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Injecting the Heart With Stem Cells Helps Chest Pain – ABC …

Posted: November 5, 2015 at 4:45 am

George Reed’s heart wasn’t doing so well: He’s 71, and after suffering a heart attack years earlier, Reed had undergone open heart surgery and was put on multiple medications. But nothing seemed to help the dizziness and chest pain he experienced daily.

“I’d get dizzy and just fall over — sometimes twice a day. I would run my head into the concrete. I was a bloody mess,” the Perry, Ohio, native says. Despite his doctor’s best efforts, Reed continued to experience angina, a type of chest pain that occurs when the heart doesn’t get enough oxygen-rich blood; it can be accompanied by dizziness. So when he was recommended for an experimental study that would inject his own stem cells into his damaged heart, Perry signed on. “I needed something to change,” he says.

Researchers gave Reed a drug commonly used in bone marrow transplants that stimulates the marrow to make more stem cells. Then they removed some of Reed’s blood, isolated the stem cells and injected them into and around the damaged areas of his heart.

“The goal was to grow new blood vessels with stem cells from the patient’s own body,” says Dr. Tim Henry, a co-author of the study and director of research at the Minneapolis Heart Institute Foundation.

Within a few months, Reed, along with many of the other 100 or so patients at 26 hospital centers who’d received this stem cell treatment, reported feeling better than he had in years.

“When it started kicking in, I felt like a kid. I felt good,” Reed says. He wasn’t passing out and falling down anymore.

For Jay Homstad, 49, who was part of the Minnesota branch of the study, he felt the changes most in his ability to walk and be active.

“My activity level increased tenfold. Before, I struggled with chest pain every day. My activity level was about as close to zero as you could get. Now I can participate … just in life. It may sound silly, but the best part is that in the wintertime I could go out and walk with my dog along the Red River. When you’re walking through snow that is waist deep, you can tell there’s a difference,” Homstad says.

Homstad had had about a dozen surgeries and nine stents put in before he enrolled in the study, but he still struggled with angina daily. Within a few months of the stem cell shots, he could walk farther, and his chest pain subsided and was kept at bay for nearly four years.

“These are people for whom other treatment hasn’t worked. They’re debilitated by their chest pain, but their other options are really limited, that’s why we picked them,” says Henry. If the positive results seen in this study hold up in the next phase of the study, which is set to begin enrollment in the fall, this type of cardiac stem cell injection could be added to the arsenal of weapons against angina. The upcoming phase three trial has already been approved by the Food and Drug Administration.

Shot to the Heart, Before It’s too Late

While several smaller studies have suggested that injecting stem cells into damaged heart tissue might be effective, this study, in its scope and rigor, was the first of its kind. A total of 167 patients were recruited and randomly assigned to receive a lower dose of stem cells, a higher dose or a placebo. The patients didn’t know who got what treatment, and neither did the doctors treating them.

When tracked for a year after the injection, patients who received the lower dose of stem cells could last longer during a treadmill exercise than those who had received the placebo, and they averaged seven fewer episodes of chest pain in a week. To put this in perspective, a popular drug to treat angina, Ranolazine, reduced chest pain by fewer than two episodes a week in clinical trials.

Although the goal of the stem cell shots was to grow new blood vessels, it’s impossible to tell if these stem cells were actually growing into blood vessels or if they were just triggering some other kind of healing process in the body, Henry says. Tests in animal models, however, do suggest that new blood vessels are forming, says Dr. Marco Costa, a co-author of the study and George Reed’s doctor at UH Case Medical Center in Cleveland.

For now, the only gauge of the injections is improvement in symptoms.

Despite the positive results of the study, cardiologists remain “cautiously optimistic” about stem cells as a treatment for angina.

“The number of patients is relatively small, so this trial would probably not carry much scientific weight,” says Dr. Jeff Brinker, a professor of cardiology at Johns Hopkins University. The results did justify the next, larger trial, he says, which would offer more answers as to whether this treatment is actually working the way researchers suspect.

The fact that lower doses of stem cells were puzzlingly more effective than larger ones is cause for caution, says Dr. Steve Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

“The jury is still out for stem cell therapies to treat heart disease,” says Dr. Cam Paterson, a cardiologist at the University of North Carolina at Chapel Hill.

But the results so far provide cautious hope for heart patients like George Reed and Jay Homstad.

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Injecting the Heart With Stem Cells Helps Chest Pain – ABC …

Statement on Stem Cells and Cell Therapies for Lung Diseases

Posted: November 4, 2015 at 6:46 am

DATE APPROVED: June 23, 2012

The American Lung Association strongly supports research to prevent lung disease, and reduce exacerbation of lung disease, discover cures and improve the diagnosis of lung disease. The research should include basic, translational clinical, biomedical, behavioral and environmental areas. In addition, research should investigate measures to eliminate disparities in lung disease morbidity and mortality for low socioeconomic and minority populations. Research should be conducted in a legal, ethical and humane manner.

The American Lung Association supports increased federal funding levels for biomedical, behavioral, epidemiological, environmental and intervention research and research training programs, including but not limited to those conducted by the National Institutes of Health, the Centers for Disease Control and Prevention, the Agency for Healthcare Research and Quality, the Department of Veterans Affairs and the Environmental Protection Agency.

The American Lung Association recognizes the critical role animal research has played in making medical advances. The American Lung Association strongly supports full compliance with the existing rules and regulations that assure the humane and compassionate management of laboratory animals. We encourage all forms of biomedical research involving animals that have been carefully scrutinized and deemed worthy by qualified experts, and we oppose all efforts to exclude the use of animals whenever they are essential for research.

The American Lung Association recognizes that research with human stem cells offer significant potential to further our understanding of fundamental lung biology and to develop cell-based therapies to treat lung disease. The American Lung Association supports the responsible pursuit of research involving the use of human stem cells.

The American Lung Association requires that the research it supports follow ethical standards including adherence to all applicable federal, state and local rules and regulations. All relevant Institutional Review Boards (IRB)/Human Subjects Committees should review and approve research proposals involving human subjects. Research involving animal subjects must also undergo committee Institutional Animal Care and Use Care (IACUC) review and approval as well as all other review processes as appropriate for the proposed research. Failure to adhere to such processes should result in termination of research support.

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Statement on Stem Cells and Cell Therapies for Lung Diseases

Front Matter | Guidelines for Human Embryonic Stem Cell …

Posted: November 4, 2015 at 6:46 am

COREY S. GOODMAN (Chair),

Renovis Inc., South San Francisco, California

ANN M. ARVIN,

Stanford University School of Medicine, Stanford, California

JEFFREY L. BENNETZEN,

University of Georgia, Athens, Georgia

RUTH BERKELMAN,

Emory University, Atlanta, Georgia

R. ALTA CHARO,

University of Wisconsin, Madison, Wisconsin

DENNIS CHOI,

Merck Research Laboratories, West Point, Pennsylvania

JEFFREY L. DANGL,

University of North Carolina, Chapel Hill, North Carolina

PAUL R. EHRLICH,

Stanford University, Palo Alto, California

JAMES M. GENTILE,

Research Corporation of America, Tucson, Arizona

ED HARLOW,

Harvard Medical School, Boston, Massachusetts

DAVID HILLIS,

University of Texas, Austin, Texas

KENNETH F. KELLER,

University of Minnesota, Minneapolis, Minnesota

RANDALL MURCH,

Virginia Polytechnic Institute and State University, Alexandria, Virginia

GREGORY A. PETSKO,

Brandeis University, Waltham, Massachusetts

STUART L. PIMM,

Duke University, Durham, North Carolina

BARBARA A. SCHAAL,

Washington University, St. Louis, Missouri

JAMES TIEDJE,

Michigan State University, East Lansing, Michigan

KEITH YAMAMOTO,

University of California, San Francisco, California

FRANCES E. SHARPLES, Director

KERRY A. BRENNER, Senior Program Officer

ROBIN SCHOEN, Senior Program Officer

MARILEE K. SHELTON-DAVENPORT, Senior Program Officer

ROBERT T. YUAN, Senior Program Officer

ADAM P. FAGEN, Program Officer

ANN REID, Program Officer

EVONNE P. Y. TANG, Program Officer

SETH STRONGIN, Senior Program Assistant

MATTHEW D. MCDONOUGH, Program Assistant

DENISE GROSSHANS, Financial Associate

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Front Matter | Guidelines for Human Embryonic Stem Cell …

Stem and Branches | Radical Botany

Posted: November 3, 2015 at 6:49 am

As they presented the herb to me they told me to drop it on the earth and when it hit the earth it took root and flowered. You could see a ray of light coming up from the flower, reaching the heavens, and all the creatures of the universe saw the light. Black Elk (in DeMaille, The Sixth Grandfather)

Apical Meristem Cell tissue – the God force

Ok, being the total plant nerd that I am; I get very excited about teaching about parts of the plant. I mean it blows my mindthat all you have to do is cut a branch, place it in water, and watch it grow roots. How does that happen? What would happen if humans could do the same and just grow new parts? (clue: stem cells)

And, a second amazing fact about stems and branches is that you can grafta branch of one plant on to another plant and promote new and interesting growth and fruit. Pure magic! (More on grafting later).

What is happening here? It all goes back to the most magical part of a plant-the meristem cell. You know, the God-particle magical cell that stores all the DNA of the plant and allows parts of the plant to regenerate, accept cells from other plants, and grow itself from an injured part.

Let me explain in more detail. (Now dont get bored with all this plant physiology facts, in the end it all is just amazing and your knowledge of living with, growing and ingesting plants will grow exponentially!)

Meristem tissue in most plants consists of undifferentiated meristematic cells. With the apical meristem cells the tissue either heading downward and becoming roots or heading upwards and becoming stem, branch, leaves and flower are considered to be indeterminate or undifferentiated, in that they do not possess any defined end fate. The meristem cells remember that they are going to grow into a tree, a shrub, a wildflower etc, but allow a variety of changes to happen to the tissue. Where ever these cells appear in the plant, there can be new growth, including growing new parts. These types of cells seem to store the DNA of any part of the plant. The apical meristem, or growing tip, is a completely undifferentiated meristematic tissue found in the buds and growing tips of roots in plants. Its main function is to begin growth of new cells in young seedlings at the tips of roots and shoots (forming buds, among other things). Meristem cells cause the plant growth to take place in a very organized yet adaptive process. Now, meristem cells can become differentiated after they divide enough times and reach a node or internode. As the plant grows upward driven by apical meristem cells the tissue begins to organize itself into stem, branch, leaves and flower. These cells divide rapidly and are found in zones of the plant where much growth can take place. That is why you can graft one part of a plant to another part of the plant if it is in the right zone or node and if the two plants share the same type of DNA. Plants must be closely related for grafting to be successful.

For tissues to knit successfully, the cambium layers (full of fast dividing meristem cells) and rootstock must be brought into firm contact. The cambium a continuous narrow band of thin-walled, regenerative cells just below the bark or rind grows to form a bridge or union between the two parts in days. The same cells are found at the joint of a branch which allows it to grow new roots at the cut. Now, not all plants can grow roots from a branch. You need to study each plant for its particular characteristics.

SEED TO STEM THE JOURNEY BEGINS

The stem begin its journey with the seed opening up and a dicot or monocot leaf revealing itself.

A monocot (a flowering plant that produces an embryo seed with single cotyledons) will produce only one leaf. A dicot will produce two embryonic seed leaves or cotyledon. The cotyledon is a seed leaf the first to appear as the seed sprouts. It appears at the same time that root tissue appears.

Next a shoot appears (new stem) and sends out growth. The apical meristem cell structure is leading the way. We assume that the stem is heading upward toward light but a contradiction to this rule would be stems that spread downward or sideways like potatoes, tulip bulbs and other tubers. A strawberry plant will create a stolon or sideways stem to propagate new growth. A vine has a long trailing stem that grows along the ground or along anything it can attach to.

The three major internal parts of a stem are the xylem, phloem, and cambium. The xylem and phloem are the major components of a plants vascular system. A cambium is a lateral meristem that produces secondary tissues by cell division. The cambium area is located just under the epithelial (outer most area of the stem) and is very active in cell growth. It is this area that is tapped into when attempting grafting.

Stem tissue is actually organized into pipe-like vascular bundles held together by pith and cortex tissues. These tissues are used for pipelines of fluid transport, connecting leaves, stems and roots. They also serve as a supportive structure for the stem. The stem is also made up of other substances that allow it to remain flexible so that it will not break easily. Depending on what kind of plant is growing, a great tree or a wildflower, the stem may become a thick trunk with layers of vascular cambium, cork and hard bark or a more herbaceous plant. The trunk of a tree is its main stem. And, yes plants can have more than one stem. The stem that branches is called a branch.

Stems may be long, with great distances between leaves and buds (branches of trees, runners on strawberries), or compressed, with short distances between buds or leaves (fruit spurs, crowns of strawberry plants, dandelions). All stems must have buds or leaves present to be classified as stem tissue.

An area of the stem where leaves are located is called a node. Nodes are areas of great cellular activity and growth, where auxiliary buds develop into leaves or flowers. The area between nodes is called the internode. Nodes are protected when pruning back a plant. Destruction of the nodes can result in long non-fruiting branches.

MODIFIED STEMS

Although typical stems are above-ground trunks and branches, there are modified stems which can be found above and below the ground. The above-ground modified stems include crowns, stolons, and spurs and the below-ground stems are bulbs, corms, rhizomes, and tubers.

STEM FUNCTION

NATIVE PLANT PROPAGATION BY CUTTINGS.

Taking cuttings from native plants to propagate them is especially helpful in preserving what is left of many species. There is no digging or destroying plants. Forest communities are not damaged.

The process of removing a plant part then having that part grow into a genetically exact replica of the original plant is called cutting propagation. It is a plant cloning technique. The plant part that is removed is called a cutting. Plants can be propagated from root cuttings, leaf cuttings, stem cuttings, etc.

Some amazing Cascadian bioregion native plants that root from branches are: Pacific Willow (Salix lucida), Hookers Willow (Salix hookeriana), Pacific Ninebarks (Physocarpus capitatus), and Snowbush (Ceanothus velutinus). All are great attractors of important pollinators and Snowbush will fix nitrogen in the soil.

The first peoples of Cascadia built summer fishing and hunting huts along marshes and streams by placing freshly cut Willow in circles. The Willow would root and grow into a shelter and hunting blind. Today, some wonderful garden trellis have been erected using live Willow.

VOCABULARY

REFERENCES

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Stem and Branches | Radical Botany

Cloning advance using stem cells from human adult reopens …

Posted: November 3, 2015 at 6:49 am

Scientists have grown stem cells from adults using cloning techniques for the first time bringing them closer to developing patient-specific lines of cells that can be used to treat a whole host of ailments, from heart disease to blindness.

The research, described in Thursdays online edition of the journal Cell Stem Cell, is a controversial advance likely to reopen the debate over the ethics of human cloning.

The scientists technique was similar to the one used in the first clone of a mammal, Dolly the sheep, which was created in 1996.

They reprogrammed an egg cell by removing its DNA and replaced it with that of an adult donor. Scientists then zapped the cell with electricity, which made it divide and multiply. The resulting cells were identical in DNA to the donor.

The first success in humans was reported last year by scientists at the Oregon Health & Science University and the Oregon National Primate Research Center. But they used donor cells from infants. In this study, the cells came from two men, a 35-year-old and a 75-year-old.

Paul Knoepfler, an associate professor at the University of California at Davis who studies stem cells, called the new research exciting, important, and technically convincing.

In theory you could use those stem cells to produce almost any kind of cell and give it back to a person as a therapy, he said.

In their paper, Young Gie Chung from the Research Institute for Stem Cell Research for CHA Health Systems in Los Angeles, Robert Lanza from Advanced Cell Technology in Marlborough, Mass., and their co-authors emphasized the promise of the technology for new therapies. What they didnt mention but was clear to those working with stem cells was that their work was also an important discovery for human cloning.

While the research published Thursday involves cells that are technically an early stage embryo, the intention is not to try to grow them into a fully formed human. However the techniques in theory could be a first step toward creating a baby with the same genetic makeup as a donor.

Bioethicists call this the dual-use dilemma.

Marcy Darnovsky, executive director of the Berkeley, Calif.-based Center for Genetics and Society, explained that many technologies developed for good can be used in ways that the inventor may not have intended and may not like.

This and every technical advance in cloning human tissue raises the possibility that somebody will use it to clone a human being, and that is a prospect everyone is against, Darnovsky said.

The research was conducted in California by a large team that included representatives from both academia and industry and was funded by a private medical foundation and South Koreas Ministry of Science.

From a technical standpoint, the technique called somatic-cell nuclear transfer is far from perfect. Chungs team attempted the cloning 39 times and only two tries produced embryos. At first they couldnt get the cells to multiply. But it turned out that if the researchers waited two hours instead of 30 minutes before trying to coax the cells, it worked.

We have reaffirmed that it is possible to generate patient-specific stem cells using [this] technology, Chung said.

Shoukhrat Mitalipov, director of the Center for Embryonic Cell and Gene Therapy at Oregon Health & Science University, developed the method that Chungs group built upon. He emphasized that the work involves eggs that have not been fertilized.

There will always be opposition to embryonic research, but the potential benefits are huge, Mitalipov said.

Seventeen years ago, news about Dollys birth led to impassioned calls for a ban on human cloning for the purpose of producing a baby who is a genetic copy of someone else. Several countries took measures to limit or outlaw such work. But in the United States, the issue became entangled in the politics of abortion, and Congress became deadlocked. Some lawmakers called for a ban on reproductive human cloning, but others refused to support such legislation unless it included a ban on human cloning whether it was for the purposes of reproduction or for the development of new therapies.

President George W. Bush brokered a compromise of sorts, restricting federal funding from stem cell research that results in harm to a human embryo.

At least 15 states have laws addressing human cloning. About half of them ban both reproductive and therapeutic cloning.

Since embryonic stem cell research began to take off 15 years ago, one of the main challenges scientists have faced is getting the material for their experiments. Many had been getting the cells from embryos left over from fertility treatments, but religious groups such as the U.S. Conference of Catholic Bishops vehemently objected to this, arguing that it involves killing a human being because the research involved fertilized eggs.

About seven years ago, scientists discovered they could use a different, molecular approach, called induced pluripotent stem cells, that could turn ordinary cells into stem cells without the need for an egg. While this technique did not present the same ethical issues, researchers soon found that some of the new cells had glitches, and there is still debate over how significant the flaws are. The research conducted by Mitalipov and Chung provides a second way of producing those cells through laboratory techniques.

Ariana Eunjung Cha is a national reporter. She has previously served as the Post’s bureau chief in Shanghai and San Francisco, and as a correspondent in Baghdad.

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Cloning advance using stem cells from human adult reopens …

Home Institute for Human Genetics at UCSF

Posted: November 3, 2015 at 6:47 am

Y.W. Kans pioneering research into the hemoglobinopathies sickle cell anemia and thalassemia has widely impacted genetic research, diagnostics, and treatment of human disease. The Institute for Human Genetics is proud to recognize Y.W. Kan with a symposium honoring his decades-long contributions.

Y.W. Kan arrived at UCSF in the 1970s when he and many others (including Herb Boyer and Bishop & Varmus) helped usher in the era of molecular genetics. With long-time collaborator Andre Dozy, he discovered the first polymorphism in human DNA by Southern blot analysis in 1978, launching the ability to map genes on human chromosomes.

He and another long-time collaborator, Judy Chang, used those same techniques in 1979 to show how missing genes cause disease. He is the recipient of many national and international awards for his contributions. He continues to investigate the treatment of these diseases using stem cell and iPS cell therapies.

The Symposium will feature presentations from James Gusella, Katherine High, Dennis Lo, Bertram Lubin, Robert Nussbaum, Stuart Orkin, and Griffin Rodgers. Stuart Orkin will be featured as the 2015 Charles J. and Lois B. Epstein Visiting Professor.

Featured topics will includegene mapping, gene therapy, hemoglobinopathies, and non-invasive prenatal testing.

The IHG Symposium will be held November 2, 2015 at 1:00-6:30 in Cole Hall on the UCSF Parnassus campus and will include a poster session and awards.

IHG Symposium website|Register Now

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Home Institute for Human Genetics at UCSF

Keystone Symposia Stem Cells and Cancer

Posted: November 2, 2015 at 10:52 am

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SUNDAY, MARCH 6

18:0020:00

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08:0009:00

Provide a stimulating and dynamic overview of some of the major ideas and trends shaping the field.

09:0011:15

Stability and reversibility of the stem cell state, lessons from model systems, comparisons with normal stem cells and self-renewal.

17:0019:00

Cooperativity, niche and immune interaction.

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08:0011:00

Control of birth, dormancy and expansion of normal and malignant stem cells/de novo human tumorigenesis.

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Exploration of the role of developmental pathways (eg. Notch, Wnt, Hippo, BMP, RSPO) in CSC biology.

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EMT, plasticity, lineage tracing, clonal tracking and tumors as evolving ecosystems.

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New therapeutic opportunities to target CSCs.

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08:0010:15

Therapeutic strategies for targeting CSC in the clinic.

17:0018:45

CSC metabolism, ROS involvement-control, epigenetics and miRNA.

18:4519:00

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Entertainment is not subsidized by conference registration fees nor any U.S. federal government grants. Funding for this expense is provided by other revenue sources.

Click here for more information on Industry Support and Recognition Opportunities.

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Keystone Symposia Stem Cells and Cancer

Stem Cells | Arizona Pain Specialists – Phoenix …

Posted: November 2, 2015 at 10:52 am

Stem cells are a specialized subset of cells within the body that are capable of dividing for the purpose of replenishing themselves and differentiating into specialized cells of the body, which are able to complete certain tasks (Bellehsen, Nagler, & Levi-Schaffer, 2008). For example, a stem cell might divide to create new stem cells, or to create a cell capable of undergoing biological transformation into a heart, lung, skin or other type of cell needed within the body.

For decades, researchers have investigated the means by which stem cells could be harnessed in medicine. Perhaps the most notable application of stem cells in medicine are the use of bone marrow and blood stem cell transplants to restore stem cells lost to chemotherapy in the treatment of cancers (ExitCare, LLC, 2011). Investigators are finding other potential uses for stem cells as well. The following are some of the conditions for which stem cells are being investigated as a potential medical treatment:

Stem cells are being investigated for many other medical applications as well, including ACL reconstruction, muscular dystrophies and more (Bagaria, et al., 2006). Stem cells are also currently used in cosmetic medical procedures. Even more exciting, however, are the stem cell therapies currently available for the treatment of conditions causing chronic pain. Many stem cell therapies have shown benefits and good outcomes during clinical studies, most of which are for the treatment of soft tissue and bony injuries. Research has shown that stem cells can aid in the recovery and replenishment of tendon, bone, cartilage and muscle tissue (Centeno, et al., 2008). Examples of painful conditions currently treated with stem cells by pain management specialists include osteoarthritis and other cartilage and tendon injuries.

There are two basic types of stem cells, embryonic and adult (Bellehsen, Nagler, & Levi-Schaffer, 2008):

One class of adult stem cells in particular, mesenchymal stem cells (MSCs), are important in emerging treatments for chronic pain. Unlike most adult stem cells, MSCs are pluripotent, thus gaining the advantages of embryonic stem cells without the ethical questionability surrounding embryonic stem cell harvesting. MSCs can be easily collected and grafted to injured tissue, thus serving as a primary source of stem cells in therapeutic applications for chronic pain (Drazin, et al., 2012).

A third type of stem cell currently gaining traction for the treatment of pain due to wounds and soft tissue and bony injuries are amniotic stem cells, which are largely comprised of MSCs (Steed, et al., 2008). These cells are harvested from the amniotic fluid that cushions and nourishes a fetus while to develops within the womb during pregnancy. These stem cells can also differentiate into a variety of different cell lines such as bone, nerve, muscle and skin.

Prior to a stem cell therapy procedure, the cells themselves must be acquired. Stem cells can originate from the patient themselves (autologous) or a close donor match (homologous or allogenic) (ExitCare, LLC, 2011). For procedures involving autologous transplant, the stem cells are first harvested from a patient, and then spun down in a centrifuge to allow gravity to separate the stem cells by weight. These stem cells can be collected via needle from blood, bone marrow or adipose tissue depending upon the procedure to be performed. For allogenic transplants, this same harvesting procedure is done with a donor, and the stem cells are stored for later use. For treatments involving amniotic stem cells, the cells are harvested from amniotic fluid during cesarean section and frozen for later use (Applied Biologics, 2011). Also, depending upon the procedure, before injection the stem cells collected may be supplemented with platelet-rich plasma (PRP). PRP consists of blood plasma concentrated to include higher than normal numbers of platelets, a cell that provides a multitude of protein growth factors involved in many other biological responses involved in healing and tissue repair (Mishra & Pavelko, 2006).

The source of stem cells may differ depending upon the type of procedure being performed. For most orthopedic applications, and procedures for the treatment of chronic musculoskeletal pain, bone marrow or peripheral blood serves as the best source of stem cells (Regenexx, 2010). For cosmetic applications of stem cells or procedures using stem cells for the treatment of nerve degeneration, adipose or fat tissue is often the best source.

The procedure for stem cell treatments differ depending upon the nature of the treatment and goals for therapy. However, all stem cell therapy procedures follow a basic outline. A patient is informed of all benefits, risks and alternatives to a stem cell therapy, before the procedure is scheduled. If harvesting of the stem cells is required, it is usually done in the morning before the procedure, such that the stem cells can be prepared before the patient returns in the afternoon. Harvesting involves using a needle to draw stem cells from the blood, adipose tissue or bone marrow by direct puncture of a flat bone, such as the hip.

Once the stem cells are prepared and available, a patient is comfortably positioned on a procedural table such that an injection or operative site is accessible to the physician (Centeno, et al., 2008). The site is then cleaned and sterilized, and the patient may be given local or general anesthesia to prevent any discomfort associated with the procedure. Once preparations are complete, a needle is guided to the target site of degenerated tissue, and the stem cell solution is injected directly to the area (Centeno, et al., 2008). The needle is often guided with radiographic assistance, such as ultrasound or fluoroscopy, a type of real-time x-ray.

For outpatient procedures, such as stem cell therapy for low back pain or soft tissue injuries, patients are often able to return home following a short period in which medical staff can monitor a patient for any adverse reactions. Any extra stem cells collected for the procedure can be cryo-stored (frozen) for future use.

Based on very early, but very promising case studies in which stem cells are used for the treatment of osteoarthritis and cartilage and tendon injuries, patients receiving stem cell therapy for chronically painful conditions can expect to see improvement in pain and in quality of life following the procedure. A major benefit of utilizing stem cell therapy for the treatment of chronic pain is that if successful, it can delay or even replace the need for surgical intervention.

As with any medical procedure involving injection or access through the protective skin barrier, infection and bleeding are a risk. These risks are minimal however, and stem cell therapy for the treatment of chronic pain associated with muscle, bone, tendon and cartilage disorders is considered very safe.

Patients should monitor their injection/operative site closely following the procedure, observing for any increased pain, redness, swelling or discharge which may require immediate medical attention. Patients can follow up with their pain management physician for any concerns.

Given the nature of stem cells ability to differentiate, and the infancy of stem cells for medical therapy, there has been significant concern in the medical community as to whether or not stem cell therapies might become cancerous. Thus far however, studies performed to assess this possibility have reported no cancerous complications associated with stem cell therapy (Centeno, et al., 2011).

In one pilot study designed to evaluate the effectiveness of implanting stem cells to treat degeneration of bone, researchers found that when compared to controls, patients receiving autologous stem cell therapy reported greater improvement in pain and other symptoms and were less likely to progress to further bone degeneration (Greenspan & Gershwin, 2008). Follow up studies have shown that stem cells can halt progression of bone degenerative disease. Many case reports report similar findings for conditions ranging from tendon injuries to osteoarthritis.

Stem cell therapies are certainly in their infancy; However, early studies show great promise for the use of stem cells in the treatment of a variety of musculoskeletal conditions causing chronic pain. With time and research over the next few years, many more applications of stem cell therapy will undoubtedly arise. Patients experiencing chronic pain should consult with a pain management specialist to find out of stem cell therapy may be appropriate for pain management, or as an alternative to surgery.

References Applied Biologics. (2011). Amniomatrix FAQ. Retrieved from Applied Biologics Website: http://www.appliedbiologics.com/index.php/frequently-asked-questions

Bagaria, V., & al., e. (2006). Stem cells in orthopedics: Current concepts and possible future applications. Ind J Med Sci , 162-169.

Bellehsen, L., Nagler, A., & Levi-Schaffer, F. (2008). Stem Cells: What Are They and Why Do We Need Them? Retrieved from MD Consult. Adkinson: Middletons Allergy: Principles and Practice, 7th ed.

Centeno, C., & al., e. (2008). Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician , (11) 343-353.

Centeno, C., & al., e. (2008). Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells. Med Hypo , (71) 900-908.

Centeno, C., & al., e. (2011). Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther , (6) 368-78.

Drazin, D., & al., e. (2012). Stem Cell Therapy for Degenerative Disc Disease. Advances in Orthopedics , 1-8.

ExitCare, LLC. (2011). Bone Marrow Transplantation & Peripheral Blood Stem Cell Transplantation: Q & A. Retrieved from MD Consult. Patient Education.

Greenspan, A., & Gershwin, M. (2008). Osteonecrosis. Retrieved from MD Consult. Firestein: Kelleys Textbook of Rheumatology, 8th ed.

Gurtner, G., & al., e. (2007). Progress and Potential for Regenrative Medicine. Annu Rev Med , 299-312.

Hendricks, W., & al., e. (2006). Predifferentiated Embryonic Stem Cells Prevent Chronic Pain Behaviors and Restore Sensory Function Following Spinal Cord Injury in Mice. Mol Med , (12) 1-3.

Mishra, A., & Pavelko, T. (2006). Treatment of Chronic Elbow Tendinosis with Buffered Platelet-Rich Plasma. Am J Sports Med , 1774-1778.

Olek, M. (2012). Treatment of progressive multiple sclerosis in adults. Retrieved from In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA.

Regenexx. (2010). Having Many Stem Cell Sources in the Toolbox benefits the Patient. Retrieved from Regenexx: http://www.regenexx.com/2010/12/having-many-stem-cell-sources-in-the-toolbox-benefits-the-patient/

Sakai, D., & al., e. (2005). Differentiation of Mesenchymal Stem Cells Transplanted to a Rabbit Degenerative Disc Model: Potential and Limitations for Stem Cell Therapy in Disc Regeneration. Spine , (30) 2379-2387.

Sakai, D., & al., e. (2003). Transplantation of mesenchymal stem cells embedded in Atelocollagens gel to the intervertebral disc:a potential therapeutic model for disc degeneration. Biomaterials , (24) 3531-3541.

Steed, D., & al., e. (2008). Amnion-derived Cellular Cytokine Solution. Eplasty .

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Stem Cells | Arizona Pain Specialists – Phoenix …

The Arizona Stem Cell Center

Posted: November 2, 2015 at 10:52 am

Welcome to the webpage for The Arizona Stem Cell Center.

We are the first and original facility offering autologous stem cell transplants derived from adipose tissue in Arizona.

Our unique and innovative process allows us to extract several million stem cells from a single fat biopsy. Our extraction technique involves minimal handling of the cells and same day transplantation. Using a patient’s own tissue as the source for cells minimizes rejection of the transplanted tissues, potentially maximizing the effectiveness of the transplant.

Here at Total Wellness/AZ Stem Cell Center, we have been using the technique of PRP (Platelet Rich Plasma) for the past decade for musculoskeletal injuries, autoimmune conditions like Lupus and Multiple Sclerosis, degenerative conditions like osteoarthritis, Parkinson’s Syndrome and ALS (Amyotrophic Lateral Sclerosis) and chronic viral conditions (including Epstein-Barr, Cytomegalovirus and Herpes viruses). This is an incredibly versatile therapy that has its roots in the eclectic European medical armamentarium of the 1930’s.

Platelet rich plasma can be employed as a matrix graft, often referred to as an autologous tissue graft. This platelet-rich plasma (PRP) matrix is defined as a “tissue graft incorporating autologous growth factors and/or autologous undifferentiated cells in a cellular matrix where design depends on the receptor site and tissue of regeneration.” (Crane D, Everts PAM. Practical Pain Management. 2008; January/February: 12- 26) 2008). We enrich the autologous tissue graft with hyaluronic acid for stem cell transplants.

The hypothesized reason why PRP with hyaluronic acid is so useful in autologous tissue grafts with stem cells is that platelets, a normal blood cell that aids in clotting, contain multiple growth factors that stimulate tissue growth. In particular, PRP stimulates the growth of collagen; the main component of connective tissue such as tendons and cartilage. These growth factors include transforming growth factor-? (TGF-B), fibroblast growth factor, platelet-derived growth factor, epidermal growth factor, connective tissue growth factor, and vascular endothelial growth factor.

These growth factors normally recruit undifferentiated stem cells to the site of injury and stimulate new tissue growth. Another constituent of platelets, stromal cell derived factor I alpha allows the newly recruited cells to adhere to the area. Hyaluronic acid is a nutritionally supportive polysaccharide substrate for stem cells that is found abundantly in embryonic tissue. When stem cells are harvested from the patient’s own tissues, PRP helps to activate the stem cells to actively become a desired tissue line and Hyaluronic Acid helps support.

In addition, when used with stem cells harvested from the patient’s own tissue, PRP messages the stem cells to multiply quickly. This inflammatory response is a major driver of appropriate healing response.

An important consideration is that PRP needs to be prepared in a way to ensure a maximal amount of platelets along with a high concentration of growth factors. Obviously, the more growth factors that can be delivered to the site of injury, the more likely tissue healing takes place. We have found that creating a matrix of Hyaluronic acid (a base connective tissue material) with the PRP and the addition of other growth factors can tremendously expedite the healing process. We are the only clinic in the world to integrate stem cell transplantation with PRP.

Neither Statements, nor products on this site, have been evaluated nor approved by the FDA. Total Wellness offers autologous stem cell treatments. These are not approved treatments, drugs, new drugs, or investigational drugs. We do not manufacture products. If you have concern with a treatment or product that we perform or produce, and think we may be violating any USA law, please contact us immediately, so that our legal team can investigate the matter or concern. All statements, opinions, and advice provided by this website, via wire, or by educational seminars, is provided for educational information only. We do not diagnose nor treat via this website or phone. We offer the above therapies via a doctor/patient established relationship which requires direct contact with the physician. Again, visitors should be aware that we are not claiming that any applications, or potential applications using these autologous treatments, are approved by the FDA, or are even effective. We do not claim that these treatments work for any listed nor unlisted condition, intended or implied.

Call for an appointment

AZ Stem Cell Center14991 W. Bell Rd. Surprise, AZ 85374 (623) 977-0077

info@azstemcellcenter.com

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The Arizona Stem Cell Center

Treatments | Arizona Pain Stem Cell Institute – Scottsdale …

Posted: November 2, 2015 at 10:52 am

Treatmentsadmin2014-09-18T23:28:24+00:00

The Arizona Pain Stem Cell Institute is committed to delivering the most advanced regenerative treatments for chronic pain conditions and studying their efficacy through research studies. These treatments include:

Blood is drawn from the patient and centrifuged. The middle layer, which is rich in platelets and growth factors necessary for healing is drawn out and injected into the site of injury/degeneration. This treatment can be used to treat shoulder, hip, knee, SI, facet joints, etc. Read More

Amniotic tissues are collected from donors after planned caesarean live births. These tissues are preserved and screened to verify tissue safety. FlGraft contains pluripotent cells (capable of differentiating into different cell lines; AKA stem cells) as well as collagen matrices that serve as scaffolding on which the body can rebuild tissues.FlGraft is injected into the patient at the target area (same areas treated with PRP). Read More

Bone marrow is drawn from the patients iliac crest (hip bone). This bone marrow is then centrifuged and the stem cell rich portion is concentrated and then injected into the patient at the targeted area. This treatment will be used to treat joints (shoulder, hip, knee, SI, facet). Read More

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Treatments | Arizona Pain Stem Cell Institute – Scottsdale …

Human genetics – An Introduction to Genetic Analysis …

Posted: November 2, 2015 at 10:50 am

In the study of rare disorders, four general patterns of inheritance are distinguishable by pedigree analysis: autosomal recessive, autosomal dominant, X-linked recessive, and X-linked dominant.

The affected phenotype of an autosomal recessive disorder is determined by a recessive allele, and the corresponding unaffected phenotype is determined by a dominant allele. For example, the human disease phenylketonuria is inherited in a simple Mendelian manner as a recessive phenotype, with PKU determined by the allele p and the normal condition by P . Therefore, sufferers from this disease are of genotype p /p , and people who do not have the disease are either P /P or P /p . What patterns in a pedigree would reveal such an inheritance? The two key points are that (1) generally the disease appears in the progeny of unaffected parents and (2) the affected progeny include both males and females. When we know that both male and female progeny are affected, we can assume that we are dealing with simple Mendelian inheritance, not sex-linked inheritance. The following typical pedigree illustrates the key point that affected children are born to unaffected parents:

From this pattern, we can immediately deduce simple Mendelian inheritance of the recessive allele responsible for the exceptional phenotype (indicated in black). Furthermore, we can deduce that the parents are both heterozygotes, say A /a ; both must have an a allele because each contributed an a allele to each affected child, and both must have an A allele because they are phenotypically normal. We can identify the genotypes of the children (in the order shown) as A /, a /a , a /a , and A /. Hence, the pedigree can be rewritten as follows:

Note that this pedigree does not support the hypothesis of X-linked recessive inheritance, because, under that hypothesis, an affected daughter must have a heterozygous mother (possible) and a hemizygous father, which is clearly impossible, because he would have expressed the phenotype of the disorder.

Notice another interesting feature of pedigree analysis: even though Mendelian rules are at work, Mendelian ratios are rarely observed in families, because the sample size is too small. In the preceding example, we see a 1:1 phenotypic ratio in the progeny of a monohybrid cross. If the couple were to have, say, 20 children, the ratio would be something like 15 unaffected children and 5 with PKU (a 3:1 ratio); but, in a sample of 4 children, any ratio is possible, and all ratios are commonly found.

The pedigrees of autosomal recessive disorders tend to look rather bare, with few black symbols. A recessive condition shows up in groups of affected siblings, and the people in earlier and later generations tend not to be affected. To understand why this is so, it is important to have some understanding of the genetic structure of populations underlying such rare conditions. By definition, if the condition is rare, most people do not carry the abnormal allele. Furthermore, most of those people who do carry the abnormal allele are heterozygous for it rather than homozygous. The basic reason that heterozygotes are much more common than recessive homozygotes is that, to be a recessive homozygote, both parents must have had the a allele, but, to be a heterozygote, only one parent must carry the a allele.

Geneticists have a quantitative way of connecting the rareness of an allele with the commonness or rarity of heterozygotes and homozygotes in a population. They obtain the relative frequencies of genotypes in a population by assuming that the population is in Hardy-Weinberg equilibrium, to be fully discussed in Chapter 24 . Under this simplifying assumption, if the relative proportions of two alleles A and a in a population are p and q , respectively, then the frequencies of the three possible genotypes are given by p 2 for A /A , 2pq for A /a , and q 2 for a /a . A numerical example illustrates this concept. If we assume that the frequency q of a recessive, disease-causing allele is 1/50, then p is 49/50, the frequency of homozygotes with the disease is q 2 =(1/50)2 =1/250, and the frequency of heterozygotes is 2pq =249/501/50 , or approximately 1/25. Hence, for this example, we see that heterozygotes are 100 times as frequent as disease sufferers, and, as this ratio increases, the rarer the allele becomes. The relation between heterozygotes and homozygotes recessive for a rare allele is shown in the following illustration. Note that the allele frequencies p and q can be used as the gamete frequencies in both sexes.

The formation of an affected person usually depends on the chance union of unrelated heterozygotes. However, inbreeding (mating between relatives) increases the chance that a mating will be between two heterozygotes. An example of a marriage between cousins is shown in . Individuals III-5 and III-6 are first cousins and produce two homozygotes for the rare allele. You can see from that an ancestor who is a heterozygote may produce many descendants who also are heterozygotes. Hence two cousins can carry the same rare recessive allele inherited from a common ancestor. For two unrelated persons to be heterozygous, they would have to inherit the rare allele from both their families. Thus matings between relatives generally run a higher risk of producing abnormal phenotypes caused by homozygosity for recessive alleles than do matings between nonrelatives. For this reason, first-cousin marriages contribute a large proportion of the sufferers of recessive diseases in the population.

Pedigree of a rare recessive phenotype determined by a recessive allele a . Gene symbols are normally not included in pedigree charts, but genotypes are inserted here for reference. Note that individuals II-1 and II-5 marry into the family; they are assumed (more…)

What are some examples of human recessive disorders? PKU has already served as an example of pedigree analysis, but what kind of phenotype is it? PKU is a disease of processing of the amino acid phenylalanine, a component of all proteins in the food that we eat. Phenylalanine is normally converted into tyrosine by the enzyme phenylalanine hydroxylase:

However, if a mutation in the gene encoding this enzyme alters the amino acid sequence in the vicinity of the enzymes active site, the enzyme cannot bind or convert phenylalanine (its substrate). Therefore phenylalanine builds up in the body and is converted instead into phenylpyruvic acid, a compound that interferes with the development of the nervous system, leading to mental retardation.

Babies are now routinely tested for this processing deficiency at birth. If the deficiency is detected, phenylalanine can be withheld by use of a special diet, and the development of the disease can be arrested.

Cystic fibrosis is another disease inherited according to Mendelian rules as a recessive phenotype. The allele that causes cystic fibrosis was isolated in 1989, and the sequence of its DNA was determined. This has led to an understanding of gene function in affected and unaffected persons, giving hope for more effective treatment. Cystic fibrosis is a disease whose most important symptom is the secretion of large amounts of mucus into the lungs, resulting in death from a combination of effects but usually precipitated by upper respiratory infection. The mucus can be dislodged by mechanical chest thumpers, and pulmonary infection can be prevented by antibiotics; so, with treatment, cystic fibrosis patients can live to adulthood. The disorder is caused by a defective protein that transports chloride ions across the cell membrane. The resultant alteration of the salt balance changes the constitution of the lung mucus.

Albinism, which served as a model of allelic determination of contrasting phenotypes in Chapter 1 , also is inherited in the standard autosomal recessive manner. The molecular nature of an albino allele and its inheritance are diagrammed in . This diagram shows a simple autosomal recessive inheritance in a pedigree and shows the molecular nature of the alleles involved. In this example, the recessive allele a is caused by a base pair change that introduces a stop codon into the middle of the gene, resulting in a truncated polypeptide. The mutation, by chance, also introduces a new target site for a restriction enzyme. Hence, a probe for the gene detects two fragments in the case of a and only one in A . (Other types of mutations would produce different effects at the level detected by Southern, Northern, and Western analyses.)

The molecular basis of Mendelian inheritance in a pedigree.

In all the examples heretofore considered, the disorder is caused by an allele for a defective protein. In heterozygotes, the single functional allele provides enough active protein for the cells needs. This situation is called haplosufficiency.

In human pedigrees, an autosomal recessive disorder is revealed by the appearance of the disorder in the male and female progeny of unaffected persons.

Here the normal allele is recessive, and the abnormal allele is dominant. It may seem paradoxical that a rare disorder can be dominant, but remember that dominance and recessiveness are simply properties of how alleles act and are not defined in terms of how common they are in the population. A good example of a rare dominant phenotype with Mendelian inheritance is pseudo-achondroplasia, a type of dwarfism ( ). In regard to this gene, people with normal stature are genotypically d /d , and the dwarf phenotype in principle could be D /d or D /D . However, it is believed that the two doses of the D allele in the D /D genotype produce such a severe effect that this is a lethal genotype. If this is true, all the dwarf individuals are heterozygotes.

The human pseudoachondroplasia phenotype, illustrated by a family of five sisters and two brothers. The phenotype is determined by a dominant allele, which we can call D , that interferes with bone growth during development. Most members of the human population (more…)

In pedigree analysis, the main clues for identifying a dominant disorder with Mendelian inheritance are that the phenotype tends to appear in every generation of the pedigree and that affected fathers and mothers transmit the phenotype to both sons and daughters. Again, the equal representation of both sexes among the affected offspring rules out sex-linked inheritance. The phenotype appears in every generation because generally the abnormal allele carried by a person must have come from a parent in the preceding generation. Abnormal alleles can arise de novo by the process of mutation. This event is relatively rare but must be kept in mind as a possibility. A typical pedigree for a dominant disorder is shown in . Once again, notice that Mendelian ratios are not necessarily observed in families. As with recessive disorders, persons bearing one copy of the rare A allele (A /a ) are much more common than those bearing two copies (A /A ), so most affected people are heterozygotes, and virtually all matings concerning dominant disorders are A /a a /a . Therefore, when the progeny of such matings are totaled, a 1:1 ratio is expected of unaffected (a /a ) to affected (A /a ) persons.

Pedigree of a dominant phenotype determined by a dominant allele A . In this pedigree, all the genotypes have been deduced.

Huntington disease is an example of a disease inherited as a dominant phenotype determined by an allele of a single gene. The phenotype is one of neural degeneration, leading to convulsions and premature death. However, it is a late-onset disease, the symptoms generally not appearing until after the person has begun to have children ( ). Each child of a carrier of the abnormal allele stands a 50 percent chance of inheriting the allele and the associated disease. This tragic pattern has led to a great effort to find ways of identifying people who carry the abnormal allele before they experience the onset of the disease. The application of molecular techniques has resulted in a promising screening procedure.

The age of onset of Huntington disease. The graph shows that people carrying the allele generally do not express the disease until after child-bearing age.

Some other rare dominant conditions are polydactyly (extra digits) and brachydactyly (short digits), shown in , and piebald spotting, shown in .

Some rare dominant phenotypes of the human hand. (a) (right) Polydactyly, a dominant phenotype characterized by extra fingers, toes, or both, determined by an allele P . The numbers in the accompanying pedigree (left) give the number of fingers in the (more…)

Piebald spotting, a rare dominant human phenotype. Although the phenotype is encountered sporadically in all races, the patterns show up best in those with dark skin. (a) The photographs show front and back views of affected persons IV-1, IV-3, III-5, (more…)

Pedigrees of Mendelian autosomal dominant disorders show affected males and females in each generation; they also show that affected men and women transmit the condition to equal proportions of their sons and daughters.

Phenotypes with X-linked recessive inheritance typically show the following patterns in pedigrees:

Many more males than females show the phenotype under study. This is because a female showing the phenotype can result only from a mating in which both the mother and the father bear the allele (for example, XA Xa Xa Y), whereas a male with the phenotype can be produced when only the mother carries the allele. If the recessive allele is very rare, almost all persons showing the phenotype are male.

None of the offspring of an affected male are affected, but all his daughters are carriers, bearing the recessive allele masked in the heterozygous condition. Half of the sons of these carrier daughters are affected ( ). Note that, in common X-linked phenotypes, this pattern might be obscured by inheritance of the recessive allele from a heterozygous mother as well as the father.

None of the sons of an affected male show the phenotype under study, nor will they pass the condition to their offspring. The reason behind this lack of male-to-male transmission is that a son obtains his Y chromosome from his father, so he cannot normally inherit the fathers X chromosome too.

Pedigree showing that X-linked recessive alleles expressed in males are then carried unexpressed by their daughters in the next generation, to be expressed again in their sons. Note that III-3 and III-4 cannot be distinguished phenotypically.

In the pedigree analysis of rare X-linked recessives, a normal female of unknown genotype is assumed to be homo-zygous unless there is evidence to the contrary.

Perhaps the most familiar example of X-linked recessive inheritance is red-green colorblindness. People with this condition are unable to distinguish red from green and see them as the same. The genes for color vision have been characterized at the molecular level. Color vision is based on three different kinds of cone cells in the retina, each sensitive to red, green, or blue wavelengths. The genetic determinants for the red and green cone cells are on the X chromosome. As with any X-linked recessive, there are many more males with the phenotype than females.

Another familiar example is hemophilia, the failure of blood to clot. Many proteins must interact in sequence to make blood clot. The most common type of hemophilia is caused by the absence or malfunction of one of these proteins, called Factor VIII. The most well known cases of hemophilia are found in the pedigree of interrelated royal families in Europe ( ). The original hemophilia allele in the pedigree arose spontaneously (as a mutation) either in the reproductive cells of Queen Victorias parents or of Queen Victoria herself. The son of the last czar of Russia, Alexis, inherited the allele ultimately from Queen Victoria, who was the grandmother of his mother Alexandra. Nowadays, hemophilia can be treated medically, but it was formerly a potentially fatal condition. It is interesting to note that, in the Jewish Talmud, there are rules about exemptions to male circumcision that show clearly that the mode of transmission of the disease through unaffected carrier females was well understood in ancient times. For example, one exemption was for the sons of women whose sisters sons had bled profusely when they were circumcised.

The inheritance of the X-linked recessive condition hemophilia in the royal families of Europe. A recessive allele causing hemophilia (failure of blood clotting) arose in the reproductive cells of Queen Victoria, or one of her parents, through mutation. (more…)

Duchenne muscular dystrophy is a fatal X-linked recessive disease. The phenotype is a wasting and atrophy of muscles. Generally the onset is before the age of 6, with confinement to a wheelchair by 12, and death by 20. The gene for Duchenne muscular dystrophy has now been isolated and shown to encode the muscle protein dystrophin. This discovery holds out hope for a better understanding of the physiology of this condition and, ultimately, a therapy.

A rare X-linked recessive phenotype that is interesting from the point of view of sexual differentiation is a condition called testicular feminization syndrome, which has a frequency of about 1 in 65,000 male births. People afflicted with this syndrome are chromosomally males, having 44 autosomes plus an X and a Y, but they develop as females ( ). They have female external genitalia, a blind vagina, and no uterus. Testes may be present either in the labia or in the abdomen. Although many such persons marry, they are sterile. The condition is not reversed by treatment with the male hormone androgen, so it is sometimes called androgen insensitivity syndrome. The reason for the insensitivity is that the androgen receptor malfunctions, so the male hormone can have no effect on the target organs that contribute to maleness. In humans, femaleness results when the male-determining system is not functional.

Four siblings with testicular feminization syndrome (congenital insensitivity to androgens). All four subjects in this photograph have 44 autosomes plus an X and a Y chromosome, but they have inherited the recessive X-linked allele conferring insensitivity to (more…)

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Human genetics – An Introduction to Genetic Analysis …

Mesenchymal stem cells in the treatment of spinal cord …

Posted: November 1, 2015 at 3:46 pm

World J Stem Cells. 2014 Apr 26; 6(2): 120133.

Venkata Ramesh Dasari, Krishna Kumar Veeravalli, Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, United States

Dzung H Dinh, Department of Neurosurgery and Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, Peoria, IL 61656, United States

Correspondence to: Dzung H Dinh, MD, Department of Neurosurgery and Illinois Neurological Institute, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61605, United States. ude.ciu@hnidd

Telephone: +1- 309-6552642 Fax: +1-309-6713442

Received 2013 Oct 30; Revised 2014 Feb 19; Accepted 2014 Mar 11.

With technological advances in basic research, the intricate mechanism of secondary delayed spinal cord injury (SCI) continues to unravel at a rapid pace. However, despite our deeper understanding of the molecular changes occurring after initial insult to the spinal cord, the cure for paralysis remains elusive. Current treatment of SCI is limited to early administration of high dose steroids to mitigate the harmful effect of cord edema that occurs after SCI and to reduce the cascade of secondary delayed SCI. Recent evident-based clinical studies have cast doubt on the clinical benefit of steroids in SCI and intense focus on stem cell-based therapy has yielded some encouraging results. An array of mesenchymal stem cells (MSCs) from various sources with novel and promising strategies are being developed to improve function after SCI. In this review, we briefly discuss the pathophysiology of spinal cord injuries and characteristics and the potential sources of MSCs that can be used in the treatment of SCI. We will discuss the progress of MSCs application in research, focusing on the neuroprotective properties of MSCs. Finally, we will discuss the results from preclinical and clinical trials involving stem cell-based therapy in SCI.

Keywords: Spinal cord injury, Mesenchymal stem cells, Bone marrow stromal cells, Umbilical cord derived mesenchymal stem cells, Adipose tissue derived mesenchymal stem cells

Core tip: Despite our deeper understanding of the molecular changes that occurs after the spinal cord injury (SCI), the cure for paralysis remains elusive. In this review, the pathophysiology of SCI and characteristics and potential sources of mesenchymal stem cells (MSCs) that can be used in the treatment of SCI were discussed. We also discussed the progress of application of MSCs in research focusing on the neuroprotective properties of MSCs. Finally, we discussed the results from preclinical and clinical trials involving stem cell-based therapy in SCI.

Traumatic spinal cord injury (SCI) continues to be a devastating injury to affected individuals and their families and exacts an enormous financial, psychological and emotional cost to them and to society. Despite years of research, the cure for paralysis remains elusive and current treatment is limited to early administration of high dose steroids and acute surgical intervention to minimize cord edema and the subsequent cascade of secondary delayed injury[1-3]. Recent advances in neurosciences and regenerative medicine have drawn attention to novel research methodologies for the treatment of SCI. In this review, we present our current understanding of spinal cord injury pathophysiology and the application of mesenchymal stem cells (MSCs) in the treatment of SCI. This review will be more useful for basic and clinical investigators in academia, industry and regulatory agencies as well as allied health professionals who are involved in stem cell research.

Direct mechanical damage to the spinal cord usually results in either partial or total loss of neural functions such as sensory perception and mobility[4]. The prevalence of people with SCI who are alive in the United States in 2013 is estimated to be approximately 273000[5]. According to census data, motor vehicle accidents (36.5%), falls (28.5%), and acts of violence (14.3%) are the most frequent causes of SCI since 2010. The average age at injury is 42.6 years and 80.7% of spinal cord injuries occur in males. Among those injured since 2010, 67.0% are Caucasian, 24.4% African American, 0.8% Native American and 2.1% Asian. The most frequent neurologic category at discharge of persons reported to the database since 2010 is incomplete tetraplegia (40.6%), followed by incomplete paraplegia (18.7%), complete paraplegia (18.0%) and complete tetraplegia (11.6%). Less than 1% of SCI patients experienced complete neurologic recovery by the time of hospital discharge. Over the last 20 years, the percentage of SCI patients with incomplete tetraplegia spinal cord injury has increased while the more devastating complete paraplegia and complete tetraplegia numbers have decreased[5]. Whether complete or incomplete injury, SCI is a devastating condition that not only paralyzes the affected individuals but also exacts tremendous emotional, social and financial burdens[6]. These patients also face increased risks of cardiovascular complications, deep vein thrombosis, osteoporosis, pressure ulcers, autonomic dysreflexia and neuropathic pain[3]. The limitation of any clinical treatment success is most likely due to the complex mechanisms of SCI and the relative inability of the human body to repair or regenerate neurons in the spinal cord[7].

The pathophysiological processes that underlie SCI comprise the primary and secondary phases of injury[1,8]. Initial physical trauma to the spinal cord includes traction injury, compression forces and direct mechanical disruption of neural elements. Immediate microvascular injuries with central gray hemorrhage and disruption of cellular membrane and blood-spinal cord barrier are followed by edema, ischemia, release of cytotoxic chemicals from inflammatory pathways and electrolyte shifts. Subsequently, a secondary injury cascade is triggered that compounds the initial mechanical injury with necrosis and apoptosis that are injurious to surviving neighboring neurons, further reducing the chance of recovery of penumbra neurons and rendering any functional recovery almost hopeless[3,8]. Pathophysiological processes that occur in the secondary injury phase are responsible for exacerbating the initial damage and creating an inhibitory milieu that is hostile to endogenous efforts of repair, regeneration and remyelination. These secondary processes include inflammation, ischemia, lipid peroxidation, production of free radicals, disruption of ion channels, axonal demyelination, glial scar formation, necrosis and programmed cell death[3]. The post-trauma inflammatory response plays a critical role in the secondary phase after SCI through modulation of a series of complex cellular and molecular interactions[9]. After SCI, the blood-spinal cord barrier is disrupted due to hemorrhage and local inflammation[10]. The activation and recruitment of peripheral and resident inflammatory cells including microglial cells, astrocytes, monocytes, T-lymphocytes, and neutrophils promotes the development of secondary damage following SCI[11]. This secondary injury can be subdivided into the acute-phase (2 h-2 d), the sub-acute phase (days-weeks), and the chronic phase (months-years), each with distinct different pathophysiological processes[12-14]. These changes include edema, ischemia, hemorrhage, reactive oxygen species (ROS) production and lipid peroxidation, glutamate-mediated excitotoxicity, ionic dysregulation, blood-spinal-cord barrier permeability, inflammation, demyelination, neuronal cell death, neurogenic shock, macrophage infiltration, microglial activity, astrocyte activity and scar formation, initiation of neovascularization, Wallerian degeneration, glial scar maturation, cyst and syrinx formation, cavity formation and schwannosis. The end of spontaneous post-SCI changes is identified as a pathophysiological phenomenon with solid glial scar formation, syrinx formation, and neuronal apoptosis[15]. However, endogenous repair and regenerative mechanisms do occur during the secondary phase of injury to minimize the extent of the lesion (through astrogliosis), reorganize blood supply through angiogenesis, clear cellular debris, and reunite and remodel damaged neural circuits, and as such, offer exploitable targets for therapeutic intervention[3], the most promising of which is stem cell-based therapy[16].

An array of new and promising strategies is being developed to improve function after SCI. At present, two main therapeutic strategies, cell-based and gene-based therapies are being investigated to repair the injured mammalian spinal cord. At this time it appears that neither strategy by itself is efficacious, whereas a combinatory strategy appears to be more promising. The targeting of an array of deleterious processes within the tissue after SCI will require a multi-factorial intervention, multi-phasic polytherapy such as the combination of cell- and gene-based approaches[17]. This review focuses only on stem cell-based therapy. Cell-based therapy faces numerous challenges including selection of a SCI model, timing and mode of cell implantation, location of cellular injection and their subsequent migration, survival, transdifferentiation, immune incompatibility and rejection, and tracking of implanted cells[17]. Cellular therapies for SCI repair may involve modification or recruitment of endogenous cells in vivo, harvest and/or alteration ex vivo of endogenous cells that are subsequently implanted as autogeneic graft or transplanted into the injured organism as allogeneic or xenogeneic grafts. Transplanted stem cells promote neural regeneration and rescue impaired neural function after SCI by parasecreting permissive neurotrophic molecules at the lesion site to enhance the regenerative capacity thereby providing a scaffold for the regeneration of axons and replacing lost neurons and neural cells[17]. Mesenchymal stem cells have recently been advocated as a promising source for cellular repair after central nervous system (CNS) injury[15]. MSCs, also known as marrow stromal cells[18] or mesenchymal progenitor cells[19] are self-renewing, multipotent progenitor cells with the capacity to differentiate into several distinct mesenchymal lineages[20]. These cells are multipotent adult stem cells present in all tissues as part of the perivascular population. As multipotent cells, MSCs can differentiate into different mesodermal tissues ranging from bone and cartilage to cardiac muscle[21]. Several small clinical trials have investigated the efficacy and safety of MSCs in diseases including chronic heart failure, acute myocardial infarction, hematological malignancies and graft vs host disease. Pre-clinical evidence suggests that MSCs exert their beneficial effects largely through immunomodulatory and paracrine mechanisms[22].

MSCs are favored in stem cell therapy for SCI for the following reasons: (1) ease of isolation and cryopreservation[23], (2) maintenance of viability and regenerative capacity after cryopreservation at -80C[24], (3) rapid replication with high quality progenitor cells and high potential of multilineage differentiation[25], and (4) minimal or no immunoreactivity and graft-versus-host reaction of transplanted allogeneic MSCs[26]. MSCs were initially identified in bone marrow and later in muscle, adipose and connective tissue of human adults[21]. Bone marrow and umbilical cord blood are rich sources of these cells, but MSC have also been isolated from fat[27], skeletal muscle[28], human deciduous teeth[29], and trabecular bone[30]. Mesenchymal stem cells are ideally suited to address many pathophysiological consequences of SCI[3]. The major goals for the therapeutic use of stem cells is regeneration of axons, prevention of apoptosis and replacement of lost cells, particularly oligodendrocytes, in order to facilitate the remyelination of spared axons[31]. In this review, we touch upon the therapeutic applications of MSCs after SCI.

Bone marrow-derived mesenchymal stem cells (BMSC) differentiate into cells of the mesodermal lineage but also, under certain experimental conditions, into cells of the neuronal and glial lineage. Their therapeutic translation has been significantly boosted by the demonstration that MSCs display significant anti-proliferative, anti-inflammatory and anti-apoptotic features. These properties have been exploited in the effective treatment of experimental autoimmune encephalomyelitis (EAE), experimental brain ischemia and in animals undergoing brain or spinal cord injury[32]. Several investigators have reported that MSCs possess immunosuppressive features[33-36]. These immunosuppressive properties, in combination with the restorative functions of BMSC reduce the acute inflammatory response to SCI, minimize cavity formation, as well as diminish astrocyte and microglia/macrophage reactivity[37-39]). BMSC transplantation in an experimental SCI model has been shown to enhance neuronal protection and cellular preservation via reduction in injury-induced sensitivity to mechanical trauma[39]. It was suggested that the beneficial effects of MSCs on hindlimb sensorimotor function may, in part, be explained by their ability to attenuate astrocyte reactivity and chronic microglia/macrophage activation[39]. These significant results demonstrated the potential of MSCs to serve as attenuators of the immune response. It was proposed that as attenuators, MSCs could potentially serve in an immunoregulatory capacity in disorders in which chronic activation of immune cells, such as reactive astrocytes and activated microglia/macrophages play a role. Studies by Hofstetter et al[40], indicated that transplanted MSC attenuates acute inflammation and promotes functional recovery following SCI. Ohta et al[41], suggested that BMSCs reduced post-SCI cavity formation and improved behavioral function by releasing trophic factors into the cerebrospinal fluid (CSF) or by direct interaction with host spinal tissues. Infusion of transplants through CSF provides no additional traumatic injury to the damaged spinal cord and BMSCs might be administered by lumbar puncture to the patients. Lumbar puncture can be done without severe invasion, so BMSCs can be repeatedly administered to maintain their effects. This study has demonstrated for the first time that the transplantation of BMSCs through CSF can promote the behavioral recovery and tissue repair of the injured spinal cord in rats, thus providing a road map for the clinical autograft of BMSCs without severe surgical infliction to human patients[41]. In another study, human mesenchymal stem cells (hMSCs) isolated from adult bone marrow were found to infiltrate primarily into the ventrolateral white matter tracts, spreading to adjacent segments rostro-caudal to the injury epicenter, and facilitate recovery from SCI by remyelinating spared white matter tracts and/or by enhancing axonal growth[42]. In our laboratory, we used mesenchymal stem cells from rat bone marrow to evaluate the therapeutic potential after SCI in rats[43]. We observed that caspase-3 mediated apoptosis after SCI on both neurons and oligodendrocytes was significantly downregulated by BMSC. Treatment with BMSC had a positive effect on behavioral outcome and better structural integrity preservation as seen in histopathological analysis. BMSC secrete protective factors that prevent neuronal apoptosis through stimulation of endogenous survival signaling pathways, namely PI3K/Akt and the MAPK/ERK1/2-cascade. Overall, these findings demonstrate that BMSC trigger endogenous survival signaling pathways in neurons that mediate protection against apoptotic insults. Moreover, the interaction between stressed neurons and BMSC further amplifies the observed neuroprotective effect[44].

Lu et al[45], investigated the nature of the chronic scar and its ability to block axon growth by testing the hypothesis that chronically injured spinal cord axons can regenerate through the gliotic scar in the presence of local growth-stimulating factors. BMSC, genetically modified to secrete neurotrophin-3 (NT-3) were injected into the lesion site of rats with cervical SCI[45]. It was observed that a modest number of axons penetrated through the chronic scar that contained a mixture of inhibitory and growth stimulating factors. Furthermore, robust axonal growth can be induced by the local provision of neurotrophic factors without resecting the chronic scar. In another study, Urdzkov et al[46], have shown that treatment with different cell populations obtained from bone marrow (MSCs, BMCs and the endogenous mobilization of bone marrow cells) has a beneficial effect on behavioral and histological outcomes after SCI. However, it is not clear whether the injection of MSCs, BMCs or granulocyte-colony stimulating factor (G-CSF) treatment induces functional and morphological improvement through the same mechanisms of action. Transplanted MSCs mollify the inflammatory response in the acute setting and reduce the inhibitory effects of scar tissue in the subacute/chronic setting to provide a permissive environment for axonal extension. In addition, grafted cells may provide a source of growth factors to enhance axonal elongation across spinal cord lesions[47]. Down-regulation of TNF- expression in macrophages/microglia was observed at an early stage after SCI in rats transplanted with a gelatin sponge (GS) scaffold impregnated with rat bone marrow-derived mesenchymal stem cells at the site of injury[48]. It was also shown that 3D gelatin sponge scaffolds allowed MSCs to adhere, survive and proliferate and also for fibronectin to deposit. In vivo transplantation experiments demonstrated that these scaffolds were biocompatible and MSCs seeded to the scaffolds played an important role in attenuating inflammation, promoting angiogenesis, and reducing cavity formation. Novikova et al[49], observed that differentiated BMSC provided neuroprotection for axotomized rubrospinal neurons and increased the density of rubrospinal axons in the dorsolateral funiculus rostral to the injury site. They suggested that BMSC induced along the Schwann cell lineage increased expression of trophic factors and have neuroprotective and growth-promoting effects after SCI[49]. Cizkova et al[50], standardized the intrathecal (IT) catheter delivery of rat MSCs after SCI in adult rats. Based on these results, it was suggested that repetitive IT transplantation, which imposes a minimal burden on the animals, may improve behavioral function when the dose, timing, and targeted IT delivery of MSCs towards the lesion cavity was optimized. Kang et al[51], indicated that therapeutic rat BMSCs in a poly (D,L-lactide-co-glycolide)/small intestinal submucosa scaffold induced nerve regeneration in a complete spinal cord transection model and demonstrated that functional recovery further depended on defect length.

Park et al[52] evaluated the therapeutic efficacy of combining autologous BMSC transplantation with granulocyte macrophage-colony stimulating factor (GM-CSF) by subcutaneous administration directly into the spinal cord lesion site of six patients with complete SCI. At the 6-mo and 18-mo follow-up periods, four of the six patients showed neurological improvements by two ASIA (American Spinal Injury Association) grade (from ASIA A to ASIA C), while another improved from ASIA A to ASIA B[52]. Moreover, BMSC transplantation together with GM-CSF was not associated with increased morbidity or mortality. In another clinical trial, the safety of autologous bone marrow cell implantation was tested in twenty patients[53]. Motor-evoked potential, somatosensory-evoked potential, magnetic resonance imaging, and ASIA scores were measured in a clinical follow-up. This study demonstrated that BMSC transplantation is a relatively safe procedure, and BMSC-mediated repair can lead to modest improvements in some injured patients. It is also anticipated that a Phase II clinical trial designed to test the efficacy will be initiated in the near future. In a study conducted by Deng et al[54], implantation of BMSC elicited de novo neurogenesis, and functional recovery in a non-human primate SCI model with rhesus monkeys achieved Tarlov grades 2-3 and nearly normal sensory responses three months after transplantation. Zurita et al[55], observed progressive functional recovery three months after SCI in paraplegic pigs injected with autologous BMSC in autologous plasma into lesion zone and adjacent subarachnoid space. Intramedullary post-traumatic cavities were filled by a neoformed tissue containing several axons, together with BMSC, that expressed neuronal or glial markers. Furthermore, in the treated animals, electrophysiological studies showed recovery of the previously abolished somatosensory-evoked potentials. Despite promising data, further research is needed to establish whether bone marrow cell treatments can serve as a safe and efficacious autologous source for the treatment of SCI[47]. However, the use of BMSC in SCI does present certain issues-migration beyond the injection site (for intraspinally delivered cells) is limited and inter-donor variability in efficacy and immunomodulatory potency might be reflected in variable clinical outcome[37], making BMSC evaluation as a therapy for SCI difficult[3]. The pathological improvements of BMSC after SCI are summarized in Table .

Overview of effects of bone marrow stromal cells after spinal cord injury

Adipose tissue is abundant in the body and contains a stromal fraction rich in stem- progenitor cells capable of undergoing differentiation into osteogenic, chondrogenic, and adipogenic lineages[56]. The in vitro as well as in vivo properties of adipose tissue-derived stromal cells (ADSCs) resemble those of MSCs obtained from bone marrow, and the liposuction procedure employed to harvest ADSCs is minimally invasive for the patient[57]. Kang et al[58], reported that intravenous infusion of oligodendrocyte precursor cells (OPCs) derived from rATSC autograft cells improved motor function in rat models of SCI. Moreover, cytoplasmic extracts prepared from adipose tissue stromal cells (ATSCs) inhibit H2O2-mediated apoptosis of cultured spinal cord-derived neural progenitor cells (NPCs) and improved cell survival[59]. ATSCs extracts mediated this effect by decreasing caspase-3 and c-Jun-NH2-terminal kinase (SAPK/JNK) activity, inhibiting cytochrome c release from mitochondria and reducing Bax expression levels in cells. Direct injection of ATSCs extracts mixed with matrigel into the spinal cord immediately after SCI also resulted in less apoptotic cell death, astrogliosis and hypo-myelination and showed significant functional improvement. Zhang et al[60], showed that ADSCs can differentiate into neural-like cells in vitro and in vivo. However, neural differentiated ADSCs did not result in any better functional recovery than did undifferentiated ones following SCI. Ryu et al[61], evaluated the implantation of allogenic adipose-derived stem cells (ASCs) for the improvement of neurological function in a canine SCI model. Using both in vitro and in vivo injury models, Oh et al[62], confirmed that hypoxic preconditioning (HP)-treated adipose tissue-derived mesenchymal stem cells (HP-AT-MSCs) increased cell survival and enhanced the expression of marker genes in DsRed-engineered neural stem cells (NSCs-DsRed). Based on their findings, it was suggested that the co-transplantation of HP-AT-MSCs with engineered neural stem cells (NSCs) can improve both cell survival and gene expression of the engineered NSCs. This novel strategy can be used to augment the therapeutic efficacy of combined stem cell and gene modulation therapy for SCI. In another study, Oh et al[63], examined the effects of co-transplanting mouse neural stem cells (mNSCs) and adipose tissue-derived mesenchymal stem cells (AT-MSCs) on mNSC viability. It was observed that mNSCs transplanted into rat spinal cords with AT-MSCs showed better survival rates than mNSCs transplanted alone, thereby suggesting that co-transplantation of mNSCs with AT-MSCs is a more effective strategy to improve the survival of transplanted stem cells into the injured spinal cord. In a more recent study, the same group investigated the effectiveness of a three-dimensional cell mass transplantation of adipose-derived stem cells (3DCM-ASCs) in hind limb functional recovery by the stimulation of angiogenesis and neurogenesis[64]. These results revealed a significantly elevated density of neovascular formations through angiogenic factors released by the 3DCM-ASCs at the lesion site, enhanced axonal outgrowth, and significant functional recovery. These findings suggest that transplantation of 3DCM-ASCs may be an effective stem cell transplantation modality for the treatment of spinal cord injuries and neural ischemia. In a similar study, Park et al[65], observed that a combination of matrigel and neural-induced mesenchymal stem cells (NMSC) reduced the expression of inflammation and/or astrogliosis markers and improved hind limb function in dogs with SCI. The predifferentiation of ASCs plays a beneficial role in SCI repair by promoting the protection of denuded axons and cellular repair that was induced mainly through paracrine mechanisms[57]. The propensity of proliferation and the potential of unchecked differentiation of stem cells raised the concern of inherent tumorigenicity and toxicity. Ra et al[66], observed that systemic transplantation of human Adipose tissue-derived mesenchymal stem cells (hAdMSCs) appeared to be safe and did not induce tumor development as none of the patients developed any serious adverse events related to hAdMSC transplantation during the three-month follow-up. Zhou et al[67], compared mesenchymal stromal cells from human bone marrow and adipose tissue for the treatment of spinal cord injury and suggested that hADSCs would be more appropriate than hBMSCs for transplantation to treat SCI. Recently, Zaminy et al[68], proved that adipose tissue-derived Schwann cells can modulate the hostile environment of the damaged spinal cord and generate a more stimulating environment to support axon regeneration and enhance functional recovery (Table ).

Overview of effects of Adipose tissue-derived mesenchymal cells after spinal cord injury

Human umbilical cord blood-derived mesenchymal stem cells (hUCBSC) offer great potential for novel therapeutic approaches targeted against many CNS diseases. Previous studies have reported that hUCBSC are beneficial in reversing the deleterious effects of SCI, even when infused five days after injury[69]. Transplanted hUCBSC differentiate into various neural cells and induce motor function improvement in SCI rat models[70]. In our laboratory, hUCBSC transplanted in rats one week after SCI were shown to transdifferentiate into neurons and oligodendrocytes and also to downregulate Fas-mediated apoptosis[71,72]. These transdifferentiated oligodendrocytes facilitated the secretion of neurotrophic hormones NT3 and BDNF and synthesized MBP and PLP, thereby promoting the remyelination of demyelinated axons in the injured spinal cord[71]. We observed that hUCBSC treatment increased myelin basic protein in vitro in PC-12 cells, which are normally not myelinated. To further confirm the ability of transplanted hUBCSC in remyelination, we injected hUBCSC into shiverer mice brains. This study clearly demonstrated that transplanted hUCBSC survived, migrated in vivo and myelinated genetically denuded axons in shiverer mice brains. The expression level of myelin basic protein, a major component of the myelin sheath, was significantly elevated in vivo and in vitro as revealed by Western blotting, reverse transcription polymerase chain reaction, immunohistochemistry, immunocytochemistry, and fluorescent in situ hybridization results. Further, transmission electron microscopic images of hUCBSC-treated shiverer mice brains showed several layers of myelin around the axons compared with a thin and fragmented layer of myelin in untreated animals (Figure ). Moreover, the frequency of shivering was diminished one month after hUCBSC treatment. Our results strongly indicated that hUCBSC transplantation played an important role in re-myelination and could be an effective therapeutic approach for demyelinating or hypomyelinating disorders[73]. Furthermore, apoptotic pathways mediated by caspase-3, Fas and TNF- were downregulated by hUCBSC[72,74]. The locomotor scale scores in hUCBSC-treated rats were significantly improved as compared to those of the control injured group. To further extend our studies, we utilized RT-PCR microarray and analyzed 84 apoptotic genes to identify the genetic modulation that occurred after traumatic SCI and after hUCBSC transplantation[75]. We observed that the genes involved in inflammation and apoptosis were up-regulated (TNF-, TNFR1, TNFR2, Fas, Bad, Bid, Bid3, Bik, and Bak1) in the injured rat spinal cords, whereas genes such as XIAP, which are involved in neuroprotection, were up-regulated in the hUCBSC-treated rats (Figure , Tables and ). Our findings from co-cultures of cortical neurons with hUCBSC and blocking of the Akt pathway by a dominant-negative Akt and Akt-inhibitor IV confirmed that the mechanism underlying hUCBSC neuroprotection involved activation of the Akt signaling pathway. These results suggested the neuroprotective potential of hUCBSC against glutamate-induced apoptosis of cultured cortical neurons[74]. Both the in vivo and in vitro studies supported our hypothesis that the therapeutic mechanism of hUCBSC was remyelination of demyelinated axons and inhibition of the neuronal apoptosis during the repair phase of the injured spinal cord. Veeravalli et al[76] reported the involvement of tissue plasminogen activator (tPA) after SCI in rats and the role of hUCBSC. The tPA expression and activity were studied in vivo in rats after SCI and in vitro in rat embryonic spinal neurons in response to injury with staurosporine, hydrogen peroxide and glutamate. Infusion of hUCBSC downregulated tPA activity in vivo in rats as well as in vitro in the spinal neurons. Furthermore, MMP-2 is upregulated after hUCBSC treatment in spinal cord injured rats and in spinal neurons injured either with staurosporine or hydrogen peroxide. Also, hUCBSC-induced upregulation of MMP-2 diminished the formation of the glial scar at the site of injury along with reduced immunoreactivity to chondroitin sulfate proteoglycans. This upregulation of MMP-2 levels and reduction of glial scar formation by hUCBSC treatment after SCI created an environment more favorable for endogenous repair mechanisms[77] (Figure ). Kao et al[78], suggested that hUCB derived-CD34+ cells can induce angiogenesis and endo/exogenous neurogenesis in SCI. In addition, Chen et al[79] recently showed that hUCB stem cells have the ability to secrete multiple neurotrophic factors. Their study demonstrated an elevation of neuroprotective cytokine serum IL-10 levels and a decrease in TNF- levels after hUCB stem cells infusion. Moreover, both GDNF and VEGF could be detected in the injured spinal cord after the transplantation of hUCBSC, thereby promoting angiogenesis and neuronal regeneration. Recently, Ning et al[80], showed that transplantation of CD34+ HUCBCs during the acute phase could promote functional recovery better than during the subacute phase after SCI by raising neovascular density. These multifaceted protective and restorative effects from hUCB grafts may be interdependent and act in concert to promote therapeutic recovery for SCI (Table ). Nevertheless, clinical studies with hUCBSC are still limited due to concerns about safety, mode of delivery, and efficiency. Among these concerns, the major histocompatibility in allogeneic transplantation is an important issue that needs to be addressed in future clinical trials for treating SCI[16].

Transmission electron micrographs of shiverer mice brain showing thin and fragmented myelin around the axons in control and WI-38- implanted mice. In contrast, human umbilical cord blood-derived mesenchymal stem cells-treated shiverer brains showing myelin …

Microarray analysis of apoptotic genes after spinal cord injury. Total RNA was extracted from sham control, 3-wk post-spinal cord injury (SCI), and 3-wk post-SCI plus human umbilical cord blood-derived mesenchymal stem cells (hUCBSC)-treated tissues, …

Changes in the expression of apoptotic genes and inhibitors after spinal cord injury and human umbilical cord blood stem cells treatment

Reduction of inflammation in human umbilical cord blood-derived mesenchymal stem cell-treated spinal cords of rats. Immunohistochemical comparison of control, injured (21 d after spinal cord injury) and human umbilical cord blood-derived mesenchymal stem …

Changes in the expression of caspase-related and nuclear factor-B-related apoptotic genes after spinal cord injury

Overview of effects of umbilical cord blood-derived mesenchymal stem cells after spinal cord injury

There are two main populations of cells with a mesenchymal character within the human umbilical cord: Whartons jelly mesenchymal stem cells (WJ-MSCs) and human umbilical cord perivascular cells (HUCPVCs)[81]. Whartons jelly cells (WJ-MSCs) can proliferate more rapidly and extensively than adult BMSCs (for a detailed review refer to Vawda and Fehlings, 2013). Yang et al[82], examined the effects of human umbilical mesenchymal stem cells (HUMSC) transplantation after complete spinal cord transection in rats. They observed that transplanted HUMSCs survived for 16 wk and produced large amounts of human neutrophil-activating protein-2, neurotrophin-3, basic fibroblast growth factor, glucocorticoid induced tumor necrosis factor receptor, and vascular endothelial growth factor receptor 3 in the host spinal cord. Zhang et al[83], used an animal model of transected SCI to test the hypothesis that co-grafted human umbilical mesenchymal stem cells-derived neurospheres (HUMSC-NSs) and BDNF can promote morphologic and functional recoveries of the injured spinal cord. Recovery of hindlimb locomotor function in SCI rats was significantly enhanced in human umbilical cord mesenchymal stem cells-grafted animals at five weeks as compared to control sham-grafted animals[84]. Using a rat model for clip SCI, Shang et al[85], showed that Neurotrophin-3 (NT-3) genetically modified human umbilical mesenchymal stem cells (NT-3-HUMSCs) promoted the morphologic and functional recovery of injured spinal cords (Table ). Although these studies involved thoracic SCI model, these positive findings will most likely apply to cervical SCI as well[3].

Overview of effects of Whartons jelly/umbilical cord matrix cells after spinal cord injury

Therapeutic application of MSCs represents a promising approach in the treatment of spinal cord injury. Nevertheless, cell-based therapy for SCI in its nascent stages is facing several challenges including translational clinical issues, regulatory and ethical concerns, as well as modalities of transplantation, timing, safety and efficacy of the transplanted cells. A better understanding is also needed of the mechanisms of action and the behavior of stem cells in the pathological environment after transplantation in order to determine the best time frame and the most efficient routes for cell delivery after the injury[86]. Although several clinical trials utilize MSCs transplantation for the treatment of SCI, the ultimate value of a translational approach needs continued exploration of basic scientific knowledge of SCI and proven therapeutic efficacy via rigorous controlled, randomized, double blind, multi-center clinical trials.

We thank Diana Meister for manuscript review. The authors wish to thank the editors of the Journal of Neurotrauma, Neurobiology of Disease and Stem Cells and Development for permission to use the figures and Tables and , which appear in this article.

Supported by A grant from Illinois Neurological Institute to DHD

P- Reviewers: Ho I, Kan L, Miller RH S- Editor: Song XX L- Editor: A E- Editor: Zhang DN

5. Birmingham, AL: University of Alabama at Birmingham, 2013

31. Dasari VR, Veeravalli KK, Rao JS, Fassett D, Dinh DH. Mesenchymal Stem Cell Therapy for Apoptosis After Spinal Cord Injury. In: Chang RCC, editor. Advanced Understanding of Neurodegenerative Diseases. Croatia: InTech; 2011. pp. 365394.

Articles from World Journal of Stem Cells are provided here courtesy of Baishideng Publishing Group Inc

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Immunoglobulin (IG or Immune Globulin or Gamma Globulin)

Posted: November 1, 2015 at 3:46 pm

Immunoglobulin (IG or Immune Globulin or Gamma Globulin)

IgG is pooled/plasma containing antibodies against a number of diseases like measles, rubella, varicella, hepatitis A, etc.

It is given in the following situations:

For passive protection against rubella, measles, chicken pox after exposure in high risk populations e.g. immunocompromised, pregnancy, less than one year of age.

For protection against Hepatitis A after exposure. It must be given within two weeks of exposure and should be given concurrently with Hepatitis A to develop active immunity. A second dose of Hepatitis A is required six months later.

For those traveling to high risk countries who do not have time to develop active immunity before departure (less than four weeks). It should be given concurrently with the first dose of Hepatitis A. A second dose is due six months later.

IG is prepared from pooled plasma through purification and sterilization. It is recommended that travelers take the Hepatitis A vaccine if time permits. IG should be used during pregnancy only when clearly needed.

Side effects after receiving IG may include: muscle stiffness, redness, warmth, pain and tenderness at injection site. Fever, chills, headache, weakness and nausea may occur. If these symptoms continue beyond 48 hours or become bothersome, contact your physician. If skin rash, swelling of hands/feet or face, or trouble breathing develop, contact your doctor immediately.

IG may interfere with the immune response to live vaccines, so discuss this with your physician before taking it. If you take IG, you will not be able to donate blood for several months.

Individuals who have had Hepatitis A disease or who have completed the series of Hepatitis A vaccine have lifetime immunity and do not require IG.

A frequently asked question concerns the difference between IG, which is a passive form of protection, and a vaccine such as Hepatitis A vaccine. IG is manufactured from antibodies and comes from another persons donated plasma. Its called passive because the body of the person receiving IG does not react to the IG but simply circulates it. Thus the recipient is given instant protection. Over a few months, this protection disappears. A vaccine or immunization, or active form of protection, stimulates the recipients immune system to build its own antibodies. The body retains the pattern so that more can be built in the future. This type of response to a vaccine may last several months to a lifetime.

If you are a registered University of Illinois student and you have questions or concerns, or need tomake an appointment, please call: Dial-A-Nurse at 333-2700

If you are concerned about any difference in your treatment plan and the information in this handout,

you are advised to contact your health care provider.

Visit the McKinley Health Center Web site at: http://www.mckinley.illinois.edu

HEd.VIII-003

The Board of Trustees of the University of Illinois, 2006.

09-22-06

immunoglobulin

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Immunoglobulin (IG or Immune Globulin or Gamma Globulin)

SlidePlayer – Upload and Share your PowerPoint presentations

Posted: November 1, 2015 at 3:46 pm

Creating a presentation is just the first step. Making it available for someone else has always been a challenge, especially when you need to present to someone who doesn’t have the presentation making software similar to yours. It is even more challenging when you need to send your presentation to multiple recipients, each with their own software bundle, OS etc.

SlidePlayer turns this process into a piece of cake. Now you make your presentation available worlwide in 3 simple steps: social network login, uploading and sharing! SlidePlayer features a unique built-in presentation player with no specific software requirements. Thanks to that, your presentation will be successfully running on Mac, Windows, Android etc. so that you no longer need to go nuts trying to adapt your presentation to various platform and software requirements.

If you are a visitor seeking for a good presentation or just a nice idea, SlidePlayer will serve you well. You can download the presentations you like in .ppt (Microsoft PowerPoint) format after you preview them with the built-in presentation player. Therefore you can avoid downloading the trash you don’t need as one should usually do when searching for a presentation online.

Please note that all the presentations published on SlidePlayer are for the informational purpose only and can not be used as commercial tools.

Don’t forget to share the presentations you have liked in various social networks. That’s how you can present a useful service to your friends and colleagues and help SlidePlayer grow and increase the number of good presentations available.

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Stem cell clinics, FDA, and giant, unapproved for-profit …

Posted: November 1, 2015 at 3:46 pm

When I started blogging in 2010 the stem cell arena was a very different place.

Back then the hot topic was the battle over the legality of federal funding of embryonic stem cell research. That battle is over, or at least in hibernation, with a2013 federal court rulingallowing such funding to continue. The stem cell debate of today, which in its own way is just as fierce as the old one, is focused on how best to regulate the clinical translation and commercialization of innovative stem cell technologies.

The stakes in this new stem cell battle on the regulatory front are very high both for the stem cell field and for patients. Too little regulation could lead to harm to patients and damage to the stem cell field at a crucial juncture in its history, while too much regulation could stifle stem cell and regenerative medicine innovations.

The goal of stem cell advocates, including myself, is to find a regulatory sweet spot where science-based, innovative stem cell medicine can advance expeditiously. On the other side we have largely physicians and lawyers along with some patients arguing for drastically-reduced regulation and acceleration of for-profit stem cell interventions to patients, even without concrete data supporting safety or efficacy.

The latter group is a key part of a rapidly-proliferating stem cell clinic industry in the US. It consists of for-profit stem cell clinics that collectively have already conducted stem cell transplants on potentially thousands of patients without federal regulatory approval. These clinics have in effect thrown down the gauntlet to the US Food and Drug Administration (FDA) with their use of non-FDA approved stem cell products on patients.

The FDA is the regulatory body legally empowered to regulate biologic products and hence stem cells in the US. However, the clinics generally argue that they and their stem cell products should not be regulated by the FDA because they believe that the products are not drugs and they as the physicians transplanting the stem cells are just conducting the practice of medicine. FDA guidance over the years has consistently conflicted with this view and indicated to the contrary that these clinics are generally producing a stem cell product that is a biological drug. Even so the clinics at this time do not have FDA approval to make and use stem cell biological drugs. Such approval can come in response to what is called anInvestigational New Drug (IND)application. The clinics do not have IND approval from the FDA for their stem cell products or devices and do not have the licensing (called aBiological License Application or BLA) needed to produce and administer biological drug products such as certain types of stem cells. Collectively, for these reasons (absence of BLA and INDs),I definesuch clinics as unlicensed and their products as unapproved or unproven. Note that the physicians practicing at such clinics generally do have medical licenses from state medical boards, so they personally are licensed in that sense. These clinic physicians frequently further point out that doctors themselves can only be directly regulated by state medical boards and not by the FDA.

Where does the FDA get its authority to regulate stem cell products and clinics? TheFederal Food, Drug, and Cosmetic (FDC) Actand thePublic Health Service (PHS) Actgive the FDA the legal authority and responsibility to regulate biologics including human stem cells. Therefore, barring a federal court specifically overturning a particular FDA decision, FDA regulations are essentially law when it comes to clinical use of stem cells in the US. The FDA is given certain authority over stem cell biological products and procedures more specifically under several regulations including 21 CFR Part 1271.10, modified by 21 CFR 1271.15, which details exceptions to its regulatory requirements. A key term to know before trying to decipher the verbiage in these regulations is human cell and tissue products or HCT/Ps, which basically means human biological products including human stem cells.

Both individual doctors doing stem cell transplants and chains of dozens of stem cell clinics have sprouted up from coast to coast in the US in the last few years. These clinics, collectively numberingmore than 20 in the state of Texas aloneand more than 100 across America, are administering stem cell transplants of one kind or another to growing numbers of patients each year, potentially generating millions of dollars in income, all without FDA approval. In doing so many of these clinics, even absent litigation against the FDA, are operationally challenging and undermining the authority of the agency by acting as medical providers using stem cell products without FDA approval or licensing. They are also a direct challenge to science-based medicine more generally. To put it more bluntly, I believe these clinics are in essence collectively doing a huge, unapproved human experiment for profit.

The FDA has issued a steady stream of regulatory guidances, supported in some cases by court decisions (e.g.US v. Regenerative Sciences Inc.), painting a clear picture that stem cell clinics in a general sense (as well as their products, devices, and procedures) are within its regulatory domain and their products can be defined as biological drugs. Furthermore, in 2012 and 2013 the FDA took numerous actions related to stem cell clinics such as warning letters issued to a number of clinicsincluding the Texas stem cell clinic Celltex, which is well-known for having treatedGovernor Rick Perry.

Strangely the FDA tookno regulatory actionregarding stem cell clinics in 2014, at least none that is evident in the public domain, but the FDA did issue important new draft guidances related to stem cells (seehere,here, andhere) that I predict will be the basis for future action. One part of these guidances focuses on minimal manipulation, which is a key term in the stem cell clinical world and more broadly the world of biologics. If a biological product is defined as more than minimally manipulated it automatically leads that product to be defined as a biological drug subject to the full spectrum of drug regulatory oversight by the FDA. While stem cell clinics frequently argue that their products are less than minimally manipulated, it is becoming clearer that a large fraction of (but certainly not all) stem cell products sold by various clinics are likely to be viewed by the FDA as more than minimally manipulated.

The FDA and the stem cell therapy industry use numeric names for products that are minimally manipulated (361) or more than minimally manipulated (351), so these can be important to know as one navigates this arena. The for-profit stem cell clinics generally argue that their products are 361s, but I believe that FDA guidance indicates instead that a large number of these products are 351 biological drugs.

It is also valuable at this point to talk about the different kinds of stem cell treatments sold by dubious clinics. The most common stem cell product transplanted into patients is something calledstromal vascular fraction or SVF, which is a product manufactured from fat tissue. While various clinics use other stem cell products including cells isolated from bone marrow and other tissues (some of which may be 361s, while others are 351s), SVF is by far the most common stem cell product sold by clinics.

Amongst other things, the new draft FDA guidances explicitly single out SVF for attention and define it as a biological drug. This is particularly notable because many stem cell clinics have argued that SVF is not a drug and hence is not subject to drug-related FDA vetting. While many includingmyselfhave asserted in the past that SVF is almost certainly a drug and needs FDA approval before use, these new guidances from the FDA articulate, far more specifically and unambiguously than in the past, how SVF is by definition more than minimally manipulated and hence a drug (emphasis mine):

Example A-1: Adipose tissue is recovered by tumescent liposuction. The adipose tissue undergoes processing or manipulation (e.g., enzymatic digestion, mechanical disruption, etc.) to isolate cellular components, commonly referred to asstromal vascular fraction, which is considered a potential source of adipose-derived stromal/stem cells for clinical therapeutic uses. This processing breaks down and eliminates the structural components that function to provide cushioning and support, thereby altering the original relevant characteristics of the HCT/P relating to its utility for reconstruction, repair, or replacement.Therefore, based on the definition of minimal manipulation for structural tissue, this processing would generally be considered more than minimal manipulation.

Because of these new FDA guidances,I believethe fat stem cell clinic industry could be subject to future FDA action. However, the FDA is slow and cautious in how it proceeds with even what seem to be relatively straightforward regulatory actions that could even be viewed as neutral such as simply visiting a stem cell clinic to obtain information on its practices, products, devices, and such. It is important that the science-based medicine community advocate for appropriate, expeditious FDA action.

Another key term in the stem cell clinical arena is homologous use. When applied to an HCT/P product, it means that the clinical use of that product must be highly consistent with (i.e. homologous to) the properties of the original tissue from which the product was made; if it is not homologous, even if minimally manipulated it will automatically be considered a 351 drug product. An example of homologous use would be the transplant of hematopoietic stem cells to treat a hematopoietic disorder. In that case, a blood-related product is used to treat a blood-related disease.

An example of non-homologous use would be the transplant of SVF (again, a fat tissue derivative) as an intervention for a neurological disorder, as fat is not homologous to the nervous system. In this regard, it is important to point out that many stem cell clinics offer up their stem cell products (most often SVF) to treat a whole menu of human diseases manifesting in tissues that having nothing to do with fat or with the other tissues of origin of the various types of stem cells.

In an example given in the new draft FDA guidance in the section on homologous use, the agency points out that use of SVF to treat a bone or joint disease is non-homologous use (emphasis mine):

Example B-2: Adipose tissue is recovered and processed for use, as reflected by the labeling, advertising, or other indications of the manufacturers objective intent,to treat bone and joint disease. Because adipose tissue does not perform this function in the donor, using HCT/Ps from adipose tissue to treat bone and joint disease is generally considered a non-homologous use.

Another way that clinics try to get around having their products defined as biological drugs is througha possible FDA exceptioncalled same surgical procedure. The idea here is that if a procedure involving biologics such as stem cells is done in an autologous manner (the patient is both donor and recipient) and is completed in a single surgical procedure, then the biological product in theory might not be defined as a biological drug. It might be exempt from that designation because such procedures may have relatively lower risks. Many stem cell clinics have made the assertion that because in some cases they use stem cells in same surgical procedures that it means that they are not subject to FDA regulation of their product as a drug even if the product is, for example, SVF. However, the reality appears to be that the more than minimal manipulation and non-homologous use definitions trump the same surgical procedure exemption, discussed further inone of the 2014 draft FDA guidancesmentioned earlier. What this means is that if your product is more than minimally manipulated or it is used in a non-homologous manner (either of these is enough), it is still automatically defined as a biological drug even if you use it in a same-day surgical procedure.

The point of these FDA biologics regulations is to protect patients. It is logical that products that are more than minimally manipulated or used in a non-homologous manner pose higher risks to patients. As a result there is an appropriately higher requirement for evidence to support the use of such products in human patients. It is therefore of substantial concern that so many stem cell clinics in the US and around the world are going ahead and using experimental stem cell drugs as the basis of for-profit interventions without evidence that such products are safe or effective.

The stem cell entities in the US that concern me the most are chains of stem cell franchising clinics. These are rapidly-growing chains of affiliated clinics selling mostly fat stem cell-based interventions without FDA approval or licensing. Two examples of such chains are Cell Surgical Network and Stem.md.

Cell Surgical Network

Cell Surgical Network is a Beverly Hills-based chain of upwards of 50 stem cell clinics around the US that share philosophies, institutional review boards (IRB), procedures, devices, and malpractice insurance. They offer up SVF-based interventions for a wide range of medical conditions. I interviewed the leaders of Cell Surgical Network, Drs. Elliot Lander and Mark Berman, on my own blog last year (seehereandhere) and thenraised my concerns about their operations, including my view that their SVF product is likely more than minimally manipulated, that they use the product in what I view as a non-homologous manner, and that the device they use is not FDA-approved for this application. Their device is a column, which is a laboratory tool used to separate cells from the rest of the components of tissues, manufactured by a company called Medikan.

In response to my question regarding the possibility that the Cell Surgical Network SVF product is a 351 biological drug (and one for which they do not have FDA approval such as an IND to use it clinically), Cell Surgical Network responded in part by invoking the same-day surgical exemption, which again to my knowledge does not apply in this case with SVF:

We produce SVF (over 40 ingredients and cant be characterized) in a surgical procedure (cant be approved by the FDA theyve never approved a surgical procedure). If the FDA cant approve a surgical procedure, why would we possibly request them to approve this procedure?

It is worth noting that although arguably the FDA cannot directly regulate doctors or surgical procedures, the FDA can and does regulate drug products, biologics production procedures and devices in a general sense, which largely challenges the Cell Surgical Networks argument as well.

I also asked Cell Surgical Network about the issue of their arguably non-homologous use of SVF to treat diverse non-fat related conditions (see their menuhere). I found their response to be rather creative, but one with which I disagree:

We do have many conditions that we are looking at and in choosing them we have attempted to exploit either the regenerative, immuno-modulatory, or anti-inflammatory properties of SVF. Although SVF is used in all of our protocols, our deployment techniques vary considerably. I think the term homologous has been used rather loosely and in the field of regenerative medicine, a new paradigm defies simplistic categorizations of cell types. After all, what type of tissue is an undifferentiated progenitor cell? Can it be homologous? Isnt it potentially everything? For example, if it forms cartilage then could it have ever been anything other than a cartilage precursor? Our comfort zone is that we are surgeons performing a type of surgical tissue transfer procedure. There is no difference than when we replace a bladder with ileum or a coronary artery with a saphenous vein from an extremity. At the end of the day, the ability to use various tissues to treat human disease is within the realm of a surgeons domain.

In this line of argument then, would anything stem cell-related be considered pan-homologous to every other tissue and could never be used in a non-homologous manner? That seems like a rather radical notion and one not consistent with FDA guidance. Further, can a surgeon pretty much do anything they want? That seems to be a rather extreme idea too.

Still, despite these concerns, to my knowledge the FDA has so far never taken any action related to Cell Surgical Network. Therefore, a reasonable question to ask is why, if from my perspective the FDA would view Cell Surgical Network as likely being non-compliant in its use of stem cells, has the agency apparently done nothing about it? The frank answer is that no one except the FDA knows why or why not they take specific actions and they do publicly discuss specific situations.

Stem.md

Stem.mdis a similar group of stem cell clinics, but one that sprouted up on the East Coast. Stem.md has dozens of clinics too, including some using SVF as well as other types of stem cell products. While the Stem.md website frequently has changed over the years,as recently as a year agothey made some rather bold claims for their stem cell transplants including the remarkable statement that they provide a treatment for every condition. Sounds like a panacea, right? They also at one point claimed their advances were FDA-approved, although they took down that claim when I pointed it out to them as being incorrect. Like some other stem cell clinics, Stem.md has made a big deal out of treating pro athletes, including in their case former Yankee Bartolo Colon, which might remind you ofthe recent case wherestem cell clinics Stemedica and Novastem arguably could have benefited from a free stem cell intervention performed on hockey legend Gordie Howe as a public relations opportunity.

Some of the same nagging issues come up with Stem.md as with Cell Surgical Network, including potential non-homologous use and more-than-minimal manipulation. However, as with Cell Surgical Network, to my knowledge the FDA has not taken any regulatory action related to Stem.md.

While the recent FDA draft guidances are a step in the right direction of increased clarity, if the FDA takes no action, or waits years to enforce its finalized guidances, the end result is that the FDA is undermining its own authority and I believe putting patients at increased risk. In principle, in the absence of FDA action, stem cell clinics can effectively argue that if their practices did violate FDA regulations then the FDA should have done something about it by now. In the absence of regulatory action, there is always the possibility that the FDA could view the clinics use of stem cell products as compliant. I would also note that my views presented in this article, of course, do not necessarily reflect those of the FDA, and the stem cell clinics view FDA regulations quite differently.

A relatively newer, but important issue related to stem cell clinics is the listing of their stem cell interventions on the official US governments clinical trials website, ClinicalTrials.gov. I recentlyinterviewedthe Director of ClinicalTrials.gov, Dr. Deborah Zarin, to ask her about key issues including specific questions related to stem cell clinic listings. I was concerned to find out that ClinicalTrials.gov largely operates on the honor system in terms of deciding whether to list trials submitted to it for consideration. For example, there is neither specific vetting of US trials (keep in mind that ClinicalTrials.gov lists trials from all over the world) for FDA compliance nor a requirement that trials list specific IRB or other key information. Trials listed on the database can also be of a for-profit nature (i.e. patients are charged simply for participating in the trial before there is concrete evidence that the product or procedure in question is safe or effective) and based on the information in the trial listing, there is no straightforward way for patients to know that reality. I believe that this situation puts patients at added risk and also puts the valuable mission of ClinicalTrials.govin jeopardy.

The end result of this situation is that many for-profit stem cell clinics have trials listed on ClinicalTrials.gov and some use that listing as a marketing tool. What kind of money is involved here? Cell Surgical Network has a clinical trial listed with a projected enrollment of3,000 patientsand hypothetically if the organization makes $5,000 profit per patient that would add up to $15 million, again before the SVF product in question is even known to be safe or effective for the particular condition in question and without FDA approval or licensing.

I believe that a number of changes are needed at ClinicalTrials.gov including a requirement that for-profit trials be labeled clearly as such near the top of their listing page, that the listing of a given trial on the site should be prohibited from being used as a marketing tool by the entity responsible for the trial, and that the ClinicalTrial.gov team vet trials located in the US for FDA compliance and as needed consult with the FDA on this matter.

If you feel likewise, this is one case where you can easily take positive action during a specific window of time. ClinicalTrials.gov has issued a Notice of Proposed Rule Making (NPRM), detailed in a very recent open accessNew England Journal of Medicinearticleby Dr. Zarin. Comments on proposed changes including suggestions such as mine can be submitted in response tothis NRPM, but only until February 19th. I encourage you to submit comments and I have dug through the websites to find thisdirect linkthat allows you to do so quickly and easily.

The overall bottom line with most stem cell clinics in the US is that collectively they could be viewed as conducting a huge, unapproved and for-profit stem cell experiment of a sort, on thousands of vulnerable patients who are often desperately looking for hope. At the very least these patients are spending money that they can ill afford to lose on stem cell transplants that probably do not help them. It is also quite possible that some of these patients are being harmed. Stem cells do not always do what we might hope and their power to potentially help patients is equaled by their potential to do harm, especially when not backed up by rigorous science andphysician training. For example, fat stem cells are typically a heterogeneous mix of a variety of cell types with variable multipotency meaning that they can not only form mature fat tissue, but also potentially blood vessels, bone, cartilage, or others. The growth of an undesired tissue in the wrong place could be a major adverse outcome. There is evidence of potential for patient harm including growth ofbone in an eyeandnose tissue in a spinefrom stem cell treatments that went awry. Some patients treated at stem cell clinics have died, including inthe US,Germany, and elsewhere.

More broadly in this new stem cell debate, the for-profit clinic argument for stem cell deregulation and weakening of the FDAs role in regulating stem cell products is a direct challenge to our system of science-based medicine. Furthermore, while to those of us in the stem cell field it may often seem clear where we can place a dividing line between the dubious clinics and the ones who follow the rules, that line is at best fuzzy for the wider community (including patients). For this reason the ever-growing unapproved human stem cell experiment poses a grave risk to the legitimate stem cell field as well. Governmental entities such as the FDA and ClinicalTrials.gov perform important services in this arena, but can and should do better to reign in the wild west mentality of the stem cell clinic industry in America today. Advocates of science-based medicine have an opportunity to make a positive impact here as well via educational outreach, participation in the FDA guidance comment process, and advocacy for responsible clinical research.

Note: a version of this piece was first posted at Sciencebasedmedicine.org.

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Stem cell clinics, FDA, and giant, unapproved for-profit …

Shocking Hcg Diet Report – Read before you buy! | Hcg Diet

Posted: November 1, 2015 at 3:44 pm

HCG

The HCG Drops utilizes the Human Chorionic Gonadotropin hormone that is usually produced by a developing embryo to support its growth during pregnancy. However, the HCG is used by both men and women as a weight loss diet supplement that is administered either as HCG drops or injections. This diet supplement was invented in 1950 by Dr. Simeons, who noticed unexplained and quick weight loss among the people who were consuming the HCG drug for other reasons.

As stated above, HCG Diet Drops is a hormone that defends the embryo during growth. By administering it, you trick your body to believing that it’s pregnant and has to protect the growing embryo by providing it with enough energy. This will in turn trigger the body to speed up the metabolic process so as to burn up the excess fat and calories before turning them to useful energy.

The HCG diet consists of three phases that each user must complete for effective results. These phases include:

Conclusion

Where to buy hcg drops?The HCG Drops is gaining a lot of popularity due to its effectiveness and quality. Its effectiveness is attributed to the fact that it uses a natural body hormone that is very safe and proficient. HCG Drops supplement that is ideal for everyone who suffers from obesity and wants to embrace a healthy and balanced lifestyle.

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Shocking Hcg Diet Report – Read before you buy! | Hcg Diet

Storing Stem Cells In Teeth For Your Familys Future Health

Posted: October 31, 2015 at 7:45 am

Protect your family’s future health.

Secure their stem cells today.

Bank the valuable stem cells found in

baby teeth and wisdom teeth.

Researchers at the National Institutes of Health (NIH) discovered a rich source of adult stem cells in teeth the stem cells that naturally repair your body. Scientists aredirecting stem cells so they grow into almost any type of human cell, including heart, brain, nerve, cartilage, bone, liver and insulin producing pancreatic beta cells.

AAOMS – American Association of Oral and Maxillofacial Surgeons

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Doctors recommend StemSave stem cell banking for the cryopreservation of powerful adult stem cells from deciduous teeth (baby teeth), wisdom teeth or permanent teethwith healthy dentalpulp.

Easy OnlineEnrollment

StemSave Stem Cell Banking exclusively recovers and stores non-embryonic stem cells. Dental Stem Cells are also known asDSC, DASC, DPSC, or SHED cellsand are classified as atype of adult stem cells.

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Storing Stem Cells In Teeth For Your Familys Future Health

Stem Cell Cryobank Cord Blood and Stem Cells for Life

Posted: October 31, 2015 at 7:45 am

Over 1 Million Parents have Banked their baby’s Cord Blood Stem Cells. Will You do the same for your Baby?

Stem Cell Cryobank is your local, AABB accredited, reliable and affordable cord blood stem cell cryopreservation company. Our offices, laboratory and storage facilities are located at Bethesda Health City in Boynton Beach, FL. convenient to both the Florida Turnpike and I 95.

We offer personalized services to our clientele. We invite each of our clients as well as their obstetricians to come and look over our facility and see where their childs cord blood will be processed and stored. We will personally pick up the collection kit after your babys cord blood has been collected and bring it back to our lab for processing and cryopreservation.

When making the decision to store your babys lifesaving cord blood stem cells, think STEM CELL CRYOBANK, your local cord blood bank.

Our Medical Director, Dr. Dipnarine Maharaj is a renowned transplant physician who operates an outpatient stem cell transplant center at South Florida Bone Marrow Stem Cell Transplant Institute, also located at Bethesda Health City.

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Stem Cell Cryobank Cord Blood and Stem Cells for Life

University of Delaware Chemical Engineering

Posted: October 31, 2015 at 7:44 am

We are delighted to welcome Joshua Enszer, who has joined the Department of Chemical and Biomolecular Engineering as assistant professor of instruction, with responsibilities that cover teaching and academic innovation in the undergraduate program. His goal is to bring knowledge from the scholarship of teaching and learning to improve opportunities in the departments undergraduate courses. He hopes to apply some of his earlier work in the areas of game-based learning and metacognition to his new position at UD. Before starting at UD in August, Enszer was a lecturer in chemical engineering at the University of Maryland Baltimore County. Prior to that, he was interim program coordinator for first-year engineering at the University of Notre Dame. Enszer holds a bachelor of science degree in chemical engineering and mathematics from Michigan Technological University and a master of science degree and doctorate in chemical engineering from Notre Dame.

The Department of Chemical and Biomolecular Engineering at the University of Delaware invites applications for a tenure-track Assistant Professor position.

Wednesday, November 4, 2015 9:30 AM – 3:30 PM Rodney Room, Perkins Student Center REGISTER NOW

Allan Ferguson was in the very first engineering class taught by the late Jon Olson at the University of Delaware. “He was absolutely brilliant, and here we were, these young, malleable minds, ready to learn the really complex things he would teach us,” the 1965 chemical engineering graduate recalls. “And then he gave the first exam.” Ferguson flunked, but he wasnt the only one.

Thomas H. Epps, III, the Thomas and Kipp Gutshall Associate Professor of Chemical and Biomolecular Engineering at the University of Delaware, has been awarded the American Physical Societys 2016 John H. Dillon Medal for “significant advances in the control, characterization and understanding of polymer nanoscale structure and energetics.” The medal recognizes outstanding research accomplishments by young polymer physicists who have demonstrated exceptional research promise early in their careers.

In the world of catalytic science and technology, the hunt is always on for catalysts that are inexpensive, highly active, and environmentally friendly. Recent efforts have focused on combining two metals, often in a structure where a core of one metal is surrounded by an atom-thick layer of a second one.

Wilfred Chen, Gore Professor of Chemical Engineering at the University of Delaware, is the recipient of the American Institute of Chemical Engineers (AIChE) 2015 D.I.C. Wang Award for Excellence in Biochemical Engineering. Chen is cited for the creative application of molecular techniques in engineering proteins and microbes to perform an extraordinary range of biotechnological tasks for bioremediation, biocatalysis, biofuel production, bioseparation and biosensing.

Polymer nanocomposites are used in a wide range of applications, from automobile parts and tires to high-tech electronics and solar cells. As with traditional composites, the properties of nanocomposites can be tailored to the requirements of specific applications, but achieving those properties can be challenging.

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University of Delaware Chemical Engineering

Eli and Edythe Broad Center of Regeneration Medicine and …

Posted: October 31, 2015 at 7:41 am

Welcome to the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF, one of the largest and most comprehensive programs of its kind in the United States.

In some 125 labs, scientists are carrying out studies, in cell culture and animals, aimed at understanding and developing treatment strategies for such conditions as heart disease, diabetes, epilepsy, multiple sclerosis, Parkinsons disease, Lou Gehrigs disease, spinal cord injury and cancer.

While the scientific foundation for the field is still being laid, UCSF scientists are beginning to move their work toward human clinical trials. A team of pediatric specialists and neurosurgeons is carrying out the second brain stem cell clinical trial ever conducted in the United States, focusing on a rare disease, inherited in boys, known as Pelizaeus-Merzbacher disease.

Others are working to develop strategies for treating diabetes, brain tumors, liver disease and epilepsy. The approach for treating epilepsy potentially also could be used to treat Parkinsons disease, as well as the pain and spasticity that follow brain and spinal cord injury.

The center is structured along seven research pipelines aimed at driving discoveries from the lab bench to the patient. Each pipeline focuses on a different organ system, including the blood, pancreas, liver, heart, reproductive organs, nervous system, musculoskeletal tissues and skin. And each of these pipelines is overseen by two leaders of international standing one representing the basic sciences and one representing clinical research. This approach has proven successful in the private sector for driving the development of new therapies.

The center, like all of UCSF, fosters a highly collaborative culture, encouraging a cross-pollination of ideas among scientists of different disciplines and years of experience. Researchers studying pancreatic beta cells damaged in diabetes collaborate with those who study nervous system diseases because stem cells undergo similar molecular signaling on the way to becoming both cell types. The opportunity to work in this culture has drawn some of the countrys premier young scientists to the center.

While the focus of the science is the future, UCSFs history in the field dates back to 1981, when Gail Martin, PhD, co-discovered embryonic stem cells in mice and coined the term embryonic stem cell. Two decades later, UCSFs Roger Pedersen, PhD, developed two of the first human embryonic stem cell lines, following the groundbreaking discovery by University of Wisconsins James Thomson, PhD, of a way to derive the cells.

Today, the Universitys faculty includes Shinya Yamanaka, MD, PhD, of the UCSF-affiliated J. David Gladstone Institutes and Kyoto University. His discovery in 2006 of a way to reprogram ordinary skin cells back to an embryonic-like state has given hope that someday these cells might be used in regenerative medicine.

Yamanakas seminal finding highlights the unexpected and dramatic discoveries that can characterize scientific research. In labs throughout UCSF and beyond, the goal is to move such findings into patients.

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