StemCell Therapy

Cell potency is a cell's ability to differentiate into other cell types[1][2][3] The more cell types a cell can differentiate into, the greater its potency. Potency is also described as the gene activation potential within a cell which like a continuum begins with totipotency to designate a cell with the most differentiation potential, pluripotency, multipotency, oligopotency and finally unipotency.

Totipotency (Lat. totipotentia, "ability for all [things]") is the ability of a single cell to divide and produce all of the differentiated cells in an organism. Spores and zygotes are examples of totipotent cells.[4] In the spectrum of cell potency, totipotency is a form of pluripotency that represents the cell with the greatest differentiation potential.

It is possible for a fully differentiated cell to return to a state of totipotency.[5] This conversion to totipotency is complex, not fully understood and the subject of recent research. Research in 2011 has shown that cells may differentiate not into a fully totipotent cell, but instead into a "complex cellular variation" of totipotency.[6] Stem cells resembling totipotent blastomeres from 2-cell stage embryos can arise spontaneously in mouse embryonic stem cell cultures[7][8] and also can be induced to arise more frequently in vitro through down-regulation of the chromatin assembly activity of CAF-1.[9]

The human development model is one which can be used to describe how totipotent cells arise.[10] Human development begins when a sperm fertilizes an egg and the resulting fertilized egg creates a single totipotent cell, a zygote.[11] In the first hours after fertilization, this zygote divides into identical totipotent cells, which can later develop into any of the three germ layers of a human (endoderm, mesoderm, or ectoderm), or into cells of the placenta (cytotrophoblast or syncytiotrophoblast). After reaching a 16-cell stage, the totipotent cells of the morula differentiate into cells that will eventually become either the blastocyst's Inner cell mass or the outer trophoblasts. Approximately four days after fertilization and after several cycles of cell division, these totipotent cells begin to specialize. The inner cell mass, the source of embryonic stem cells, becomes pluripotent.

Research on Caenorhabditis elegans suggests that multiple mechanisms including RNA regulation may play a role in maintaining totipotency at different stages of development in some species.[12] Work with zebrafish and mammals suggest a further interplay between miRNA and RNA-binding proteins (RBPs) in determining development differences.[13]

In cell biology, pluripotency (Lat. pluripotentia, "ability for many [things]")[14] refers to a stem cell that has the potential to differentiate into any of the three germ layers: endoderm (interior stomach lining, gastrointestinal tract, the lungs), mesoderm (muscle, bone, blood, urogenital), or ectoderm (epidermal tissues and nervous system).[15] However, cell pluripotency is a continuum, ranging from the completely pluripotent (or totipotent) cell that can form every cell of the embryo proper, e.g., embryonic stem cells and iPSCs (see below), to the incompletely or partially pluripotent cell that can form cells of all three germ layers but that may not exhibit all the characteristics of completely pluripotent cells.

Induced pluripotent stem cells, commonly abbreviated as iPS cells or iPSCs, are a type of pluripotent stem cell artificially derived from a non-pluripotent cell, typically an adult somatic cell, by inducing a "forced" expression of certain genes and transcription factors.[16] These transcription factors play a key role in determining the state of these cells and also highlights the fact that these somatic cells do preserve the same genetic information as early embryonic cells.[17] The ability to induce cells into a pluripotent state was initially pioneered in 2006 using mouse fibroblasts and four transcription factors, Oct4, Sox2, Klf4 and c-Myc;[18] this technique, called reprogramming, earned Shinya Yamanaka and John Gurdon the Nobel Prize in Physiology or Medicine 2012.[19] This was then followed in 2007 by the successful induction of human iPSCs derived from human dermal fibroblasts using methods similar to those used for the induction of mouse cells.[20] These induced cells exhibit similar traits to those of embryonic stem cells (ESCs) but do not require the use of embryos. Some of the similarities between ESCs and iPSCs include pluripotency, morphology, self-renewal ability, a trait that implies that they can divide and replicate indefinitely, and gene expression.[21]

Epigenetic factors are also thought to be involved in the actual reprogramming of somatic cells in order to induce pluripotency. It has been theorized that certain epigenetic factors might actually work to clear the original somatic epigenetic marks in order to acquire the new epigenetic marks that are part of achieving a pluripotent state. Chromatin is also reorganized in iPSCs and becomes like that found in ESCs in that it is less condensed and therefore more accessible. Euchromatin modifications are also common which is also consistent with the state of euchromatin found in ESCs.[21]

Due to their great similarity to ESCs, iPSCs have been of great interest to the medical and research community. iPSCs could potentially have the same therapeutic implications and applications as ESCs but without the controversial use of embryos in the process, a topic of great bioethical debate. In fact, the induced pluripotency of somatic cells into undifferentiated iPS cells was originally hailed as the end of the controversial use of embryonic stem cells. However, iPSCs were found to be potentially tumorigenic, and, despite advances,[16] were never approved for clinical stage research in the United States. Setbacks such as low replication rates and early senescence have also been encountered when making iPSCs,[22] hindering their use as ESCs replacements.

Additionally, it has been determined that the somatic expression of combined transcription factors can directly induce other defined somatic cell fates (transdifferentiation); researchers identified three neural-lineage-specific transcription factors that could directly convert mouse fibroblasts (skin cells) into fully functional neurons.[23] This result challenges the terminal nature of cellular differentiation and the integrity of lineage commitment; and implies that with the proper tools, all cells are totipotent and may form all kinds of tissue.

Some of the possible medical and therapeutic uses for iPSCs derived from patients include their use in cell and tissue transplants without the risk of rejection that is commonly encountered. iPSCs can potentially replace animal models unsuitable as well as in vitro models used for disease research.[24]

Recent findings with respect to epiblasts before and after implantation have produced proposals for classifying pluripotency into two distinct phases: "naive" and "primed".[25] The baseline stem cells commonly used in science that are referred as Embryonic stem cells (ESCs) are derived from a pre-implantation epiblast; such epiblast is able to generate the entire fetus, and one epiblast cell is able to contribute to all cell lineages if injected into another blastocyst. On the other hand, several marked differences can be observed between the pre- and post-implantation epiblasts, such as their difference in morphology, in which the epiblast after implantation changes its morphology into a cup-like shape called the "egg cylinder" as well as chromosomal alteration in which one of the X-chromosomes undergoes random inactivation in the early stage of the egg cylinder, known as X-inactivation.[26] During this development, the egg cylinder epiblast cells are systematically targeted by Fibroblast growth factors, Wnt signaling, and other inductive factors via the surrounding yolk sac and the trophoblast tissue,[27] such that they become instructively specific according to the spatial organization.[28] Another major difference that was observed, with respect to cell potency, is that post-implantation epiblast stem cells are unable to contribute to blastocyst chimeras,[29] which distinguishes them from other known pluripotent stem cells. Cell lines derived from such post-implantation epiblasts are referred to as epiblast-derived stem cells which were first derived in laboratory in 2007; despite their nomenclature, that both ESCs and EpiSCs are derived from epiblasts, just at difference phases of development, and that pluripotency is still intact in the post-implantation epiblast, as demonstrated by the conserved expression of Nanog, Fut4, and Oct-4 in EpiSCs,[30] until somitogenesis and can be reversed midway through induced expression of Oct-4.[31]

Multipotency describes progenitor cells which have the gene activation potential to differentiate into discrete cell types. For example, a multipotent blood stem cell and this cell type can differentiate itself into several types of blood cell types like lymphocytes, monocytes, neutrophils, etc., but it is still ambiguous whether HSC possess the ability to differente into brain cells, bone cells or other non-blood cell types.[citation needed]

New research related to multipotent cells suggests that multipotent cells may be capable of conversion into unrelated cell types. In another case, human umbilical cord blood stem cells were converted into human neurons.[32] Research is also focusing on converting multipotent cells into pluripotent cells.[33]

Multipotent cells are found in many, but not all human cell types. Multipotent cells have been found in cord blood,[34] adipose tissue,[35] cardiac cells,[36] bone marrow, and mesenchymal stem cells (MSCs) which are found in the third molar.[37]

MSCs may prove to be a valuable source for stem cells from molars at 810 years of age, before adult dental calcification. MSCs can differentiate into osteoblasts, chondrocytes, and adipocytes.[38]

In biology, oligopotency is the ability of progenitor cells to differentiate into a few cell types. It is a degree of potency. Examples of oligopotent stem cells are the lymphoid or myeloid stem cells.[2] A lymphoid cell specifically, can give rise to various blood cells such as B and T cells, however, not to a different blood cell type like a red blood cell.[39] Examples of progenitor cells are vascular stem cells that have the capacity to become both endothelial or smooth muscle cells.

In cell biology, a unipotent cell is the concept that one stem cell has the capacity to differentiate into only one cell type. It is currently unclear if true unipotent stem cells exist. Hepatoblasts, which differentiate into hepatocytes (which constitute most of the liver) or cholangiocytes (epithelial cells of the bile duct), are bipotent.[40] A close synonym for unipotent cell is precursor cell.

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Cell potency - Wikipedia

Stem cells are the foundation for every organ and tissue in your body. There are many different types of stem cells that come from different places in the body or are formed at different times in our lives. These include embryonic stem cells that exist only at the earliest stages of development and various types of tissue-specific (or adult) stem cells that appear during fetal development and remain in our bodies throughout life.

All stem cells can self-renew (make copies of themselves) and differentiate (develop into more specialized cells). Beyond these two critical abilities, though, stem cells vary widely in what they can and cannot do and in the circumstances under which they can and cannot do certain things. This is one of the reasons researchers use all types of stem cells in their investigations.

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Embryonic stem cells are obtained from the inner cell mass of the blastocyst, a mainly hollow ball of cells that, in the human, forms three to five days after an egg cell is fertilized by a sperm. A human blastocyst is about the size of the dot above this i.

In normal development, the cells inside the inner cell mass will give rise to the more specialized cells that give rise to the entire bodyall of our tissues and organs. However, when scientists extract the inner cell mass and grow these cells in special laboratory conditions, they retain the properties of embryonic stem cells.

Embryonic stem cells are pluripotent, meaning they can give rise to every cell type in the fully formed body, but not the placenta and umbilical cord. These cells are incredibly valuable because they provide a renewable resource for studying normal development and disease, and for testing drugs and other therapies. Human embryonic stem cells have been derived primarily from blastocysts created by in vitro fertilization (IVF) for assisted reproduction that were no longer needed.

Tissue-specific stem cells (also referred to as somatic or adult stem cells) are more specialized than embryonic stem cells. Typically, these stem cells can generate different cell types for the specific tissue or organ in which they live.

For example, blood-forming (or hematopoietic) stem cells in the bone marrow can give rise to red blood cells, white blood cells and platelets. However, blood-forming stem cells dont generate liver or lung or brain cells, and stem cells in other tissues and organs dont generate red or white blood cells or platelets.

Some tissues and organs within your body contain small caches of tissue-specific stem cells whose job it is to replace cells from that tissue that are lost in normal day-to-day living or in injury, such as those in your skin, blood, and the lining of your gut.

Tissue-specific stem cells can be difficult to find in the human body, and they dont seem to self-renew in culture as easily as embryonic stem cells do. However, study of these cells has increased our general knowledge about normal development, what changes in aging, and what happens with injury and disease.

You may hear the term mesenchymal stem cell or MSC to refer to cells isolated from stroma, the connective tissue that surrounds other tissues and organs. Cells by this name are more accurately called stromal cells by many scientists. The first MSCs were discovered in the bone marrow and were shown to be capable of making bone, cartilage and fat cells. Since then, they have been grown from other tissues, such as fat and cord blood. Various MSCs are thought to have stem cell, and even immunomodulatory, properties and are being tested as treatments for a great many disorders, but there is little evidence to date that they are beneficial. Scientists do not fully understand whether these cells are actually stem cells or what types of cells they are capable of generating. They do agree that not all MSCs are the same, and that their characteristics depend on where in the body they come from and how they are isolated and grown.

Induced pluripotent stem (iPS) cells are cells that have been engineered in the lab by converting tissue-specific cells, such as skin cells, into cells that behave like embryonic stem cells. IPS cells are critical tools to help scientists learn more about normal development and disease onset and progression, and they are also useful for developing and testing new drugs and therapies.

While iPS cells share many of the same characteristics of embryonic stem cells, including the ability to give rise to all the cell types in the body, they arent exactly the same. Scientists are exploring what these differences are and what they mean. For one thing, the first iPS cells were produced by using viruses to insert extra copies of genes into tissue-specific cells. Researchers are experimenting with many alternative ways to create iPS cells so that they can ultimately be used as a source of cells or tissues for medical treatments.

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Types of Stem Cells

What Are Stem Cells?

They are cells that maintain a state of open-mindedness thoughout the life of the individual from fetal life senescence, to enable them to participate in repair, replacement and regeneration of the tissue they happen to be in, in addition to affecting tissues in other parts of the body by migration and by producing growth factors and cytokines. They are regarded as undifferentiated and are found in different tissues of the body, throughout life. The early fetal stem cells are pluripotent with a vast potential; while non-embryonic adult mesenchymal stem cells are multipotent. This means they are less versatile than those of the fetus, but non-the-less can turn into several different kinds of cells within any tissue type.

Undifferentiated, non-embryonic adult mesenchymal stem cells are found everywhere in the body, in all tissues, but especially infat tissue, bone marrow and blood- in that order. The stem cells found in blood and bone marrow are hematopoietic stem cells because, under normal circumstances, they are destined to form red blood cells (RBCs), white blood cells (WBCs), and platelets; and those stem cells that are found in fat (adipose) tissue, among fat cells, are called adipose stem cells.

GCSC&RMC uses adipose stem cells because they are approximately 2,500 times as abundant as hematopoietic stem cells, per a given mass of tissue. Furthermore, no organs are hurt or disturbed in the process of harvesting adipose tissue, which only requires local anesthesia.

Stem cells have the potential to repair human tissue and certain internal organs by forming new cells and producing substances to regenerate cartilage, bone, ligaments, tendons, nerve, fat, muscle, and blood vessels. Stem cells are being investigated and researched as an innovative therapy option for more than 70 major diseases and conditions that affect millions of people worldwide. These include diabetes mellitus, Parkinsons, Alzheimers, multiple sclerosis, ALS (Lou Gehrigs Disease), spinal cord injuries, various eye conditions, and HIV/AIDS.

Gulf Coast Stem Cell & RMC has a specific SVF harvest and injection protocol. First, a couple of ounces of fat are harvested from the love handle areas of the back, under surgically sterile conditions and local anesthesia, by minimally-invasive mini-liposuction. This procedure lasts a mere 20 minutes; and this small amount of fat yields millions of stem cells (at least half a million per ml of fat). In fact, it is possible to obtain well over 50 million cells from a single harvest.

After the cells are harvested, the stem cells are separated from the fat cells and are ready for deployment within 90 minutes or less from harvest. They can then be injected into a vein to reach wider targets throughout the entire body, and directly into target areas likethe spinal space, joints and specific tissues.

Stem cell therapy is a minimally invasive, low-risk option that may help patients who suffer from the daily discomforts of orthopedic conditions such as osteoarthritis, rheumatoid arthritis, sports-related injuries, spine disease, and general problems with shoulders, elbows, hands/wrists, hips, knees, or ankles. Research indicates that most orthopedic issues are fundamentally caused by inflammatory, autoimmune, or degenerative processes. Stem cells have the potential to reduce discomfort by decreasing inflammation, modulating autoimmunity, and repairing or replacing bone, tendons, and ligaments that have deteriorated due to injury or a degenerative joint disease. This investigational therapy could benefit the near 350 million people worldwide who are afflicted by arthritis, about 50 million of whom live in the United States, including over a quarter million children.

Over one billion people worldwide suffer from neurological diseases. In universities and medical research centers around the world, stem cells are being explored for their regenerative potential. We at GCSC&RMC have research protocols for many neurological conditions, including multiple sclerosis, peripheral neuropathy, Parkinsons disease, muscular dystrophy, spinal cord injuries, and more. Beyond their ability to become different kinds of cells, stem cells are able to cross the blood-brain barrier, aided by hygroscopic molecules like Mannitol. This potential for transmigration, or crossing the barrier, means that stem cells can reach broader areas of brain tissue that have been affected by injuries or degenerative diseases. This has been shown to be the case in a rat model. Subtle differences in brain function can affect mood, balance, thought processes, and other areas that have significant impacts on a patients overall quality of life.

Cardiac disease is the most common killer in the United States. Every day, 2,200 people die from cardiovascular diseasesthats 1 in every 3 deaths. Stem cell therapy has the potential to help with cardiac and pulmonary conditions such as a heart attacks, myocardial infarctions, congestive heart failure, ischemic heart disease, COPD, and pulmonary fibrosis. The purpose of our researchprotocols is to target inflammation, reducing it; regenerating cells lost in cardiac ischemia, replacing damaged or diseased heart-muscle cells, and promoting the development of new coronary artery branches. The latter can be effected throughthe production of substances like the angiogenesis factor. When an intravenous dose of SVF or stem cells is given, the infused molecules and cells pass through the heart to the vastcapillary network of the lungs, where a significant proportion of the cells stay. There they participate in various repair processes, which, according to published results and our own, often improve gaseous exchange and may result clinical improvement.

Autoimmune diseases happen when the bodys immune system turns against itself and starts mistakenly attacking healthy cells. Many disease processes are considered autoimmune, and many of those conditions have shown response to research protocols using stem cell therapy, including lupus, hepatitis, Crohns disease, rheumatoid arthritis, scleroderma, myasthenia neuropathy, CIDP, and ulcerative colitis. Deploying stem cells in these diseases may reduce inflammation of affected organs and tissues, regenerate damaged cells and tissue, and help modulate the immune response by possibly block compliment reactions.

Intersticial Cystitis (IC) and Lichen Sclerosis are among the most distressing, chronic conditions that can afflict women and men, although they are much commoner in women. There are anestimated 108 million peoplesuffering from lichen sclerosis around the world. When women are afflicted, the labia may fuse together, adding to the distress. Our research findings, as well as those of others in our group (CSN), indicate that SVF deployment mayhelp both women and men who suffer with those conditions. Furthermore, according to our research findings, patients who had local injections of filtered fat (nanofat) into the labia and surrounding skin, in addition to the SVF appeared to have better outcomes. Clearly, in those who benefit the stem cells as well as growth factors and cytokines re-direct the atrophic, inflammatory process towards healing and resolution.

Erectile Dysfunction may be a very distressing entity to those afflicted and the condition afflictsapproximately 50% of men over 40, to some degree. Naturally the causes may be multifactorial, but research results indicate that combining pressure wave therapy with SVF may result in significant improvement in over 60-70% of men. In those who benefit, stem cells may have the potential to stimulate the growth of the smooth muscle lining of vessels and improve endothelial function, repair and rejuvenate damaged and effete cells and boost blood flow to erectile tissues.

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The Healing Power of Stem Cells - Gulf Coast Stem Cell Center

What is a rheumatologist, and what specialties of doctors treat arthritis?

A rheumatologist is a medical doctor who specializes in the nonsurgical treatment of rheumatic illnesses, especially arthritis.

Rheumatologists have special interests in unexplained rash, fever, arthritis, anemia, weakness, weight loss, fatigue, joint or muscle pain, autoimmune disease, and anorexia. They often serve as consultants, acting like medical detectives at the request of other doctors.

Rheumatologists have particular skills in the evaluation of the over 100 forms of arthritis and have special interests in inflammatory arthritis such as rheumatoid arthritis, seronegative arthritis, spondylitis, psoriatic arthritis, systemic lupus erythematosus, antiphospholipid syndrome, Still's disease, dermatomyositis, Sjgren's syndrome, vasculitis, scleroderma, mixed connective tissue disease, sarcoidosis, Lyme disease, osteomyelitis, osteoarthritis, back pain, gout, pseudogout, relapsing polychondritis, Henoch-Schnlein purpura, serum sickness, reactive arthritis, Kawasaki disease, fibromyalgia, erythromelalgia, Raynaud's disease, growing pains, iritis, osteoporosis, reflex sympathetic dystrophy, and others.

Classical adult rheumatology training includes four years of medical school, one year of internship in internal medicine, two years of internal-medicine residency, and two years of rheumatology fellowship. There is a subspecialty board for rheumatology certification, offered by the American Board of Internal Medicine, which can provide board certification to approved rheumatologists.

Pediatric rheumatologists are physicians who specialize in providing comprehensive care to children (as well as their families) with rheumatic diseases, especially arthritis.

Pediatric rheumatologists are pediatricians who have completed an additional two to three years of specialized training in pediatric rheumatology and are usually board-certified in pediatric rheumatology.

Other doctors who treat arthritis include pediatricians, internists, general-medicine doctors, family medicine doctors, and orthopedic surgeons.

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Arthritis Causes, Treatment & Types

Our Cell Therapy Center offers advanced patented methods of stem cell treatment for different diseases and conditions. The fetal stem cells we use have the highest potential for differentiation into other cell types and are not rejected by the recipients body read more...

Stem cell therapy has proven to be effective for tissue restoration, and integrated care for the incurable and obstinate diseases. We treat patients with diabetes mellitus, multiple sclerosis, Parkinsons disease, Duchenne muscular dystrophy, joint and autoimmune diseases, and other diseases and conditions. We also offer innovative anti-aging programs. Stem cell treatment allows for achieving effects that are far beyond the capacity of any other modern method read more...

For over 23 years, we have performed more than 9,400 transplantations of fetal stem cells to people from many countries, such as China, the USA, Saudi Arabia, UAE, Egypt, Great Britain, etc. Our stem cell treatments helped to prolong life and improve life quality to thousands of patients including those suffering from the incurable diseases who lost any hope for recovery.

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Stem Cell Therapy & Stem Cell Treatment - Cell Therapy Center ...

If chronic joint pain is limiting your daily routine or preventing you from activities you enjoy; regenerative medicinemay be the answer youve been looking for!

The pharmaceutical approach to these conditions is still not effective for some 20% to 40% of those suffering from arthritis or other degenerative joint conditions. According to the National Institute of Health, Stem Cell Therapy provides a promising alternative to surgery by promoting safe and natural healing. The less invasive approach Stem Cell Therapy offers attracts thousands each year.Texas Spine and Sports Therapy Center is one of the few clinics in the country to offer Stem Cell Therapy. With convenient locations nearAustin, we are ready to get you back to the activity levels you desire.

Stem cells are found in all of us and play a key role in the bodys healing process. They lie latent in your body until they receive signals that the body has suffered an injury and then they follow your platelets to the injured site. Stem cells are able to transform into the same type of cell that was injured to promote healing. They are tasked to heal injured ligaments, tendons, tissues and bones. After an injury, or as a natural result of aging, the amount of stem cells needed in certain areas of the body declines. Stem Cell Therapy solves this problem by delivering a high concentration of stem cells into the injured area promoting natural healing.

The Stem Cell Therapy procedure is simple and takes just 15 minutes with pain relief in 24-48 hours. The therapy can be performed right in the Texas Spine and Sports Therapy Centeroffice and provides pain relief without the risks of surgery, general anesthesia, hospital stays or prolonged recovery. There is zero recovery time after Stem Cell Therapy. Most experience complete joint restoration of ligaments, tendons and cartilage in 28 days. Stem Cell Therapy is very safe and effective. The injections have been used over 10,000 times in the United States with no reported adverse side effects and have a 100% safety record in Europe with 100,000s of patients.

Stem cell treatment takes advantage of the bodys ability to repair itself. With Stem Cell Therapy, your Texas Spine and Sports Therapy CenterProvider will inject stem cells into your body. Similar to cortisone and steroid shots, stem-cell injections have anti-inflammatory properties, but offer far more benefits than those of standard injection therapies. While cortisone and other drugs only provide temporary pain relief, stem cells actually restore degenerated tissue while providing pain relief. The growth factors in Stem Cells may replace damaged cells in your body. Additionally, stem cell injections contain hyaluronic acid, which lubricates joints and tendons, easing the pain and helping restore mobility.

The Stem Cells can turn into any type of tissue found in joints other than nerve tissue. Depending on the different tissues that are damaged, the stem cells can turn into whatever your joint needs which can quite often be a combination of cartilage, ligament, tendon, bone or muscle. This is a curative treatment. You can literally grow new joints tissue. Once your joint is healed, it is healed. The oldest research to date shows that 100% of recipients who benefited from stem cell therapy were still pain free 4 years later. Stem Cell Therapy allows our state-of-the-art clinics across the Texas Hill Countryto treat and rehabilitate your pain and injuries without drugs or surgery.

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Stem Cell Therapy for Joints & Spine in Austin Texas

The Integrative Medicine Department at Highlands Hospital combines evidence-based complementary and alternative medicine with traditional or western medicine. Integrative Medicine thus refers to the synergistic blending of these two distinct types of care providing a more holistic approach to healing.

Integrative Medicine therapies are based on the bodys innate ability to heal itself. The focus is on the whole person- physical, emotional social and spiritual. Integrative Medicine involves nurturing touch, sensitive listening, comforting environment and social networking.

A partnership between patient/client and practitioner is essential to the healing process. We are the coach and facilitator but the driving force to heal comes from the heart of each individual. Integrative Medicine empowers each person with the skills to be in charge of his/her own health care.

The program at Highlands Hospital is designed to be gentle yet powerful using learned techniques to deal with stress and negative emotions. A few of the modalities that we use are breathing techniques, progressive relaxation and guided imagery, bio-energy techniques, HealthRHYTHMS drumming and music therapy.

Highlands Hospital is pleased to welcome Jeanne Brinker RN BSN as an Integrative Medicine Healing Arts Practitioner to oversee the program. Jeanne is a consultant and pioneer in Integrative Medicine with 20 years of holistic health care experience in hospital and community environments. She was the former director of Integrative Medicine at Windber Medical Center. In that capacity, she has worked to bring complementary and alternative (CAM) to diverse patient populations from prenatal care, newborns and their families, pre and post-surgical care, critical and cardiac care, cancer survivors, hospice and palliative care, grief and loss support for families, incarcerated young adults and healthy teens, adults and seniors.

Westmoreland Guide to Good Health Brochure Winter 2017 Issue (PDF)

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Highlands Hospital Integrative Medicine

UCHealth offers physician-managed care that emphasizes the wellness and healing of the entire person.

Integrative medicine is the blending of Complementary and Alternative Medicine (CAM) therapies with conventional care for the prevention and treatment of health conditions and the pursuit of wellness.

This melding of traditional medical care with the centuries-old healing arts can help decrease stress, strengthen the immune system, reduce pain, and speed recovery.

Our holistic approach treats each patient for balance and wellness of the mind, body, and spirit. Services are customized for your unique needs.

We believe that wellness is not defined by the presenceor absenceof disease. Rather, wellness is the pursuit of the best quality of life in your present circumstances regardless of your medical condition.

Whether youre fighting a disease, recovering from a disease, or striving to maintain good health, we can help you achieve optimal well-being.

Conditions that benefit from integrative medicine

Integrative medicine services & therapies

Our integrative medicine team collaborates with each other, your other healthcare providers at UCHealth, and any outside providers to help you get the most from the integration of CAM and conventional care.

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Integrative Medicine | Fort Collins, Denver & Colorado Springs

New Integrative Medicine Clinic at Wake Forest Baptist Health

We are pleased to announce that Wake Forest Baptist Health now offers patients integrative medicine services. At this new clinic, physicians and healerswork side by side to provide collaborative services to address diverse health conditions. We partner with patients of all ages to provide whole person, preventative care to improve overall health and wellbeing. Physicians with specialty training in integrative medicine, internal medicine, family medicine, neurology, pain management, pediatrics, and physical medicine and rehabilitation collaborate with professionals providing acupuncture, psychology, nutrition and integrative energy therapies in an effort to provide patients with comprehensive, evidence based care.

Our services are commonly used to help treat a variety of health conditions, including acute or chronic pain, menopausal-related symptoms, allergies, gastrointestinal symptoms, anxiety, and fatigue, just to name a few. Our Integrative Medicine specialists can help determine if our services are right for your specific health condition.

With more than 30 years of experience in both conventional and integrative medicine, Dr. Greenfield graduated from the Program in Integrative Medicine at the University of Arizonas College of Medicine and was one of the first four physicians to train there under Andrew Weil, MD.He has worked with Harris Teeter as a consultant on its yourwellness initiative, and helped forward Integrative Medicine within the VA nationally in service to veterans and their families. Prior to joining Wake Forest Baptist Health, Dr. Greenfield treated patients through Greenfield Integrative Healthcare, his own integrative healthcare consultancy.Dr. Greenfield is Board Certified in Emergency Medicine, earned his medical degree from the Chicago Medical School, and completed his residency and fellowship training in emergency medicine at Harbor/UCLA Medical Center.

Learn more about Dr. Greenfield | Request an Appointment with Dr. Greenfield

Dr. Coeytaux serves as the Director of the Center for Integrative Medicine, the Caryl J Guth, MD Chair in Integrative Medicine, and Professor of Family and Community Medicine. He is a family physician and clinical epidemiologist with experience both as a clinical scientist and administrator, and before joining us full-time, served as Associate Professor of Community and Family Medicine at Duke University and a faculty member of the Duke Clinical Research Institute.Dr. Coeytaux received his AB from Brown University, his MD from Stanford University, and his PhD in Epidemiology from the UNC Gillings School of Global Public Health. He is a former Robert Wood Johnson Clinical Scholar and Bravewell Collaborative Integrative Medicine Fellow.

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Wunian Chen is licensed by the National Certification Commission for Acupuncture and Oriental Medicine (NCCAOM) to offer acupuncture and Oriental medicine services. He has 30 years of experience delivering acupuncture treatments and helping patients use Chinese herbal treatments to improve their health.While studying acupuncture at the Hubei College of Traditional Chinese Medicine, Dr. Chen studied the principles of both Chinese and Western medicine. He graduated in 1983 with the equivalent of a U.S. medical degree. Since then, he has worked with patients to address a variety of conditions both in China and here in the United States. Dr. Chen uses acupuncture to help people with high blood pressure, back pain, depression, joint pain, fibromyalgia, hot flashes, fatigue, and headaches.

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Deborah Larrimore is a nurse educator who specializes in integrative energy therapies. She provides Healing Touch services and strives to understand healing and how we can affect the process of disease. Deborah focuses her teachings on the sacredness of life and is dedicated to the idea that we can improve lives simply through the act of caring, while partnering with patients to help them discover their own path to wholeness.Deborah is a registered nurse, a licensed Massage and Bodywork Therapist, a Certified Healing Touch Practitioner and a Certified Healing Touch Instructor. She received her BSN from East Carolina University, and served for 15 years as a critical care nurse in intensive care at Wake Forest University Baptist Medical Center. Following that, she spent four years as a Nurse Educator for Hospice of Winston-Salem/Forsyth County. In her role as a Certified Healing Touch Instructor, she has locally, nationally and internationally taught many health care professionals the art of Healing Touch. Deborah has remained affiliated with Wake Forest Baptist Health for over 40 years and launched a former volunteer-based Healing Touch Consult Service for patients of the Medical Center.

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Vanessa Baute is an integrative neurologist and Assistant Professor of Neurology and Director of Education with the Center for Integrative Medicine at Wake Forest Baptist Health. She enjoys partnering with patients to promote their healing and manages a variety of neurologic conditions such as peripheral neuropathy and headache. She has a specific interest in the role of nutrition on neurohealth and has led seminars regionally and nationally on this topic. She teaches and mentors medical students and residents the importance of self-care and how to serve as role models of wellness. She completed her neurology residency and clinical neurophysiology fellowship at the Medical College of Georgia then went on to complete a two year fellowship in Integrative Medicine at the University of Arizona training there under Andrew Weil, MD.

Jeff Feldman has a special interest in helping individuals cope with chronic pain, headache, and other chronic and life-changing health conditions that can generate depression and anxiety. He works to tailor his approach to the individual, treating patients with a combination of mind-body techniques including relaxation, meditation, hypnosis, cognitive-behavioral and other brief therapy and stress management approaches. He has been a faculty member at all the International Congresses for Ericksonian Psychotherapy and Hypnosis since 1983, and presented at numerous other national and international meetings. An Associate Professor in the Department of Neurology, he joined the faculty of Wake Forest School of Medicine in 1999.Dr. Feldman is a graduate of Rutgers College of Rutgers University, received his Masters and Doctorate degrees in clinical psychology from Case Western Reserve University, and completed an internship at NYU Medical Center Bellevue Hospital. He has served as the Director of the Wake Forest Center for Integrative Medicine from 2013 until 2016, and as Chair of the Clinical Working Group of the Academic Consortium for Integrative Medicine and Health.

Dr. Karvelas grew up in North Carolina and attended both undergraduate and medical school at the University of North Carolina-Chapel Hill. He then completed Physical Medicine and Rehabilitation (PM&R) residency in Chicago at Northwestern Memorial/Rehabilitation Institute of Chicago. He specializes in conservative musculoskeletal pain and chronic pain management with a focus on functional improvement. His interest in integrative medicine stems from his time living in San Francisco between undergraduate school and medical school when he attended art school and completed an Internship in Integrative Medicine at California Pacific Medical Center (CPMC) with a focus on Expressive Arts Therapy for both adult and pediatric inpatients. He then used this training in a Schweitzer Fellowship program in medical school providing expressive arts therapy for pediatric and adult cancer patients at UNC. Although he no longer serves as an expressive arts therapist, this training and experience has molded his approach to treating patients holistically. He plans on completing the fellowship in Integrative Medicine offered to physicians in practice.

William Satterwhite, a native of Winston-Salem, received his bachelors degree from Davidson College and his law degree from UNC Chapel Hill. After practicing law for five years in Charlotte, he went to medical school at Wake Forest School of Medicine and completed his residency in pediatrics at Wake Forest Baptist in 2000. He has practiced pediatrics since then, developing significant experience and expertise treating children with ADHD and anxiety.At the Integrative Medicine Clinic, Satterwhite treats children with ADHD or anxiety who need a deeper, more holistic look into what might be causing their symptoms and what other remedies might lessen or even eliminate the need for traditional prescription medications.

Location and Hours of Operation

The Integrative Medicine Clinic is conveniently located near Pavilions Shopping Center in Winston-Salem, at 755 Highland Oaks Drive.

Clinical Coordinator: Kyle Washburn

755 Highland Oaks DriveSuite 102Winston-Salem, NC 27103(clinic map)

Patient Appointments: 336-713-6100Fax: 336-659-8759

Monday - Friday: 8:00 a.m. - 6:00 p.m.

Insurance coverage varies by provider, but most are in-network with most plans. We suggest you contact your insurance provider to verify coverage.

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Integrative Medicine Clinic - Wake Forest Baptist, North Carolina

Integrative Medicine means different things to different people, depending on who is defining it. For many docs using the term, it is just the blending of the best of conventional and alternative medicine based on the research evidence. Some people emphasize the doctor-patient relationship, but that should always simply be part of good medical practice.

Some docs are using the Integrative Medicine label for their own branding and self-promotion. Some are even trying to coopt the term in order to own it in one way or another.

For the most part, Integrative Medicine does not exist. The MDs are doing complementary medicine. They are complementing their main-stream medical approaches with a few alternative therapies. They aren't really trained in these other therapies, and they will always neglect one or more of the alternative therapies, based upon their prejudices.

The patients are going to the acupuncturist, chiropractor and herbalist, but those practitioners are not talking with the MD. And the MD is certainly not talking with them. The supplements and vitamins are being prescribed by the home shopping channel or the guy in the health food store. The MD and the other practitioners rarely know what's going on.

So for the vast majority of instances, Integrative Medicine does not exist. It's a nice idea, but it's not happening, and it's not going to happen. The best we can do is to get our patients to keep records of the various things they are doing for their health, so that we can at least look it over for safety issues.

Patients will always try some new pill or run off to Aunt Millie's homeopath. That's OK -- they have that right. But it's really hard to keep track of all this, even for the patient.

Five percent of Medicare enrollees cost Medicare 43% of its payout. This 5% of Medicare patients has on average 5 major medical problems, and they have on average 14 doctors in their medical records. Do you really think that all 14 of these doctors are integrating or coordinating their care? Even a few of them?

There are only 3 or 4 of us in the U.S. who have the full cross-training to be able to actually do the integration of alternative therapies with conventional medicine for patients in our offices. But even for us, it's a challenge. So for the most part, Integrative Medicine doesn't really exist.

Good health to you -

James

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What is integrative medicine? | Integrative Medicine - Sharecare

Molecular geneticists look at genes and ways to manipulate them for use in areas including medicine or industry. They may discover a treatment for a genetic disease. If molecular genetics sounds appealing to you, read on to learn more.

The primary focus of molecular genetics is the molecular-level study of the function and structure of genes. Molecular geneticists study the evolution and inheritance of genes. They are curious about how genes control the development and function of organisms. Molecular genetics has lead to mapping the human genome to identify disease-related genetic abnormalities, analyzing genetic changes in tumors and developing new procedures and tests. Genes are the focus, but molecular genetics also involves developmental, cellular and molecular biology.

The educational background needed to work in molecular genetics includes coursework in math, physics, chemistry and biology. Students may earn a bachelor's, master's or doctoral degree in molecular genetics. Courses may include developmental and cell biology, molecular genetics, genetic analysis, DNA transactions, human genetics and biochemistry. Dual degree programs combine molecular genetics with other sciences, such as microbiology. A Ph.D. in Molecular Genetics involves students conducting original research and writing a dissertation for faculty review. The following Study.com pages contain more information on programs, courses and degrees.

Nowadays, science courses are widely available online. View these Study.com pages for more information about online and hybrid programs for aspiring molecular geneticists.

There are many career options for students pursuing a degree in molecular genetics. The list below contains only a few examples, so be sure to visit other Study.com pages for more information.

Molecular genetics offers varied career opportunities with excellent potential for growth and salaries. The U.S. Bureau of Labor Statistics (BLS) expected job prospects for medical scientists in the decade 2012-2022 to grow by 13% (www.bls.gov). Employment for laboratory technicians was expected to grow by 30% in the same period. The BLS reported that, as of May 2012, the median annual wage for medical and clinical laboratory technicians was $37,240; biological science professors, $74,180; and medical scientists, $76,980. Payscale.com reported in March 2014 that most geneticists made a salary of between $30,000 and $132,839 annually.

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Molecular Genetics - Study.com

2007228 5-Fluorouracil (5-FU) Toxicity and Chemotherapeutic Response, 5 Mutations 5-Fluorouracil Sensitivity 5-FU, 5-Fluorouracil Toxicity and Chemotherapeutic Response Panel, Pharmacogenetics (PGx), Colorectal Cancer 2012166 Dihydropyrimidine Dehydrogenase (DPYD) Genotyping, 3 Mutations 5-Fluorouracil Sensitivity DYPD 5-Fluorouracil toxicity5-FU toxicity5-FU toxicity5FU toxicityAdrucil (DPYD) Genotyping, 3 MutationsXeloda (capecitabine) (DPYD) Genotyping, 3 Mutations DPDUftoral (tegafur/uracil) (DPYD) Genotyping, 3 Mutations 0051266 Achondroplasia (FGFR3) 2 Mutations Achondroplasia AD PCR, Skeletal Dysplasias, Neuroblastoma 0051265 Achondroplasia Mutation, Fetal Achondroplasia AD PCR FE, Skeletal Dysplasias 2011708 Alpha Globin (HBA1 and HBA2) Sequencing and Deletion/Duplication Alpha Thalassemia AG FGA, 2011622 Alpha Globin (HBA1 and HBA2) Deletion/Duplication Alpha Thalassemia HBA DD, Alpha thalassemia, alpha globin mutations, alpha globin gene analysis, A globin 0051495 Alpha Thalassemia (HBA1 & HBA2) 7 Deletions Alpha Thalassemia ALPHA THAL, Hemoglobinopathies 2002398 Alport Syndrome, X-linked (COL4A5) Sequencing and Deletion/Duplication Alport Syndrome ALPORT FGARenal disease, chronic kidney disease, hematuria 0051786 Alport Syndrome, X-linked (COL4A5) Sequencing Alport Syndrome ALPORT FGSRenal disease, chronic kidney disease, hematuria 2013341 Apolipoprotein E (APOE) Genotyping, Alzheimer Disease Risk Alzheimer's Disease APOE AZ 2005077 Angelman Syndrome and Prader-Willi Syndrome by Methylation Angelman Syndrome AS PWS, Angelman, Prader-Willi, Neurocognitive Impairments 2005564 Angelman Syndrome (UBE3A) Sequencing Angelman Syndrome UBE3A FGS 2012232 Angelman Syndrome and Prader-Willi Syndrome by Methylation, Fetal Angelman Syndrome AS PWS FE Prader-Labhart-Willi Syndrome, AS, PWS 2006540 Aortopathy Panel, Sequencing and Deletion/Duplication, 21 Genes Aortopathies AORT PANEL, Thoracic aortic aneurysms, dissections, familial thoracic TAAD AAT, ACTA2 (AAT6), FBN1, MYH11 (AAT4), MYLK (AAT7), SMAD3, TGFBR1 (AAT5), TGFBR2 (AAT3), SLC2A10, FBN2, COL3A1ACTA2, CBS, COL3A1, COL5A1, COL5A2, FBN1, FBN2, MYH11, MYLK, PLOD1, SKI, SLC2A10, SMAD3, SMAD4, TGFB2, TGFBR1, TGFBR2 2005584 Marfan Syndrome (FBN1) Sequencing and Deletion/Duplication Aortopathies FBN1 FGA 2005589 Marfan Syndrome (FBN1) Sequencing Aortopathies FBN1 FGS 2002705 TGFBR1 & TGFBR2 Sequencing Aortopathies LDS FGS, Loeys-Dietz, aortic aneurysm see Loeys-Dietz Syndrome Aortopathies see Marfan Syndrome and FBN1-Related Disorders Aortopathies 0055654 Apolipoprotein B Mutation Detection (G9775A, C9774T) Apolipoprotein B (APOB) APO B, Risk Markers - CVD (Non-traditional) 2013341 Apolipoprotein E (APOE) Genotyping, Alzheimer Disease Risk Apolipoprotein E (APOE) APOE AZ 2013337 Apolipoprotein E (APOE) Genotyping, Cardiovascular Risk Apolipoprotein E (APOE) APOE CR 0051415 Ashkenazi Jewish Diseases, 16 Genes Ashkenazi Jewish Panel (16 disorders) AJP, Jewish Genetic, Fanconi's, Fanconis,ABCC8, TMEM216, NEB, G6PC, DLD, BCKDHB, CLRN1, PCDH15 2013725 ABCC8-Related Hyperinsulinism, 3 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013745 NEB-Related Nemaline Myopathy, 1 Variant Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 0051433 Bloom Syndrome (BLM),1 Variant Ashkenazi Jewish Panel (16 disorders) BLM, Jewish Genetic 0051453 Canavan Disease (ASPA), 4 Variants Ashkenazi Jewish Panel (16 disorders) ASPA, Jewish Genetic 0051463 Dysautonomia, Familial (IKBKAP), 2 Variants Ashkenazi Jewish Panel (16 disorders) IKBKAP, Jewish Genetic Disease 0051468 Fanconi Anemia Group C, (FANCC), 2 Variants Ashkenazi Jewish Panel (16 disorders) FANCC, Jewish, Ashkenazi, Fanconi's, Fanconis, carrier testing, DNA 0051438 Gaucher Disease (GBA), 8 Variants Ashkenazi Jewish Panel (16 disorders) GBA, Jewish Genetic, Glucocerebrosidase, Glucosylceramidase 2013740 Glycogen Storage Disease, Type 1A (G6PC), 9 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013909 Joubert Syndrome Type 2 (TMEM216), 1 Variant Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013735 Lipoamide Dehydrogenase Deficiency (DLD), 2 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2013730 Maple Syrup Urine Disease, Type 1B (BCKDHB), 3 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 0051448 Mucolipidosis Type IV (MCOLN1), 2 Variants Ashkenazi Jewish Panel (16 disorders) MCOLN1, Jewish Genetic, lysosomal 0051458 Niemann-Pick, Type A (SMPD1), 4 Variants Ashkenazi Jewish Panel (16 disorders) SMPD1, Jewish Genetic, acid sphingomyelinase, ASM, NP-A, lysosomal storage, L302P, 1bp del fsP330, R496L, R608del 0051428 Tay-Sachs Disease (HEXA), 7 Variants Ashkenazi Jewish Panel (16 disorders) HEXA, Jewish Genetic, Hex A, GM2 gangliosidosis, hexosaminidase, lysosomal storage, delta 7.6kb, IVS9(+1)G>A, 1278insTATC, IVS12(+1)G>C, G269S, R247W, R249W 2013750 Usher Syndrome, Types 1F and 3 (PCDH15 and CLRN1), 2 Variants Additional Technical Information Ashkenazi Jewish Panel (16 disorders) 2014314 Autism and Intellectual Disability Comprehensive Panel Autism Creatine, epilepsy, amino acids, organic acids, mucopolysaccharidoses (MPS), MPS, acylcarnitine, mental retardation, Fragile X, microarray 0051614 Rett Syndrome (MECP2), Full Gene Analysis Autism RETT FGA, MECP2-related, Rett, atypical Rett, neonatal encephalopathy, PPM-X, neurocognitive impairments 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Autism PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2004935 CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication Autism CDKL5 FGA, X-linked infantile spasm 2005077 Angelman Syndrome and Prader-Willi Syndrome by Methylation Autism AS PWS, Angelman, Prader-Willi, Neurocognitive Impairments 2005564 Angelman Syndrome (UBE3A) Sequencing Autism UBE3A FGS 2010117 Beta Globin (HBB) Sequencing and Deletion/Duplication Beta Globin BG FGA, Beta thalassemia, beta globin, HBB 0050388 Beta Globin (HBB) Sequencing, Fetal Beta Globin BG SEQ FE 0051422 Beta Globin (HBB) HbS, HbC, and HbE Mutations, Fetal Beta Globin HB SCE FE 0051700 Biotinidase Deficiency (BTD), 5 Mutations Biotinidase Deficiency BTD MUT, Multiple carboxylase 0051730 Biotinidase Deficiency (BTD) Sequencing Additional Technical Information Biotinidase Deficiency BTD FGS, Multiple carboxylase 0051368 Rh Genotyping D Antigen (RhD positive/negative and RhD copy number) Blood Genotyping RHD, Hemolytic Disease of the Newborn, fetal erythroblastosis, isoimmunization, alloimmune hemolytic 0050421 RhCc Antigen (RHCE) Genotyping Blood Genotyping RH C, Hemolytic Disease of the Newborn, fetal rhesus type, alloimmunization, alloantibodies, maternal-fetal Rh incompatibility 0050423 RhEe Antigen (RHCE) Genotyping Blood Genotyping RH E, Hemolytic Disease of the Newborn, fetal rhesus type, alloimmunization, alloantibodies, maternal-fetal Rh incompatibility 0051644 Kell K/k Antigen (KEL) Genotyping Blood Genotyping KEL, Hemolytic Disease of the Newborn, K/k, Kell/Cellano 0051433 Bloom Syndrome (BLM),1 Variant Bloom Syndrome BLM, Jewish Genetic 2012026 Breast and Ovarian Hereditary Cancer Panel, Sequencing and Deletion/Duplication, 20 Genes Breast Cancer BOCAPAN, Breast Cancer, Tumor Markers, FISH, ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MEN1, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53 2011949 Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing and Deletion/Duplication Breast Cancer BRCA FGA, BRACA, HBOC 2011954 Breast and Ovarian Hereditary Cancer Syndrome (BRCA1 and BRCA2) Sequencing Breast Cancer BRCA FGS, BRACA, HBOC 2002722 PTEN-Related Disorders Sequencing Breast Cancer PTEN FGS, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Breast Cancer PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Breast Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Breast Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2008398 Peutz-Jeghers Syndrome (STK11) Sequencing and Deletion/Duplication Breast Cancer STK11, STK11 FGA, hamartomatous polyps, mucocutaneous hypergigmentation 2008394 Peutz-Jeghers Syndrome (STK11) Sequencing Breast Cancer STK11, STK11 FGS, hamartomatous polyps, mucocutaneous hypergigmentation 0051453 Canavan Disease (ASPA), 4 Variants Canavan Disease ASPA, Jewish Genetic 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Cancer, Hereditary CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2010183 Cardiomyopathy and Arrhythmia Panel, Sequencing (85 Genes) and Deletion/Duplication (83 Genes) Cardiomyopathy CARDIACPAN, Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM), Arrhythmogenic right vernticular cardiomyopathy (ARVC), Left ventricular noncompaction (LVNC), catecholaminergic polymorphic ventricular tachycardia (CPVT), Brugada syndrome (BrS), Long QT syndrome (LQTS), Romano-Ward, Short QT syndrome (SQTS), ABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, CACNA1C, CACNB2, CASQ2, CAV3, CORIN, COX15, CSRP3, CTF1, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FKRP, FKTN, FXN, GAA, GLA, GPD1L, ILK, JPH2, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNQ1, KLHL3, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYH10, MYL2, MYL3, MYLK2, MYOT, MYOZ2, MYPN, NEXN, OBSCN, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCO2, SGCA, SGCB, SGCD, SGCG, SLC25A4, SNTA1, SYNE1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, TTR, VCLABCC9, ACTC1, ACTN2, AKAP9, ANK2, ANKRD1, CACNA1C, CACNB2, CASQ2, CAV3, CORIN, COX15, CSRP3, CTF1, DES, DMD, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FKRP, FKTN, FXN, GAA, GLA, GPD1L, ILK, JPH2, JUP, KCNE1, KCNE2, KCNE3, KCNH2, KCNJ2, KCNQ1, KLHL3, LAMA4, LAMP2, LDB3, LMNA, MYBPC3, MYH6, MYH7, MYH10, MYL2, MYL3, MYLK2, MYOT, MYOZ2, MYPN, NEXN, OBSCN, PKP2, PLN, PRKAG2, RBM20, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCO2, SGCA, SGCB, SGCD, SGCG, SLC25A4, SNTA1, SYNE1, TAZ, TCAP, TGFB3, TMEM43, TMPO, TNNC1, TNNI3, TNNT2, TPM1, TRPM4, TTN, TTR, VCL, arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular noncompaction (LVNC), long QT syndrome (LQTS), Romano-Ward, short QT syndrome (SQTS) 2004203 Carnitine Deficiency, Primary (SLC22A5) Sequencing and Deletion/Duplication Carnitine Deficiency PCD FGA, OCTN2, carnitine uptake 0051682 Carnitine Deficiency, Primary (SLC22A5) Sequencing Carnitine Deficiency PCD FGS, OCTN2, carnitine uptake 0051415 Ashkenazi Jewish Diseases, 16 Genes Carrier Screening Panels AJP, Jewish Genetic, Fanconi's, Fanconis,ABCC8, TMEM216, NEB, G6PC, DLD, BCKDHB, CLRN1, PCDH15 2014674 Expanded Carrier Screen Genotyping Carrier Screening Panels ECS GENO 2014671 Expanded Carrier Screen Genotyping with Fragile X Carrier Screening Panels ECS GEN FX 2014680 Expanded Carrier Screen by Next Generation Sequencing Carrier Screening Panels ECS SEQ 2014677 Expanded Carrier Screen by Next Generation Sequencing with Fragile X Carrier Screening Panels ECS SEQ FX 2004931 CDKL5-Related Disorders (CDKL5) Sequencing Additional Technical Information CDKL5-Related Disorders CDKL5 FGS, X-linked infantile spasm 2004935 CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication CDKL5-Related Disorders CDKL5 FGA, X-linked infantile spasm 2005018 Celiac Disease (HLA-DQA1*05, HLA-DQB1*02, and HLA-DQB1*03:02) Genotyping Do not use in the initial evaluation for celiac disease. Useful in ruling out celiac disease (CD) (high negative predictive value) in selective clinical situations such as: Equivocal small-bowel histologic finding (Marsh I-II) in seronegative individuals Evaluation of individuals on a gluten-free diet (GFD) in whom no testing for CD was done before GFD Celiac Disease HLA CELIAC 2002965 Von Hippel-Lindau (VHL) Sequencing and Deletion/Duplication Central Nervous System Cancer VHL FGA, Brain Tumors, Pheochromocytoma 2002970 Von Hippel-Lindau (VHL) Sequencing Central Nervous System Cancer VHL FGS, Congenital polycythemia 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Central Nervous System Cancer CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Central Nervous System Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Central Nervous System Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2012160 Charcot-Marie-Tooth Type 1A (CMT1A)/Hereditary Neuropathy with Liability to Pressure Palsies (HNPP), PMP22 Deletion/Duplication Charcot-Marie-Tooth Disease CMT DD, AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012155 Charcot-Marie-Tooth (CMT) and Related Hereditary Neuropathies, PMP22 Deletion/Duplication with Reflex to Sequencing Panel Charcot-Marie-Tooth Disease CMT REFLEX,AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012151 Charcot-Marie-Tooth (CMT) and Related Hereditary Neuropathies Panel Sequencing Charcot-Marie-Tooth Disease CMT SEQ, AARS, AIFM1, ARHGEF10, ATL1, ATP7A, BAG3, BICD2, BSCL2, CCT5, DCTN1, DHTKD1, DNAJB2, DNM2,DNMT1, DYNC1H1, EGR2, FAM134B, FBLN5, FGD4, FIG4, GAN, GARS, GDAP1, GJB1, GNB4, HARS, HEXA, HINT1, HK1, HOXD10,HSPB1, HSPB3, HSPB8, IGHMBP2, IKBKAP, INF2, KARS, KIF1A, KIF1B, KIF5A, LAS1L, LITAF, LMNA, LRSAM1, MARS, MED25, MFN2,MPZ, MTMR2, MYH14, NDRG1, NEFL, NGF, NTRK1, PDK3, PLEKHG5, PMP22, PRNP, PRPS1, PRX, RAB7A, REEP1, SBF1, SBF2, SCN9A,SETX, SH3TC2, SLC12A6, SLC5A7, SOX10, SPTLC1, SPTLC2, TDP1, TFG, TRIM2, TRPV4, WNK1, YARS 2012609 CHARGE Syndrome, CHD7 Sequencing CHARGE Syndrome 2012717 CHARGE Syndrome (CHD7) Sequencing, Fetal CHARGE Syndrome 2002065 Chimerism, Recipient Pre-Transplant Chimerism STR-PRE 2002067 Chimerism, Donor Chimerism STR-DONOR 2002064 Chimerism, Post-Transplant, Sorted Cells Chimerism STR-POSTSC 2002066 Chimerism, Post-Transplant Chimerism STR-POST 2006356 Chronic Granulomatous Disease (CYBB Gene Scanning and NCF1 Exon 2 GT Deletion) with Reflex to CYBB Sequencing Chronic Granulomatous Disease CGD PANEL, Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 2006361 Chronic Granulomatous Disease, X-linked (CYBB) Gene Scanning with Reflex to Sequencing Chronic Granulomatous Disease CYBB, Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 2006366 Chronic Granulomatous Disease (NCF1) Exon 2 GT Deletion Chronic Granulomatous Disease NCF1, Cytochrome b-Positive, Type I, NCF1 Deficiency, Niemann-Pick Disease Type A, p47-PHOX, Soluble Oxidase Component II 2006261 Citrin Deficiency (SLC25A13) Sequencing Citrin Deficiency CITRIN FGSCitrin DeficiencyCitrullinemia Type II Failure to Thrive and Dyslipidemia Caused by Citrin Deficiency Neonatal Intrahepatic Cholestasis Caused by Citrin Deficiency 2007069 Citrullinemia, Type I (ASS1) Sequencing Citrullinemia, Type I 2011157 Cobalamin/Propionate/Homocysteine Metabolism Related Disorders Panel, Sequencing (25 Genes) and Deletion/Duplication (24 Genes) Cobalamin/Propionate/Homocysteine Metabolism Related Disorders VB12 PANEL, "ABCD4, ACSF3, AMN, CBS, CD320, CUBN, GIF, HCFC1, LMBRD1, MAT1A, MCEE, MMAA, MMAB, MMACHC, MMADHC, MTHFR, MTR, MTRR, MUT, PCCA, PCCB, SUCLA2, SUCLG1, TCN1, TCN2Methylmalonic aciduria and homocystinuria, cblJ typeCombined malonic and methylmalonic aciduriaMegaloblastic anemia-1, Norwegian typeHomocystinuria due to cystathionine beta-synthase deficiencyMethylmalonic aciduria due to transcobalamin receptor defectMegaloblastic anemia-1, Finnish typeIntrinsic factor deficiencyMethylmalonic acidemia and homocysteinemia, cblX type Methylmalonic aciduria and homocystinuria, cblF typeMethionine adenosyltransferase deficiencyMethylmalonyl-CoA epimerase deficiencyMethylmalonic aciduria, cblA typeMethylmalonic aciduria, cblB typeMethylmalonic aciduria and homocystinuria, cblC typeMethylmalonic aciduria and homocystinuria, cblD typeHomocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activityHomocystinuria-megaloblastic anemia, cblG typeHomocystinuria-megaloblastic anemia, cbl E typeMethylmalonic aciduria due to methylmalonyl-CoA mutase deficiencyPropionic acidemiaMitochondrial DNA depletion syndrome 5 (encephalomyopathic with or without methylmalonic aciduria)Mitochondrial DNA depletion syndrome 9 (encephalomyopathic type with methylmalonic aciduria)Transcobalamin I deficiencyTranscobalamin II deficiency 2013386 Congenital Adrenal Hyperplasia (CAH) (21-Hydroxylase Deficiency) Common Mutations Congenital Adrenal Hyperplasia (CAH) 2006220 Congenital Amegakaryocytic Thrombocytopenia (CAMT) Sequencing Congenital Amegakaryocytic Thrombocytopenia CAMT FGS, GeneDx 2008610 Creatine Transporter Deficiency (SLC6A8) Sequencing and Deletion/Duplication Creatine SLC6A8 FGA, SLC6A8-Related Creatine Transporter Deficiency, SLC6A8 Deficiency 2008615 Creatine Transporter Deficiency (SLC6A8) Sequencing Additional Technical Information Creatine SLC6A8 FGS, SLC6A8-Related Creatine Transporter Deficiency, SLC6A8 Deficiency 0051110 Cystic Fibrosis (CFTR) Sequencing Cystic Fibrosis CF-CFTR, Diagnostic, CF 0051640 Cystic Fibrosis (CFTR) Sequencing with Reflex to Deletion/Duplication Cystic Fibrosis CFTR FGA, Diagnostic, CF 2013661 Cystic Fibrosis (CFTR), 165 Pathogenic Variants Cystic Fibrosis CF VAR 2013662 Cystic Fibrosis (CFTR), 165 Pathogenic Variants, Fetal Cystic Fibrosis CF VAR FE 2013663 Cystic Fibrosis (CFTR), 165 Variants with Reflex to Sequencing Cystic Fibrosis CF VAR SEQ 2013664 Cystic Fibrosis (CFTR), 165 Variants with Reflex to Sequencing and Reflex to Deletion/Duplication Cystic Fibrosis CFVAR COMP 2014547 Cytochrome P450 2D6 (CYP2D6) 15 Variants and Gene Duplication Cytochrome P450 CYP 2D6, Tamoxifen, Pharmacogenetics (PGx), Schizophrenia, Breast Cancer, breast biomarkers 2012769 Cytochrome P450 2C19, CYP2C19 - 9 Variants Cytochrome P450 CYP2C19, Pharmacogenetics (PGx), Schizophrenia, Breast Cancer, breast biomarkers 2012766 Cytochrome P450 2C9, CYP2C9 - 2 Variants Additional Technical Information Cytochrome P450 CYP2C9, Warfarin Sensitivity, Pharmacogenetics (PGx) 2012740 Cytochrome P450 3A5 Genotyping, CYP3A5, 2 Variants Cytochrome P450 2013098 Cytochrome P450 Genotype Panel Cytochrome P450 CYP PAN 2006234 Diamond-Blackfan Anemia (RPL5) Sequencing Diamond-Blackfan Anemia RPL5 FGS, GeneDx 2006236 Diamond-Blackfan Anemia (RPL11) Sequencing Diamond-Blackfan Anemia RPL11 FGS 2006238 Diamond-Blackfan Anemia (RPS19) Sequencing Diamond-Blackfan Anemia RPS19 FGS 2011241 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication with Reflex to Sequencing Duchenne/Becker Muscular Dystrophy DMD REFLEX, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011235 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication Duchenne/Becker Muscular Dystrophy DMD DD, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011153 Duchenne/Becker Muscular Dystrophy (DMD) Sequencing Duchenne/Becker Muscular Dystrophy DMD SEQ, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011231 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication, Fetal Duchenne/Becker Muscular Dystrophy DMD DD FE, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2006244 Dyskeratosis Congenita, Autosomal (TERC) Sequencing Dyskeratosis Congenita TERC FGS, GeneDx 2006228 Dyskeratosis Congenita, X-linked (DKC1) Sequencing Dyskeratosis Congenita DKC1 FGS 2011241 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication with Reflex to Sequencing Dystrophinopathies DMD REFLEX, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011235 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication Dystrophinopathies DMD DD, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011153 Duchenne/Becker Muscular Dystrophy (DMD) Sequencing Dystrophinopathies DMD SEQ, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 2011231 Duchenne/Becker Muscular Dystrophy (DMD) Deletion/Duplication, Fetal Dystrophinopathies DMD DD FE, Dystrophin, Duchenne, Becker, Dystrophinopathy, Dystrophinopathies, DMD, BMD 0080351 Ehlers-Danlos Syndrome Type VI Screen, Urine Ehlers-Danlos Syndrome Type VI (Kyphoscoliotic Form) EDS6Ehlers-Danlos Syndrome, Kyphoscoliotic FormEDS Kyphoscoliotic FormEDS Type VIEDS VIEhlers-Danlos Syndrome Type VILysyl-Hydroxylase DeficiencyEhlers-Danlos Syndrome Type VIANevo SyndromePLOD1Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1EDSVIEDS6EDS 6 2005559 Ehlers-Danlos Syndrome Kyphoscoliotic Form, Type VI (PLOD1) Sequencing and Deletion/Duplication Ehlers-Danlos Syndrome Type VI (Kyphoscoliotic Form) EDS-VI FGA 2005360 Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing and Deletion/Duplication Endocrine Cancer MEN1 FGA, Multiple endocrine adenomatosis, Wermer syndrome, Multiple Endocrine Neoplasias (MEN) 2005359 Multiple Endocrine Neoplasia Type 1 (MEN1) Sequencing Endocrine Cancer MEN1 FGS, Multiple endocrine adenomatosis, Wermer syndrome, Multiple Endocrine Neoplasias (MEN) 0051390 Multiple Endocrine Neoplasia Type 2 (MEN2), RET Gene Mutations by Sequencing Endocrine Cancer MEN2 SEQ, Thyroid Cancer, Pheochromocytoma, Multiple Endocrine Neoplasias (MEN), MEN 2A, MEN 2B, familial medullary thyroid carcinoma, FMTC, RET proto-oncogene 2002965 Von Hippel-Lindau (VHL) Sequencing and Deletion/Duplication Endocrine Cancer VHL FGA, Brain Tumors, Pheochromocytoma 2002970 Von Hippel-Lindau (VHL) Sequencing Endocrine Cancer VHL FGS, Congenital polycythemia 2007167 Hereditary Paraganglioma-Pheochromocytoma (SDHB, SDHC, and SDHD) Sequencing and Deletion/Duplication Panel Endocrine Cancer 2012032 Cancer Panel, Hereditary, Sequencing and Deletion/Duplication, 47 Genes Endocrine Cancer CANCERPAN, Lynch syndrome, breast cancer, multiple endocrine neoplasia, melanoma, retinoblastoma, paraganglioma, Li-Fraumeni, familial adenomatous polyposis, Peutz-Jegher, HNPCC, inherited cancer, renal cancer, GI cancer, colorectal cancer, NGS cancer panel 2006948 SDHB with Interpretation by Immunohistochemistry Endocrine Cancer 2007108 Hereditary Paraganglioma-Pheochromocytoma (SDHB) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2007117 Hereditary Paraganglioma-Pheochromocytoma (SDHC) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2002722 PTEN-Related Disorders Sequencing Endocrine Cancer PTEN FGS, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2007122 Hereditary Paraganglioma-Pheochromocytoma (SDHD) Sequencing and Deletion/Duplication Additional Technical Information Endocrine Cancer 2002470 PTEN-Related Disorders Sequencing and Deletion/Duplication Endocrine Cancer PTEN FGA, PTEN hamartoma tumor, PHTS, Cowden, CS, Bannayan-Riley-Ruvalcaba, BRRS, Proteus, PS, Proteus-like, PSL, macrocephaly, autism 2009313 Li-Fraumeni (TP53) Sequencing and Deletion/Duplication Endocrine Cancer TP53 FGA, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2009302 Li-Fraumeni (TP53) Sequencing Endocrine Cancer TP53 FGS, p53, TP53, Li Fraumeni, adrenocortical, sarcoma, chompret 2007533 Progressive Myoclonic Epilepsy (PME) Panel, Sequence Analysis and Exon-Level Deletion/Duplication Additional Technical Information Epilepsy PROG EPIL, seizures, PME, myoclonus, Lafora, Unverricht-Lundborg, neuronal ceroid lipofuscinoses, NCL, PRICKLE1, EPM2A, EPM2B, NHLRC1, CSTB, PPT1, CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8, CLN10, TPP1, MFSD8, CTSD, GeneDx 2006069 Febrile Seizures Panel Epilepsy FEBRIL PAN 2007545 Childhood-Onset Epilepsy Panel, Sequencing and Deletion/Duplication Additional Technical Information Epilepsy CHILD EPIL, Early-onset epileptic encephalopathy, SCN1A, Sodium channel protein type 1 alpha, PCDH19, Protocadherin-19, SLC2A1, Solute carrier family 2, facilitated glucose transporter member 1, POLG, DNA polymerase subunit gamma-1, SCN2A, Sodium channel protein type 2 alpha, Generalized epilepsy with febrile seizures plus, GEFS+, SCN1A, Sodium channel protein type 1 alpha, SCN1B, Sodium channel subunit beta-1, GABRG2, Gamma-aminobutyric acid receptor subunit gamma-2, SCN2A, Sodium channel protein type 2 alpha, Juvenile Myoclonic Epilepsy, JME, EFHC1, EF-hand domain-containing protein 1, CACNB4, Voltage-dependent L-type calcium channel subunit beta-4, GABRA1, Gamma-aminobutyric acid receptor subunit alpha-1, Progressive Myoclonic Epilepsy, EPM2A, Laforin, NHLRC1, EPM2B, NHL repeat-containing protein 1, malin, CSTB, Cystatin-B, PRICKLE1, Prickle-like protein 1, Autosomal Dominant Focal Epilepsies, CHRNA4, Neuronal acetylcholine receptor alpha-4, CHRNB2, Neuronal acetylcholine receptor beta-2, CHRNA2, Neuronal acetylcholine receptor alpha-2, LGI1, Leucine-rich glioma-inactivated protein 1, atypical Rett syndromes, MECP2, Methyl CpG binding protein 2, CDKL5, Cyclin-dependent kinase-like 5, FOXG1, Forkhead box protein G1, Angelman, Angelman-like, Pitt-Hopkins, UBE3A, Ubiquitin protein ligase E3A, SLC9A6, Sodium/hydrogen exchanger 6, TCF4, Transcription factor 4, NRXN1, Neurexin-1, CNTNAP2, Contactin-associated protein-like 2, Mowat-Wilson, ZEB2, Zinc finger E-box-binding, homeobox 2, Creatine deficiency, GAMT, Guanidinoacetate N-methyltransferase, GATM, Glycine amidinotransferase, mitochondrial, Neuronal Ceroid Lipofuscinoses, NCL, PPT1, CLN1, Palmitoyl-protein thioesterase 1, TPP1, CLN2,Tripeptidyl-peptidase 1, CLN3, Battenin, CLN5, Ceroid-lipofuscinosis neuronal protein 5, CLN6, Ceroid-lipofuscinosis neuronal protein 6, MFSD8, CLN7, Major facilitator superfamily domain-containing protein 8, CLN8, Ceroid-lipofuscinosis neuronal protein 8, CTSD, CLN10, Cathepsin D, Adenosuccinate lyase deficiency, ADSL, Adenylosuccinate lyase, SYN1, Synapsin-1, Microcephaly with early-onset intractable seizures and developmental delay, MCSZ, PNK, Bifunctional polynucleotide, phosphatase/kinase, seizures, GeneDx 2007535 Infantile-Onset Epilepsy Panel, Sequencing and Deletion/Duplication Additional Technical Information Epilepsy INFANT EPIL; SCN1A; PCDH19; SLC2A1; POLG; SCN2A; SCN1A; SCN1B; GABRG2; EFHC1; CACNB4; GABRA1; EPM2A; NHLRC1; EPM2B; CSTB; PRICKLE1; CHRNA4; CHRNB2; CHRNA2; LGI1; MECP2; CDKL5; FOXG1; UBE3A; SLC9A6; TCF4; NRXN1; CNTNAP2; ZEB2; GAMT; GATM; PPT1; CLN1; TPP1; CLN2; CLN3; CLN5; CLN6; MFSD8; CLN7; CLN8; CTSD; CLN10; ADSL; SYN1; PNKP; benign familial neonatal seizures; generalized epilepsy with febrile seizures; juvenile myoclonic epilepsy; progressive myoclonic epilepsy; autosomal dominant focal epilepsies; Rett/atypical Rett syndromes; Angelman/Angelman-like/Pitt-Hopkins syndromes; Mowat-Wilson syndrome; creatine deficiency syndromes; neuronal ceroid lipofuscinoses; adenosuccinate lyase deficiency; epilepsy with variable learning and behavioral disorders; microcephaly with early onset intractable seizures and developmental delay", GeneDx 2006332 Exome Sequencing with Symptom-Guided Analysis Exome EXOME SEQ 2006336 Exome Sequencing Symptom-Guided Analysis, Patient Only Exome EXOSEQ PRO 0030192 APC Resistance Profile with Reflex to Factor V Leiden Factor V Leiden APC R, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 0097720 Factor V Leiden (F5) R506Q Mutation Factor V Leiden FACV, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 2001549 Factor V, R2 Mutation Factor V Leiden F5 R2, Venous thrombosis, Thromboembolism, Thrombophilia, clotting, A4070G 2003220 Factor XIII (F13A1) V34L Variant (assess thrombotic risk in Caucasians) Factor XIII (F13A1) V34L Variant FAC 13 MUT, Venous thrombosis, Thromboembolism, Thrombophilia, clotting 2004915 Familial Adenomatous Polyposis Panel: APC Sequencing, APC Deletion/Duplication, and MYH 2 Mutations Familial Adenomatous Polyposis FAP Panel, Familial Adenomatious Polyposis familial cancer, Colorectal Cancer, colon cancer, CRC, polyps, FAP, familial cancer 2004863 Familial Adenomatous Polyposis (APC) Sequencing Familial Adenomatous Polyposis APC FGS, Colorectal Cancer, colon cancer, CRC, polyps, Familial Adenomatious Polyposis FAP, familial cancer 2004911 MUTYH-Associated Polyposis (MUTYH) 2 Mutations Familial Adenomatous Polyposis MYH SEQ, Hereditary Colorectal Cancer, MAP, MUTH Associated Polyposis 2006191 MUTYH-Associated Polyposis (MUTYH) Sequencing Familial Adenomatous Polyposis MUTYH, FGS, MYH 2006307 MUTYH-Associated Polyposis (MUTYH) 2 Mutations with Reflex to Sequencing Familial Adenomatous Polyposis MUTYH RFLX MYH 0051463 Dysautonomia, Familial (IKBKAP), 2 Variants Familial Dysautonomia IKBKAP, Jewish Genetic Disease 2002658 Familial Mediterranean Fever (MEFV) Sequencing Familial Mediterranean Fever (MEFV) FMF FGS, DNA 2001961 Familial Mutation, Targeted Sequencing

The following genes are available:ACADVL, ACADM, ACVRL1, APC, ASS1, ATP7A, BMPR1A, BMPR2, BTD, CCM1, CCM2, CCM3, CDKL5, CFTR, COL4A5, CYP1B1, ENG, F8, F9, FBN1, G6PD, GALT, GJB2; HBA1, HBA2, HBB, INSR, LMNA, MECP2,MEFV, MEN1, MLH1, MSH2; MSH6, MUTYH, MYH3, NF1, OTC, PLOD1, PMS2; PRSS1, PTEN, PTPN11, RASA1, RET, SDHB, SDHC, SDHD, SLC22A5, SLC25A13, SMAD4, SPRED1, SPINK1, SOS1, STK11, TACI, TGFBR1, TGFBR2, UBE3A, VHL, VWF

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Molecular Genetics | ARUP Laboratories

The Department of Microbiology, Immunology & Molecular Genetics is part of theLong School of Medicineat theUniversity of Texas Health Science Center at San Antonio. Our faculty conducts research on the immune system, infectious agents and cancer. Accordingly, the department is the nucleus for research and education in immunological and microbiological topics for the five schools at theUniversity of Texas Health Science Center at San Antonio, and provides a dynamic environment for scientific discovery and training.

Our mission is to further research in molecular immunology, microbial pathogenesis, tumor immunology,autoimmunity, immunodeficienciesand development of the immune system, in order to build the knowledge necessary for vaccines and therapies of the future. We use molecular genetics and epigenetics approaches in conjunction with next-generation sequencing tools to dissect mechanisms for generations of antibodies and lymphocytes that protect against viruses, bacteria, fungi, as well as tumor cells. We also strive to understand molecular mechanisms of tumorigenesis, with particular emphasis on B lymphocyte neoplastic transformation in the context of the developing immune system. To this end, basic and translational research are of equal importance, to foster discovery of biological truths and translate those discoveries into new therapeutics.

We are committed to developing the next generation of scientists in biomedical research with an emphasis on molecular immunology, and to this end, we offer a spectrum of training opportunities. We house anUndergraduate Research Program,in addition to aMaster of Science Program in Immunology and Infection. Our faculty also teach and mentor PhD students through theInfection, Inflammation and Immunity Discipline of the Integrated Biomedical Science Program in the Graduate School of Biomedical Sciences, in addition to providing the teaching in immunology and infection to our medical students. Finally, in addition to undergraduate and graduate trainees,Postdoctoral Fellowsare important in our overall research effort. Postdoctoral fellowships are available in most laboratories of the Department of Microbiology, Immunology & Molecular Genetics.

The Department of Microbiology, Immunology & Molecular Genetics supports a variety of learning and training opportunities in seminars, lectures and events, including:

Contact the Program Coordinators at: immunity@uthscsa.edu

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Microbiology, Immunology & Molecular Genetics - Microbiology

The basis of human longevity and healthy aging, and how to achieve these desirable phenotypes, remain among the principal challenges of biology and medicine. While an understanding of lifestyle and environmental factors will maximize our ability to prevent disease and maximize health in the general population, studying the genetic basis of longevity and healthy aging in exceptional individuals is providing important biological insights. In model organisms it has been possible to demonstrate effects of mutations in genes that can extend lifespan nearly tenfold (Ayyadevara et al. 2008). Studies of inbred lab strains and of natural genetic variants in model organisms including yeast and worms (Tissenbaum and Guarente 2002), flies (Paaby and Schmidt 2009) and mice (Yuan et al. 2011) have clearly implicated many specific genes in the lifespan of these organisms. Our understanding of human lifespan stands in contrast to this, with only one consistently replicable genetic association, APOE, observed to date in several genome-wide association scans (GWAS) of longevity-related traits. This may be because healthy aging and longevity are particularly complex traits, involving not only maintenance of long-term function but also absence or reduction of disease and other morbidities. It has been proposed that human lifespan is influenced not only by longevity assurance mechanisms and disease susceptibility loci but also by the environment, geneenvironment interactions, and chance (Cournil and Kirkwood 2001). It will be important to understand the effects of environment (lifestyle) and of genetics, as well as how they interact to affect health and lifespan.

The importance of age and aging is underscored by the recognition that all common complex diseases increase with age. Questions remain about whether aging is the cause or effect of such diseases (Hekimi 2006). The study of desirable phenotypes like longevity and healthy aging has been referred to as positive biology (Farrelly 2012). Its premise is that understanding the basis for such desirable traits may allow us to design interventions to improve human health.

This review was intended to summarize our current understanding of genetic factors affecting the phenotypes of longevity and healthy aging in humans, including the definition and heritability of these traits, and linkage, association, and sequencing studies. The surprising and novel findings that centenarians do not appear to have a relative lack of common complex disease risk alleles, and that some genetic variants appear to buffer or protect against specific risk alleles, are discussed in detail. Shorter summaries of the findings related to somatic mosaicism and the promising study of epigenetics of aging are included for completeness.

The phenotypes used in studies of the genetics of human aging are usually lifespan (age at death), longevity (long life, usually defined as being a specific advanced age or older at the time of study), exceptional longevity (defined as attaining or exceeding a specific exceptional age), or healthy aging (a combination of old age and health, often defined as freedom from specific disorders or desirable performance levels on functional tests). Longevity studies focus on long-lived individuals (LLI), often centenarians aged 100 or more years. One advantage of such studies is the simplicity of phenotype definition. Healthy aging can be defined in various ways, usually with regard to reaching an at least moderately old age in the absence of certain diseases or disabilities, and/or in the presence of desirable traits such as intact cognition or mobility. Both types of studies should be differentiated from the study of the fundamental biological processes of aging (for example, cellular senescence).

A major difference between longevity and healthy aging studies is that the former focuses on lifespan, whereas the latter is focused on healthspan. Lifespan and healthspan are intimately related, however, and individuals who live exceptionally long also tend to be healthy for much of their lives. A landmark study of the health of supercentenarians (aged 110119), semisupercentenarians (aged 105109), centenarians (in this context aged 100104), nonagenarians, and younger controls found that the older the age group, the greater the delay in onset of major disease (Andersen et al. 2012). Remarkably, for every category of increasing age, the hazard ratio for each of six disorders (cancer, cardiovascular disease (CVD), dementia, hypertension, osteoporosis, and stroke) was <1.0 relative to the next oldest group. This delay in disease development and postponement of cognitive and physical decline in the oldest group amounted to a compression of morbidity (Fries 1980). Based on these findings, Andersen et al. (2012) suggest that a realistic and practical limit of human lifespan is 110115years, close to that of the oldest documented person in the world to date, who lived to 122 (Robine and Allard 1998).

Women have a lower mortality rate than men at every age, and women live longer than men in most human populations. Any given exceptional age, therefore, is more exceptional for men than for women. As noted by Sebastiani and Perls (2012) 1% of US women (but only 0.1% of men) born circa the turn of the last century lived to be 100. Potential explanations for this difference include hormonal and immune differences, hemizygosity of the X-chromosome in men (which may allow manifestation of unfavorable sex-linked variants), and unrecognized confounders [reviewed in Newman and Murabito (2013)].

Age at death in adulthood has a heritability of approximately 25% (summarized in Murabito et al. 2012). A population-based study of 2,872 Danish twin pairs born between 1870 and 1900 found that the heritability of adult lifespan was 0.26 in men and 0.23 in women (Herskind et al. 1996). This cohort was not only population-based but nearly non-censored and, with follow-up for 94years, encompassed essentially the entire human lifespan. Importantly, the heritability of longevity increases with greater age. The heritability of living to at least 100 has been estimated at 0.33 in women and 0.48 in men (Sebastiani and Perls 2012). Male and female siblings of US centenarians were 17-fold and eightfold more likely (compared with US Social Security data) to reach the age of 100, respectively (Perls et al. 2002). The increase in heritability of longevity at greater age is consistent between several studies. In over 20,000 Scandanavian twins, heritability of longevity was negligible from age 660, but increased with age thereafter (Hjelmborg et al. 2006). Long life was heritable in Icelanders aged over 70years (Gudmundsson et al. 2000). The siblings of Okinawan centenarians show increased adult survival probability that starts at age 55 and increases with age (Willcox et al. 2006); the authors speculate based in part on absence of many age-related diseases from Okinawan (Bernstein et al. 2004) and other centenarians (Evert et al. 2003), that these individuals have genetic factors that confer resistance to such diseases and increase the likelihood of reaching exceptional old age. The estimation of heritability also depends on how it is studied; Murabito et al. (2012) note that the Framingham heart study cohorts give much greater estimates of heritability when longevity is studied as a dichotomous trait (36% heritability for survival to 65 and 40% for survival to 85), compared with 16% heritability when age at death is treated as a continuous trait.

Clustering of longevity and healthy aging is observed in families. Parents of centenarians born in approximately 1870 were sevenfold more likely than their contemporaries to have lived to age 9099; offspring of centenarian parents showed lower prevalence of age-related disease than age-matched control groups (Atzmon et al. 2004). Exceptional familial clusters of extreme longevity have also been reported (Perls et al. 2000). Healthy aging is also heritable. Reed and Dick (2003) defined wellness in male twins as achieving the age of 70 free of heart attack, coronary surgery, stroke, diabetes or prostate cancer, and showed that this trait had a heritability exceeding 50%.

Environment and lifestyle likely constitute much of the remaining influence on human lifespan and healthspan. These factors have varied greatly over time and may not reflect the extrinsic factors that will affect the lifespan of babies born today. Many members of the elderly and centenarian cohorts under study today lived through times of caloric restriction (e.g., the Great Depression) and grew up before the use of antibiotics and vaccines became commonplace. The selective pressures that influenced their mortality are not identical to those experienced by later generations, and this is an important consideration for study design.

Phenotype definition is particularly important in genetic studies; it affects the interpretation and meaning of results, and the ability to compare to the results of other studies. Studies of longevity can include extreme longevity (defined as living beyond a specific extreme age) or age at death. Studies of healthy aging may use age to disease onset, successful aging or wellness (which can also have a variety of definitions), or other phenotypes (Manolio 2007). Linkage or family-based association study designs, longitudinal cohort studies, or case/control designs have been used. Family-based designs have the advantage of being robust to population stratification. Longitudinal cohorts have the advantage of limiting sampling bias, but take time and due to practical limits of size may not contain many individuals of extreme age. Sample size is a consideration for all these study designs. To date, the largest studies of LLI are in the low thousands of subjects; this is much smaller than the largest studies of common complex diseases (which now include over 100,000 subjects), despite the likely similar modest size of many of the genetic factors being sought.

Choice of a comparison group to contrast with exceptionally long-lived or exceptionally healthy elderly individuals is also critical. Health data for LLI can be compared with archived data for deceased individuals of the same birth cohort, but DNA samples from an ideal comparison group (such as their birth cohort) are not available. Case/control molecular genetic studies of long-lived or healthy aged individuals often compare elderly cases to younger controls. Potential pitfalls of such studies include inadequate detection and control for population stratification, particularly for populations that have experienced immigration of different ethnicities over time (Nebel and Schreiber 2005). The use of principal components analysis (Price et al. 2006) or genomic controls (Devlin and Roeder 1999) can mitigate this problem, as can the conduct of studies within specific ethnic groups (Barzilai et al. 2001). In the case/control design, the control group is also expected to contain individuals who will go on to become equivalent to cases; their presence in the control group reduces power. Environmental factors must be acknowledged in such studies as potential confounders; inevitably, the cases and controls have lived in different times and experienced different lifestyles. A way to mitigate some of these problems; however, is to choose controls that are no older than 50 (Halaschek-Wiener et al. 2008) because in modern day developed countries, mortality before age 50 is minimal. Choosing a comparison group <50years of age makes the control group essentially an unselected group with regard to mortality from age-related diseases. Choosing a control group in their 70 or 80, however, would exacerbate this issue, as the control group would fail to include individuals who died in their 50s or 60s.

Several studies, such as the Longevity Gene Study (Barzilai et al. 2001), the Leiden Longevity Study (LLS) (Mooijaart et al. 2011), the New England Centenarian Study (NECS) (Terry et al. 2004), and the Long Life Family Study (LLFS) (Newman et al. 2011) include comparisons of the offspring of LLI (who are assumed to have inherited some longevity factors) to contemporary age-matched controls. They have observed that the offspring of LLI have more favorable blood lipid profiles (Barzilai et al. 2001; Newman et al. 2011) and lower prevalence of hypertension and metabolic and cardiovascular disease (Atzmon et al. 2004; Westendorp et al. 2009; Newman et al. 2011) and all-cause mortality (Terry et al. 2004) than age-matched controls. Comparison of the offspring of LLI with their contemporaries controls for cohort effects such as variation in BMI in human populations over time; it has the limitation, however, of under-estimating the difference in phenotypes and genotypes that would presumably be observed if the LLI could be compared with their largely long-deceased birth cohort.

Linkage studies of long-lived sibships or extended pedigrees with exceptionally long-lived individuals have identified several putative and one replicated longevity linkage. In 2001, the NECS (Puca et al. 2001) reported a 10-cM sib-pair based linkage scan of 308 individuals in 137 sibships with exceptional longevity (defined as having a proband of at least 98 and a 91-year-old male or 95-year-old female sib). They found significant evidence for linkage of longevity to a region around D4S1564. Suggestive support for this region was obtained through analysis of 95 concordant pairs of fraternal male twins with a wellness phenotype (age at least 70 with no overt CVD or prostate cancer) (Reed et al. 2004). Initial convergence of two linkage studies with very different phenotypes led to excitement about this region and its suspected role in longevity and health. Subsequent study of the region focused in part on a regional biological candidate gene, microsomal triglyceride transfer protein (MTP), identified through haplotype analysis (Geesaman et al. 2003).

In 2010 a larger and higher density linkage study (Boyden and Kunkel 2010) expanded on the initial NECS resource, with a genome-wide linkage study of 279 families with multiple long-lived sibs 90years and older, including 129/137 of those previously described (Puca et al. 2001). A limitation of this study was the use of expected life span (estimated from age- and gender-specific life expectancies) for the 70% of subjects who were still living. This analysis of 9,751 SNPs found just-significant LOD scores at 3p22-24 and 9q31-34, as well as modest evidence for linkage at the original site, 4q22-25 and possibly at 12q. A larger study (Kerber et al. 2012) replicated the linkage of 3p22-24 to extreme longevity and identified possible additional loci. Working with 732 subjects from the Utah population database and database and population controls, including 433 Caucasian individuals aged 86109 who showed a phenotype including both excess individual longevity (the difference between observed and expected lifespan) and excess familial longevity (a weighted average of excess longevity for all family members), they used a linkage screen with 1,100 microsatellite markers to identify a strongly suggestive peak at 3p at the same position as Boyden and Kunkel. Meta-analysis of linkage in the Utah and New England data sets supported linkage at the chromosome 3 locus. Other linkage peaks were observed in the Utah data at 18q23-24, 8q23, and 17q21; meta-analysis provided additional support but not outright replication for 8q, 9q, and 17q. The new data; however, did not support linkage to chromosome 4 or chromosome 12. Larger sample sets and denser and more informative linkage analyses were pointing away from the original chromosome 4 linkage observation, and converging instead most strongly at 3q24-22.

Two linkage studies of successful aging in Amish individuals over 80years of age within a single 13-generation pedigree showed linkage to chromosomes 6, 7, and 14, different regions than those found in the longevity linkage studies. Successful aging was defined as cognitively intact and without depression, high functioning, and satisfied with life. These studies (Edwards et al. 2011; Edwards 2012) analyzed 263 cognitively intact Amish over 80years old (74 successfully aged and 189 normally aged) within 12 sub-pedigrees using 630,309 autosomal SNPs. Linkage was found at 6q25-27, as well as association of a SNP, rs205990, in the interval linked to the successfully aged phenotype. The chromosome 6 linkage identified in the Amish is different from those identified in the Utah and New England studies; this may reflect the different phenotype, or may be due to genetic factors specific to the Amish founder population.

The largest linkage study to date was done in the multi-site European Genetics of Healthy Aging (GEHA) Study, which looked at 2118 European full sib-pairs over 90years old (Beekman et al. 2013). GEHA found linkage at 4 regions: 14q11.2, 17q12-q22, 19p13.3-p13.11, and 19q13.11-q13.32. The chromosome 14 linkage is at a different site from that observed in the Amish study; the large chromosome 17 region overlaps the 17q21 locus observed by Kerber et al. Fine mapping of these linkage regions using GWAS data in a subset of 1228 unrelated nonagenarians and 1907 controls identified a SNP near APOE at the 19q locus as significantly associated with longevity. Apolipoprotein E (apoE) isoforms are known risk factors for cardiovascular disease (CVD) and Alzheimer disease (AD), likely due to their involvement in inflammation, elevated lipid levels, and oxidative stress (Huebbe et al. 2011). ApoE has three main isoforms: apoE2, apoE3 and apoE4. Combined modeling in the GEHA study showed that APOE4 (p=0.02) and APOE2 (p=1.0105) account for the linkage at 19q. The APOE linkage was characterized by absence of APOE4, but enrichment for APOE2 among the nonagenarians. In this study the APOE2 allele is the stronger association, and the authors refer to APOE as a longevity gene.

The multiple linkage signals observed in these studies likely indicate genetic heterogeneity of longevity and healthy aging in human populations. Interestingly, the GEHA study observed heterogeneity among its multiple geographic regions; Northern European subjects contribute most to some of the linkage peaks they observe, including the APOE locus. Gender-specific effects were also observed, with a male-specific linkage peak at 8p and female-specific ones at 15q and the 19q APOE locus (Beekman et al. 2013). While the lack of association at the other linkage regions in the GEHA study may be due to power limitations, it could also imply that multiple rare or private variants contribute to linkage but not association at these loci.

Candidate genes examined for association with longevity or healthy aging or related phenotypes fall into several categories. They include genes nominated based on observations of lifespan extension in model organisms; and genes involved in lipid metabolism, immune response and inflammation, stress response, and others. Candidate genes tested for association with longevity and related phenotypes have been the subject of several excellent reviews (Christensen et al. 2006; Wheeler and Kim 2011; Ferrario et al. 2012; Newman and Murabito 2013); an exhaustive listing is beyond the scope of this review.

Of the candidate genes assessed for association with longevity, variants in APOE and FOXO3A have been most consistently replicated, though some candidate genes have been associated with longevity phenotypes in more than one population but not in all populations tested; many more have been associated in a single study but failed to replicate in others (reviewed by (Christensen et al. 2006)). In a study of 1,344 healthy Italians aged 2290, APOE4 was found at lower frequency and APOE2 at higher frequency in elderly and centenarians than in younger individuals (e.g., Seripa et al. 2006); APOE2 is a putative protective factor in this context and APOE4 can be considered a frailty allele (Gerdes et al. 2000). FOXO3A is a homologue of the C. elegans Daf-16 gene that is important in control of lifespan in the worm (Hsin and Kenyon 1999); it is part of the insulin/IGF1 signaling pathway. FOXO3A variants have been associated with longevity in many populations (reviewed in Wheeler and Kim 2011).

Additional genes show promise of great relevance to healthy aging. A variant at CETP, for example, though inconsistently associated with longevity in different populations (reviewed by (Christensen et al. 2006)), in 213 Ashkenazi Jewish individuals of average age 98 is associated not only with longevity but also with additional aging-related phenotypes including a desirable lipid profile (Barzilai et al. 2003) and preservation of cognitive function (Barzilai et al. 2006). Other recent studies with extensive replication data are also encouraging. Association of a SNP in a heat shock factor gene, HSF2 with all-cause mortality was seen in the longitudinal Rotterdam Study (5,974 participants and 3,174 deaths), with replication in eight population-based cohorts (Broer 2012).

Other candidate genes have been associated with longevity or healthy aging phenotypes in some but not all studies. MTP, identified as a regional candidate at the 4q25 locus, failed to show replication of association with longevity in larger studies of approximately 1500 LLI each (Beekman et al. 2006; Bathum et al. 2005; Nebel et al. 2005). Progeria genes have shown association with longevity in some studies. A haplotype of SNPs at LMNA, the gene that is mutated in Hutchinson-Gilford progeria, was associated with long life (age >95years) in 873 LLI and 443 controls, and remained significant upon meta-analysis of 3,619 subjects from four independent samples (Conneely et al. 2012). Polymorphisms at WRN have shown inconsistent associations with age (Castro et al. 2000; Kuningas et al. 2006). Sirtuins mediate the effects of caloric restriction, a non-genetic factor known to increase life span in many organisms. The effect of polymorphisms in sirtuin genes (SIRT1-7) on longevity and age-related diseases was reviewed by Polito et al. (2010). There is evidence that variants in SIRT3 (Rose et al. 2003) are associated with longevity. A functional promoter variant at DNA repair gene EXO1 was associated with longevity in female centenarians (Nebel et al. 2009), but tagSNPs in the gene showed no association with longevity in men (Morris 2013).

Given the multifactorial nature and likely genetic heterogeneity of healthy aging and longevity, as well as environmental influences on these complex traits, it may not be reasonable to expect that replication of candidate gene studies would be uniform between populations. Reasons for lack of replication include limitations of sample size, rarity (low minor allele frequency) of actual variants, and small true effect sizes. Poorly designed or under-powered studies will result in false positives that legitimately fail to replicate. For studies of longevity and healthy aging, in particular, differences in phenotype or type of study will also result in findings that are non-uniform between studies. While larger case/control studies are frequently suggested as a solution to the limitations of present-day association studies, combining data from populations with different lifestyles and genetic backgrounds, even if well-matched for ethnicity, may obscure true association signals.

To date, SNPs in or near APOE are the only ones to achieve genome-wide significance (GWS, generally p5108) in genome-wide association studies (GWAS) of lifespan-related traits. In three GWAS of long-lived individuals vs. younger controls, APOE was significantly associated with longevity at the genome-wide level. The first of these included 763 long lived (94110years) and 1,085 control (4577years) from German biobanks and replication in an independent set of German samples (754 cases aged 95108, 860 controls aged 6075) (Nebel et al. 2011). Only rs4420638 near APOC1 and in linkage disequilibrium (LD) with APOE achieved GWS. GWAS of 403 unrelated nonagenarians (average age 94) from longevity families in the LLS vs. 1,670 controls (average age 58) showed similar results (Deelen et al. 2011a). Only one of 62 SNPs carried forward to meta-analysis with 4,149 nonagenarian cases and 7,582 younger controls from the Rotterdam study, the Leiden 85+ study and the Danish 1905 Cohort reached GWS, rs2075650 at TOMM40 near APOE. Meta-analysis of the APOE2 and APOE4 SNPs showed significant associations of both SNPs with longevity, with E2 being protective of long life (OR 1.31, CI 1.171.46, p=1.35106), and E4 being deleterious (OR 0.62, CI 0.560.68, p=1.331023). A third longevity GWAS (Sebastiani et al. 2012) included three phases: a discovery phase with 801 New England centenarians (aged 95119, many with a family history of extreme longevity) vs. 914 controls genetically matched by means of principal components analysis; a first replication in 253 centenarians (89114) vs. 341 genetically matched controls; and a second replication with 60 additional centenarians (100114) and unmatched controls. Of 243,980 SNPs analyzed only one, TOMM40 SNP rs2075650 near APOE, reached GWS. Inverse association of APOE4 with longevity (p=5.3103) was also detectable in the Southern Italian centenarians study (SICS) of 440 LLIs aged 90109 and 553 young controls aged 1845 (Malovini et al. 2011), despite the known lower frequency of the E4 allele in Southern, as compared with Northern, Europe (Haddy 2002).

Other GWAS of lifespan-related phenotypes revealed no associations that were significant at the genome-wide level. A GWAS of the Framingham health study (Lunetta et al. 2007) (258 Original Cohort and 1,087 Offspring individuals, members of the 330 largest families in the study) revealed no GWS SNPs for any of five aging-related phenotypes. Newman et al. (Newman et al. 2010) meta-analyzed four cohort studies in the cohorts for heart and aging research in genomic epidemiology (CHARGE) Consortium for survival to at least 90years of age. Cases were 1,836 people who achieved survival to at least 90; controls were 1,955 participants who died aged 5580. SNPs were genotyped and imputed in subjects of European ancestry, with systematic elimination of outliers and correction for population stratification. Replication was carried out in the LLS (950 long-lived probands and 744 partners of their offspring and 680 blood bank donors) and the Danish 1905 Cohort Survey (2,262 long-lived participants and 2007 Danish twin study controls aged 4668). No SNPs reached genome-wide significance.

Walter et al. (2011) conducted a meta-analysis of GWAS of nine longitudinal cohort studies in the CHARGE Consortium, including 25,000 unselected people of European ancestry. They analyzed two continuous traits, all-cause mortality, and event-free survival (where event was defined as myocardial infarction, heart failure, stroke, dementia, hip fracture, or cancer). No SNPs reached GWS for either phenotype. SNPs near APOE reached only nominal significance in the CHARGE study (Walter et al. 2011), in contrast to the results of GWAS of centenarians, in which APOE has been a significant and replicable finding. The CHARGE meta-analysis contained few extremely old individuals, and so in comparison with centenarian studies or those targeting long-lived healthy individuals, has examined earlier mortality and events, a different phenotype. The Framingham Study GWAS (Lunetta et al. 2007), which also showed no GWS SNPs also represents a much younger group, on average, than studies of oldest old or centenarians. This may mean that different genes and variants may come into play in different phases of aging, with APOE being most relevant at older ages. Earlier mortality is often related to lifestyle as well, and the heritability of aging is lower at younger ages, as described above.

A genome-wide association study of copy number variants (CNVs) in the Rotterdam study RS1 cohort, with replication in the RS2 cohort and the FHS, found that large common deletions are associated with mortality (vs. survival) at old age (Kuningas et al. 2011a). They tested 312 common CNV regions and measures of CNV burden for association with mortality during follow-up. A higher burden of CNVs of 500kb or more in size was associated with mortality. Two specific regions were also associated with mortality, 11p15.5 and 14q21.3. The 11p15.5 association, which would survive Bonferroni correction for 312 tests, includes insertions and deletions which were analyzed together relative to non-carriers; it contains 41 genes including some related to longevity or complex diseases. The 14q21.3 region contains no genes and is characterized only by deletions. Runs of homozygosity, which can indicate presence of recessive loci, were not associated with survival to old age in this cohort (Kuningas et al. 2011b).

Analyses of phenotypes that may influence long-term good health have also been undertaken. Personality traits are associated with healthy aging and longevity (Terracciano et al. 2008). In the LLFS, a GWAS of five personality factors in 583 families with 4,595 individuals and replication in 1,279 other subjects identified a locus associated with agreeableness, and identified several significant ageSNP interactions that may affect longevity through effects on personality (Bae et al. 2013).

In contrast to the results of longevity GWAS, GWAS of common complex diseases have revealed hundreds of SNPs associated with cancers, CVD, diabetes and other age-related diseases, albeit with increasing numbers of associations found with increasing GWAS size. One explanation for this may be that the phenotypes of healthy aging and longevity may be much more complex than those of these complex diseases, in part because they often (depending on phenotype definition) involve absence of specific complex diseases. If GWAS studies of survival to elderly ages are even more confounded by environmental (E) factors than GWAS of diseases, combining studies from different populations in pooled or meta-analyses may complicate the E effects even more. In studies of older individuals, it is particularly hard to control for E factors experienced over many decades of life.

SNPs at only one locus, APOE, have achieved Bonferroni-corrected levels of GWS in GWAS of longevity. By current standards these GWAS, which involved fewer than 1,000 centenarians, or a few 1,000 nonagenarians, are modest in size. Larger GWAS may in theory allow additional SNPs to achieve this threshold. There are other indications, however, that support the idea that SNPs that do not reach this threshold of GWS may be biologically important, either individually or through their joint effects. Several studies used a variety of techniques to analyze collections of nominally longevity-associated SNPs to determine if they act in concert to affect lifespan.

In the Framingham study GWAS of 5 aging-related phenotypes (Lunetta et al. 2007) observed that SNPs in some candidate genes, including SNPs near the Werner syndrome gene WRN and FOXO1A, as well as GAPDH, KL, LEPR, PON1, PSEN1, and SOD2 were associated with age at death. Kulminski and Culminskaya (2011) used Framingham Affymetrix 50K SNP data to perform GWAS of four endophenotypes (CVD, cancer, systolic blood pressure, and total cholesterol) to identify 63 SNPs that were associated at p<106 with at least one endophenotype. 76 genes at or near these SNPs were enriched in terms of Gene Ontology annotations related to aging-relevant processes. Yashin et al. (2010) hypothesized that lifespan depends on the number of small-effect longevity alleles present in individual genomes. They re-analyzed Framingham 550K SNP data and identified 169 SNPs associated at p<106. The number of these SNPs carried by an individual correlated with lifespan and explained 21% of its variance; in contrast, randomly chosen SNPs did not correlate with lifespan.

Gene set analysis of GWAS data from the LLS and Rotterdam studies was used to show that genes in the insulin/IGF-1 signaling (IIS) and telomere maintenance TM pathways are associated with longevity (Deelen 2011b). 1021 and 88 GWAS SNPs were identified within 10kb of 68 IIS and 13 TM genes, respectively. Both pathways were associated with longevity. Nine IIS genes (AKT1, AKT3, FOXO4, IGF2, INS, PIK3CA, SGK, SGK2, and YWHAG) and one TM gene (POT1) were the main determinants of the association.

Sebastiani et al. (2012) constructed a model in which 281 SNPs showed 89% sensitivity and 89% specificity to predict longevity in their GWAS Discovery set, and 5861% specificity and 5885% sensitivity in independent sets. They call this a genetic signature of exceptional longevity. These SNPs explain nearly 20% of the heritability of extreme longevity. They find that the TOMM40 SNP near APOE alone has poor predictive value; removing it from the model reduces specificity and sensitivity by only 1%. The 281 SNPs include 137 in 130 genes, including LMNA, WRN, SOD2, CDKN2A, SORCS1 and SORCS2, and GIP. This set of 130 genes is highly and significantly enriched for those related to Alzheimer disease (38 genes), 42 related to dementia, 38 to tauopathies, 24 to CAD, and several to neoplasms.

GWAS of the SICS Study of 410 LLI and 553 younger controls identified 67 SNPs that reached a permutation-defined level of genome-wide significance of p<104 (Malovini et al. 2011). Among them was rs10491334 at the calcium/calmodulin-dependent protein kinase IV (CAMKIV) that replicated in 116 additional LLI and 160 controls. Malovini et al. demonstrate that CAMK4 phosphorylates and activates survival proteins FOXO3A, AKT, and SIRT1. Homozygous carriers of the minor allele had lower CAMKIV protein expression and were under-represented among LLIs, consistent with a deleterious effect of this allele on longevity.

The biological relevance of other SNPs besides those at APOE is also strongly supported by similarities between the results of human GWAS and mouse lifespan studies. Eight of the ten top CHARGE SNPs detected by GWAS, but which did not achieve GWS, correspond to mouse lifespan quantitative trait loci (QTL) (Murabito et al. 2012). These studies connect GWAS findings that do not reach GWS with many genes that are relevant to aging or age-related diseases. In several cases, this convergence with genes of biological interest is statistically unlikely to be due to chance and is likely to reflect the presence of true association signals that are not consistent enough to be replicated predictably as candidate genes or achieve GWS, or have effects that are too subtle to be detected individually. Such potential true signals may be more affected by E factors than those that have been replicated, i.e., APOE and FOXO3A. As pointed out by Yashin et al., the same sets of variants would not be expected to work in all populations because of differences in environment (Yashin et al. 2010).

Several recent studies have shown that centenarians do not carry smaller numbers of risk alleles for common complex diseases than average people. In an important paper in 2010, Beekman et al. (2010) studied two case/control collections: (1) 723 nonagenarian siblings (mean age 94) from the LLS vs. 721 unrelated younger controls (mean age 52), and (2) 979 long-lived individuals over 85 (mean age 87) from the pop-based Leiden 85+ study vs. 1,167 younger controls (mean age 41) from the Netherlands Twin Register. They looked at 30 SNPs known to be associated with CVD, cancer or type 2 diabetes (T2D). The cases and controls each carried an average of 27 disease risk alleles. The distribution of risk alleles was the same in elderly and young subjects. Beekman et al. note that GWAS-identified disease risk alleles do not compromise human longevity and suggest that a lack of rare disease factors, or the presence of protective factors, is at work in the long-lived individuals. It is important to note, however, that CVD, cancer, and T2D are diseases that have very clear lifestyle components and that part of the effect could be due to lifestyle differences.

Mooijaart et al. (2011) extended this observation the following year, showing that SNPs associated with T2D and identified by GWAS are not major determinants of the beneficial glucose tolerance that characterizes familial longevity. They compared the offspring of the LLS long-lived individuals with the offsprings spouses and other controls. The LLS offspring had a better metabolic profile and better glucose tolerance than same-age controls, although the frequency of 15 known T2D SNPs did not differ between the two groups. When individuals were compared within each group, however, glucose levels did correlate with the number of T2D SNPs. They speculate that the LLS offspring may have protective factors that improve their metabolic profile and glucose tolerance in spite of the presence of T2D GWAS SNPs. This comparison, using same-age groups of individuals, clearly points to protective genetic factors contributing to preservation of a healthy phenotype, rather than lifestyle and environmental factors that should be very similar (at least in adulthood) between the offspring and their spouses.

Sebastiani et al. (2012) also noted that there was not a substantial difference in the numbers of 1,214 known disease-associated SNPs in centenarians and controls. A similar observation was made in their whole genome sequence data from one male and one female supercentenarian (Sebastiani et al. 2011).

These important and perhaps surprising results show that extreme longevity, and the long-term good health that often accompanies it, is not incompatible with the presence of many disease risk alleles. At least for the common SNPs associated with common complex diseases, it is not the absence of bad alleles, but more likely the presence of good alleles that influences longevity, though effects of good environmental factors may also contribute. Protective factors of some kind may allow these risk variants to not be manifest. These results also have implications beyond the study of longevityin an age when substantial effort is being invested in personalized disease risk prediction, the presence of many disease alleles that are non-penetrant in some individuals potentially complicates predictions of disease.

One mechanism for a lack of effect by an undesirable allele is the buffering mechanism explored by Barzilai et al. They propose that some individuals who show exceptional longevity may do so despite the presence of unfavorable alleles because those alleles are buffered by favorable alleles in other genes (Bergman et al. 2007). They suggest that buffering gene variants (longevity variants) will show a monotonic increase in frequency from early old age (65) to later ages; examples of buffering genotypes are CETP VV, APOC3 CC, and a +2019 deletion in ADIPOQ. Buffered alleles, in contrast, should show a U-shaped frequency curve, higher at younger ages, dipping low in early old age, and then increasing in the exceptionally old (who have the buffering protective genotype that allows disease-related variants to accumulate); examples of buffered genotypes are heterozygotes for deleterious alleles of KLOTHO and LPA. Importantly, Bergman et al. use a cross-sectional study design, with 1,200 subjects in their 611th decades of life to show experimental support for the buffering hypothesis; their data support the idea that CETP VV genotype buffers the deleterious effects of an LPA genotype. They show a genetic interaction between CETP genotype and LPA; LPA heterozygotes with the CETP IV/II genotypes monotonically decrease in frequency with age, but those in CETP VV individuals increase from age 70 onward. They argue that case/control analyses are insufficient to reveal this effect because it does not reveal the shape of the allele frequency age curve.

Earlier observations are also explained by a buffering mechanism. De Benedictis et al. (1998) described an age-related convex trajectory of a 3APOB-VNTR genotype that they interpret as consistent with crossing mortality curves relevant to subgroups of individuals with different genotypes. A X-sectional study of 800 healthy aging subjects from 18 to 109years free of clinically apparent disease genotyped variants in APOA1, APOC3, and APOA4 (Garasto et al. 2003). They noted that an allele of APOA1 that correlated with higher serum LDL-C was paradoxically increased in frequency in the oldest old. The authors called it another genetic paradox of centenarians. While this observation could reflect population stratification in the different age groups, it may also be due to the U-shaped curve of a buffered gene.

The buffering mechanism may also explain some of the inconsistency in the findings for MTP. Huffman et al. (2012) find that MTP CC is a deleterious genotype that is buffered by any of three longevity genotypes of CETP, APOC3, or ADIPOQ. MTP CC shows a U-shaped curve, declining ages 5585, and then dramatically increasing in those who live 90 or more years. If this MTP genotype is observed at high frequency in centenarians, but only in the presence of specific protective variants, this may in part explain why the linkage at chromosome 4 was not observed consistently between studies.

Buffering has been described in model organisms. The heat-shock protein Hsp90 is known to buffer genetic variation in Drosophila, allowing it to accumulate under neutral conditions (Rutherford and Lindquist 1998). Such a gene is known as a phenotypic capacitor, and it masks the presence of phenotypic variation. It is interesting to speculate that protective genetic variants carried by centenarians may be capacitors for the disease risk variants we now know they carry at, on average, the same frequency as other people. Identification of buffering/capacitor genes and study of their function will be necessary to understand the longevity phenotype. It will also be important to determine if such capacitors operate in healthy aging as well as extreme longevity. Because such variants are likely rare, intensive study of rare individuals at the upper ends of the human lifespan and healthspan, perhaps by whole genome sequencing and examination of unusual variants they carry, is paramount.

The interaction between buffering and buffered genes and genotypes also has implications for study design. The exquisite studies carried out by Barzilais group are done in a single well-defined ethnicity, Ashkenazi Jewish individuals. Since a buffered gene will only show a distinctive U-shaped curve in the presence of its buffer, and a buffer may only be advantageous in the presence of a deleterious gene that it buffers, this underscores the importance of avoiding population stratification in such studies. If some of the associations detected to date in case/control studies of healthy aging and longevity are actually underlain by genotypes with U-shaped curves, the choice of ages for the cases and controls will greatly affect whether an association is detected, and may explain some failures of associations to replicate. Finally, the concept of buffering genes has implications for the use of centenarians, or exceptionally healthy elderly individuals as super-controls for disease studies; if the exceptional elderly are healthy because of a protective factor rather than lack of a disease allele, their use as an extreme comparison group may not necessarily be helpful.

Given that lifestyle is expected to have a greater impact than genetics on healthy aging, it seems unlikely that differences in lifestyle are not confounding association studies of longevity and healthy aging. It is challenging to quantify lifestyle in an optimal comparison group for, for example, centenarians. Younger control groups inevitably have different lifestyles than the elderly had at their age. For example, the CHARGE consortium (Newman et al. 2010), which compared individuals who survived to at least 90 to those who died aged 5580, found that the younger controls had higher rates of smoking.

The Longevity Gene Study overcame the birth cohort limitation using pre-existing lifestyle data from 3,164 NHANES controls of the same birth cohort as 477 Ashkenazi Jewish individuals aged 96109 (Rajpathak et al. 2011). They found no obvious differences in lifestyle and suggested that the long-lived individuals may interact with lifestyle factors differently than others. This study, however, did note subtle differences between the long-lived and comparison groups. They saw significantly fewer obese men, more overweight women, and fewer obese women in the long-lived group; in addition, more control men smoked. These differences, combined with recall limitations of the long-lived group, imply that this analysis may have missed many small lifestyle differences that could add up to substantial health differences. It will likely be difficult to take into account all but the largest lifestyle factors when planning GxE studies of longevity and healthy aging. Biomarkers of exposures may vary not only with exposure but also over time, complicating the use of such methods for these phenotypes.

Mitochondria are thought to be important to aging due to their key roles in oxidative phosphorylation, cell metabolism, and apoptosis. A relationship of variation in the mitochondrial genome with health and/or longevity is implied by the observation that age at death correlates more closely with the age at death of a persons mother more so than that of the father (Brand et al. 1992). Associations of mitochondrial genome sequence variants or haplogroups (combinations of specific variants that correlate with specific populations) with healthy aging or longevity have been noted in many populations including, for example, Italian (De Benedictis et al. 1999), Japanese (Tanaka et al. 1998), Amish (Courtenay et al. 2012), Chinese Uygur (Ren et al. 2008), Costa Rican (Castri et al. 2009), Ashkenazi Jewish (Iwata et al. 2007), Irish (Ross et al. 2001), and Finnish individuals (Niemi et al. 2003). The associations observed are inconsistent between populations and do not involve the same variant or haplogroup. This lack of consistency may be due in part to the relatively small size of many of these studies. Three common problems have been noted about such studies: inadequate matching of cases and controls, inadequate correction for multiple tests, and undetected population stratification (Shlush et al. 2008).

Interestingly, when the frequencies of different mitochondrial haplogroups are plotted for Italian individuals aged 20 to over 100, the curve shapes observed include monotonic increase for haplogroup J, and a U-shaped curve for haplotype H (de Benedictis et al. 2000), reminiscent of the longevity and buffered variants described earlier. A variant at the origin of replication of the mitochondrial heavy strand, C150T, has been observed at higher frequencies in centenarians, both through inheritance and through somatic increase in frequency, with some individuals achieving homoplasmy for this variant in their lymphocytes and monocytes, but not in granulocytes; a selective advantage of achieving high frequency of this variant in at least some cell types has been suggested (Zhang et al. 2003). Interactions between nuclear genome variants and both inherited and somatic mitochondrial variants have also been suggested to play a role in aging and longevity (Santoro et al. 2006; Tranah 2011).

Sebastiani et al. (2011) recently reported the whole genome sequencing of one male and one female supercentenarian of European ancestry from the NECS. The genomes of these exceptionally long-lived individuals were similar, in terms of the rate of nonsynonymous SNPs and number of indels, to other genomes sequenced to date. They have a similar number of known disease-associated variants to other genomes showing that their exceptional lifespan does not seem to be due to lack of known disease-associated variants. It is possible, though, that they failed to inherit a combination of variants that would have acted together to cause disease. Both supercentenarians lacked APOE4 alleles. They do not carry most of the longevity variants reported previously in the literature, implying that these known variants are not necessary for longevity. It is possible that they carry as yet undiscovered protective variants. One per cent of the variants observed were novel. Interestingly, an excess of coding region variants was seen in genes closest to GWAS-identified longevity variants, an observation that supports the idea that rare variants of these genes may contribute to the longevity phenotype.

Telomeres are indisputably important to aging. Telomeres shorten with age and are considered to be a biomarker of age. The role of telomere biology in healthy aging and disease was recently reviewed (Zhu et al. 2011). Leukocyte telomere length (LTL) has been correlated with measures of health and ability in elderly individuals. In a community-based cohort of 70- to 79-year-olds, LTL was associated with more years of healthy life; LTL was suggested to be a biomarker of healthy aging (Njajou et al. 2009). Louisiana Healthy Aging Study results concurred with this observation; LTL was correlated with measures of healthy aging in an age-dependent way (Kim et al. 2012). LTL was also found to correlate positively with physical ability (but not cognitive function) in Danish twins aged at least 77years (Bendix et al. 2011) and inversely with disability in American seniors (Risques et al. 2010). Ashkenazi centenarians and their offspring also showed longer telomeres, for their age, than controls; longer telomeres correlated with less disease (Atzmon et al. 2010). In contrast, in a study of Canadian Super-Seniors (individuals aged at least 85 and never diagnosed with cancer, cardiovascular disease, Alzheimer disease, major pulmonary disease or diabetes) the healthy oldest-old did not have exceptional telomere length for their age, but showed less variability in telomere length than mid-life controls, implying that they may be selected for optimal rather than extreme telomere length (Halaschek-Wiener et al. 2008).

Variation in genes involved in telomere maintenance has also been associated with longevity. One SNP at SIRT1 (Kim et al. 2012) and one in TERC (Soerensen et al. 2012) are associated with both LTL and longevity. Detailed analysis of TERT and TERC in Ashkenazi centenarians showed an excess of genetic variation in both genes in the centenarians and identified a TERT haplotype associated with extreme longevity (Atzmon et al. 2010). Gene set analysis of GWAS data also supported the relevance of telomere maintenance (Deelen et al. 2013). Overall, the relationship between telomeres, aging, healthy aging, and longevity is multi-layered. Telomere maintenance is an important process in aging, and also a biomarker of it. LTL is a biomarker of aging and of healthy aging. Variation in telomere maintenance genes appears to affect both telomere length, and life span and health span in humans.

Two recent large-scale analyses of data from GWAS studies have established that mosaicism for large genomic alterations increases with age (Laurie et al. 2012; Jacobs et al. 2012). In one study, data for 50,222 subjects found that <0.5% of people aged <50, and 23% of elderly (2.7% in subjects >80years), have detectable mosaicism in peripheral blood. Age was a significant predictor of mosaic status, but sex, ancestry, and smoking status were not. The second study used data from 31,717 cancer cases and 26,136 controls from 13 GWAS studies and found detectable clonal mosaicism in 0.87% of individuals. In the cancer-free controls, they found mosaicism in 0.23% of those <50years old and in 1.91% of those aged 7579, a significant difference (p=4.8108). Somatic mosaicism (heteroplasmy) of the mitochondrial genome also increases over the lifespan (Sondheimer et al. 2011). Of course, telomere shortening is another somatic genomic change that occurs over the human lifespan. Such somatic changes are both a genetic aspect of aging and an aging-related phenotype.

Epigenetics, at the interface between the genome and the environment, is emerging as an important factor in longevity, and has been the subject of recent excellent reviews (Gravina and Vijg 2010; Ben-Avraham et al. 2012). Methylation patterns change with age, and discordance in methylation between MZ twins also increases with age (Talens et al. 2012), an observation consistent with the effect of environment and lifestyle on the epigenome. Studies of DNA methylation support the idea that aging is associated with a relaxation of epigenetic control and that this epigenetic drift may affect the development of aging-related diseases (Gravina and Vijg 2010). An epigenome-wide association scan (EWAS) identified age-related differentially methylated regions as well as differentially methylated regions associated with age-related phenotypes (Bell et al. 2012). Whole genome bisulfite sequencing of DNA from CD4+ T cells of a centenarian and a newborn identified differentially methylated regions that were usually hypomethylated and less correlated with methylation of adjacent CpG dinucleotides in the centenarian (Heyn et al. 2012). These results support the idea that small cumulative DNA methylation changes accumulate over a lifetime. Age-related temporal changes in DNA methylation also show significant familial clustering, indicating that methylation maintenance is a familial trait (Bjornsson et al. 2008). A study of DNA methylation in centenarians and their offspring compared with the offspring of non-long-lived individuals and young individuals showed that the offspring of the centenarians delay age-related methylation changes (Gentilini 2012). A landmark paper by Hannum et al. (2013) offers an explanation for this familiality. They used methylome analysis to compare human aging rates in individuals of age 19101 and identify methylation QTLs (meQTLs) (including one at methyl-CpG binding domain protein 4) that affect it. Indeed, trans-generational epigenetic inheritance of extended lifespan has been demonstrated in C. elegans (Greer et al. 2011).

It is likely that the effects of epigenetic changes manifest in part by effects on gene expression. Longevity-selected lines of Drosophila show gene expression profiles that are similar to younger control flies (Sarup et al. 2011). This type of observation is more difficult to make in humans, however. Several human studies have compared gene expression between LLI and younger individuals. Blood miRNA expression differences between LLI and younger controls identified genes known to be differentially expressed in age-related diseases (ElSharawy et al. 2012). This study design, however, does not allow discrimination between genes that are differentially expressed because they are involved in longevity, related to chronological age, or affected by environmental differences between the old and young groups. A cross-sectional analysis of individuals aged 5090, and centenarians, was used to identify a miRNA, miR-363*, whose expression declined with age but was preserved at youthful levels in the centenarians (Gombar et al. 2012). The Leiden Longevity Study, however, used LLI and their offspring to show that RPTOR in the mTOR pathway is differentially expressed between the offspring of the LLI and their spouses (Passtoors et al. 2013). The study design issues that are important to avoid confounding by lifestyle factors in studies of inherited factors will be even more important in gene expression studies. It seems likely that as yet unidentified genetic factors and lifestyle practices that help us maintain a favorable epigenetic profile and optimal gene expression will be important in longevity and healthy aging.

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Genetics of healthy aging and longevity | SpringerLink

Overview

The type and severity of the side effects from high-dose chemotherapy and allogeneic stem cell transplant are influenced by the degree of HLA matching between donor and recipient; the condition and age of the patient; the specific high-dose chemotherapy treatment regimen; and the degree of suppression of the immune system. The safety of allogeneic transplant has improved a great deal because of advancements in supportive care to manage the many potential side effects. While high doses of chemotherapy and radiation therapy can potentially affect any of the bodys normal cells or organs, the more common side effects are well described and include the following:

Bone Marrow Suppression

High-dose chemotherapy directly destroys the bone marrows ability to produce white blood cells, red blood cells and platelets. Patients experience side effects from low numbers of white blood cells (neutropenia), red blood cells (anemia) and platelets (thrombocytopenia). Patients usually need blood and platelet transfusions to treat anemia and thrombocytopenia until the new graft beings producing blood cells. The duration of bone marrow suppression can be shortened by infusing an optimal number of stem cells and growth factors that hasten the recovery of blood cell production.

Infections

During the 2-3 weeks it takes the new bone marrow to grow and produce white blood cells, patients are susceptible to infection and require the administration of antibiotics to prevent bacterial and fungal infections. Bacterial infections are the most common during this initial period of neutropenia. Stem cells collected from peripheral blood tend to engraft faster than bone marrow and may reduce the risk of infection by shortening the period of neutropenia. The growth factor Neupogen also increases the rate of white blood cell recovery and has been approved by the Food and Drug Administration for use during allogeneic stem cell transplant.

The immune system takes even longer to recover than white blood cell production, with a resultant susceptibility to some bacterial, fungal and viral infections for weeks to months. Patients are often required to take antibiotics to prevent infections from occurring for weeks to months after initial recovery from allogeneic stem cell transplant. Prophylactic antibiotic administration can prevent Pneumocystis carinii pneumonia and some bacterial and fungal infections. Prophylactic antibiotics can also decrease the incidence of herpes zoster infection, which commonly occurs after high-dose chemotherapy and allogeneic stem cell transplant.

Mucositis

Mucositis is an inflammation of the lining of the mouth or gastrointestinal (GI) tract. This condition is also commonly referred to as mouth sores. Mucositis is one of the most common side effects of the intensive therapy that precedes stem cell transplantation. The majority of patients treated with a stem cell transplant will develop mucositis. In fact, patients undergoing stem cell transplantation have complained that mucositis is the single most debilitating side effect from treatment.[1]

Chemotherapy and radiation therapy are effective at killing rapidly dividing cells, a hallmark characteristic of some cancers. Unfortunately, many normal cells in the body are also rapidly dividing and can sustain damage from chemotherapy as well. The entire GI tract, including the mouth and the throat, is made up of cells that divide rapidly. For this reason, the GI tract is particularly susceptible to damage by chemotherapy and radiation treatment, which results in mucositis.

Until recently, the only approaches to managing oral mucositis included good oral care; mouthwashes; cryotherapy (sucking on ice chips) to minimize the damage from chemotherapy drugs; Salagen, a drug that stimulates salivary flow; and other investigational treatments.

A promising new approach to the prevention and treatment of mouth sores is the use of growth factors. Growth factors are natural substances produced by the body to stimulate cell growth. The body produces many different types of growth factors. Kepivance (palifermin)is a type of growth factor that is made through laboratory processes to mimic the natural compound made in the body. Kepivance has properties that stimulate the cells that line the mouth and GI tract (called epithelial cells) to grow and develop, which may help to reduce mucositis.

Kepivance is the first FDA-approved drug for the prevention and treatment of oral mucositis. In clinical trials, Kepivance has demonstrated the ability to protect the epithelial cells from the damaging effects of radiation, and chemotherapy in patients undergoing autologous stem cell transplants[2],[3],[4],[5] and is being further evaluated to determine whether it may benefit patients undergoing allogeneic stem cell transplantation.

Veno-Occlusive Disease of the Liver (VOD)

High-dose chemotherapy can result in damage to the liver, which can be serious and even fatal. This complication is increased in patients who have had a lot of previous chemotherapy and/or radiation therapy, a history of liver damage or hepatitis. Veno-occlusive disease of the liver typically occurs in the first 2 weeks after high-dose chemotherapy treatment. Patients typically experience symptoms of abdominal fullness or swelling, liver tenderness and weight gain from fluid retention. Development of strategies to prevent or treat veno-occlusive disease is an active area of clinical investigation.

Interstitial Pneumonia Syndrome (IPS)

High-dose chemotherapy can cause damage directly to the cells of the lungs. This may be more frequent in patients treated with certain types of chemotherapy and/or radiation therapy given prior to the transplant. This complication of transplant may occur anytime from a few days after high-dose chemotherapy to several months after treatment. This often occurs after a patient has returned home from a transplant center and is being seen by a local oncologist.

Patients typically experience a dry non-productive cough or shortness of breath. Both patients and their doctors often misinterpret these early symptoms. Patients experiencing shortness of breath or a new cough after allogeneic transplant should bring this to the immediate attention of their doctor since this can be a serious and even fatal complication.

Graft-versus-Host Disease (GVHD)

Graft-versus-host disease is a common complication of allogeneic stem cell transplant. Lymphocytes contained in donated marrow or blood stem cells cause a reaction called graft-versus-host disease. In this reaction, lymphocytes from the donor attack cells in the body of the recipient especially in the skin, gastrointestinal tract and liver. The common symptoms of acute graft-versus-host disease are skin rashes, jaundice, liver disease and diarrhea. Graft-versus-host disease also increases a patients susceptibility to infection. Graft-versus-host disease can develop within days or as long as 3 years after transplantation. Generally, graft-versus-host disease that develops within 3 months following transplantation is called acute graft-versus-host disease, whereas graft-versus-host disease that develops later is called chronic graft-versus-host disease.

Removal of T-lymphocytes from the stem cell collection and immunosuppressive drugs such as methotrexate, cyclosporine, prednisone and other new agents administered after bone marrow or blood stem cell infusion are used to prevent or ameliorate graft-versus-host disease. Graft-versus-host disease can also have an anti-cancer effect because donor lymphocytes can kill cancer cells as well as normal cells. When donor lymphocytes kill cancer cells, doctors refer to this as agraft-versus-cancer effect. There are ongoing studies attempting to control this graft-versus-cancer reaction for therapeutic purposes.

Graft Failure

Graft failure occurs when bone marrow function does not return. The graft may fail to grow or be rejected in the patient resulting in bone marrow failure with the absence of red blood cell, white blood cell and platelet production. This results in infection, anemia and bleeding. Insufficient immune system suppression is the main cause of graft rejection. Graft failure may also occur in patients with extensive marrow fibrosis before transplantation, a viral illness or from the use of some drugs (such as methotrexate). In leukemia patients, graft failure often is associated with a recurrence of cancer; the leukemic cells may inhibit the growth of the transplanted cells. In some cases, the reasons for graft failure are not known.

Long-Term Side Effects of Allogeneic Stem Cell Transplant

There are several long-term or late side effects that result from the chemotherapy and radiation therapy used with allogeneic stem cell transplant. The frequency and severity of these problems depends on the radiation or chemotherapy that was used to treat the patient. It is important to have the doctors providing your care explain the specific long-term side effects that can occur for the actual treatment they propose. Some examples of complications you should be aware of include the following:

Cataracts:Cataracts occur in the overwhelming majority of patients who receive total body irradiation in their treatment regimen. In patients who receive chemotherapy without total body irradiation, cataracts are much less frequent. The onset of cataracts typically begins 18-24 months following treatment. Patients who have received large doses of steroids will have an increased frequency and earlier onset of cataracts. Patients are advised to have slit lamp eye evaluations annually and early correction with artificial lenses.

Infertility:The overwhelming majority of women who receive total body irradiation will be sterile. However, some prepubertal and adolescent females do recover ovulation and menstruation. In patients who receive chemotherapy only preparative regimens, the incidence of sterility is more variable and more age related, i.e., the older the woman is at the time of treatment the more likely chemotherapy will produce anovulation. These are important considerations because of the need for hormone replacement. All females should have frequent gynecologic follow-up.

The overwhelming majority of men who receive total body irradiation will become sterile. Sterility is much more variable after chemotherapy only regimens. Men should have sperm counts done to determine whether or not sperm are present and should be examined over time, as recovery can occur.

New cancers:Treatment with chemotherapy and radiation therapy is known to increase the risk of developing a new cancer. These are called secondary cancers and may occur as a late complication of high-dose chemotherapy. Patients treated with high-dose chemotherapy and allogeneic stem cell transplantation appear to have an increased risk of developing a secondary cancer. In a report evaluating almost 20,000 patients treated with allogeneic stem cell transplantation, 80 patients developed a new cancer. This represents an approximate 2.5% greater risk compared to normal individuals

The longer patients survived after high-dose chemotherapy and allogeneic stem cell transplantation, the greater the risk of developing a secondary cancer. Patients treated with total body irradiation appear to be more likely to develop new cancer than those treated with lower radiation doses or high-dose chemotherapy. High-dose chemotherapy and allogeneic stem cell transplant is increasingly used to treat certain cancers because it improves cure rates. Patients should be aware of the risk of secondary cancer following high-dose chemotherapy treatment and discuss the benefits and risks of high-dose chemotherapy with their primary cancer physician.

References

1. Bellm LA, Epstein JB, Rose-Ped A, et al. Patient Reports of Complications of Bone Marrow Transplantation. Support Care Cancer. 2000;8:33-39.

2. Spielberger R, Emmanouilides C, Stiff P. Use of recombinant human keratinocyte growth factor (rHuKGF) can reduce severe oral mucositis in patients (pts) with hematologic malignancies undergoing autologous peripheral blood progenitor cell transplantation (auto-PBPCT) after radiation-based conditioning results of a phase 3 trial. Proceedings of the 39th meeting of the American Society of Oncology 2003;22: Abstract #3642.

3. Emmanouilides C, Spielberger R, Stiff P, Rong A, et al. Palifermin Treatment of Mucositis in Transplant Patients Reduces Health Resource Use: Phase 3 Results. Proc Am Soc Hem. Blood. 2003;102(11):251a, Abstract #883.

4. Syrjala KL, Hays RD, Kallich JD, Farivar SS, et al. Impact of Oral Mucositis and Its Sequelae on Quality of Life. Proc Am Soc Hem. Blood. 2003;102(11):751a, Abstract #2771.

5. Stiff P, Bensinger W, Emmanouilides C, Gentil T, et al. Treatment of Mucositis with Palifermin Improves Patient Function and Results in a Clinically Meaningful Reduction in Mouth and Throat Soreness (MTS): Phase 3 Results. Proc Am Soc Hem. Blood 2003;102(11):194a, Abstract #676.

Continued here:
Complications or Side Effects of Allogeneic Stem Cell ...

Recognition.The antigen or cell is recognized as nonself. To differentiate self from nonself, unique molecules on the plasma membrane of cells called themajor histocompatibility complex (MHC)are used as a means of identification.

Lymphocyte selection.The primary defending cells of the immune system are certain white blood cells called lymphocytes. The immune system potentially possesses billions of lymphocytes, each equipped to target a different antigen. When an antigen, or nonself cell, binds to a lymphocyte, the lymphocyte proliferates, producing numerous daughter cells, all identical copies of the parent cell. This process is calledclonal selectionbecause the lymphocyte to which the antigen effectively binds is selected and subsequently reproduces to make clones, or identical copies, of itself.

Lymphocyte activation.The binding of an antigen or foreign cell to a lymphocyte may activate the lymphocyte and initiate proliferation. In most cases, however, a costimulator is required before proliferation begins. Costimulators may be chemicals or other cells.

Destruction of the foreign substance.Lymphocytes and antibodies destroy or immobilize the foreign substance. Nonspecific defense mechanisms (phagocytes, NK cells) help eliminate the invader.

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Specific Defense (The Immune System) - Written by Teachers

What is the Immune System?

Just like the human immune system, the animal immune system is an amazingly intricate and complex system that keeps animals healthy and protects them against all sorts of invaders including viruses, bacteria, microbes, parasites and toxins. The subject of immunity and the immune system is one that regularly crops up in conversation, in the newspaper and in magazines not to mention the vast number of adverts promoting products aimed at working with this system.

If the immune system is weakened, every body system in the animal body is at risk. In order to understand the true importance of the immune system, we firstly need to understand a little bit about how the immune system works.

How does the animal Immune System Work?

The animal immune system has many different components both inside and outside the animal body. If we start from the outside we will see that an animals body has many different barriers that form part of his or her immune system.

While an animals skin is obviously a physical barrier to many germs and toxins, it also contains special immune cells that act as warning bells to alert the immune system to any foreign material, while also regulating the immune response to this material this is evident in the skin of an animal reacting to fleas or certain plants.

The skin also secretes antibacterial substances that hinder the growth of excess bacteria on the skin. An animals eyes, nose and mouth are all possible ports of entry for invading germs but an animals tears, nasal secretions and saliva all contain enzymes or cells of the immune system to keep the invaders at bay.

The mucous membrane linings of the respiratory, gastrointestinal, and genitourinary tracts also provide the one of the first lines of defense against invasion by microbes or parasites. Internal defense mechanisms for an animal include the Lymphatic system, Thymus gland, bone marrow, spleen, white blood cells and antibodies.

The immune system is amazingly resilient and powerful system, protecting an animal daily from a wealth of viruses, bacteria, foreign cells and an animals own body cells that have "gone bad" such as cancer cells. However, like with most amazing systems, sometimes things go wrong.

Many animals suffer from allergies that are caused by a hypersensitivity reaction of the immune system to certain allergens in the environment. When these antigens enter the body system, the immune system tends to over react and antibodies quickly cause the release of histamine which results in an allergic reaction.

These reactions differ in severity and may include itchiness, lesions, blocked sinus, Asthma, Eczema and Contact dermatitis. When cells of the immune system are over-produced, they become out of control and the result is cancer or auto immune diseases, for example in humans when the body over produces white blood cells, the result is leukemia.

Antibiotics are created for the purpose of treating bacterial infections when an animals immune system cannot mount an adequate response. So does it not stand to reason that if an animals immune system were strong enough it would not need the antibiotics? Antibiotics are specific chemicals aimed at killing off the targeted bacteria.

They are not effective against viruses and should not be given to a pet for a viral infection. Unfortunately antibiotics have been excessively and improperly used -The more you give your animals antibiotics, the more you depress their immune systems - and the more depressed their immune systems are, the more likely they are to get another infection and if they get another infection they are given another antibiotic and so the vicious cycle continues!

There is a lot that can be done naturally to help boost your pets immune system. A strong, healthy immune system is the best armor you can give your animal. Here are some of the lifestyle factors that you can employ with your pets to keep their immune systems in peak condition and able to ward off recurrent infections:

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Immune System - PetAlive

HIV, AIDS and the Immune SystemAIDS, HIV and The Immune SystemIntroductionThe virus responsible for the condition known as AIDS (Acquired Immunodeficiency Syndrome), is named HIV (Human Immunodeficiency Virus). AIDS is the condition whereby the body's specific defense system against all infectious agents no longer functions properly. There is a focused loss over time of immune cell function which allows intrusion by several different infectious agents, the result of which is loss of the ability of the body to fight infection and the subsequent acquisition of diseases such as pneumonia. We will examine the virus itself, the immune system, the specific effect(s) of HIV on the immune system, the research efforts presently being made to investigate this disease, and finally, how one can try to prevent acquiring HIV.The VirusHIV is one member of the group of viruses known as retroviruses. The term "retrovirus" stems from the fact that these kinds of viruses are capable of copying RNA into DNA. No other organism so far discovered on earth is capable of this ability. The virus has two exact copies of single-stranded RNA as its basic genetic material (genome) in the very center of the organism. The genome is surrounded by a spherical core made of various proteins in tightly-packed association with one another. The core is itself surrounded by a membrane (called an "envelope", made of fat [lipids] and various membrane-bound proteins). One of the membrane-boundproteins can bind to a particular protein on the surface of certain immune cells, called T-cells (we'll talk about these in a minute) which results in the virus becoming physically attached. Upon binding, the virus is brought inside of the T-cell (cells do this kind of thing all of the time), and the envelope is removed by enzymes normally present inside the cell. The internal core is thus exposed, and it too is broken-down. This last phase results in exposure of the virus's RNA genetic material. An enzyme attached to the RNA, known as "reverse transcriptase", begins to make a complimentary base-pair single-strand copy of the RNA into DNA (please see What the Heck is PCR? ). The single strand of DNA is also copied by the same enzyme to form double-stranded DNA. This DNA inserts somewhere into one of the 46 chromosomes within our cells, and there it is used as a template for production of all of the things necessary to form new virus particles ( replication of the virus). These new virus particles can be subsequently released from the infected cell, and can infect adjacent cells.The Immune SystemThe immune system is a system within all vertebrates (animals with a backbone) which in general terms, is comprised of two important cell types: the B-cell and the T-cell. The B-cell is responsible for the production of antibodies (proteins which can bind to specific molecular shapes), and the T-cell (two types) is responsible either for helping the B-cell to make antibodies, or for the killing of damaged or "different" cells (all foreign cells except bacteria) within the body. The two main types of T-cells are the "helper"T-cell and the cytotoxic T-cell. The T-helper population is further divided into those which help B-cells (Th2) and those which help cytotoxic T-cells (Th1). Therefore, in order for a B-cell to do its job requires the biochemical help of Th2 helper T-cells; and, for a cytotoxic T-cell to be able to eliminate a damaged cell (say, a virally-infected cell), requires the biochemical help of a Th1 helper T-cell.

Whenever any foreign substance or agent enters our body, the immune system is activated. Both B- and T-cell members respond to the threat, which eventually results in the elimination of the substance or agent from our bodies. If the agent which gains entry is the kind which remains outside of our cells all of the time (extracellular pathogen), or much of the time (virus often released) the "best" response is the production by B-cells of antibodies which circulate all around the body in the bloodstream, and eventually bind to the agent. There are mechanisms available which are very good at destroying anything which has an antibody bound to it. On the other hand, if the agent is one which goes inside one of our cells and remains there most of the time (intracellular pathogens like viruses or certain bacteria which require the inside of one of our cells in order to live), the "best" response is the activation of cytotoxic T-cells (circulate in the bloodstream and lymph), which eliminate the agent through killing of the cell which contains the agent (agent is otherwise "hidden"). Both of these kinds of responses (B-cell or cytotoxic T-cell) of course require specific helper T-cell biochemical information as described above. Usually, both B-cell and cytotoxic T-cell responses occur against intracellular agents which provides a two-pronged attack. Normally, these actions are wonderfully protective of us. The effect of HIV on the immune system is the result of a gradual(usually) elimination of the Th1 and Th2 helper T-cell sub-populations.

The fight between the virus and the immune system for supremacy is continuous. Our body responds to this onslaught through production of more T-cells, some of which mature to become helper T-cells. The virus eventually infects these targets and eliminates them, too. More T-cells are produced; these too become infected, and are killed by the virus. This fight may continue for up to ten years before the body eventually succumbs, apparently because of the inability to any-longer produce T-cells. This loss of helper T-cells finally results in the complete inability of our body to ward-off even the weakest of organisms (all kinds of bacteria and viruses other than HIV) which are normally not ever a problem to us. This acquired condition of immunodeficiency is called, AIDS.

Our immune system's ability to recognize any foreign substance or agent, depends entirely upon how the substance or agent "looks" with respect to the molecular shapes displayed - just as your elbow looks different than someone else's elbow - even though each are clearly elbows. Therefore, while an individual may become infected with a single strain of HIV, over several years of many, many viral generations, an individual may have 10 different strains of HIV present. Further, to date no two people have been identified to have been infected with the same strain of HIV. Consequently, against which strain should a population be immunized? In such cases, one tries to identify molecular shapes which are common to all known strains - in this way, all strains would theoretically be recognizable by our immune system. Sadly, this research has failed to provide an effective vaccine. This virus is subtle, and can do some very covert things using biochemical mechanisms we do not yet understand. Because of recent basic research in the field of immunology (the discipline which develops an understanding of the intricate workings of the immune system), based upon years of previous basic research in this and other fields however, some light is beginning to emerge which may help us.

It is becoming clear that the two helper T-cell types identified only a few years ago may be significantly more important than first assumed. Remember, the Th1 helper-cell helps generate a cytotoxic T-cell response, and the Th2 helper-cell helps generate an antibody response. As it turns out, certain intracellular pathogens primarily elicit a Th2 response in certain in-bred strains of mice, while in a different in-bred mouse strain, the same pathogen primarily elicits a Th1 response. In this example, all mice which respond primarily with antibody (B-cell; Th2 help), die; and, all mice which primarily respond with a cytotoxic T-cell response (Th1 help), live! Such is not the case for every intracellular pathogen - some responses are very balanced with respect to B-cell and cytotoxic T-cell contributions, and others are imbalanced in one or the other direction. The balance in contribution of these two paths to an immune response, appears to not only depend upon the particular infectious organism, but also upon the particular genetic background of the infected animal. Thus, one can imagine that one may be able to find a way to tip the balance towards the most effective response path against a given organism, e.g., either antibody production by B-cells, or development of cytotoxic T-cells. This research is one of the prime areas under investigation with regard to HIV. There are very limited data to date; but, those individuals who have had HIV for a really long time, but have not yet acquired AIDS (there are indeed now a number of such individuals), appear to have their immune response shifted towards the cytotoxic side (Th1 help). This limited information on HIV, in combination with basic research information on several different diseases using animal models (mice), has generated a quick response within the research community. Consequently, there are efforts currently underway to identify the biochemical substances which are involved in directing a response along the Th1 path, and efforts to determine how the immune system might be manipulated to direct a response along a given path. Such experimentation is long and difficult, and requires money, skill, unflinching commitment, and an abiding faith that this problem can be solved.

Under normal circumstances, the design of the immune system's various tissues and connections, allows the agent to be focused within a regional lymph node, which greatly improves the probability of an effective defensive response. In the case of HIV, however, this ability either brings the target cells to the virus, or brings the virus to the target cells. Consequently, the only way to prevent exposure to the virus, is to avoid situations which allow the potential for entry of the virus. Such situations are overwhelmingly associated with sexual intercourse, intravenous drug use, and exposure of a cut in one's skin to the bodily fluids (secretions, blood) of an HIV-infected individual. Such situations do not include hugging, touching, or other nonfluid-exchange expressions of caring for someone infected with HIV.

Oral, vaginal, and anal intercourse can lead to tiny abrasions of the mucosal tissue in these areas; and, within the tissues of the mouth (gums in particular) there will almost always be tiny abrasions present under any circumstances. These openings provide access by the virus to the blood and lymphatic streams, as well as to cells within the tissue. If a person is infected with HIV, there will be virus within the secretions of the person (particularly the seminal fluid of males), and in the blood of the person.Consequently, the direct exposure to bodily fluids (secretions, blood) can potentially occur between both partners (female/female, male/male, female/male) during any kind of sexual intercourse, whether or not ejaculation by a male partner occurs. While the body may be able to ward-off a small amount of virus, repeated exposure to such amounts places a person, particularly women having vaginal intercourse, and men and women having anal intercourse with an HIV-infected partner, at significant risk of HIV infection. Under any circumstance, there is a risk of HIV infection through only one sexual intercourse encounter. The use of a condom for the male partner, in combination with chemical substances which kill viruses, is recommended. Multiple sexual partners, unprotected sexual intercourse, anal sexual intercourse, the presence of other sexually-transmitted disease, and intravenous drug usage significantly increase the risk of HIV infection.

One can be tested for the presence of HIV through an appointment with one's local Health Department (state-supported). Health department test results are completely confidential and inaccesible to anyone but the patient and testing physician at the public-health clinic. While a personal physician's records are also confidential, these records are however, subject to examination at any time by the health insurer(s) of the physician.No matter where one chooses to be examined, one will be required to undergo a pre-test and post-test psychological counseling session.

Recent Statistics (January, 1995): The CDC report showed 401,749 cases of AIDS in the U.S. through the middle of 1994, while approximately one-million within the U.S. are infected with HIV. Twenty percent of all AIDS cases within the U.S. are within the 20s age-group - (apparently contracted HIV while teenagers).

The CDC AIDS Hotlines are:English: 800-342-2437 (800-342-AIDS)Spanish: 800-344-7432 (800-344-SIDA)Deaf: 800-243-7889.Your local Health Department is also a good source of information. Become informed.

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AIDS, HIV and The Immune System - Single Sign-On | The ...

The U.S. Department of Agriculture's Food Safety and Inspection Service (FSIS) announced that H-E-B Meat Plant, a San Antonio, Tex. establishment, is recalling approximately 1,150 pounds of diced chicken thighs due to misbranding and undeclared allergens. There have been no confirmed reports of adverse reactions due to consumption of these products.

Sid Wainer & Son of New Bedford, MA announced the recall of Jansal Valley brand Dried Chili De Arbol Peppers due to presence of allergen, peanuts. No illnesses have been reported to date in connection with this problem. During repacking, the peanut contamination was discovered in the sealed bulk containers of the product.

TAI FOONG USA of Seattle, WA announced the recall of Royal Asia Shrimp Wonton Noodle Soup due to undeclared egg. One allergic reaction complaint has been confirmed to date, due to consumption of the recalled product.

Prestage Foods, Inc., a St. Pauls, N.C. establishment, is recalling approximately 38,475 pounds of ground turkey that may be contaminated with extraneous materials. The fresh ground turkey was produced on September 25 and 26, 2017. There have been no confirmed reports of adverse reactions due to consumption of these products.

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Overview of PBSCT

Peripheral blood stem cell transplants, or PBSCT's, are procedures that restore stem cells that have been destroyed by high doses of chemotherapy. Stem cells are cells that give rise to the blood cells -- red blood cells that carry oxygen, white blood cells that help the body to fight infections, and platelets that help make the blood clot.

It used to be that stem cell transplants came from donated bone marrow.

Though most of the stem cells are present in bone marrow, some are out circulating -- in the peripheral blood stream. These can be collected and then transfused in patients to restore their stem cell reserve. Most stem cell transplants (but not all for a number of reasons) are now PBSCT's. Prior to donating stem cells, donors are given a medication which increases the number of stem cells in the blood. Peripheral blood stem cells work very well when compared with bone marrow transplants, and in fact, in some cases may result in platelets and a type of white blood cells known as neutrophils "taking" even better, when the donor is not related to the recipient.

In order to really understand how stem cell transplants work, it can help to talk a little more about what stem cells really are. As noted above, stem cells -- also known as hematopoietic stem cells - give rise to all the different types of blood cells in the body.

By transplanting stem cells which can subsequently differentiate and evolve into the different types of blood cells - a process called hematopoiesis - a transplant can replace a deficiency in all of the type of blood cells.

In contrast, medical treatments to replace all of these cells are intensive and carry many complications.

For example, you can give platelet transfusions, red blood cell transfusions, and give medications to stimulate both the formation of red blood cells and white blood cells, but this is very intensive, difficult, and has many side effects and complications.

Chemotherapy delivered in high doses destroys cancers better, but also destroys stem cells present in the bone marrow. Stem cell transplants help restore the bone marrow so that the patient can tolerate the high doses of chemotherapy.

There are three types of stem cell transplant:

PBSC donation involves taking circulating blood stem cells, rather than cells from the bone marrow, so theres no pain from accessing the bone marrow. But in PBSC, the medication given to boost the number of stem cells in the donors circulation can be associated with body aches, muscle aches, headaches, and flu-like symptoms.

These side effects generally stop a few days after the last dose of the stem-cell-boosting medication.

There are many possible complications of PBSCT's. The high dose chemotherapy prior to the transplant poses a serious risk of infection due to a lack of white blood cells (immunosuppression) as well as problems related to a lack of red blood cells (anemia) and low platelets (thrombocytopenia.)

A common risk after transplant is that of graft versus host disease (GvH), which happens to some degree in almost all stem cell transplants. In GvH disease the transplanted cells (from the donor) recognize the host (the recipient of the transplant) as foreign, and attack.

For this reason people are given immunosuppresive drugs following a stem cell transplant.

Yet the immunosuppressive drugs also pose risks. The decrease in immune response due to these drugs increases the risk of serious infections, and also increases the risk of developing other cancers.

Undergoing a PBSCT is a major procedure. Not only is it preceded by very aggressive chemotherapy, but the symptoms of graft versus host disease, and complications of immunosuppressive drugs make it a procedure that is usually reserved for younger, and in general very healthy, people.

One option that may be considered for patients who are older or in compromised health is a non-myeloablative stem cell transplant. In this procedure, instead of ablating (essentially destroying) the bone marrow with very high dose chemotherapy, a lower dose of chemotherapy is used. The secret behind these forms of transplants actually lies in a type of graft versus host disease. Yet, instead of the graft - the transplanted stem cells - attacking "good" cells in the recipients body, the transplanted stem cells attack the cancerous cells in the recipients body. This behavior is termed "graft versus tumor."

Also Known As:

PBSCT, Peripheral Blood Stem Cell Transplantation

Related Terms:

HSCT = hematopoietic stem cell transplantation

HCT = hematopoietic cell transplantation

SCT = stem cell transplant

G-CSF = Granulocyte-colony stimulating factor -- a growth factor, a stem cell boosting medication, sometimes given to donors to mobilize hematopoietic stem cells from the bone marrow into the peripheral blood.

Sources:

National Cancer Institute. Stem Cell Transplant. Updated 04/19/15. http://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant

Singh, V., Kumar, N., Kalsan, M., Saini, A., and R. Chandra. Mechanism of Induction: Induced Pluripotent Stem Cells (iPSCs). Journal of Stem Cells. 2015. 10(1):43-62.

Wu, S., Zhang, C., Zhang, X., Xu, Y., and T. Deng. Is peripheral blood or bone marrow a better source of stem cells for transplantation in cases of HLA-matched unrelated donors? A meta-analysis. Critical Reviews in Oncology and Hematology. 2015. 96(1):20-33.

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Peripheral Blood Stem Cell Transplant (PBSCT) - Verywell