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Archive for August, 2016

Issues Archive – Cell Therapy News

Thursday, August 4th, 2016

Biogen Announces Collaboration with University of Pennsylvania on Multiple Gene Therapy Programs

Biogen announced a broad collaboration and alliance with the University of Pennsylvania to advance gene therapy and gene editing technologies. The expansive research and translational development collaboration has multiple objectives, but will primarily focus on the development of therapeutic approaches that target the eye, skeletal muscle and the central nervous system. [Biogen] PressRelease

State Stem Cell Agency Awards Stanford Researchers

Albert Wong receives $2.9 million to develop vaccine for glioblastoma; four others awarded $240,000 each to study bladder, heart and eye conditions. [Stanford School of Medicine] PressRelease

MJFF Supports Stem Cell Projects to Explore Therapies and Provide Research Tools

The Michael J. Fox Foundation (MJFF) announced funding for two projects leveraging the promise of engineered stem cells to speed new therapies and deeper understanding of Parkinsons disease. [The Michael J. Fox Foundation] PressRelease

Novel Immunotherapy Trial for Lymphoma Offers Hope to Patients at Sylvester

Researchers are testing a novel cellular immunotherapy approach to treating patients with diffuse large B-cell lymphoma who have failed standard therapy. This investigational anti-CD19 chimeric antigen receptor T cell therapy, known as KTE-C19, is being studied in a Phase II clinical trial for patients with aggressive non-Hodgkins lymphoma. [University of Miami Miller School of Medicine] PressRelease

Asterias Biotherapeutics Announces Positive New Long-Term Follow-Up Results for AST-OPC1

Asterias Biotherapeutics, Inc. announced new positive long-term follow-up results from its Phase I clinical trial assessing the safety of AST-OPC1 (oligodendrocyte progenitor cells) in patients with spinal cord injury. [Asterias Biotherapeutics, Inc.] PressRelease

FDA Grants Roches Cancer Immunotherapy Tecentriq (Atezolizumab) Accelerated Approval for People with a Specific Type of Advanced Bladder Cancereneration CAR Modifications for Enhanced T-Cell Function

Roche announced that the U.S. Food and Drug Administration (FDA) granted accelerated approval to Tecentriq for the treatment of people with locally advanced or metastatic urothelial carcinoma. [F. Hoffmann-La Roche Ltd.] PressRelease

Nano Dimension and Accellta Joined Forces to Successfully BioPrint Stem Cell-Derived Tissues

Nano Dimension Ltd. announced it has successfully lab-tested a proof of concept 3D Bioprinter for stem cells. The trial was conducted in collaboration with Accellta Ltd. [Nano Dimension Ltd. (PR Newswire Association LLC.)] PressRelease

Regen BioPharma, Inc. Announces ucVax: Universal Donor Cancer Cellular Immunotherapy

Regen BioPharma, Inc. and announced initiation of a preclinical development program aimed at creating the first cord blood based cancer immunotherapeutic product leveraging its NR2F6 immunological checkpoint. [Regen BioPharma, Inc. (PR Newswire Association LLC.)] PressRelease

VM BioPharma Announces FDA Fast Track Designation Granted for Investigational Gene Therapy VM202 for Patients with Amyotrophic Lateral Sclerosis (ALS)

VM BioPharma announced that the U.S. Food and Drug Administration (FDA) has granted Fast Track designation for the companys lead investigational drug, VM202, a Phase II novel gene therapy for the potential treatment of Amyotrophic Lateral Sclerosis. [VM BioPharma] PressRelease

Cryoport to Provide Cold Chain Logistics Support for International Stem Cell Corporations Phase I Clinical Trial for the Treatment of Parkinsons Disease

Cryoport, Inc. announced that it will provide global logistics support to International Stem Cell Corporations (ISCO) Phase I clinical trial in Australia for the treatment of moderate to severe Parkinsons disease. ISCO commenced patient enrollment for the study earlier this month. [Cryoport, Inc.] PressRelease

WPI Team Awarded Patent for Reprograming Skin Cells

Cell therapies for a range of serious conditions, including heart attacks, diabetes, and traumatic injuries, will be accelerated by research at Worcester Polytechnic Institute (WPI) that yielded a newly patented method of converting human skin cells into engines of wound healing and tissue regeneration. [Worcester Polytechnic Institute] PressRelease

Caladrius Biosciences Licenses Cell Therapy Technology for Ovarian Cancer and Subleases Irvine Facility to AiVita Biomedical

Caladrius Biosciences, Inc. announces that it has licensed to AiVita Biomedical, Inc. the exclusive global rights to its tumor cell/dendritic cell technology for the treatment of ovarian cancer. [Caladrius Biosciences] PressRelease

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Issues Archive - Cell Therapy News

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NIHSeniorHealth: Taking Medicines – Personalized Medicines

Thursday, August 4th, 2016

Medicines: One Size Does Not Fit All

Studies have shown that bad reactions to properly prescribed medicines cause a number of hospitalizations each year. Researchers believe that many of these errors show that when it comes to taking medicines, "one size does not fit all."

For example, allergy medicines simply don't work for everyone who takes them. For some people, taking the standard dosage of a prescription pain reliever such as codeine offers no pain relief, and can even cause side effects that are uncomfortable or life-threatening.

As the body ages, fat and muscle content change, affecting how the body absorbs and processes drugs. Many other factors -- exercise habits, diet, and general state of health -- also influence how a person responds to medications.

Another key factor is heredity -- the genes we inherit from our parents and other ancestors. Genes can influence the way people respond to many types of medicines, such as Tylenol#3, which is acetaminophen plus codeine; antidepressants like Prozac, also called fluoxetine; and many blood pressure and asthma medicines.

Your genes determine the shape and function of your proteins. As drugs travel through the body, they interact with dozens of proteins.

Everyones genes are slightly different, so everyones proteins are different. Variations in some proteins can affect the way we respond to medicines. Such proteins include those that help the body absorb, metabolize, or eliminate drugs.

Many scientists around the country are conducting research to understand how genes affect the way people respond to medicines. This type of research is called pharmacogenomics.

Pharmacogenomics research aims to identify all the possible variations in genes that play a role in drug response. To identify which versions of a certain gene a person has, researchers examine DNA from that person. Researchers can obtain this DNA in an easy, painless and risk-free way using a cotton swab to collect mouth cells from inside the persons cheek. The scientists then isolate the DNA from the mouth cells.

Uncovering differences in people's genetic backgrounds will help doctors prescribe the right medicine in the right amount for each person, making medicines more safe and effective for everyone.

Scientists will also better understand the role that genes play in causing or contributing to diseases including cancer, heart disease, diabetes, depression, and many others. Research in pharmacogenomics will help scientists make future medicines as safe and effective as possible.

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NIHSeniorHealth: Taking Medicines - Personalized Medicines

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Herbs for the Immune System – Blessed Maine

Thursday, August 4th, 2016

This article will introduce you to a number of herbs that can safely be relied upon to strengthen the immune system, protect you from a wide array of disease-causing organisms and assist you in maintaining vibrant and robust health.

Your immune system is an incredibly complex interaction between organs, glands, body systems, surfaces, cells and chemicals. This symphonic concert of processes requires nourishment in order to function optimally.

Many herbs and other substances are used by cultures around the world to nourish and support immunity and protect us from a multitude of disease causing micro-organisms, including influenza, the Herpes simplex virus, or fungal growths such as Candida. I know a few of these protective and immune strengthening herbs on an intimate level, and would like to introduce you to some of them here. We'll cover astragalus, usnea, sage, garlic, honey, shitake and reishi mushrooms, hyssop, and St. Johns wort.

Milk Vetch Astragalus membranaceus Astragalus has been growing in our gardens for over ten years now. It is quite hardy, and withstands even the coldest Maine winter. It grows into a large bush, quite feathery, bright green and very pretty looking, with dainty, fan-like yellow flowers in mid to late summer.

Oftentimes in nature you will find that the gifts of a plant make themselves known to you in the manner in which the plant grows, the conditions it requires, and its degree of hardiness. When a plant thrives no matter what, take a deeper look, and you may find that it will help you to do the same. Astragalus strikes me as such a plant. Rugged, resilient, strong, powerful, long-lived, graceful, and elegant.

Astragalus is a tonic and restorative food and a potent medicine plant. The Chinese have been using this plant to strengthen immunity for centuries. They say it "strengthens the exterior", or protects against illness. Known as Huang-qi, astragalus is written about in the 2,000 year old Shen Nong Ben Cao Jing, and is still considered to be one of the superior tonic roots in traditional Chinese medicine. It's name literally means yellow leader; yellow referring to the inside of the root, and leader to its medicinal potency.

Mildly sweet, and slightly warm, astragalus invigorates vital energy, is restorative, strengthens resistance, restores damaged immunity, promotes tissue regeneration, is cancer inhibiting, antiviral, adaptogenic, protects and strengthens the heart and the liver, is tonic to the lungs and enhances digestion.

Many scientific studies have verified its immune enhancing action. Astragalus is a powerful "non-specific" immune system stimulant. Instead of activating our defense system against a specific disease organism, astragalus nourishes immunity by increasing the numbers and activity of roving white blood cells, the macrophages.

As an immunostimulant, astragalus engages and activates every phase of of our immune system into heightened activity. In one study, the activity of macrophages was significantly enhanced within six hours of treatment with astragalus, and remained so for the next seventy-two hours.

In Chinese medicine astragalus roots are said to tonify the Spleen, Blood, and Chi. They are used as a tonic for the lungs, for those with pulmonary disease, frequent colds, shortness of breath, and palpitations. Astragalus is also prescribed for those who suffer from fatigue, from any source, chronic nephritis, night sweats, uterine prolapse, or prolapse of the rectum.

It's tissue regenerating and anti-inflammatory abilities make astragalus an excellent ally to heal chronic ulcerations and persistent external infections, as well as to heal hard-to-heal sores and wounds, and to drain boils and draw out pus. Astragalus processed in honey is a specific against fatigue, used to boost vital energy, to nourish the blood, and also against incontinence, bloody urine or diarrhea.

In a study conducted by the University of Texas Medical Center, in Houston, researchers compared damaged immune cells from cancer patients to healthy cells. Astragalus extracts were found to completely restore the function of the cancer patients' damaged immune cells, in some cases surpassing the health and activity of the cells from healthy individuals.

The extract of astragalus was also shown to significantly inhibit the growth of tumor cells in mice, especially when combined with lovage Ligustrum lucidum. According to a study reported in Phytotherapy Research, astragalus appears to restore immunocompetence and is potentially beneficial for cancer patients as well as those suffering with AIDS. It increases the number of stem cells present in the bone marrow and lymph tissue and stimulates their differentiation into immune competent cells, which are then released into the tissues, according to one study reported in the Journal of Traditional Chinese Medicine.

Astragalus also stimulates the production of Interferon, increases its effectiveness in treating disease, and was also found to increase the life span of human cells in culture.

Astragalus protects adrenal cortical function while undergoing chemotherapy or radiation, and helps modify the gastrointestinal toxicity in patients recieving these therapies. Chinese doctors use astragalus against chronic hepatitis, and many studies have demonstrated that astragalus protects the liver against liver-toxic drugs and anti-cancer compounds commonly used in chemotherapy, such as stilbenemide. When used as an adjunct to conventional cancer treatments, astragalus appears to increase survival rates, to increase endurance, and to be strongly liver protective.

Astragalus helps lower blood pressure, due to its ability to dilate blood vessels, and protects the heart. Scientists in the Soviet Union have shown that astragalus protects the heart muscle from damage caused by oxygen deprivation and heart attack.

According to reports in the Chinese Medical Journal, doctors at the Shanghai Institute of Cardiovascular Diseases found that astragalus showed significant activity against Coxsackie B virus, which can cause an infection of the heart called Coxsackie B viral myocarditis, and for which there is no effective treatment. In a follow-up study, researchers found that astragalus helped maintain regular heart rhythms, and beating frequency, and that Coxsackie B patients showed far less damage from the viral infection (as much as 85%).

In Chinese medicine, astragalus is often combined with codonopsis. This compound is said to strengthen the heart and increase the vital energy, while invigorating the circulation of blood throughout the body. It is also traditionally combined with ginseng, and used as a tonic against fatigue, chronic tiredness, lack of energy, enthusiasm, or appetite, and to ease "spontaneous perspiration" or hot flashes.

Japanese physicians use astragalus in combination with other herbs in the treatment of cerebral vascular disease. According to a research paper published by Zhang in 1990, adolescent brain dysfunction improved more with a Traditional Chinese Medicine formula containing astragalus in combination with codonopsis and other herbs than with Ritilin.

Integrating astragalus roots into your winter-time diet, as the Asians have been doing for years, turns out to be a very good idea. Scientists have demonstrated that astragalus will not only prevent colds, but cut their duration in half. Astragalus possesses strong antiviral properties, and in one study regenerated the bronchial cells of virus-infected mice.

Astragalus has been safely used throughout Asia for thousands of years. The Chinese typically slice astragalus roots and add them, along with other vegetables, to chicken broth to create a nourishing and tonic soup. Discard the root after cooking, and consume the broth. No toxicity from the use of astragalus has ever been shown in the millennia of its use in China.

The genus Astragalus is the largest group of flowering plants, with over 2,000 different species, most of which are found in the northern temperate regions. Plants in this genus are amazingly diverse, some are nourishing and medicinal, some useful as raw materials, and others, such as the locoweeds, are toxic. Astragalus membranaceus grows in the wild along the edges of woodlands, in thickets, open woods and grasslands. It is native to the Northeastern regions of China, but grows excellently in Maine soils and temperatures, as do most Chinese medicinal plants we've attempted to grow thus far. Astragalus appreciates deep, well drained, somewhat alkaline soil.

Seeds are easily gathered and when planted in the fall require no prior soaking. They will germinate the following spring as soon as conditions are right. The seeds have a hard seed coat, and some people nick the covering with a file, or soak the seed overnight to hasten germination. Give each plant plenty of room, as much as a foot all around, and harvest after the fourth or fifth year of growth. Use whole or sliced, fresh or dried root for tinctures, honey, infusions, syrup, or in soups.

Astragalus Tincture

St. John's wort Hypericum perforatum St. John's wort contains numerous compounds that possess documented biological actions, and are the focus of much study. Those constituents that have generated the most interest thus far, include the naphthodianthrones, hypericin and pseudohypericin, a wide range of flavonoids, including quercetin, quercitrin, amentoflavone and hyperin, and the phloroglucinols, hyperforin and adhyperforin. Also of interest to researchers are the essential oils, and xanthones.

Wise herbalists have always used the whole herb, and researchers agree, that it is an interaction between the many constituents in St. John's wort, rather than any one active ingredient, that is responsible for the wide range of beneficial actions this healing herb offers.

All parts of the herb are used medicinally, with hypericin content concentrated in the buds and flowers, and also present in top and bottom leaves, as well as the stem, though to a lesser degree.

Activity of Constituents:

Amentoflavone is antiinflammatory and antiulcer.

GABA is a sedative.

Hyperforin is an antibacterial agent active against gram-positive bacteria, is wound healing, a potential anticarcinogenic, and a neurotransmitter inhibitor.

Hypericin is strongly antiviral

Proanthocyanidins are antioxidant, antimicrobial, antiviral, and vasorelaxant.

Pseudohypericin is antiviral and

Quercitrin is a MAO inhibitor, as are the Xanthones.

Xanthones are antidepressant, antimicrobial, antiviral, diuretic, and cardiotonic.

St. John's wort is an excellent wound healer. It possesses strong antimicrobial properties, is a significant antifungal and antibacterial agent, and is especially effective against gram-positive bacteria. It inactivates Escherichia coli at dilutions of 1:400 or 1:200, and is also active against Staphloccus aureus.

Two constituents of the herb, hyperforin and adhyperforin possess antibiotic effects stronger than that of sulfonilamide.

Burns heal rapidly with the application of St. John's wort. In one study using St. Johns'wort oil, first, second, and third degree burns healed at least three times as rapidly than those treated with conventional treatments, and scaring was minimal. Orally administered St. John's wort tincture demonstrated a remarkable healing of incisions, excision and dead space wounds, and has also been shown to inhibit keloid formation.

Studies indicate St. John's wort may enhance coronary blood flow as well as hawthorn, due to the activity of the procyanidins. It significantly increases the production of nocturnal melatonin, which means taking it will help you sleep better, and feel better.

St. John's wort has also shown promise in the treatment of chronic tension headaches, and also appears to be liver-protective. It is a proven antidepressant, best used by those who are mildly to moderately depressed. It is also historically used to treat neurological conditions such as anxiety, insomnia, restlessness, irritability, neuralgia, neuroses, migraines, fibrosis, dyspepsia, and sciatica.

St. Johns wort is an ally when dealing with any fungal problem, such as candida (infusion as sitz bath), thrush (infusion as mouth wash), or an infection on the skin or nails(frequent soaks in infusion). Frequent applications of St. Johns wort oil will also help in healing these infections.

Use the oil to rub on to tired, sore, achy, painful, overworked muscles. St. Johns wort oil is legendary for relieving the pain and inflammation of back-ache, stiff neck, sore shoulders, bad knees, tennis elbow, and anything else that hurts.

St. Johns'wort has shown to be of considerable benefit to patients with Acquired Immune Deficiency Syndrome. (AIDS)

In one study, 16 out of 18 patients stabilized or improved during a 40 month period during which they were treated with St. John's wort. Only 2 of the 16 experienced an opportunistic infection during the time they took the herb.

Many studies have proven that St. John's wort inhibits a variety of viruses, including herpes simplex types 1 and 2, and HIV-1 viruses associated with AIDS. Researchers have concluded that both hypericin and pseudohypericin are uncommonly effective antiviral agents.

The antiviral activity of St. John's wort appears to be somewhat photo-dynamic, involving a photoactivation process to become more intensely effective. Internal use of St. John'swort is not recommended if you are currently taking a pharmaceutical antidepressant.

St. John's wort Tincture

St. John's wort Oil

Sage Salvia officinalis The ancients used aromatic sage to bring the virtues of wisdom, strength and clear thinking. Modern day researchers in Great Britain found that sage inhibits the breakdown of acetylcholine, and so helps to preserve the compound used to prevent and treat Alzheimers.

Sage is loaded with antioxidants, so is anti-aging, and also offers lots of calcium, magnesium, the essential oil, thujone, flavonoids and phytosterols. It is sedating and soothing, and has a tonic effect on the nerves.

Sage is a potent broad spectrum antibiotic, and immune stimulant. It possesses antibacterial, and antiseptic properties and is active against Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa. E. coli, Candida albicans, Klebsiella pneumoniae, and Salmonella spp.

Some native tribes like the Mohican, commonly chewed the leaves of sage as a strengthening tonic, and people all over the world use sage to build strength and enhance vitality.

Expectorant and diaphoretic, sage is especially effective against sore throat and upper respiratory illness, and infections where there is an excess of mucous. Sage dries up secretions. Sage is also traditionally used, and effective against, dysentery. Its astringent tannins make it an ally for healing mouth sores, canker sores, bleeding gums, and gingivitis, when used as a mouth rinse. A study done in Germany showed that drinking sage infusion on an empty stomach, reduced the blood sugar levels in diabetic patients.

In Italy sage is very commonly used as a seasoning herb. One cannot help but notice the vibrant health and strength of the elder people, which I attribute, at least in part, to their copious use of sage in the diet.

Sage Tincture

Antibiotic Spray

Garlic Allium sativum

Garlic is not only antibacterial, but antiviral, antiseptic, antiparasitic, immune-stimulating, antispasmodic, hypotensive, diaphoretic, antiprotozoan, antifungal, anthelmintic, and cholagogue.

You can rely on the regular use of this spice to keep your body toned and functioning optimally. It will help keep that all-important and vital organ, the heart toned, help keep blood pressure down, as well as help lower cholesterol. Repeated studies have shown that garlic has a beneficial effect on the heart and circulatory system. Chop some into your salad, throw it, simmered in olive oil, over noodles and sprinkle with parsley.

Garlic is rich in antibiotic powers and strengthens the immune system. It is active against both gram positive and gram negative bacteria, including Shigella dysenteriae, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, Escherichia coli, Streptococcus spp., Salmonella spp., Camphylobacter spp., Proteus mirablis, and Bacillius anthraxis.

Garlic is also active against herpes simplex, influenza B, HIV and many other serious illnesses. Note that it is active against the food-borne pathogens so often found in commercial foods, Shigella, E. coli, and Salmonella. Garlic kills bacteria in the gastrointestinal tract immediately on contact. To treat an active intestinal bacterial infection, consume lots of raw or cooked garlic, or take garlic capsules.

Garlic in the diet has also been shown to have a beneficial effect on those dealing with cancer, stress, and fatigue. Garlic stimulates the isles of langerhans, increases insulin production, and lowers blood sugar levels, thus aids diabetics in the control of this debilitating disease.

Garlic also helps increase the senovial fluids, and so is an ally for those dealing with arthritis. The sulfur in garlic helps break up the crystallization of uric acid in the joints, and so aids in the relief of gout. Garlic stimulates the brain and has a positive effect on brain functioning, helping to keep us alert and energized. Scientists have found that garlics anti-aging properties not only slowed the destruction of brain cells, but also caused new brain neurons to branch out. An old Ukrainian recipe to keep the mind sharp includes one pound of garlic, ground and added to a jar with the juice of 24 lemons. Leave covered for one moon cycle, then take one teaspoon each night.

Honey Honey is, an ancient Islamic saying goes, the food of foods, the drink of drinks, and the remedy of remedies. The ancient Greeks, Romans and Egyptians all kept honeybees, and extolled the virtues of honey. Some call honey a sweet medicine of heaven, others, elixir of long life. I use honey everyday and you probably should too. Heres why:

Honey is a rejuvenating, revitalizing, invigorating, natural antibiotic substance created by those magical insects, bees. Bees have been called messengers of the gods, and were associated with Great Goddess since the most ancient times. Many legends hint that bees, and their special creation, honey, played a very important role in our human development. It is said that the gifts of honey are long life, good health, and reverence for spirit. Honey has an ancient reputation as a life force increasing, immune strengthening, potency promoting, aphrodisiac elixir.

Honey consists of invert sugar (fructose, dextroglucose) and other sugars. It also contains a complex assortment of enzymes, antibiotic and antimicrobial compounds, organic acids, minerals such as iron, copper, phosphorus, sulfur, potassium, manganese, magnesium, sodium, silicon, calcium, iodine, chlorine, zinc, formic acid, and high concentrations of hydrogen peroxide. Honey also contains varying degrees (it depends on what flowers and herbs the bees are taking their nectar from) of vitamin C, the entire B complex, vitamins D, E, and K, pantothenic acid, niacin, and folic acid, amino acids, hormones, alcohols, and essential oils.

Honey can, and should be, thought of as a super food. It is a live food, stores its vitamins and minerals indefinitely, and is very easily digested by the body. Honey is an all around health and vitality enhancing substance. Wildflower honey, the concentrated nectar of wildflowers, the essence of all the combined medicinal qualities of all the diverse and abundant wild herbs, is thought to be the most medicinal.. All natural, unheated honey is antibiotic, antiviral, antifungal, anti-inflammatory, anticarcinogenic, expectorant, antiallergenic, laxative, antianemic, tonic, immune stimulating, and cell regenerating.

Bees gather the nectar from flowers and store it in their stomach while transporting it back to the hive. During their transport, the dew-laden nectars become concentrated by evaporation. The nectars also combine, in some as yet unexplained way, with the bees digestive enzymes, producing entirely unique compounds. Scientists have measured over 75 different compounds in honey, some of them so complex they have yet to be identified. One thing we can identify however, is the fact that when used as a consistent additive to food and drink, honey increases vitality, energy, immunity, libido, and life force.

Honey is proven more effective than any pharmaceutical antibiotic in the treatment of stomach ulceration, gangrene, surgical wound infections, and speedy healing of surgical incisions. Honey is unsurpassed for the protection of skin grafts, corneas, blood vessels, and bones during storage and transport. In fact, honey is such an excellent preservative of living tissue that it was commonly used to keep dead bodies from decomposing while being transported back to their homeland for burial. After his death in a foreign land, Napoleon was sent home in a huge vat of honey.

The fact that fist size ulcers and third degree burns heal beautifully with frequent applications of pure raw honey is clinically proven, and something I can personally attest to. A few years ago, I got a large third degree burn on my heel during a misstep on a motorcycle tailpipe. It was a deep wound and definitely hampered my ability to get around all that summer. I soaked my burned foot morning and night in lavender and rose salts and after each soaking applied a bandage liberally smeared with pure honey directly over the burn. I kept a thick layer of honey over that burn for a couple of months, and tried as much as possible not to walk on it. Today there is barely a trace of that huge burn hole on the heel of my foot. Since that time, honey is my first treatment of choice for any burn, first, second or third degree, any wounds, no matter how deep, skin ulcers, impetigo, and infections. I just keep whatever it is covered with a thick layer of pure honey. And keep eating it by the spoonful, or drinking it in water, or as mead, depending on what you are trying to nourish and heal.

Honey is active against staph Staphylococcus aureus, strep Streptococcus spp., and Helicobacter pylori, responsible for stomach ulcers, and enterococcus. Honey is also one of my top choices for treating any respiratory condition, whether a cold, flu, or respiratory infection. Honey will be your ally against bronchitis, chronic bronchial and asthmatic problems, rhinitis and sinusitis. Those dealing with chronic fatigue, any wasting disease, a depressed immune system, will all feel the benefits of integrating this sweet medicine of the bees into their daily diets.

Syrups made with pure honey

Usnea Usnea spp. Usnea, or old man's beard as it is commonly called, is a common lichen found hanging from trees around the world. It possesses strong antibacterial and antifungal agents and is a potent immune stimulant.

Usnea has been shown to be more effective than penicillin against some bacterial strains. It completely inhibits the growth of staphylococcus aureus, streptococcus spp., and pneumonococcus organisms. Usnea is effective against tuberculosis, triconomas, candida spp., enterococcus, and various fungal strains, and has also been reported active against Salmonella typhimurium and E.coli.

Usnea is actually two plants in one. The inner plant looks like a thin white stretchy thread or rubber band, especially when wet. The outer plant gives usnea its color and grows around the inner plant. The inner part is a potent immune stimulant, the outer part strongly antibacterial.

Among the known constituents of usnea are usnic acid, protolichesterinic acid, and oreinol derivatives. Usnea is traditionally used around the world against skin infections, upper respiratory and lung infections, and vaginal infections.

It can be dusted as a powder, drank as tea or infusion, used as a wash, bath, soak, douche, or spray. Usnea is also effective in tincture form, 30-60 drops, 4 times daily to boost immunity, 6 times daily to treat an active infection. Drink 2-4 cups of infusion for acute illness. Use 10 drops in an ounce of water and use as a nasal spray to treat sinus infections.

Usnea can sometimes be irritating to delicate mucous membranes of the mouth, nose, and throat, so the tincture should always be diluted in water before using. We walk out into the woods to a big old spruce tree beautifully decorated with long strands of this unique and potent lichen which we gather to make our medicine. Usnea easily absorbs heavy toxic metals and can be potentially toxic, so gather in a clean place.

Usnea Tincture

Shitake Mushroom Lentinus edodes Reishi Ganoderma lucidum, Western reishi/artists conk Ganoderma applanatum Immune activating fungi have been used as allies against disease for millennia. Mysterious mushrooms and fungi are classed in a kingdom all their own. They cannot be called plants, as they are much more primitive, nor are they animal. Fungi actually possess some characteristics of both plant and animal.

There are many common medicinal mushrooms with immune enhancing properties, including maitake, the abundant birch polypores, turkey tails, honey mushrooms, and hens of the woods.

The polypores are commonly given to chemotherapy and radiation patients in Japan, and have been shown to increase survival rates. The body receives deep nourishment from medicinal fungi, as the nutrients and medicinal properties of mushrooms penetrates deep into the bone marrow. So much so, that some have referred to using medicinal mushrooms as herbal bone marrow transplants!

We'll take a deeper look at two of the most widely used medicinal mushrooms, shitake and reishi.

Shitake mushrooms have been used in China for thousands of years to mobilize the immune system to fight off disease. An immunostimulant, shitake increases the activity of the human immune system against any invading organism.

Antiviral, antitumor shitake has been effectively used to treat viral infections, parasites, and cancer. One of its most important constituents, lintinan, has been shown to stimulate immune competent cells, stimulate T-cell production, and increase macrophage activity.

In one study of 23 people with low killer cell activity, and associated fever and fatique for over 6 months, all responded well to taking lintinan, despite not having responded to conventional therapies, including antibiotics and antipyretics.

Studies have shown shitake to be active against viral encephalitis. It also possesses potent anti-tumor activities, and has been shown to prevent metastasis of cancer to the lungs.

Shitake mushrooms are usually added to soups and stews, cooked for about two hours, and then allowed to sit for an additional two hours. Remove the mushrooms before consuming the broth.

Called reishi in Japan, and Ling zhe in China, all the Ganodermas are powerfully immune enhancing, and adaptogens with potent anti cancer properties.

Both sweet and bitter, the Ganodermas are powerful free radical scavengers, eliminating these highly reactive chemicals from the blood stream before they can damage the DNA of healthy cells. Ganodermas are strongly cancer protective, and have been shown to actually help break down and dissolve tumors.

Ganodermas are an excellent addition to the diet of any one who is run down, has been suffering from long term stress, and has low immune function. Either of the Ganodermas effectively increases leukocyte production, promotes lymphatic health, promotes phagocytosis, stimulates T-cells, induces the generation of immunoglobulins, and promotes the multiplication of antibodies.

Scientists from the Tokyo Medical and Dental University demonstrated that the ganoderic acid in these fungi could reduce the cholesterol production in the liver by as much as 95%.

The Ganodermas are heart warming, heart opening, promote serenity, and are said to enhance spiritual powers.

Reishi and artists conk are hard and woody, and are often referred to as shelf mushrooms. They grow on the side of either dead or living trees, and are often found on birch and other hardwoods, or hemlock. Sometimes you will find them growing on the fresh stump of a recently cut or fallen tree, and sometimes on an old stump.

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Herbs for the Immune System - Blessed Maine

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Integrative Medicine | Maharishi University of Management

Thursday, August 4th, 2016

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Integrative medicine isincreasingly becoming mainstream 30% of Americans use integrative medicine, according to the National Center for Complementary and Integrative Medicine.

What is Integrative Medicine?

Integrative medicine, the future of healthcare, is the integration of traditional alternative medicine with conventional modern medicine. This means, the physician pulls from both alternative and modern medicine methods to find the best approach and healing plan for each individual patient. Integrative medicine puts the patient front and center by looking at the whole person (mind, body, spirit, environment, relationships, and more). This personalized health care approach gives both the physician and patient a greater understanding of the root causes of the disease or discomfort.

Learn more about Integrative Medicine in our free download.

What is Alternative Medicine?

Alternative medicine is the umbrella term used to describe alternative healing techniques such as homeopathy, acupuncture, meditation, ayurveda, yoga, special diets, natural products and other non-invasive techniques. Integrative medicine utilizes these techniques when appropriate, while also relying on western medicine. MUM offers different degree programs and online courses on MaharishiAyurVedaas well as integrative medicine.

How Does Integrative Medicine Work?

Lets look at a simplified example. A patient comes in complaining about frequent headaches. The standard approach might be to run some tests, or simply even just give the patient a prescription for pain relievers. On the other hand, an integrative medicine practitioner would spend time getting to know the patient and what might be the deeper root cause of this issue. They might offer diet and lifestyle changes, suggest some herbs or natural products, or recommend yoga or acupuncture, and so on. If the root cause was potentially more serious, the physician would then pick from western medicine techniques, such as surgeries, scans, tests, and medicine.

There Are Many Practices of Integrative Medicine. Some Include:

To keep up with the growing demand for integrative medicine, about one third of US hospitals now offer integrative medicine health care services, and almost half of all US medical schools have centers or departments for integrative medicine.

Interested in studying integrative medicine? MUM has many degree programs to choose from, including: an undergraduate Pre-Integrative Medicine degree for those that are preparing for medical school, an MD in modern medicine with a concurrent MS in Maharishi AyurVeda and Integrative Medicine with our partner medical school (AUIS), as well as on-campus and online versions of our MS in Maharishi AyurVeda and Integrative Medicine.

Annalisa Fredrickson graduated from MUM with a BFA in Graphic Design and a minor in Business. She is a writer, social media and marketing consultant, health coach and yoga teacher. She loves to travel, create recipes and be in nature.

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Integrative Medicine | The George Washington University

Thursday, August 4th, 2016

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Human nutrition, the gut microbiome, and immune system …

Thursday, August 4th, 2016

Nature. Author manuscript; available in PMC 2012 Mar 9.

Published in final edited form as:

PMCID: PMC3298082

NIHMSID: NIHMS360404

Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO 63108

*Contributed equally

1Current address: Section of Microbial Pathogenesis and Microbial Diversity Institute, Yale School of Medicine, New Haven CT 06536

Dramatic changes in socioeconomic status, cultural traditions, population growth, and agriculture are affecting diets worldwide. Understanding how our diet and nutritional status influence the composition and dynamic operations of our gut microbial communities, and the innate and adaptive arms of our immune system, represents an area of scientific need, opportunity and challenge. The insights gleaned should help address a number of pressing global health problems.

A number of reviews have appeared recently about efforts to decipher the interactions between the innate and adaptive immune system and the tens of trillions of microbes that live in our gastrointestinal tracts (the gut microbiota). Here we emphasize how the time is right and the need is great to better understand the interrelationships between diet, nutritional status, the immune system and microbial ecology in humans at different stages of life, living in distinct cultural and socioeconomic settings. Why now? The answer lies in a confluence of forces occurring at the present time that will affect the future. First, there is enormous pressure to devise new ways to feed healthy foods to a human population whose size is predicted to expand to 9 billion by 2050. At the same time, the solutions will have to address the challenges of developing sustainable forms of agriculture in the face of constrained land and water resources 1. Second, there is a great need to develop new translational medicine pipelines for more rigorously defining the nutritional value of foods we consume currently and that we envision creating in the future. These pipelines are required to evaluate health claims made about food ingredients. Third, there is increasing evidence that the nutritional value of food is influenced in part by the structure and operations of a consumers gut microbial community, and that food in turn shapes the microbiota and its vast collection of microbial genes (the gut microbiome) (e.g. ref 2). Therefore, to better define the nutritional value of foods and our nutritional status, we need to know more about our microbial differences and their origins, including how our lifestyles influence the assembly of gut microbial communities in children, and about the transmission of these communities within and across generations of a kinship 3. Fourth, we are learning how our gut microbial communities and immune systems co-evolve during our lifespans and how components of the microbiota impact the immune system. At the same time, we are obtaining more information about how our overall metabolic phenotypes (metabotypes) reflect myriad functions encoded in our human genomes and gut microbiomes. These observations raise the question of how gut microbial community metabolism of the foods we consume affects our immune systems. Fifth, the link between infections that occur within and outside the gut, and the development of nutritional deficiencies has been emphasized for many years. Poor nutrition in turn, increases the risk for infection. Nonetheless, there is still a dearth of mechanistic information that explains these observations. Sixth, only five years remain to achieve the UNs eight Millennium Development Goals (http://www.undp.org/mdg/). Two of these goals relate to human nutrition: goal 1 seeks to eradicate extreme poverty and hunger while goal 4 aims to reduce by two thirds the under-five mortality rate. Up to one billion people suffer from undernutrition of varying degrees, including silent or asymptomatic malnutrition (http://www.fao.org/publications/sofi/en/), making this condition an enormous global health problem. Of the ~10 million children under the age of 5 who die each year, undernutrition contributes in some fashion to >50% of deaths 4. Sadly, children who survive periods of severe undernutrition can suffer long-term sequelae including stunting and neurodevelopmental deficits 5. Moreover, the effects of undernutrition can be felt across generations. Undernourished mothers suffer higher rates of morbidity and mortality and are more likely to give birth to low birth weight children who in turn have increased risk for developing type 2 diabetes, hypertension, dyslipidemia, cardiovascular pathology, and obesity as adults 6. One testable hypothesis is that the gut microbiota may contribute to the risk and pathogenesis of undernutrition through effects on nutrient metabolism and on immune function (). Similarly, does the experience of undernutrition in childhood affect the development of metabolic capacities by this microbial organ in ways that result in persistent metabolic dysfunction or inadequate function, thereby contributing to the sequelae of malnutrition? Finally, if we define malnutrition as the inadequate or excessive consumption of dietary ingredients leading to development of disease, then we need to also consider the alarming epidemic of obesity that is sweeping the world and its relationship to the gut microbiome and immune system.

A schematic of envisioned interrelationships between the gut microbiota, the immune system and diet that underlies the development of malnutrition

We believe that the marriage of two approaches, one involving culture-independent (metagenomic) methods for describing the gut microbiota/microbiome and the other involving gnotobiotics (the rearing of animals under germ-free conditions, with or without subsequent exposure at various stages of postnatal life or adulthood to a microbial species or species consortium) represents a potentially powerful way to address a number of questions related to the interrelationships between diet, nutritional status, the assembly and dynamic operations of gut microbial communities, and the nature of the interkingdom communications between the gut microbiota and host (including host-microbial co-metabolism, and the co-evolution of the immune system2,7,8). Without dismissing caveats related to the use of gnotobiotic models (see below), we describe ways that may be useful for joining gnotobiotics and metagenomic methods to compare and contrast the functional properties of various types of gut microbial communities, to explicitly test or generate hypotheses, and to develop new experimental (and computational) approaches that together inform the design, execution, and interpretation of human studies.

Changes in dietary consumption patterns affect many aspects of human biology. A full understanding of the determinants of nutritional status requires that we know what people are eating and how these diets are changing. Unfortunately, accurate information of this type is hard to obtain and when available generally covers a relatively limited time period. As a corollary, searchable databases that effectively integrate information obtained from the surveillance efforts of many international and national organizations (e.g., WHO, the UN Food and Agriculture Organization, the United States Department of Agriculture (USDA) Economic Research Service) are needed to monitor changing patterns of food consumption in different human populations. Analysis of USDA data tracking the availability of over 200 common food items between 1970 and 2000 reveals that diets in the USA have changed both in terms of overall caloric intake and the relative amounts of different food items (http://www.ers.usda.gov/Data/FoodConsumption). Linear regression of total caloric intake over time shows that the average number of kcal consumed per day increased markedly over this 30-year period (R2=0.911, P<1015). This is consistent with estimates from the US National Health and Nutrition Examination Survey (NHANES), which indicate that adult men and women increased their daily calorie intake by 6.9% and 21.7%, respectively, during the same period 9. If total caloric intake is analogous to primary productivity in macro-ecosystems, where primary productivity is used as a proxy for available energy, then increasing the amount of energy input from the diet would be predicted to affect the number of microbial species living in the gut of a single host, as well as the magnitude of the compositional differences that exist between different hosts or even different regions of a single gut (for discussions about the mechanisms underlying productivity-species richness relationships in macro-ecosystems see refs. 10,11). Intriguingly, metagenomic studies of bacterial composition in the fecal microbiota of obese and lean twin pairs living in the USA have shown that obesity is associated with decreased numbers of bacterial species 3. Reductions in diversity could impact community function, resilience to various disturbances, and the host immune system.

During the past 30-plus years, the American diet has also shifted in terms of the relative contributions of different foods to total energy intake. Since 1970, two dietary epochs can be distinguished based on the contribution of grains to overall calories (mean increase in daily carbohydrate intake for men and women during this period, 62.4g and 67.7g, respectively9). Consumption of other food items has also changed: Spearmans rank correlations between food availability and time, followed by adjustments of p-values to reflect false discovery rates, reveal that the representation of 177 of 214 items tracked by the USDA has either increased or decreased significantly in American diets since 1970. For example, Americans now eat less beef and more chicken, and corn-derived sweeteners have increased at the expense of cane and beet sugars. Additionally, methods of food modification and preparation have changed. Comparable data are needed for other countries with distinct cultural traditions, including countries where people are undergoing dramatic transformations in their socioeconomic status and lifestyles.

We know from metagenomic studies of the human gut microbiota and microbiome that (i) early postnatal environmental exposures play a very important role in determining the overall phylogenetic structure of an adult human gut microbiota, (ii) assembly of the microbiota towards an adult configuration occurs during the first three years of life 12, and (iii) features of the organismal and gene content of gut communities are shared among family members and transmitted across generations of a kinship 3. We also know that dietary habits influence the structure of the human genome. For example, populations that consume diets high in starch have a higher number of copies of the salivary amylase gene (AMY1) than those consuming low-starch diets 13. We know that these habits also affect the gut microbiome. A wonderful illustration of the latter point is the acquisition of a -porphyranase gene that degrades seaweed-associated glycans from marine microbes associated with non-sterile food consumed by Japanese populations. Zobellia galactanivorans is a marine Bacteroidetes that is able to process porphyran derived from marine red algae belonging to the genus Porphyra. Homologs of porphyranases from Z. galactanivorans are present in the human gut bacterium Bacteroides plebeius and prominently represented in the gut microbiomes of Japanese but not North Americans, leading to the suggestion that porphyranases from Z. galactanivorans or another related bacterium were acquired, perhaps through horizontal gene transfer, by a resident member of the microbiota of Japanese consumers of non-sterile food, and that this organism and gene was subsequently transmitted to others in Japanese society14. Together, these observations lead to the notion that systematic changes in overall dietary consumption patterns across a population might lead to changes in the microbiota/microbiome with consequences for host nutritional status and immune responses.

We also know from work in gnotobiotic mice that have received human fecal microbial community transplants that the relative abundances of different bacterial species and genes in the gut microbiota are highly sensitive to the proportions of different foods in the diet 2. Gnotobiotic mice harboring defined collections of sequenced human gut symbionts or transplanted human fecal microbial communities could provide an approach for modeling the effects of different dietary epochs on the gut microbiota and on different facets of host biology. If the desired result is an account of the effects of individual food items or nutrients, then feeding the animals a series of defined diets, each with a different element removed or added might be an appropriate strategy if the food ingredients for the epoch are known and available. If the focus is on the effects of overall differences in dietary habits within or between groups of humans, then diets should reflect the overall nutritional characteristics of the different groups without merely being representative of a single individual. Designing such diets requires detailed accounts of the identity and quantity of each food item consumed, ideally for a large number of people, as well as the methods used for food preparation. The American diet presents a rare opportunity for such an approach, as NHANES datasets (http://www.cdc.gov/nchs/tutorials/Dietary/) provide one-day dietary recall data at multiple timepoints dating back to the early 1970s.

The nexus between nutrient metabolism and the immune system occurs at many levels, ranging from endocrine signaling to direct sensing of nutrients by immune cells. Leptin provides a case study of features of these complex interrelationships. Leptin serves to regulate appetite and is a pleiotropic cytokine, maintaining thymic output and cellularity, and promoting the dominance of Th1 cells over Th2 cells 15,16 while inhibiting the proliferation of T regulatory cells (Tregs) 17. Low levels of leptin may account for the decreased cellular immunity associated with periods of nutrient deprivation 16. Leptin also impacts innate immune cells, ranging from promotion of neutrophil activation and migration to activation of monocytes and macrophages 15. Elegant experiments using mice deficient in the leptin receptor in different cellular compartments traced a requirement for leptin signaling in intestinal epithelial cells for preventing severe disease following exposure to Entamoeba histolytica. Comparisons of db/db mice that lack a functional leptin receptor and their wild-type littermates revealed that leptin controls infectivity and prevents severe inflammatory destruction of the intestine, thereby impacting mortality 18. These studies were extended to mice with engineered mutations in the leptin receptor that are found in human populations (T1138S and T985L, both of which disrupt signaling), Each of these mutations rendered mice more susceptible to E. histolytica infection 18. Leptin levels are significantly reduced in the sera of germ-free mice 19. Moreover, genetically obese leptin-deficient ob/ob mice have marked differences in the taxonomic and gene content of their gut microbial communities 20. To our knowledge, the effects of leptin-receptor deficiency on the gut microbiota have not been reported. Nonetheless, leptin receptor deficiency and E. histolytica pathogenesis provide a setting where the intersections between the endocrine and immune systems, enteric infection, and gut microbial ecology can be explored.

The ability to use macronutrients is essential for the generation and maintenance of a protective effector immune response. Following TCR stimulation and co-stimulation through CD28, the metabolic needs of T cells are met by a dramatic increase in uptake and utilization of glucose, amino acids and fatty acids 21,22. A deficiency in glucose uptake negatively impacts numerous facets of T cell function with impairment of both proliferation and cytokine expression. Similarly, deficiencies in amino acids such as tryptophan arginine, glutamine and cysteine reduce immune activation. Furthermore, TCR stimulation in the absence of co-stimulation, which leads to T cell anergy, has been linked to a failure to upregulate metabolic machinery associated with amino acid and iron uptake 21,22.

Short chain fatty acids (SCFAs) provide one of the clearest examples of how nutrient processing by the microbiota and host diet combine to shape immune responses. SCFAs are end-products of microbial fermentation of macronutrients, most notably plant polysaccharides that cannot be digested by humans alone because our genomes do not encode the large repertoire of glycoside hydrolases and polysaccharide lyases needed to cleave the varied glycosidic linkages present in these glycans 23. These missing enzymes (dining utensils) are provided by the microbiome. The luminal concentration of intestinal SCFAs can be modified by the amount of fiber in the diet: this in turn affects the composition of the microbiota 24. In addition to acting as an energy source for the host, SCFAs exert significant effects on host immune responses. Butyrate can modify the cytokine production profile of helper T cells 25 and promote intestinal epithelial barrier integrity 26, which in turn can help limit exposure of the mucosal immune system to luminal microbes and prevent aberrant inflammatory responses. Production of another SCFA, acetate, by the microbiota promotes the resolution of intestinal inflammation via the G protein-coupled receptor, Gpr43 27. A recent study highlighted the important role of acetate production in preventing infection with the enteropathogen, E. coli 0157:H7. This effect was linked to its ability to maintain gut epithelial barrier function 28. Intriguingly, acetylation of lysine residues may be regulated by SCFA 29 and appears to affect proteins involved in a variety of signaling and metabolic processes. The role of this covalent modification in modulating the activity of proteins intimately involved in innate and adaptive immune responses needs to be explored. It is tempting to speculate that covalent or non-covalent linkage of a variety products of microbial metabolism to host proteins produced within the intestine, or at extra-intestinal sites, will be discovered and found to have important regulatory effects. These different protein modifications could represent a series of mechanisms by which microbial community metabotype is imprinted on the host.

If nutrients and derived metabolites reflect the functional activity of the microbiota, sensors of nutrient/metabolite availability can be considered akin to microbe-associated molecular patterns (MAMPs) that convey information regarding microbes to the host. Several families of innate receptors are involved in recognition of MAMPs: they include Toll-like receptors (TLRs), inflammasomes, C-type lectins such as dectin-1, and RNA-sensing RIG-like helicases such as RIG-I and MDA5. The accompanying review by Maloy and Powrie in this issue provides an overview of this area. Here we would like to emphasize that classical innate immune recognition pathways have evolved to assess the nutrient environment. TLR4 can sense the presence of free fatty acids 30 while ATP is in important activator of the inflammasome 31. A variety of other immune cell-associated sensors serve to couple information about the local nutrient/metabolite environment to the co-ordination of local immune responses. Examples include mTOR (mammalian Target Of Rapamycin), a serine/threonine kinase32, PKR (double stranded RNA-activated protein kinase) 33, the aryl hydrocarbon receptor (AhR) 34, and various nuclear hormone receptors such as liver-X-receptor (LXR) and peroxisome-proliferator activated receptors (PPAR-, , ) 35 ( and ). The mTOR pathway represents an example of how energy availability impacts immune responses. mTOR is activated by PI3 kinase and AKT activity and is inhibited by AMP-activated protein kinase (AMPK), which is a sensor of cellular energy resources. Genetic and pharmacologic approaches (the latter using rapamycin) indicate that mTOR-signaling affects both the innate and adaptive arms of the immune system, including maturation and effector activity of dendritic cells (DCs), inhibition of Treg development, promotion of the differentiation of Th1, Th2 and Th17 cells, regulation of CD8+ T cell trafficking, and inhibition of memory T cell formation 32,36. PKR couples the presence of free fatty acids to immune activation and has been implicated in the pathogenesis of obesity in mice fed a high fat diet, including their immunoinflammatory and insulin-resistant phenotypes 33 (see below). AhR is activated by a variety of agonists, including kynurenine, a product of tryptophan metabolism by indolamine-2,3-dioxygenase (IDO) 37,38. AhR modulates the differentiation of DCs 39 as well as promoting Th17 and Treg differentiation and effector activity 40,41. Withdrawal of tryptophan and arginine controls immune responses 42,43. The presence of an intact amino acid starvation (AAS) response in T cells is essential for the immunosuppressive activity of tryptophan depletion by IDO 44. This example illustrates how the ability of T-cells to sense levels of a nutrient (tryptophan) in its local environment, rather than using the nutrient solely as a fuel source, is an important determinant of cell fate. If assessment of local nutrient levels or metabolites is an important feature in the immune decision-making process, and if the products of microbial metabolism represent heretofore unappreciated agonists or antagonists of immune cell receptors, then an important challenge is to devise in vitro and in vivo models, including genetically manipulatable gnotobiotic animals (e.g., mice or zebrafish) to identify the array of metabolites produced by a microbiota (and host) as a function of different defined diets.

Metabolic sensors that help co-ordinate immune responses

The intestinal microbiota has the capacity to synthesize a variety of vitamins involved in myriad aspects of microbial and host metabolism, including cobalamin (vitamin B12), pyridoxal phosphate (active form of vitamin B6), a cofactor in a variety of enzymatic interconversions involved in amino acid metabolism, pantothenic acid (vitamin B5), niacin (vitamin B3), biotin, tetrahydrofolate (generated from dietary forms of folate) and vitamin K. In addition to vitamin B12, gut microbes produce a range of related molecules (corrinoids) with altered lower ligands including methyladenine, p-cresol, and other analogs. Over 80% of non-absorbed dietary vitamin B12 is converted to these alternate corrinoids 45,46. There is preliminary evidence that syntrophic relationships among members of the human microbiota, and the fitness of some taxa, may be based on the ability to generate, utilize, or further transform various corrinoids46,47.

The ability of the gut microbiota to produce folate and cobalamin could affect host DNA methylation patterns, while acetate produced from microbial fermentation of polysaccharides could modify chromatin structure and gene transcription via histone acetylation. Thus, inheritance of a mammalian genotype, intergenerational transmission of a microbiome, together with a complex dynamic where the microbiome is viewed both as an epigenome per se and as a modifier of the host epigenome during the postnatal period when host, host diet and microbial community co-evolve, could together shape human physiological phenotypes that are manifest during childhood or later in life.

Numerous observational studies indicate that deficiencies in vitamins A, D, E and zinc can adversely impact immune function, particularly T-cell responses. Although a significant body of work exists detailing the myriad effects of vitamin A, D and E on host immune responses, to date there is little evidence for a role of the microbiota in the biosynthesis or metabolism of these vitamins. However, stimulation of dendritic cells via TLR2 increases the expression of host genes associated with generation of the immunoactive form of vitamin A (retinoic acid) while enteric infection has been linked to vitamin A deficiency 48,49. Intriguingly, a recent study demonstrated that vitamin A deficiency leads to a complete loss of Th17 cells in the small intestine of specified pathogen-free mice, and an associated significant reduction in the abundance of segmented filamentous bacteria (SFB) 50, a member of the Clostridiaceae that drives intestinal Th17 responses in mice 51,52. Thus, vitamin A has the potential to modulate immune responses through direct interactions with immune cells, or indirectly by modulating the composition of the microbiota.

The microbiota also affects the absorption of key minerals. Perhaps the best characterized micronutrient in terms of its interaction with both the microbiota and immune system is iron. Iron-deficient mice are resistant to the development of experimental autoimmune encephalomyelitis, and have reduced delayed type hypersensitivity responses and lower levels of IgM and IgG. Iron deficiency also impairs innate immune responses, as it is required for the respiratory burst 53. Likewise, iron is an essential micronutrient for bacteria. Given the low solubility of Fe3+, microbes have evolved the capacity to produce a variety of high affinity iron-binding siderophores.. Microbes take up soluble Fe3+ siderophore complexes via a variety of active transporters. Early studies in gnotobiotic animals revealed a link between the gut microbiota and development of iron deficiency. Germ-free but not conventionally-raised rats become anemic when fed a low iron diet. Germ-free rats also exhibit increased loss of iron in their feces compared to their conventionally-raised counterparts 54. The iron balance that exists between host and microbiota is disturbed in a mouse model of Crohns disease where there is dysregulation of TNF- expression: oral (but not parenteral) iron supplementation in these animals causes a shift in gut microbial community composition, as defined by 16S rRNA-based surveys, and exacerbates their ileitis 55.

Metagenomic methods need to be applied to further delineate the role of the microbiota in iron and other forms of micronutrient deficiency. For example, what is the impact of developing iron deficiency on the configuration of the gut microbiota and microbiome, including its content of siderophores? Does iron repletion return the microbiota/microbiome to a normal pre-deficient state, or are there persistent structural and functional perturbations that require continued nutritional supplementation to correct? Do particular configurations of the microbiota/microbiome predispose the host to iron or other types of micronutrient deficiency? How does the iron content of mothers milk during post-natal life impact the assembly and metabolic operations of the microbiota? In principle, these questions can be first addressed in a variety of gnotobiotic mouse models, and also extended to macronutrient-deficient states.

Obesity, metabolic syndrome and diabetes illustrate the role the diet-microbiota-immune axis plays in shaping human systems biology. Although the dramatic increase in obesity worldwide can be linked to an ever-growing trend towards excessive calorie intake, the microbiota has also been implicated in this disorder. Studies of a cohort of twins living in the USA indicate that the bacterial phylogenetic composition of the fecal microbiota and the representation of microbial genes involved in several aspects of nutrient metabolism in the fecal microbiome are different in lean versus obese twin pairs 3. Different groups applying different primers for amplifying bacterial 16S rRNA genes for culture-independent analyses of gut microbial ecology, and studying different human populations consuming different diets have reported differing results concerning the bacterial phylogenetic composition of the microbiota in lean versus obese individuals 56.

Evidence that a link exists between the microbiota and obesity comes from transplant experiments in gnotobiotic mice: gut communities from leptin-deficient ob/ob mice or mice with diet-induced obesity produce a greater increase in adiposity when transferred to germ-free recipients than do communities from wild-type littermates or mice that have been given a healthy calorically less dense diet 20,57. Germ-free mice are resistant to diet-induced obesity. Additional studies have revealed that the gut microbial community regulates expression of genes that affect fatty acid oxidation and fat deposition in adipocytes. For example, production of the secreted lipoprotein lipase inhibitor angipoietin-like protein 4 (Angptl4; also known as fasting-induced adipose factor) is suppressed by the microbiota: studies of germ-free and conventionalized wild-type and Angptl4/ animals established that microbiota-mediated suppression of gut epithelial expression of this secreted LPL inhibitor results in increased LPL activity and fat storage in white adipose tissue 19,58. TLR5-deficient mice harbor a gut microbiota with a configuration distinct from that encountered in littermate controls. Moreover, when their gut microbiota is transplanted to wild-type germ-free recipients, food intake is increased compared to recipients of microbiota transplants from wild-type mice: increased adiposity and hyperglycemia ensue 59. The mechanism underlying the increase in food consumption remains to be defined although the authors of this study speculate that inflammatory signaling may desensitize insulin signaling in ways that lead to hyperphagia.

Obesity in mice and humans is associated with infiltration of adipose tissue by macrophages, CD8+ T cells 60, and CD4+ T cells 61,62 expressing inflammatory cytokines and chemokines such as TNF-, CCL2, IL-6, IFN- and IL-17 60,62,63. In contrast, adipose tissue in lean mice is home to a population of immunosuppressive regulatory T cells (Treg) that serve to prevent inflammation 64. Mice deficient in the chemokine receptor CCR2 and with obesity induced by consumption of a high-fat diet have reduced macrophage infiltration of the adipose tissue and improved glucose tolerance relative to CCR2-sufficient controls 60, highlighting the role played by factors recruiting inflammatory immune cells and their associated pro-inflammatory products in the pathogenesis of metabolic abnormalities associated with obesity. Blockade of TNF- 65 or expanding Tregs using anti-CD3 mAbs 62 serves to prevent the onset of obesity-associated insulin resistance in a mouse model of diet-induced obesity.

Inflammation drives development of insulin resistance through phosphorylation of insulin receptor 1 (IRS1) via TNF- activated JNK, IKK-, protein kinase C (PKC) or mTOR activity 60. Although MyD88 signals promote development of type 1 diabetes in specified pathogen-free NOD (non-obese diabetic) mice, germ-free MyD88 deficient NOD animals are susceptible to this disorder 66. These findings suggest that particular intestinal microbial configurations can promote or prevent inflammatory immune responses that drive metabolic dysfunction.

Mice fed a high fat diet have increased serum LPS 67. Furthermore, genetically obese mice deficient in leptin or its receptor have reduced intestinal barrier function 68. As noted above, SCFA produced by microbial fermentation affect barrier function. Thus, it will be important to assess whether or not obese humans display similar reductions in barrier function: one scenario is that a high fat diet alters the structure of the intestinal microbiota leading to a reduction in intestinal barrier integrity, enhanced translocation of microbes and/or their antigens resulting in increased microbial antigen load at extra-intestinal sites, enhanced immune stimulation, and the development of insulin-resistance. Furthermore, nutrients are known to directly activate inflammatory arms of the immune system 69. The capacity of the intestinal microbiota to shape immune responses outside of intestine is well documented. Studies have highlighted the ability of the microbiota and specifically SFB to support the development of autoimmune arthritis 70 and experimental allergic encephalomyelitis 71, both of which have been linked to excessive Th17 responses.

Unfortunately, we have scant knowledge of the spatial relationships between members of the microbiota as well as their proximity to elements of the gut-associated immune system in healthy individuals, or individuals with mucosal barrier dysfunction. Gnotobiotic mouse models of obesity may help provide important insights about the biogeography of microbial communities along the length and width of the gut, including whether microbial consortia occupy ectopic sites that could impact the development and perpetuation of barrier dysfunction (e.g., in the crypts of Lieberkuhn where multipotential gut stem cells reside as described in the accompanying article by Medema and Vermeulen). Newer methods, such as CLASI-FISH 72, offer a great deal of promise for characterizing the spatial features of microbe-microbe and microbe-host cell interactions in the gut mucosa, especially if they are applied to gnotobiotic models.

Undernutrition can have a variety of clinical manifestations ranging from mild asymptomatic micronutrient deficiencies to severe, life-threatening conditions such as kwashiorkor or marasmus. Estimates are that implementing current best practice interventions, including lengthening the time of breastfeeding, supplementing diets with zinc and vitamins, improving handwashing and other hygiene measures, and optimizing treatment of acute severe malnutrition, could reduce mortality during the first three years of life by only 25%, even if there is near perfect compliance 5. While a variety of environmental and genetic factors have long been postulated to influence the development of moderate to severe forms of malnutrition 73, the underlying mechanisms remain poorly defined. Food availability, while certainly a major factor, is not the only contributor. For example, in Malawi, the concordance for severe malnutrition between twins within the same household and fed similar diets is only 50% (M. Manary, personal communication). This observation raises a number of questions. Do different configurations of the microbiota predispose one co-twin to kwashiorkor or marasmus? What is the impact of nutrient deficiency, in either the mother or her child, on the configuration of the gut microbiota and microbiome in the developing gut? Does nutrient deficiency in the mother impact the assembly of the microbiota via changes in the mothers gut microbiota or in the nutrient and immune content of her breast milk: both the microbiota and milk are transmitted to the infant yet we have much to learn about how the biochemical and immunologic features of breast-milk change and how breast milk and infant microbiota co-evolve during the suckling period when a mother is healthy or when she is malnourished (see below). If malnutrition delays the maturation of the guts microbial metabolic organ or skews it towards a different and persistent configuration that either lacks necessary functions for health or that expresses functions that may increase the risk for disease, including immunoinflammatory disorders, does nutrient repletion return the microbiota/microbiome to a normal pre-deficient state, or are there persistent structural and functional perturbations that require continued nutritional supplementation to correct? Are there microbiome configurations that correlate with vaccine responsiveness 74?

Studies of severe forms of malnutrition indicate that these patients often have many characteristics of environmental enteropathy 75. Environmental enteropathy, also known as tropical sprue or tropical enteropathy, is a poorly characterized chronic inflammatory disease that primarily affects the small intestine. This disorder afflicts individuals who reside for relatively long periods of time in areas with poor sanitation and who have high exposure to fecal-contaminated water and food. As an example, Peace Corps volunteers returning to the USA from such areas would report a history of diarrheal disease and have signs and symptoms of chronic malabsorption and nutritional deficiencies 76. The malabsorption associated with environmental enteropathy is often subtle, manifesting itself clinically only as stunting due to chronic undernutrition 76. The breakdown in intestinal mucosal barrier function in this disorder can lead to increased susceptibility to enteropathogen infections. Recurrent infections predispose to nutritional deficiencies and further compromise of barrier function, leading to a vicious cycle of further susceptibility to infection and worsening nutritional status77.

Efforts to break this cycle have focused on vaccines that could prevent infection. However, there is significant heterogeneity in the responses to vaccination between children living in highly Westernized societies and children living in certain developing countries. Oral rotavirus vaccine elicits responses in >95% of children living in Westernized societies but only 49% in Malawi 78. Lower oral polio vaccine (OPV) efficacy has been reported in populations with greater enteric disease burden 79. Studies in Chilean children have demonstrated a negative correlation between oral cholera vaccine responses and small bowel bacterial overgrowth 80. In addition, patients with celiac disease, which as noted below, shares phenotypic features with environmental enteropathy, can have a blunted response to parenteral hepatitis B vaccination, but only when their disease is active 81.

Traditionally, the most definitive test for environmental enteropathy has been small intestinal biopsy. Biopsies typically show reductions in small intestinal villus height, increased numbers of intraepithelial lymphocytes, and increased infiltration of the underlying lamina propria by T cells with a predominant Th1 phenotype 75. Some of these features are found in patients with celiac disease, where a luminal antigen (gliadin) drives a T-cell response that, in turn, results in epithelial destruction, reduced absorptive surface area, and malabsorption 76. Unlike celiac disease, the antigens that drive the host immune response in environmental enteropathy are unknown, but there may be an association with certain HLA alleles (e.g., Aw-31 82).

The pathologic events that lead to the development of environmental enteropathy are poorly understood, in part because of the absence of a robust set of readily assayed biomarkers that would improve the ability to diagnose, classify and potentially subcategorize individuals that exhibit the broadly defined clinical manifestations which define this disorder. Epidemiologic data showing a strong association of environmental enteropathy in areas with poor sanitation, occasional epidemic spread of the disease and its responsiveness to antibiotic treatment reinforce the long-standing belief that there is an infectious etiology. While cultures of jejunal aspirates from individuals with environmental enteropathy have suggested contamination of the proximal small bowel by aerotolerent Gram-negative bacteria 83, no single pathogen or set of pathogens has been identified in the gut microbiota of the majority of affected individuals. There is a distinct possibility that this enteropathy is not the result of a single pathogen but rather the result of colonization with microbial consortia that are inflammogenic in the context of a susceptible host. In fact, what constitutes a normal immune repertoire in a healthy gut likely varies considerably depending upon environmental exposures and the configuration of a microbiota. Moreover, most metagenomic studies of the microbiota have focused on members of the domain Bacteria that dominate these communities. Additional tools need to be developed so that they can be extended to viral and eukaryotic components. The latter include parasites that compete for nutrients within the intestines of infected individuals. Parasites can interact directly with bacterial members of the microbiota during their life cycle in ways that promote hatching of parasite eggs, and can shape immune function through factors such as excretory-secretory (ES) products which have been shown to modulate cytokine production, basophil degranulation, immune cell recruitment and interference with TLR signaling 84.

It seems reasonable to posit that individuals living in regions with high oral exposures to fecal contaminated water and foods, and/or with a eukaryotic component of their gut community that includes parasites, will have gut associated-immune systems with significantly different structural and functional configurations than those without these exposures. In this sense, including the term environmental together with enteropathy is logical and emphasizes the need to place a hosts immune and gut microbiome phenotypes in the context of their various exposures.

Comparative metagenomic studies could provide important new diagnostic tools in the form of microbial taxa, and microbiome gene functions whose representation in the gut communities of affected individuals versus healthy controls correlates with environmental enteropathy. In addition, they could provide pathophysiological insights about relationships between host diet, enteropathogen representation in the microbiota, and microbiome gene composition and expression (including expressed metabolic functions). A major challenge will be to correlate this data with the results of quantitative phenotyping of the human guts innate and adaptive immune system. This will require new and safe approaches for sampling system components, especially in the gut mucosa. Similarly, as noted above, we have scant knowledge of the spatial relationships between members of the microbiota, as well as their proximity to elements of the gut-associated immune system in healthy individuals or in individuals with mucosal barrier dysfunction.

Breast milk is known to protect newborns from infection, in part because of the copious amount of maternally generated antibodies that it contains. While these antibodies have specificity for components of the microbiota, the microbial targets are not well defined for given maternal- infant dyads, or as a function of time after delivery. In addition to antibodies, breast milk contains other immunoactive compounds including cytokines (e.g., IL-10), growth factors (e.g., EGF) and antimicrobial enzymes such as lysozyme. The impact of maternal nutritional status on the glycan, protein, lipid and cytokine landscape of breast milk needs to be defined further. This analysis should have a temporal axis that explores co-evolution of the immunological/nutrient properties of mothers milk and the postnatal assembly and maturation of the infant gut microbiota and of the innate and adaptive immune system. Important feedback systems may be revealed. Similarly, knowledge of the vaginal and cutaneous microbiota of mothers prior to and following birth, as a function of their nutritional status could be very informative. For example, are there common configurations of microbial communities occupying these body habitats that correlate with the development of environmental enteropathy in mothers and their offspring?

As noted above, studies have demonstrated the ability of intestinal microbial communities to rapidly re-shape themselves in response to changes in diet. These observations raise the question of whether and how malnourished states impact (i) the spatial/functional organization of the microbiota and the niches (professions) of its component members; (ii) the capacity of the community to respond to changes in diet; (iii) the ability of components of the microbiota to adaptively forage on host-derived mucosal substrates, and (iv) the physical and functional interactions that occur between the changing microbial communities and the intestinal epithelial barrier (including its overlying mucus layer). One way of developing the experimental and computational tools and concepts needed to examine these challenging questions in humans is to turn to gnotobiotic mice who have been humanized by transplantation of gut communities from human donors with distinct physiological phenotypes and to feed these mice diets that are representative of those of the microbiota donor.

We have used metagenomic methods to show that gut (fecal) communities can be efficiently transplanted into germ-free mice and the mice then fed diets that resemble those consumed by the human microbiota donors, or diets whose ingredients are deliberately manipulated in various ways 2. Transplanted human gut microbial communities can be transmitted from gnotobiotic mothers to their pups. In principle, by using mice humanized with microbiota from individuals residing in different regions of the world, and giving them diets that are representative of their cultural traditions, proof-of-principle global clinical trials of the nutritional value of foods and their impact on the microbiota and immune system can be performed.

Transplantation of a human fecal microbiota into germ-free mice can be viewed as capturing an individuals microbial community at a moment in time and replicating it in multiple recipient gut ecosystems. The humanized mice can be followed over time under highly controlled conditions where potentially confounding variables can be constrained in ways that are not achievable in human studies. This type of personalized gnotobiotics also provides an opportunity to determine the degree to which human phenotypes can be transmitted via the gut microbiota as a function of diet. Moreover, the documented responses of microbial lineages and genes encoding metabolic pathways in the transplanted, replicated communities may provide mechanistic insights about differences in the adaptations of healthy versus diseased gut microbiomes (and host immune system) to changes in diets, plus new biomarkers of nutritional status and the impact of various therapeutic interventions, including those based on dietary manipulations. Putative microbial biomarkers obtained from studies of these mice can in turn be used to query datasets generated directly from the human donor(s).

Despite the potential power of using humanized mice to study interactions between the host immune and metabolic systems and the intestinal microbiota under highly controlled conditions, this approach has caveats. Recent work on Th17 responses suggests that unlike the mouse microbiota, which contains SFB, a fecal microbiota from a human donor is not sufficient to drive immune-gene expression in the small intestine of ex-germ free mice52. This raises the possibility that humanization may not fully recapitulate the capacity of a mouse microbiota to mature the intestinal immune system in mice. However, earlier studies on the effects of human microbiota on the mouse immune system revealed that the ability of E. coli heat labile enterotoxin (LT) to break oral tolerance to ovalbumin in germ-free mice can be inhibited by transplantation of either a human or mouse microbiota during the neonatal period 85. Further, a single component of a human gut symbiont, the polysaccharide A component of B. fragilis, is able to mature components of the CD4+ T cell response in mice 86. Finally, we have observed a similar increase in the frequency of TCR-+ cells in the mesenteric lymph nodes of gnotobiotic recipients of a human or mouse microbiota, when compared to germ-free controls (P. Ahern, V. Ridaura and J. Gordon, unpublished observations). This suggests that although not all components of the immune system will be matured by a human gut microbiota, the immune system is not likely to remain ignorant of these communities. In addition, any differences detected in direct comparisons of the effects of two different human communities may represent responses relevant to the human immune system.

We have recently shown that the human fecal microbiota consists largely of bacteria that can readily be cultured87. Metagenomic analysis suggests that the majority of predicted functions in a humans microbiome are represented in its cultured members. In gnotobiotic mice, both complete and cultured communities exhibit similar properties and responses to dietary manipulations. By changing the diet of the host, the community of cultured microbes can be shaped so that it becomes enriched for taxa suited to that diet. These culture collections of anaerobes can be clonally arrayed in multi-well formats: this means that personalized, taxonomically defined culture collections can be created from donors representing different human populations and physiologic phenotypes, and where the microbes have co-evolved and co-existed together within a single human beings gut habitat.

Together, these advances yield a translational medicine pipeline for examining the interplay between food and food ingredients, the microbiota, the immune system and health. Goals for such a human translational medicine pipeline are to (i) identify individuals with interesting phenotypes, (ii) assess transmissibility of their phenotypes via human microbiota transplants into gnotobiotic animals, (iii) select candidate disease-modifying taxa (retrieved from clonally-arrayed, taxonomically defined personal bacterial culture collections), (iv) sequence selected taxa and (v) reunite them in various combinations in gnotobiotic mice as defined model gut communities, so that their interactions with one another and their impact on host biology can be further explored, using a variety of methods [e.g., RNA-Seq, mass-spec based proteomics and metabolomics, multi-label FISH (for biogeographical studies of the microbiota), whole genome transposon mutagenesis (to identify fitness factors for microbes under various dietary contexts 46), immune profiling and other measurements of mucosal barrier function]. Knowing the degree to which tractable bacterial taxa are able to influence host physiology, and how dietary components can be used to affect specific organisms in the microbiota in ways that provide benefit to the host may be very useful for discovering new generations of pro- and prebiotics.

With massive prospective national surveys planned and being implemented, such as the NIHs National Childrens Study that will follow a representative sample of 100,000 children from before birth to age 21, the time is right for an initiative to evaluate the interrelationships between our diets, nutritional status, microbiomes and immune systems. Many components could comprise this initiative. We can readily envision several of these.

As noted above, there is a need to create more and improved databases for monitoring changing patterns of food consumption that integrates the surveillance efforts of a number of organizations. This tool and other interdisciplinary approaches could be used to define a set of study populations representative of established and emerging food consumption patterns in distinct cultural and socioeconomic settings. An emphasis could be placed on comparing humans living in Westernized societies versus those living in developing countries undergoing marked transitions in lifestyles/cultural traditions. New, reliable, cost-effective and generalizable methods will be needed for acquiring quantitative data about the diets consumed by individual humans in these study populations, and the resulting data deposited in searchable databases together with defined annotation standards. Moreover, guidelines need to be further developed related to ethical and legal aspects of human subjects research involving observational and interventional nutritional studies of pregnant women and their offspring.

Readily procured human biospecimens could be used together with high throughput, targeted and nontargeted (quantitative) profiling of metabolites in comprehensive time series studies to define the relationship between diet, nutritional status, and microbiome configuration in healthy individuals at various stages of life (e.g., in women before, during and after pregnancy and in their children during the first 5 years after birth). This could be accompanied by studies of malnourished individuals before, during and after well justified, defined nutritional interventions. In addition to these data, genomes (genotypes), epigenomes and microbiomes could be characterized in these study cohorts together with a variety of clinical parameters (e.g., vaccine responses) and environmental parameters (e.g., water sanitation). The resulting datasets would be deposited in annotated searchable databases. A translational medicine pipeline that includes relevant cellular and animal models would help guide the design and interpretation of these human studies.

As noted above, a major challenge is to obtain cellular and molecular biomarkers for quantitative profiling of the innate and adaptive immune system, including biomarkers of mucosa-associated barrier function. Given the small quantities of biomaterials available from some body sites, this initiative should help advance enabling miniaturizing technology for quantitative measurements of cells and biofluids. Non-invasive imaging-based biomarkers are also needed.

Aspirational goals include identifying new host and microbial biomarkers and mediators of nutritional status, the nutritional value of various foods, the functioning of the human adaptive/innate immune system (including mucosal barrier integrity and mucosal immunity), and the dynamic operations of the microbiota. This information would be used for demonstration projects that rigorously define nutritional health and test preventive or therapeutic recommendations for micro- and macronutrient consumption, for example in pregnant women and infants/children, and their impact on the assembly and operations of their immune systems. The microbiome component could also help define a previously uncharacterized axis of human genetic evolution (our microbiome-evolution) reflecting in part our changing dietary habits. It could also produce testable hypotheses about unappreciated aspects of the pathophysiology of Western diseases, and yield new microbiome-based strategies for disease prevention or treatment.

We are grateful to members of our lab, plus our colleagues Clay Semenkovich and Andrey Shaw, for many helpful discussions. Work cited from our laboratory was supported by grants from the NIH (DK30292, DK70977, DK078669), the Crohns and Colitis Foundation of America, and the Bill and Melinda Gates Foundation.

1. Whitacre PT, Fagen AP, Husbands JL, Sharples FE. Implementing the New Biology: Decadal Challenges Linking Food, Energy, and the Environment. National Research Council of The National Academies of Science; Washington, D.C.: 2010.

11. Mittelbach GG, et al. What is the observed relationship between species richness and productivity? Ecology. 2001;82:23812396.

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Human nutrition, the gut microbiome, and immune system ...

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Gut flora – Wikipedia, the free encyclopedia

Thursday, August 4th, 2016

Gut flora (gut microbiota, or gastrointestinal microbiota) is the complex community of microorganisms that live in the digestive tracts of humans and other animals, including insects. The gut metagenome is the aggregate of all the genomes of gut microbiota.[1] The gut is one niche that human microbiota inhabit.[2]

In humans, the gut microbiota has the largest numbers of bacteria and the greatest number of species compared to other areas of the body.[3] In humans the gut flora is established at one to two years after birth, and by that time the intestinal epithelium and the intestinal mucosal barrier that it secretes have co-developed in a way that is tolerant to, and even supportive of, the gut flora and that also provides a barrier to pathogenic organisms.[4][5]

The relationship between gut flora and humans is not merely commensal (a non-harmful coexistence), but rather a mutualistic relationship.[2]:700 Human gut microorganisms benefit the host by collecting the energy from the fermentation of undigested carbohydrates and the subsequent absorption of short-chain fatty acids (SCFAs), acetate, butyrate, and propionate.[3][6] Intestinal bacteria also play a role in synthesizing vitamin B and vitamin K as well as metabolizing bile acids, sterols, and xenobiotics.[2][6] The systemic importance of the SCFAs and other compounds they produce are like hormones and the gut flora itself appears to function like an endocrine organ,[6] and dysregulation of the gut flora has been correlated with a host of inflammatory and autoimmune conditions.[3][7]

The composition of human gut flora changes over time, when the diet changes, and as overall health changes.[3][7]

The microbial composition of the gut flora varies across the digestive tract. In the stomach and small intestine, relatively few species of bacteria are generally present.[8][9] The colon, in contrast, contains a densely-populated microbial ecosystem with up to 1012 cells per gram of intestinal content.[8] These bacteria represent between 300 and 1000 different species.[8][9] However, 99% of the bacteria come from about 30 or 40 species.[10] As a consequence of their abundance in the intestine, bacteria also make up to 60% of the dry mass of feces.[11]Fungi, archaea, and viruses are also present in the gut flora, but less is known about their activities.[12]

Over 99% of the bacteria in the gut are anaerobes, but in the cecum, aerobic bacteria reach high densities.[2] It is estimated that these gut flora have around a hundred times as many genes in aggregate as there are in the human genome.[13]

Many species in the gut have not been studied outside of their hosts because most cannot be cultured.[9][10][14] While there are a small number of core species of microbes shared by most individuals, populations of microbes can vary widely among different individuals.[15] Within an individual, microbe populations stay fairly constant over time, even though some alterations may occur with changes in lifestyle, diet and age.[8][16] The Human microbiome project has set out to better describe the microflora of the human gut and other body locations.

The four dominant phyla in the human gut are Firmicutes, Bacteroidetes, Actinobacteria, and Proteobacteria.[17] Most bacteria belong to the genera Bacteroides, Clostridium, Faecalibacterium,[8][10]Eubacterium, Ruminococcus, Peptococcus, Peptostreptococcus, and Bifidobacterium.[8][10] Other genera, such as Escherichia and Lactobacillus, are present to a lesser extent.[8] Species from the genus Bacteroides alone constitute about 30% of all bacteria in the gut, suggesting that this genus is especially important in the functioning of the host.[9]

The currently known genera of fungi of the gut flora include Candida, Saccharomyces, Aspergillus, and Penicillium.

Archaea constitute another large class of gut flora which are important in the metabolism of the bacterial products of fermentation.

An enterotype is a classification of living organisms based on its bacteriological ecosystem in the human gut microbiome not dictated by age, gender, body weight, or national divisions.[18] There are indications that long-term diet influences enterotype.[19] Three human enterotypes have been discovered.[18][20]

Due to the high acidity of the stomach, most microorganisms cannot survive. The main bacterial inhabitants of the stomach include: Streptococcus, Staphylococcus, Lactobacillus, Peptostreptococcus, and types of yeast.[2]:720Helicobacter pylori is a Gram-negative spiral organism that establishes on gastric mucosa causing chronic gastritis and peptic ulcer disease and is a carcinogen for gastric cancer.[2]:904

The small intestine contains a trace amount of microorganisms due to the proximity and influence of the stomach. Gram positive cocci and rod shaped bacteria are the predominant microorganisms found in the small intestine.[2] However, in the distal portion of the small intestine alkaline conditions support gram-positive bacteria of the Enterobacteriaceae.[2] The bacterial flora of the small intestine aid in a wide range of intestinal functions. The bacterial flora provide regulatory signals that enable the development and utility of the gut. Overgrowth of bacteria in the small intestine can lead to intestinal failure.[21] In addition the large intestine contains the largest bacterial ecosystem in the human body.[2] Factors that disrupt the microorganism population of the large intestine include antibiotics, stress, and parasites.[2]

Bacteria make up most of the flora in the colon[22] and 60% of the dry mass of feces.[8] This fact makes feces an ideal source to test for gut flora for any tests and experiments by extracting the nucleic acid from fecal specimens, and bacterial 16S rRNA gene sequences are generated with bacterial primers. This form of testing is also often preferable to more invasive techniques, such as biopsies. Somewhere between 300[8] and 1000 different species live in the gut,[9] with most estimates at about 500.,[23][24] However, it is probable that 99% of the bacteria come from about 30 or 40 species, with Faecalibacterium prausnitzii being the most common species in healthy adults.[10][25]Fungi and protozoa also make up a part of the gut flora, but little is known about their activities.

Research suggests that the relationship between gut flora[26] and humans is not merely commensal (a non-harmful coexistence), but rather is a mutualistic, symbiotic relationship.[9] Though people can (barely) survive with no gut flora,[23] the microorganisms perform a host of useful functions, such as fermenting unused energy substrates, training the immune system via end products of metabolism like propionate and acetate, preventing growth of harmful species, regulating the development of the gut, producing vitamins for the host (such as biotin and vitamin K), and producing hormones to direct the host to store fats.[2]:713ff Extensive modification and imbalances of the gut microbiota and its microbiome or gene collection are associated with obesity.[27] However, in certain conditions, some species are thought to be capable of causing disease by causing infection or increasing cancer risk for the host.[8][22]

It has been demonstrated that there are common patterns of microbiome composition evolution during life.[29] In general, the diversity of microbiota composition of fecal samples is significantly higher in adults than in children, although interpersonal differences are higher in children than in adults.[30] Much of the maturation of microbiota into an adult-like configuration happens during the three first years of life.[30]

As the microbiome composition changes, so does the composition of bacterial proteins produced in the gut. In adult microbiomes, a high prevalence of enzymes involved in fermentation, methanogenesis and the metabolism of arginine, glutamate, aspartate and lysine have been found. In contrast, in infant microbiomes the dominant enzymes are involved in cysteine metabolism and fermentation pathways.[30]

Studies and statistical analyses have identified the different bacterial genera in gut microbiota and their associations with nutrient intake. Gut microflora is mainly composed of three enterotypes: Prevotella, Bacteroides, and Ruminococcus. There is an association between the concentration of each microbial community and diet. For example, Prevotella is related to carbohydrates and simple sugars, while Bacteroides is associated with proteins, amino acids, and saturated fats. One enterotype will dominate depending on the diet. Altering the diet will result in a corresponding change in the numbers of species.[19]

Malnourished human children have less mature and less diverse gut microbiota than healthy children, and changes in the microbiome associated with nutrient scarcity can in turn be a pathophysiological cause of malnutrition.[31][32] Malnourished children also typically have more potentially pathogenic gut flora, and more yeast in their mouths and throats.[33]

Gut microbiome composition depends on the geographic origin of populations. Variations in trade off of Prevotella, the representation of the urease gene, and the representation of genes encoding glutamate synthase/degradation or other enzymes involved in amino acids degradation or vitamin biosynthesis show significant differences between populations from USA, Malawi or Amerindian origin.[30]

The US population has a high representation of enzymes encoding the degradation of glutamine and enzymes involved in vitamin and lipoic acid biosynthesis; whereas Malawi and Amerindian populations have a high representation of enzymes encoding glutamate synthase and they also have an overrepresentation of -amylase in their microbiomes. As the US population has a diet richer in fats than Amerindian or Malawian populations which have a corn-rich diet, the diet is probably a main determinant of gut bacterial composition.[30]

Further studies have indicated a large difference in the composition of microbiota between European and rural African children. The fecal bacteria of children from Florence were compared to that of children from the small rural village of Boulpon in Burkina Faso. The diet of a typical child living in this village is largely lacking in fats and animal proteins and rich in polysaccharides and plant proteins. The fecal bacteria of European children was dominated by Firmicutes and showed a marked reduction in biodiversity, while the fecal bacteria of the Boulpon children was dominated by Bacteroidetes. The increased biodiversity and different composition of gut flora in African populations may aid in the digestion of normally indigestible plant polysaccharides and also may result in a reduced incidence of non-infectious colonic diseases.[34]

On a smaller scale, it has been shown that sharing numerous common environmental exposures in a family is a strong determinant of individual microbiome composition. This effect has no genetic influence and it is consistently observed in culturally different populations.[30]

In humans, a gut flora similar to an adult's is formed within one to two years of birth.[4] The gastrointestinal tract of a normal fetus has been considered to be sterile, however recently it has been acknowledged that microbial colonisation may occur in the fetus.[35] During birth and rapidly thereafter, bacteria from the mother and the surrounding environment colonize the infant's gut.[4] As of 2013, it was unclear whether most of colonizing arise from the mother or not.[4] Infants born by caesarean section may also be exposed to their mothers' microflora, but the initial exposure is most likely to be from the surrounding environment such as the air, other infants, and the nursing staff, which serve as vectors for transfer.[36] During the first year of life, the composition of the gut flora is generally simple and it changes a great deal with time and is not the same across individuals.[4]

The initial bacterial population are generally facultative anaerobic organisms; investigators believe that these initial colonizers decrease the oxygen concentration in the gut, which in turn allows purely aneorobic bacteria like Bacteroides, Actinobacteria, and Firmicutes to become established and thrive.[4] Breast-fed babies become dominated by bifidobacteria, possibly due to the contents of bifidobacterial growth factors in breast milk.[37][38] In contrast, the microbiota of formula-fed infants is more diverse, with high numbers of Enterobacteriaceae, enterococci, bifidobacteria, Bacteroides, and clostridia.[39]

Bacteria in the gut fulfill a host of useful functions for humans, including digestion of unutilized energy substrates,[40] stimulating cell growth, repressing the growth of harmful microorganisms, training the immune system to respond only to pathogens, and defending against some diseases.[8][9][41]

Without gut flora, the human body would be unable to utilize some of the undigested carbohydrates it consumes, because some types of gut flora have enzymes that human cells lack for breaking down certain polysaccharides.[6] Rodents raised in a sterile environment and lacking in gut flora need to eat 30% more calories just to remain the same weight as their normal counterparts.[6] Carbohydrates that humans cannot digest without bacterial help include certain starches, fiber, oligosaccharides, and sugars that the body failed to digest and absorb like lactose in the case of lactose intolerance and sugar alcohols, mucus produced by the gut, and proteins.[3][6]

Bacteria turn carbohydrates they ferment into short-chain fatty acids (SCFAs)[10][24] by a form of fermentation called saccharolytic fermentation.[24] Products include acetic acid, propionic acid and butyric acid.[10][24] These materials can be used by host cells, providing a major source of useful energy and nutrients for humans,[24] as well as helping the body to absorb essential dietary minerals such as calcium, magnesium and iron.[8] Gases and organic acids, such as lactic acid, are also produced by saccharolytic fermentation.[10] Acetic acid is used by muscle, propionic acid helps the liver produce ATP, and butyric acid provides energy to gut cells and may prevent cancer.[24] Evidence also indicates that bacteria enhance the absorption and storage of lipids[9] and produce and then facilitate the body to absorb needed vitamins like vitamin K.

Another benefit of SCFAs is that they increase growth of intestinal epithelial cells and control their proliferation and differentiation.[8] They may also cause lymphoid tissue near the gut to grow. Bacterial cells also alter intestinal growth by changing the expression of cell surface proteins such as sodium/glucose transporters.[9] In addition, changes they make to cells may prevent injury to the gut mucosa from occurring.[41]

In humans, a gut flora similar to an adult's is formed within one to two years of birth.[4] As the gut flora gets established, the lining of the intestines - the intestinal epithelium and the intestinal mucosal barrier that it secretes - develop as well, in a way that is tolerant to, and even supportive of, commensurate microorganisms to a certain extent and also provides a barrier to pathogenic ones.[4] Specifically, goblet cells that produce the muscosa proliferate, and the mucosa layer thickens, providing an outside mucosal layer in which "friendly" microorganisms can anchor and feed, and an inner layer that even these organisms cannot penetrate.[4][5] Additionally, the development of gut-associated lymphoid tissue (GALT), which forms part of the intestinal epithelium and which detects and reacts to pathogens, appears and develops during the time that the gut flora develops and established.[4] The GALT that develops is tolerant to gut flora species, but not to other microorganisms.[4] GALT also normally becomes tolerant to food to which the infant is exposed, as well as digestive products of food, and gut flora's metabolites produced from food.[4]

The human immune system creates cytokines that can drive the immune system to produce inflammation in order to protect itself, and that can tamp down the immune response to maintain homeostasis and allow healing after insult or injury.[4] Different bacterial species that appear in gut flora have been shown to be able to drive the immune system to create cytokines selectively; for example Bacteroides fragilis and some Clostridia species appear to drive an anti-inflammatory response, while some segmented filamentous bacteria drive the production of inflammatory cytokines.[4][42] Gut flora can also regulate the production of antibodies by the immune system.[4][43] These cytokines and antibodies can have effects outside the gut, in the lungs and other tissues.[4]

The resident gut microflora positively control the intestinal epithelial cell differentiation and proliferation through the production of short-chain fatty acids. They also mediate other metabolic effects such as the syntheses of vitamins like biotin and folate, as well as absorption of ions including magnesium, calcium and iron.[16]Methanogenic archae such as Methanobrevibacter smithii are involved in the removal of end products of bacterial fermentation such as hydrogen.[2]

Altering the numbers of gut bacteria, for example by taking broad-spectrum antibiotics, may affect the host's health and ability to digest food.[44] Antibiotics can cause antibiotic-associated diarrhea (AAD) by irritating the bowel directly, changing the levels of gut flora, or allowing pathogenic bacteria to grow.[10] Another harmful effect of antibiotics is the increase in numbers of antibiotic-resistant bacteria found after their use, which, when they invade the host, cause illnesses that are difficult to treat with antibiotics.[44]

Changing the numbers and species of gut flora can reduce the body's ability to ferment carbohydrates and metabolize bile acids and may cause diarrhea. Carbohydrates that are not broken down may absorb too much water and cause runny stools, or lack of SCFAs produced by gut flora could cause the diarrhea.[10]

A reduction in levels of native bacterial species also disrupts their ability to inhibit the growth of harmful species such as C. difficile and Salmonella kedougou, and these species can get out of hand, though their overgrowth may be incidental and not be the true cause of diarrhea.[8][10][44] Emerging treatment protocols for C. difficile infections involve fecal microbiota transplantation of donor feces. (see Fecal transplant). Initial reports of treatment describe success rates of 90%, with few side effects. Efficacy is speculated to result from restoring bacterial balances of bacteroides and firmicutes classes of bacteria.[45]

Gut flora composition also changes in severe illnesses, due not only to antibiotic use but also to such factors as ischemia of the gut, failure to eat, and immune compromise. Negative effects from this have led to interest in selective digestive tract decontamination (SDD), a treatment to kill only pathogenic bacteria and allow the re-establishment of healthy ones.[46]

Antibiotics alter the population of the gastrointestinal (GI) tract microbiota, may change the intra-community metabolic interactions, modify caloric intake by using carbohydrates, and globally affects host metabolic, hormonal and immune homeostasis.[47]

Probiotics are microorganisms that are believed to provide health benefits when consumed.[48][49] With regard to gut flora, prebiotics are typically non-digestible, fiber compounds that pass undigested through the upper part of the gastrointestinal tract and stimulate the growth or activity of advantageous gut flora by acting as substrate for them.[24][50]

Synbiotics refers to food ingredients or dietary supplements combining probiotics and prebiotics in a form of synergism.[51]

The term "pharmabiotics" is used in various ways, to mean: pharmaceutical formulations (standardized manufacturing that can obtain regulatory approval as a drug) of probiotics, prebiotics, or synbiotics;[52] probiotics that have been genetically engineered or otherwise optimized for best performance (shelf life, survival in the digestive tract, etc.);[53] and the natural products of gut flora metabolism (vitamins, etc.).[54]

There is some evidence that treatment with some probiotic strains of bacteria may be effective in irritable bowel syndrome and chronic idiopathic constipation. Those organisms most likely to result in a decrease of symptoms have included:

Gram positive bacteria present in the lumen may be associated with extending the duration of relapse for ulcerative colitis.[56]

Women's gut microbiota change as pregnancy advances, with the changes similar to those seen in metabolic syndromes such as diabetes. The change in gut flora causes no ill effects. The newborn's gut biota resemble the mother's first-trimester samples. The diversity of the flora decreases from the first to third trimester, as the numbers of certain species go up.[58]

Weight loss initiates a shift in the bacteria phyla that compose gut flora. Specifically, Bacteroidetes increase nearly linearly as weight loss progresses.[59] While there is a high level of variation in bacteria species found among individual people, this trend is prominent and distinct in humans.[60]

Bacteria in the digestive tract can contribute to disease in various ways. The presence or overabundance of some kinds of bacteria may contribute to inflammatory disorders such as inflammatory bowel disease.[8] Additionally, metabolites from certain members of the gut flora may influence host signaling pathways, contributing to disorders such as obesity and colon cancer.[8] Alternatively, in the event of a breakdown of the gut epithelium, the intrusion of gut flora components into other host compartments can lead to sepsis.[8]

Some genera of bacteria, such as Bacteroides and Clostridium, have been associated with an increase in tumor growth rate, while other genera, such as Lactobacillus and Bifidobacteria, are known to prevent tumor formation.[8]

As the liver is fed directly by the portal vein, whatever crosses the intestinal epithelium and the intestinal mucosal barrier enters the liver, as do cytokines generated there.[61] Dysbiosis in the gut flora has been linked with the development of cirrhosis and non-alcoholic fatty liver disease.[61]

Normally-commensal bacteria can be very harmful to the host if they get outside of the intestinal tract.[4][5]Translocation, which occurs when bacteria leave the gut through its mucosal lining, the border between the lumen of the gut and the inside of the body, can occur in a number of different diseases, and can be caused by too much growth of bacteria in the small intestine, reduced immunity of the host, or increased gut lining permeability.[5]

If the gut is perforated, bacteria can invade the body, causing a potentially fatal infection. Aerobic bacteria can make an infection worse by using up all available oxygen and creating an environment favorable to anaerobes.[2]:715

In a similar manner, Helicobacter pylori can cause stomach ulcers by crossing the epithelial lining of the stomach. Here the body produces an immune response. During this response parietal cells are stimulated and release extra hydrochloric acid (HCl+) into the stomach. However, the response does not stimulate the mucus-secreting cells that protect and line the epithelium of the stomach. The extra acid sears holes into the epithelial lining of the stomach, resulting in stomach ulcers.[29]

Inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are all chronic inflammatory disorders of the gut, and asthma and diabetes have been described as inflammatory disorders as well; the causes of these disease are unknown and issues with the gut flora and its relationship with the host have been implicated in these conditions.[7][62][63][64]

Two hypotheses have been posed to explain the rising prevalence of these diseases in the developed world: the hygiene hypothesis, which posits that children in the developed world are not exposed to a wide enough range of pathogens and end up with an overreactive immune system, and the role of the Western pattern diet which lacks whole grains and fiber and has an overabundance of simple sugars.[7] Both hypotheses converge on the changes in the gut flora and its role in modulating the immune system, and as of 2016 this was an active area of research.[7]

Similar hypotheses have been posited for the rise of food and other allergies.[65]

As of 2016 it is not clear if changes to the gut flora cause these auto-immune and inflammatory disorders or are a product of them or adaptation to them.[7][66]

The gut flora has also been implicated in obesity and metabolic syndrome due to the key role it plays in the digestive process; the Western pattern diet appears to drive and maintain changes in the gut flora that in turn change how much energy is derived from food and how that energy is used.[64][67]

Aside from mammals, some insects also possess complex and diverse gut microbiota that play key nutritional roles.[68] Microbial communities associated termites can constitute a majority of the weight of the individuals and perform important roles in the digestion of lignocellulose and nitrogen fixation.[69] These communities are host-specific, and closely related insect species share comparable similarities in gut microbiota composition.[70][71] In cockroaches, gut microbiota have been shown to assemble in a deterministic fashion, irrespective of the inoculum;[72] the reason for this host-specific assembly remains unclear. Bacterial communities associated with insects like termites and cockroaches are determined by a combination of forces, primarily diet, but there is some indication that host phylogeny may also be playing a role in the selection of lineages.[70][71]

For more than 51 years we have known that the administration of low doses of antibacterial agents promotes the growth of farm animals to increase weight gain.[47]

In a study performed on mice by Ilseung Cho,[47] the ratio of Firmicutes and Lachnospiraceae was significantly elevated in animals treated with subtherapeutic doses of different antibiotics. By analyzing the caloric content of faeces and the concentration of small chain fatty acids (SCFAs) in the GI tract, they concluded that the changes in the composition of microbiota lead to an increased capacity to extract calories from otherwise indigestible constituents, and to an increased production of SCFAs. These findings provide evidence that antibiotics perturb not only the composition of the GI microbiome but also its metabolic capabilities, specifically with respect to SCFAs.[47]

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Fasting for three days can regenerate entire immune system …

Thursday, August 4th, 2016

Fasting for as little as three days can regenerate the entire immune system, even in the elderly, scientists have found in a breakthrough described as "remarkable".

Although fasting diets have been criticised by nutritionists for being unhealthy, new research suggests starving the body kick-starts stem cells into producing new white blood cells, which fight off infection.

Scientists at the University of Southern California say the discovery could be particularly beneficial for people suffering from damaged immune systems, such as cancer patients on chemotherapy.

It could also help the elderly whose immune system becomes less effective as they age, making it harder for them to fight off even common diseases.

The researchers say fasting "flips a regenerative switch" which prompts stem cells to create brand new white blood cells, essentially regenerating the entire immune system.

"It gives the 'OK' for stem cells to go ahead and begin proliferating and rebuild the entire system," said Prof Valter Longo, Professor of Gerontology and the Biological Sciences at the University of California.

"And the good news is that the body got rid of the parts of the system that might be damaged or old, the inefficient parts, during the fasting.

Now, if you start with a system heavily damaged by chemotherapy or ageing, fasting cycles can generate, literally, a new immune system."

Prolonged fasting forces the body to use stores of glucose and fat but also breaks down a significant portion of white blood cells.

During each cycle of fasting, this depletion of white blood cells induces changes that trigger stem cell-based regeneration of new immune system cells.

In trials humans were asked to regularly fast for between two and four days over a six-month period.

Scientists found that prolonged fasting also reduced the enzyme PKA, which is linked to ageing and a hormone which increases cancer risk and tumour growth.

"We could not predict that prolonged fasting would have such a remarkable effect in promoting stem cell-based regeneration of the hematopoietic system," added Prof Longo.

"When you starve, the system tries to save energy, and one of the things it can do to save energy is to recycle a lot of the immune cells that are not needed, especially those that may be damaged," Dr Longo said.

"What we started noticing in both our human work and animal work is that the white blood cell count goes down with prolonged fasting. Then when you re-feed, the blood cells come back. So we started thinking, well, where does it come from?"

Fasting for 72 hours also protected cancer patients against the toxic impact of chemotherapy.

"While chemotherapy saves lives, it causes significant collateral damage to the immune system. The results of this study suggest that fasting may mitigate some of the harmful effects of chemotherapy," said co-author Tanya Dorff, assistant professor of clinical medicine at the USC Norris Comprehensive Cancer Center and Hospital.

"More clinical studies are needed, and any such dietary intervention should be undertaken only under the guidance of a physician.

"We are investigating the possibility that these effects are applicable to many different systems and organs, not just the immune system," added Prof Longo.

However, some British experts were sceptical of the research.

Dr Graham Rook, emeritus professor of immunology at University College London, said the study sounded "improbable".

Chris Mason, Professor of Regenerative Medicine at UCL, said: There is some interesting data here. It sees that fasting reduces the number and size of cells and then re-feeding at 72 hours saw a rebound.

That could be potentially useful because that is not such a long time that it would be terribly harmful to someone with cancer.

But I think the most sensible way forward would be to synthesize this effect with drugs. I am not sure fasting is the best idea. People are better eating on a regular basis.

Dr Longo added: There is no evidence at all that fasting would be dangerous while there is strong evidence that it is beneficial.

I have received emails from hundreds of cancer patients who have combined chemo with fasting, many with the assistance of the oncologists.

Thus far the great majority have reported doing very well and only a few have reported some side effects including fainting and a temporary increase in liver markers. Clearly we need to finish the clinical trials, but it looks very promising.

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Tampa Stem Cell Therapy | PRP | Knee | Joint Replacement …

Thursday, August 4th, 2016

Featured in the News Across the Nation: Dr. Dennis Lox, an Expert in Sports & Regenerative Medicine, Discusses Knee Stem Cell Therapy, Hip Stem Cell Therapyand Ankle Stem Cell Therapy.

Since 1990, Dennis M. Lox, M.D. has been helping patients increase their quality of life by reducing their pain. He emphasizes non-surgical treatments and appropriate use of medications, if needed.

Many patients are turning to stem cell therapy as a means of nonsurgical joint pain relief when their mobility and quality of life are severely affected by conditions like osteoarthritis, torn tendons, and injured ligaments. Dennis M. Lox, M.D. specializes in this progressive, innovative treatment that may be able to help you return to an active, fulfilling life.

Each week, Dr. Dennis Lox receives inquiries from aroundthe worldregarding stem cell therapy.

TRAVEL ARRANGEMENTS CAN BE MADE FOR YOU LOCAL OR INTERNATIONAL

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Stem cell therapy for joint injuries and osteoarthritis is suited for many individuals, fromprofessional athletes to active seniors. Adult mesenchymal stem cells, not embryonic stem cells, are used in this procedure, which is performed right in the comfort of Dr. Loxs state-of-the-art clinic. The cells are simply extracted from the patients own body (typically from bone marrow or adipose/ fat tissue), processed in our office, and injected directly into the site of injury. Conditions that can be addressed with stem cell treatment include osteoarthritis, degenerative disc disease, knee joint issues (such as meniscus tears), shoulder damage (such as rotator cuff injuries), hip problems (such as labral tears), and tendonitis, among others. For many patients, a stem cell procedure in the knee, hip, shoulder, or another area of the body relieves pain, increases mobility, and may be able to delay or eliminate the need for more aggressive treatments like joint replacement surgery.

If you have questions about adult stem cell therapy for joint injuries and arthritis, how the procedure is performed, and how the stem cells work to repair injured joints and tissues, Dr. Lox would be happy to educate you about the entire process.

If you are searching for effective, nonsurgical joint replacement alternatives, regenerative therapies like stem cell treatments and PRP therapy may be the ideal solution. At Florida Spine and Sports Medicine, we focus on helping patients return to mobile, independent lives without the need for the risks and downtime associated with highly invasive surgery.PRP Therapy, Stem Cell Treatments & Other Joint Replacement Alternatives for Patients in Tampa, Clearwater, New Port Richey & throughout the U.S.A. and the world.

PRP (platelet rich plasma) therapy can be used alone, or adult stem cell therapy is often used in conjunction with PRP as a means of promoting healing in degenerated or injured joints, cartilage, muscles, and tendons. From knee pain to spine pain, there are a wide range of conditions that may respond to these forms of regenerative medicine. Some of the most common issues that Dr. Lox treats at Florida Spine and Sports Medicine include knee arthritis, meniscal tears, S/I joint pain, hip conditions, shoulder pain, and ankle pain, among others.

If you live in Clearwater, St. Petersburg, New Port Richey, Tampa, or anywhere else in the nation and would like to schedule a consultation to discuss PRP therapy, stem cell therapy, or other alternatives to joint surgery with Dr. Lox, please contact Florida Spine and Sports Medicine today.

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8 Social, Legal, and Ethical Implications of Genetic …

Thursday, August 4th, 2016

disorder was untreatable as when the disorder was treatable (53 percent would contact a relative about the risk of Huntington disease; 54 percent about the risk of hemophilia A). Since most people at risk for Huntington disease have not chosen testing to see if they have the genetic marker for the disorder,67 geneticists may be overestimating the relative's desire for genetic information and infringing upon the relative's right not to know. They may be causing psychological harm if they provide surprising or unwanted information for which there is no beneficial action the relative can take.

In the legal realm, there is an exception to confidentiality: A physician may in certain instances breach confidentiality in order to protect third parties from harm, for example, when the patient might transmit a contagious disease68 or commit violence against an identifiable individual.69 In a landmark California case, for example, a psychiatrist was found to have a duty to warn the potential victim that his patient planned to kill her.70

The principle of protecting third parties from serious harm might also be used to allow disclosure to an employer when an employee's medical condition could create a risk to the public. In one case, the results of an employee's blood test for alcohol were given to his employer.71 The court held the disclosure was not actionable because the state did not have a statute protecting confidentiality, but the court also noted that public policy would favor disclosure in this instance since the plaintiff was an engineer who controlled a railroad passenger train.

An argument could be made that health care professionals working in the medical genetics field have disclosure obligations similar to those of the physician whose patient suffers from an infectious disease or a psychotherapist with a potentially violent patient. Because of the heritable nature of genetic diseases, a health professional whothrough research, counseling, examination, testing, or treatmentgains knowledge about an individual's genetic status often has information that would be of value not only to the patient, but to his or her spouse or relatives, as well as to insurers, employers, and others. A counterargument could be made, however, that since the health professional is not in a professional relationship with the relative and the patient will not be harming the relative (unlike in the case of violence or infectious diseases), there should be no duty to warn.

The claims of the third parties to information, in breach of the fundamental principle of confidentiality, need to be analyzed, as indicated earlier, by assessing how serious the potential harm is, whether disclosure is the best way to avert the harm, and what the risk of disclosure might be.

The genetic testing of a spouse can give rise to information that is of interest to the other spouse. In the vast majority of situations, the tested individual will share that information with the other spouse. In rare instances, the information will not be disclosed and the health care provider will be faced with the issue of

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Home: Feinberg School of Medicine: Northwestern University

Thursday, August 4th, 2016

How to manage stress when the world is filled with worry

A little stress can actually be a good thing, motivating us to work hard and get ahead, experts say. But constant stress and worry over the long haul can damage our bodies. "The stress response was made for short-term acute stress, like needing to run away from a bear or a saber tooth tiger," said David Victorson, an associate professor of medical social sciences at the Northwestern University Feinberg School of Medicine and a health psychologist at Northwestern Medicine. "It's been a part of the human process since the beginning. But stressors today can be much more chronic and we're ill equipped to deal with that.

Garfield, an associate professor of pediatrics at the Northwestern University Feinberg School of Medicine, said research on fatherhood is a fairly recent phenomenon, so it's difficult to compare dads of today with fathers in the '60s, for example. But he said change is in the air, as evidenced not only by formal studies, but by cultural phenomena such as the rise of 'dad-vertising,' in which fathers are portrayed as capable, hands-on parents, rather than workaholics or bumbling oafs.

Researchers in Illinois have unveiled the third gene linked with Parkinsons, a discovery that comes following the death of legendary boxer Muhammad Ali, who suffered from the neurodegenerative disease for three decades. Scientists findings, published Monday in Nature Genetics, suggest the genetic mutation TMEM230 was present among Parkinsons patients in North America and Asia, and had similar protein trafficking characteristics as the other two genetic mutations linked with Parkinsons, according to a Northwestern University press release. They found TMEM230 produced a protein involved in the packaging of dopamine in neurons, which is significant because Parkinsons is marked by the breakdown of dopamine-producing neurons.

Not getting a good night's sleep can result in a number of problems including poor concentration, weight gain, and a greater likelihood of accidents. For shift workers and individuals who experience chronic sleep deprivation, new research suggests insufficient sleep could also increase the risk of heart disease. In humans, as in all mammals, almost all physiological and behavioral processes, in particular the sleep-wake cycle, follow a circadian rhythm that is regulated by an internal clock located in the brain," said Daniela Grimaldi, M.D., Ph.D., lead author and a research assistant professor at Northwestern University, said in a press release. "When our sleep-wake and feeding cycles are not in tune with the rhythms dictated by our internal clock, circadian misalignment occurs."

Low-income families with children with allergies spend more than twice as much on visits to emergency rooms and hospitals than mid- to high-income families, recent research from Northwestern University found. And about 40 percent of those children surveyed also reported experiencing life-threatening reactions to food, such as trouble breathing and a drop in blood pressure. "The fact that they were able to open up a food pantry for kids who can't afford the special foods for food allergies incredible," said Dr. Ruchi Gupta, an associate professor of pediatrics who led the Northwestern study, which was published in April.

We need a lot more nonsteroidal options, and [crisaborole] looks like it may be an important addition to our armamentarium, says Jonathan Silverberg, a dermatologist at Northwestern University Feinberg School of Medicine. We have limited options for the thing we can safely give patients without worries about their long term use.

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DPH Disease Information: Diabetes Info – Delaware

Thursday, August 4th, 2016

The Delaware Diabetes and Heart Disease Prevention and Control Program (DHDPCP) goal is to decrease the states emotional, physical, and financial burden from diabetes and heart disease by preventing the diseases and reducing their complications. Our program supports community clinical linkages, health systems interventions, environmental approaches, and epidemiology and surveillance.

The program is funded by a cooperative agreement with the Centers for Disease Control and Prevention (CDC), with additional support from the Delaware Health Fund. The program collects and publicizes current, accurate information about diabetes and heart disease, develops approaches for reducing the impact of the diseases, promotes healthy lifestyle habits for prevention and control, and coordinates efforts of public and private health organizations.

Please note: Some of the files available on this page are in Adobe PDF format which requires Adobe Acrobat Reader. A free copy of Adobe Acrobat Reader can be downloaded directly from Adobe . If you are using an assistive technology unable to read Adobe PDF, please either view the corresponding text only version (if available) or visit Adobe's Accessibility Tools page.

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Philadelphia Pennsylvania Office of the American Diabetes …

Thursday, August 4th, 2016

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Pennsylvanians and Delawareans are increasingly feeling the effects of diabetes as thousands of people suffer from the disease, and many others may have diabetes and not know it!

It is estimated that one out of every three children born after 2000 in the United States will be directly affected by diabetes.

That is why the American Diabetes Association's Philadelphia office is so committed to educating the public about how to stop diabetes and support those living with the disease.

We are here to help.

The Philadelphia office serves Eastern Pennsylvania and Delaware.

Additional Events

The American Diabetes Association's Eastern Pennsylvania and Delaware office serves the community with a variety of programs, workshops and awareness campaigns for people living with diabetes, their friends and family. Learn about our available programs.

The following Eastern Pennsylvania and Delaware businesses and organizations have been designated Health Champions from the American Diabetes Association. This designation recognizes organizations that inspire and encourage organizational well-being and is part of the Association's Wellness Lives Here initiative. Learn more.

Christiana Care Health System Delaware Division of Public Health Drexel University Einstein Medical System Health Partners Plans Independence Blue Cross Jefferson Health Navient Novo Nordisk Inc. Nutrisystem Quest Diagnostics The Children's Hospital of Philadelphia University of Pennsylvania Health System YMCA of Greater Brandywine

If you would like a representative from the American Diabetes Association to speak at your event or if you would like materials to distribute at a health fair or expo, please contact 610-828-5003 or bala_office@diabetes.org.

We welcome your help.

Your involvement as an American Diabetes Association volunteer whether on a local or national level will help us expand our community outreach and impact, inspire healthy living, intensify our advocacy efforts, raise critical dollars to fund our mission, and uphold our reputation as the moving force and trusted leader in the diabetes community.

Find volunteer opportunities in our area through the Volunteer Center.

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7. Stem Cells and Diabetes [Stem Cell Information]

Thursday, August 4th, 2016

Diabetes exacts its toll on many Americans, young and old. For years, researchers have painstakingly dissected this complicated disease caused by the destruction of insulin producing islet cells of the pancreas. Despite progress in understanding the underlying disease mechanisms for diabetes, there is still a paucity of effective therapies. For years investigators have been making slow, but steady, progress on experimental strategies for pancreatic transplantation and islet cell replacement. Now, researchers have turned their attention to adult stem cells that appear to be precursors to islet cells and embryonic stem cells that produce insulin.

For decades, diabetes researchers have been searching for ways to replace the insulin-producing cells of the pancreas that are destroyed by a patient's own immune system. Now it appears that this may be possible. Each year, diabetes affects more people and causes more deaths than breast cancer and AIDS combined. Diabetes is the seventh leading cause of death in the United States today, with nearly 200,000 deaths reported each year. The American Diabetes Association estimates that nearly 16 million people, or 5.9 percent of the United States population, currently have diabetes.

Diabetes is actually a group of diseases characterized by abnormally high levels of the sugar glucose in the bloodstream. This excess glucose is responsible for most of the complications of diabetes, which include blindness, kidney failure, heart disease, stroke, neuropathy, and amputations. Type 1 diabetes, also known as juvenile-onset diabetes, typically affects children and young adults. Diabetes develops when the body's immune system sees its own cells as foreign and attacks and destroys them. As a result, the islet cells of the pancreas, which normally produce insulin, are destroyed. In the absence of insulin, glucose cannot enter the cell and glucose accumulates in the blood. Type 2 diabetes, also called adult-onset diabetes, tends to affect older, sedentary, and overweight individuals with a family history of diabetes. Type 2 diabetes occurs when the body cannot use insulin effectively. This is called insulin resistance and the result is the same as with type 1 diabetesa build up of glucose in the blood.

There is currently no cure for diabetes. People with type 1 diabetes must take insulin several times a day and test their blood glucose concentration three to four times a day throughout their entire lives. Frequent monitoring is important because patients who keep their blood glucose concentrations as close to normal as possible can significantly reduce many of the complications of diabetes, such as retinopathy (a disease of the small blood vessels of the eye which can lead to blindness) and heart disease, that tend to develop over time. People with type 2 diabetes can often control their blood glucose concentrations through a combination of diet, exercise, and oral medication. Type 2 diabetes often progresses to the point where only insulin therapy will control blood glucose concentrations.

Each year, approximately 1,300 people with type 1 diabetes receive whole-organ pancreas transplants. After a year, 83 percent of these patients, on average, have no symptoms of diabetes and do not have to take insulin to maintain normal glucose concentrations in the blood. However, the demand for transplantable pancreases outweighs their availability. To prevent the body from rejecting the transplanted pancreas, patients must take powerful drugs that suppress the immune system for their entire lives, a regimen that makes them susceptible to a host of other diseases. Many hospitals will not perform a pancreas transplant unless the patient also needs a kidney transplant. That is because the risk of infection due to immunosuppressant therapy can be a greater health threat than the diabetes itself. But if a patient is also receiving a new kidney and will require immunosuppressant drugs anyway, many hospitals will perform the pancreas transplant.

Over the past several years, doctors have attempted to cure diabetes by injecting patients with pancreatic islet cellsthe cells of the pancreas that secrete insulin and other hormones. However, the requirement for steroid immunosuppressant therapy to prevent rejection of the cells increases the metabolic demand on insulin-producing cells and eventually they may exhaust their capacity to produce insulin. The deleterious effect of steroids is greater for islet cell transplants than for whole-organ transplants. As a result, less than 8 percent of islet cell transplants performed before last year had been successful.

More recently, James Shapiro and his colleagues in Edmonton, Alberta, Canada, have developed an experimental protocol for transplanting islet cells that involves using a much larger amount of islet cells and a different type of immunosuppressant therapy. In a recent study, they report that [17], seven of seven patients who received islet cell transplants no longer needed to take insulin, and their blood glucose concentrations were normal a year after surgery. The success of the Edmonton protocol is now being tested at 10 centers around the world.

If the success of the Edmonton protocol can be duplicated, many hurdles still remain in using this approach on a wide scale to treat diabetes. First, donor tissue is not readily available. Islet cells used in transplants are obtained from cadavers, and the procedure requires at least two cadavers per transplant. The islet cells must be immunologically compatible, and the tissue must be freshly obtainedwithin eight hours of death. Because of the shortage of organ donors, these requirements are difficult to meet and the waiting list is expected to far exceed available tissue, especially if the procedure becomes widely accepted and available. Further, islet cell transplant recipients face a lifetime of immunosuppressant therapy, which makes them susceptible to other serious infections and diseases.

Before discussing cell-based therapies for diabetes, it is important to understand how the pancreas develops. In mammals, the pancreas contains three classes of cell types: the ductal cells, the acinar cells, and the endocrine cells. The endocrine cells produce the hormones glucagon, somatostatin, pancreatic polypeptide (PP), and insulin, which are secreted into the blood stream and help the body regulate sugar metabolism. The acinar cells are part of the exocrine system, which manufactures digestive enzymes, and ductal cells from the pancreatic ducts, which connect the acinar cells to digestive organs.

In humans, the pancreas develops as an outgrowth of the duodenum, a part of the small intestine. The cells of both the exocrine systemthe acinar cellsand of the endocrine systemthe islet cellsseem to originate from the ductal cells during development. During development these endocrine cells emerge from the pancreatic ducts and form aggregates that eventually form what is known as Islets of Langerhans. In humans, there are four types of islet cells: the insulin-producing beta cells; the alpha cells, which produce glucagon; the delta cells, which secrete somatostatin; and the PP-cells, which produce pancreatic polypeptide. The hormones released from each type of islet cell have a role in regulating hormones released from other islet cells. In the human pancreas, 65 to 90 percent of islet cells are beta cells, 15 to 20 percent are alpha-cells, 3 to 10 percent are delta cells, and one percent is PP cells. Acinar cells form small lobules contiguous with the ducts (see Figure 7.1. Insulin Production in the Human Pancreas). The resulting pancreas is a combination of a lobulated, branched acinar gland that forms the exocrine pancreas, and, embedded in the acinar gland, the Islets of Langerhans, which constitute the endocrine pancreas.

Figure 7.1. Insulin Production in the Human Pancreas. The pancreas is located in the abdomen, adjacent to the duodenum (the first portion of the small intestine). A cross-section of the pancreas shows the islet of Langerhans which is the functional unit of the endocrine pancreas. Encircled is the beta cell that synthesizes and secretes insulin. Beta cells are located adjacent to blood vessels and can easily respond to changes in blood glucose concentration by adjusting insulin production. Insulin facilitates uptake of glucose, the main fuel source, into cells of tissues such as muscle.

( 2001 Terese Winslow, Lydia Kibiuk)

During fetal development, new endocrine cells appear to arise from progenitor cells in the pancreatic ducts. Many researchers maintain that some sort of islet stem cell can be found intermingled with ductal cells during fetal development and that these stem cells give rise to new endocrine cells as the fetus develops. Ductal cells can be distinguished from endocrine cells by their structure and by the genes they express. For example, ductal cells typically express a gene known as cytokeratin-9 (CK-9), which encodes a structural protein. Beta islet cells, on the other hand, express a gene called PDX-1, which encodes a protein that initiates transcription from the insulin gene. These genes, called cell markers, are useful in identifying particular cell types.

Following birth and into adulthood, the source of new islet cells is not clear, and some controversy exists over whether adult stem cells exist in the pancreas. Some researchers believe that islet stem cell-like cells can be found in the pancreatic ducts and even in the islets themselves. Others maintain that the ductal cells can differentiate into islet precursor cells, while others hold that new islet cells arise from stem cells in the blood. Researchers are using several approaches for isolating and cultivating stem cells or islet precursor cells from fetal and adult pancreatic tissue. In addition, several new promising studies indicate that insulin-producing cells can be cultivated from embryonic stem cell lines.

In developing a potential therapy for patients with diabetes, researchers hope to develop a system that meets several criteria. Ideally, stem cells should be able to multiply in culture and reproduce themselves exactly. That is, the cells should be self-renewing. Stem cells should also be able to differentiate in vivo to produce the desired kind of cell. For diabetes therapy, it is not clear whether it will be desirable to produce only beta cellsthe islet cells that manufacture insulinor whether other types of pancreatic islet cells are also necessary. Studies by Bernat Soria and colleagues, for example, indicate that isolated beta cellsthose cultured in the absence of the other types of islet cellsare less responsive to changes in glucose concentration than intact islet clusters made up of all islet cell types. Islet cell clusters typically respond to higher-than-normal concentrations of glucose by releasing insulin in two phases: a quick release of high concentrations of insulin and a slower release of lower concentrations of insulin. In this manner the beta cells can fine-tune their response to glucose. Extremely high concentrations of glucose may require that more insulin be released quickly, while intermediate concentrations of glucose can be handled by a balance of quickly and slowly released insulin.

Isolated beta cells, as well as islet clusters with lower-than-normal amounts of non-beta cells, do not release insulin in this biphasic manner. Instead insulin is released in an all-or-nothing manner, with no fine-tuning for intermediate concentrations of glucose in the blood [5, 18]. Therefore, many researchers believe that it will be preferable to develop a system in which stem or precursor cell types can be cultured to produce all the cells of the islet cluster in order to generate a population of cells that will be able to coordinate the release of the appropriate amount of insulin to the physiologically relevant concentrations of glucose in the blood.

Several groups of researchers are investigating the use of fetal tissue as a potential source of islet progenitor cells. For example, using mice, researchers have compared the insulin content of implants from several sources of stem cellsfresh human fetal pancreatic tissue, purified human islets, and cultured islet tissue [2]. They found that insulin content was initially higher in the fresh tissue and purified islets. However, with time, insulin concentration decreased in the whole tissue grafts, while it remained the same in the purified islet grafts. When cultured islets were implanted, however, their insulin content increased over the course of three months. The researchers concluded that precursor cells within the cultured islets were able to proliferate (continue to replicate) and differentiate (specialize) into functioning islet tissue, but that the purified islet cells (already differentiated) could not further proliferate when grafted. Importantly, the researchers found, however, that it was also difficult to expand cultures of fetal islet progenitor cells in culture [7].

Many researchers have focused on culturing islet cells from human adult cadavers for use in developing transplantable material. Although differentiated beta cells are difficult to proliferate and culture, some researchers have had success in engineering such cells to do this. For example, Fred Levine and his colleagues at the University of California, San Diego, have engineered islet cells isolated from human cadavers by adding to the cells' DNA special genes that stimulate cell proliferation. However, because once such cell lines that can proliferate in culture are established, they no longer produce insulin. The cell lines are further engineered to express the beta islet cell gene, PDX-1, which stimulates the expression of the insulin gene. Such cell lines have been shown to propagate in culture and can be induced to differentiate to cells, which produce insulin. When transplanted into immune-deficient mice, the cells secrete insulin in response to glucose. The researchers are currently investigating whether these cells will reverse diabetes in an experimental diabetes model in mice [6, 8].

These investigators report that these cells do not produce as much insulin as normal islets, but it is within an order of magnitude. The major problem in dealing with these cells is maintaining the delicate balance between growth and differentiation. Cells that proliferate well do not produce insulin efficiently, and those that do produce insulin do not proliferate well. According to the researchers, the major issue is developing the technology to be able to grow large numbers of these cells that will reproducibly produce normal amounts of insulin [9].

Another promising source of islet progenitor cells lies in the cells that line the pancreatic ducts. Some researchers believe that multipotent (capable of forming cells from more than one germ layer) stem cells are intermingled with mature, differentiated duct cells, while others believe that the duct cells themselves can undergo a differentiation, or a reversal to a less mature type of cell, which can then differentiate into an insulin-producing islet cell.

Susan Bonner-Weir and her colleagues reported last year that when ductal cells isolated from adult human pancreatic tissue were cultured, they could be induced to differentiate into clusters that contained both ductal and endocrine cells. Over the course of three to four weeks in culture, the cells secreted low amounts of insulin when exposed to low concentrations of glucose, and higher amounts of insulin when exposed to higher glucose concentrations. The researchers have determined by immunochemistry and ultrastructural analysis that these clusters contain all of the endocrine cells of the islet [4].

Bonner-Weir and her colleagues are working with primary cell cultures from duct cells and have not established cells lines that can grow indefinitely. However the cells can be expanded. According to the researchers, it might be possible in principle to do a biopsy and remove duct cells from a patient and then proliferate the cells in culture and give the patient back his or her own islets. This would work with patients who have type 1 diabetes and who lack functioning beta cells, but their duct cells remain intact. However, the autoimmune destruction would still be a problem and potentially lead to destruction of these transplanted cells [3]. Type 2 diabetes patients might benefit from the transplantation of cells expanded from their own duct cells since they would not need any immunosuppression. However, many researchers believe that if there is a genetic component to the death of beta cells, then beta cells derived from ductal cells of the same individual would also be susceptible to autoimmune attack.

Some researchers question whether the ductal cells are indeed undergoing a dedifferentiation or whether a subset of stem-like or islet progenitors populate the pancreatic ducts and may be co-cultured along with the ductal cells. If ductal cells die off but islet precursors proliferate, it is possible that the islet precursor cells may overtake the ductal cells in culture and make it appear that the ductal cells are dedifferentiating into stem cells. According to Bonner-Weir, both dedifferentiated ductal cells and islet progenitor cells may occur in pancreatic ducts.

Ammon Peck of the University of Florida, Vijayakumar Ramiya of Ixion Biotechnology in Alachua, FL, and their colleagues [13, 14] have also cultured cells from the pancreatic ducts from both humans and mice. Last year, they reported that pancreatic ductal epithelial cells from adult mice could be cultured to yield islet-like structures similar to the cluster of cells found by Bonner-Weir. Using a host of islet-cell markers they identified cells that produced insulin, glucagon, somatostatin, and pancreatic polypeptide. When the cells were implanted into diabetic mice, the diabetes was reversed.

Joel Habener has also looked for islet-like stem cells from adult pancreatic tissue. He and his colleagues have discovered a population of stem-like cells within both the adult pancreas islets and pancreatic ducts. These cells do not express the marker typical of ductal cells, so they are unlikely to be ductal cells, according to Habener. Instead, they express a marker called nestin, which is typically found in developing neural cells. The nestin-positive cells do not express markers typically found in mature islet cells. However, depending upon the growth factors added, the cells can differentiate into different types of cells, including liver, neural, exocrine pancreas, and endocrine pancreas, judged by the markers they express, and can be maintained in culture for up to eight months [20].

The discovery of methods to isolate and grow human embryonic stem cells in 1998 renewed the hopes of doctors, researchers, and diabetes patients and their families that a cure for type 1 diabetes, and perhaps type 2 diabetes as well, may be within striking distance. In theory, embryonic stem cells could be cultivated and coaxed into developing into the insulin-producing islet cells of the pancreas. With a ready supply of cultured stem cells at hand, the theory is that a line of embryonic stem cells could be grown up as needed for anyone requiring a transplant. The cells could be engineered to avoid immune rejection. Before transplantation, they could be placed into nonimmunogenic material so that they would not be rejected and the patient would avoid the devastating effects of immunosuppressant drugs. There is also some evidence that differentiated cells derived from embryonic stem cells might be less likely to cause immune rejection (see Chapter 10. Assessing Human Stem Cell Safety). Although having a replenishable supply of insulin-producing cells for transplant into humans may be a long way off, researchers have been making remarkable progress in their quest for it. While some researchers have pursued the research on embryonic stem cells, other researchers have focused on insulin-producing precursor cells that occur naturally in adult and fetal tissues.

Since their discovery three years ago, several teams of researchers have been investigating the possibility that human embryonic stem cells could be developed as a therapy for treating diabetes. Recent studies in mice show that embryonic stem cells can be coaxed into differentiating into insulin-producing beta cells, and new reports indicate that this strategy may be possible using human embryonic cells as well.

Last year, researchers in Spain reported using mouse embryonic stem cells that were engineered to allow researchers to select for cells that were differentiating into insulin-producing cells [19]. Bernat Soria and his colleagues at the Universidad Miguel Hernandez in San Juan, Alicante, Spain, added DNA containing part of the insulin gene to embryonic cells from mice. The insulin gene was linked to another gene that rendered the mice resistant to an antibiotic drug. By growing the cells in the presence of an antibiotic, only those cells that were activating the insulin promoter were able to survive. The cells were cloned and then cultured under varying conditions. Cells cultured in the presence of low concentrations of glucose differentiated and were able to respond to changes in glucose concentration by increasing insulin secretion nearly sevenfold. The researchers then implanted the cells into the spleens of diabetic mice and found that symptoms of diabetes were reversed.

Manfred Ruediger of Cardion, Inc., in Erkrath, Germany, is using the approach developed by Soria and his colleagues to develop insulin-producing human cells derived from embryonic stem cells. By using this method, the non-insulin-producing cells will be killed off and only insulin-producing cells should survive. This is important in ensuring that undifferentiated cells are not implanted that could give rise to tumors [15]. However, some researchers believe that it will be important to engineer systems in which all the components of a functioning pancreatic islet are allowed to develop.

Recently Ron McKay and his colleagues described a series of experiments in which they induced mouse embryonic cells to differentiate into insulin-secreting structures that resembled pancreatic islets [10]. McKay and his colleagues started with embryonic stem cells and let them form embryoid bodiesan aggregate of cells containing all three embryonic germ layers. They then selected a population of cells from the embryoid bodies that expressed the neural marker nestin (see Appendix B. Mouse Embryonic Stem Cells). Using a sophisticated five-stage culturing technique, the researchers were able to induce the cells to form islet-like clusters that resembled those found in native pancreatic islets. The cells responded to normal glucose concentrations by secreting insulin, although insulin amounts were lower than those secreted by normal islet cells (see Figure 7.2. Development of Insulin-Secreting Pancreatic-Like Cells From Mouse Embryonic Stem Cells). When the cells were injected into diabetic mice, they survived, although they did not reverse the symptoms of diabetes.

Figure 7.2. Development of Insulin-Secreting Pancreatic-Like Cells From Mouse Embryonic Stem Cells. Mouse embryonic stem cells were derived from the inner cell mass of the early embryo (blastocyst) and cultured under specific conditions. The embryonic stem cells (in blue) were then expanded and differentiated. Cells with markers consistent with islet cells were selected for further differentiation and characterization. When these cells (in purple) were grown in culture, they spontaneously formed three-dimentional clusters similar in structure to normal pancreatic islets. The cells produced and secreted insulin. As depicted in the chart, the pancreatic islet-like cells showed an increase in release of insulin as the glucose concentration of the culture media was increased. When the pancreatic islet-like cells were implanted in the shoulder of diabetic mice, the cells became vascularized, synthesized insulin, and maintained physical characteristics similar to pancreatic islets.

( 2001 Terese Winslow, Caitlin Duckwall)

According to McKay, this system is unique in that the embryonic cells form a functioning pancreatic islet, complete with all the major cell types. The cells assemble into islet-like structures that contain another layer, which contains neurons and is similar to intact islets from the pancreas [11]. Several research groups are trying to apply McKay's results with mice to induce human embryonic stem cells to differentiate into insulin-producing islets.

Recent research has also provided more evidence that human embryonic cells can develop into cells that can and do produce insulin. Last year, Melton, Nissim Benvinisty of the Hebrew University in Jerusalem, and Josef Itskovitz-Eldor of the Technion in Haifa, Israel, reported that human embryonic stem cells could be manipulated in culture to express the PDX-1 gene, a gene that controls insulin transcription [16]. In these experiments, researchers cultured human embryonic stem cells and allowed them to spontaneously form embryoid bodies (clumps of embryonic stem cells composed of many types of cells from all three germ layers). The embryoid bodies were then treated with various growth factors, including nerve growth factor. The researchers found that both untreated embryoid bodies and those treated with nerve growth factor expressed PDX-1. Embryonic stem cells prior to formation of the aggregated embryoid bodies did not express PDX-1. Because expression of the PDX-1 gene is associated with the formation of beta islet cells, these results suggest that beta islet cells may be one of the cell types that spontaneously differentiate in the embryoid bodies. The researchers now think that nerve growth factor may be one of the key signals for inducing the differentiation of beta islet cells and can be exploited to direct differentiation in the laboratory. Complementing these findings is work done by Jon Odorico of the University of Wisconsin in Madison using human embryonic cells of the same source. In preliminary findings, he has shown that human embryonic stem cells can differentiate and express the insulin gene [12].

More recently, Itskovitz-Eldor and his Technion colleagues further characterized insulin-producing cells in embryoid bodies [1]. The researchers found that embryonic stem cells that were allowed to spontaneously form embryoid bodies contained a significant percentage of cells that express insulin. Based on the binding of antibodies to the insulin protein, Itskovitz-Eldor estimates that 1 to 3 percent of the cells in embryoid bodies are insulin-producing beta-islet cells. The researchers also found that cells in the embryoid bodies express glut-2 and islet-specific glucokinase, genes important for beta cell function and insulin secretion. Although the researchers did not measure a time-dependent response to glucose, they did find that cells cultured in the presence of glucose secrete insulin into the culture medium. The researchers concluded that embryoid bodies contain a subset of cells that appear to function as beta cells and that the refining of culture conditions may soon yield a viable method for inducing the differentiation of beta cells and, possibly, pancreatic islets.

Taken together, these results indicate that the development of a human embryonic stem cell system that can be coaxed into differentiating into functioning insulin-producing islets may soon be possible.

Ultimately, type 1 diabetes may prove to be especially difficult to cure, because the cells are destroyed when the body's own immune system attacks and destroys them. This autoimmunity must be overcome if researchers hope to use transplanted cells to replace the damaged ones. Many researchers believe that at least initially, immunosuppressive therapy similar to that used in the Edmonton protocol will be beneficial. A potential advantage of embryonic cells is that, in theory, they could be engineered to express the appropriate genes that would allow them to escape or reduce detection by the immune system. Others have suggested that a technology should be developed to encapsulate or embed islet cells derived from islet stem or progenitor cells in a material that would allow small molecules such as insulin to pass through freely, but would not allow interactions between the islet cells and cells of the immune system. Such encapsulated cells could secrete insulin into the blood stream, but remain inaccessible to the immune system.

Before any cell-based therapy to treat diabetes makes it to the clinic, many safety issues must be addressed (see Chapter 10. Assessing Human Stem Cell Safety). A major consideration is whether any precursor or stem-like cells transplanted into the body might revert to a more pluripotent state and induce the formation of tumors. These risks would seemingly be lessened if fully differentiated cells are used in transplantation.

But before any kind of human islet-precursor cells can be used therapeutically, a renewable source of human stem cells must be developed. Although many progenitor cells have been identified in adult tissue, few of these cells can be cultured for multiple generations. Embryonic stem cells show the greatest promise for generating cell lines that will be free of contaminants and that can self renew. However, most researchers agree that until a therapeutically useful source of human islet cells is developed, all avenues of research should be exhaustively investigated, including both adult and embryonic sources of tissue.

Chapter 6|Table of Contents|Chapter 8

Historical content: June 17, 2001

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7. Stem Cells and Diabetes [Stem Cell Information]

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Blood stem cells: the pioneers of stem cell research …

Thursday, August 4th, 2016

About blood stem cells

Blood stem cells are also known as haematopoietic stem cells. Like other stem cells, they can self-renew, or copy themselves. They also produce the different types of specialized cells found in the blood: both red blood cells and the many kinds of white blood cells needed by the bodys immune system.

The tree of blood: Blood stem cells are at the origin of all blood cell types. Once a blood stem cell divides, its daughter cells take various differentiation routes to produce different types of specialized blood cells.

Specialized blood cells do not live very long, so the body needs to replace them continuously. Blood stem cells do this job. They are found in the bone marrow of long bones such as the femurs (thigh bones), and in the hips or pelvis, the vertebrae (backbones) and the rib cage. They can also be obtained from the umbilical cord blood and the placenta at birth.

Blood stem cells need to make just the right number of each type of blood cell to keep the body healthy. This is a carefully controlled process. When it goes wrong, the result may be a blood disease such as leukaemia or anaemia.

Blood stem cells are already widely used to treat such diseases. A survey in 2008 showed that more than 26,000 patients are treated with blood stem cells in Europe each year. These blood stem cells come from three different sources bone marrow, the bloodstream of an adult or umbilical cord blood.

Scientists are still learning about how blood stem cells develop in the embryo, how they are controlled in the adult body and what goes wrong in certain blood diseases. But they are also using todays understanding of blood stem cells to investigate new ways to treat patients. A bone marrow transplant is only possible if a compatible donor is available. The patient and donor must be very carefully matched to avoid immune rejection of the transplant. Even when a suitable donor can be found, there is still a small risk of rejection. Umbilical cord blood does not need to be matched quite so precisely to the patient, but there are not enough stem cells in an umbilical cord to treat an adult. So we need to find alternatives.

Researchers are investigating ways to produce large numbers of blood stem cells in the laboratory. They are also developing methods for growing specialized blood cells from blood stem cells, for example to produce red blood cells for blood transfusions.

Red blood cells frompluripotent stem cells Red blood cells carry oxygen around the body. Patients who lose a lot of blood need to have it replaced straight away by a blood transfusion. There are not enough blood donors to meet patient needs, so researchers are looking for an alternative solution. Sincepluripotent stem cells have the potential to make any cell type of the body, they could potentially provide an unlimited supply of red blood cells. It is already possible to make small numbers of red blood cells frompluripotent stem cells in the lab. Now the real challenge is to develop techniques for producing the large numbers of red blood cells that are needed for transfusion.

Growing blood stem cells in the lab Red blood cells, like other mature blood cells, are short-lived and specialized for a particular job. To cure disease in the long-term, doctors need to transplant something that can keep producing new blood cells throughout the patients life: blood stem cells. Scientists are searching for ways to grow a limitless supply of blood stem cells. One possibility might be to collect stem cells from the bone marrow then grow and multiply them in the lab. Researchers are also trying to make blood stem cells from embryonic stem cells or induced pluripotent stem (iPS) cells. iPS cells could be made from a patients own skin and then used to produce blood stem cells. This would overcome the problem of immune rejection.

Stem cells for blood - making red blood cells from embryonic stem cells EuroStemCell FAQ page on umbilical cord blood banking The European Group for Blood and Marrow Transplantation UK National Health Service information on bone marrow transplantations Original scientific paper by Till and Mcculloch identifying blood stem cells for the first time

This factsheet was created by Christle Gonneau and reviewed by Lesley Forrester and Cristina Pina.

Lead image of blood cells by Anne Weston/Wellcome Images. Blood stem cell photograph reproduced with permission from Taoudi et al. (2005) "Progressive divergence of definitive haematopoietic stem cells from the endothelial compartment does not depend on contact with the foetal liver", Development 132: 4179- 4191. 'Tree of blood' diagram by Christele Gonneau, with blood cell drawings courtesy of Jonas Larsson, Lund Univeristy, Sweden. All other images courtesy of Joanne Mountford at the University of Glasgow.

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318. On His Blindness. John Milton. The Oxford Book of …

Thursday, August 4th, 2016

Select Search World Factbook Roget's Int'l Thesaurus Bartlett's Quotations Respectfully Quoted Fowler's King's English Strunk's Style Mencken's Language Cambridge History The King James Bible Oxford Shakespeare Gray's Anatomy Farmer's Cookbook Post's Etiquette Brewer's Phrase & Fable Bulfinch's Mythology Frazer's Golden Bough All Verse Anthologies Dickinson, E. Eliot, T.S. Frost, R. Hopkins, G.M. Keats, J. Lawrence, D.H. Masters, E.L. Sandburg, C. Sassoon, S. Whitman, W. Wordsworth, W. Yeats, W.B. All Nonfiction Harvard Classics American Essays Einstein's Relativity Grant, U.S. Roosevelt, T. Wells's History Presidential Inaugurals All Fiction Shelf of Fiction Ghost Stories Short Stories Shaw, G.B. Stein, G. Stevenson, R.L. Wells, H.G. Verse > Anthologies > Arthur Quiller-Couch, ed. > The Oxford Book of English Verse CONTENTSBIBLIOGRAPHIC RECORD Arthur Quiller-Couch, ed. 1919. The Oxford Book of English Verse: 12501900. John Milton.16081674 318.On His Blindness WHEN I consider how my light is spent E're half my days, in this dark world and wide, And that one Talent which is death to hide, Lodg'd with me useless, though my Soul more bent To serve therewith my Maker, and present 5 My true account, least he returning chide, Doth God exact day-labour, light deny'd, I fondly ask; But patience to prevent That murmur, soon replies, God doth not need Either man's work or his own gifts, who best 10 Bear his milde yoak, they serve him best, his State Is Kingly. Thousands at his bidding speed And post o're Land and Ocean without rest: They also serve who only stand and waite.

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Arthritis: Causes, Types, Symptoms & Treatment Options …

Thursday, August 4th, 2016

Arthritis is a condition associated with swelling and inflammation of the joints, which often results in pain and restriction of movement. The most common forms of arthritis are osteoarthritis, which is a breakdown of the cartilage in the joints, and rheumatoid arthritis, which is an inflammation of the tissue lining the joints and in severe cases inflammation of other body tissues. In the joints, sustained inflammation leads to hypertrophy of the synovium and the formation of a "pannus", which spreads over the joint causing erosive destruction of the bone and cartilage. Rheumatoid arthritis occurs when the body's immune system starts attacking it's own organs (joints, bones, internal organs).

Arthritis is a result of a breakdown in cartilage or inflammation.

Cartilage protects joints and enables smooth movement by absorbing shock when pressure is placed on a joint. Without the usual amount of cartilage, the bones rub together and this causes pain, swelling (inflammation), and stiffness.

Joint inflammation can occur for a variety of reasons, including:

Often, the inflammation goes away once the injury has healed, the disease is treated, or once the infection has been cleared. However, with some injuries and diseases, the inflammation does not go away or the cartilage is destroyed and long-term pain and deformity results. When this happens, the disease is called chronic arthritis.

Osteoarthritis is the most common type of arthritis and is more likely to occur with increasing age. It can occur in any of the joints but is most common in the hips, knees or fingers.

Risk factors for osteoarthritis include:

Arthritis can occur in both men and women and in individuals of all ages. Some forms of arthritis also affect children.

As mentioned earlier, the most common forms of arthritis are Osteoarthritis and Rheumatoid arthritis. However, there are numerous forms of arthritis, including:

A person suffering from arthritis may experience any of the following:

A doctor will first note your symptoms and will then look at your medical history in detail to see if arthritis or another musculoskeletal problem is the likely cause of those symptoms.

Your doctor will then perform a thorough physical examination to see if there is any fluid collecting around the joint (an abnormal build up of fluid around a joint is called "joint effusion."). The joint may be tender when gently pressed, and it may also be warm and red (especially if you have infectious arthritis or autoimmune arthritis). You may also find it painful or difficult to rotate the joints in some directions (this is known as "limited range-of-motion").

After this initial physical examination, your doctor may then ask you to undertake a number of different tests, depending on what they suspect to be the cause of your symptoms. Often, you will need to have a blood test and joint x-rays. You may also need to have a test where joint fluid is removed from the joint with a needle; the fluid will then be examined under a microscope to check for infection and for other causes of arthritis, such as crystals, which cause gout.

If arthritis is diagnosed and treated early, you can prevent joint damage. Find out if you have a family history of arthritis and share this information with your doctor, even if you have no joint symptoms. In some autoimmune forms of arthritis, the joints may become deformed if the disease is not treated. Osteoarthritis may be more likely to develop if you over-use your joints. Take care not to overwork a damaged or sore joint. Similarly, avoid excessive repetitive motions. Excess weight also increases the risk for developing osteoarthritis in the knees, and possibly in the hips and hands.

The treatment of arthritis depends on the particular cause of the disease, on the joints that are affected, on the severity of the disorder and on the effect it has on your daily activities. Your age and occupation will also be taken into consideration when your doctor works with you to create a treatment plan.

If possible, treatment will focus on eliminating the underlying cause of the arthritis. However, sometimes the cause is NOT curable, as with osteoarthritis and rheumatoid arthritis. In this case, the aim of treatment will be to reduce pain and discomfort and prevent further disability. Symptoms of osteoarthritis and other long-term types of arthritis can often be improved without medications. Making lifestyle changes without medications is preferable for osteoarthritis and other forms of joint inflammation. If needed, medications should be used in addition to lifestyle changes.

Your doctor will select the most appropriate medication for your form of arthritis.

Most people can take acetaminophen without any problems so long as they do not exceed the recommended dose of 4 grams in 24 hours (taken in 4 divided doses every 4 to 6 hours). It reduces mild pain but does not help with inflammation or swelling. Acetaminophen is available as a combination with other mild pain relief medicines for mild osteoarthritic pain, and with narcotics for severe pain. Acetaminophen with aspirin and or caffeine are over-the-counter medicines. Acetaminophen with codeine, propoxyphene or narcotics are prescription medicines.

Although NSAIDs work well, long-term use of these medicines can cause gastrointestinal problems, such as stomach ulcers and bleeding. In April 2005, the FDA asked manufacturers of NSAIDs to include a warning label on their products that alerts users of an increased risk of cardiovascular events (heart attacks and strokes) and gastrointestinal bleeding.

Taking a combination of NSAIDs or NSAIDs and aspirin together increases the incidence of stomach ulcers or bleeding.

These contain a non steroidal anti-inflammatory drug and a stomach protecting agent, to prevent or treat the gastrointestinal side effects which may be caused by NSAIDs.

COX-2 inhibitors block an inflammation-promoting enzyme called COX-2. This class of drugs was initially believed to work as well as traditional NSAIDs, but with fewer stomach problems. However, numerous reports of heart attacks and strokes have prompted the FDA to re-evaluate the risks and benefits of the COX-2 inhibitors. Rofecoxib (Vioxx) and valdecoxib (Bextra) have been withdrawn from the U.S. market following reports of heart attacks in some patients taking the drugs. The available medicines in this class have been labeled with strong warnings and a recommendation that these be prescribed at the lowest possible dose and for the shortest duration possible.

Corticosteroids have been used to reduce inflammation in rheumatoid arthritis for more than 40 years but it is not known whether they can slow down the progression of disease. It can be used in conjunction with other rheumatoid arthritis medicine.

Potential long-term side effects of corticosteroids limit the use of oral corticosteroids to short courses and low doses where possible. Side effects may include bruising, psychosis, cataracts, weight gain, susceptibility to infections and diabetes, high blood pressure and thinning of the bones (osteoporosis). A number of medications can be administered with steroids to minimize the risk of osteoporosis.

Intra-articular steroid injections can effectively relieve pain, reduce inflammation, increase mobility and reduce deformity in one or a few joints. If repeated injections are required then the dose of DMARDs should be increased.

Corticosteroids suppress the immune system and also reduce pain and inflammation. They are commonly used in severe cases of osteoarthritis and they can be given orally or by injection. Steroid injections are given directly into the joint (intra-articular). Steroids are used to treat autoimmune forms of arthritis but they should be avoided if you have infectious arthritis. Steroids have multiple side effects, including upset stomach and gastrointestinal bleeding, high blood pressure, thinning of bones, cataracts, and increased infections. The risks are most pronounced when steroids are taken for long periods of time or at high doses. Close supervision by a physician is essential.

DMARDs are the most effective agents available for controlling rheumatoid arthritis, but they all have a slow onset of action. Mechanisms of action for most of these agents are not known and they all are different but they all appear to slow or stop the changes in the joints. They can alter laboratory characteristics of disease activity and delay the progression of bone damage.

Patients taking DMARDs generally show some response within 8 to 10 weeks. However, this is variable depending on the patient and drug. Dose of DMARDs is titrated up as far as side effects allow. An additional DMARD is added when the maximum dose is reached, or the initial DMARD is stopped and switched to another.

Most DMARDs require monitoring (such as full blood count, liver function test, urea and electrolyte level test) to ensure drug safety, as the majority can cause bone marrow toxicity and some can cause liver toxicity as well. Regular blood or urine tests should also be done to determine how well medications are working.

Methotrexate is probably the most commonly used DMARD. It is effective in reducing signs and symptoms of rheumatoid arthritis and slows down damage to the joint. Results can be seen in 6 to 8 weeks. Other DMARDs such as hydroxychloroquine and sulfasalazine can used in conjunction with methotrexate.

Hydroxychloroquine, an antimalarial drug, is effective in the treatment of rheumatoid arthritis. It is usually used in combination with methotrexate and sulfasalazine for added benefits.

Sulfasalazine is also an effective DMARD. It can reduce symptoms and slow down the joint damage.

Leflunomide shows similar effectiveness to methotrexate and can be used in patients who cannot take methotrexate.

Tumor necrosis factor (TNF) inhibitors are a relatively new class of medications used to treat autoimmune disease. They include etanercept, infliximab, adalimumab, tocilizumab, certolizumab and golimumab. TNF Inhibitors are also called "Biologics" biological response modifiers.

Tumor necrosis factor alpha is produced by macrophages and lymphocytes, and acts on many cells in the joints and in other organs and body systems. It is a pro-inflammatory cytokine known to mediate most of the joint damage. In rheumatoid arthritis it is produced by the synovial macrophages and lymphocytes. By inhibiting TNF alpha the inflammation process, which attacks or damages the joint tissue, is halted or slowed.

Methotrexate can be used with TNF inhibitors to increase the effectiveness of therapy.

Gold is also effective in the treatment of rheumatoid arthiritis, particularly when given intramuscularly. It isn't used as often now due to its side effects and slow onset of action. Oral gold preparation is available but is less efficacious compared to the intramuscular preparation.

Abatacept decreases T cell proliferation and inhibits the production of the cytokines tumor necrosis factor (TNF) alpha, interferon-?, and interleukin-2.

Rituximab depletes the B cells, which have several functions in the immune response. Rituximab has reduced signs and symptoms of rheumatoid arthritis, and manages to slow down the joint destruction.

The Interleukin-1 Inhibitor, Anakinra, is a new synthetic protein that blocks the inflammatory protein interleukin-1. Anakinra is used to slow progression of moderate to severe active rheumatoid arthritis in patients who have not responded to one or more of the DMARDs.

Alkylating agents, such as cyclophosphamide, are drugs that suppress the immune system and are sometimes used in people who have failed other therapies. These medications are associated with toxic side effects and usually reserved for severe cases of rheumatoid arthritis.

Many people find that over-the-counter nutraceuticals and vitamins, such as glucosamine and chondroitin sulfate help relieve the symptoms of osteoarthritis. There is some evidence that these supplements are helpful in controlling pain, although they do not appear to grow new cartilage.

Bioflavonoids are found in the rind of green citrus fruits and in rose hips and black currants. They have been used historically in a variety of disease states including rheumatic fever, habitual abortion, poliomyelitis, prevention of bleeding, rheumatoid arthritis, periodontal disease, diabetic retinitis, and others.

Diclofenac topical is a non-steroidal anti-inflammatory drug. Although it is applied topically it is still absorbed systemically and may cause systemic effects such as gastrointestinal side effects.

Trolamine salicylate is a topical salicylate pain reliever, used for minor pain and inflammation. It works by reducing swelling and inflammation in the muscle and joints.

Capsaicin is extracted from chillies (genus Capsicum). Capsaicin topical causes a decrease in a substance (substance P) in the body that causes pain. It is used to relieve minor aches and pains of muscle and joints associated with arthritis, simple backache, strains and sprains.

Hyaluronic acid is normally present in joint fluid, and in osteoarthritis sufferers this gets thin. Hyaluronic acid can be injected into the joint to help protect it. This may relieve pain for up to six months.

Non-drug treatment is also important. It is important to make lifestyle changes. Exercise helps maintain joint and overall mobility. Ask your health care provider to recommend an appropriate home exercise routine. Water exercises, such as swimming, are especially helpful. You also need to balance rest with activity. Non-drug pain relief techniques may help to control pain. Heat and cold treatments, protection of the joints and the use of self-help devices are recommended. Good nutrition and careful weight control are important. Weight loss for overweight individuals will reduce the strain placed on the knee and ankle joints.

Physical therapy can be useful for improving muscle strength and motion at stiff joints. Therapists have many techniques for treating osteoarthritis. If therapy does not make you feel better after 3-6 weeks, then it is likely that it will not work at all.

Splints and braces can sometimes support weakened joints. Some prevent the joint from moving, while others allow some movement. You should use a brace only when your doctor or therapist recommends one. The incorrect use of a brace can cause joint damage, stiffness and pain.

Surgery to replace or repair damaged joints may be needed in severe, debilitating cases.

Surgical options include:

Arthroplasty - total or partial replacement of the deteriorated joint with an artificial joint e.g. knee arthroplasty, hip arthroplasty.

Arthroscopic - surgery to trim torn and damaged cartilage and wash out the joint.

Cartilage Restoration - For some younger patents with arthritis, cartilage restoration is a surgical option to replace the damaged or missing cartilage.

Osteotomy - change in the alignment of a bone to relieve stress on the bone or joint.

Arthrodesis - surgical fusion of bones, usually in the spine.

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Pet Arthritis: Laser Therapy Staves Off Arthritis of Dogs …

Thursday, August 4th, 2016

Bill Dougherty's trusty 135-pound German shepherd, Rex, has suffered from a limp and joint pain for the past two years. This man's best friend, 70 in dog years, 10 in people years, needed treatment for his arthritic pain. But rather than opting for traditional pills or surgery, Dougherty tried a new, seemingly magical, laser therapy that the local veterinary clinic, Village Animal Clinic in North Palm Beach, Fla., was offering to arthritic dog and cats.

"Rex was always a very active dog, but he started exhibiting some problems with his shoulders," said Dougherty, who owns three other dogs. "He probably has about two years left, and we didn't want to take out six months of his life for surgery, so we tried this."

Dougherty said that Rex's limp and overall activity and happiness improved almost immediately after the first laser treatment.

"We used to say that Rex was like the old man on the hill," said Dougherty. "He'd point out the distraction and then the younger ones would go after it. But now, he's back and a part of the gang."

Mike Berkenblit, owner of Village Animal Clinic and lead veterinarian on site, performed the laser therapeutic procedure on Rex, and many other animals. Other pet owners have seen similar dramatic improvements in their dogs and cats who underwent the treatment.

The cold laser therapy is a noninvasive procedure that uses light to stimulate cells and increase blood circulation. At the correct laser wavelength, pain signals are reduced and nerve sensitivity decreases. The procedure also releases endorphins, or natural painkillers, but it is not recommended for animals that have cancer because the device can stimulate blood flow to cancer cells.

The procedure is based on the idea that light is absorbed into the cells. The process, known as photo-biotherapy, stimulates protein synthesis and cell metabolism, which improves cell health and functionality.

The therapy can take as little as eight to 10 minutes on a small dog or cat, or about a half hour for bigger dogs with more arthritic areas. And to create the appropriate atmosphere, Berkenblit and his staff work to make the dog as comfortable as possible. The animal reclines in a room, the lights are turned down low and soothing music plays in the background.

"We always say that Rex is going to the spa when he goes to get his laser treatment," said Dougherty. "He used to hate going to the vet, but now he loves it. It's where he can go to relax and listen to Beyonce."

Hey, what dog wouldn't love a little soothing Beyonce to set the mood?

This isn't the first time that Berkenblit has put laser treatment to the test. Eight years ago, Berkenblit tried a laser procedure on his own yellow Lab, Woody, but he was unimpressed with the results on his beloved dog.

But about a year ago, he learned of new and improved laser procedures and was convinced to try again.

"I was very skeptical about the treatment at first," said Berkenbilt. "But technology has rocketed ahead and evolved. Now, almost immediately after treatment, people call and say that their animal is doing stuff that he hasn't done in years. It's been a lifesaver for some pets."

Dougherty was so impressed by the results in Rex that he looked into buying a laser device for personal use on his dogs. But the $30,000 price tag hit the bank a bit too hard.

But at $250 for six treatments, Dougherty said that he'll continue to pay for Rex's laser treatments to keep him happy and painfree.

Berkenblit said that the treatment does has not shown any adverse effects so far, although a small portion of dogs and cats will not respond as dramatically to the treatment as Rex and others. About 70 percent of the animals show improvement in arthritic pain. Thirty percent do not experience any change.

Other veterinarians have also been convinced by the buzz surrounding the procedure.

"This is important, exciting stuff," said "Good Morning America's" family doctor for pets Marty Becker. "I'm at the world's largest veterinary meeting in Vegas and seminars on rehab and booths of laser companies are packed."

Most dogs begin showing arthritic symptoms at 6 or 7 years old. While some arthritis can be prevented by maintaining an ideal body weight in one's dog or cat, most dogs will experience some sort of arthritic pain as they grow into old age.

"Laser therapy is a very effective modality to speed and direct healing in dogs with painful arthritis, strains and sprains and other injuries or effects of aging," said Dr. Christine Zink, director of the department of molecular and comparative pathobiology at Johns Hopkins School of Medicine. "It has been used in humans for a long time and dogs now can reap the benefits, too."

And it's Berkenblit himself who put that idea to the test. After spending days crawling around his house after throwing out his back, he finally thought to make his way to the clinic, where he used the laser device on his own back. "I walked out that door and I thought, 'That's pretty cool,'" he said.

Berkenbilt said that other nurses and technicians often use the device for their personal aches and pains, too.

Some may still wonder how lasers can ward off arthritis and pain, but several research studies provide evidence about the benefits of laser therapy treatment.

Dr. Bradley Frederick, director of doctors at the International Sports Science Center and founder of American Health Lasers, uses high-powered lasers to treat people, even professional athletes, on a wide range of injuries and inflammatory conditions.

"We have seen increases in the rate of production of energy after treatment," said Frederick. "The laser stimulates cellular activity to cells that it hits. The key is hitting the cell to accelerate oxidation."

In 2002, the Food and Drug Administration approved its first trial on laser treatment for cell damage. The double-blind studies from Baylor College of Medicine improved carpal tunnel disease in patients about 70 percent more than in the control group using traditional physical therapy programs.

Another study, published in August 2000 in the Journal of Rheumatology, found that cold laser therapy reduced pain by 70 percent and increased tip-to-palm flexibility by more than 1 centimeter, when compared with those in the placebo group.

And finally, a July 2007 study from Wellman Center for Photomedicine at Massachusetts General Hospital in Boston showed that low-level laser therapy was highly effective in reducing swelling in patients with knee-joint arthritis.

Frederick, who has treated several L.A. Clippers basketball players, said that patients often come to him for help when they cannot find any other options to help heal their pain. Different wavelengths and power outlets can treat a variety of injuries, from diabetic ulcers to arthritis and acute injuries.

"I've seen patients who have arthritis so bad that it's bone-on-bone with no cartilage whatsoever," said Frederick. "They will convince me to try and treat them, and I tell them they're probably not going to see any improvements, but there are several who are now at the gym, in the garden, or taking care of their grandkids."

Frederick said the dramatic results, even now, can still sometimes surprise him but warns there are a lot of misconceptions.

"It's a Wild West out there with laser technology," said Frederick. "You're going to see a lot of this used in the future. ...There is an efficacy in this device that just needs a proper amount of energy and delivery system. And we've seen some pretty phenomenal results."

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Pet Arthritis: Laser Therapy Staves Off Arthritis of Dogs ...

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Stem Cell Therapy or Knee Replacement Adelaide

Thursday, August 4th, 2016

What is stem cell therapy?

Stem cell therapy is the use of your bodys own stem cells to repair a joint. The procedure involves four main steps.

After the procedure it is recommended that you have a follow up appointment with Norwood Day Surgery 3 days, 2 weeks, 2 months and 6 months after your procedure. Your doctor will discuss your progress with you and may utilise standardised pain tests such as WOMAC or HOOS depending on the joint where you received treatment.

In a study at our practice 100osteoarthritis patients were treated with stem cell therapy and assessed each month for 6 months. It was reported that over 75% of patients treated, showed a significant improvement between 50 100% in pain and mobility of the joint.

Approximately 15% of patients treated were non-responders and had an improvement of less than 20% after 3 months.

The repair process takes time with the improvement at its maximum level by 6 months. Whether young or old the improvement after receiving stem cell therapy was the same. It is too early to determine the lifespan of the treatment as this treatment has only been available since 2009, with only 10% of our patients needing a second treatment.

Many thousands of patients with osteoarthritis have now been treated with stem cell therapy. We know that it is a safe procedure if done carefully.

Minor adverse events have been observed on the day of the procedure in a small percentage of patients and include: slight fever, rash, euphoria followed by a transient depression and cramps in the toes and feet.

Common liposuction short-term side effects may include: abdominal pain, bruising (which may last up to two weeks), and leakage of anaesthetic fluid for 24 hours. One case of bleeding has occurred from a sensitivity to intravenous injection of stromal vascular fraction.

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Stem Cell Therapy or Knee Replacement Adelaide

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Patent Docs: Personalized Medicine

Thursday, August 4th, 2016

By Kevin E. Noonan --

The promise of an era of "personalized medicine" has been pursued for a generation, being one of the rationales for and purported benefits of the Human Genome Project. It has become such a sought-for goal that it has been used to drive policy: it is something that health care reform is banking on (literally), since by making medicine more individualized, success rates and fewer failed therapies are envisioned. It crept into the gene patenting debate, with Judge Bryson in his dissent crediting the ACLU's claim that gene patents will inhibit development of personalized medicine (they won't). But as others have noted (for example, Nicholas Wade, "A dissenting voice as the genome is sifted to fight disease," The New York Times, September 15, 2008), a promise is all it remains: achieving a personalized medicine future has proven (so far) to be much more daunting than its proponents believed (or told the rest of us to believe).

The results of a cancer study in the New England Journal of Medicine last week may have shed some light on what this has been so. The report, "Intratumor heterogeneity and branched evolution revealed by multiregion sequencing," a team of physicians and scientists from the UK and Harvard revealed that the genetics of human tumors is much more complicated than previously thought (Gerlinger et al., 2012, N. Engl. J. Med. 366: 883-92). These researchers obtained multiple biopsy samples from different regions of the same tumor (primary and metastatic) and performed multilocus genomic sequencing. The tumors were all a particular subtype of primary renal cell carcinoma, clear cell carcinoma (CCC) from patients that had been treated with everolimus (Zortress, an mTOR inhibitor) therapy before and after nephrectomy. Whole exome multiregion spatial DNA sequencing (see below) was performed on extracted tissue from fresh frozen samples as well as SNP analysis and mRNA expression profiling using gene arrays.

Exome Sequencing - Part I:

Exome Sequencing - Part 2

The results showed a significant amount of genetic heterogeneity that could be related to chemotherapeutic drug resistance and differential metastatic potential. In one CCC patient, nine regions of the primary tumor and three regions of metastatic tumors (as well as the germline DNA sequences) were assayed. A 2 bp deletion in the von Hippel-Lindau (VHL) tumor suppressor gene was found, a genetic characteristic of CCC. These analyses revealed 101 nonsynonymous point mutations and 32 instances of insertion or deletion (indels), with the assays showing a low false negative rate of detection. From a total of 128 mutations detected in the various samples, 40 were "ubiquitous" mutations (found in all samples), 59 were shared by "several but not all" regions, and 29 were unique to a particular region (called "private mutations"). Of the "shared" mutations, 31 were shared by most of the primary tumor samples, and 28 shared by most of the metastatic tumor samples. "The detection of private mutations suggested an ongoing regional clonal evolution," the authors concluded from this data.

From these results, the workers constructed a phylogenetic tree that revealed "branching rather than linear" tumor evolution. Deeper analysis showed that, in some regions, the primary tumor shared more mutation with the metastases than with other areas of the primary tumor, suggesting the existence of two "clonal populations of progenitor cells in this region." The study also compared these results with results from a "single" tumor biopsy study, which detected 70 somatic mutations (about 55% of the total detected using the multiregional approach). These figures were put into context by noting that only 31-34% of all mutations detected using the multiregional sampling/sequencing were detected in all regions. Finally, any major effect of the everolimus treatment on these results was discounted by finding that 67/71 mutations found after treatment were present in the tumor samples pretreatment, and that 64/66 chest wall metastasis mutations were found in post-treatment metastatic tumors. These results indicated to the researchers that "the two main branches of the phylogenetic tree were present before drug treatment" and that "60% of the mutations in pretreatment samples of the primary tumor and chest-wall metastases were not shared by both biopsy samples," i.e., evidence of clonal evolution that would have required reversion of somatic mutations during treatment (not very likely).

A conventional measure of tumor heterogeneity, ploidy analysis (i.e., how many chromosomes and chromosome fragments were present in the tumor cells) was also performed. While the primary tumor was predominantly diploid (i.e., facially "normal") there were two regions in the metastatic tumors that were subtetraploid (i.e., a few fewer than twice the [n]o limited by sample quality issues showed ubiquitous "allelic imbalance" on the short arm of the 3rd chromosome (3p) characterized by loss of heterozygosity at multiple allelic loci), including VHL and histone H3K36 methyltransferase SETD2. Even here, "tumor regions shared identical allelic-imbalance profiles, and heterogeneity of allelic imbalance within metastases, which is probably driven by aneuploidy, indicates that chromosomal aberrations contribute to genetic intratumor heterogeneity."

The study also compared the mutational status of genes known to be mutated in CCC, including VHL, SETD2, KDM5C, and mTOR. Only the VHL gene was ubiquitously mutated in all regions sampled, contrasted in the study by the mutational nature of SETD2: the metastases all showed a missense mutation while one primary region had a splice site mutation and the others showed a 2 bp frameshift deletion (which was also present in the region with the frameshift mutation). Convergent evolution was detected with regard to SETD2 histone methylation using functional assays; such convergent genetic evolution in tumor cells was also detected for the X chromosome-encoded histone methyltransferase KDM5C.

Another gene, mTOR, showed a missense mutation in the portion of the gene encoding a kinase domain; this mutation was found in all but one of the primary tumor regions tested. The researchers also reported that a currently used test for CCC, a 110-gene signature that assesses patient prognosis, displayed anomalous results: the metastases and one primary tumor sample showed the "good" prognostic pattern while all the other primary sites showed the "poor" prognostic pattern. The authors caution that "prognostic gene-expression signatures may not correctly predict outcomes if they are assessed from a single region of a heterogeneous tumor."

The workers performed similar analyses on three other patients. In one, patient 2, the researchers found 119 somatic mutations what also showed a branching pattern of clonal genetic evolution in this patient's tumor. Here, ~31-37 of the mutations were found ubiquitously (the lower number was obtained when the metastases were included). While no ploidy imbalance was detected in these tumor samples, allelic imbalance was found ubiquitously in all tested regions for 3p and on the long arm of chromosome 10 (10q). In addition to some of the 3p mutations found in patent 1's tumor, mutations were found for genes residing on 10q, including PTEN. Convergent evolution was also observed for the PTEN gene. Similar results were obtained and briefly noted for tumor samples obtained from patients 3 and 4 (patient 4's tumors showed allelic imbalance on chromosomes 5 (5q) and6 (6q)). However, "[t]hese early ubiquitous events were outnumbered by non-ubiquitous aberrations, indicating that the majority of chromosomal events occurred after tumors diverged, providing further evidence of branching evolution." Patient 4 also showed tumor heterogeneity in genes like SETD2 that had been detected in other tumor samples.

The authors summarized their results by noting that they had detected genetic heterogeneity in each tumor assayed, showing "spatial separated heterogeneous somatic mutations and chromosomal imbalances." These genetic lesions lead to phenotypic heterogeneity, with 63-69% of the mutations not detected in every tumor region sampled. Their detection of "ubiquitous alterations on the trunk of the tumor phylogenetic tree . . . may account for the benefits of cytoreductive nephrectomy" because it reduces the "reservoir" of primary tumors cells capable of genetic instability and failure to respond to more "conventional" regions of the tumor. Finally, the authors state that:

Genomics analyses from single tumor-biopsy specimens may underestimate the mutational burden of heterogeneous tumors. Intratumor heterogeneity may explain the difficulties encountered in the validation of oncology biomarkers owing to sampling bias, contribute to Darwinian selection of preexisting drug-resistant clones, and predict therapeutic resistance. Reconstructing tumor clonal architectures and the identification of common mutations located in the trunk of the phylogenetic tree may contribute to more robust biomarkers and therapeutic approaches.

These results illustrate a few things. First, the gene patenting debate per se is anachronistic and ten if not thirty years out of date. The complexity revealed by this study provides one reason why approaches tried thus far for implementing personalized medicine have not worked out as well as planned. This complexity suggests that it will take far more time to produce a worthwhile personalized medicine paradigm that fulfills all its unfulfilled promises and that the "gene age" will likely be long past by that time.

This very same complexity reinforces the risk in making any broad pronouncements against the patent-eligibility of "products to nature." With this level of complexity, the number of "false negatives" (and, presumably, false positives) may make it possible to identify diagnostic genetic markers for disease prognosis that can be protected without patents. As noted by the authors, identification of the "trunk" mutations (shared by the largest number of tumor samples) provide the best information on the tumor for treatment, prognosis and otherwise. The negative consequences of changing the incentives from disclosure (protected by patenting) and non-disclosure (protected, inter alia as a trade secret) has been discussed here before; this study points to ways that could be profitable for the company that develops the test at the cost of reaching the goal of personalized medical care. Because the alternative may be no personalized medical care at all, it behooves participants in the policy debate about gene patents, genetic diagnostic testing, and innovation to consider this study to be but the first in a long series demonstrating that, indeed, we are only at the beginning of the road when it comes to developing a robust personalized medicine system.

Images of exome sequencing (above) by SarahKusala, from the Wikipedia Commons (Part I & Part 2) under the Creative Commons Attribution 3.0 Unported license.

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Patent Docs: Personalized Medicine

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