StemCell Therapy

Ethical, Legal and SocialIssues in Genomic Medicine

Genomics is the study of an organism's whole hereditary information that is present in its genes (DNA) and the use of its genes. It deals with the use of genome information associated with other information to provide answers in biology and medicine.

Genomic research may greatly change the practice of health care. But genomic research alone is not enough to apply this new knowledge to improving human health. We need to carefully study the many ethical, legal and social issues raised by this research. Such study is crucial to being able to use genomic research to help patients and to preventing misuse of new genetic technologies and information.

Ethical, legal and social issues raised by genomic research include:

Controversial issues such as cloning, stem cell research and eugenics also need to be carefully studied.

Since the beginning of the Human Genome Project, the National Human Genome Research Institute (NHGRI) has understood the need to address these issues as part of advancing the science of genomic research. We have an Ethical, Legal and Social Implications (ELSI) program, which is the federal government's largest funding source for study of these issues. Within NHGRI, the Division of Policy, Communications, and Education (DPCE) examines the intersection of ELSI issues with legislative policy and provides recommendations for federal policy and legislation. NHGRI also works to increase public awareness of ELSI issues in genomic research.

To learn more about ethics and policy topics and other resources for more information, follow these links to the Policy and Ethics section of this website.

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Last Updated: October 31, 2013

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Ethical, Legal and Social Issues in Genomic Medicine

Dental tooth loss and consequences -- an update Compiled by Walter Sorochan

Posted August 24, 2012 Updated September 24, 2012; updated September 30, 2015; Disclaimer

Update Sept 30, 2015: Oral health is the most overlooked health issue in conventional and integrative medicine:

"The issue of bone loss after tooth loss has been ignored in the past by traditional dentistry. [according to Skinner] This is so because dentistry had no treatment to stop or prevent the process of bone loss and its consequences. As a result, doctors had to ignore the inevitable bone loss after tooth extraction. Today, the profession knows about bone loss and that implants [ if done at proper time ] can stop bone loss because implants stimulate the bone, similar to the way the tooth did prior to its loss." Skinner: effects of tooth loss 2008

The statistics on tooth loss are a bit staggering: 7 out of 10 adults age 35 to 44 have lost at least one tooth and a quarter of those aged 65 or older [or about 20 million people] have lost all their permanent teeth.Hill: stem cells grow new teeth 2012 There are numerous dental controversies, for example --- whether fluoridation is really effective in preventing dental caries. Many other issues about dentistry are not discussed. Fortunately, there are new developments in dentistry that may help all of us to deal with our dental problems.

"The next stem cell advance I expect is the availability of regenerative dental kits, which will give dentists the ability to deliver stem cell therapies in their own office. The delivery of stem cell therapies by the dentist is complicated, and these kits will simplify the process and make the treatment more affordable." Murray: latest dental stem cell 2012

Many dentists are not explainingthe silent issues in dentistry todayto their patients! Some dentists are not up to date on the new developments in dentistry. Even though all the hype about how brushing, flossing and cleaning teeth every six months to stop dental caries is good, it does not replace the information you need to know about missing teeth, how your jaw bones work and how to keep your teeth and jaw bones healthy. The new info about dentistry today is how teeth and implants can keep your jaw bones healthy!

The author decided to research about the consequences of missing teeth. Here is what your dentist may not share with you about teeth in general.

Normal jaw bone function: Teeth stimulate the jaw bone to maintain good health. Keeping your jaw bones healthy is probably more important than keeping your teeth clean.

When a tooth is lost, the lack of stimulation causes loss of the jaw bone. Whenever a tooth is extracted, nature will remove the bone that used to surround it. Teeth on either side will shift or tip into the empty space.[ orange rectangle around upper molar teeth in diagram ] If there is a tooth directly above or below the space it will over erupt, as there will not be anything to prevent it from coming out of the gum tissue. The majority of bone degeneration will occur within the first six months but will slowly continue for years. The movement of the adjacent teeth will not occur immediately; rather it will become noticeable after three to five years. How fast it occurs will depend on the density of bone in the area, your bite and how well your teeth occlude or interlock with each other. If you have missing teeth and you do not replace them, these movements will occur.

These movements may create gum problems and /or decay and could lead to the loss of other teeth. As you lose more teeth, you will be forced to chew in other areas, and this often leads to tooth fracture from overloading, excessive wear and/or TMJ (jaw joint) problems. Eventually more extensive and expensive dentistry may be required in the future. Bhanumathi: consquences missing teeth

Thus, when a tooth is extracted from a young person, by the time that person is middle aged, a great deal of bone will be missing. Did your dentist tell you this?

Have your dentist discuss your 'fix' options when you have a sore tooth: e.g.

Toothaches: Common dental causes of toothaches include dental cavities, dental abscess, gum disease, irritation of the tooth root, cracked tooth syndrome, temporomandibular joint [TMJ] disorders, impaction, and eruption.

The most common cause of a toothache is a dental cavity or carie. [ Refer to above diagram ] Dental cavities or caries are holes in the two outer layers of a tooth called the enamel and the dentin. Small, shallow cavities may not cause pain and may be unnoticed by the patient. The larger deeper cavities can be painful and collect food debris. The inner living pulp of the affected tooth can become irritated by bacterial toxins or by foods and liquids that are cold, hot, sour, or sweet, thereby causing toothaches. Severe injury to the pulp can lead to the death of pulp tissue, resulting in tooth infection, also referred to as dental abscess.

A tooth abscess, also known as root abscess, is a collection of pus that results from bacterial infection. The infection starts with the soft pulp of the tooth and becomes more severe finally leading to pus formation at the bottom of the tooth root.

Saving teeth with crowns and root canals: Saving teeth is what a dentist does best!Treatment of a small and shallow cavity usually involves a dental filling. Treatment of a larger cavity involves an onlay or crown. Treatment for a cavity that has penetrated and injured the pulp or for an infected tooth is either a root canal procedure or extraction of the affected tooth. The root canal procedure may involve draining the pus, removing the dying pulp tissue and replacing it with an inert filling material. The procedure is used in an attempt to save the dying tooth from extraction. You should be aware that root canals may not last a long time.

The only alternative to a root canal procedure is having the tooth extracted and replaced with a bridge, implant, or removable partial denture to restore chewing function and prevent adjacent teeth from shifting. WebMD: root canals

Fixing cavities and infected teeth requires that a dentist use a local anesthetic to numb your tooth and jaw bone. There is now controversy about the safety of local anesthetics like novocaine or provaine. Nickel: toxicities from local anestheics Stockton: 2004

It is normal procedure for a dentist to numb the jaw - tooth area before working on a painful tooth. He injects a local anesthetic that numbs the jaw-tooth area. The numbness normally wears off in about two to three hours. Sometimes the numbness can last for several days and even months. This prolonged numbness can occur when the needle passes through a nerve in the area of injection and damages a nerve. This complication of numbness is referred to as paresthesia. Garisto: Paresthesia 2011

Bone Resorption: Missing teeth cause changes in the jaw bone structure. The bone that supported the missing teeth begins to shrink or thin away. There is a loss of width and height of the jaw bone. The process is referred to as bone resorption. This is a natural process of your body saving bone nutrients and structure it is no longer using. Jaw bone loss happens most rapidly during the first year of tooth loss and is four times greater in the lower jaw than in the upper. Uditsky: fixing loss teeth lower jaw 2012 The images below help to illustrate this process:

"Both skulls above are real. The one on the right belonged to an elderly person who lost his teeth many years before he died. When he was young and he had teeth, his skull used to look like the one on the left. The first thing that jumps out at you is how thin the bone of his lower jaw is in comparison to the bone on the lower jaw of the skull on the left. But another thing that is not so apparent is the loss of the bone in the upper jaw.

Notice that both skulls are positioned with their lower jaws mounted so that the bone of the lower jaw is about parallel with the bone of the upper jaws. This tells you that the teeth are together. Even the skull on the right---if it had teeth. This gives you an idea of the amount of bone that that has been lost since this man had all his teeth extracted." Spiller: Bone Resorption

Most of us, 70%, have at least one tooth missing and have never had it replaced. Misch: consequences losing teeth 2011Spiller: index 2000 A vast majority do not suffer major problems like eating, speaking or the way they look. On the other hand, a few, especially some women, tend to develop the joint problems, headaches, neck aches or ear aches typical of jaw joint or TemporoMandibular Joint [TMJ]. When a tooth is lost, the lack of stimulation causes loss of the jaw bone. There is a 25% decrease in width of jaw bone during the first year after tooth loss and an overall 4 millimeters decrease in height over the next few years. Misch: consequences losing teeth 2011

One Lost Tooth Causes a Chain Reaction: The loss of a single tooth starts a chain reaction in the jaw bone. After a back molar tooth is lost, a series of destructive events occur including the shifting of other teeth, decay, tilt, drift and gum pocket formation. Eventually, bone loss and periodontal disease will cause further destruction. If you fail to replace a lost tooth in the back of your jaw, you could eventually lose all your teeth. Dentist Steinbergexplains how this can happen in his article: Replacing lost teeth 2011

Without chewing pressure to stimulate the bone, the jawbone begins to dissolve away immediately after extraction and continues forever unless an implant is placed. This is a very important piece of information that you need to be aware of!

Consequences of lost teeth: Skinner: effects of tooth loss 2008 Spiller: Bone Resorption Steinberg: Replacing lost teeth 2011 Misch: consequences losing teeth 2011

Facial changes naturally occur in relation to the aging process. When the teeth are lost, this process is grossly accelerated with more rapid facial aging. The loss of teeth can add 10 or more years to a person's face. A decrease in face height occurs as a result of the collapse of bone height when teeth are lost. Skinner: effects of tooth loss 2008 Patients are often unaware that bone, gum and facial changes are due to the loss of teeth. Instead, they blame these problems on aging, weight loss, or the dentist for making a poor denture. Besides several facial changes, there are other consequences of losing teeth and not replacing them:

Many people, who lost teeth, upon later wanting to repair the damage caused by the loss of the tooth find that repair is much more expensive because of the movement in the adjacent and opposing teeth.Spiller: index 2000 Indeed, the changes to the jaw may be so great that fixing the damage may be very difficult or impossible .... and expensive!

Ways to deal with missing teeth:

What are dental implants?

Dental implants [ illustration above ] are replacements for the roots of teeth, the parts that are below the gumline and anchored in bone. They are usually covered with a crown that shows above the line of the gums. Uditsky: fixing loss teeth lower jaw 2012 Spiller: index 2000 A primary reason to consider dental implants to replace missing teeth is the maintenance of jaw bone. As you may recall, bone needs stimulation to stay healthy. The implant takes the place of the missing tooth and stimulates the jaw bone to work normally.Misch: consequences losing teeth 2011 Bone resorption can be prevented by replacing natural teeth with dental implants soon after they are extracted. Key is soon!

Most importantly, implants reduce the amount of bone resorption. Studies have shown about 75% less resorption in parts of the jaw with implants compared to areas without them. Since most of the bone loss occurs within the first year after tooth loss, it is important to place implants within this time period. Uditsky: fixing loss teeth lower jaw 2012

Fixed bridge:

"Up until now, the most common but not necessarily the best option for replacing a single back tooth has been a three-unit fixed partial denture (FPD), also called a fixed bridge. In this case, the two teeth on either side of the gap, known as abutment teeth, are crowned and the two crowns together support a pontic a false tooth in the middle [from the French word for bridge].

This type of prosthesis [false replacement] can be fabricated within one to two weeks and provides normal shape, function [eating, talking and smiling], comfort, aesthetics and health. Because of these benefits, FPDs have been the treatment of choice. Misch: consequences losing teeth 2011

The bad side of doing a fixed bridge is that this procedure requires cutting down the healthy teeth on either side of the missing tooth. Tooth preparation of the adjacent teeth is irreversible and involves destroying quite a bit of tooth structure. Appleton: replacing missing teeth 2012 You and your dentist-orthodontist need to have a really good reason to do this procedure!

A well made fixed bridge can look natural, function well, and potentially last a lifetime. However, 75% of fixed bridges fail within 7 years. The fixed bridge is at least three teeth connected together with the false tooth (the replacement tooth) in the middle. Because the teeth are connected, you cannot pop dental floss between them. Instead you must thread the floss through underneath where the teeth are connected or use a special small brush to get under the connectors. People tend to neglect to perform this inconvenient extra step in their oral hygiene routine. This contributes to the relative high rate of failure of fixed bridges. Also, the extra stress on the teeth supporting the fixed bridge can lead to mechanical breakdown and thus adds to the failure rate. In spite of these potential problems, the fixed bridge is still the treatment of choice for many patients. Appleton: replacing missing teeth 2012

How Implants Stop Bone Loss: Dental implants fused and integrated into the jaw-bone serve as anchors to support teeth. They function the same as natural teeth in that the implant provides pressure stimulus on the opposite side tooth. As you may recall, bone needs stimulation to stay healthy. An implant-supported tooth, or teeth, allow for normal function of the whole jaw including the nerves, muscles and jaw joints. Moreover dental implants fuse to the bone, stabilizing and stimulating it to maintain its dimension and density.Misch: consequences losing teeth 2011

Missing teeth may cause sinus problems

Patients are often not quite clear that sinus problems may be related to missing teeth in the upper jaw and that these can be a very expensive fix.

Image courtesy Young: Sinus Lift

The maxillary sinuses are behind your cheeks and on top of the upper teeth [ upper diagram ]. These sinuses are cavities with empty, air-filled spaces. Some of the roots of the natural upper teeth extend up into the maxillary sinuses. When teeth in the upper jaw are removed and not replaced, the jaw bone can shrivel up and the sinus will expandfurther down toward the jaw ridge from the inside of the jaw bone. This often causes a thin wall of bone separating the maxillary sinus and the mouth, making it difficult or impossible to place dental implants in the jaw bone. Young: Sinus Lift Gougaloff: Sinus Lift Procedure 2008

However, the thin jaw bone can be regrown and the thin sinus wall can be restored by a procedure known as "sinus lifting." This procedure strengthens the growing bone in the upper jaw, allowing dental implants to be placed in the new bone growth. This restores the missing teeth. For more detailed information on bone grafts see bone graft post or link to Robert Gougaloff s website.

Finally, dental implants are now available in different sizes and length, making it more easy than in the past, to fix missing teeth in the jaw bones. You need to consult with your dental specialist for more information.

Is jaw bone loss reversible? Yes!

In cases where there is not enough bone to support a successful implant, the surgeon may perform a bone graft. A synthetic bone grafting compound may be used that is easier and more successful than bone on bone grafting. It can usually be done at the time of the implant surgery, allowing everything to heal into place together, which ultimately makes for a more solid implant.

Your dental health future is in dental stem cells:

Dentists are optimistic that stem cells will allow them to deliver more miraculous therapies that will benefit their patients and improve patient quality of life. The hope is that these dental stem cells could be used to heal the patients when they need it in the future. Research is now taking place about growing a bio-tooth, made from self-generated or self-produced [autogenous] Dental Pulp Stem Cells or DPSCs to regenerate lost teeth. DPSCs can be used in the same individual without the danger of an immune rejection response.

A dental study in 2009 used stem cells to heal jaw bone tissue.Nat Dental Pulp Lab: dental stem cells The stem cells come from a substance called dental pulp from within the interior chamber of our teeth. This pulp is made up of living soft tissue and stem cells.Dental stem cells are adult stem cells present in both baby (deciduous) teeth, and adult teeth. The stem cells consist of dental mesenchymal stem cells and dental epithelial cells. Dental epithelial cells give rise to enamel, while dental mesenchymal stem cells give rise to all of the other tissues of the tooth, including pulp, dentin, cementum, periodontal ligament, and surrounding alveolar bone. The ability to harvest cells from extracted wisdom teeth and supernumerary teeth that would otherwise be discarded as waste makes these tissues unique and valuable stem cell sources. Murray: latest dental stem cell 2012

A three month study, the first in dentistry, used dental stem cells to completely regenerate the injury site in the jaw and restore periodontal tissue. dAquino: stem cell healing in dentistry 2009 This study demonstrated that stem cells have great promise in helping to fix dental problems.

More recently in 2012, endodontics professor Dr. Peter Murray and colleagues from the College of Dental Medicine at Nova Southeastern University (NSU) have developed methods to control adult stem cell growth toward generating dental tissue and real replacement teeth. "Teeth can be grown separately, then inserted into a patients mouth, or the stem cells can be grown within the mouth, reaching a full-sized tooth within a few months. So far, teeth have been regenerated in mice and monkeys, and clinical trials with humans are underway, but whether the technology can generate teeth that are nourished by the blood and have full sensations remains to be seen." Hill: stem cells grow new teeth 2012

Why stem cells may be better than durable implants such as titanium dental implants? A short answer to this question is that stem cells lead to the regeneration of teeth with periodontal ligament that can remodel with the host. Mao: stem cells & future dental care 2008 Mao elaborates on this concept of stem cell use:

"Stem cells can be seeded in biocompatible scaffolds in the shape of the anatomical structure that is to be replaced. Stem cells may elaborate and organize tissues in vivo, especially in the presence of vasculature. Finally, stem cells may regulate local and systemic immune reactions of the host in ways that favor tissue regeneration.

Much of what dentists know is evolving into a new dentistry in which dental care is delivered increasingly by biologically based approaches. For example, biomolecules will be used for periodontal regeneration; stem cells will be used in the regeneration of dentin and/or dental pulp; biologically viable scaffolds will be used to replace orofacial bone and cartilage; and the defective salivary gland will be partially or completed regenerated." Mao: stem cells & future dental care 2008 Hill: stem cells grow new teeth 2012

So .... what do you do?

Using stem cells to safely regenerate missing teeth may be a few years in the future.Dentists predict that the technology should be available within the next decade. Hill: stem cells grow new teeth 2012 Meanwhile you should do the following:

1. Continue taking good care of your teeth == brushing and flossing regularly.

2. Pay immediate attention to missing teeth! Missing teeth are an overlooked item and need much more priority than brushing teeth because replacing lost teeth can prevent jaw bone loss and thereby keep your teeth and jaw bones healthy when you get older.

3. Be aware that dentistry is a business. Some dentists and prosthodontists may be more eager to have your money than fix your missing teeth!

4. Consider getting dental insurance if you have not done so. Today's available dental insurance coverage is better than none at all! Check to find out whether you have dental insurance coverage through your employer.

Some dental insurance plans may have an annual maximum benefit limit. Thus, once the annual maximum benefit is exhausted and additional treatments may become the patient's responsibility. Each year that annual maximum is reissued.

The problem with dental insurance is that companies selling dental insurance coverage have ceilings on how much dental insurance companies will cover, the kind of dental problems covered and so on; a form of rationing dental services. Many dental problems that occur in middle and senior stages of life; like replacing lost teeth, are expenses that the elderly cannot pay for and insurance companies place a limit on the amount they will pay.Unable to afford expensive fixes for loss of teeth, many elderly end up with continuing eating and jaw problems. It is the opinion of this author that we need a massive overhaul of the dental insurance system.

5. Make a partnership with your dentist so your dentist works for your health and that the partnership is a two-way street.This may be the new way of dentistry. In the past, many patients came to the dentist in pain and in need for immediate dental care. This 'one-way street' placed the patient in an uncompromising position of needing immediate dental care over dental information. Challenge your dentist!

6. Update your dentist with the information in this article .... to make him aware that you are an informed patient.

7. Check the references for some surprises.

Questions to ask:

Though one can easily find first-class experienced implant surgeons in some of the respected institutions, it is important to check the qualification, experience, profile and percentage of successful implant procedures of the implant surgeon you choose. You should never hesitate to ask any sort of questions related to your dental well-being in your next meeting:

What are your dental fix options? Have your dentist outline ALL of your options! For example, lose a tooth or save a tooth?

What kind of anesthetic will your dentist use: novocaine = trade name procaine Wiki: Procaine, lipocaine, mepivicane, lidocaine, bupiricane, demerol, other?

How big a dose will the anesthetic be? Is it related to body size?

How long will it take for the anesthetic to detoxify?

Are you allergic to the anesthetic? How does the dentist know?

What could potential side-effects be from the anesthetic? Nickel: toxicities from local anesthetics

What are the risks of a dental implant? or a root canal?

Why didn't your dentist prescribe a probiotic along with the antibiotic --- to restore the desirable good bacteria killed off by the antibiotic?

When was the last time your dentist went to a dental seminar or conference to update his background and skills?

Is there enough jaw bone to consider a dental implant? For example, it is important that you know everything related to the implant procedure much earlier than it happens.

Is your dentist going to get certified in dental stem cell surgery?

The author confesses that doing this article research about what should be new priorities in dentistry was not just informative but totally revealing.This author needed this information to be able to make better decisions about his own dental wellbeing. Sharing all this information in one location is done for your convenience. Hopefully you have become a little more informed about your dental health. Your feedback is most appreciated:

Your feedback is most appreciated: E-mail to: Author Walter Sorochan

To return to: web-site main page

References:

American Academy of Peredontonology [AAP], "Dental Implant Placement Options," Perio.org. AAP: Implant options

Appleton Richard, "What's the best way to replace a missing tooth or teeth?" HubPages, Explore Health (33,263) Oral Health (472), January 26, 2012. Appleton: replacing missing teeth 2012

Bubalo Marija, Zoran Lazi, Radomir Milovi, Anika ukovi, "Rehabilitation of Severely Resorbed Mandible Treated With Mini Dental Implants and Iliac Crest Bone Grafts: Case Report," Scientific Journal of the Faculty of Medicine in Ni 2011;28(3):183-188. Bubalo: rehab resorbed mandible 2011

Bhanumathi C.K, "Consequences Of Missing Teeth," WherincityMedical, October 22, 2009. Bhanumathi: consquences missing teeth

Changes in the Jaw Bones, Teeth and Face after Tooth Loss, Images. Images of bone-dental changes

Cosmetic dentistry grants, Free dental implants. Dental Grants

dAquino R, A De Rosa, V Lanza, V Tirino, L Laino, A Graziano, V Desiderio, G Laino, G Papaccio, "Human mandible bone defect repair by the grafting of dental pulp stem/progenitor cells and collagen sponge biocomplexes," European Cells and Materials journal, November 12, 2009, Volume No 18 pages 75-83. dAquino: stem cell healing in dentistry 2009 The first human study using dental stem cells in dentistry.

Dental Lab Direct, "Temporary Bridge," Temporary Bridge or TempoBridge is now available for individuals that are in need of a false tooth for a short period of time. If you have a missing tooth, a bridge will be custom made to fill in the space with a false tooth; in the meantime, you may use a temporary bridge. This false tooth is attached within a clear retainer - bridging them together, sometimes called a flipper. The TempoBridge is designed for a short amount of time (5 months or less), cannot be used while eating, and can have only one, possibly two teeth. A better solution is the FLEXIBLE PARTIAL, it's well worth the additional dollars. Dental Lab Direct: Temp dental bridges

Gougaloff Robert, "Sinus Augmentation or Sinus Lift Procedure," Implant Laser Dentistry, September 10, 2008. Gougaloff: Sinus Lift Procedure 2008

Gougaloff Robert, "Stem Cells in Dentistry?" Implant Laser Dentistry, November 25, 2008. Gougaloff: stem cells 2008

Garisto Gabriella A., Andrew Gaffen, Herenia Lawrence, Howard Tenenbaum and Daniel Haas, Occurrence of Paresthesia After Dental Local Anesthetic Administration in the United States, Journal of American Dental Association, July 2010;141(7):836-844. Garisto: Paresthesia 2011

Hill David J., "Toothless No More Researchers Using Stem Cells to Grow New Teeth," Singularity Hub, May 10th, 2012. Hill: stem cells grow new teeth 2012

Mao Jeremy J., "Stem Cells and the Future of Dental Care," NYSDJ, March, 2008. Mao: stem cells & future dental care 2008

Here is the original post:
Dental tooth loss and consequences - an update - Freegrab

2.1. Stem cell sources

Many different types of stem cells have been used in the research, testing and treatment of diabetes mellitus, including stem cells that can be used to regenerate pancreatic islets, e.g. embryonic stem cells, adult stem cells and infant stem cells (umbilical cord stem cells isolated from umbilical cord blood).

Human embryonic stem cells (ESCs) were first isolated at the University of Wisconsin-Madison in 1998 by James Thomson (Thomson et al., 1998). These cells were established as immortal pluripotent cell lines that are still in existence today. The ESCs were derived from blastocysts donated by couples undergoing treatment for infertility using methodology developed 17 years earlier to obtain mouse ESCs. Briefly, the trophectoderm is first removed from the blastocyst by immunosurgery and the inner cell mass is plated onto a feeder layer of mouse embryonic broblasts (Trounson et al., 2001; 2002). However, cells can also be derived from early human embryos at the morula stage (Strelchenko et al. 2004) after the removal of the zona pellucida using an acidified solution, or by enzymatic digestion by pronase (Verlinsky et al., 2005). Nowadays, ESCs can be isolated from many different sources (Fig. 1).

ESCs are pluripotent, which means that they can differentiate into any of the functional cells derived from the three germ layers, including beta cells or insulin-producing cells (IPCs). The differentiation of ESCs into IPCs is prerequisite for their use as a diabetes mellitus treatment, and may occur either in vivo (after transplantation) or in vitro (before transplantation). In vivo differentiation is based on micro environmental conditions at the graft site, whereas in vitro differentiation requires various external factors that induce the phenotypic changes required to produce IPCs. This means that diabetes mellitus can be treated either by direct transplantation of ESCs, or by indirect transplantation of IPCs that have been differentiated from ESCs. However, Naujok et al. (2009) showed that ESCs could modify gene expression and exhibit a phenotype similar to that of islet cells when transplanted into the pancreas only if they are first differentiated in vitro, and that in vitro differentiation is a prerequisite for successful in vivo differentiation (Naujok et al., 2009). Moreover, using ESCs for pancreatic regeneration carries with it the risk of tumour formation after transplantation.

Therefore, the in vitro differentiation of ESCs into IPCs is necessary before they can be used to treat diabetes mellitus. Studies looking at the in vitro differentiation of ESCs into IPCs were first performed in 2001 using mouse cells (Lumelsky et al., 2001). However, the results could not be repeated in subsequent studies (Rajagopal et al., 2003; Hansson et al., 2004; Sipione et al., 2004). Researchers then developed a strategy for selecting ESCs expressing genes related to pancreatic cells (e.g. nestin), and successfully generated IPCs from these ESCs (Soria et al., 2000; Leon-Quinto et al., 2004). Other workers succeeded in creating IPCs from ESCs using gene transfer (Blyszczuk et al., 2003; Schroeder et al., 2006), or phosphoinositol-3 kinase inhibitors (Hori et al., 2002). The differentiation of ESCs into IPCs usually involves differentiation into embryoid bodies. This relatively long process comprises two phases: the embryoid body stage (45 days) and the differentiation stage (3040 days). In 2005, Shi et al. decreased the time taken for this differentiation process to 15 days (Shi et al., 2005).

ESC sources. ESCs can be isolated from fresh, frozen, dead, excess and genetically deficient embryos, by parthenogenesis and somatic nucleus transfer, from biopsies, and from pluripotent stem cells obtained from adult tissues.

In 2001, Assady et al. reported that IPCs could be generated by spontaneous differentiation of human ESCs. Although the IPC number and insulin content of these cells was low, this was the first proof-of-principle experiment indicating that human ESCs were a potential source of -like cells. Recent reports from D'Amour et al. and Kroon et al. described the differentiation of pancreatic lineage cells from human ESCs in vitro. To date, many groups have reported the in vitro generation of IPCs from human ESCs (D'Amour et al., 2006; Jiang et al., 2007; Jiang et al., 2007).

First created by Takahashi et al. (2007) and Yu et al. (2007), induced pluripotent stem cells (IPSCs) are a new source of embryonic-like stem cells, and are considered a technical breakthrough in stem cell research. IPSCs have several advantages over ESCs. One major advantage is that IPSCs can be created from any cell-type; thus, creating patient-specific stem cells (Park et al., 2008; Dimos et al., 2008). Similar to ESCs, IPSCs can differentiate into many different cell types, including neurons (Dimos et al., 2008; Chambers et al., 2008), heart muscle cells (Zhang et al., 2009) and insulin-secreting cells (Tateishi et al., 2008; Zhang et al., 2009).

IPSCs can be created from many different cell types via a simple process. First-generation IPSCs are obtained by transferring four genes (Oct-3/4, Sox-2, c-Myc and Klf4; Shinya Yamanaka et al., 2006) or Oct-3 / 4, Sox-2, Nanog and LIN28 into mice. Second-generation IPSCs are derived using only Oct-3/4, Sox-2 and Klf4, because c-Myc is an oncogene (Nakagawa et al., 2008). Third-generation IPSCs are generated using only two genes, Oct-3/4 and Sox-2, and the histone deacetylase inhibitor, valproic acid (VPA) (Danwei Huangfu et al., 2008).

A recent study shows that IPSCs can be successfully created from adult fibroblasts derived from type 1 diabetic patients (Rene'Maehr et al., 2009). These cells were differentiated into IPCs and used to successfully treat diabetic rats (Alipio et al., 2010).

A recent report by Harry Heimbergs group (Heimberg et al., 2008) describes the existence of pancreatic stem cells in mice. In their most recent study, Heimberg's group ligated the ducts that secrete pancreatic enzymes in adult mice. The result was a doubling in the number of beta cells within two weeks. Also, the pancreases of the experimental animals began to produce more insulin; evidence that the newly generated beta cells were functional (Xu et al., 2008). Another research team showed that the production of new beta cells was dependent on the gene neurogenin 3 (Ngn3), which plays a role in the pancreas during embryonic development, and successfully isolated and established a murine pancreatic stem cell line (Noguchi et al., 2008; 2009).

Human pancreatic stem cells have also been successfully differentiated into IPCs (Noguchi et al., 2010). Islet cells were isolated from the pancreases of human donors using the Ricordi technique modified by the Edmonton protocol. The isolated cells were then cultured in media specifically designed for mouse or human pancreatic embryonic stem cell culture. The cells were differentiated for 2 weeks in induction media containing exendin-4, nicotinamide, keratinocyte growth factor, PDX-1 protein, or protein BETA2/NeuroD. However, according to Davani et al. (2007), human islet precursor cells derived from human pancreases exhibit the properties of mesenchymal stem cells (MSCs) in that they adhere to plastic, express CD73, CD90 and CD105, and differentiate in vitro into adipocytes, chondrocytes, and osteocytes. Davani et al. also identified a rare population of CD105+/CD73+/CD90+ cells in adult human islets that express low levels of insulin mRNA (Davani et al., 2007).

MSCs are multipotent stem cells that can differentiate into a variety of cell types, such as osteoblasts (bone cells), chondrocytes (cartilage cells) and adipocytes (fat cells) (Anna et al., 2008). This cell type was first discovered in 1924 by the cell morphologist Alexander A. Maximo, who described a type of cell within the mesenchyme that develops into various types of blood cell. Ernest A. McCulloch and James E. Till first revealed the clonal nature of marrow cells in 1963 (Becker et al., 1963; Siminovitch et al., 1963). Subsequently, ex vivo clonogenic assays were used to examine the potential of multipotent marrow cells (Friedenstein et al., 1974, 1976). In these assays, stromal cells or MSCs were used as colony-forming unit-fibroblasts (CFU-f). The characteristics of MSCs are as follows: they adhere to culture vessels; they have a fibroblast-like shape; they express Stro-1, CD133, CD29, CD44, CD90, CD105 (SH2), SH3, SH4 (CD73), c-kit, CD71, and CD106; and they can differentiate into specialised cells, e.g. bone, cartilage and fat.

MSCs have been isolated from many different tissues, including bone marrow (Oyajobi et al.. 1999; Majumdar et al., 2000; Prockop et al., 2001; Smith et al., 2004; Titorencu et al., 2007; Wolfe et al., 2008; Gronthos and Zannettino et al., 2008; Phadnis et al., 2011; Bao et al., 2011), adipose tissue (Katz et al., 2005; Baptista et al., 2009; Caviggioli et al., 2009; Baer et al., 2010; Bruyn et al., 2010; Estes et al., 2010; Tucker, Bunnell, 2011), peripheral blood (Kassis et al., 2006), umbilical cord blood (Erices et al., 2000; Rosada et al., 2003; Hutson et al., 2005; Reinisch et al., 2007; Bieback and Klter et al., 2007; Perdikogianni et al., 2008; Zhang et al., 2011), banked umbilical cord blood (Phuc et al., 2011), umbilical cords (Cutler et al., 2010; Farias et al., 2011), umbilical cord membranes (Deuse et al., 2010; Kita et al., 2010), umbilical cord veins (Santos et al., 2010), Wharton's jelly from the umbilical cord (Zeddou et al., 2010; Peng et al., 2011), placenta (Miao et al., 2006; Battula et al., 2007; Huang et al., 2009; Semenov et al., 2010; Pilz et al., 2011), decidua basalis (Macias et al., 2010; Lu et al., 2011), the ligamentum flavum (Chen et al., 2011), amniotic fluid (Feng et al., 2009; Choi et al., 2011, Shuang-Zhi et al., 2010), amniotic membrane (Chang et al., 2010; Marongiu et al., 2010), dental pulp (Agha-Hosseini et al., 2010; Karaz et al., 2010; Yalvac et al., 2010; Spath et al., 2010), chorionic villi from human placenta (Poloni et al., 2008), foetal membranes (Soncini et al., 2007), menstrual blood (Meng et al., 2007; Hida et al., 2008; Musina et al., 2008; Kyurkchiev et al., 2010), and breast milk (Patki et al., 2010) (Fig. 2).

Sources of MSCs. MSCs can be derived from several adult or infant tissues.

MSCs have been successfully differentiated into IPCs in vitro and can reduce blood glucose levels in both animals and humans after transplantation. The in vitro differentiation of MSCs into IPCs requires certain substances combined with medium stress. Most successful protocols for the differentiation of MSCs into IPCs used nicotinamide and/or exendin-4 inducers. Changes in the glucose concentration within the culture medium are necessary to trigger this process. MSCs are commonly cultured in low glucose medium to initiate differentiation before they can be induced to differentiate into IPCs by nicotinamide. In some studies, epidermal growth factor (EGF) was added to the culture medium during the IPC maturation phase in addition to nicotinamide. Currently, IPCs can be generated from MSCs obtained from human umbilical cord blood (Gao et al., 2008; Parekh et al., 2009; Wang et al., 2010), banked human umbilical cord blood (Phuc et al., 2011), placenta (Kadam et al., 2010), bone marrow (Sun et al., 2007; Xie et al., 2009; Phadnis et al., 2011), menstrual blood (Li et al., 2010), amniotic fluid (Trovato et al., 2009), Whartons jelly (Chao et al., 2008; Wu et al., 2009), amnion (Kadam et al., 2010), and adipose tissue (Chandra et al., 2009). Other studies report the successful use of transgenesis to differentiate MSCs into IPCs, or up-regulation of genes (mainly PDX-1 or betacellulin) related to signalling pathways that trigger this process (Karnieli et al., 2007; Li et al., 2007; Li et al., 2008; Hisanaga et al., 2008; Limbert and Seufert., 2009; Yuan et al., 2010; Paz et al., 2011). Moreover, coating the tissue culture flasks with substrates such as fibronectin or laminin can also induce MSCs to differentiate into IPCS (Moriscot et al., 2005; Chang et al., 2008; Gao et al., 2008; Lin et al., 2010; Lin et al., 2011).

Recent reports suggest that pancreatic duct cells, liver cells, spleen cells, and other cell types have the ability to differentiate into islet cells. Although it is difficult to differentiate adult cells into insulin-producing pancreatic cells, some researchers have shown evidence of pancreatic duct regeneration in mouse models. When gastrin was injected into mice to induce acinar cells to differentiate into duct cells, these cells became a cellular substrate for the formation of new beta cells, similar to the effects seen in rats receiving glucose injections (Weir and Bonner-Weir et al., 2004).

Liver cells originating from the endothelium may also be candidates for this specialised insulin-secreting role (Meivar-Levy et al., 2006). Yang et al. (2002) reported that exposure to high glucose concentrations caused oval cells in the liver to differentiate into cells with a phenotype similar to that of pancreatic islet cells (Yang et al., 2002). Another strategy involves the in vivo gene transfer of the pdx-1 gene into liver cells using an adenovirus vector to induce endogenous pdx-1 gene expression. Pdx-1, along with other beta cell genes, is associated with insulin secretion (Zalzman et al., 2005; Sapir et al., 2005; Shternhall-Ron et al., 2007; Aviv et al., 2009; Gefen-Halevi et al., 2010; Meivar-Levy and Ferber, 2010). Similar to pdx-1, betacellulin and neuro-D expression by liver cells yielded sufficient insulin-producing cells in a streptozocin (STZ)-induced diabetic mouse model. These techniques not only induce liver cells to differentiate into beta cells, but also create new islets within the liver itself (Kojima et al., 2003). Other studies showed that human foetal liver cells transfected with telomerase and pdx-1 can produce insulin and release it into the body. These cells cured diabetes mellitus when transplanted into immuno-deficient diabetic mice.

Fibroblasts are a relatively new source of islets and are easily isolated from skin. In a recent study, 61 single-cell-derived dermal fibroblast clones were established from human foreskin using a limiting dilution technique. These cells were able to differentiate into islet-like clusters when induced using pancreatic-inducing medium and several hormones, including insulin, glucagon and somatostatin, were detectable at both the mRNA and protein levels after induction. Moreover, transplantation of these islet-like clusters resulted in the release insulin in response to glucose in vitro (Bi et al. 2010).

Transplantation of stem cells/IPCs to treat diabetes mellitus has been investigated in both animal models and humans. Many different types of stem cells have been tested using different methods. Cells can be grafted underneath the kidney capsule (Rackham et al., 2011; Figliuzzi et al., 2009; Ito et al., 2010; Lin et al., 2009; Kodama et al., 2009; Kodama et al., 2008; Zhang et al., 2010; Ohmura et al., 2010; Xiao et al., 2008; Berman et al., 2010), delivered via intra-peritoneal injection (Boroujeni et al., 2011; Chandra et al., 2009; Koya et al., 2008; Shao et al., 2011; Kadam et al., 2010; Phuc et al., 2011; Lin et al., 2009) or intra-portally (Shyu et al., 2011; Trivedi et al., 2008; Li et al., 2010; Wu et al., 2007; Longoni et al., 2010; Itakura et al., 2007), grafted into the liver (Chao et al., 2008; Zhu et al., 2009; Xu et al., 2007; Chen et al., 2009; Wang et al., 2010) or injected into the tail vein (Dinarvand et al., 2010; Koblas et al., 2009; Kajiyama et al., 2010; Jurewicz et al., 2010) (Fig. 3). However, there is little research comparing the efficiency of these methods. Chen et al. (2009) showed that transplantation of stem cells into the liver produces better results than transplantation into the renal capsule. Although diabetes mellitus is caused by destruction of the beta cells within the pancreatic islets, no studies have attempted transplantation directly into the pancreas. This is because the pancreas is very sensitive organ and is vulnerable to mechanical intervention.

Methods of stem cell/IPC transplantation. Stem cells or IPCs can be transplanted via the tail vein, intraperitoneally, under the kidney capsule, into the liver, or via the portal vein.

Unlike IPC transplantation, the mechanisms underlying islet regeneration and the reductions in blood glucose levels seen in diabetic patients require further study. The main questions that need to be answered are: 1) what role do grafted stem cells play in the regeneration of pancreatic islets? 2) How will stem cells behave when grafted into the body rather than the pancreas?

One type of stem cell that has been used to treat diabetes mellitus and investigated extensively in animal models is MSCs. Almost all research on MSC transplantation shows that in vitro or in vivo transplantation of MSCs results in a reduction of blood glucose levels, weight gain and increased longevity. However, MSCs can play multiple roles. Grafted stem cells can move into the pancreatic islets and differentiate into IPCs (Sorvi et al., 2005; Sordi, 2009). In an in vitro model using MSCs derived from human bone marrow and pancreatic islets, Sorvi et al. (2005) demonstrated crosstalk between MSCs and pancreatic cells mediated by various chemokines and their receptors. A minority of BM-MSCs (225%) express chemokine receptors (CXC receptor 4 [CXCR4], CX3C receptor 1 [CX3CR1], CXCR6, CC chemokine receptor 1 [CCR1], and CCR7) and, accordingly, show chemotactic migration in response to chemokine CXC ligand 12 (CXCL12), CX3CL1, CXCL16, CC chemokine ligand 3 (CCL3), and CCL19. These factors, released from the islets, were then able to attract MSCs. Moreover, MSCs were detected within the pancreatic islets of mice injected with green fluorescent protein (GFP)-positive MSCs (Sorvi et al., 2005). This result was subsequently confirmed in 2009 by Sordi, who hypothesised that the crosstalk between MSCs and pancreatic islets was driven by the CXCR4-CXCL12 and CX3CR1-CX3CL1 axes (Sordi, 2009). Movement of MSCs into the pancreas after transplantation was also confirmed by Lin et al. (2009) and Phadnis et al. (2011). Using bone marrow-derived MSC transplantation coupled with down-regulation of neurogenin 3 (Ngn3) induced by a recombinant lentivirus encoding two different small hairpin RNAs (shRNAs) for specific interference, they showed the successful engraftment of MSCs. In addition, they found that the endogenous pancreatic stem cells differentiated into IPCs and played a major role in reversing hyperglycaemia (Lin et al., 2009). However, there are cases in which stem cells derived from human umbilical cord blood also move into the pancreas and differentiate into IPCs in immunocompromised diabetic animals without improving hyperglycaemia (Koblas et al., 2009). Hasegawa et al. (2007) used Nos3 (-/-) mice as a model of impaired bone marrow-derived cell mobilisation and showed that the hyperglycaemia-improving effects of bone marrow transplantation were inversely correlated with the severity of myelo-suppression and delays in peripheral white blood cell recovery. Thus, stem cell mobilisation is critical for bone marrow transplantation-induced beta cell regeneration after injury. Therefore, they suggested that, during bone marrow transplantation, grafted cells first move into the recipients bone marrow and, subsequently, into the injured periphery to regenerate the recipients pancreatic beta cells (Hasegawa et al., 2007).

Another study showed that MSCs display immunomodulatory functions. MSCs prevented beta-cell destruction and development of diabetes mellitus by inducing regulatory T cells (Madec et al., 2009). Thus, MSC transplantation may prevent islet cell destruction by the immune system seen in type 1 diabetes mellitus and the pancreatic islets can be gradually restored. The result was a decrease in blood sugar levels and weight gain. While in a more recent study, it is said that MSCs protected islets from hypoxia/reoxygenation (H/R)-induced injury by decreasing apoptosis and increasing the expression of HIF-1, HO-1, and COX-2 mRNA. The MSCs induced the expression of anti-apoptotic genes, thereby enhancing resistance to H/R-induced apoptosis and dysfunction (Lu et al., 2010).

The use of ESCs for treating diabetes mellitus is limited because of high levels of tumour formation. So there were a few researches using the ESCs for treating diabetes mellitus. In one study, pancreatic cell ontogeny within ESCs transplanted into the renal capsule of STZ-induced mice resulted in pancreatogenesis in situ or beta cell neogenesis. Immunohistochemistry was performed on excised pancreatic tissues using antibodies against stage- and lineage-specific pancreatic markers. Twenty-one days post-transplantation, PDX-1+ pancreatic foci appeared in the renal capsule, which expressed exocrine enzymes (amylase) and endocrine hormones (insulin, glucagon, and somatostatin). These multi-hormonal endocrine cells, a characteristic of beta cell regeneration, suggested possible divergence from embryonic islet cell development (Kodama et al., 2008). In another study, Kodama et al. (2009) showed that transplanted ESCs could migrate into the injured pancreas. Cell tracing analysis showed that significant beta cell neogenesis occurred 2 to 3 weeks after injury. Importantly, whereas pancreas-localised ESC or their derivatives were found adjacent to the sites of regeneration, neogenic pancreatic epithelia, including Ngn3+ cells, were endogenous. Transplantation efficiency was confirmed by enhanced endogenous regeneration and increased beta cell differentiation from endogenous progenitor cells (Kodama et al., 2009).

Based on the successful transplantation of beta cells, or pancreatic islets, for the treatment of diabetes mellitus (Ris et al., 2011; Wahoff et al., 1995; 1996), transplantation of IPCs differentiated from stem cells is seen as a promising therapy for diabetic patients, particularly in light of the lack of tissue donors and the many side effects of insulin injections. Unlike stem cells, transplanted IPCs produce insulin directly. IPC transplantation using different grafting methods has been studied in mouse models. Routes of administration include the portal vein, intra-peritoneal injection, the liver, the tail vein, and the kidney capsule. IPCs, differentiated from bone marrow-derived MSCs, were successfully allografted into the portal vein in a rat model of diabetes mellitus. After transplantation, the IPCs migrated into the liver where they expressed islet hormones, resulting in reduced glucose levels between Days 6 and 20 post-injection (Wu et al., 2007). Xenotransplantation of IPCs derived from fresh or banked human umbilical cord blood into diabetic mice also showed positive results. These IPCs, transplanted via the portal vein (Wang et al., 2010) or intraperitoneally (Phuc et al., 2011), reduced the blood glucose levels in diabetic mice. When IPCs were grafted into the portal vein, human C-peptides were detected in the mouse livers by immunohistochemistry (Wang et al., 2010). Similar to these results, xenotransplantation of IPCs differentiated from the Whartons jelly from human umbilical cords restored normoglycaemia, body weight and a normal glucose tolerance test, indicating that the cells are functional when grafted via the portal vein (Kadam et al., 2010) or liver (Chao et al., 2008).

Zhang et al. (2010) injected IPCs differentiated from human islet-derived progenitor cells under the renal capsule of immunodeficient mice. One month later, 19/28 mice transplanted with progenitor cells and 4/14 mice transplanted with IPCs produced human C-peptide that was detectable in the blood. This indicates that the in vivo environment further facilitates the maturation of progenitor cells. Moreover, 9/19 mice transplanted with progenitor cells, and 2/4 mice transplanted with IPCs, secreted C-peptide in response to glucose (Zhang et al., 2010). Allotransplantation of IPCs differentiated from islet progenitor cells produced similar results (Shyu et al. 2011). In this study, progenitor cells cultured in matrigel differentiated into IPCs following transplantation into diabetic mice.

ESCs were also differentiated into IPCs and used to treat diabetes mellitus in animal models. After transplantation, these cells did not induce teratoma formation in STZ-induced mice and treatment reduced blood glucose levels to almost normal levels (Kim et al., 2003). Another study indicated that ESCs could differentiate into IPCs; however, transplantation of these pancreatic progenitor clusters into STZ-induced mice failed to reverse the hyperglycaemic state. This indicates that ESCs can differentiate into pancreatic progenitor cells and commit to a pancreatic islet cell fate, but are unable to perform the normal functions of beta cells (Chen et al., 2008). While most studies have focused on experimental treatments using IPC transplantation, another study used liver cells (rather than IPCs) to treat diabetes mellitus. Hepatic cells were differentiated from bone marrow-derived MSCs. Transplantation of syngeneic hepatic cells into STZ-induced mice cured their diabetes mellitus. Treatment of mice with hyperglycaemia and islet cell destruction resulted in repair of the pancreatic islets. Blood glucose levels, intra-peritoneal glucose tolerance tests, and serum insulin levels recovered significantly in the treated group. In addition, both body weight and the number of islets were significantly increased (Dinarvand et al., 2010).

Due to their properties of self-renewal and capacity for multipotent differentiation, stem cells are thought to be the best vector for delivering genes and therapeutic gene-coded proteins into the body. Gene transfer experiments that cause stem cells to differentiate into beta cells, or that transfer specific genes coding for insulin, have also been conducted in recent years. There are several possible reasons why the use of stem cell gene therapies can be used to treat diabetes mellitus. However, no study has compared the difference between IPCs produced by chemical induction and those derived from gene transfer. Some researchers hypothesise that the key is the genetic transfer of the signalling pathways related to differentiation from stem cells into IPCs, which will create IPCs more similar to stem cells in vivo. Others argue that genetic modifications, e.g. PDX-1, betacellulin, or Neuro-D transfer, induce cells to differentiate into beta cells, while yet others suggest that the efficiency of IPC transplantation is low because IPCs are mature, specialised cells. For long-term effectiveness, a source of insulin with a long-term regenerative capacity is needed. Early studies by Xu et al. (2007), looking at transferring insulin into MSCs, showed that the resulting MSCs did express human insulin. The body weight of diabetic mice treated with these MSCs increased by 6% within 6 weeks of treatment, and average blood glucose levels were 10.40 +/- 2.80 mmol/l (Day 7) and 6.50 +/- 0.89 mmol/l (Day 42), compared with 26.80 +/- 2.49 mmol/l (Day 7) and 25.40 +/- 4.10 mmol/l (Day 42) in untreated animals (p < 0.05). Experimental diabetes mellitus was effectively relieved for up to 6 weeks after intrahepatic transplantation of murine MSCs expressing human insulin (Xu et al., 2007). In other studies, STZ-treated mice transplanted with Pdx1-transduced adipose tissue-derived MSCs (Pdx1-MSCs) showed significant decreases in blood glucose levels and increased survival compared with control mice (Lin et al., 2009; Kajiyama et al., 2010).

Transplantation IPCs offers a potential cell replacement therapy for patients with type 1 diabetes mellitus. However, because of the inadequate number of cells obtained from donors, other stem cell sources have drawn significant attention from many research groups. The efficacy of these approaches is limited because they typically necessitate the administration of immunosuppressive agents to prevent rejection of transplanted cells. The use immunosuppressive drugs can have deleterious side effects, such as increased susceptibility to infection, liver and kidney damage, and an increased risk of cancer. In addition, immunosuppressive drugs may have unexpected effects on the transplanted tissues. For example, some reports have shown that cyclosporine can inhibit insulin secretion by pancreatic cells.

Immuno-isolation is a promising technique that protects the implanted tissues from rejection. One of the most common immuno-isolation techniques is to encapsulate cells within a semi-permeable membrane, such as alginate, that physically protects the grafts from the hosts immune cells while simultaneously allowing nutrients and metabolic products to diffuse into or out of the capsule. To achieve this, the cells are encapsulated within a hydrogel or alginate membrane using gravity, electrostatic forces, or coaxial airflow to form the capsule. Allogeneic and xenogeneic transplantation of encapsulated islets of Langerhans restores normal blood glucose levels in mice (Dufrane et al., 2006; Fan et al., 1990; Omer et al., 2003), dogs (Soon-Shiong et al., 1992a,b; 1993) and non-human primates (Sun et al., 1996) with diabetes mellitus induced by autoimmune diseases or chemical injury, without on the need for immunosuppressive agents. In most of these studies, transplantation was via intraperitoneal injection of islet cells. However, Dufrane et al. (2006) recently reported the generation of encapsulated porcine islets using a Ca-alginate material. These capsules were implanted under the kidney capsule of nondiabetic Cynomolgus monkeys. The implanted porcine islets survived for up to 6 months after implantation without immunosuppression, even in animals injected with porcine IgG. Moreover, C-peptide was detected in 71% of the animals. After 135 and 180 days, the explanted capsules still synthesised insulin and responded to glucose stimulation (Dufrane et al., 2006).

In another study, transplantation of alginate-encapsulated IPCs from an embryo-derived mouse embryo progenitor-derived insulin-producing-1 (MEPI-1) cell line lowered hyperglycaemia in immuno-competent, allogeneic diabetic mice. After transplantation, hyperglycaemia was reversed and was followed by a 2.5-month period of normal to moderate hypoglycaemia before relapse. Relapse occurred within 2 weeks in mice transplanted with non-encapsulated MEPI-1 cells. Blood glucose levels, insulin levels, and the results of an oral glucose tolerance test all correlated directly with the number of viable cells remaining in the capsules in the transplanted animals (Shao et al., 2011). Moreover, encapsulation of IPCs differentiated from amnion-derived MSCs, or adipose tissue-derived MSCs in polyurethane-polyvinyl pyrrolidone macrocapsules, or IPCs in calcium alginate, resulted in the restoration of normoglycaemia without immunorejection (Chandra et al., 2009; Kadam et al., 2010) in diabetic rats

Allogeneic islet/IPC transplantation is an efficient method for maintaining normal glucose levels and for the treatment of diabetes mellitus. However, limited sources of islets/IPCs, high rates of islet/IPC graft failure and the need for long-term immunosuppression are major obstacles to the widespread application of these therapies. To overcome these problems, co-transplantation of pancreatic islets/IPCs and adult stem cells is considered as a potential target for the near future. In fact, new results suggest that co-transplantation of stem/precursor cells, particularly MSCs, and islets/IPCs promotes tissue engraftment and beta cell/IPC survival. This theory proposes that stem cells also act as "feeder" cells for the islets, supporting graft protection, tissue revascularisation, and immune acceptance (Sordi et al., 2010).

Overcoming the loss of islet mass is important for successful islet transplantation. Adipose tissue-derived stem cells (ADSCs; referred to as MSCs by some authors) have angiogenic and anti-inflammatory properties. Co-transplantation of ADSCs and islets into mice promotes survival, improves insulin secretion by the graft, and reduces the islet mass required for treatment (Ohmura et al., 2010). In another study, MSCs derived from adipose tissue were differentiated into IPCs and co-transplanted with cultured bone marrow cells into 11 diabetic patients (7 male, 4 female; disease duration, 124 years; age range, 1343 years). Their mean exogenous insulin requirements were 1.14 units/kg BW/day, the mean glycosylated haemoglobin (Hb1Ac) level was 8.47%, and the mean c-peptide level was 0.1 ng/mL. All the patients received successful transplants and the mean follow-up period was 23 months. The results showed a decreased mean exogenous insulin requirement of 0.63 units/kgBW/day, a reduced Hb1Ac of 7.39%, and raised serum c-peptide levels (0.38 ng/mL). The patients reported no diabetic ketoacidosis events and a mean weight gain of 2.5 kg on a normal vegetarian diet and physical activity (Vanikar et al., 2010). However, a previous report indicated that similar results were obtained with undifferentiated MSC-derived adipose tissue co-transplanted with cultured bone marrow. In this study, human adipose tissue-derived MSCs were transfused along with unfractionated cultured bone marrow into five insulinopenic diabetic patients (2 male, 3 female; age range, 1428 years; disease duration, 0.6 to 10 years) being treated with human insulin (1470 U/d). The patients had postprandial blood sugar levels between 156 and 470 mg%, Hb1Ac levels of 6.8% to 9.9%, and c-peptide levels of 0.02 to 0.2 ng/mL. After successful transplantation, all patients showed a 30% to 50% reduction in their insulin requirements along with a 426-fold increase in serum c-peptide levels during a mean follow-up period of 2.9 months (Trivedi et al., 2008).

After transplantation, MSCs appear to play an immunomodulatory role, thereby promoting graft acceptance. In a cynomolgus monkey model, allogeneic MSCs were co-transplanted with islets intra-portally on postoperative Day 0 and intravenously with donor marrow on postoperative Days 5 and 11. Increased co-transplantation efficiency was associated with increased numbers of regulatory T-cells in the peripheral blood, indicating that co-transplantation of MSCs and islets may be an important method of enhancing islet engraftment and, thereby, decreasing the number of islets required (Berman et al., 2010). Co-transplantation may also downregulate the production of pro-inflammatory cytokines. These results also suggest that MSCs may prevent acute rejection and improve graft function after portal vein pancreatic islet transplantation (Longoni et al., 2010), or that they may induce haematopoietic chimerism and subsequent immune tolerance without causing graft-versus-host disease (Itakura et al., 2007). Moreover, MSC-stimulated graft vascularisation and improved islet graft function are both associated with co-transplanted islets (Figliuzzi et al. 2009; Ito et al. 2010). In addition, interleukin (IL)-6, IL-8, vascular endothelial growth factor-A, hepatocyte growth factor, and transforming growth factor-beta were detected at significant levels in MSC culture medium. These are trophic factors secreted by human MSCs that enhance the survival and function of the islets after transplantation (Park et al., 2010).

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Stem Cell Therapy for Islet Regeneration | InTechOpen

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Angela D. Hawkes Greensboro Medical Associates PA 1511 Westover Ter Ste 201 Greensboro, NC 27408 (336) 373-1537

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Anthony S. Anderson Greensboro Medical Associates PA 1511 Westover Ter Ste 201 Greensboro, NC 27408 (336) 373-1537

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William W. Truslow William W Truslow MD 409 Parkway Ste A Greensboro, NC 27401 (336) 379-7597

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James F. Beekman Greensboro Medical Associates PA 1511 Westover Ter Ste 201 Greensboro, NC 27408 (336) 373-1537

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Michelle Young Greensboro Medical Associates 1511 Westover Ter Ste 201 Greensboro, NC 27408 (336) 373-0611

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Erin J. Gray Regional Physicians Jamestown 5710 High Point Rd Ste I Greensboro, NC 27407 (336) 299-7000

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Erin J. Gray Greensboro Medical Associates PA 1511 Westover Ter Ste 201 Greensboro, NC 27408 (336) 373-1537

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Shaili B. Deveshwar Piedmont Orthopedics 1313 Carolina St Ste 101 Greensboro, NC 27401 (336) 275-0927

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Tauseef G. Syed Novant Health Franklin Family Medicine 445 Pineview Dr Ste 200 Kernersville, NC 27284 (336) 564-4410

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Aldona Ziolkowska Medical Arts Clinic 1814 Westchester Dr Ste 301 High Point, NC 27262 (336) 802-2025

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George W. Kernodle Kernodle Clinic West 1234 Huffman Mill Rd Burlington, NC 27215 (336) 538-1234

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Brett Smith Wake Forest Baptist Health Rheumatology 301 Medical Center Blvd Winston-Salem, NC 27157 (336) 716-4209

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Amer Alkhoudari Wake Forest Baptist Health Rheumatology 301 Medical Center Blvd Winston-Salem, NC 27157 (336) 716-4209

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Nilamadhab Mishra Wake Forest Baptist Health Rheumatology 301 Medical Center Blvd Winston-Salem, NC 27157 (336) 716-4209

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Nihad Yasmin Wake Forest Baptist Health Rheumatology 301 Medical Center Blvd Winston-Salem, NC 27157 (336) 716-4209

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Sadiq Ali Wake Forest Baptist Health Rheumatology 301 Medical Center Blvd Winston-Salem, NC 27157 (336) 716-4209

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Julio R. Bravo Novant Health Franklin Family Medicine 1995 Bethabara Rd Winston-Salem, NC 27106 (336) 896-1477

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Nkechinyere Emejuaiwe Wake Forest Baptist Health Rheumatology 301 Medical Center Blvd Winston-Salem, NC 27157 (336) 716-4209

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Dennis Ang Wake Forest Baptist Health Rheumatology 301 Medical Center Blvd Winston-Salem, NC 27157 (336) 716-4209

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Kenneth S. O'Rourke Wake Forest Baptist Health Rheumatology 301 Medical Center Blvd Winston-Salem, NC 27157 (336) 716-4209

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Erin K. Shiner Novant Health Franklin Family Medicine 1995 Bethabara Rd Winston-Salem, NC 27106 (336) 896-1477

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Douglas L. Metcalf Novant Health Franklin Family Medicine 1900 S Hawthorne Rd Ste 652 Winston-Salem, NC 27103 (336) 277-0361

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Elliott L. Semble Salem Rheumatology 180 Kimel Park Dr Ste 250 Winston-Salem, NC 27103 (336) 659-4585

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Nicole W. Klett Triangle Orthopedic Associates 120 William Penn Plz Durham, NC 27704 (919) 220-5306

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George B. Brothers Chapel Hill Internal Medicine 940 Martin Luther King Jr Blvd Chapel Hill, NC 27514 (919) 942-5123

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Anne K. Toohey Triangle Orthopedic Associates PA 120 William Penn Plz Durham, NC 27704 (919) 220-5306

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Joanne M. Jordan UNC Rheumatology Allergy Immunology Clinic 101 Manning Dr Chapel Hill, NC 27514 (919) 966-4131

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Rakesh C. Patel Rowan Diagnostic Clinic 611 Mocksville Ave Salisbury, NC 28144 (704) 633-7220

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Stacy D. Kennedy Rowan Diagnostic Clinic 611 Mocksville Ave Salisbury, NC 28144 (704) 633-7220

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Durga D. Adhikari University Of North Carolina Rheumatology Clinic 6013 Farrington Rd Ste 301 Chapel Hill, NC 27517 (919) 966-4191

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Jennifer L. Rogers UNC Rheumatology Allergy & Immunology Clinic 6013 Farrington Rd Ste 301 Chapel Hill, NC 27517 (919) 962-4824

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Jennifer L. Rogers University Of North Carolina Rheumatology Clinic 6013 Farrington Rd Ste 301 Chapel Hill, NC 27517 (919) 966-4191

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Summary Clinical characteristics.

If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress.

The diagnosis of biotinidase deficiency is established in a proband whose newborn screening or biochemical findings indicate multiple carboxylase deficiency based on either detection of deficient biotinidase enzyme activity in serum/plasma OR identification of biallelic pathogenic variants in BTD on molecular genetic testing.

Treatment of manifestations: All symptomatic children with profound biotinidase deficiency improve when treated with 5-10 mg of oral biotin per day. All individuals with profound biotinidase deficiency, even those who have some residual enzymatic activity, should have lifelong treatment with biotin. Children with vision problems may benefit from vision aids; those with hearing loss will usually benefit from hearing aids or cochlear implants, and those with developmental deficits from appropriate interventions.

Prevention of primary manifestations: Children with biotinidase deficiency identified by newborn screening should remain asymptomatic if biotin therapy is instituted early and continuously lifelong.

Surveillance: Annual vision and hearing evaluation, physical examination, and periodic assessment by a metabolic specialist.

Agents/circumstances to avoid: Raw eggs because they contain avidin, an egg-white protein that binds biotin and decreases the bioavailability of the vitamin.

Evaluation of relatives at risk: Testing of asymptomatic sibs of a proband ensures that biotin therapy for affected sibs can be instituted in a timely manner.

Biotinidase deficiency is inherited in an autosomal recessive manner. With each pregnancy, a couple who has had one affected child has a 25% chance of having an affected child, a 50% chance of having a child who is an asymptomatic carrier, and a 25% chance of having an unaffected child who is not a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are options if the pathogenic variants in the family are known.

Clinical issues and frequently asked questions regarding biotinidase deficiency have been addressed in a review [Wolf 2010].

Biotinidase deficiency should be suspected in infants with positive newborn screening results, untreated individuals with clinical findings, and persons with suggestive preliminary laboratory findings [Wolf 2012]:

Virtually 100% of infants with either profound biotinidase deficiency or partial biotinidase deficiency can be detected in the US by newborn screening (see National Newborn Screening Status Report).

Newborn screening utilizes a small amount of blood obtained from a heel prick for a colorimetric test for biotinidase activity:

Children or adults with untreated profound biotinidase deficiency usually exhibit one or more of the following non-specific features (which are also observed in many other inherited metabolic disorders):

Seizures

Hypotonia

Respiratory problems including hyperventilation, laryngeal stridor, and apnea

Developmental delay

Hearing loss

Vision problems, such as optic atrophy

Features more specific to profound biotinidase deficiency include the following:

Eczematous skin rash

Alopecia

Conjunctivitis

Candidiasis

Ataxia

Older children and adolescents may exhibit limb weakness, paresis, and scotomata. Some have exhibited findings suggestive of a myelopathy and have been initially incorrectly diagnosed and treated as having another disorder before biotinidase deficiency is correctly diagnosed [Wolf 2015].

Children or adults with untreated partial biotinidase deficiency may exhibit any of the above signs and symptoms, but the manifestations are mild and occur only when the person is stressed, such as with a prolonged infection.

The following findings are sugggestive of biotinidase deficiency:

Metabolic ketolactic acidosis

Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency; however, 3-hydroxyisovalerate may be the only metabolite present). Note: Urinary organic acids can be normal even in individuals with biotinidase deficiency who are symptomatic.

Hyperammonemia

The diagnosis of biotinidase deficiency is established in a proband whose newborn screening or biochemical findings indicate multiple carboxylase deficiency based on either:

Biotinidase enzyme activity in serum. The working group of the American College of Medical Genetics Laboratory Quality Assurance Committee has established technical standards and guidelines for the diagnosis of biotinidase deficiency [Cowan et al 2010] (full text).

Molecular genetic testing is performed by single-gene testing. Sequence analysis of BTD is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

Molecular Genetic Testing Used in Biotinidase Deficiency

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Test characteristics. See Clinical Utility Gene Card [Kry et al 2012] for information on test characteristics including sensitivity and specificity.

Individuals with biotinidase deficiency who are diagnosed before they have developed symptoms (e.g., by newborn screening) and who are treated with biotin have normal development [Mslinger et al 2001, Weber et al 2004] (see also Management, Prevention of Primary Manifestations). Neurologic problems occur only in those individuals with biotinidase deficiency who have recurrent symptoms and metabolic compromise prior to biotin treatment.

Early onset. Symptoms of untreated profound biotinidase deficiency (<10% mean normal serum biotinidase activity) usually appear between ages one week and ten years, with a mean age of three and one-half months [Wolf et al 1985b].

Some children with biotinidase deficiency manifest only a single finding, whereas others exhibit multiple neurologic and cutaneous findings.

The most common neurologic features in individuals with untreated, profound biotinidase deficiency are seizures and hypotonia [Wolf et al 1983a, Wolf et al 1985b, Wastell et al 1988, Wolf 1995, Wolf 2011]. The seizures are usually myoclonic but may be grand mal and focal; some children have infantile spasms [Salbert et al 1993b]. Some untreated children have exhibited spinal cord involvement characterized by progressive spastic paresis and myelopathy [Chedrawi et al 2008]. Older affected children often have ataxia and developmental delay.

Many symptomatic children with biotinidase deficiency exhibit a variety of central nervous system abnormalities on brain MRI or CT [Wolf et al 1983b, Wastell et al 1988, Lott et al 1993, Salbert et al 1993b, Grnewald et al 2004]. These findings may improve or become normal after biotin treatment.

Sensorineural hearing loss and eye problems (e.g., optic atrophy) have also been described in untreated children [Wolf et al 1983b, Taitz et al 1985, Salbert et al 1993a, Weber et al 2004]. Approximately 76% of untreated symptomatic children with profound biotinidase deficiency have sensorineural hearing loss that usually does not resolve or improve but remains static with biotin treatment [Wolf et al 2002].

Cutaneous manifestations include skin rash, alopecia, and recurrent viral or fungal infections caused by immunologic dysfunction.

Respiratory problems including hyperventilation, laryngeal stridor, and apnea can occur.

One death initially thought to be caused by sudden infant death syndrome was subsequently attributed to biotinidase deficiency [Burton et al 1987].

Late onset. A number of children with profound biotinidase deficiency were asymptomatic until adolescence, when they developed sudden loss of vision with progressive optic neuropathy and spastic paraparesis [Ramaekers et al 1992, Lott et al 1993, Ramaekers et al 1993]. After several months of biotin therapy, the eye findings resolved and the spastic paraparesis improved. In other individuals with enzyme deficiency, paresis and eye problems have occurred during early adolescence [Tokatli et al 1997, Wolf et al 1998, Wolf 2015].

Individuals with partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may develop symptoms only when stressed, such as during infection.

One child with partial biotinidase deficiency who was not treated with biotin exhibited hypotonia, skin rash, and hair loss during an episode of gastroenteritis at approximately age six months. When treated with biotin, the symptoms resolved.

Genotype/phenotype correlations are not well established. Deletions, insertions, or nonsense variants usually result in complete absence of biotinidase enzyme activity, whereas missense variants may or may not result in complete loss of biotinidase enzyme activity. Those with absence of all biotinidase enzyme activity are likely to be at increased risk for earlier onset of symptoms.

Although genotype-phenotype correlations are not well established, in one study, children with symptoms of profound biotinidase deficiency with null variants were more likely to develop hearing loss than those with missense variants, even if not treated for a period of time [Sivri et al 2007].

Certain genotypes correlate with complete biotinidase deficiency and others with partial biotinidase deficiency:

Profound biotinidase deficiency (<10% mean normal serum biotinidase activity):

Most BTD pathogenic variants cause complete loss or near-complete loss of biotinidase enzyme activity. These alleles are considered profound biotinidase deficiency alleles; a combination of two such alleles, whether homozygous or compound heterozygous, results in profound biotinidase deficiency. Affected individuals are likely to develop symptoms if not treated with biotin.

Partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity)

Heterozygotes

Individuals with one profound or one partial biotinidase deficiency BTD variant are carriers of biotinidase deficiency and do not exhibit symptoms [B Wolf, personal observation]. Such individuals do not require biotin therapy.

Individuals who are homozygous for the p.Asp444His pathogenic variant are expected to have approximately 45%-50% of mean normal serum biotinidase enzyme activity (which is similar to the activity of heterozygotes for profound biotinidase deficiency) and do not require biotin therapy.

Almost all children with profound biotinidase deficiency become symptomatic or are at risk of becoming symptomatic if not treated.

Several reports describe adults with profound biotinidase deficiency who have offspring who also have profound biotinidase deficiency identified by newborn screening, but who have never had symptoms [Wolf et al 1997, Baykal et al 2005]. In addition, several enzyme-deficient sibs of symptomatic children have apparently never exhibited symptoms. It is possible that these individuals would become symptomatic if stressed, such as with a prolonged infection.

Profound and partial biotinidase deficiency is the accepted nomenclature for this disorder.

Individuals with partial biotinidase deficiency were previously described as having late-onset or juvenile multiple or combined carboxylase deficiency.

Biotinidase deficiency should not be confused with holocarboxylase synthetase deficiency (see Differential Diagnosis), previously refered to as early-onset or infantile multiple or combined carboxylase deficiency.

Based on the results of worldwide screening of biotinidase deficiency [Wolf 1991], the incidence of the disorder is:

One in 137,401 for profound biotinidase deficiency;

One in 109,921 for partial biotinidase deficiency;

One in 61,067 for the combined incidence of profound and partial biotinidase deficiency.

The incidence of biotinidase deficiency is generally higher in populations with a high rate of consanguinity (e.g., Turkey, Saudi Arabia).

The incidence appears to be increased in the Hispanic population [Cowan et al 2012] and it may be lower in the African American population.

Carrier frequency in the general population is approximately one in 120.

Clinical features including vomiting, hypotonia, and seizures accompanied by metabolic ketolactic acidosis or mild hyperammonemia are often observed in inherited metabolic diseases. Individuals with biotinidase deficiency may exhibit clinical features that are misdiagnosed as other disorders (e.g., isolated carboxylase deficiency) before they are correctly identified [Suormala et al 1985, Wolf & Heard 1989]. Other symptoms that are more characteristic of biotinidase deficiency (e.g., skin rash, alopecia) can also occur in children with nutritional biotin deficiency, holocarboxylase synthetase deficiency, zinc deficiency, or essential fatty acid deficiency. See .

The biotin cycle

Free biotin enters the cycle from dietary sources or from the cleavage of biocytin or biotinyl-peptides by the action of biotinidase. The free biotin is then covalently attached to the various apocarboxylases, propionyl-CoA (more...)

Biotin deficiency. Biotin deficiency can usually be diagnosed by dietary history. Individuals with biotin deficiency may have a diet containing raw eggs or protracted parenteral hyperalimentation without biotin supplementation.

Low-serum biotin concentrations are useful in differentiating biotin and biotinidase deficiencies from holocarboxylase synthetase deficiency; however, it is important to know the method used for determining the biotin concentration as only methods that distinguish biotin from biocytin or bound biotin yield reliable estimates of free biotin concentrations.

Isolated carboxylase deficiency. Urinary organic acid analysis is useful for differentiating isolated carboxylase deficiencies from the multiple carboxylase deficiencies that occur in biotinidase deficiency and holocarboxylase synthetase deficiency:

The multiple carboxylase deficiencies are biotin responsive, whereas the isolated carboxylase deficiencies are not. A trial of biotin can be useful for discriminating between the disorders.

Isolated carboxylase deficiency can be diagnosed by demonstrating deficient enzyme activity of one of the three mitochondrial carboxylases in peripheral blood leukocytes (prior to biotin therapy) or in cultured fibroblasts grown in low biotin-containing medium, and normal activity of the other two carboxylases.

Holocarboxylase synthetase deficiency (OMIM). Both biotinidase deficiency and holocarboxylase synthetase deficiency are characterized by deficient activities of the three mitochondrial carboxylases in peripheral blood leukocytes prior to biotin treatment. In both disorders, these activities increase to near-normal or normal after biotin treatment.

The symptoms of biotinidase deficiency and holocarboxylase synthetase deficiency are similar, and clinical differentiation is often difficult.

The age of onset of symptoms may be useful for distinguishing between holocarboxylase synthetase deficiency and biotinidase deficiency. Holocarboxylase synthetase deficiency usually presents with symptoms before age three months, whereas biotinidase deficiency usually presents after age three months; however, there are exceptions for both disorders.

Organic acid abnormalities in biotinidase deficiency and holocarboxylase synthetase deficiency are similar and may be reported as consistent with multiple carboxylase deficiency. However, the tandem mass spectroscopic methodology that is being incorporated into many newborn screening programs should identify metabolites that are consistent with multiple carboxylase deficiency. Because most children with holocarboxylase synthetase deficiency excrete these metabolites in the newborn period, the disorder should be identifiable using this technology.

Definitive enzyme determinations are required to distinguish between the two disorders:

Individuals with holocarboxylase synthetase deficiency have deficient activities of the three mitochondrial carboxylases in extracts of fibroblasts that are incubated in medium containing only the biotin contributed by fetal calf serum (low biotin), whereas individuals with biotinidase deficiency have normal carboxylase activities in fibroblasts. The activities of the carboxylases in fibroblasts of individuals with holocarboxylase synthetase deficiency become near-normal to normal when cultured in medium supplemented with biotin (high biotin).

Sensorineural hearing loss (see Deafness and Hereditary Hearing Loss Overview). Sensorineural hearing loss has many causes. Biotinidase deficiency can be excluded as a cause by determining biotinidase enzyme activity in serum. This test should be performed specifically on children with hearing loss who are exhibiting other clinical features consistent with biotinidase deficiency.

To establish the extent of disease and needs in a symptomatic individual diagnosed with biotinidase deficiency, the following evaluations are recommended:

History of seizures, balance problems, feeding problems, breathing problems, loss of hair, fungal infections, skin rash, conjunctivitis

Physical examination for hypotonia, ataxia, eye findings such as optic atrophy, eczematous skin rash, alopecia, conjunctivitis, breathing abnormalities such as stridor, thrush, and/or candidiasis

Evaluation for psychomotor deficits

Evaluation for sensorineural hearing loss

Ophthalmologic examination

Identification of cellular immunologic abnormalities because of the increased risk of recurrent viral or fungal infections caused by immunologic dysfunction

Consultation with a metabolic specialist or clinical geneticist

To establish the extent of disease and needs in infants or children diagnosed with biotinidase deficiency following newborn screening, the following evaluations are recommended:

Physical examination for neurologic findings (e.g., hypotonia, ataxia), eye findings (e.g., conjunctivitis), skin findings (eczematous rash, alopecia), breathing abnormalities (e.g., stridor) and fungal infections caused by immunologic dysfunction (thrush and/or candidiasis).

Evaluation for psychomotor deficits

Evaluation for sensorineural hearing loss

Ophthalmologic examination (for finding such as optic atrophy)

Consultation with a metabolic specialist or clinical geneticist

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Biotinidase Deficiency - GeneReviews - NCBI Bookshelf

Robert A. Freitas Jr., Nanomedicine, Volume I: Basic Capabilities, Landes Bioscience, Georgetown, TX, 1999; http://www.nanomedicine.com/NMI.htm

Nanomedicine, Vol. I: Basic Capabilities (Landes Bioscience, 1999). The first volume of the Nanomedicine book series describes the set of basic capabilities of molecular machine systems that may be required by many, if not most, medical nanorobotic devices, including the physical, chemical, thermodynamic, mechanical, and biological limits of such devices. Specific topics include the abilities to recognize, sort and transport important molecules; sense the environment; alter shape or surface texture; generate onboard energy to power effective robotic functions; communicate with doctors, patients, and other nanorobots; navigate throughout the human body; manipulate microscopic objects and move about inside a human body; and timekeep, perform computations, disable living cells and viruses, and operate at various pressures and temperatures.

Japanese language version of Nanomedicine, Vol. I, published in 2007 by Yakuji Nippo, Ltd:

1999 Robert A. Freitas Jr. All Rights Reserved.

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NMI Table of Contents Page - Nanomedicine

New York College of Health Professions has been a pioneer in Holistic Health and Wellness for 30 years. It is the only private non-profit institutionally accredited college of its kind in the New York metropolitan area. The College mission is to provide education and community service in these areas.

The campus is conveniently located in Syosset, Long Island, with 3 additional locations in New York City in Manhattan on the upper west side at the world famous Riverside Church (120th Street near Columbia University and Barnard College), downtown on Houston Street in the University Settlement in the Soho/Chinatown neighborhood and in a new midtown site at the NY Open Center on East 30th Street. New York College also owns a facility in China where students and friends can visit.

The College has one of the finest and largest Holistic Health Clinics which provides affordable treatments to the public in Massage Therapy, Acupuncture, Reflexology and Herbal Medicine.

New York College is the only private non-profit institutionally accredited college of its kind in the tri-state area. It has institutional accreditation by the New York State Board of Regents and the Commissioner of Education*, a nationally recognized accrediting agency, and accreditation from the Accreditation Commission for Acupuncture and Oriental Medicine** (ACAOM) for its Masters programs. *located at 89 Washington Avenue, Albany, NY 12234 (518) 474-3852. **ACAOM: 14502 Greenview Dr., ste 300B, Laurel, MD 20708 (301) 313-0855

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New York College of Health Professions

LASIK is a surgical procedure for correcting near sightedness(myopia), far sightedness(hyperopia) and cylindrical(astigmatic) refractive errors. LASIK stands for Laser-Assisted in Situ Keratomileusis.

Have you been thinking of laser vision correction? Shed your doubts, concerns, specs and contact lenses, because blade free LASIK has arrived. With this technology, laser vision correction procedure has become 100 percent blade-free and completely safe.

In any LASIK procedure the first step is to create a corneal flap. In standard LASIK the surgeon uses a hand-held oscillating blade called microkeratome to cut the corneal flap. The flap is then folded and the Excimer laser treats the cornea to correct the refractive error.

In blade free LASIK, femtosecond laser has replaced the steel blade for creation of the corneal flap which improves visual outcome and post-operative comfort for the patient.

When you opt for advanced blade free LASIK procedure you get a completely integrated, personalized vision correction procedure based on cutting edge technology at every step. NASA recommends blade free LASIK to aspiring astronauts to get rid of their specs, as it can withstand high gravitational forces and has been found to be stable and secure even in extreme environmental conditions.

Advantages

For people with nearsightedness (myopia), farsightedness (hyperopia) or astigmatism, LASIK surgery could be the key to a life free of bulky spectacles or contact lenses. But not everybody is a suitable candidate for this type of laser eye surgery. Here are the few main questions a LASIK surgeon is likely to ask you during a consultation.

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Lasik eye surgery - Centre For Sight

J Nat Sci Biol Med. 2015 Jan-Jun; 6(1): 2934.

Department of Conservative Dentistry and Endodontics, Institute of Dental Sciences, Sehora, Jammu and Kashmir, India

1Department of Physiology, Government Medical College, Patiala, Punjab, India

This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Teeth are the most natural, noninvasive source of stem cells. Dental stem cells, which are easy, convenient, and affordable to collect, hold promise for a range of very potential therapeutic applications. We have reviewed the ever-growing literature on dental stem cells archived in Medline using the following key words: Regenerative dentistry, dental stem cells, dental stem cells banking, and stem cells from human exfoliated deciduous teeth. Relevant articles covering topics related to dental stem cells were shortlisted and the facts are compiled. The objective of this review article is to discuss the history of stem cells, different stem cells relevant for dentistry, their isolation approaches, collection, and preservation of dental stem cells along with the current status of dental and medical applications.

Keywords: Cell culture techniques, stem cells, stem cell research, tissue banks, tissue engineering

Regenerative capacity of the dental pulp is well-known and has been recently attributed to function of dental stem cells. Dental stem cells offer a very promising therapeutic approach to restore structural defects and this concept is extensively explored by several researchers, which is evident by the rapidly growing literature in this field. For this review article a literature research covering topics related to dental stem cells was made and the facts are compiled.

A web-based research on Medline (www.pubmed.gov) was done. To limit our research to relevant articles, the search was filtered using terms review, published in the last 10 years and dental journals. Various keywords used for research were regenerative dentistry (128 articles found), dental stem cells (111 articles found), dental stem cells banking (2 articles found), stem cells from human exfoliated deciduous teeth (SHED) (11 articles found). For each heading in the review, relevant articles were chosen and arranged in chronological order of publication date so as to follow the development of the research topic. This review screened about 250 articles to get the required knowledge update. Relevant data were then compiled with aim of providing basic information as well as latest updates on dental stem cells.

Stem cells also known as progenitor or precursor cells are defined as clonogenic cells capable of both self-renewal and multi-lineage differentiation.[1] In 1868, the term stem cell for the first time appeared in the works of German biologist Haeckel.[2] Wilson coined the term stem cell.[3] In 1908, Russian histologist, Alexander Maksimov, postulated existence of hematopoietic stem cells at congress of hematologic society in Berlin.[4] There term stem cell was proposed for scientific use.

Stem cells have manifold applications and have contributed to the establishment of regenerative medicine. Regenerative medicine is the process of replacing or regenerating human cells, tissues or organs for therapeutic applications.[5] The concept of regeneration in the medical field although not new has significantly advanced post the discovery of stem cells and in recent times have found its application in dentistry following identification of dental stem cells. Although, the concept of tooth regeneration was initially not accepted the ground-breaking work by stomatologist G. L. Feldman (1932) showed evidence of regeneration of dental pulp under certain optimal biological conditions. This work introduced the biological-aseptic principle of tooth therapy to achieve pulp regeneration using dentine fillings as building material for stimulating pulp regeneration.[6] Nevertheless subsequent researchers further improved this work.[6] Major breakthrough in dental history was achieved in year 2000 when Gronthos et al. identified and isolated odontogenic progenitor population in adult dental pulp.[7] These cells were referred to as dental pulp stem cells (DPSCs). Since this discovery several researchers have reported varieties of dental stem cells, which are described below:

Human dental stem cells that have been isolated and characterized are:

Stem cells from various sources and their features studied by various researchers are presented in .[7,8,11,12,13,14,15,16,17,18]

Stem cells and their features studied by various researchers (at full page width)

DPSCs are mesenchymal type of stem cells inside dental pulp.[19] DPSCs have osteogenic and chondrogenic potential in vitro and can differentiate into dentin, in vivo and also differentiate into dentin-pulp-like complex.[7] Recently, immature dental pulp stem cells[20] were identified which are a pluripotent sub-population of DPSC generated using dental pulp organ culture.

DPSCs are putative candidate for dental tissue engineering due to:[21]

Easy surgical access to the collection site and very low morbidity after extraction of the dental pulp.

DPSCs can generate much more typical dentin tissues within a short period than nondental stem cells.

Can be safely cryopreserved and recombined with many scaffolds.

Possess immuno-privilege and anti-inflammatory abilities favorable for the allotransplantation experiments.

Four commonly used stem cell identification techniques[22] are:

Fluorescent antibody cell sorting: Stem cells can be identified and isolated from mixed cell populations by staining the cells with specific antibody markers and using a flow cytometer.

Immunomagnetic bead selection.

Immunohistochemical staining.

Physiological and histological criteria, including phenotype, proliferation, chemotaxis, mineralizing activity and differentiation.

Various conventional methods to isolate stem cells from dental pulp are listed below:

Enzymatic digestion of whole dental pulp tissue in solution of 3% collagenase Type I for 1 h at 37C is done. Through process of filtering and seeding, cells with diameter between 3 and 20 m are obtained for further culture and amplification. Based on this approach, small-sized cell populations containing a high percent of stem cells can be isolated.

Enzymatic digestion of the dental pulp tissue is done to prepare single cell suspension cells of which are used for colony formation containing 50 or more cells that is further amplified for experiments.

Is an immune-magnetic method used for separation of stem cell populations based on their surface antigens (CD271, STRO-1, CD34, CD45, and c-Kit). MACS is technically simple, inexpensive and capable of handling large numbers of cells but the degree of stem cell purity is low.

Is convenient and efficient method that can effectively isolate stem cells from cell suspension based on cell size and fluorescence. Demerits of this technique are a requirement of expensive equipment, highly-skilled personnel, decreased viability of FACS-sorted cells and this method is not appropriate for processing bulk quantities of cells.

Dr. Songtao Shi discovered SHED in 2003. Miura et al.[8] confirmed that SHED were able to differentiate into a variety of cell types to a greater extent than DPSCs, including osteoblast-like, odontoblast-like cells, adipocytes, and neural cells. Abbas et al.[23] investigated the possible neural crest origin of SHED. The main task of these cells seems to be the formation of mineralized tissue, which can be used to enhance orofacial bone regeneration.

Types of stem cells present in human exfoliated deciduous teeth are

Advantages of banking SHED cells[25] include: It's a simple painless technique to isolate them and being an autologous transplant they dont possess any risk of immune reaction or tissue rejection and hence immunosuppressive therapy is not required. SHED may also be useful for close relatives of the donor such as grandparents, parents and siblings. Apart from these, SHED banking is more economical when compared to cord blood and may be complementary to cord cell banking. The most important of all these cells are not subjected to same ethical concerns as embryonic stem cells.

Step 1: Tooth collection

Freshly-extracted tooth is transferred into vial containing hypotonic phosphate buffered saline solution (up to four teeth in one vial). Vial is then carefully sealed and placed into thermette, after which the carrier is placed into an insulated metal transport vessel. Thermette along with insulated transport vessel maintains the sample in a hypothermic state during transportation. This procedure is described as sustentation. The time from harvesting to arrival at processing storage facility should not exceed 40 h.

Step 2: Stem cell isolation

Tooth surface is cleaned by washing three times with Dulbecco's phosphate buffered saline without Ca2+ and Mg2+. Disinfection is done and again washed with PBSA. Pulp tissue is isolated from the pulp chamber and is placed in a sterile petri dish, washed at least three times with PBSA. The tissue digestion is done with collagenase Type I and dispase for 1 h at 37C. Isolated cells are passed through a 70 um filter to obtain single cell suspensions. Then the cells are cultured in a MSC medium. Usually isolated colonies are visible after 24 h.

Step 3: Stem cell storage.

The approaches used for stem cell storage are: (a) Cryopreservation (b) magnetic freezing.

It is the process of preserving cells or whole tissues by cooling them to sub-zero temperatures. Cells harvested near end of log phase growth (approximately. 8090% confluent) are best for cryopreservation. Liquid nitrogen vapour is used to preserve cells at a temperature of <150C. In a vial 1.5 ml of freezing medium is optimum for 12 106 cells.

This technology is referred to as cells alive system (CAS), which works on principle of applying a weak magnetic field to water or cell tissue which will lower the freezing point of that body by up to 67C. Using CAS, Hiroshima University (first proposed this technology) claims that it can increase the cell survival rate in teeth to 83%. CAS system is a lot cheaper than cryogenics and more reliable.

Primary incisors and canines with no pathology and at least one third of root left can be used for SHED banking. Primary molar roots are not recommended for sampling as they take longer time to resorb, which may result in an obliterated pulp chamber that contains no pulp, and thus, no stem cells.[26] However in some cases where deciduous molars are removed early for orthodontic reasons, it may present an opportunity to use these teeth for stem cell banking.

MSCs residing in the apical papilla of permanent teeth with immature roots are known as SCAP. These were discovered by Sonoyama et al.[9] SCAP are capable of forming odontoblast-like cells, producing dentin in vivo, and are likely cell source of primary odontoblasts for the formation of root dentin. SCAP supports apexogenesis, which can occur in infected immature permanent teeth with periradicular periodontitis or abscess. SCAP residing in the apical papilla survive such pulp necrosis because of their proximity to the periapical tissue vasculature. Hence even after endodontic disinfection, SCAP can generate primary odontoblasts, which complete root formation under the influence of the surviving epithelial root sheath of Hertwig.[9]

Seo et al.[11] described the presence of multipotent postnatal stem cells in the human periodontal ligament (PDLSCs). When transplanted into rodents, PDLSCs had the capacity to generate a cementum/periodontal ligament-like structure and contributed to periodontal tissue repair. These cells can also be isolated from cryopreserved periodontal ligaments while retaining their stem cell characteristics, including single-colony strain generation, cementum/periodontal-ligament-like tissue regeneration, expression of MSC surface markers, multipotential differentiation and hence providing a ready source of MSCs.[27]

Using a mini pig model, autologous SCAP and PDLSCs were loaded onto hydroxyapatite/tricalcium phosphate and gelfoam scaffolds, and implanted into sockets in the lower jaw, where they formed a bioroot encircled with the periodontal ligament tissue and in a natural relationship with the surrounding bone.[28] Trubiani et al.[29] suggested that PDLSCs had regenerative potential when seeded onto three dimensional biocompatible scaffold, thus encouraging their use in graft biomaterials for bone tissue engineering in regenerative dentistry, whereas Li et al.[30] have reported cementum and periodontal ligament-like tissue formation when PDLSCs are seeded on bioengineered dentin.

Although tooth banking is currently not very popular the trend is gaining acceptance mainly in the developed countries. BioEden (Austin, Texas, USA), has international laboratories in UK (serving Europe) and Thailand (serving South East Asia) with global expansion plans. Stem cell banking companies like Store A- Tooth (Provia Laboratories, Littleton, Massachusetts, USA) and StemSave (Stemsave Inc, New York, USA) are also expanding their horizon internationally. In Japan, the first tooth bank was established in Hiroshima University and the company was named as Three Brackets (Suri Buraketto) in 2005. Nagoya University (Kyodo, Japan) also came up with a tooth bank in 2007. Taipei Medical University in collaboration with Hiroshima University opened the nation's first tooth bank in September, 2008. The Norwegian Tooth Bank (a collaborative project between the Norwegian Institute of Public Health and the University of Bergen) set up in 2008 is collecting exfoliated primary teeth from 1,00,000 children in Norway. Not last but the least, Stemade introduced the concept of dental stem cells banking in India recently by launching its operations in Mumbai and Delhi.

Most research is directed toward regeneration of damaged dentin, pulp, resorbed root, periodontal regeneration and repair perforations. Whole tooth regeneration to replace the traditional dental implants is also in pipeline. Tissue-engineering applications using dental stem cells that may promote more rapid healing of oral wounds and ulcers as well as the use of gene-transfer methods to manipulate salivary proteins and oral microbial colonization patterns are promising and possible.[31]

Adult MSCs recently identified in the gingival connective tissues (gingival mesenchymal stem cells [GMSCs]) have osteogenic potential and are capable of bone regeneration in mandibular defects. GMSCs also suppress the inflammatory response by inhibiting lymphocyte proliferation and inflammatory cytokines and by promoting the recruitment of regulatory T-cells and anti-inflammatory cytokines. Thus, GMSCs potentially promote the right environment for osseous regeneration and is currently being therapeutically explored.[32]

Researchers of the Chinese Academy of Sciences and Guangdong Provincial Key Laboratory of Stem Cell Biology and Regenerative Medicine, reported a possible method for growing teeth from stem cells obtained in urine.[33] In this study, pluripotent stem cells derived from human urine were induced to generate tooth-like structures in a group of mice with a success rates of up to 30%. The generated teeth had physical properties similar to that of normal human teeth except hardness (about one-third less in hardness of human teeth). The reported advantages to such an approach were being noninvasive technique, low cost, and use of somatic cells (instead of embryonic) that are wasted anyways. Interestingly urine-derived stem cells do not form tumors when transplanted in the body unlike other stem cells; more over autologous sourcing of these cells reduces the likelihood of rejection.

Dental stem cells have the potential to be utilized for medical applications like heart therapies,[34] regenerating brain tissue,[35] for muscular dystrophy therapies[36] and for bone regeneration.[37,38] SHED can be used to generate cartilage[39] as well as adipose tissue.[40] In 2008 first advanced animal study for bone grafting was announced resulting in reconstruction of large size cranial bone defects in rats with human DPSCs.[41]

Researchers have observed promising results in several preclinical animal studies and numerous clinical trials are now on-going globally to further validate these findings. The Obama administration has made stem cell research one of the pillars of his health program. The U.S. Army is investing over $250 million in stem cell research to treat injured soldiers in a project called Armed Forces Institute for Regenerative Medicine. It is likely that the next stem cell advance is the availability of regenerative dental kits, which will enable the dentists the ability to deliver stem cell therapies locally as part of routine dental practice. An innovative method that holds promising future is to generate induced stem cells from harvested human dental stem cells. This approach reprograms dental stem cells into an embryonic state, thus expanding their potential to differentiate into a much wider range of tissue types. Researchers have so far succeeded in making specific dental tissues or tooth like structures although in animal studies but future advances in dental stem cell research will be the regeneration of functional tooth in humans.

As human stem cell research is a relatively new area, companies developing cell therapies face several types of risks as well, and some are not able to manage them thus pushing this venture into a highly speculative enterprise. Present clinical trials are being performed on recombinant human fibroblast growth factor-2, human platelet-derived growth factor, and tricalcium phosphate (GEM-21). Looking at the ongoing clinical trials, it is too early to speculate whether all therapies based on stem cells will prove to be clinically effective.[42]

Stem cells of dental origin have multiple applications nevertheless there are certain limitations as well. The oncogenic potential of these cells is still to be determined in long-term clinical studies. Moreover, the research is mainly confined to animal models and their extensive clinical application is yet to be tested. Other major limitations are the difficulty to identify, isolate, purify and grow these cells consistently in labs. Immune rejection is also one of the issues, which require a thorough consideration; nevertheless use of autologous cells can overcome this. Lastly, stem/progenitor cells are comparatively less potent than embryonic stem cells. Teeth-like structures cannot replace actual teeth, thus a considerable research research and development efforts is required to advance the dental regenerative therapeutics. Researchers still need to grow blood and nerve supply of teeth to make them fully functional. Although not currently available, these approaches may one day be used as biological alternatives to the synthetic materials currently used. Like other powerful technologies, dental stem cell research poses challenges as well as risks. If we are to realize the benefits, meet the challenges, and avoid the risks, stem cell research must be conducted under effective, accountable systems of social-responsible oversight and control, at both the national and international levels.[43]

Source of Support: Nil.

Conflict of Interest: None declared.

3. Wilson EB. 1st ed. New York: Macmillan Company; 1996. The Cell in Development and Inheritance.

4. Maximow A. The lymphocyte as a stem cell, common to different blood elements in embryonic development and during the post-fetal life of mammals. Folia Haematol. 1909;8:12334.

6. Polezhaev LV. 1st ed. Jerusalem: Keterpress; 1972. Restoration of lost regenerative capacity of dental tissues. In: Loss and Restoration of Regenerative Capacity in Tissues and Organs of Animals; pp. 14152.

23. Abbas, Diakonov I, Sharpe P. Neural crest origin of dental stem cells. Pan European Federation of the International Association for Dental Research (PEF IADR) Seq #96-Oral. Stem Cells. 2008 Abs, 0917.

26. Reznick JB. Continuing education: Stem cells: Emerging medical and dental therapies for the dental professional. Dentaltown Mag. 2008;Oct:4253.

31. Jain A, Bansal R. Regenerative medicine: Biological solutions to biological problems. Indian J Med Spec. 2013;4:416.

Articles from Journal of Natural Science, Biology, and Medicine are provided here courtesy of Medknow Publications

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Multipotent Cell-Secreted Extracellular Matrix Supports Cartilage Formation Histogen to present at International Cartilage Repair Society 2015

CHICAGO, May 8, 2015 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, will present new research on its human extracellular matrix (hECM) material in the promotion of cartilage regeneration during the International Cartilage Repair Society (ICRS) 2015 Meeting, taking place May 8-11, 2015 in Chicago, IL. The orthobiologic applications of all of Histogen's products are being developed by its worldwide joint venture, PUR Biologics LLC.

Histogen has previously shown that hypoxia-induced multipotent cells produce soluble and insoluble materials that contain components associated with stem cell niches in the body and with scarless healing. These proteins include a variety of laminins, osteonectin, decorin, hyaluronic acid, collagen type IV, SPARC, CXCL12, NID1, NID2, NOTCH2, tenascin, thrombospondin, fibronectin, versican, and fibrillin-2. In vitro studies further demonstrated that the CCM and ECM promote the adhesion, proliferation and migration of bone marrow-derived human mesenchymal stem cells (MSCs).

In this latest research, in vivo studies with the hECM were undertaken to determine their potential as orthobiologics. Rabbit studies demonstrated the potential of the hECM to promote regeneration and repair of full-thickness articular cartilage defects. Eight weeks following hECM treatment of femoral osteochondral defects, mature bone and hyaline cartilage formation was seen, exemplified by the presence of a tide mark and integration into the adjacent cartilage. This work is currently being repeated in a goat cartilage defect model, with similar results to date.

"The efficacy we have seen with the multipotent cell-secreted ECM in bone and cartilage regeneration is unprecedented," said Ryan Fernan, CEO of PUR Biologics. "The preclinical work overwhelmingly supports use of the material as an orthobiologic to reduce inflammation and promote cartilage regeneration in the articulating joint and intervertebral spinal disc. We look forward to entering human trials for these indications, as well as to continuing our research on utilizing the product for soft tissue repair in a variety of sports injuries."

Histogen's cell conditioned media (CCM) and hECM were also evaluated in an ex vivo rabbit intervertebral spinal disc model to study the effects of these materials in an environment where an extensive inflammatory response was induced by thrombin injection. Compared to untreated controls, both the CCM and ECM treatment significantly down regulated the expression of the inflammatory cytokine genes IL-1, IL-6, TNF-alpha, as well as the genes encoding the extracellular matrix degrading enzymes MMP3, and ADAMTS4, while upregulating aggrecan expression in the annulus fibrosus and nucleus pulposus tissue.

Dr. Gail Naughton, CEO of Histogen, will present "Human Cell Conditioned Media and Extracellular Matrix Reduce Inflammation and Support Hyaline Cartilage Formation" at the ICRS 2015 meeting in Chicago on May 9, 2015. Following the event, the presentation will be available upon request.

About PUR Biologics PUR Biologics is dedicated to providing regenerative biologic solutions to address musculoskeletal surgical needs, including spine, dental, ligament and medical device coating applications. In addition to distribution of approved allograft and biologic products, PUR is focused on development of next-generation orthopedic products based upon human protein and growth factor materials for bone and tissue regeneration. For more information visit http://www.purbiologics.com.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

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Novel Immunomodulatory Treatment Induces Apoptosis in Melanoma Histogen to present data at 2015 Society of Investigative Dermatology Annual Meeting

ATLANTA, May 6, 2015 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, will present new research on its 105F immunomodulatory treatment candidate for melanoma during the 2015 Society of Investigative Dermatology (SID) Annual Meeting, taking place May 6-9, 2015 in Atlanta, GA.

Histogen has previously shown that hypoxia-induced multipotent cells produce a soluble material with anti-oncologic properties, with potential benefit in the treatment of a wide range of cancers. Studies to characterize the active components of the material have identified a low molecular weight fraction (105F) which directly induces apoptosis, or controlled cell death, in 21 human cancer cell lines. In its latest research, Histogen sought to further examine the mechanism of action of 105F in melanoma through in vitro and in vivo studies.

After treatment with 105F, melanoma cells were shown to release Interleukin 6 (IL-6) and TNF a, pro-inflammatory cytokines acting as signals to the immune system. This induction of an immune "flare" in combination with tumor cell apoptosis could be critically important in recruiting immune cells to the tumor for cytotoxic attack.

"We were excited to see the dual activity of 105F, both directly inducing cancer cell death and activating an anti-tumorigenic immune response to reduce metastatic disease," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen. "These results represent a potential treatment for melanoma and other solid tumors that works through multiple channels to eliminate cancer cells, but is not toxic to the body's healthy cells."

An in vivo model of lung metastasis in C57Bl/6 mice further showed the efficacy of 105F in the treatment of melanoma. Daily intravenous injections of 105F over 14 days resulted in a significant (p=0.0049) reduction in lesions and marked immune cell infiltration as compared to controls.

Dr. Naughton will present "105F is a novel immunoadaptive treatment candidate for melanoma that induces apoptosis and the secretion of pro-inflammatory IL-6" at the 2015 SID Annual Meeting in Atlanta beginning May 6, 2015. Following the event, the presentation will be available upon request.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

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Histogen's Composition for Oncology Treatments Receives US Patent

SAN DIEGO, October 8, 2014 - Histogen Oncology, a company developing innovative cancer therapies based on Histogen's regenerative medicine technology, today announced that the United States Patent & Trademark Office has issued patent 12/363,479 entitled "Extracellular matrix compositions for the treatment of cancer" to Histogen.

The patent, which is the fifth U.S. patent issued to Histogen, covers the soluble and insoluble compositions of proteins and cofactors that are secreted by multipotent stem cells through Histogen's technology process for use in the treatment of cancer. The patent claims support of the use of the compositions alone or as a delivery system for traditional chemotherapeutic agents.

Through the recent formation and funding of the Histogen Oncology joint venture, research and development of the unique, naturally secreted compositions is progressing toward a Phase I clinical trial for end stage pancreatic cancer.

"We are pleased about the timely issuance of our U.S. patent for the treatment of cancer," said Dr. Gail K. Naughton, Histogen CEO and Chairman of the Board. "Our collaborations with top institutions continue to produce mounting evidence supporting the unique mechanism of action of our secreted material in preventing metastasis and reducing tumor load while having no toxic affect on normal cells."

Histogen's composition has shown effectiveness in inhibiting over 21 human cancer cell lines both in vitro as well as in animal models. The mechanism of action of the secreted material is through the induction of apoptosis (controlled cell death) primarily in malignant cells, so there is little to no toxicity to normal cells. Histogen Oncology is studying the efficacy of a small molecular weight fraction of the cell secreted composition as a stand alone treatment as well as in combination therapy to evaluate whether effectiveness can be demonstrated with less toxic drug doses.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen Oncology Created to Develop Novel Biologic Cancer Treatments Histogen, Inc. and Wylde, LLC Form Joint Venture

SAN DIEGO, July 8, 2014 - Histogen Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, has partnered with Southern California medical device group Wylde, LLC to create Histogen Oncology. This joint venture will focus on the development of unique cell-derived materials for cancer applications.

Under this joint venture, Histogen Oncology has acquired exclusive rights to Histogen's human multipotent cell conditioned media (CCM) and extracellular matrix (ECM) materials, as well as their derivatives, for oncology applications throughout North America. Histogen Oncology's initial clinical focus is pancreatic cancer, a highly treatment-resistant cancer in which a sub-fraction of the CCM has shown substantial preclinical promise.

"We have been very impressed with the results of Histogen's preliminary oncology work, not only because of the significant survival benefit but also because it is a naturally-derived material that is showing no toxicity," said Christopher Wiggins of Wylde, LLC. "There are so many patients out there who are not candidates for existing therapies due to the toxic nature of available drugs. This is particularly true in pancreatic cancer, where 80% of people diagnosed already have stage four disease."

In post-resection nude mouse models, intravenous treatment with the CCM sub-fraction resulted in prolonged survival by more than three fold in a majority of treated animals. In non-resection models, more than 50% of treated mice lived twice as long as the control. These results point to a potentially significant outcome for pancreatic cancer patients, and Histogen Oncology intends to progress the material toward a Phase I clinical trial for no-option pancreatic cancer patients in the coming 18 months.

Research on the mechanism responsible for cancer cell inhibition by the CCM shows the upregulation of Caspase 9 and cleaved Caspase 3, which causes cancer cells to enter apoptosis, or programmed cell death.

"The activity of the CCM sub-fraction is unique in a number of ways. Whereas most cancer therapies target rapidly dividing cells but not cancer stem cells, the inhibitory effect of this material is seen in malignant cells and circulating tumor cells as well," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen, Inc. "In addition, the activity is selective for malignant cells, supporting the proliferation of human dermal fibroblasts, embryonic stem cells and mesenchymal stem cells, while inhibiting tumor growth."

Histogen Oncology will be supported by Histogen's research group and funded by Wylde, LLC., made up of experts from the surgery and medical device industries. The creation of this joint venture allows for dedicated development of the CCM sub-fraction as a cancer treatment, as Histogen continues to allocate resources to the Company's revenue-generating aesthetic and promising therapeutic programs.

"We are extremely excited to fuel and push the next stage of development for this innovative and potentially life-saving therapy," said Wiggins. "The next generation of cancer treatment will have cell-signaling at its core, be beneficial in combination with existing therapies as well as stand alone, and provide an option to patients who currently have none. We believe Histogen's material has all of those characteristics and more."

About Histogen Aesthetics Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of multipotent human proteins that have been shown to support stem cell growth and differentiation. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen Aesthetics Acquires CellCeuticals Biomedical Skin Treatments

SAN DIEGO, March 10, 2014 - Histogen Aesthetics, a subsidiary of regenerative medicine company Histogen, Inc. focused on skin care and cosmeceuticals, announced today that the Company has acquired the CellCeuticals Biomedical Skin Treatments line of skincare products.

Histogen Aesthetics will continue sales of the eleven existing CellCeuticals Biomedical Skin Treatments skincare products, while bringing new innovation to the line through the addition of a unique regenerative medicine technology, working to improve skin aging at a cellular level.

"We have long admired the science, clinical data and elegant formulas behind the CellCeuticals line, and see it as an ideal fit for our recently revitalized aesthetics subsidiary," said Dr. Gail K. Naughton, CEO and Chairman of Histogen, Inc. "We are very excited to begin infusing unique cell-signaling factors into the CellCeuticals regimen, to truly transform skin one cell at a time."

Dr. Naughton has spent more than 30 years in tissue engineering and regenerative medicine, and holds over 100 patents in the field. She founded Histogen in 2007, focused on developing therapies that work to stimulate the stem cells in the body to regenerate tissues and organs. Through this work, she has also seen how different compositions of human proteins can have cosmetic benefits, particularly in anti-aging and rejuvenation.

"I am pleased that the CellCeuticals Biomedical Skin Treatments will evolve, and see Histogen Aesthetics as an excellent home for this innovative product line," said Paul Scott Premo, co-founder of CellCeuticals Skin Care, Inc. "I believe the addition of this regenerative medicine technology will be the opportunity to introduce a new generation of products that are the vanguard of regenerative skin care."

The CellCeuticals system is made up of eleven distinctive products including the Extremely Gentle Skin Cleanser, CellGenesis Regenerative Skin Treatment, and PhotoDefense Color Radiance SPF55+ with proprietary and patented PhotoPlex technology. The line is currently available at retailers including QVC.com, Dermstore.com, and Nordstrom.com, as well as http://www.cellceuticalskincare.com.

About Histogen Aesthetics Histogen Aesthetics LLC, formed in 2008 as a subsidiary of Histogen, Inc., focuses on the development of innovative skin care products utilizing regenerative medicine technology. Histogen Aesthetics' technology is based on the expertise of founder Dr. Gail K. Naughton, in which fibroblasts are grown under unique conditions, producing a complex of naturally-secreted proteins and synergistic bio-products known to stimulate skin cells to regenerate and rejuvenate tissues. In 2014, Histogen Aesthetics acquired CellCeuticals Biomedical Skin Treatments, a line of scientifically-proven products that reactivate cells to help aging skin perform and look healthier and younger. For more information, visit http://www.cellceuticalskincare.com.

About Suneva Medical, Inc. Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process is also being researched for oncology applications, and in orthopedics through joint venture PUR Biologics, LLC. For more information, please visit http://www.histogen.com.

Contacts Eileen Brandt, (858) 200-9520 ebrandt@histogeninc.com

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Histogen and Suneva Medical Expand License for Cell Conditioned Media-based Aesthetic Products Internationally

SAN DIEGO, CA, January 14, 2014 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, today announced that they have entered into an international license agreement with Suneva Medical, Inc. for physician-dispensed aesthetic products containing Histogen's proprietary multipotent cell conditioned media (CCM).

This agreement is an amendment to the existing license between Histogen and Suneva Medical, through which Suneva has exclusively licensed the Regenica skincare line within the United States since February 2012. Under the terms of the international agreement, Suneva Medical is now the exclusive licensee for the distribution of Regenica through the physician-dispensed channel in Europe, most of Asia, South America, Canada, Australia, and the Middle East.

"Not only has Suneva had sales success, but they have generated enthusiasm around the Regenica product line and our technology here in the US," said Gail K. Naughton, Ph.D., CEO and Chairman of the Board of Histogen. "We are excited about expanding our skincare partnership internationally, and look forward to an exciting year for Regenica."

Regenica contains Histogen's proprietary Multipotent Cell Conditioned Media, made up of soluble cell-signaing proteins and growth factors which support the body's epidermal stem cells and renew skin throughout life. Through Histogen's technology process, which mimics the embryonic environment including conditions of low oxygen and suspension, cells are triggered to become multipotent, and naturally produce these proteins associated with skin renewal and scarless healing.

"We believe that Regenica truly is the next generation in growth factor technology, and we are extremely pleased that the products will now have a presence around the world," said Nicholas L. Teti, Jr., Chairman and Chief Executive Officer of Suneva Medical. "Our relationship with Histogen in the US physician market has been a valuable asset to Suneva, and has laid the groundwork for international success."

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

About Suneva Medical, Inc. Suneva Medical, Inc. is a privately-held aesthetics company focused on developing, manufacturing and commercializing novel, differentiated products for the general dermatology and aesthetic markets. The company currently markets Artefill in the US, Korea, Singapore and Vietnam; Refissa and Regenica Skincare in the U.S.; and Bellafill in Canada. For more information, visit http://www.sunevamedical.com.

Regenica is a trademark of Suneva Medical, Inc. The Multipotent Cell Conditioned Media Complex is covered by U.S. patents #8,257,947 and #8,524,494.

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Multipotent Stem Cell Proteins Support Soft Tissue Regeneration Histogen to present data at TERMIS AM Annual Conference in Atlanta

ATLANTA, November 13, 2013 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, announced that Dr. Michael Zimber will give a podium presentation entitled "Human Multipotent Stem Cell Proteins Support Soft Tissue Regeneration" today at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) Americas Annual Meeting in Atlanta, GA.

Through its proprietary technology process that simulates the conditions of the embryonic environment, Histogen has developed a human extracellular matrix (hECM) material composed of stem cell-associated proteins including SPARC, decorin, collagens I,III,IV, V, fibronectin, fibrillin, laminins, and hyaluronic acid. The hECM's distinctive composition of growth factors and other proteins are known to stimulate stem cells in the body, regenerate tissues, and promote scarless healing.

Histogen sought to examine whether the hECM may promote scarless healing in full thickness wounds, similar to that seen in fetal healing, using a variety of forms of the material, including hollow spheres to maximize void fill volume. In preclinical studies, all hECM-treated wounds healed rapidly with minimum contractions, and the hECM microspheres had a statistically significant improvement in healing as compared to the controls (p<0.05) and produced a 25% thicker dermis. In addition, hECM applied topically after microneedling resulted in up to a 3X dermal thickening.

"We are very pleased that our propriety materials produced by hypoxia-induced human multipotent stem cells have shown significant healing results in both soft and hard tissues," said Dr. Gail Naughton, CEO and Chairman of the Board of Histogen. "These results open new therapeutic markets, show tremendous potential for our material in cutaneous wound care and orthopedics, as well as support the expansion of our aesthetic pipeline to include soft tissue fillers."

In addition to "Human Multipotent Stem Cell Proteins Support Soft Tissue Regeneration", Dr. Zimber will also be presenting "Human Multipotent Stem Cell Proteins Support Osteogenesis In Vitro" during the TERMIS AM Annual Meeting taking place November 10-13, 2013 in Atlanta. Following the event, these presentations will be available upon request.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Multipotent Stem Cell Proteins Support Rejuvenation while Inhibiting Skin Cancer Histogen to present data at TERMIS AP Annual Conference in Shanghai

San Diego, October 24, 2013 - Histogen, Inc., a regenerative medicine company developing solutions based on the products of cells grown under simulated embryonic conditions, announced that the Company's Chairman and CEO, Dr. Gail Naughton, will present today at the Tissue Engineering and Regenerative Medicine International Society (TERMIS) Asia Pacific Annual Meeting in Shanghai, China.

Through its proprietary technology process that simulates the conditions of the embryonic environment, Histogen is uniquely able to trigger the de-differentiation of skin cells into multipotent stem cells without genetic manipulation. The cells express key stem cell markers including Oct4, Sox2 and Nanog, and secrete a distinctive composition of growth factors and other proteins known to stimulate stem cells in the body, regenerate tissues, and promote scarless healing.

It is the soluble and insoluble compositions of multipotent proteins and growth factors resulting from this process that have been shown to both promote skin regeneration and induce controlled cell death in multiple skin cancers.

"The anti-aging and rejuvenation benefits of human multipotent stem cell proteins have been shown in several clinical studies, and have resulted in the material's use as a thriving next-generation ingredient for skin care," said Dr. Naughton. "In parallel, we have also been studying the anti-cancer activity of these proteins, and have shown that, just as in the embryonic environment, they support normal tissue growth while resulting in the controlled death of cancer cells".

In vitro studies performed with Histogen's material have shown reduction in Squamous Cell Carcinoma (SCC), Basal Cell Carcinoma, and Melanoma cell number through the mechanism of apoptosis, or controlled cell death, induced by the upregulation of Caspase in these cancer cells. In one in vivo model, melanoma load was reduced by up to 80% versus the control (p<0.05) by the addition of the insoluble multipotent stem cell proteins, and a dose response curve was seen. Similar inhibition was seen with SCC. In subcutaneous mouse experiments, tumor growth was inhibited by 70-90%.

"Human Multipotent Stem Cell Proteins Stimulate Skin Regeneration While Inducing Skin Cancer Cell Apotosis" will be presented by Dr. Naughton during the TERMIS AP Annual Meeting taking place October 23-26, 2013 in Shanghai. Further information and data on the ability of multipotent stem cell proteins to induce apoptosis in skin cancers can be found in the publication Journal of Cancer Therapy at file.scirp.org/Html/1-8901700_33923.htm.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Histogen to present at 2013 STEM CELL MEETING ON THE MESA

San Diego, October 11, 2013 - Histogen, Inc., a regenerative medicine company developing therapies for conditions including hair loss and cancer, announced today that Histogen CEO Gail K. Naughton, Ph.D. will give a company presentation at the 3rd Annual Regen Med Partnering Forum, part of the Stem Cell Meeting on the Mesa to be held October 14-16 in La Jolla, CA.

Histogen's solutions are based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. The technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of proteins that have been shown to support stem cell growth and differentiation.

"It is an exciting time for Histogen, as we continue to move the technology forward with expanded partnerships in skincare, compelling clinical data in both male and female hair loss, and early but exciting results in orthopedics," said Dr. Naughton. "We look forward to sharing our story during the Stem Cell Meeting on the Mesa, and to progressing our products even further through growing relationships with industry leaders and through our potential merger with Stratus Media to form publicly-traded Restorgenex."

Organized by the Alliance for Regenerative Medicine (ARM), the California Institute for Regenerative Medicine (CIRM) and the Sanford Consortium for Regenerative Medicine, the 2013 Stem Cell Meeting on the Mesa is a three-day conference aimed at bringing together senior members of the regenerative medicine industry with the scientific research community to advance stem cell science into cures. The Regen Med Partnering Forum, held October 14 &15 at the Estancia La Jolla Hotel, is the only partnering meeting organized specifically for the regenerative medicine and advanced therapies industry.

The following are specific details regarding Histogen's presentation at the conference:

Event: Regen Med Partnering Forum - 2013 Stem Cell Meeting on the Mesa Date: October 14, 2013 Time: 3:15pm Location: Estancia La Jolla Hotel & Spa, 9700 North Torrey Pines Road, La Jolla

A live video webcast of all company presentations will be available at: stemcellmeetingonthemesa.com/webcast and will also be published on ARM's website shortly after the event. Histogen will also make a copy of Dr. Naughton's presentation available at http://www.histogen.com.

About Histogen Histogen is a regenerative medicine company developing solutions based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. Through this unique technology process, newborn cells are encouraged to naturally produce the vital proteins and growth factors from which the Company has developed its rich product portfolio. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products. For more information, please visit http://www.histogen.com.

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Stratus Media Group and Histogen Execute Letter of Intent for Biotechnology Merger

LOS ANGELES, October 07, 2013 - Stratus Media Group, Inc. (OTCQB:SMDI) announced today that it was planning to expand its entrance into the biotechnology industry with the execution of a letter of intent between the Company and Histogen, Inc., a regenerative medicine company developing innovative therapies for conditions including hair loss and cancer.

The non-binding letter of intent outlines the primary terms of a merger of San Diego-based Histogen into Stratus, to be renamed Restorgenex Corporation. The letter of intent has been approved by the board of directors of both companies, and the parties are engaged in completing a formal merger agreement.

Histogen's solutions are based upon the products of cells grown under proprietary conditions that mimic the embryonic environment, including low oxygen and suspension. The technology focuses on stimulating a patient's own stem cells by delivering a proprietary complex of proteins that have been shown to support stem cell growth and differentiation. Histogen's lead product, Hair Stimulating Complex (HSC) has shown success in two Company-sponsored clinical trials as an injectable treatment for alopecia. In addition, the human multipotent cell conditioned media produced through Histogen's process can be found in skincare products including ReGenica, which is distributed by Suneva Medical in partnership with Obagi Medical Products.

"Histogen's technology platform opens a spectrum of potential product opportunities in both aesthetics and therapeutics, an ideal fit with our vision for Restorgenex," said Sol J. Barer, Ph.D., who will assume the position of Chairman of the Board of Restorgenex effective November 1, 2013. "The expertise of the Histogen team in developing regenerative products from concept to market, along with the success Histogen has already found in skincare partnering, will add significant value to our Company."

Following successful completion of this proposed merger, the company's goal is to build Restorgenex into a world-class cosmeceutical and pharmaceutical company in the large and expanding fields of dermatology and hair restoration. The parties intend to move toward a formal merger agreement in which Histogen would become a wholly-owned subsidiary, Histogen founder Gail K. Naughton, Ph.D. would assume the position of Chief Executive Officer of Restorgenex, and the corporate headquarters of Restorgenex would be located in San Diego. The merger will require, among other things, the satisfaction of customary closing conditions including the approval of Histogen's shareholders.

"I am very excited about the potential of a merger between Histogen and Restorgenex, and look forward to moving into the next stage," said Dr. Naughton. "It is an honor to be working with biotechnology visionaries Dr. Sol Barer and Isaac Blech, and to have them recognize the promise of Histogen's products is a true testament to the unique and exciting nature of our technology."

Dr. Naughton has spent more than 25 years extensively researching the tissue engineering process, holds more than 95 U.S. and foreign patents, and has been honored for her pioneering work in the field by prestigious organizations including receiving the Intellectual Property Owners Association Inventor of the Year Award.

Prior to founding Histogen in 2007, Dr. Naughton oversaw the design and development of the world's first up-scaled manufacturing facility for tissue engineered products, was pivotal in raising over $350M from the public market and corporate partnerships, and brought four human cell-based products from concept through FDA approval and market launch as President of Advanced Tissue Sciences.

"I believe the potential acquisition of Histogen, and the expertise and vision Dr. Naughton will bring as Chief Executive Officer will be a tremendous asset in ushering the Company into the biotechnology industry," said Jerold Rubinstein, current Chairman and Chief Executive Officer of Stratus.

http://www.histogen.com http://www.stratusmediagroup.com

Forward-Looking Statements Statements in this press release relating to plans, strategies, projections of results, and other statements that are not descriptions of historical facts may be forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 and the Securities Acts of 1933 and 1934. Forward-looking information is inherently subject to risks and uncertainties, and actual results could differ materially from those currently anticipated due to a number of factors. Although the company's management believes that the expectations reflected in the forward-looking statements are reasonable, it cannot guarantee future results, performance or achievements. The company has no obligation to update these forward-looking statements.

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Histogen - About Histogen - Latest news, upcoming events ...

I received a disturbing call from a woman in Texas recently. She was having some complications from the stem cell treatment that she received in her hometown.

In what is becoming a more common email or call from people not our patients, she revealed that she believed that her doctor was inexperienced in the Stem Cell procedure and did not know how to address her complications.

Even though I did not have the luxury of examining her, I tried to ask some questions to help her with her situation.

It seems, that she had received placental cells.They were injected into her knee and it caused a severe inflammatory response that left her with a great deal of pain. I did wish her the best and try to offer some advice, but also let her know that it is not legal nor recommended to inject placental cells into a patient.

While we have found the use of stem cells for the symptomatic treatment of arthritis and pain to be very helpful in our practice, one must be very cautious as to know what they are receiving.

As I mentioned, placental cells are not only illegal, but are immature cells that can have mutagenic properties. That is, they have the ability to turn into cancer cells and furthermore it is uncertain if the body can reject them since they are not harvested from the person who is receiving the treatment. These cells, also differentiate to form both blood cells and tissue cells so there is a great deal of insufficiency if you are looking to heal damaged tissue.

Bone marrow derived stem cells also have this same property of containing cell lines that turn into blood cells. There are certain areas, like the tibia, where the bone marrow contains many more blood cells then areas such as the hip, which contain more mesenchymal cells. Certain doctors have recommended tibial bone marrow draws for the use of bone marrow prolotherapy from the tibia, but this has very little scientific backing to be included as a stem cell source. There is also no research whatsoever showing its efficacy.

Many other doctors use bone marrow from the hip in their stem cell procedure. While this is a richer source of mesenchymal cells when compared to the tibia it is still a very poor source of stem cells.

Results from stem cell procedures not only depend on the cell type and where they are injected, but also the diagnostic skill and approach of the physician. While stem cells may have amazing properties, they are not so magical where we can just inject stem cells into a joint and hope for good results. As a physician, it is our job to evaluate and treat any problem surrounding, above and below the joint using a very careful physical examination. A comprehensive approach, not a single sided approach, will yield the best results for the patient.

Growth hormone has also been touted by one physician as useful in a stem cell mixture. That physician is conducting a study on this, but it still remains unproven. We had used this in power injection solution well over 10 years ago and stopped because it did not produce any significant clinical benefit. Furthermore, stem cells do need to be combined with a variety of growth factors in order to further their differentiation into new tissue. This can be achieved by using specialized forms of PRP along with the stem cell mixture. Both ourselves with our partners at Kensey and Dr. Centeno from Regenexx has done laboratory tests to look at the importance of this. There is a large variation in how stem cells perform based upon the environment that they are given with the PRP.

In summary, while these procedures have tremendous potential, we need to follow in the best of our knowledge base and follow our outcomes. Eventually, our technology will expand, and in the future we will have the capability to harvest stem cells in less than a half hour But this will take several years of development.

Scott Greenberg MD

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Stem Cell Therapy dangers and risks the wrong stem cells

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A human embryo can split into twins or triplets until about 14 days after fertilization

Egg and sperm: some people believe an embryo must be fully protected from conception onwards (Wellcome Images/Spike Walker)

Human blastocyst on the tip of a pin: embryonic stem cells can be grown from cells found in the blastocyst (Wellcome Images/Yorgos Nikas)

Some people think an embryo deserves special protection from about 14 days after fertilization

Many patients could one day benefit from embryonic stem cell research

The rules controlling embryonic stem cell research vary around the world and have been the topic of much discussion

Embryonic stem cell research poses a moral dilemma. It forces us to choose between two moral principles:

In the case of embryonic stem cell research, it is impossible to respect both moral principles.To obtain embryonic stem cells, the early embryo has to be destroyed. This means destroying a potential human life. But embryonic stem cell research could lead to the discovery of new medical treatments that would alleviate the suffering of many people. So which moral principle should have the upper hand in this situation? The answer hinges on how we view the embryo. Does it have the status of a person?

Chapter 1 of this film introduces some of the key ethical arguments. Watch this film and others on our films page.

The moral status of the embryo is a controversial and complex issue. The main viewpoints are outlined below.

1. The embryo has full moral status from fertilization onwards Either the embryo is viewed as a person whilst it is still an embryo, or it is seen as a potential person. The criteria for personhood are notoriously unclear; different people define what makes a person in different ways.

Development from a fertilized egg into to baby is a continuous process and any attempt to pinpoint when personhood begins is arbitrary. A human embryo is a human being in the embryonic stage, just as an infant is a human being in the infant stage. Although an embryo does not currently have the characteristics of a person, it will become a person and should be given the respect and dignity of a person.

An early embryo that has not yet implanted into the uterus does not have the psychological, emotional or physical properties that we associate with being a person. It therefore does not have any interests to be protected and we can use it for the benefit of patients (who ARE persons).

The embryo cannot develop into a child without being transferred to a womans uterus. It needs external help to develop. Even then, the probability that embryos used for in vitro fertilization will develop into full-term successful births is low. Something that could potentially become a person should not be treated as if it actually were a person

2. There is a cut-off point at 14 days after fertilization Some people argue that a human embryo deserves special protection from around day 14 after fertilization because:

3. The embryo has increasing status as it develops An embryo deserves some protection from the moment the sperm fertilizes the egg, and its moral status increases as it becomes more human-like.

There are several stages of development that could be given increasing moral status:

1. Implantation of the embryo into the uterus wall around six days after fertilization. 2. Appearance of the primitive streak the beginnings of the nervous system at around 14 days. 3. The phase when the baby could survive if born prematurely. 4. Birth.

If a life is lost, we tend to feel differently about it depending on the stage of the lost life. A fertilized egg before implantation in the uterus could be granted a lesser degree of respect than a human fetus or a born baby.

More than half of all fertilized eggs are lost due to natural causes. If the natural process involves such loss, then using some embryos in stem cell research should not worry us either.

We protect a persons life and interests not because they are valuable from the point of view of the universe, but because they are important to the person concerned. Whatever moral status the human embryo has for us, the life that it lives has a value to the embryo itself.

If we judge the moral status of the embryo from its age, then we are making arbitrary decisions about who is human. For example, even if we say formation of the nervous system marks the start of personhood, we still would not say a patient who has lost nerve cells in a stroke has become less human.

If we are not sure whether a fertilized egg should be considered a human being, then we should not destroy it. A hunter does not shoot if he is not sure whether his target is a deer or a man.

4. The embryo has no moral status at all An embryo is organic material with a status no different from other body parts.

Fertilized human eggs are just parts of other peoples bodies until they have developed enough to survive independently. The only respect due to blastocysts is the respect that should be shown to other peoples property. If we destroy a blastocyst before implantation into the uterus we do not harm it because it has no beliefs, desires, expectations, aims or purposes to be harmed.

By taking embryonic stem cells out of an early embryo, we prevent the embryo from developing in its normal way. This means it is prevented from becoming what it was programmed to become a human being.

Different religions view the status of the early human embryo in different ways. For example, the Roman Catholic, Orthodox and conservative Protestant Churches believe the embryo has the status of a human from conception and no embryo research should be permitted. Judaism and Islam emphasize the importance of helping others and argue that the embryo does not have full human status before 40 days, so both these religions permit some research on embryos. Other religions take other positions. You can read more about this by downloading the extended version of this factsheet below.

Extended factsheet with a fuller discussion of the issues by Kristina Hug (pdf) EuroStemCell film "Conversations: ethics, science, stem cells" EuroStemCell factsheet on ethical issues relating to the sources of embyronic stem cells EuroStemCell factsheet on the science of embryonic stem cells EuroStemCell FAQ on human embryonic stem cells and their use in research EuroStemCell summaries of regulations on stem cell research in Europe Booklet for 16+ year olds about stem cells and ethics from the BBSRC Research paper on the ethics of embryonic stem cell research by Kristina Hug

This factsheet was created by Kristina Hug and reviewed by Gran Hermern.

Images courtesy of Wellcome Images: Egg and sperm by Spike Walker; Blastocyst on pin by Yorgos Nikas; Diabetes patient injecting insulin by the Wellcome library, London.

Other images from "Conversations : ethics, science, stem cells", a film by EuroStemCell.

Originally posted here:
Embryonic stem cell research: an ethical dilemma | Europe ...

Sports and exercise are great ways to stay healthy, challenge yourself and have fun. So when an injury sidelines you, you want doctors with the expertise to get you back in the game as quickly as possible.

Youll find that expertise at Rush, home to the team physicians for the Chicago White Sox, Chicago Bulls, DePaul University Blue Demons, U.S. soccer and rugby, Hubbard Street Dance Company, and many other teams, schools and organizations.

Sports medicine physicians at Rush diagnose and treat athletes of all ages from weekend warriors to pro athletes and have the know-how to treat even the most complex injuries. They strive to relieve your pain and restore function, whether you're suffering from a throwing injury, "jumper's knee," a stress fracture, a muscle strain or tear, or another problem.

These highly-skilled specialists have pioneered numerous treatments for sports injuries, including cartilage transplants and arthroscopic surgical approaches for ACL and rotator cuff repair. They also have extensive experience evaluating and treating failed knee and shoulder surgeries, and performing shoulder replacement.

Sports injuries can happen any time of day. And when it comes to orthopedic injuries, you don't want to spend hours sitting in the ER. Now, you can get prompt medical care for your injury at the Sports Injury Immediate Care Clinic at Rush, with two convenient locations: downtown and in Westchester.

Staffed by board certified sports medicine doctors, the clinics are open until 7 p.m. on weeknights and from 8 a.m. to noon on Saturdays for immediate treatment including X-rays, bracing and casting or consultation.

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Sports Medicine Program - Rush University Medical Center

Are applicants for a driver's license asked questions about diabetes?

The driver's license application (first-time and renewal) asks an applicant whether he or she has, within the past six months, had a physical or mental condition that affected his or her ability to drive and if, within the past six months, he or she has had a fainting spell, blackout, seizure, or episode of loss of consciousness. If an applicant answers yes to either of these questions, he or she is required to have a physician complete an examination and submit a medical evaluation form before he or she may be licensed. See generally Mich. Admin. Code r. 257.853(1), (3) (2013) (requiring statement of physical history before licensing if reason to believe physical disability affects safe driving).

What other ways does the state have to find out about people who may not be able to drive safely because of a medical condition?

The state accepts reports of potentially unsafe drivers from police officers, the courts, physicians, family members, friends, other citizens, and hospitals. The licensing agency does not accept anonymous reports and investigates the source of a report if the source's relationship to the driver is not clear. See Mich. Comp. Laws 257.309(1) (2013) (licensing agency may refuse to grant a license without an examination based on information of physical condition received from any source). A concerned third party may make a report by submitting a Request for Driver Evaluation (OC-88) form. This report must contain identifying information about the driver, as well as specific information to justify the reevaluation of his or her driving ability. See Mich. Dept. of State, "Request for Driver Evaluation," Form OC-88 (Rev. 09/11). Drivers also may be required to have medical evaluations if they have impairments which are observed by licensing agency personnel during the licensing process, Mich. Comp. Laws 257.309(1) (2013), if they have been involved in at-fault crashes involving a fatality, have accumulated significant numbers of accidents or points during a two-year period, or when driving privileges are to be restored following a revocation or suspension. See Mich. Comp. Laws 257.320(1)(a)-(e) (2013).

What is the process for medical evaluations of drivers?

When the licensing agency has reason to believe that a driver may be medically unqualified to operate a motor vehicle, either because the driver gave positive answers to medical questions on the license application or because of a report from one of the other sources listed above, it will require the driver to submit to a medical evaluation. Mich. Comp. Laws 257.320(1)(a) (2013); Mich. Admin. Code r. 257.853(1) (2013). When this happens, a medical evaluation form is sent to the individual, which must be completed, in part, by his or her physician. See Mich. Admin. Code r. 257.853(6)-(9) (2013) (setting forth standards for physician's statement). The Physician's Statement of Examination must be returned to the licensing agency, where it is evaluated and a licensing decision is made. See Mich. Admin. Code r. 257.853(1), (3) (2013).

The Physician's Statement of Examination (DI4P) asks the driver to indicate whether he or she has diabetes. See Mich. Dept. of State, "Physician's Statement of Examination," Form DI-4P (03/05/2013). It also asks about seizures, blackouts, or fainting. Id. The driver must explain any of the conditions listed. Further questions relate to the number of accidents or incidents of lost consciousness within the last five years, and current medications being taken. Id. The physician must indicate if they have concerns about the driver's ability to operate vehicle, and why. Id. A full section asks detailed questions about medical conditions, prescribed medicine, control of condition, and episodes of lost consciousness. Id. Finally, the physician must indicate whether restrictions or further evaluations should be conducted. Id.

The licensing agency may request additional medical information from the physician or order further tests before making a decision. Mich. Admin. Code r. 257.853(9) (2013). Periodic follow-up medical evaluations may be required. Mich. Admin. Code r. 257.853(10) (2013).

Are physicians required by law to report drivers who have medical conditions that could affect their ability to drive safely?

There is no statutory authority requiring physicians to report drivers with medical conditions that could affect their ability to drive safely to a central state agency. Physicians and optometrists may voluntarily report a patient's physical qualifications to safely operate a vehicle. Mich. Comp. Laws 333.5139(1) (2013).

Are physicians who report drivers with medical conditions immune from legal action by the patient?

Yes. Physicians and optometrists are immune from civil and criminal liability for making a report, so long as they are acting in good faith and exercising due care. Mich. Comp. Laws 333.5139(3) (2013). Conversely, a physician who voluntarily chooses not to make a report is also immune from any liability for any subsequent injuries caused by the unsafe driver. Mich. Comp. Laws 333.5139(1) (2013).

Who makes decisions about whether drivers are medically qualified?

Licensing decisions are made by staff in the licensing agency's medical unit after reviewing an individual's medical information and giving strong consideration to the opinion of his or her physician. Mich. Comp. Laws 257.320(2) (2013) (licensing agency has authority to restrict, suspend, or revoke license). The licensing agency may appoint health consultations, Mich. Admin. Code r. 257.852 (2013), and has created a Medical Advisory Board. An expert in endocrinology may be a health consultant. Mich. Admin. Code r. 257.852(2)(n) (2013). The health consultants may advise the department concerning physical and mental standards for motor vehicle licensing. Mich. Admin. Code r. 257.852(3) (2013). Upon request, the consultants may advise the department concerning an applicant's or licensee's physical or mental ability to drive motor vehicle. Mich. Admin. Code r. 257.852(4) (2013). Nevertheless, the opinions of health consultants are advisory and the licensing agency retains ultimate authority over licensing decisions. Mich. Admin. Code r. 257.852(5) (2013). For more information, see Michigan Secretary of State, "(Terri Lynn) Land Creates Medical Advisory Board." (describing creation of Medical Advisory Board).

What are the circumstances under which a driver may be required to undergo a medical evaluation?

A driver may be required to undergo a medical evaluation if the licensing agency has reason to believe that he or she has a physical or mental disability that affects his or her ability to safely operate a motor vehicle. Mich. Comp. Laws 257.320(1)(a) (2013); Mich. Admin. Code r. 257.853(3) (2013). These reasons may include observation by licensing agency staff. Mich. Comp. Laws 257.320(1) (2013). The licensing agency may also consider information from a Request for Driver Evaluation (OC-88) submitted by a physician or optometrist or any other concerned third party. Mich. Comp. Laws 257.320(3) (2013) (physician or optometrist report should be considered for examination). A driver may also be required to undergo a medical evaluation for driving violations: 1) if he or she has in one or more instances been involved in an accident resulting in the death of a person; 2) he or she, within a 24-month period, has been involved in three accidents resulting in personal injury or damage to the property of a person for moving violations; 3) he or she has charged against him or her a total of 12 or more points within a period of two years; or 4) he or she has been convicted of violating restrictions, terms, or conditions of his or her license. Mich. Comp. Laws 257.320(1)(b)-(e) (2013); see also Mich. Comp. Laws 257.320a (2013) (providing for point system for various driving violations).

Has the state adopted specific policies about whether people with diabetes are allowed to drive?

No. Michigan has adopted no specific medical guidelines related to diabetes, except for its guidelines related to episodes of loss of consciousness. However, the Physician Examination form specifically asks the driver whether he or she has diabetes. Mich. Dept. of State, "Physician's Statement of Examination," Form DI-4P (03/05/2013).

What is the state's policy about episodes of altered consciousness or loss of consciousness that may be due to diabetes?

If an applicant or a licensee experiences an "episode," his or her license will be denied or indefinitely suspended after reexamination. Mich. Admin. Code r. 257.854(1) (2013). An episode is defined as any "condition which causes or contributes" to lapse of consciousness, blackout, seizure, fainting spells, syncope, or other impairments of the level of consciousness. Mich. Admin. Code r. 257.851(1)(e)(i)-(ii) (2013). It also includes any condition which causes or contributes to "violent or aggressive action" related to driving a motor vehicle. Mich. Admin. Code r. 257.851(1)(e)(iii) (2013). In order to regain his or her license, the driver must submit a Physician's Statement of Examination (DI-4P). Mich. Admin. Code r. 257.854(1) (2013). The physician must certify that the driver's condition is under control by medical or other treatment. All symptoms or conditions which would affect safe driving must have been controlled for at least 6 months. Mich. Admin. Code r. 257.854(2)(a) (2013). The physician must certify that the individual has not experienced an episode of loss of consciousness within the previous 6 months. Mich. Admin. Code r. 257.854(2)(b) (2013); see also Mich. Admin. Code r. 257.853(4)-(8) (2013) (specifying what information the Physician's Statement of Examination must contain). For chauffeurs and persons endorsed to operate trucks or buses, the requirements of the Physician's Statement of Examination are identical with the exception that the relevant episode-free period is 12 months. Mich. Admin. Code r. 257.854(3)(a)-(b) (2013). The licensing agency may require that an individual submit periodic follow-up medical evaluations as a condition of licensure. Mich. Admin. Code r. 257.853(10) (2013).

Does the state allow for waivers of this policy, e.g., a waiver for a one-time episode of severe hypoglycemia that has mitigating factors (e.g., recent change in medication, illness, etc.) or that has been addressed with a physician?

Yes. The 6-month or 12-month period may be reduced or eliminated based upon a departmental review of the specific recommendation of a qualified physician or any other information that may come to the licensing agency, including evidence that the episode of loss of consciousness resulted from medical intervention or medically supervised experimentation with prescribed medication, as well as the evaluation of other evidence. Mich. Admin. Code r. 257.854(4) (2013). Additionally, the licensing agency maintains that any action taken on the basis of a physical or mental condition or disability will be reassessed upon receipt of new medical evidence and documentation that the condition or disability has changed or abated or no longer exists. Mich. Admin. Code r. 257.853(11) (2013). All medical information submitted is reviewed by licensing agency personnel and at times in consultation with the Medical Advisory Board.

What is the process for appealing a decision of the state regarding a driver's license?

A driver may seek appeal to the licensing agency's administrative hearing officer or the circuit court. See Mich. Comp. Laws 257.322-.323 (2013); see also Mich. Admin. Code r. 257.856 (2013) (providing the right to appeal final decisions of the licensing agency). A request for an administrative hearing must be made in writing within 14 days of the denial or suspension of the license. Mich. Comp. Laws 257.322(2) (2013). To request a hearing, an individual may submit a Driver's License Appeals Hearing Request. At the hearing, an individual may present evidence and testimony, and before its commencement, the hearing officer may compel production of documents and transcripts of testimony. Mich. Comp. Laws 257.322(2)-(3) (2013). Following the hearing, the hearing officer may affirm, modify, or set aside the final determination of the licensing agency. Mich. Comp. Laws 257.322(5) (2013).

Alternately, an individual may request review of the licensing agency's decision in the circuit court of the county where the suspension or revocation was imposed or that of his or her residence by filing a petition within 63 daysor within 182 days with a showing of good cause. Mich. Comp. Laws 257.323(1) (2013). The court will set a date for a cause for hearing not more than 63 days after receipt of the petition for review. Mich. Comp. Laws 257.323(2) (2013). After presentation of evidence and testimony, the court will affirm, modify, or set aside the final determination of the licensing agency. Mich. Comp. Laws 257.323(3) (2013). The circuit court will not grant an individual restricted driving privileges, and it will set aside the licensing agency's final determination only if the petitioner's substantial rights have been prejudiced. Mich. Comp. Laws 257.323(4) (2013).

May an individual whose license is suspended or denied because of diabetes receive a probationary or restricted license?

Yes. The licensing agency may issue limited or restricted licenses or endorsements to individuals that have experienced episodes of loss of consciousness on a case-by-case basis. Mich. Admin. Code r. 257.854(4) (2013); see also Mich. Comp. Laws 257.312 (2013) (providing for restricted operator's and chauffeur's licenses); Mich. Admin. Code r. 257.3 (2013) (describing specific license restrictions).

Is an identification card available for non-drivers?

Yes, with proper identification and payment of a fee. Identification cards are issued at no charge to persons age 65 and over and to individuals whose licenses have been suspended due to medical reasons. See Mich. Dept. of State, "Driver's License or ID Requirements," Form SOS-428, (04/13). For more information, see Michigan Secretar of State, "Driver's License and State ID."

Resources

Driver licensing in Michigan is administered by the Department of State.

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Michigan: American Diabetes Association

Living with Diabetes

The Diabetes programs within MidMichigan Health help people with diabetes take control of their illness so they can live full and active lives here in the middle of Michigan.

Diabetes is a disease that prevents the body from correctly utilizing glucose the fuel that is made from the carbohydrates we eat. There are several types of diabetes:

Learn more about risk factors, symptoms and free screenings throughout the middle of Michigan

If you have diabetes, working with a team, including your physician, a diabetes nurse and a diabetes dietitian, will help you establish a plan for treatment.Learn more about the diagnosis and treatment of diabetes.

Diabetes is a risk factor for many other conditions and complications, including heart disease, eye problems, kidney disease, foot problems and depression. But there are many things you can do to manage your disease and prevent complications:

MidMichigan is committed to providing self-management tools to help you stay in control of your diabetes, including:

You may want to check with your insurance plan to see which programs and services are covered.

The diabetes education programs at MidMichigan Medical Centersin Clare,Gladwin, Midland, and MidMichigan Health ParkMt. Pleasant havebeenrecognized by the American Association of Diabetes Educatorsfor meeting national quality standards.These programs have also earned state certification by theMichigan Department of Community Health.

The diabetes instructors at the Diabetes Center of MidMichigan Medical Center in Midland arecertified diabetes educators (CDEs), which assures that they have met specific requirements of the National Certification Board of Diabetes Educators.

Diabetes services and programs are available in severallocations in central Michigan:

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Diabetes - MidMichigan Health

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Journal of Advanced Sciences Applied Engineering