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Chapter 1. Pilot Study: The Effects of Stem Cells and Platelet Rich Plasma on Recovery from Laser Resurfacing. Robert Bowen M.D., FCCP, FASLMS
ABSTRACT
INTRODUCTION
PILOT STUDY. Stem Cells
Materials and Methods
Results
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 2. Cell-Assisted Facial Fat Transfer – The Natural Filler. Robert Bowen M.D., FCCP, FASLMS
ABSTRACT
INTRODUCTION
CELL-ASSISTED FACIAL FAT TRANSFER. Technique
Transplantation. Candidates
Pre-Op Consultation
Anesthesia
Implantation
Post-Op Care
Complications
Legal
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 3. Innovations in the Treatment of Chronic Wounds. Robert E. Bowen, M.D., FCCP, FSLMS
ABSTRACT
INTRODUCTION. Thermal Injuries
Chronic Wounds
TREATMENT OF CHRONIC WOUNDS. Conventional Treatment
Innovative Treatments. Vacuum Assisted Closure (VAC)
Growth Factors
Mesenchymal Stem Cells
FUTURE PROSPECTS
REFERENCES
ABOUT THE AUTHOR
Chapter 4. Nitric Oxide: The Overlooked Molecule in Patient Care. Nathan S. Bryan, Ph.D
ABSTRACT
INTRODUCTION
AGE-DEPENDENT DECLINE IN NITRIC OXIDE PRODUCTION
HUMAN NITROGEN CYCLE
NITRIC OXIDE DIAGNOSTICS
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 5. Testosterone Pellet Implantation. Stephen Center, M.D
ABSTRACT
INTRODUCTION
TESTOSTERONE DEFICIENCY
TESTOSTERONE DELIVERY VIA PELLETS
Male Clinical Studies
Female Clinical Studies
Hormone Implants and Breast Cancer
Pellet Dosing Options. Men
Women
New Options for Testosterone Implantation
Retesting Testosterone Levels
Target Therapeutic Levels
Men
Women
The Procedure
Possible Complications
Signs and Symptoms of Testosterone Excess
RECOMMENDATIONS. Recommendation 1
Recommendation 2
Recommendation 3
REFERENCES
FOR FURTHER INFOFRMATION
ABOUT THE AUTHOR
Chapter 6. Iodine: Roles in Human Health and Toxicology. Alan Christianson, NMD. ABSTRACT
INTRODUCTION
IODINE AND HUMAN HEALTH. Biological Functions of Iodine
Metabolism of Iodine
Thyroid Hormones
Dietary Iodine. Variations in Dietary Iodine
Goitrogens
Dietary Sources of Iodine
Human Requirements for Iodine
Assessment of Iodine Status
American Iodine Status
Non Nutritional Medical Uses of Iodine
TOXICITY OF IODINE
Safe Upper limit
CONCLUDING REMARKS. Proponents of Pharmacologic Iodine
Relevance of Iodine to the Integrative Physician
REFERENCES
ABOUT THE AUTHOR
Chapter 7. Assessment of Biological Aging & Treatment of Metabolic Inflammatory Diseases. Nick Delgado Ph.D., CHT
ABSTRACT
INTRODUCTION
PHYTOCHEMICALS
FREE RADICAL SCAVENGERS
HEALTHY DIET
MITOCHONDRIA
FITNESS
CONCLUDING REMARKS
REFERENCES
FOR FURTHER INFORMATION
ABOUT THE AUTHOR
Chapter 8. The Role of Hormonorestorative Therapy as a Part of Physiology Optimization in the Management of Patients with Hypercholesterolemia. Sergey A. Dzugan1; George W. Rozakis1; Konstantine S. Dzugan1; Less Emhof1; Sergey S. Dzugan2; Dyno Xydas3; Christos Michaelides3; Janet Chene1; Michael Medvedovsky1;Armond Scipione4; Alexander S. Kuznetsov5
ABSTRACT
INTRODUCTION
METHODS AND MATERIALS
RESULTS
DISCUSSION
CONCLUDING REMARKS
REFERENCES
FOR FURTHER INFORMATION
ABOUT THE AUTHOR
Chapter 9. The Beneficial Confluence of Stem Cell Therapy and Physiology Optimization. Sergey A. Dzugan, M.D., Ph.D
ABSTRACT
INTRODUCTION
Hematologic Endocrinology
HORMONES AND STEM CELLS
Restoration and Stimulation of Stem Cell Function
Conventional Medicine versus Physiologic Medicine
Practical Application
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 10. Modified Citrus Pectin and Galectin-3 and Their Role in Health and Illness. Isaac Eliaz, M.D., M. S., L.Ac
ABSTRACT
INTRODUCTION
FDA Approved Galectin-3 Serum Assay
MODIFIED CITRUS PECTIN
MCP Anticancer Research
MCP Chelation Research
MCP Immune Research
GALECTIN-3
Galectin-3 Interactions Enhance Formation of Cancer and Metastasis
Research on Galectin-3 in Inflammation and Fibrosis. Cardiovascular Disease
Diabetes and Metabolic Syndrome
Rheumatoid Arthritis
Inflammatory Gastrointestinal Conditions
Hepatic Diseases
Asthma
Binding of Galectin-3 with Modified Citrus Pectin Effective in Reducing Kidney Injury
CONCLUDING REMARKS
REFERENCES
Chapter 11. Small RNA Fragments Support White Blood Cell and Platelet Proliferation in Cancer Patients Undergoing Chemotherapy. John L. Hall, Ph.D.1; James F. Grutsch, Ph.D.2
ABSTRACT
INTRODUCTION. The Functions and Reputations of Nucleic Acids
RNA Primers in DNA Synthesis
Beljanski’s RNA Fragments as Stimulators of White Blood Cells and Platelets
Thrombocytopenia and Chemotherapy
Consequences of Thrombocytopenia
A PHASE I CLINICAL TRIAL WITH BELJANSKI’S RNA FRAGMENTS
Patients and Protocols
Effect of Myelosuppressive Drugs on Platelet Levels
Results with E. coli RNA Fragments
Results with Yeast RNA Fragments
A Comparison of the Results from the E. coli and Yeast Arms
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHORS
Chapter 12. Curcumin Signaling Targets in Acute and Chronic Injury: Basis for Repair of Burns and Photodamaged Skin. Madalene C.Y. Heng, M.D., FRACP, FACD, FAAD
ABSTRACT
INTRODUCTION
MECHANISMS OF INJURY. Burns and Scalds
Solar Induced Injury
SIGNALING PATHWAYS INDUCED BY INJURY. NF-kB Dependent Signaling Pathways
Role of NF-kB, a Transcription Regulator in Injury Pathways
Activation of NF-kB and IkBα Kinase
Role of Phosphorylase Kinase in NF-kB and IkB Kinase Activation: Blocked by Curcumin2
CLINICAL EVIDENCE OF EFFICACY OF CURCUMIN GEL IN THE REPAIR OF ACUTE AND CHRONIC INJURY
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 13. Prevention of Alzheimer’s Disease. Richard S. Isaacson, M.D
ABSTRACT
INTRODUCTION
Alzheimer’s Disease: The Facts
The Cognitive Spectrum
A MULTIMODAL APPROACH TO ALZHEIMER’S DISEASE PREVENTION
Pharmacologic Interventions
Fish Oils
Curcumin
Statins
Folic Acid
Caffeine
Nonpharmacologic Interventions. Physical Exercise
Mental Exercise
Music Therapy
Diet
OTHER CONSIDERATIONS
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 14. Environmental Links to Disease: A Literature Review. Dr. Ronald Klatz, M.D., D.O., President. Dr. Robert Goldman, M.D., Ph.D., D.O., FAASP, Chairman
abstract
introduction
LITERATURE REVIEW. Air Pollution. Chronic Exposure to Air Pollution Triggers Systemic Inflammation
Costly Health Effects of Air Pollution
Air Pollution Linked to Chronic Heart Disease
Ozone in Air Pollution Harms the Heart
Air Quality. Warmer Temperatures Raise Death Rates
Thirdhand Smoke Poses Significant Health Risks to Nonsmokers
Beware the Office Air
Endocrine Disruptors. Plastic Food Wrap Poses Food Safety Risk
High Levels of Bisphenol A Common in Paper Products Around the World
Widespread Prevalence of Endocrine Disruptor Compounds in Personal Care Products
BPA "Is a Breast Carcinogen in Humans"
concluding remarks
ABOUT THE AUTHORS
Chapter 15. Osteopathic Medicine: A Brief Introduction. Martin S. Levine, D.O., MPH, FACOFP dist
ABSTRACT
INTRODUCTION
CORE PRINCIPLES OF OSTEOPATHIC MEDICINE
OSTEOPATHIC MEDICINE IN THE MEDICAL LITERATURE. Manipulation of the Joints
Treatment of Influenza
Lymphatic Pump Techniques
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 16. Metabolic Treatment of Cancer. Joseph Maroon, M.D
Jeff Bost, PAC
Darren LePere, BS
Jose Joaquin Puello, M.D., Neurosurgeon
Giulio Zuccoli, M.D
Thomas Seyfried, Ph.D
Matt El Kadi, M.D., Ph.D. Professor of Neurosurgery, University of Pittsburgh Medical Center. ABSTRACT
INTRODUCTION
STANDARD TREATMENT OF GBM
Survival Statistics
METABOLIC TREATMENT OF CANCER. Contributions of Dr. Otto Warburg: Cancer Cells and Anaerobic Respiration
Understanding the Restrictive Ketogenic Diet
Therapeutic Uses of the (Restrictive) Ketogenic Diet
Current Clinical Trial
Hyperbaric Oxygen Therapy
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHORS
Chapter 17. Toxic Metals as Endocrine Disrupters. L. Charles Masur, M.D
ABSTRACT
INTRODUCTION
COMMON METAL ENDOCRINE DISRUPTORS
Arsenic
Cadmium
Mercury
INVESTIGATION, DIAGNOSIS, AND MANAGEMENT OF METAL TOXICITY
Assessing the Body Burden of Toxic Metals
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 18. Putting it All Together: The Nuts and Bolts of Hormone Restoration, Nutrition, Detoxification, and Balancing the Mind and Body. Sangeeta Pati, M.D., FACOG
ABSTRACT
INTRODUCTION
A RESTORATIVE MEDICINE MODEL. Hormone Restoration
Bioidentical Hormones – The Only Choice for Hormone Replacement
NUTRITION
DETOXIFICATION
PUTTING THE MEDICAL MODEL INTO PRACTICE
CASE STUDIES. Case Study: Typical 40-Year-Old Female Patient
Case Study: 40-Year-Old Male Patient with a Diagnosis of Fibromyalgia
CONCLUDING REMARKS
ABOUT THE AUTHOR
Chapter 19. The Use of Platelet-Rich Plasma (PRP) Injections and Stem Cells in an Office Setting. Joseph Purita M.D., FACS, FAAOS, FAAMP
ABSTRACT. The aim of this paper is to consider the practicalities of using platelet-rich plasma (PRP) and stem cells to treat musculoskeletal conditions in the office setting. The science behind PRP and stem cells, treatment protocols, and contraindications are all discussed
INTRODUCTION. There is currently a revolution in the use of biologics. A few years ago, the use of stem cells was thought to be a treatment modality that would someday become a commonplace treatment for various afflictions of the human body. Well, someday has come right now. Stem cells and platelet-rich plasma (PRP) injections are now commonplace treatments for a variety of musculoskeletal conditions. This paper will discuss the use of stem cells and PRP injections in the use and treatment of musculoskeletal conditions. A major gap has existed for the treatment options between conservative treatments and surgery. This gap is now filled by PRP and stem cell injections. The goal of this presentation is to enable the physician to perform stem cell injections and PRP injections in an office setting in an efficient, safe, and economical manner. The use of stem cells, PRP, and scaffolding material such as fat grafts, form what can be called the healing trinity – all of these aspects work together to achieve healing in the musculoskeletal system. PLATELET-RICH PLASMA. At one time, it was thought that platelets were basically responsible for clotting the blood and that was all. Nothing could be further from the truth. When the platelets are concentrated the growth factors are also concentrated. These growth factors are what cause things to heal. They recruit stem cells and have direct effects on many different types of tissue. PRP contains a number of different kinds of cells including:
The real power of the platelets rests in the growth factors which they contain. Platelets are composed of two unique types of granules. These are the alpha and the dense granules. The alpha granules contain a variety of hemostatic proteins (coagulation proteins), as well as growth factors, cytokines, chemokines (pro-inflammatory activation-inducible cytokines), and other proteins such as adhesion proteins. Of primary interest to the clinician are the three adhesion molecules and seven growth factors present in the alpha granule. The dense granules contain factors that promote platelet aggregation (ADP, calcium, serotonin). For our purposes the alpha granules are the most important granules. The growth factors present in the alpha granules stimulate mesenchymal stem cells to help produce endothelial, fibroblastic, and osteoblastic components. They also promote the growth and differentiation of chondrocytes, fibroblasts, and osteoblasts. Perhaps the most important thing that the platelet growth factors accomplish is the establishment of a blood supply. Without a blood supply the stem cells themselves will by and large be doomed due to their inability to obtain the necessary growth factors they require. A good analogy is to think of the stem cells as an army that is advancing and the blood supply as its supply lines. In most cases, if the army advances beyond its supply lines it leads to defeat. Figure 1 is a good summation of these growth factors and other aspects of PRP components
PRP IN THE OFFICE SETTING. A PRP graft is made in the office setting with the use of one of several available tabletop centrifugation machines. For the clinician first starting out to do PRP injections, it is best to use one of several companies that produce tabletop machines. Basically, each machine has a separate disposable unit that concentrates platelets in a small amount of plasma, typically 10 ml. The use of tabletop models offers a safe, reliable, and reproducible method of obtaining PRP. They also insure a sterile environment for the PRP. Some companies may loan a centrifuge on the assumption that you will use their separate disposable self-contained units that concentrate the platelets in a small amount of plasma. These units have a one-time use and cost anywhere from $150 to $250. Once injected into the tissue PRP will begin initially with the inflammatory phase, which includes activation of the platelets, release of growth factors, and a myriad of other reactions. The next phase is the proliferative phase. In this phase various types of cells begin to proliferate and subsequently go onto the next phase, which is the remodeling phase. The modeling phase includes tissue repair that starts with the production and breakdown of collagen products. Typically this phase can last for over a year. Are all PRP Preparations the Same?
Sample Injection Therapy Protocol. When performing PRP injections, the amount of blood utilized depends somewhat on the problem that is to be tackled. For instance, when treating an elbow, foot, or hand, approximately 22 ml of whole blood is utilized. For larger applications, such as a shoulder, knee, or hip joint, approximately 60 ml of whole blood will be utilized. Using 22 ml of whole blood typically produces 3 ml of PRP, while 60 ml of whole blood will produce anywhere from 7 to 10 ml of PRP. Once the blood is obtained from the patient it is then necessary to centrifuge the blood to separate the platelets from the other remaining blood products. What we obtain from the disposable units are platelets and leukocytes. The platelets can be found directly above the leukocytes and this is called a buffy coat of centrifuge blood. Since the buffy coat contains elevated levels of leukocytes, the PRP is essentially bactericidal. The only organisms that PRP does not seem to have bactericidal effects on include Klebsiella pneumoniae, Enterococcus and Pseudomonas.3. It is not currently known what the actual optimal concentration of PRP-enhanced growth factors should be. There seems to be a perception among various researchers that a 4 to 6-fold increase in the number of platelets may have a bit more of an anti-inflammatory effect rather than inflammatory. It seems that higher concentrations of platelets seem to push the scale more towards an inflammatory nature, although this may be related to the fact that there may be more white blood cells in the concentrate. However, there are ways of ameliorating any inflammatory effects and these will be discussed. The use of thrombin as a way of producing a gel matrix and releasing growth factors is mentioned many times in the literature. At this point, it is important to note that thrombin is not necessary for the activation of PRP. On the contrary, thrombin may lead to potential complications, such as life-threatening coagulopathies. We have not used thrombin in our clinic for several years and have not seen any change in our results. However, if you do wish to use thrombin, there is a recombinant thrombin on the market and there is also a way to make autogenous thrombin, but that is beyond the scope of this paper. Once the graft is prepared it is then time to place the PRP graft in a proper area. Injections should be given via whatever method the physician feels most comfortable with. Ultrasound guidance or other means of guidance, such as radiographic, palpation, or clinical examination to locate the area of concern, can all be used. However, the most important diagnostic aide is “road testing” the patient. By road testing, we mean giving the patient lidocaine anesthetic in the area of pathology. If you are then able to eliminate the patient’s pain in this area than this is the area we want to inject the PRP into, as it is this area that obviously has the pathology that is causing the patient his symptomatology. We are all too well aware that various scans can show many different findings and only some of these findings are clinically significant. If you road test the patient and eliminate his pain, this is where you put your graft. By using this method you will have very little problems and will have high a success rate. Firstly, Betadine should be used to disinfect the skin and then lidocaine should be used to anesthetize the area. It is important to avoid the use of Marcaine® (bupivacaine) as some studies suggest that Marcaine® could be toxic to the stem cells, furthermore it is known that Marcaine® can be toxic to chondrocytes. The technique for injecting the area of pathology depends on the clinician’s sense of clinical acumen. The actual injection technique depends upon the site involved. For instance, for a joint it is only necessary to place the PRP anywhere into the joint as it will spread to the involved areas on its own. Thus, it is not necessary to use any real guidance to place the PRP for a meniscus tear since the cells will travel throughout the knee. However, for a tendon it is best to inject the PRP into the tendon sheath and then the tendon itself in a peppering fashion. A 23 gauge needle is acceptable to use for this. If we have a musculotendinous junction it is actually a good idea to go many times down to the bone itself. Numerous common musculoskeletal conditions are treated with PRP, these include:
As with any technique, certain patients will not be candidates for PRP injections. Various blood diseases would very much negate the use of PRP injections in patients. The consistent use of nonsteroidal anti-inflammatories (NSAIDs) is somewhat more controversial. A few years ago it was thought to be gospel that patients have to stop taking NSAIDs when undergoing PRP injections. However, after further study and personal communications with Drs. Sherwin Kevy and May Jacobson. Of the CBR Institute for Biomedical Research at Harvard University, I feel that the use of NSAIDs do not seem to make a difference either way. Some theorize that they would perhaps interfere with the release of growth factors, though experience shows that NSAIDS do not appear to have any significant effect on the release and function of growth factors. At present, we restrict the use of NSAIDs for about two days – one day before and one day after the PRP injection. After that they are not a problem. Cortisone injections at the site of treatment or systemic use of cortisone are probably somewhat detrimental to the PRP injection. Active cancers should act as a contraindication for PRP use. Infections especially Pseudomonas, Klebsiella, and Enterococcus should also negate the use of PRP. In summary, PRP injections offer the clinician a new and exciting method of treating many injuries which, until this point, were the realm of the orthopedic surgeon in the operating room. These injections will respond very well for numerous musculoskeletal conditions. Note: It is vital to tell the patient that these injections do take time. The analogy to use with a patient is that PRP injections are very much like renovating a house – it takes time. One final point to remember is that whenever we are carrying out a primary PRP injection, we are typically also using a fat graft (a fat graft is not typically used on a second PRP injection). We feel the fat graft is a source of stem cells and also acts as a scaffold. The preparation of the fat graft is discussed later. STEM CELLS. Stem cells are generally defined as undifferentiated cells that are capable of self-renewal through replication. These are cells that differentiate into specific cell lineages. Adult stem cells are necessary to maintain tissue and organ mass during cellular turnover. There are a number of terms that one needs to know when talking about stem cells. These terms are:
For our purposes there are four types of stem cells that we deal with – embryonic stem cells (ESCs), adult mesenchymal stem cells (MSCs), hematopoietic stem cells (HSCs), and induced pluripotential stem cells (iPSs). Each has its strong and weak points. Embryonic Stem Cells. ESCs are by far the most controversial type of stem cell. The US government has lifted some of its bans on ESCs, but the FDA still significantly restricts their use in people. ESCs seem to present the most potential for correcting and curing certain conditions due to their plasticity or ability to morph into many cell types. In addition to certain ethical issues, ESCs pose a number of scientific reasons why at present they will not be used in mainstream treatment:
Hematopoietic Stem Cells. HSCs are the cells that form blood products, such as white and red blood cells. They help establish a blood supply where there previously had not been one. The principle of establishing a blood supply is very important in stem cell science. Due to their plasticity, HSCs have the ability to turn into other types of stem cells. For our purposes they would turn into MSCs. With HSCs it is best to stimulate their production and let the body deliver them to the involved areas by other methods (PRP and other stem cell injections). HSCs can be obtained by apheresis. However, the equipment needed for apheresis is very expensive and the cost of each procedure is at least $1000, which makes this an impractical procedure for an office-based practice. Furthermore, HSCs are not the best cells for our purposes. Induced Pluripotential Stem Cells. iPS cells are produced from manipulating adult cells into becoming stem cells by enzymatic or viral means. This process works by inducing a “forced” expression of specific genes. iPS cells seem to act in a similar manner to natural pluripotent stem cells. The use of viruses in these cells poses a significant risk since it may trigger oncogenes, however cells treated with certain proteins may not pose this risk. The larger problem with iPS cells is that their telomeres are shortened. Remember, these are adult cells whose telomeres are old and shortened. The best analogy one can use concerns Dolly the cloned sheep. Dolly died of old age at a young age due to telomere shortening. Basically, Dolly's DNA was old. Telomere shortening is probably going to become an important aspect of stem cell science. As we can see in Figure 8, there is a distinct difference between the telomere length of an ESC and an adult stem cell
Although it has not been proven it appears that telomere length may have a direct effect on the plasticity of the stem cell. However, if we can find ways to increase telomere length than we might be able to dramatically ramp up the efficiency of the stem cells to repair problems. Scientists are searching for compounds which stimulate the production of telomerase, the enzyme which places the lost DNA strand back on the chromosome. This research is headed by Dr. William Andrews of Sierra Labs, who is considered to be the pre-eminent telomere expert in the world. Telomeres are an important consideration not just for iPS cells but for all stem cells. Mesenchymal Stem Cells. MSCs are the cells that repair muscle, bone, cartilage, or tendons. MSCs are commonly called adult stem cells. These stem cells are autologous (meaning that they come from the patient) and therefore there is no risk of genetic disease transmission. MSCs are the bodies’ repairmen; acting as construction managers and helping other cells repair and build new tissue. MSCs are the most important cells for our purpose. The good news is that since these cells are the patient’s own, there are minimal risks to the patient. It appears to be within FDA guidelines to use these cells as long as they are put back into the same patient and they are minimally manipulated. There are some studies that suggest that culturing these cells outside the body can diminish their effectiveness. The reason for this might be that the telomeres are affected. Culturing these cells also misses a host of other cells and growth factors that are crucial in the overall repair process, furthermore we are unclear on the FDA’s stance on culturing MSCs, and there is the possibility that the FDA may consider cultured MSCs to be a drug. MSCs are commonly found in the bone marrow, fat cells (especially the lower abdominal fat), circulating blood (not many), and in the joints (very few). In practical terms the stem cells available for an office setting include HSCs, MSCs obtained from bone marrow, and adipose stem cells. Adipose Stem Cells. Adipose stem cells are the richest source of MSCs in the body. The adipose stem cell has the ability to differentiate into chondrocytes, fibroblasts, and other musculoskeletal tissue. They seem to have very similar properties to bone marrow MSCs. The use of fat stem cells is a unique and promising approach and it holds key advantages over stem and regenerative cells from other sources. The abundance of stem cells in adipose tissue and the ability to easily collect large amounts of adipose tissue via liposuction eliminates the need for tissue culturing. Depending on the article one reads, there is anywhere between 500 and 2500-times the number of stem cells in adipose tissue as compared to bone marrow (Fig. 9)
Adipose tissue also contains a number of cytokines, which help regenerate tissue. The major cytokines are:
The current methods of obtaining adipose stem cells are: the Cytori System, the Tissue Genesis system, the simple liposuction technique, and the simple liposuction technique combined with fat stem cell extraction. The Cytori and Tissue Genesis systems have very high costs for the office. The cost of these systems can be several hundred thousand dollars, and the kits that are used on a one-time basis cost upwards of $2500. Another system that has recently come upon the landscape is the Intellicell Biosciences. The advantage of these systems is that they prepare the fat graft and the fat stem cells for direct injection, thus eliminating most of the work for the technician. On the other hand, the simple liposuction technique is simple, cost effective, safe, and requires minimal learning and time investment. The total cost for this system is approximately $10-15. Fat stem cell (SVF) isolation is a process that utilizes cell washings, centrifugation, and enzymatic digestion. This process extracts the stem cells from fat producing 100-150 million stem cells per case. Typically 50 ml of fat will produce 1-2 ml of SVF. The enzyme normally used in this process is collagenase. The technique for liposuction is relatively simple. The first step is to prep the skin with Betadine and then administer a local anesthetic consisting of approximately 3 ml of 1% lidocaine and 3 ml of 1% lidocaine with epinephrine. The second step is to administer anywhere from 20 ml to 80 ml of a solution consisting of 40cc of 1% lidocaine with one amp of epinephrine in 500 ccs of saline. The amount of fluid should correspond to at least the amount of fat that needs to be harvested. The anesthesia then needs about 10-15 minutes to take effect. The next step is to make a small puncture wound in the skin using an 11-blade scalpel. Then a reusable liposuction cannula can be used to slowly aspirate the fat tissue. This needs to be performed by hand, as mechanical aspiration may be too harsh on the cells. Once the fat graft is obtained it is important to allow gravity to separate the various fluids in the graft. Gravity will pull the blood and other fluids to the bottom while the oil from the fat will float to the top. Our interest is in the middle layer of tissue. Better results will be obtained if the graft is free of whole blood, as whole blood seems to have an inhibitory effect on the regenerative process. The technique for fat stem cell extraction is the same as for liposuction, however the fat harvested (50-60 ml) is then subjected to cell washing, enzymatic digestion, and centrifugation. It is important to remember that you also need to have some fat set aside as a fat graft. The amount of fat used as a graft depends upon the joint being treated. Most tendons need no more than 3 ml of fat graft, while rotator cuff tears require 6 ml, and most joints will need 6-9 ml (with the exception of the hip, which usually accommodates only 3-6 ml of fat graft. The fat graft has two purposes, it acts as a scaffold and it supplies some adipose stem cells. Bone Marrow Stem Cells. The technique for obtaining bone marrow stem cells is a simple aspiration technique, much as a hematologist does (Fig. 10). The key to obtaining bone marrow stem cells is to adequately anesthetize the periosteum. This is usually achieved with a combination of Marcaine® and lidocaine. Once the periosteum is adequately anesthetized, a bone marrow aspiration needle is gently introduced through the periosteum, and approximately 60 ml of aspirate is removed. The aspirate then undergoes centrifugation. This will produce 7-10 ml of bone marrow aspirate concentrate (BMAC). It is very important to draw the bone marrow aspirate slowly in order to minimize the amount of blood in the concentrate. In addition, remember that the concentrate also contains PRP. The problem with BMAC is that the numbers of MSCs present dramatically diminishes with age. In a newborn 1 in every 10,000 cells is a stem cell; however by the time a person reaches their 80th birthday just 1 in every 2,000,000 cells is an MSC. Despite this, there are many other factors that make BMAC very important in the regenerative stem cell world
Other Materials and Techniques that Can Affect Stem Cells. Human Growth Hormone. Human growth hormone (HGH) has been successfully used to help grow cartilage in joints. Dunn showed that HGH will cause tissue such as cartilage to grow by injecting it intraarticularly.4 There appears to be little in the way of side effects since this is injected into the joint and the body absorbs very little. The usual dosage of HGH is 0.2 mg. Note: It is vital that you do not use HGH when treating professional athletes. Dexamethasone. Dexamethasone is injected in a dosage of 10 ng. At this low dose the dexamethasone acts as a growth factor. Calcitonin. Calcitonin nasal spray is useful when dealing with any joint problem. The calcitonin helps to stabilize bone lesions under the diseased cartilage. It also seems to help stabilize (and may help promote the growth of) articular cartilage. 5,6. Hyaluronic Acid. Hyaluronic acid seems to enhance the function of stem cells in the joint.7 In this study Saw and Wallin performed a microfracture surgery (arthroscopic surgery where small holes are made in arthritic bone to allow for bleeding). One week after surgery they injected peripheral blood stem cells and 2 ml of hyaluronic acid. This mixture was injected at weekly intervals for five weeks. Biopsy results showed hyaline cartilage regeneration. Dietary Supplements. Supplements are a very important aspect of stem cell treatment. Most of these supplements will contain vitamin D3, carnosine, green tea extract, omega-3 fatty acids, Chlorella, and a host of other compounds. Do not underestimate the power of supplements as they can have potent stimulatory effects on stem cell release from the marrow. Hyperbaric Oxygen. Hyperbaric oxygen seems to mobilize stem cells in the body making them available for repair. Thom showed that hyperbaric oxygen will cause rapid mobilization of stem cell in humans.8 This mobilization is thought to be caused by a nitric oxide (NO)-dependent mechanism. Over a course of 20 treatments the output of CD34+ cells increased 8-fold. It is thought that NO synthesis in the bone marrow triggers the release of an enzyme that mediates stem/progenitor cell release. So, hyperbaric oxygen does its repair work not by providing more oxygen to the tissues but by increasing stem cell output. Supplements that increase NO production may also increase stem cell production. Arginine seems to help NO production, which in turn stimulates stem cell release. Arginine also has a direct effect on the pituitary gland and may help stimulate HGH production. One caution with arginine is that it may also cause a viral release from the body. DC Electrical Stimulation
Photomodulation. Photomodulation seems to work on both PRP and stem cell components of treatment.16 Photo modulation seems to have far ranging effects. Low-level monochromatic lights have been shown to have positive effects on wound healing and pain relief, as well as immunomodulatory and anti-infectious properties. Blue, green, and red light appears to increase the release of NO, which increases stem cell output. Blue light decreases proliferation of cells. Red and yellow light increases cell proliferation. Red light mitigates pain. Blue light has a microbiocidal effect. Photo-activated PRP produces both potent growth factors and the potent anti-inflammatory agent interleukin-1 receptor antagonist (IL-1RA), thus providing us with a PRP injection that has both healing (growth factors) and anti-inflammatory properties. Photo-activated PRP is both PRP and autologous conditioned serum. Autologous conditioned serum is very similar to a German treatment called Orthokine®. This treatment involves incubating blood in glass beads for 24-36 hours, and produces IL-1RA, among other things. At the current time I do not think that this process is allowable in the United States under current FDA guidelines. Monocytes and neutrophils are known to be the main producers of pro-inflammatory cytokines in human blood. Since cytokine content is not restored after the light-induced drop of tumor necrosis factor alpha (TNFα) and interleukin (IL)-6 levels, it is hypothesized that photo modulation blocks the synthesis of the acute phase of pro-inflammatory cytokines and most likely, simultaneously “switches on” in the synthesis of anti-inflammatory cytokines. However, the astonishingly high rate and synchronicity of the “disappearance” of some cytokines from blood plasma and the “appearance” of some others suggests that their level is determined not only by processes of synthesis, but also by some other light-induced events. It is also thought that photomodulation produces beta-endorphins from the WBCs. Another major aspect of photomodulation is the positive effect it has upon stem cell proliferation (Fig.11)
Regenerative Photonic Therapy. Regenerative photonic therapy (RPT)17 is a treatment using special forms of monochromatic lights (including laser) that are applied to damaged (pathological) tissue in a live body in order to accelerate or improve tissue repair or regenerate it to normal condition. These special forms of monochromatic light are called therapeutic optical windows (TOWs). TOWs can improve or reverse to normal various pathological tissue conditions. Several TOWs are used in one therapeutic session to improve underlying tissue pathologies. Among other things, RPT activates cell and tissue metabolism. This activation results in proliferation of cells, increased synthesis of ATP, and increased microcirculation to the area. RPT seems to have a very beneficial effect on the inflammatory phase in the healing cycle as it helps to reduce oxidative stress, increase availability of antioxidants, increase ATP production, and achieve pH balance. When we are describing the "healing cycle" we are including four distinct phases. The first is the coagulation phase. The second is the inflammatory phase. The third is the fibroblastic repair phase, and the fourth is the maturation or remodeling phase. At each phase of tissue repair specific goals are accomplished by key cells, which are controlled by specific cellular messengers. For instance, the inflammatory phase requires substantial ATP; however this may not be readily available in chronic injuries. Injuries often get “stuck” in the inflammatory phase and thus go on to be chronic injuries, but RPT helps to create the proper environment needed to deal with the inflammatory phase and actually speed up its course. RPT helps clean up the cellular debris, thus enabling the body to move on to the fibroblastic or repair phase. When someone has a painful reaction to a PRP or stem cell injection it is often due to the cellular debris and the cytokines or inflammatory factors that are released. RPT reduces the reactive oxygen species (ROS) that cause cell damage, and at the same time helps to increase NO, which helps to increase circulation, stem cell output and a host of other important cellular messengers. The products that RPT produces can be called photoceuticals, as they are compounds that are produced by the effect of light. RPT alone seems to work quite well, however when it is used in combination with PRP and stem cell injections there seems to be some great synergy
Contraindications for Stem Cell Injections. One should avoid using bone marrow stem cells in any type of bone marrow derived cancer such as lymphoma. This is because there may still be some cancer cells lurking in the bone marrow. If the patient has a history of a non-bone marrow derived cancer or has metastatic disease it is vital to check with the patient’s oncologist – even if the patient’s cancer is declared cured. These provisions do not apply when using fat derived stem cells. If the patient has anemia or other blood problems this is a relative contraindication. Also anyone with an infection should probably not be treated with either stem cells or PRP. Another thing that should be avoided is the use of cortisone. This is a relative contraindication. The use of cortisone as an intraarticular injection needs to be avoided. If the patient needs to take cortisone for a medical condition than the stem cell injection may possibly be given. Inactivity needs to be avoided. The body is able to repair itself under duress. There is no need to restrict the patient’s activity. Perhaps for a few days after the injection the patient’s pain may preclude vigorous activity but as the patient recovers activity may be resumed. It should also be mentioned that Plavix® (clopidogrel bisulfate) and Coumadin® (warfarin) are not contraindications for stem cell or PRP injections. Also, as previously stated NSAIDS are probably not a contraindication. CONCLUDING REMARKS: STEM CELLS VERSUS PRP INJECTIONS. Stem cell injections are more important in areas of low oxygen tension. The reason for this is that the bone marrow is an area of low oxygen tension. A severely arthritic joint or disc is also an area of low oxygen tension. Furthermore, areas of low oxygen tension also have limited blood supplies. Stem cells seem to thrive in these areas. However, remember that stem cells need the growth factors from the PRP in order to do their work. The best rule of thumb to follow is that stem cells of some type should be used in a joint while PRP with a fat graft should be done on tendons and similar type of problems. A more difficult question is when to use bone marrow derived stem cells (BMAC) versus fat derived stem cells (SVF). Each has its purpose. BMAC contains many different growth factors, many of which are still not discovered. BMAC does appear to contain insulin-like growth factor (IGF)-1, while SVF does not, hence it is especially important to use HGH with SVF. BMAC probably has the same number of total stem cells but SVF contains many more MSCs. If possible, try to use both SVF and BMAC. If cost truly is a factor then consider using SFV due to the lower cost involved and the number of MSCs produced. I should say that that this is a hunch on my part and I am not able to back it up with hard evidence. Right now in the stem cell world there are two schools of thought as to whether BMAC or SVF is better for regenerative purposes. Speaking from the review of the results in our clinic, the results with SVF, a fat graft, and PRP seem to rival the results with BMAC, PRP, and fat graft. SVF seems to work faster, possibly secondary to the greater number of injected MSCs. The timeframe in which results are seen varies with the patient and the condition treated. Some results can be seen in as little as 2 weeks. Tell your patients to expect a roller-coaster effect. Some patients report that pain can leave as if a light switch were turned off. The results in the clinic exceed 85% “excellent” results after performing thousands of cases for a variety of musculoskeletal conditions. One bit of advice when one is learning is to start out slowly by first performing PRP and fat graft injections, once competency is achieved with PRP techniques then move on to the more involved techniques such as BMAC and SVF. REFERENCES
ABOUT THE AUTHOR
Chapter 20. Hormone Myths Versus Medical Evidence. Ron Rothenberg, M.D
ABSTRACT
INTRODUCTION
HORMONE MYTHS. Myth 1: Thyroid Hormone is Dangerous for the Heart
Myth 2: Testosterone Causes Prostate Cancer to Grow
Myth 3: Testosterone Causes Angry and Aggressive Behavior
Myth 4: Growth Hormone Causes Cancer
Myth 5: Adult Growth Hormone Deficiency is Only Seen in Patients with Severe Multiple Pituitary Deficiencies Since Childhood
Myth 6: Progesterone Treatment is Only for Menopausal Women who Have a Uterus and are Being Treated with Estrogens
Myth 7: Progesterone Equals Progestin
Myth 8: The Many Vitamin D Myths
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 21. Hypothyroidism and Thyroid Optimization. Ron Rothenberg, M.D
ABSTRACT
INTRODUCTION
HYPOTHYROIDISM
Causes of Hypothyroidism
Signs and Symptoms of Hypothyroidism
Diagnosing Hypothyroidism
THYROID OPTIMIZATION. To Combine or Not?
What to Use
Risks Associated with Thyroid Optimization
CONCLUDING REMARKS
REFERENCES
FURTHER READING
ABOUT THE AUTHOR
Chapter 22. Energy Medicine: Role in Control of Pain, Depression, and Aging. C. Norman Shealy, M.D., Ph.D
ABSTRACT
INTRODUCTION
USING ENERGY MEDICINE TO IMPROVE HEALTH
Cranial Electrical Stimulation
GigaTENS
Intracellular Magnesium
Taurine
Telomere Rejuvenation
Reducing Free Radical Production
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 23. The Role Inflammation Plays in Health. Pamela W. Smith, M.D., MPH
ABSTRACT
INTRODUCTION
INFLAMMATION AND HEALTH. The Basics of Inflammation and Inflammatory Disease
What Causes Inflammation?
Inflammation is a Whole-Body Issue
Inflammation and Vitamin D
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
Chapter 24. Fingertip Regeneration: Integrating Stem Cell Activation Therapy into Fingertip Regenerative Medicine. Pramod Vora, B.S
ABSTRACT
INTRODUCTION
POST-AMPUTATION FINGERTIP REGENERATION
Case Study 1: Fingertip Regeneration with Nano Silver Induced Stem Cell Activation
FINGERTIP REGENERATION IN ADULTS
Old Injured Fingertips Covered With a Skin Flap. Prior to the Research of Dr. Robert O. Becker
New Insights into Improving Fingertip Regeneration
Case Study 2: Adult Fingertip Regeneration with Stem Cell Activation Therapy
Case Study 3: Regeneration of Fingertip with Full Skin Coverage
SUMMARY
CONCLUDING REMARKS
REFERENCES
FOR FURTHER INFORMATION
ABOUT THE AUTHOR
Protocol Chapter 1. Nitric Oxide Protocol for Patients. Nathan S. Bryan, Ph.D
ABSTRACT
ASSESSMENT
TREATMENT
ABOUT THE AUTHOR
Protocol Chapter 2. Protocol for the Use of Curcumin Gel to Enhance Repair of Burns and Photo-aged Skin. Madalene C.Y. Heng M.D., FRACP, FACD, FAAD
INTRODUCTION
SUGGESTED PROTOCOLS. Initial Assessment. Burns and Scalds
Photodamaged Skin
Biopsies and Excisions
Photography
Curcumin Gel Therapy. Burns and Scalds
Photodamaged Skin
ABOUT THE AUTHOR
Protocol Chapter 3. Provocative Testing and Detoxification Protocols for Toxic Metals. L. Charles Masur, M.D
INTRODUCTION
Chelation
Provocation Testing
Assessment of Renal Function
Adverse Reactions
Comprehensive Laboratory Analysis
Treatment Protocols
Informed Consent
TESTING WITH PROVOCATIVE AGENTS. Patient Preparation Prior to Provocative Testing
Pre-Provocative Urine Testing
Post-Provocative Urine Testing
The Importance of Combined Pre- and Post-Provocative Testing
Relative Affinities of Chelating/Complexing Agents for Various Metals
DMSA Protocols for Provocation and Detoxification/Treatment
DMSA Provocation Protocol (DMSA Challenge Testing)
Metal Detoxification Protocol Using DMSA
DMPS Protocols for Provocation and Detoxification/Treatment
ORAL DMPS Provocation Protocol (Oral DMPS Challenge Testing)
Intravenous DMPS Provocation Protocol (IV DMPS Challenge Testing)
Oral Metal Detoxification Protocol Using DMPS
Intravenous Metal Detoxification Protocol Using DMPS
Ca-Na2-EDTA Protocols for Provocation and Detoxification/Treatment
Ca-Na2-IV EDTA Provocation Protocol (IV Ca-Na2-EDTA Challenge Testing)
Intravenous Ca-Na2-EDTA Treatment Protocol
CONCLUDING REMARKS
REFERENCES
ABOUT THE AUTHOR
* Denotes speaker at Spring 2011 Session of the Annual World Congress on Anti-Aging Medicine & Regenerative Biomedical Technologies;
** Denotes speaker at Winter 2011 Session.
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Dr. Nathan Bryan is an Assistant Professor of Molecular Medicine within the Brown Foundation Institute of Molecular Medicine, part of the School of Medicine at the University of Texas Health Science Center at Houston (Texas, USA). He is also on faculty within the Department of Integrative Biology and Pharmacology and Graduate School of Biomedical Sciences at the University of Texas Houston Medical School. Dr. Bryan is an active member of the Nitric Oxide Society, Society for Free Radical Biology and Medicine, and numerous other organizations.
We find that men are much more conscious of achieving substantial benefits than women are, so in my practice it is common to given generous doses to men and then titrate back down if needed, for example if metabolite levels (E2 and DHT) become elevated, or if the patient start to experience aggressiveness, severe acne, or prostate symptoms. However, this is very uncommon.
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