Study Points To The Liver, Not The Brain, As The Origin Of Alzheimer's Plaques

Study points to liver, not brain, as origin of Alzheimer's plaques


Unexpected results from a Scripps Research Institute and ModGene, LLC study could completely alter scientists' ideas about Alzheimer's disease—pointing to the liver instead of the brain as the source of the  "amyloid" that deposits as brain plaques associated with this devastating condition. The findings could offer a relatively simple approach for Alzheimer's prevention and treatment.

The study was published online today in The Journal of Neuroscience Research.

In the study, the scientists used a mouse model for Alzheimer's disease to identify genes that influence the amount of amyloid that accumulates in the brain. They found three genes that protected mice from brain amyloid accumulation and deposition. For each gene, lower expression in the liver protected the mouse brain. One of the genes encodes presenilin—a cell membrane protein believed to contribute to the development of human Alzheimer's.

"This unexpected finding holds promise for the development of new therapies to fight Alzheimer's," said Scripps Research Professor Greg Sutcliffe, who led the study. "This could greatly simplify the challenge of developing therapies and prevention."

An estimated 5.1 million Americans have Alzheimer's disease, including nearly half of people age 85 and older. By 2050, the number of people age 65 and over with this disease will range from 11 million to 16 million unless science finds a way to prevent or effectively treat it. In addition to the human misery caused by the disease, there is the unfathomable cost. A new report from the Alzheimer's Association shows that in the absence of disease-modifying treatments, the cumulative costs of care for people with Alzheimer's from 2010 to 2050 will exceed $20 trillion.

A Genetic Search-and-Find Mission

In trying to help solve the Alzheimer's puzzle, in the past few years Sutcliffe and his collaborators have focused their research on naturally occurring, inherited differences in neurological disease susceptibility among different mouse strains, creating extensive databases cataloging gene activity in different tissues, as measured by mRNA accumulation. These data offer up maps of trait expression that can be superimposed on maps of disease modifier genes.

As is the case with nearly all scientific discovery, Sutcliffe's research builds on previous findings. Several years ago, researchers at Case Western Reserve mapped three genes that modify the accumulation of pathological beta amyloid in the brains of a transgenic mouse model of Alzheimer's disease to large chromosomal regions, each containing hundreds of genes. The Case Western scientists used crosses between the B6 and D2 strains of mice, studying more than 500 progeny. 

Using the results from this study, Sutcliffe turned his databases of gene expression to the mouse model of Alzheimer's, looking for differences in gene expression that correlated with differences in disease susceptibility between the B6 and D2 strains. This intensive work involved writing computer programs that identified each genetic difference that distinguished the B6 and D2 genomes, then running mathematical correlation analysis (known as regression analysis) of each difference. Correlations were made between the genotype differences (B6 or D2) and the amount of mRNA product made from each of the more than 25,000 genes in a particular tissue in the 40 recombinant inbred mouse strains. These correlations were repeated 10 times to cover 10 tissues, the liver being one of them.

"A key aspect of this work was learning how to ask questions of massive data sets to glean information about the identities of heritable modifier genes," Sutcliffe said. "This was novel and, in a sense, groundbreaking work: we were inventing a new way to identify modifier genes, putting all of these steps together and automating the process. We realized we could learn about how a transgene's pathogenic effect was being modified without studying the transgenic mice ourselves."

Looking for a Few Good Candidates

Sutcliffe's gene hunt offered up good matches, candidates, for each of the three disease modifier genes discovered by the Case Western scientists, and one of these candidates—the mouse gene corresponding to a gene known to predispose humans carrying particular variations of it to develop early-onset Alzheimer's disease—was of special interest to his team.

"The product of that gene, called Presenilin2, is part of an enzyme complex involved in the generation of pathogenic beta amyloid," Sutcliffe explained. "Unexpectedly, heritable expression of Presenilin2 was found in the liver but not in the brain. Higher expression of Presenilin2 in the liver correlated with greater accumulation of beta amyloid in the brain and development of Alzheimer's-like pathology."

This finding suggested that significant concentrations of beta amyloid might originate in the liver, circulate in the blood, and enter the brain. If true, blocking production of beta amyloid in the liver should protect the brain.

To test this hypothesis, Sutcliffe's team set up an in vivo experiment using wild-type mice since they would most closely replicate the natural beta amyloid-producing environment. "We reasoned that if brain amyloid was being born in the liver and transported to the brain by the blood, then that should be the case in all mice," Sutcliffe said, "and one would predict in humans, too."

The mice were administered imatinib (trade name Gleevec, an FDA-approved cancer drug), a relatively new drug currently approved for treatment of chronic myelogenous leukemia and gastrointestinal tumors. The drug potently reduces the production of beta amyloid in neuroblastoma cells transfected by amyloid precursor protein (APP) and also in cell-free extracts prepared from the transfected cells. Importantly, Gleevec has poor penetration of the blood-brain barrier in both mice and humans.

"This characteristic of the drug is precisely why we chose to use it," Sutcliffe explained. "Because it doesn't penetrate the blood-brain barrier, we were able to focus on the production of amyloid outside of the brain and how that production might contribute to amyloid that accumulates in the brain, where it is associated with disease."

The mice were injected with Gleevec twice a day for seven days; then plasma and brain tissue were collected, and the amount of beta amyloid in the blood and brain was measured. The findings: the drug dramatically reduced beta amyloid not only in the blood, but also in the brain where the drug cannot penetrate. Thus, an appreciable portion of brain amyloid must originate outside of the brain, and imatinib represents a candidate for preventing and treating Alzheimer's.

As for the future of this research, Sutcliffe says he hopes to find a partner and investors to move the work into clinical trials and new drug development.

More information: "Peripheral reduction of β-amyloid is sufficient to reduce brain Aβ: implications for Alzheimer's disease," http://onlinelibra … 603/abstract

Provided by The Scripps Research Institute (news : web)

Birth Control Methods and Their Effects on Women With Chronic Health Conditions

The most important thing for you, if you have a chronic condition, is to have an understanding of birth control methods and how they can affect your health. Some of these methods can present specific concerns for certain rheumatic conditions. If you have antiphospholipid syndrome or antiphospholipid antibodies in your blood, lupus or RA, here is what is known about the concerns and the appropriate birth control methods.

Antiphospholipid antibodies and antiphospholipid syndrome: APL or antiphospholipid antibodies are proteins that affect the balance in the blood between clotting and bleeding and are a risk factor for blood clots. APS or antiphospholipid syndrome, is an autoimmune disorder that is characterized by antiphospholipid antibodies, blood clotting, and miscarriages and the syndrome can happen alone or with lupus, even though you have the antibodies you may not have lupus.

If you have antiphospholipid antibodies you are more likely to develop blood clots if you have another risk factor for blood clotting such as a severe illness, surgery, prolonged bed rest, malignancy, or pregnancy or it can be a lifestyle risk factor such as smoking or using combination contraceptives. That's why this second risk factor can be one of the variants in the blood that makes clotting possible. When you have lupus and antiphospholipid antibodies you are more likely to have other medical risk factors for a stroke or heart attack, like migraines, atherosclerosis or clogged arteries, or elevated cholesterol levels.

Contraceptives with estrogen are know to increase the risk of blood clots and when you have moderate to high antiphospholipid antibodies you should stay away from combination hormonal contraceptives. If you have low or borderline levels of the antiphospholipid antibodies, it may depend on whether you have had other risk factors for blood clots, to determine if you should stay clear from the combination hormonal contraceptives. Progesterone-only contraception is a good alternative for you if you have antiphospholipid antibodies and are unable to safely take estrogen. This method is also an effective way to decrease the heavy menstrual flow if you are on blood-thinning medications like warfarin, also known as Coumadin, which is often used to treat APS, Antiphospholipid syndrome.

Systemic lupus erythematosus: It was thought for many years that estrogen increased disease activity in lupus. This assumption was based on the findings in laboratory animals, and the fact that lupus is found mostly in women, 4 out of 5 people with lupus are women, and the reports of birth control pills and pregnancy where women said their lupus got worse. There are early reports that suggested there was an increase risk of lupus flares with the use of contraceptives containing estrogen. But, there are more recent studies that were better-designed, using large numbers of participants and standardized methods of measuring flares that found that estrogen-containing contraceptives are safe in some women with lupus.

And there were two randomized clinical trials published at the end of 2005 that found combination birth control pills don't significantly increase the risk of flares in women with inactive or stable, moderate lupus. The Safety of Estrogens in Lupus Erythematosus National Assessment, or SELENA, trial included 183 women with inactive or stable, moderate lupus and compared the effects of a standard combination birth control pill with the effects of an inactive placebo pill. Women who had active lupus, a history of blood clots, or antiphospholipid antibodies couldn't take participant in the study and the number and severity of the lupus flares showed no difference in the two groups. There was another study of 162 women with stable mild-to-moderate lupus that also found no adverse effects on flare rates whether the women used a combination pill, a progesterone-only pill or a copper IUD.

Based on these studies, it would appear that combination pills are safe for you if you have inactive or stable, moderate lupus and don't have antiphospholipid antibodies. Remember, though, that you may not even be able to tell how active your lupus is and often lupus activity can only be detected through blood test or other tests. So if you have lupus and you want to use a combination pill, your rheumatologist must be involved in the decision making. Since about 1/3 of the women with lupus have antiphospholipid antibodies, you have lupus you should be screened for the antibodies before starting a combination birth control pill.

It seems that it would be smart for you if you have lupus to avoid the contraceptive patch, Ortho Evra, given the recent FDA warning that it increases the risk of blood clots above that of combination pills. There's also the birth control pills that contain drospirenone, Yasmin, Yaz, that are more likely to elevate blood levels of potassium, an important consideration for you if you have lupus-related kidney problems. The safety of IUDs, if you are taking immunosuppressive drugs to treat your lupus, is not certain, because the drugs and the IUDs can raise the risk of infection. If you have active lupus, barrier methods or progesterone-only contraceptives are your options. Depo-Provera injections may be a problem if you are taking corticosteroids, because both the Depo-Provera and the corticosteroids increase the risk of bone loss.

Rheumatoid arthritis: There are some who believe that if you have RA you might actually benefit from treatment with estrogen-containing birth control pills because your symptoms improve during pregnancy. But, there's little research into using the pill to treat RA and research does suggest that women with RA have normal estrogen levels but lower than normal androgen levels, so hormonal therapy attempts have focused on supplementing androgens (androgens are primarily male sex hormones, but women have small amounts of them), with mixed results and no clear benefit. Postmenopausal estrogen therapy has also been studied in women with RA but showed no effect on the activity of the RA, and although there are no grounds for saying that combination hormonal contraceptives reduce the activity in Ra, there's no evidence that suggest their use would make a flare more likely to happen. Combination pills or the patch, may be effective and convenient for you if you have RA, but there is a concern that the risk of blood clots from the patch is higher than the risk from the pill. Inserting a vaginal ring or a diaphragm may be difficult if you have severe RA and like with lupus, it's not sure how safe IUDs are if you are taking immunosuppressive drugs such as ethotrexate, corticosteroids, or cyclosporine to treat their RA. There are no studies that have addressed this question specifically with newer RA medicines such as the biologics, among them Enbrel, Remicade and Humira.

There are other concerns as well and they are the hormone containing contraceptives can interact with other medicines, and this can reduce your medicine's effectiveness or increase its side effects. Some of these medicines are used to treat arthritis and related conditions. Some anticonvulsants like anti-seizure medications that are used to treat seizures, headaches, or chronic pain disorders may decrease the effectiveness of birth control pills. There are also, corticosteroids, warfin, and cyclosporine that can interact with the contraceptives even though the interactions are weak. Other medications that are used to treat other health conditions, some antibiotics, may also interact with hormone containing contraceptives and if you are using one of these contraceptives you should always remind your doctor of that fact when your doctor prescribes you new medications.

When you have rheumatic conditions and you have to stay in bed for a while, maybe because of a flare-up of the condition, or after surgery you should stop using combination birth control pills, the patch and the vaginal ring. Also, and especially if you have antiphospholipid antibodies, your doctor should give you low doses of a blood-thinning medicine. If you are planning elective surgery, you should talk to your doctor about stopping you combination hormonal contraceptive two months in advance, because estrogen's effects on blood clotting takes up to six weeks to reverse.

There are so many different types of birth control available to you today that if you have a rheumatic condition you can choose a safe and effective method. There are also many factors that have to be taken into consideration and it's essential that you, your gynecologist, and your rheumatologist work together to decide which of these methods is best for you.

Mechanical Problems or Osteoarthritis

There was a review published in January of 2009 that challenges the conventional thinking that cartilage problems and joint damage that are visible on x-rays are the keys to osteoarthritis, or OA. The authors of this review, saw OA as a painful reaction to mechanical problems, with the muscles surrounding the joint and subchondral bone, the slightly spongy bone under the cartilage, as the main players of OA.

They point to evidence, although this evidence is from small studies, showing that actions to stop excessive mechanical stress on joints can stop OA damage and even allow the regrowth of the bone and cartilage. Even though the replacement tissue may not be as good, it may be good enough for careful movements and a life without pain.

Sources of excessive stress or the force on joints include genetic and developmental defects, obesity, trauma, poor alignment of bones, and tiny missteps or falls, and whether alone or in combination, these can lead to repeated micro-damage to the bone and to the cartilage. The review looks at inflammation as a result of and a secondary contributor to mechanical stress. The unmanageable forces on a joint can chip off minute bits of bone and cartilage and if these bits are ground into the joint they can cause further erosion and then they will attract the attention of the immune system. Our immune system will respond to these bits of bone and cartilage causing inflammation and pain and this response will weaken the tissues even further.

The authors of this review also said that the body has several types of “shock absorbers” to reduce these forces on the cartilage and that the main ones are the muscles around the joint and the subchondral bone. Muscles are like rubber bands, stretching to absorb and disperse the load or force and the subchondral bone cushions the force by releasing fluid out from tiny pores as the force is applied. The micro-damage to the joints occurs when these shock absorbers fail, when reflexes are slow to alert the muscles, when force is applied too quickly, or when the muscles or bones aren't strong enough or healthy enough. Aging, weakness, “micro” missteps, and damaged nerves and reflexes all take a toll on the muscles and joints.

The body's constant repair of the micro-damage may even cause the subchondral bone to be replaced by even more damaged dense tissue, making it less effective in absorbing shock. The overgrowth of the replacement tissue may even cause the cartilage to crack and flake making your osteoarthritis worse.

The authors believe that their colleagues focus too much on x-rays for signs of OA, which can bear little relationship to pain and disability since half of the individuals whose x-rays showed advanced OA, had no pain. Doctors find it difficult to identify the source of pain OA, but their general efforts to reduce the mechanical stress may offer some relief. These efforts include losing weight, preventing injuries, and eliminating chores that require knee bending and heavy loads.

This review should get doctors rethinking about OA. One of the drawbacks is that there has not been a large clinical trial directly and complete testing of the new hypothesis, which is that ongoing mechanical injury is more fundamental to OA than the loss of cartilage.

Conclusion On Natural Approach For Chronic Joint Pain & Inflammation -- Anti-Aging Barron Report

A Five-Pronged Natural Approach For Chronic Joint Pain & Inflammation -- Anti-Aging Barron Report

Conclusion on Chronic Joint Pain

This formula now offers a five pronged approach to systemically relieving chronic joint pain and inflammation.

1. It incorporates ASU to increase aggrecan levels, thereby helping to repair and rebuild damaged cartilage in the weight bearing joints.
2. It makes use of the unique ability of the undenatured type II chicken collagen found in UC-II™ to train the body's immune system to stop attacking joint cartilage.
3. It makes use of ginger's ability to directly reduce pain and inflammation.
4. It makes use of CMO's ability to lubricate joints, to support the rebuilding of cartilage, and stop the immune system from attacking joint tissue.
5. And it makes use of the ability of 5-LOXIN to control inflammation.

Things To Take With this Formula

Immune boosters and pathogen destroyers. Once again, the "scientific community" is years late in acknowledging the commonly known fact that, in most cases, joint pain is related to a compromised immune system. Take rheumatoid arthritis, for example. The Journal of Clinical Pathology has finally endorsed what the Mayo Clinic demonstrated conclusively years ago: that bacteria are involved. And new research is indicating that mycoplasma infections may be responsible for as much as 50% of all chronic disease, including arthritis.

Glucosamine and chondrotin sulfate are not a cure, but for some people 1,000-2,000 mg a day may provide some relief. Studies are decidedly mixed, but if it works for you, that's all that counts.

Systemic proteolytic enzymes can be remarkably effective in reducing inflammation throughout the body. Reducing the imflammation can go a long way in stopping the damage from progressing any further -- in addition to reducing the pain.

Omega-3 fatty acids as found in fish and krill oil are also helpful in reducing inflammation.

MSM is a naturally occurring sulfur compound found in our bodies and in many foods. When taken as a supplement, it can play a major role in reducing joint inflammation.

2 More Natural Approachs For Chronic Joint Pain & Inflammation -- Anti-Aging Barron Report

A Five-Pronged Natural Approach For Chronic Joint Pain & Inflammation -- Anti-Aging Barron Report

4. CMO (cetyl myristoleate)

Cetyl myristoleate (CMO) is the common name for cis-9-cetyl myristoleate. (You can think of it as a relative of the Omega-9 fatty acid found in olive oil.) It is a completely natural medium chain fatty acid found in certain animals, including cows, whales, beavers, and mice -- but not in people. CMO was discovered in 1972 by Harry W. Diehl, Ph.D., a researcher at the National Institutes of Health. At the time, Dr. Diehl was responsible for testing anti-inflammatory drugs on lab animals. In order for him to test the drugs, he first had to artificially induce arthritis in the animals by injecting a heat-killed bacterium called Freund's adjuvant. Dr. Diehl discovered that Swiss albino mice did not get arthritis after injection of Freund's adjuvant. Eventually, he was able to determine that cetyl myristoleate was the factor present naturally in mice that was responsible for this protection. When CMO was injected into various strains of rats, it offered the same protection against arthritis. There have been three notable studies on humans.

Studies

The first double blind study was conducted in 1997 under the auspices of the Joint European Hospital Studies Program. Of the 106 people who received cetyl myristoleate, 63% showed improvement vs just 15% for the 226 people in the placebo group.

In 2001, a study of 1814 arthritis patients found that over 87% of the subjects in the study had greater than 50% recovery and over 65% of those showed from 75% - 100% recovery following a sixteen day regimen. All types of arthritis were positively affected by CMO. Only those subjects with liver damage or digestive problems or those taking immune suppressing medications were not helped.

In 2002, a double blind study of 64 people with chronic knee pain, published in the Journal of Rheumatology, concluded that CMO provided a significant functional improvement in range of motion vs placebo. In fact, the study concluded that CMO “may be an alternative to the use of nonsteroidal antiinflammatory drugs for the treatment of osteoarthritis."

What It Means

The 500 mg of CMO I added to the formula provides four distinct benefits:

1. It serves as a lubricant for the joints and muscles, virtually equivalent to silicone in its effectiveness.
2. It facilitates the rebuilding of cartilage.
3. It functions as an immunomodulator -- helping to stop an errant immune system from attacking joint cartilage.
4. It functions like a fatty acid in that it mediates inflammatory processes.

5. 5-LOXIN®

Dried extracts of boswellia serrata have been used since the dawn of history to treat inflammatory conditions. (Note: the common name for boswellia is frankincense. It's not an accident that it was one of the biblical gifts of the Magi.) Over the last few years, boswellia has attracted much attention in the world medical community because it possesses anti-inflammatory properties that are equal to prescription medications without the unpleasant/dangerous side effects. For example, research conducted in India found that an extract of boswellia was more beneficial for rheumatoid arthritis and less toxic and more potent than the standard drug of choice at the time, benzoyl hydrotropic acid.

Other research

In animal studies, dogs suffering from osteoarthritis received boswellia extract once daily for six weeks. After just two weeks, 71% of the animals showed significant improvement in clinical symptoms of arthritis, including reduced pain, stiffness, and lameness.

In a human study, boswellia was similarly shown to be effective in adults with osteoarthritis. Thirty subjects with osteoarthritis of the knee took part in a 16-week, randomized, double-blind, placebo-controlled trial. All of those who took a boswellia supplement reported less pain and swelling, increased knee flexion, and the ability to walk a greater distance.

But it's not just arthritis. Boswellia seems to have the ability to reduce all forms of inflammation. In studies, bronchial asthma was reduced in 70% of 40 patients treated with 300 mg three times daily for 6 weeks in a double-blind trial. It has also proven effective in helping control the inflammation associated with Crohn's disease and colitis.

How it works

Boswellia works through entirely different mechanisms than anti-inflammatory drugs. Whereas most drugs function as Cox enzyme inhibitors, boswellia works by inhibiting lipoxygenase enzymes (LOX), which are powerful contributors to inflammation and disease. By inhibiting LOS enzymes, boswellia effectively blocks leukotriene synthesis. Leukotrienes play a major role in promoting a whole host of age-associated, inflammation-related diseases including joint problems, intestinal disorders, cancer, and lung related disease.

In addition, it appears that boswellia can inhibit the breakdown of connective tissues caused by tumor necrosis factor-alpha, a potent inflammatory agent in the body.

And finally, it appears that boswellia has the ability to modulate the immune system and inhibit inflammatory activity, thereby helping with a number of autoimmune conditions, including rheumatoid arthritis.

Or to put it in simpler terms, the boswellic acids in boswellia seem to have the ability to suppress the proliferating tissue found in inflamed areas of the body and prevent the concomitant breakdown of connective tissue. In addition, boswellia has been found to improve blood supply to the joints and restore the integrity of weakened blood vessels, again with no side effects as seen with the traditional drugs of choice.

What It Means

Boswellia is a great herb for helping with inflammation related conditions -- with two caveats.

• Quality is erratic.
• And even with standardized extracts, it takes a lot (1-3 grams per day) to get the desired effect.

Which brings us to 5-LOXIN.

5-LOXIN is a new, patent-pending boswellia extract that provides 30% acetyl-11-keto-beta boswellic acid (the most bio-active compound found in boswellia) at levels ten times more concentrated than ordinary extracts. It allows us to use much lower dosages of boswellia (100 mg) while achieving much greater results. As an added bonus, 5-LOXIN has been shown to inhibit matrix metalloproteinase (MMP's), a class of enzymes that breaks down cartilage, collagen, and connective tissues -- and is a major contributor to certain forms of heart disease.

Ginger -- Anti-Aging Barron Report

A Five-Pronged Natural Approach For Chronic Joint Pain & Inflammation -- Anti-Aging Barron Report

3. Ginger

There are two cyclo-oxygenase (COX) enzymes present in the human body, COX-1 and COX-2. The COX-1 enzyme is found in most tissues and is necessary for a variety of important internal functions, such as protecting the stomach lining, maintaining renovascular function and platelet aggregation. The COX-2 enzyme, though, has an entirely different function. It is a necessary component of the inflammation process, which is a normal, healthy attempt by the body to heal itself. However, when inflammation gets out of control (such as in the case of arthritis or other chronic inflammatory disorders), ongoing pain and discomfort is the result. Prescription COX-2 inhibitors such as Vioxx and Celebrex have proven helpful in relieving out of control inflammation and its accompanying pain -- but with notable side effects such as an increased risk of heart attacks and strokes. That's where botanical COX-2 inhibitors such as ginger can help. Botanical COX-2 inhibitors block the action of the COX-2 enzyme in much the same way as prescription drugs do, but without the side effects.

Although it's probably better known for its anti-nausea properties, ginger is also an effective COX-2 inhibiting anti-inflammatory herb that has historically been used for arthritis and rheumatism. In a study of patients with rheumatoid arthritis, osteoarthritis, and muscular discomfort, the majority of those who received ginger experienced, to varying degrees, relief of pain and swelling. None of the patients reported adverse effects during the period of ginger consumption, which ranged from three months to 2.5 years. Another double blind trial found ginger extract to be effective at relieving pain in people with osteoarthritis of the hip or knee. Likewise, in another double blind study, ginger was significantly more effective than a placebo in pain relief and overall improvement.

Ginger contains very potent anti-inflammatory compounds called gingerols. These substances explain why so many people with osteoarthritis or rheumatoid arthritis experience reductions in their pain levels and improvements in their mobility when they consume ginger regularly. In two clinical studies involving patients who responded to conventional drugs and those who didn't, physicians found that 75% of arthritis patients and 100% of patients with muscular discomfort experienced relief of pain and/or swelling.

A twelve month placebo-controlled, double-blind, crossover study published in Osteoarthritis Cartilage magazine (no really, that's its name) tracked 29 patients with painful arthritis in the knee (6 men and 23 women ranging in age from 42-85 years). By the end of the first six months, those given ginger were experiencing significantly less pain on movement and handicap than those given placebo. Pain on movement decreased from a score of 76.14 at baseline to 41.00, while handicap decreased from 73.47 to 46.08. In contrast, those who were switched from ginger to placebo experienced an increase in pain of movement (up to 82.10) and handicap (up to 80.80) from baseline. In the final phase of the study when all patients were getting ginger, pain remained low in those already taking ginger in phase 2, and decreased again in the group that had been on placebo.

Not only did participants' subjective experiences of pain lessen, but swelling in their knees, an objective measurement of lessened inflammation, dropped significantly in those treated with ginger. The mean target knee circumference in those taking ginger dropped from 43.25cm when the study began to 39.36cm by the 12th week. When this group was switched to placebo in the second phase of the study, their knee circumferences increased, while those who had been on placebo but were now switched to ginger experienced a decrease in knee circumference. In the final phase, when both groups were given ginger, mean knee circumference continued to drop, reaching lows of 38.78 and 36.38 in the two groups.

What It Means

Ginger extract helps to relieve chronic pain by reducing inflammation.

2. UC-11 Undenatured Chicken Collagen -- Anti-Aging Barron Report

A Five-Pronged Natural Approach For Chronic Joint Pain & Inflammation -- Anti-Aging Barron Report

2. UC-II ® Undenatured Chicken Collagen

Although ASU works directly to build and repair joint cartilage, it doesn't address a major aspect of the problem (in fact few things address this particular aspect). A key component of most joint destruction (sometimes an initial cause as in rheumatoid arthritis and sometimes a secondary factor triggered by an initial trauma to the tissue as in osteoarthritis) is when the immune system goes out of control and starts attacking the cartilage. In other words, once a person starts down the road of joint pain, either early on or later in the process, at some point the immune system usually "goes wrong" and becomes a factor in the gradual destruction of joint tissue. Literally, the immune system reprograms itself to treat joint tissue as a foreign invader and "eat it up." Re-reprogramming the immune system through the use of immunomodulators is often an essential step in stopping and reversing this damage.

In the past, I have recommended several immunomudulators including CMO (cetyl myristoleate) and L-Carnosine, but UC-II seems to represent a choice uniquely suited to dealing with joint and cartilage problems. Although this discussion ultimately applies to all forms of joint damage, for the moment, let's focus our attention specifically on rheumatoid arthritis.

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a common autoimmune disease in which killer T-cells of the body's own immune system (most likely triggered by invading bacteria) reprogram themselves to attack joint cartilage, resulting in inflammation and joint destruction. The current treatment strategies of suppressing immunity and inflammation offer only limited success. "Oral tolerance," on the other hand, is a long-recognized mechanism for inducing immune tolerance -- that is, suppressing a misdirected immune response. But rather than suppressing the entire immune system, oral tolerance targets specific immune cells responsible for tissue damage. Inducing the immune system to tolerate joint cartilage, rather than identifying it as a "foreign" substance, requires a specific sequence of events to take place within that part of the immune system found in the gastrointestinal tract lining.Studies have shown that small doses of undenatured type II collagen can indeed trigger this particular sequence of events, thereby deactivating killer T-cell attacks of joint cartilage in humans.Other studies have demonstrated that the undenatured type II chicken collagen found in UC-II retains its activity when exposed to human digestive fluids, which is not necessarily true of other sources. Time-dose measurements by ELISA immuno-assay of UC-II activity have shown that it retains approximately 50% activity even after as long as 90 minutes after exposure to digestive juices.

What is UC-II?

Most type II chicken collagen sold in dietary supplements is denatured, or hydrolyzed, which is another way of saying that the chemicals and high-heat used to process and refine it have changed its molecular configuration. An undenatured extract is made using little or no heat and limited processing. It is usually extracted using pepsin with just enough processing to concentrate the collagen and make it soluble. Denatured or hydrolyzed extracts, on the other hand, typically use high heat, acids, and enzymes to make the protein molecules more soluble; but these methods fundamentally alter the structure of the protein. Denatured proteins are often called hydrolyzed proteins -- thus denatured collagen is often called hydrolyzed collagen. This does not make it useless. Hydrolzyed type II chicken collagen still has value as a source of some of the components of aggrecan, including collagen itself, hyaluronic acid, chondrotin sulfate, and glucosamine. But to receive this benefit you need to consume it in large amounts, as much as 3-10 grams a day. But more importantly, one significant thing does change in the process of denaturing. When denatured, type II chicken collagen loses its immunomodulating ability. Type II collagen must be in its native (undenatured) form to be effective in this capacity.

UC-II is extracted from chicken sternum cartilage using a patented, low-temperature process that ensures the undenatured biological activity of the type II collagen even when exposed to digestive juices for 90 minutes or more. As mentioned earlier, undenatured collagen administered orally works with the immune system to promote healthy joints by a process called oral tolerization. This process helps the body to differentiate between foreign invaders, such as bacteria, and elements that are good for the body, such as nutrients. The process of oral tolerization takes place in the small intestine where food is absorbed. Through a complex process, lymphoid tissue in the mucosal lining of the small intestine screens incoming compounds and serves as a "switch," turning the body's immune response on or off to foreign substances, depending upon what that substance is. In the case of undenatured type II chicken collagen, small amounts (typically around 10 milligrams) taken orally have been shown to correct a faulty immune response specifically targeted at the type II collagen present in bone joint cartilage -- in effect, modulating the body's immune response so it works correctly once again. At a cost of over $17,000 per kilogram of active ingredient, UC-II is undoubtedly the single most expensive ingredient I have ever used in a formula. Fortunately, it only takes 10 mg a day of its active ingredient for maximum effect. (In fact, it loses effectiveness if too much is used, losing all effectiveness at levels over 20 mg a day). But cost aside, the fact that it specifically addresses the problem of the immune system destroying the body's own cartilage mandates its inclusion in the formula.

Studies on Joint Mobility and Flexibility

There have been a number of studies conducted with UC-II on both animals and humans, including research at the Harvard University Medical school -- all of which have shown that the undenatured type II chicken collagen found in UC-II effectively reprograms the immune system to promote healthy joints and increase joint mobility and flexibility.

In a pilot clinical study, for example, 5 older women (58-78 years old) suffering from significant joint pain were given undenatured type II chicken collagen (10 mg/day) for 42 days. Improvements in pain reduction and joint flexibility were reported, along with reduced morning stiffness. In another study, researchers at Harvard Medical School found that six of ten rheumatoid arthritis patients taking undenatured type II collagen for three months showed substantial improvement, while one patient recovered completely. In addition, there were no side effects. And finally, in a 90-day, double-blind, placebo-controlled, follow-up study on patients with severe rheumatoid arthritis, Harvard scientists found that 28 patients taking undenatured type II collagen showed significant improvement compared to the placebo group, while four patients recovered completely.

An Important Note on Supplement Amounts

When we talk about a 10 mg dose, we're talking about 10 mg of active glycosylated undenatured type II chicken collagen. But there are no readily available pure sources of this component. Standard hydrolyzed chicken collagen, as explained earlier, has virtually none. And most sources of undenatured collagen offer it in the range of 10-25% concentrations. In UC-II, for example, active glycosylated undenatured type II chicken collagen comprises 25% of the whole. That means it takes 40 mg a day of UC-II to get 10 mg of active undenatured collagen. I have noticed that several of the supplement providers who are using UC-II in their formulas have mistakenly used 10 mg of UC-II itself. That means they are only providing 2.5 mg of active undenatured collagen. Given the cost, I can see why, but from your perspective, you want a full 10 mg, which requires 40 mg a day of UC-II -- or more from other sources.

What It Means

For anyone suffering from progressive cartilage damage (which ultimately means anyone suffering from rheumatoid arthritis or long term osteoarthritis), reprogramming the immune system with undenatured type II chicken collagen as found in UC-II is an essential component of his or her joint repair regimen.