several degrees for two days following his injury. Now he's slowly learning to walk again.

''I think the treatment really does work,'' Gomez says.

His doctor, Dr. Steven Vanni, agrees -- but adds that hypothermia is only one piece of a larger treatment puzzle. And the kind of solid research that would definitively prove whether hypothermia works for spinal cord trauma has not yet been done, Green says.

The research is further along in other fields. Two studies published in the New England Journal of Medicine in 2002 found that patients who were cooled after suffering cardiac arrest were more likely to survive and less likely to have severe brain damage than patients who were not cooled.

Both studies focused on a small sub-set of patients researchers thought most likely to benefit from hypothermia; patients had to meet several criteria, including having hearts that stopped before they were admitted to the hospital, suffering from a particular abnormal rhythm and remaining in a coma after their heartbeat had been restored by CPR.

The evidence compelled the American Heart Association to endorse the procedure last year for patients like those in the studies. Dr. Vinay Nadkarni, a University of Pennsylvania intensive care specialist who served on the committee that issued the endorsement, called hypothermia ``the most promising intervention for CPR outcomes over the past 40 years.''

He cautioned, though, that more research is needed to figure out whether a broader pool of patients would benefit from hypothermia, and to determine the best methods for cooling and rewarming.

ICE PACKS, COOL AIR

Doctors in one of the cardiac arrest studies used ice packs; in the other they used a device that blows cool air under a blanket. In both studies it took several hours, on average, to drop body temperatures by a few degrees. Some believe they can do better by using other devices that can lower temperatures in minutes rather than hours.

At the Baptist Cardiac and Vascular Institute in Miami, Dr. Ramon Quesada will soon begin enrolling heart attack patients in a multi-center study using a device that circulates cool fluid within a closed plastic tube threaded into the patient's veins. A study published last year showed promising results using tiny caps to cool the heads of newborns at risk for brain damage because they didn't get enough oxygen at birth.

The original idea behind hypothermic therapy is simple: Hypothermia slows metabolism, allowing cells to survive longer when deprived of oxygen -- as in the rare cases when someone falls into a frozen lake and survives after spending 20 minutes or more underwater.

Inspired by cases like these, researchers experimented with hypothermia in the 1940s and 1950s. Cooling patients became popular as a protective measure during heart and brain surgeries. But using hypothermia as therapy fell out of favor in the 1960s and 1970s with the emergence of promising new drugs and growing concerns over the risks -- including potentially deadly abnormal heart rhythms -- of inducing profound hypothermia.

The work of Dietrich and others in the 1980s showing the benefits of mild or moderate hypothermia -- lowering body temperature by a few degrees -- revived interest.

BROADER INSIGHT

Since then, scientists have gained new insight into the way cooling reduces the problems that follow injury, such as widespread inflammation and the release of harmful chemicals that can set off a cascade of damage to surviving tissue. Hypothermia may also reduce many of the harmful chemical reactions that occur when blood flow is restored after a stroke or heart attack.

One possible problem: Mild hypothermia may inhibit the immune system and make the patient more susceptible to infection, Dietrich says. Also, it can be necessary to prescribe drugs and, in some cases, temporarily paralyze the patient to prevent shivering, which carries a low risk. A small risk is also associated with inserting a catheter to cool a patient. But in general, the risks of mild cooling appear minimal, particularly when applied in cases where the outlook is grim, doctors say.

The devil remains in the details: Which patients will benefit most? What is the best way to cool patients? How soon after injury does cooling need to begin? Should the whole body be cooled, or just one region? How cool, and for how long? And how should a patient be re-warmed?

''The great hope would be that in the near future we could appropriately identify . . . the patients at risk who could benefit, and who could be cooled quickly and safely,'' said Nadkarni, reflecting on the prospects for hypothermia in cardiac arrest patients. ``If we can do that, we've got the intervention of the century on our hands.''

By JACOB GOLDSTEIN
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Monday, May 01, 2006

Novel Stem Cell Technology Leads to Better Spinal Cord Repair

By University of Rochester Medical Center, Researchers believe they have identified a new way, using an advance in stem-cell technology, to promote recovery after spinal cord injury of rats, according to a study published in today's Journal of Biology.

Scientists from the New York State Center of Research Excellence in Spinal Cord Injury showed that rats receiving a transplant of a certain type of immature support cell from the central nervous system (generated from stem cells) had more than 60 percent of their sensory nerve fibers regenerate. Just as importantly, the study showed that more than two-thirds of the nerve fibers grew all the way through the injury sites eight days later, a result that is much more promising than previous research. The rats that received the cell transplants also walked normally in two weeks.

The University of Rochester Medical Center, Rochester, N.Y., and Baylor College of Medicine, Houston, collaborated on the work. Researchers believe they made an important advance in stem cell technology by focusing on a new cell type that appears to have the capability of repairing the adult nervous system.

"These studies provide a way to make cells do what we want them to do, instead of simply putting stem cells into the damaged area and hoping the injury will cause the stem cells to turn into the most useful cell types," explains Mark Noble, Ph.D., co-author of the paper, professor of Genetics at the University of Rochester, and a pioneer in the field of stem cell research. "It really changes the way we think about this problem."

The breakthrough is based on many years of stem cell biology research led by Margot Mayer-Proschel, Ph.D., associate professor of Genetics at the University of Rochester. In the laboratory, Mayer-Proschel and colleagues took embryonic glial stem cells and induced them to change into a specific type of support cell called an astrocyte, which is known to be highly supportive of nerve fiber growth. These astrocytes, called glial precursor-derived astrocytes or GDAs, were then transplanted into the injured spinal cords of adult rats. Healing and recovery of the GDA rats was compared to other injured rats that received either no treatment at all or treatment with undifferentiated stem cells.

The rats without the GDA cell transplant did not show any nerve fiber regeneration and still had difficulty walking four weeks after surgery.

"We demonstrated that we can treat these precursor cells, in culture, with signals we know to be important in the development of astrocytes and push these stem cell-like cells down a pathway that supports regeneration of the nervous system," said Stephen Davies, Ph.D., the study's lead investigator and assistant professor of Neurosurgery at Baylor.

"At the heart of stem cell transplantation research is finding the right cell for the right job," Noble added. "In this case the work of this team has identified a cell that provides many more benefits than those seen with other cell types and thus, it gives us hope that we are on a better track."

The GDA cells seem to work by signaling the tissue to repair in several ways, such as by suppressing scar tissue, rescuing motor pathway neurons in the brain and aligning damaged tissue at the injured site. More investigation is needed, however, before the new technology could be used in humans, researchers said.

- Journal of Biology
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Stem Cell Technology Gives Hope in Spinal Cord Injuries

Recent research using stem-cell technology in rats with spinal-cord injuries has allowed them to walk again within two weeks . The results of the study show promise for people with traumatic spinal-cord injuries.

According to lead author Dr. Stephen Davies, assistant professor of neurosurgery at Baylor College of Medicine in Houston the rats were given immature immune system support cells called astrocytes and this resulted in a 40-percent rise in nerve-fiber growth at the site of the injury in only eight days.

The results of the research is published in the April 26 in the open-access Journal of Biology. The Christopher Reeve Foundation has partly funded this research.

Stem cell technology for the repair of the central nervous system in humans has been the focus of several studies over many years. This study has shown advances in the use of that technology. Stem cells have the ability to respond to signals in tissue to become cells of that particular type of tissue.

Stem cells can be either of adult or embryonic origin. Adult stem cells are derived from the body?s tissue or organs whereas embryonic stem cells are derived from eggs fertilized in vitro.

Davies explains that the body normally creates scar tissue to prevent infection during any injury including a spinal cord injury. However this mechanism can have disastrous consequences on the spinal cord because scars inhibit nerve-fiber regeneration thereby leading to paralysis and other problems.

And for this very reason transplanting adult stem cells into an injured spinal cord does not encourage nerve growth. .

This led the Davies team to think of signaling cells similar to stem cells known as the glial-restricted precursors, or GRPs, to become a particular type of embryonic astrocyte which was considered to have a remarkable ability of repairing embryonic spinal cord. This in turn was considered for transplantation into adult spinal cord injuries that could inhibit scarring while encouraging nerve growth at the same time.

For this purpose a specific type of astrocyte support cell was generated from the GRPs, discovered by cell biologist Margot Mayer-Proschel of the University of Rochester Medical Center.

It was observed that rats given this specialized astrocyte cell showed less scar tissue and nerve damage in contrast to the control group, which was transplanted with un-cultured cells. Amazingly their locomotion improved to such an extent that they could walk completely normally within two weeks of the treatment

In addition it was observed that the brains of these rats also demonstrated improvement. This was unusual because degeneration of neurons often occurs with spinal cord injuries due to the degeneration of their nerve fibers running down the spinal cord. However with the astrocyte transplant up to 80 percent of nerve degeneration was suppressed.

Dr. Wise Young, a neuroscientist and director of Rutgers University`s W.M. Keck Center for Collaborative Neuroscience has been a pioneer in treating spinal-cord injury. He has organized clinical trials in China, where the influence of umbilical-cord blood stem cells in the central nervous system is planned.

According to Young 'The paper shows very compelling data for moving GRPs to clinical trial as soon as compatible human cells can be obtained.?

However Davies points out that the lack of availability of stem-cell lines in the United States was a big hurdle to be crossed as hundreds of thousands of the GRP cells would be required to act in a person.

Young still remains optimistic that the day was not too far when scientists would be able to make any cell into a stem cell.

In the future Davies hopes to use the new technology to repair central nervous system injuries in people, as well as other neurodegenerative diseases.
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Spinal Cord Injuries Repaired By New Type of Stem Cells - GDA

Spinal Cord Injuries Repaired By New Type of Stem Cells - GDA ( Glial Precursor Derived Astrocytes) Work Better Then Regular Stem Cells

Researchers have found that transplanting a certain type of immature support cell from the central nervous system could regenerate more than 60% of the nerves that are damaged after a spinal cord injury. Amazingly, two thirds of the nerve fibers grew all the way through the injury sites eight days later.

This is more promising than previous research, according to the University of Rochester researchers in New York. Rats that received the cell transplants also walked normally after two weeks.

Researchers from the Rochester Medical Center, Rochester, N.Y., in collaboration with Baylor College of Medicine, Houston, focused on a new cell type that appears to have the capability of repairing the adult nervous system.

Co-author, Mark Noble, Ph.D. explains ?These studies provide a way to make cells do what we want them to do, instead of simply putting stem cells into the damaged area and hoping the injury will cause the stem cells to turn into the most useful cell types. It really changes the way we think about this problem." Mark is professor of Genetics at the University of Rochester, and a pioneer in stem cell research.

These special cells, called astrocytes, are highly supportive of nerve fiber growth. These astrocytes, called glial precursor-derived astrocytes (GDAs), were transplanted into the injured spinal cords of adult rats. The scientists compared rats treated with these GDAs and rats that received either no treatment or treatment with undifferentiated stem cells.

Rats without the GDA cell transplant did not show any nerve fiber regeneration and still had difficulty walking four weeks after surgery. Stephen Davies, Ph.D., the study's lead investigator and assistant professor of Neurosurgery at Baylor said ?We demonstrated that we can treat these precursor cells, in culture, with signals we know to be important in the development of astrocytes and push these stem cell-like cells down a pathway that supports regeneration of the nervous system.?

Noble added ?"At the heart of stem cell transplantation research is finding the right cell for the right job. In this case the work of this team has identified a cell that provides many more benefits than those seen with other cell types and thus, it gives us hope that we are on a better track."

The GDA cells seem to work on several fronts. First they signal the tissue to repair by suppressing scar tissue. Then they ?rescue? motor pathway neurons in the brain and align the tissue at the injured site. The researchers say that more investigation is needed before the new technology can be used on humans.
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Purdue Researchers Work on Drug to Relieve Spinal Cord Injuries

Purdue University researchers are working to develop a drug that could reverse some spinal cord injuries as well as other neurological traumas.

Richard Borgens, founder of the Center for Paralysis Research and a leader of the team, said the team got the idea for the new drug after discovering that a blood pressure medication called hydralazine can act as an antidote to acrolein, a poison that damaged nerve cells release to destroy themselves.

Borgens, professor of applied neurology, said hydralazine itself cannot be used to treat spinal cord injuries because it lowers blood pressure.

"You could give it, but you'd have to use accessory drugs to get blood pressure up," he said.

Instead, the team aims to develop a new drug that acts as an antidote to acrolein without lowering blood pressure.

Borgens said the new drug could reverse spinal cord injuries because in these injuries, the damaged cells do not die right away.

"Cells will continue to die, sometimes for weeks after the event. It's a progression related to the severity of the injury," he said. The delayed nature of the cells' death could give doctors time to reverse the damage.

Borgens said if the drug is developed, it has the potential to cure nerve cells damaged not only by spinal cord injuries, but by a broad range of medical disorders, including arthritis and Parkinson's disease. The drug could even facilitate the recovery of people who narrowly escape drowning.

Riyi Shi, associate professor of basic medical science and a leader of the study, said developing the drug will probably take about one to two years.

"It takes another three to four years to go through clinical testing, although it is difficult to predict the length of such process," he said.

To design the drug, Dr. Dan Smith, postdoctoral research fellow in industrial and physical Pharmacy and a member of the team, is looking at the structure of hydralazine. Smith said understanding hydralazine will help the team develop a drug that neutralizes acrolein without lowering blood pressure.

"Unfortunately, how hydralazine works to lower blood pressure is not fully understood," he said.

But he said the team still has some idea of what part of the hydralazine molecule neutralizes acrolein.

"We can build a new molecule around the active part," he said.

The team has already started developing the new drug. Smith is creating new compounds that might fulfill the team's objectives. Research team member Peishan Liu-Snyder is working on testing their efficacy.

Smith said while the medication has a wide range of applications, one type of nerve cell damage the team is focusing on is the damage caused by traumatic stroke.

By Joy Nyenhuis-Rouch
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