Richard G. Petty, MD

Minocycline and Neurological Disease

We recently talked about the fascinating new data on the use of the antibiotic minocycline for treating stroke. The reason is that minocycline is also an anti-inflammatory and it also prevents “apoptosis” or programmed cell death. It has been found to be neuroprotective in animal models of stroke, traumatic brain injury and neurodegenerative disorders. Minocycline also prolongs survival and reduces the loss of motor neurons in transgenic mouse models of amyotrophic lateral sclerosis (ALS), a.k.a. motor neuron disease, a.k.a. Lou Gehrig's disease.

But as with any new research, we always have to go back and re-check and replicate everything. How many times have you heard a news item about some major breakthrough, and then you never again hear anything about it?

An article in today’s issue of the Lancet has indicated that minocycline may be harmful to people with ALS. This is important and will have implications for several clinical trials that are either planned or in progress for trying minocycline in people with dementia, stroke, Huntington's disease and multiple sclerosis.

The United States Western ALS Study Group based at Columbia University in New York, undertook a randomized phase III trial to test the efficacy of minocycline as a treatment for ALS in 412 patients. Patients who took minocycline deteriorated at a 25% faster rate compared with people on placebo.

Therefore the authors suggest that trials of minocycline in other neurological diseases should be reassessed. It is possible that minocycline might be detrimental in patients with other neurological diseases as well.

There is also an editorial comment by Mike Swash, who was once one of my teachers. He talks about the importance of early diagnosis in ALS:

"Clinicians and patients alike would prefer ALS therapy to be tested as early as possible, but there are unresolved difficulties with accurate early diagnosis, particularly the absence of a specific diagnostic test. Might some of the compounds that have failed in clinical trials show benefit if tested at disease onset in human beings?" He concludes that the time has come for new approaches to trial design: "The aim must be to design informative, short, inexpensive, and sensitive phase I/II studies before large phase III studies are attempted".

This is another one of those examples where a medicine introduced for one indication may have many others. In contrast to an antibiotic being used to treat neurological problems, there has recently also been a great deal of interest in the antibiotic potential of some medicines used to treat depression and psychosis.

There is a mountain of new information on this topic, which promises to revolutionize many of our concepts of health and disease. I shall keep you posted as more material is published.

A Virus Linking Depression, Aging and Heart Disease

We have known for a long time that there are close links between depression, aging and heart disease, but the nature of the link has remained elusive. Most of the smart money has been on inflammation, but there could be other candidates.

New research in the journal Brain, Behavior and Immunity has linked an increase in two inflammatory proteins in the immune system with a latent viral infection and proposes a chain of events that might accelerate cardiovascular disease. It is possible that the same process may be involved in a number of other ailments that can afflict us, as we get older. The findings also suggest that chronic depression may play a key role in initiating the cascade that can lead to the development of coronary artery disease.

It has been known for some time that increased levels of the proinflammatory cytokines, TNF-α and IL-6, predict mortality and morbidity. High levels of each of them are found in the plasma and in atherosclerotic lesions of people with cardiovascular disease.

The levels of IL-6 in the body increase as the immune system ages. Some of the IL-6 is generated by immune cells - macrophages - that go to the site of an infection or injury. Earlier work by the team also showed that increases in psychological stress and depression could substantially raise the levels of IL-6 and TNF-α in the body.

Increased stress and depression can also trigger latent viruses to reactivate and begin reproducing inside cells. The viruses of greatest interest are some herpes viruses such as the Epstein-Barr virus (EBV). We know that up to 90% of the people in North America have been infected by EBV by the time they are adults.

If EBV begins to multiply in cells in the body, it produces a protein called dUTpase that, in turn, can stimulate macrophages to make yet more IL-6.

The researchers developed a model to test these linkages by using endothelial cells that line the inside of veins in umbilical cord tissue. I spent years working with these cells myself, and they provide an excellent substrate for examining vascular responses and the interaction between blood vessels and macrophages when exposed to the virus as well as the dUTpase protein.

As expected, the production of IL-6, as well as TNF-a, were increased just as they would be as part of the inflammatory process in the body. Such chronic incidents of inflammation are integral to the onset of atherosclerosis and an array of other diseases.

This work suggests a new way of thinking about how vascular diseases develop. We carry around these latent herpes viruses in our bodies virtually all our lives and periodically they can hurt us as we age, develop depression or, perhaps a nutritional imbalance.

Taken together with the recent data on the physical effects of loneliness, if you want to live a long and healthy life:

• Watch you mood: depression can kill you
• Stay socially engaged: loneliness can be fatal
• Maintain a balanced diet
• Take some physical exercise every day
• Learn – and practice! – some simple stress management techniques. You can obtain some at RichardGPettyMD.com

Molecules of Loneliness

It is well known that our social environment has a major impact on our health, wellness and longevity. Lonely, socially isolated adults have a higher mortality than those who are socially engaged.

There has been a lot of speculation about the factors involved, and there is a fascinating study published in the current issue of the journal Genome Biology.   

Researchers from UCLA identified a distinct pattern of gene expression in the white blood cells of people who experience chronically high levels of loneliness. The findings suggest that feelings of social isolation are linked to alterations in the activity of some of the genes that drive inflammation providing a molecular framework for understanding why social factors are linked to an increased risk of heart disease, viral infections and cancer.

Lonely people suffer from higher mortality than people who are not, and the debate has been whether that risk is a result of reduced social resources, or whether it is biological.

In this study the researchers used DNA microarrays to survey the activity of all known human genes in white blood cells from 14 individuals in the Chicago Health, Aging, and Social Relations Study. Six participants scored in the top 15% of the UCLA Loneliness Scale, a widely used measure of loneliness that was developed in the 1970s; the others scored in the bottom 15%. The researchers found 209 gene transcripts that were differentially expressed between the two groups, with 78 being over-expressed and 131 under-expressed. Genes over-expressed in lonely individuals included many involved in immune system activation and inflammation. At the same time, several other key gene sets were under-expressed, including those involved in antiviral responses and antibody production.

The first author on the study s Steve Cole, an associate professor of medicine in the division of Hematology-Oncology at the David Geffen School of Medicine, and a member of the UCLA Cousins Center for Psychoneuroimmunology, and he had this to say:

"What this study shows is that the biological impact of social isolation reaches down into some of our most basic internal processes the activity of our genes.
We found that changes in immune cell gene expression were specifically linked to the subjective experience of social distance. The differences we observed were independent of other known risk factors, such as health status, age, weight, and medication use. The changes were even independent of the objective size of a person's social network."

“We found that what counts at the level of gene expression is not how many people you know, it's how many you feel really close to over time.”

This study was supported by the National Institutes of Health, the Mind, Body, Brain and Health Initiative of the John D and Catherine T MacArthur Foundation, the Norman Cousins Center at UCLA, the John Templeton Foundation, and the James B Pendelton Charitable Trust.

Although small, this is remarkable and shows how much nature not only abhors a vacuum, but also dislikes isolation. We are social animals and anything that gets in the way of that will likely lead to a very poor outcome.

It is fitting that Norman Cousins, for whom the UCLA center is named, had this to say:
“The eternal quest of the individual human being is to shatter his loneliness.”

“The most terrible poverty is loneliness and the feeling of being unloved.”
-Mother Teresa of Calcutta (Albanian-born Indian Nun, Humanitarian and, in 1979, Winner of the Nobel Peace Prize, 1910-1997)

The Curse of Crystal Meth

I have the dubious distinction of living in a part of the United States with one of the highest rates of methamphetamine abuse in the country. Around here most of the first time users are teenage girls who are trying to lose weight.

In the last few years the spread of methamphetamine abuse across the United States has been as rapid as it has been alarming. Until about six years ago, methamphetamine use was seen mostly in the western and rural United States. Then it jumped over the Mississippi and continued its demonic march to the sea and Georgia has been hit like a ton of bricks.

Not only can crystal met ravage the brains of users, they can get a wide range of physical problems including inflammatory and immune problems throughout the body.

Methamphetamine abuse has now expanded rapidly throughout the rest of the country and across different ethnic groups. According to the 2005 National Survey on Drug Use and Health it is estimated that 10.4 million Americans ages 12 or older have used methamphetamine at least once in their lifetimes for non-medical reasons.

There is a new and important study from the Scripps Institute that has shown that long-term methamphetamine use changes circulating proteins in drug users, causing aberrant immune responses. As a result, increased levels of pro-inflammatory cytokines - proteins that are involved in immune responses - may initiate a previously unrecognized molecular mechanism for the development of cardiovascular disorders including vasculitis, an inflammation of the blood vessels.

It appears that methamphetamine can add sugars (a.k.a. “glycate”) proteins. The researchers found that the immune system responds dramatically to this methamphetamine-induced glycation, which may lead to vascular inflammation. There was a direct relationship between methamphetamine intake and the level of circulating antibodies in animal models. This immune response, coupled with antibodies binding to methamphetamine, might make the drug less biologically available leading to an increased need for higher and higher doses, a problem found among chronic methamphetamine users.

The resulting glycated proteins are called advanced glycation end products (AGEs) that modify the function of proteins and are associated with a number of diseases including diabetes and Alzheimer's disease.

Methamphetamine-AGE proteins not only increased antibody production, but also were strong enough to overcome the drug's natural immunosuppressive qualities. Furthermore, a wide range of cytokines directly linked to AGE exposure were increased in rats that self-administered methamphetamine.

The study also showed that even limited daily access to the drug was enough to produce an over-expression of vascular endothelial growth factor which is a potent signaling cytokine involved in angiogenesis and vasodilatation.

If you know anyone tempted to dice with this vile toxin, ask them to have a look here. 

Exercise May Be the Best Anti-inflammatory

It is almost twenty years since I was awarded my research doctorate and some of what I said at the time was controversial: I made a lot about the link between inflammation, diabetes mellitus and cardiovascular disease. Now we know more, and the link is a lot less controversial.

A number of studies have suggested that regular exercise reduces inflammation but it is still not clear whether there is a definite link. And if there is a link, how does it work? One candidate that we have discussed before has been a link between the autonomic nervous system – sympathetic and parasympathetic - and inflammation. When we exercise, the sympathetic nervous system increases our heart rate and improves lung function, while the parasympathetic system helps to slow things down as we stop exercising.

A recent study by kinesiology and community health researchers at the University of Illinois provides evidence that may help explain some of the underlying biological mechanisms that take place as the result of regular exercise. 

The objective of the research was to examine the independent effect of the “tone” in the parasympathetic nervous system by assessing heart rate recovery after exercise, and whether there was a link between heart rate recovery and circulating levels of C-reactive protein (CRP). CRP, which is mainly produced by the liver, circulates in the bloodstream and is a standard marker for inflammation in the body. We also know that CRP levels tend to rise as we get older, and it may one of the factors involved in the increasing rates of cardiovascular diseases, diabetes and Alzheimer’s disease as we age.

This was a cross-sectional study that focused on baseline test results from 132 sedentary, independently living individuals aged 60 to 83 (47 males; 85 females) who had been recruited to participate in the Immune Function Intervention Trial (ImFIT), a randomized longitudinal trial designed by Woods and funded by the National Institute on Aging to examine the relationship between exercise and immune function.

Participants included only individuals who did not take medications that included corticosteroids, which could interfere with immune measurements. Smokers and/or those with severe arthritis, a history of cancer or inflammatory disease, chronic obstructive pulmonary disorder, uncontrolled diabetes mellitus, congestive heart failure, recent illness or vaccination, or a positive stress test were excluded.

The physical fitness of subjects was assessed through a battery of tests that measured such variables as fatigue, blood pressure, oxygen intake and carbon dioxide elimination and heart-rate recovery in conjunction with exercise on a walking treadmill. Tests also were administered to determine the subjects' levels of physical activity, physical fitness, emotional stress and body composition, including bone density and body fat. Blood samples also were drawn to measure CRP levels.

The results were published in a recent issue of the Journal of the American Geriatrics Society.

It is important that they measured body fat. We know that increasing the amounts of intra-abdominal fat lead to an increase in inflammation: a fat tummy becomes a factory for inflammatory mediators.

The most interesting findings related to heart rate recovery following exercise.

The speed at which people were able to get back to their resting heart rate after a strenuous exercise test was inversely related to the levels of CRP. That means that individuals who had better parasympathetic tone had lower levels of inflammation.

And as any gym rat will tell you, one of the best-known ways improve parasympathetic tone is with aerobic exercise. When an unfit person exercises it can take a long time for his or her heart rate to come back to normal. As you get back into doing regular exercise, your resting pulse rate falls and so does the time that it takes for your heart rate to recover after exercise.

Since the study was cross-sectional, i.e. the researchers took a snapshot of the participants' reactions and measurements at a single, fixed point we cannot say anything about cause and effect relationships.

The research confirms the conclusions of previous research that has indicated that high body fat is related to high inflammation and high fitness to low inflammation, though the researchers did not parcel out total body and abdominal fat. But this new research also suggests that physical fitness may be associated with a decrease in inflammation that is independent of body fat, and that it may be mediated by the parasympathetic nervous system: high parasympathetic tone is related to low inflammation.

So the nervous system may be the key player linking fitness, fatness and inflammation.

If this is correct, exercise alone will likely not be the whole answer. We also need to address other factors that modulate the activity of the parasympathetic nervous system including:

• Physical, psychological and social stress
• Adequate good quality sleep
• Diet and nutrition: there may be foods that can increase stress on the autonomic nervous system
• Adequate hydration: dehydration can be a major stressor on the body
• Breathing: shallow breathing and hyperventilation are all known to stimulate the sympathetic nervous system and damp down the calming activities of the parasympathetic nervous system

Diabetes, Inflammation and the Heart

One of the most worrying signs in people with type 1 diabetes is damage to the nerves supplying the heart. This is called cardiovascular autonomic neuropathy, and one of its first signs is a reduction in the normal heart rate variability (HRV).

It has been known for many years that people with both type 1 and type 2 diabetes have low grade inflammation, and inflammation can have profound effects on the activity of the autonomic nervous system.

A study from Sabadell in Spain has tried to sort out these links in a study of 120 people with longstanding type 1 diabetes.

They measured a great many things including tumor necrosis factor, alpha-receptors 1 and 2, IL-6, and C-reactive protein; insulin resistance and HRV in response to deep breathing and the Valsalva maneuver" forcibly exhaling against with mouth and nose closed.

They did indeed find a link between low-grade inflammation and early alterations in the nerve supply to the heart.

This is important information: when we proposed that inflammation might be an important player in diabetes back in the 1980s, it was greeted with disbelief. Twenty years on it looks as if we might have a whole new line of treatment on the horizon, which will include nutrition and exercise as well as supplements and medications.

Obsessive-Compulsive Disorder and Inflammation

We have recently talked about the growing evidence that several types of mental illness are associated with inflammation. There are some odd neuropsychiatric illnesses that are known to be associated not just with inflammation, but with disturbances of the immune system. One of the most marked in the so-called PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections) in which people may get a constellation of symptoms after a streptococcal infection. Amongst the symptoms are obsessive compulsive disorder (OCD)-like symptoms, and that has lead to the question whether OCD itself might be some kind of autoimmune illness.

OCD can  be a debilitating illness in which people have obsessive, distressing, intrusive thoughts and related compulsions (tasks or "rituals") with which they try to neutralize the obsessions. It is classified as an anxiety disorder, and it is listed by the World Health Organization as one of the top twenty most disabling illnesses in terms of lost income and diminished quality of life.

Jack Nicholson did a very good job of portraying someone with OCD in As Good As It Gets, and Tony Shalhoub's  Adrian Monk is close to reality, though few people have quite the number of different and ever-changing obsessions as the character in the show.

Now new research (NR239) presented last week at the 2007 Annual Meeting of the American Psychiatric Association in San Diego has found a link between inflammation and OCD.

Researchers from Zonguldak Karaelmas University in Turkey measured the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) in 31 drug free outpatients with OCD.

Both TNF-α and IL-6 levels were significantly higher in people with OCD compared with healthy volunteers.

What this tells us is that there may well be some involvement of the immune system in the pathophysiology of OCD, and, if confirmed, that in itself might suggest some new approaches to treatment.

The next step will be to replicate the study with a larger number, and then to do a longitudinal study, to see if these inflammatory markers rise as people are getting worse, and go down as they improve.

Breast Cancer and the Gang of Four

People of a certain age will remember the ominous "Gang of Four" who were primarily blamed for the events of the Cultural Revolution in China.

Now new research published in the journal Nature has exposed an equally ominous "Gang of Four," but this time it is a set of four genes is responsible for the lethal spread of breast cancer.

A team in New York with researchers now working at the Hospital Clinic de Barcelona and the Institute for Research in Biomedecine in Spain, has identified four key genes in human breast cancer cells that play a role in metastasis, or the spread of the cancer, to the lungs.

A number of genes are already known to contribute to the spread to the lungs. But Prof Joan Massagué and colleagues at Memorial Sloan Kettering Cancer Centre, New York, now show how four co-operate to promote the formation of new tumour blood vessels, the release of cancer cells into the bloodstream, and the penetration of tumour cells from the bloodstream into the lung.

The gene set comprises EREG, MMP1, MMP2 and cyclooxygenase (COX2). (That is the same COX2 that you will have heard about as a target for some arthritis and anti-inflammatory medicines. It is the abnormal activation of all four that enables the breast cancer to invade the lungs. Although shutting off these genes individually can slow cancer growth and metastasis, the researchers found that turning off all four had a dramatic effect.

Prof Massagué said:

"The remarkable thing was that while silencing these genes individually was effective, silencing the quartet nearly completely eliminated tumour growth and spread."

In experiments on human breast tumours implanted in mice, the researchers also found that they could reduce the growth and spread of the disease by simultaneously targeting two of the proteins produced by these genes, using drugs already on the market.

"We found that the combination of these two inhibitory drugs was effective, even though the drugs individually were not very effective," said Prof Massagué. "This really nailed the case that if we can inactivate these genes in concert, it will affect metastasis."

The researchers now want to test combination therapy with the drugs - cetuximab (Erbitux) and celecoxib (Celebrex) - to treat breast cancer metastasis.

The other two genes are matrix metalloproteinases (MMP1 and MMP2) that are involved in the formation of new blood vessels.

A second study, also published in Nature, reports that investigators in Texas have isolated 87 genes that seem to affect how sensitive human cancer cells are to certain chemotherapy drugs.

The study highlights a new way to screen for alterations in cancer cells that make them specifically sensitive to treatments, so that they may leave normal tissue relatively unharmed.

This is important work that unlocks  another piece of the mystery of at least one type of cancer.

It will not be the whole story: we still need to find out why tumors can spread to other organs and how environmental factors, including states of mind, may have an impact on the spread of tumors.

And it is yet more evidence that inflammation is one aspect of the spread of tumors.

Blood Pressure and the Brain

We have known for almost a century that regions of the brain are involved in the control of blood pressure.

Yet over the last three decades most of the emphasis in research into hypertension (high blood pressure) has focused on blood vessels, the heart and kidneys.

Now research from Bristol University in England has been published in this month’s issue of the journal Hypertension, and it may put the brain back into the center of research into the causes and treatment of high blood pressure.

Working with rats, the researchers isolated a protein called JAM-1 (junctional adhesion molecule-1), that is located in the walls of blood vessels in the brain. It appears to trap white blood cells causing obstruction of blood flow in some of the smallest blood vessels. This can cause inflammation and result in poor oxygen supply to the brain, which may in turn trigger events that raise blood pressure.

Though this work is in its early stages, this is exciting stuff: if confirmed, it might be possible to treat hypertension with drugs that reduce blood vessel inflammation and increase blood flow within the brain.

It also ties in with other recent research from Imperial College, London and Oxford University, in which a team of neurosurgeons and physiologists discovered changes in blood pressure while fitting brain electrodes to 15 patients for pain control.

Deep brain stimulation involves placing very thin electrodes on very exact locations in the brain and is already used to relieve pain and to help Parkinson's disease patients with their movement.

The researchers found that they could make patients' blood pressure increase or decrease by stimulating very specific regions of the brain with the electrodes. Regions that have been associated with blood pressure control in the past. If they stimulated an area deep down in the midbrain called the ventral periventricular/periaqueductal gray matter, blood pressure went down, and if they stimulated the dorsal periventricular/periaqueductal gray matter it went up.

Nobody is suggesting that we should start sticking electrodes in peoples’ brain, but this chance observation may have profound implications, particularly for people who drop their blood pressure too far when they are treated with standard medicines.

These two pieces of research may also help explain why a balanced inflammation–reducing diet and relaxation may both reduce blood pressure.

Fats, Inflammation and Depression

We have talked before about the associations between inflammation and psychiatric illnesses.

There is yet more evidence in the shape of a study just published in the journal Psychosomatic Medicine. by Janice K. Kiecolt-Glaser and her colleagues from Ohio State University College of Medicine in Columbus.

The study involved 43 older adults with a mean age of 66.67 years, and the results suggests that the imbalance of omega-6 and omega-3 fatty acids in the typical American diet could be associated with the sharp increase in heart disease and depression seen over the past century. The more omega-6 fatty acids people had in their blood compared with omega-3 fatty acid levels, the higher their levels of the inflammatory mediators tumor necrosis factor-alpha and interleukin-6, and the greater the chance that they would suffer from depression. These are the same inflammatory mediators associated with insulin resistance, type 2 diabetes and coronary artery disease, all of which are more common in depression. And depression is more common in diabetes, arthritis and coronary artery disease than expected.

Our hunter-gatherer ancestors consumed two or three times as much omega-6 as omega-3, but today the average Western diet contains 15- to 17-times more omega-6 than omega-3. There were 6 individuals in the study who had been diagnosed with major depression, and they had nearly 18 times as much omega-6 as omega-3 in their blood, compared with about 13 times as much for subjects who didn't meet the criteria for major depression.

Depressed patients also had higher levels of tumor necrosis factor alpha, interleukin-6, and other inflammatory compounds. And as levels of depressive symptoms rose, so did the omega 6 and omega 3 ratio. So it seems as if the effects of diet and depression enhance each other. People who had few depressive symptoms and/or were on a well-balanced diet had low levels of inflammation in their blood. But when they became more depressed and their diets became worse – which is very common when people are depressed – then the inflammatory mediators in the blood surged.

Omega-3 fatty acids are found in foods such as fish, flax seed oil and walnuts, while omega-6 fatty acids are found in refined vegetable oils used to make everything from margarine to baked goods and snack foods. The amount of omega-6 fatty acids in the Western diet increased sharply once refined vegetable oils became part of the average diet in the early 20th century.

Depression alone is known to increase inflammation, the researchers note in their report, while a number of studies have found omega-3 supplements prevent depression.

So this more evidence for the value of eating fatty fish like salmon, mackerel or sardines two or three times a week, but be sure to avoid fish that may contain a lot of mercury. If you add more fruits and vegetables to your diet, you will also reduce your levels of omega-6 fatty acids.

I have just finished analyzing all the new literature on using fish oils for the prevention and treatment of psychological and psychiatric problems, and I am going to post my findings in the next couple of days.

Oral Health and Pointless Tests

I really like the Fox News Channel, but I sometimes worry about some of the medical advice that they dish out. The other morning I heard a dentist recommend that people should ask for a blood test to measure inflammation. She was saying that everyone should have the test, called C-Reactive Protein (CRP). This is really bad advice that is based on a fundamental misunderstanding of research data.

Yes, there is a link between dental disease and arteriosclerosis. And yes, there is a link between CRP and arteriosclerosis. But there is no good evidence that we should be measuring it on a routing basis.

The CRP Molecule

So what’s the problem about measuring CRP? If it is elevated, then what? There is no point in measuring anything at all unless you can take some action, or it guides prognosis. No good doctor would ever recommend treating a lab value. So if the CRP is elevated that would not just mean that it’s time to have a look at his or her pearly whites, it would mean a total body workup. There are dozens of causes for an elevated CRP. I know a lot about the topic: sixteen years ago I wrote one of the early scientific papers on CRP. It may go up if you have a fat tummy, have arthritis, allergies or if you are depressed, have fibromyalgia or irritable bowel syndrome. It also goes up as you get older, if you are physically inactive, or if you happen to have one of the genetic variants that can push it up.

In fact the questions of whether or not measuring CRP would improve coronary risk prediction is the subject of three papers and two editorials in the July 10, 2006 issue of the Archives of Internal Medicine and the July 4, 2006 issue of the Annals of Internal Medicine. In the July 10, 2006 issue of the Archives of Internal Medicine, a team led by Dr Aaron R. Folsom from the University of Minnesota in Minneapolis reported the results of the Atherosclerosis Risk in Communities (ARIC) study, which assessed the association of 19 novel risk markers with incident CHD in 15 792 adults followed up since 1987-1989.

The participants underwent a physical examination, including assessment of major risk factors, at the beginning of the study and every three years afterward. At four times during the follow-up period, researchers collected blood and DNA samples for analysis. Patients continue to be tracked for the development of CHD.

Novel markers included measures of inflammation, endothelial function, fibrin formation, fibrinolysis, B vitamins, and antibodies to infectious agents.

Folsom concluded that:

"C-reactive protein level does not emerge as a clinically useful addition to basic risk-factor assessment for identifying patients at risk of a first CHD event. Routine screening is not warranted for any of the other 18 novel risk factors tested, either."

Another study from Brigham and Women's Hospital in Boston did suggest that CRP might be helpful in predicting coronary disease in some women. But in an editorial, George Davey Smith from the University of Bristol in England had this to say:

"There are many reasons for skepticism about the role of CRP as a predictor of CHD: CRP may not be causally related to CHD; it remains more expensive than asking patients about their health, lifestyle, and socioeconomic background; and it adds only modest additional predictive ability over conventional risk factors, even in Cook and colleagues' (i.e. the Brigham and Women’s) study."

The moral of the story? Random measurements of CRP have not been shown to be of much value.

And be a bit cautious about medical advice on Fox News.

Asthma, Air and Allergies

After a couple of weeks away I was distressed to see that I was going to be returning to a city which has just been rated as the most challenging place in America for people with asthma.

This is the list according to the Asthma and Allergy Foundation of America:

1. Atlanta
2. Philadelphia
3. Raleigh, North Carolina
4. Knoxville, Tennessee
5. Harrisburg, Pennsylvania
6. Grand Rapids, Michigan
7. Milwaukee
8. Greensboro, North Carolina
9. Scranton, Pennsylvania
10. Little Rock, Arkansas

I am pleased to say that I do not have asthma, though I have a strong family history of it. If you live in one of these cities, or any other with a high rate of pollution, there is nothing much to be done apart from:

Staying indoors when the weather is bad

Using an air purifier

Keep to a diet designed to reduce your risk of inflammation

Use homeopathy and tapping therapies to help when necessary.

And sadly, for some people, medicines are the only option. But I always try the other approaches as well.

A Promising New Treatment for Lupus Kidney Disease

Systemic lupus erythematosus (SLE) is an out-of-control, malignant attack on the body by its own immune system. It can be a horrible illness that may affect virtually every organ of the body. One of the worst things is that it can lead to renal (kidney) failure. Until now, the treatments of SLE have been either symptomatic or "disease-modifying." The second is what we really want: to prevent the illness from progressing. But it has been very difficult to do that, and I have seen some real tragedies in my career.

We now have a new approach that highlights a new approach to illness in general. Students are usually taught that there are diagnostic tests for illnesses like SLE or prostate cancer. The idea of using the tests for treatment is fairly new. So one of the proteins that goes up in prostate cancer becomes the target for treatment.

But what about SLE?

SLE is a chronic inflammatory disease in which the body produces antibodies against the nuclear components of its own cells. The most worrying are  antibodies to double-stranded DNA (dsDNA). These antibodies can be triggered by  genetics, environmental  factors like sunlight and some drugs.

The antibodies attack the body’s cells and tissue, resulting in inflammation and tissue damage. SLE can affect any part of the body, but most often damages the heart, joints, skin, lungs, blood vessels, liver, kidneys and nervous system.

La Jolla Pharmaceutical Company just announced positive interim antibody results from its ongoing double-blind, placebo-controlled randomized Phase 3 trials of Riquent(R) (abetimus sodium). This is a drug candidate for SLE. Analyses of interim antibody data indicate that patients treated with 900 mg or 300 mg per week doses of Riquent had greater reductions in dsDNA antibodies than patients treated with 100 mg per week or placebo. The results showed a significant dose response when comparing all Riquent-treated patients to placebo-treated patients (p < 0.0001), and each Riquent dose group to the placebo dose group (p < 0.0015 for 100 mg, p < 0.0001 for 300 mg and 900 mg).

For people not used to looking at statistics, these are impressive data.

Clearly other analysts feel the same way: the price of the company's shares went up 40% on the announcement.

We shall keep an eye on the development of this new medicine to see if it fulfills this early promise. At this moment the data are very exciting.

Anti-inflammatories and Colon Cancer

I just had a very good question after I published my list of Twelve Tips to Reduce Your Risk of Colorectal Cancer.

Dear Dr. Petty,

“That’s a great list, but I am wondering why you haven’t included aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs)? I thought that they had been shown to reduce the risk of colon cancer.”

This is an excellent question, and I deliberately omitted mention of anti-inflammatories because the research suggests that they may cause more harm than good.

There is a report in today’s edition of the Annals of Internal Medicine from the United States Preventive Services Task Force, a highly regarded and independent panel of experts in primary care and prevention, that confirms that screening for colorectal cancer is still important and everyone over 50 should have it. But they urge caution on taking preventive drugs, saying that on balance the health risks of aspirin outweigh the benefits when it comes to preventing colon cancer. This advice holds even for those people with a family history of the disease, as long as they have only an average risk of colon cancer. (20 per cent of people who get colorectal cancer also have a close relative with the disease, with proportionally more cases among African Americans than other races.)

They found good evidence that high doses of aspirin (i.e. 300 mg a day or more) and possibly ibuprofen protect against colorectal cancer but this comes with increased risk of intestinal bleeding, stroke and kidney failure.

In low doses - under 100 mg a day - the Task Force says that good evidence supports the notion that aspirin protects against heart disease. However, at this dosage it will have no preventive effect on colorectal cancer.

The US Preventive Services Task Force regularly reviews the available research evidence and issues advice based on what they regard the strength of the evidence to be. They use a grades to help guide practice. For example a grade A recommendation is equal to "strongly recommends", while a B is just "recommends", and C is "no recommendation for or against".

In this case the Task Force has issued a grade D "recommends against" to the routine use of aspirin and NSAIDs to prevent colorectal cancer.

So for now I recommend following the Twelve Tips that I published yesterday.

Deep Vein Thrombosis

I am sorry to hear that the United States Vice-President Dick Cheney has just developed a blood clot in his leg and is being treated with anticoagulants (blood-thinning medications) that he will need to be on for several months.

He experienced some discomfort in his lower left leg this morning, and the diagnosis of deep vein thrombosis was made.

Mr Cheney is now 66 years old and has a history of cardiac problems. He has suffered at least four  myocardial infarctions (heart attacks) and has a pacemaker.

He had quadruple bypass surgery in 1988 after his third heart attack.He also had an operation to remove blood clots around his knees in 2005.

Mr Cheney recently returned to Washington after long flights to Japan, Australia, Pakistan and Afghanistan.

As I discussed a few months ago deep vein thrombosis - often shortened to "DVT" - can be associated with long-distance flying because it leads to inactivity and dehydration. Not, as was formerly thought, low oxygen pressure.

Blood clots in the legs are not in themselves life-threatening but they can be dangerous if they become wedged in the lungs (pulmonary embolism) or other organs, which can in severe cases be fatal.

Although the venous and arterial sides of the circulation are often thought of as quite different, it is not that unusual for someone to have problems in both, either because of immobility, metabolic disturbances or low grade inflammation.

With Spring Break and early summer vacations coming up, please don't forget to keep moving when you are on planes, limit the alcohol and coffee cnsumption, and have plenty of water to drink.

Bon voyage!

Acupuncture and Parkinson's Disease

Over the last 25 years I have used acupuncture to try and help a great many people with Parkinson's disease. It has certainly helped a lot of the symptoms, but in my experience has not often done much to change the course of the illness. That being said, I have seen a few people who had remarkable improvements that were sustained for months and even years. The best results have usually come when we have used a combination of acupuncture, diet and homeopathy, in addition to regular medications.

So I was very interested to see a study in the journal Brain Research, even though the work used animals, and I've had a longstanding aversion to animal experiments.

There is a chemical called MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) that damages and kills some types of dopaminergic neurons in the brain, so it can produce Parkinsonian symptoms in humans and in some animals.

Mice were injected with MPTP and then some of them received acupuncture every two days in two spots, one behind the knee and one on top of the foot. In humans, these are two of the points that are traditionally considered to be involved in muscle movement. Another group of mice received acupuncture in two spots on the hips that are not believed to be effective for acupuncture. A third group had no acupuncture at all.

By the end of seven days, the MPTP injections had decreased dopamine levels both in the mice that had not received acupuncture, and in the mice that received fake acupuncture, to about half the normal amount. But in the acupuncture-treated group, dopamine levels declined much less steeply, and nearly 80% of the dopamine remained.

The mechanism for such an effect remains unknown. The most likely mechanism is that it is reducing the inflammation in the brain often accompanies and worsens other symptoms of Parkinson's disease. So acupuncture might maintain dopamine levels by preventing this inflammation. The same team of researchers from South Korea has already reported that acupuncture also prevents loss of dopamine neurons in rats.

The clinical studies in humans have been less encouraging, and more closely reflect my clinical experience. The problem is that by the time most people get to see an acupuncturist, they have already lost huge numbers of dopamine neurons and it is difficult to do very much. If acupuncture is to be helpful, we would probably need to be able to identify someone with Parkinson's disease extremely early, perhaps even before clinical signs have appeared, and so far we have no reliable way of doing that.

Here Comes the Sun: To Screen or Not To Screen?

I have been worried to see some people - all, I think, without scientific training - proclaiming that there is no need to protect ourselves against the sun because there is no evidence that sulight causes any health problems.

Ultraviolet radiation (UVR) from the sun has been part of the environment since the first cells began to form. When we discuss the effects of UVR on human health and the environment, the range of UV wavelengths is often subdivided into:

• UVA (400–315 nm), also called Long Wave or "blacklight"
• UVB (315–280 nm), also called Medium Wave
• UVC (< 280 nm) also called Short Wave or "germicidal”

The key questions are these:
Can sunlight cause health problems?
Do the benefits of sunlight outweigh their risks?”

UVB is required for the conversion of 7-deoxycholesterol to vitamin D, (the sunshine vitamin!) which is critically important in the maintenance of healthy bones, although there may also be another mechanism by which vitamin D is generated in the body. As we have seen research is making clear that vitamin D has other potential roles in the maintenance of human health. Low levels of vitamin D have been linked to:

• Rickets
• Osteomalacia
• Osteoporosis
• Maintaining the integrity of cell membranes
• Type 2 diabetes mellitus
• Schizophrenia
• Multiple sclerosis
• Pre-eclampsia (hypertension and accompanying problems during the late stages of pregnancy)
• Some types of cancer
• Fibromyalgia-like pains
• Immune deficiency: Africa Americans do not generate enough of a protein needed to ward off tuberculosis. Why? Because the protein needs vitamin D to be activated, and dark skin is inefficient at absorbing and converting UVR. It may also be that we see epidemics of colds and flu in the winter because that is when we have low levels of vitamin D, which allows the viruses to overwhelm our immune defenses.

This does not necessarily mean that taking extra vitamin D will ward off all of these problems.

In the days before the Industrial Revolution, unless we lived in the frozen North, we had no trouble in getting the amount of vitamin D that we needed. In most of the United States, during the summer months, 10-15 minutes outdoors at midday will generate around 10,000 international units (IU’s) of vitamin D in an average fair-skinned person. This is far in excess of the government’s dietary recommendations of 200 IU’s/day in people up to age 50, 400 IU’s up to age 70 and 600 IU’s in people over 70. Not surprisingly many experts – me included – believe and have provided evidence that these daily requirements are much too low. (Have a look at the comments here.)

Of course many of us do not spend much time outside and don’t take in as much in the way of vitamin D containing foods - such as milk and salmon – as we should. I’ve seen evidence to suggest that we in Atlanta are probably at the Northernmost point in the United States were we could hope to get enough sunshine and therefore vitamin D from modest winter exposure to the sun.

Recent data has suggested that if you spend no time at all in the sun, then you may need as much as 4,000 IU’s of vitamin D/day, though that figure has not yet been widely accepted.

Exposure to UVR, whether of solar or artificial origin, also carries potential risks to human health. UVR is a known carcinogen and excessive exposure, at least to the solar radiation in sunlight, increases the risk of cancer of the lip, basal cell, and squamous cell carcinoma of the skin and melanoma, particularly in fair-skinned populations. There is also evidence that solar UVR increases risk of several diseases of the eye, including cortical cataract, some conjunctival neoplasms, and perhaps also melanoma of the eye.

We have good data for the existence of a threshold amount of UV-B exposure that may lead to the formation of cataracts. The amount needed to cause cataracts depends in part on the amount of pigment in the eye, so albino rats get cataracts with much lower exposures to UV-B.

So what to do?

Sunlight has a definite benefit in preventing or treating many clinical problems and it is no surprise that after 3000 millennia we are adapted to make use of the sun’s largesse. What is less easy to understand is why an excess of sunlight can cause so many problems, unless it is our hairlessness and environmental change that has lead to a loss of the ozone layer.

Some years ago it was suggested that sunscreens may themselves cause skin cancer, but the data has shown that to be false. Indeed modern sunscreens almost certainly reduce melanoma risk.
So how do we balance the positive and negative effects of sunlight? A recent review precisely reflects my own thinking:

• We need some sunlight
• Depending on where you live, you need only a few minutes each day
• Sunscreens confer protection on the skin without blocking all the health benefits
• If you have a medical reason for avoiding sunlight, then your health care provider should measure your vitamin D status.

 

Toxoplasmosis and Behavior

Last August I wrote an article about some extraordinary new evidence implicating Toxoplasma gondii in some psychological and psychiatric illnesses. Latent infection with Toxoplasma gondii is amongst the most prevalent of human infections and it had been generally assumed that it is asymptomatic unless there is congenital transmission or reactivation because a person has an immune system that has become depressed or compromised. That assumption is being completely re-evaluated. 

The article generated some extremely interesting correspondence and some spirited discussions.

Here is a very insightful letter from a physician:

Dear Dr. Petty,

I thought about the concept of psychological illness caused by a virus or other organism. I was wondering what would be the mode of dispersion of such a virus. Upper respiratory tract infections, skin and gastrointestinal infections spread by cough, by touch and hand to mouth respectively. How would such a brain virus or protozoal organism promote itself? Of course it could be by the above methods but it seems that there should some way that the specific disease process is connected to a behavior that helps it to spread itself. 

Then I got to thinking; diseases have learned physical ways to disseminate themselves, I wonder if a disease could change behavior to promote it's own dissemination and survival? I imagine that if that were true, people with the flu would be sociable, people with infectious diarrhea would be sociable and hungry, people with AIDS would have increased libido. I haven't yet seen any data for this. Although I've always felt that there was one disease that did alter behavior in a way that is conducive to disseminating itself, and that is rabies. The host goes from being docile, to seeing all others as the enemy. He then attacks them, bites them and thus passes on the organism. A true mind altering virus, although it's psychology works better with animals than with people. Do you think that there are other diseases that spread purely by behavior, that cause the host to seek out the next host and not just pass the disease from one to another just due to proximity?

This was my response:

What great questions!

And believe it or not, there's quite a lot of empirical research on these very topics.

There is a whole textbook on the behavioral effects of parasites edited by Janice Moore entitled  Parasites and the Behavior of Animals. Here's an interesting one: rats and mice are hard wired to avoid cats. Millions of years of programming have ensured that Tom's very presence would send Jerry packing. Cats carry Toxoplasma gondii and if mice or rats become infected with it, usually by eating cat poop, they lose their fear of felines. So now Tom can have lunch at his leisure.

I've also talked about the way in which people with creativity and schizotypal personality disorder (i.e. carriers of genetic risk) tend to be promiscuous, while people with schizophrenia have fewer children. Both groups tend to get more sexually transmitted diseases than the general population. It would be tempting to think that toxoplasmosis can be spread that way, however there's a 32-year old study in German that showed that Toxoplasma was not transmitted by intercourse. However, cytomegalovirus, a common partner to Toxoplasma may be. And both modulate dopamine activity in the regions of the brain involved in salience.

I have done a very detailed literature search encompassing papers written in all the languages that I can read, and have not been able to find any clear evidence of behavior change induced by HIV, influenza or infectious diarrhea: what interesting and important questions to research.

We do have some more data confirming the effects of Toxoplasma infections on the behavior of rats: they become less anxious and therefore do not respond to environmental threats as quickly as uninfected rodents. An antipsychotic medication (haloperidol), a mood stabilizer (valproic acid) and two chemotherapeutic agents - pyrimethamine or Dapsone – have all been shown to prevent the development of Toxoplasma-induced behavioral change.

Another recent study from the Departments of Parasitology, Microbiology and Zoology, Charles University, the Centre of Reproductive Medicine and GynCentrum, in the Czech Republic also speaks to the significance of latent Toxoplasma infections: the presence of the parasite in the blood of pregnant women increases their chance of giving birth to boys. The increased survival of male embryos in infected women may be explained by Toxoplasmosis infections modulating and suppressing the immune system.

If Toxoplasma plays a part in the development of some psychiatric illnesses, yet a high proportion of the population carries it without any problems, one obvious question is what activates it? Environmental stress might, perhaps, cause the Toxoplasma to become reactivated and play a part in the development of specific psychiatric symptoms.

This story is continuing to develop and I am going to watch it closely. If it is confirmed, it could open up some brand new avenues for helping treat and perhaps even prevent some types of psychiatric illness.

Parkinson's Disease and Cholesterol

Within the last week we have talked about the association between Helicobacter pylori and Parkinson's disease and the way in which Parkinson's disease may often get better if people are treated with a cocktail of antibiotics. We have also discussed the association between Parkinson's disease, allergies and inflammation.

Now new research from the University of North Carolina at Chapel Hill has  found that people with low levels of LDL cholesterol are more likely to have Parkinson's disease than people with high LDL levels. This is the form of cholesterol sometimes referred to as "bad cholesterol." This study followed the strange observation that people with Parkinson's disease have a lower rates of heart attack and stroke than people who do not have the disease. It is also known that known that cigarette smoking, which increases a person's risk for cardiovascular disease, is also associated with a decreased risk of Parkinson's disease. 

Few scientific stories are clear cut: it usually takes a while to get things right. Just to prove it, a study from the Netherlands found that high total cholesterol levels were associated with lower rates of Parkinson's disease, but only in women.

So what to make of all this: infections, allergies and now cholesterol?

To try and understand this, I think that we need to introduce another actor to the stage. Since the early 1950s the medical community has been concerned about a striking concentration of amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia among the Chamorro people on the island of Guam. A number of lines of evidence have suggested that this group of illnesses has been caused by some neurotoxic agent in the environment, though nobody has been able to work out exactly what it is. One of the most attractive recent theories is that it might have something to do with toxins from Cycas plants. So the idea is that similar cholesterol-containing neurotoxins can come either from Helicobacter or from eating Cycas plants, or animals that have fed on the plants.

There is a complex inter-relationship between LDL- and HDL-cholesterol, and HDL-cholesterol appears to be anti-inflammatory: high levels of HDL-cholesterol are associated with low levels of inflammation. And it has recently been shown that simvastatin may cut the risk of developing Parkinson's and Alzheimer's diseases. Not just by lowering cholesterol but from its inflammatory activity.

It may also be that low levels of cholesterol may impair the activity of another factor: one that interests me is coenzyme Q10.

From a practical perspective, this new evidence reinforces a point that I made in Healing, Meaning and Purpose and on this blog: "boosting" one component of the blood or lowering another is not sensible. Whether dealing with cholecterol or immunity, we need to moduate and harmonize all the systems of our bodies and our minds.

Follow our systems for modulating the inflammatory mediators in your body and that alone should - theoretically - reduce your risk of many illnesses.

I shall keep you posted as this story continues to develop.

Parkinson's Disease, the Intestine and Infections

Early in my career, one of my mentors was the eminent scientist and clinician Robert Mahler. He recently passed away at the age of 81, but in the last two years of his life he was an author on two papers (1, 2) about an ailment with which he struggled for many years: Parkinson's disease.

Despite the best treatment, he was severely incapacitated by the illness, at one stage needing a wheelchair to get from his car to his office. But his fine mind remained undimmed by the illness, and he was intrigued by reports of an association between stomach ulcers and Parkinson's disease and of dramatic improvements in the symptoms of some people with Parkinson's disease who were being treated with antibiotics for gastric ulcers. (Last year Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine for their pioneering work on Helicobacter - a bacterium associated with peptic ulcers. I mentioned in an earlier post that I have a strong sense that there are more prizes to come on the interaction between infectious agents, inflammation, genes, the psyche and the environment.)

Robert was one of the test subjects in a research study and his Parkinsonian symptoms got much better when he was treated with antibiotics. There are now several important pieces of research on the fascinating topic. In some people eradicating Helicobacter may convert rapidly progressive Parkinsonism to a quieter disease, although only a minority of sufferers have evidence of current infection.

There seems to be an interaction between aging, genes and this infectious agent. Clearly not everyone is helped by antibiotic treatment, but this is a whole new line of very promising research.

Multiple Sclerosis and Vitamin D

I have commented before that the increasing rates of multiple sclerosis as we move away from the equator has lead to speculation that it might have something to do with lack of sunlight and therefore reduced production of vitamin D in the skin.

A lack of vitamin D may also explain the increased rates of both type 1 and type 2 diabetes, as well as cluster headache at higher latitudes.

Vitamin D is not a single vitamin, but is instead a group of fat-soluble prohormones as well as the metabolites and analogues of these substances. There are two major forms of vitamin D: D₂ (or ergocalciferol) and D₃ or cholecalciferol. Vitamin D₃ is produced in skin exposed to sunlight, specifically ultraviolet B radiation. Very few foods are naturally rich in vitamin D, and most vitamin D intake is in the form of fortified products including milk and cereal grains.

It used to be that we all made plenty of Vitamin D simply by being outside in the sun, but our time outside has been steadily falling since the beginning of the Industrial Revolution, and there are the increasing concerns about exposure to sunlight and some skin cancers.

Vitamin D is involved in many critically important chemcial reactions in the body, and Vitamin D receptors are found in cells in most organs in the body, including the brain, heart, skin, gonads, prostate, and breast. Apart from its effects on regulating calcium and phosphorus, Vitamin D is involved in maintaining the integrity of cell membranes and in modulating the immune system. There is some evidence that a modest increase in Vitamin D intake may reduce the risk of colon, breast and ovarian cancers.

There is a risk of overdosing with Vitamin D. The U.S. Dietary Reference Intake Tolerable Upper Intake Level (UL) of vitamin D for childern and adults is 50 micrograms/day (2000 IU/day). In adults, a daily intake of 2500 μg/day (100,000 IU) can, over a period of weeks and months, produce toxicity  and, if taken for years, as little as 50 to 75 μg/day (2000 to 3000 IU) can produce toxicity.

In this week's issue of the Journal of the American Medical Association, there is an important report that endorses everything that we have been saying. Researchers from several prominent institutions in the United States have examined the hypothesis that higher levels of 25-hydroxyvitamin D are associated with a lower risk of multiple sclerosis.

The study confirmed the hypothesis: the risk of multiple sclerosis (MS) fell as blood levels of the vitamin rose.

The researchers uncovered 257 cases of MS among more than seven million military personnel who had given blood samples to the US Department of Defense.

Amongst white personnel, there was a 41% decrease in MS risk for every 50 nanomoles per litre increase in 25-hydroxyvitamin D, the key form of the vitamin found in the blood.

Those whose vitamin level was in the top 20% had a 62% lower risk of MS than those whose level was in the bottom 20%.

The researchers found no such association among black and hispanic personnel, but this could be a reflection of the smaller size of these sample groups.

This new research ties in with other work that has shown that Vitamin D supplements can prevent or favourably affect the course of a disease similar to MS in mice, as well as evidence that if you live in the Northern Hemisphere, being born in May is associated with a lower risk of MS than if you were born in the winter. If you are born in May, your mother will probably have been exposed to more sunlight - and therefore have produced more Vitamin D - during the later part of pregnancy when the final development of the nervous system takes place. Or alternatively you may have had a heathy dose of sunlight in the weeks immediately after your birth.

It is most likely that the Vitamin D helps by modulating the immune system and suppressing autoimmune reactions caused by specialised T helper 1 cells attacking myelin, the insulating material that sheathes most nerves. It is these attacks that are thought by most experts to play a key role in the development of MS.

If confirmed, the finding suggests that many cases of MS could be prevented or its severity reduced by increasing our levels of Vitamin D.

The data also confirm a point that we have made before: we should not be aiming to "boost" our immune systems, but to "modulate" them.

If you see an advertisement for some potion that is supposed to boost your immune system to help you ward off colds, the flu or something more serious, be suspicious: if the seller does not know the  difference between boosting and modulating, it would be best to move on.

Another Reason Why Breast Is Usually Best

Last month we looked at some of the extraordinary benefits of breast feeding.

There is an interesting paper in this month's issue of the journal Pediatrics.

Approximately 19 percent of children are prone to the chronic and recurrent ear infections collectively known as otitis media. These infections can cause deafness and thereefore interfere with the development of language and lead to learning difficulties. We have known for many years that there can be a genetic predisposition to otitis media, but there has been little research to try and pinpoint the specific genes involved. There is also a complex relationship between genes, specific infectious agents and environmental factors such as exposure to cigarette smoke and breast-feeding.

The new research from the University of Texas Medical Branch at Galveston examined genetic samples taken from 505 children in Texas and Kentucky, about 60 percent of whom were classified as "otitis media susceptible" because they had:

• Suffered an ear infection before the age of 6 months
• Or undergone three or more episodes of acute otitis media within a six-month period
• Or four or more episodes within a 12-month period
• Or had six or more episodes by age 6.
• Or had required drainage tubes to reduce recurrent or persistent ear infections

The researchers looked for small genetic variations called "single-nucleotide polymorphisms," - or SNPs - in three important genes that produce inflammatory signaling molecules for the immune system.

Two genes known known to generate the immune proteins known as tumor necrosis factor-alpha (TNF-alpha) and  interleukin 6 (IL-6). SNPs in each individual gene were enough to create an increased risk for childhood ear infections, and simultaneous SNPs in both genes increased the risk even further. These particular genetic variations cause a greater production of inflammatory signaling molecules and reduce the effectiveness of the immune system.

But here is the fascinating thing: the researchers found that the genetic effect could be counteracted by breast-feeding, which is well known to increase immune resistance.

We have here another fine example of how a healthy practice can overcome a genetic predisposition to illness. Remember what I have said many times before: Biology is not destiny.

On the hand another environmental factor - exposure to cigarette smoke - increased vulnerability to otitis media in children with the TNF-alpha gene variation. Cigarette smoke exposure alone was not enough to increase the risk for ear infections. 

Stress and the Skin

You have probably noticed how stress can have an impact on some people’s skin. Increasing stress can initiate or worsen skin disorders such as psoriasis and atopic dermatitis. There has also been a lot of discussion about whether stress can also exacerbate acne and cause cold sores to erupt.

A new study published in the December issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology sheds important light on this association.

It is well known that one of the physical effects of stress is to increase levels of a range of steroid hormones called glucocorticoids. The best known glucocorticoid is cortisol or hydrocortisone. So the question was whether the missing link between stress and skin problems might be one or other of the glucocorticoids.

Researchers from the Veterans Affairs Medical Center, San Francisco and the University of California at San Francisco and Yonsei University Wonju College of Medicine, Wonju, Korea decided to study this possible connection.

You may have heard that the skin is the largest organ in the body and provides the critical barrier between the environment and the internal organs. Its most important function is providing a permeability barrier that prevents us from drying out. When we are healthy we are approximately 65-70 percent water. We are able to survive and function in dry environments because the skin forms a permeability barrier that prevents the loss of water.

The physical location of the permeability barrier is in the outermost layer of the epidermis that is known as the stratum corneum. The stratum corneum is composed of dead cells surrounded by lipid membranes. The stratum corneum layer continuously sloughs off, and therefore has to be constantly regenerated. The epidermal cells in the lower epidermis are continuously proliferating to provide new cells, which then differentiate, move toward the surface and ultimately die, to form a new the stratum corneum. This process is going on in your skin right now, though it can be disrupted by damage such as sunburn. If the process becomes overactive, it can lead to the development of thick, hardened skin.

It was already known that psychological stress disturbs this elegantly balanced system by decreasing the proliferation of epidermal cells and inhibiting their differentiation. As a result the function of the permeability barrier is impaired.

To test the hypothesis that glucocorticoids would have adverse effects on skin function, they stressed some hairless mice by putting them in small cages in constant light and forcing them to listen to the radio for 48 hours.

Before being stressed one group of mice was treated with mifepristone, which you may know by its two other names, RU-486, or the “morning after” pill, which blocks the action of glucocorticoids. A second group was given a drug called antalarmin, which blocks glucocorticoid production. A third group was stressed but received neither drug and a fourth group remained unstressed in ordinary cages and without the continuous light and sound to which the other groups were exposed.

The mice that received mifepristone or antalarmin showed significantly better skin function compared to the stressed mice that did not receive either treatment.

The experiment demonstrated the important role that glucocorticoids play in inducing the skin abnormalities brought on by psychological stress. Although we hope that the study will lead to a way to treat people who suffer from these skin conditions, there is still a long way to go. It’s always difficult to extrapolate from mice to people. Second, there may be serious side effects of modulating glucocorticoid activity. Glucocorticoids are essential hormones that play many important roles. Blocking their action could have negative outcomes. This is one of the reasons why we are skeptical about advertisements that claim that some herbal concoction can “cure” cortisol-related obesity. If something could really modify the activity of cortisol or other glucocorticoids in the body, it would likely have many most undesirable effects.

The research team is now looking at the effect of psychological stress on the skin's production of antimicrobial peptides, which play a role in defense against infection. It has long been thought that psychological stress might also reduce the ability of the skin to protect from infections.

I never like to leave a report involving animal experiments without also saying a heartfelt thank you to the animals that participated in the experiments.

This research is interesting and may have a number of spin offs. But I have another rather obvious question: since we already know that there is a link between stress and some skin problems, why not focus on stress management techniques, rather than trying to find new medicines to help counteract the biochemical effects of stress?

Genes, Environment and the Brain

We recently looked at the worrying suggestion that environmental toxins could, in susceptible individuals, be contributing to the apparent increase in autism over the last three decades.

There is increasing evidence that there are complex genetic and environmental interactions that contribute to abnormal aging and neurodegenerative disorders like Alzheimer’s, Parkinson’s and Huntington’s diseases.

A new study from Duke University Medical Center in Durham, North Carolina, has done more to dissect this interaction. They collected information on 1136 consecutive patients who presented to the Joseph and Kathleen Bryan Alzheimer Disease Research Center. They showed possible significant contributions of toxic environmental and occupational exposures to pathological aging in 21% of the patients, and interactions of these exposures with common genetic polymorphisms that affect cell injury and inflammation. They found a series of genes that could partially account for differences in the type of cognitive problems that people experience, the age at which they developed them as well as the rate of progression.

The researchers targeted three genes in particular - apolipoprotein E, alpha-1-antitrypsin and the hemochromatosis gene. All three are expressed in the liver and in macrophages: cells that play a critical role in immune responses, inflammation and the body’s response to stress and infections. The first two genes are particularly involved in the metabolism of lipids and the third in the balance of iron and trace minerals. This ties in with another observation. Many chronic illnesses are associated with anemia. It is now thought that this also is a defensive reaction. Not to chronic illness, but to the problem that was far more common during evolution, and that was infection. The liver pulls iron out of the circulation so that bacteria cannot use it for their own growth. This is one of a number of adaptive responses that I discuss in the book and CD series, Healing, Meaning and Purpose.

But it was also clear form this new study that genes were not the only factor. I have spoken before about the small number of strategies that can dramatically reduce our risk of developing Alzheimer’s disease. The authors of this study agree about the importance of factoring in environmental factors including, alcohol use, nutritional deficiencies and sleep and mood disorders, all of which can have an impact on cognition.

This study is yet another step toward clarifying the role of genes, inflammation and cell injury in the development of degenerative changes in the brain.

While pharmacologists can use this information to help devise new ways to protect your brain, you can use it immediately. There is a range of behavioral and dietary strategies that can reduce the burden of inflammation in the body. I shall write about some of them in articles and an eBook in the near future.

We do not know whether these strategies can reduce the risk of Alzheimer’s and Parkinson’s diseases, but there are some intriguing suggestions that they can.

Multiple Sclerosis and Stem Cells

If you have been reading my recent posts about multiple sclerosis (MS), you may be interested in an useful resource from the New York Academy of Sciences.

I have the privilege of being a member of the Academy and I've been impressed by its increasing efforts to educate the general public. There are regular "eBriefings" that are well written and succinct.

This one on stem cells and MS is timely and encouraging. It is also a good jumping off point if you want to follow up on some of the issues.

The existence of stem cells in the central nervous system has already raised some intriguing possibilities for treatments based on activating and directing them in the brain. The second idea, of dismantling the diseases immune system and replacing it with a new clean one, is not science fiction but part of a concerted effort to reprogram the body.

This is precisley the kind of approach that we advocate when we use "Information Medicine," designed to correct faulty information that produces faulty DNA and ultimately faulty proteins and organs.

Chloroquine, Insulin and Inflammation

Your humble reporter was fascinated to read about some new research using the anti-malarial agent chloroquine as a potential treatment for the insulin resistance syndrome.

I have a personal reason for being interested. Hypoglycemia (low blood glucose) is an occasional feature of treatment with chloroquine and in 1980 a study first indicated that chloroquine might slow the break down of insulin by the liver. In the early 1980s there were a flurry of papers indicating that chloroquine did some subtle things to insulin and insulin receptors in many tissues. So we came up with the idea of measuring its effects in humans. There was a memorable occasion on which I was doing an outpatient clinic with an intravenous line in my arm. (English doctors are well known for doing experiments on themselves: I had a professor in medical school who said that you should never do to a patient what you haven’t had done to yourself. I shall leave it to you, gentle reader, to wonder if I've tried everything....).

So there I am doing my clinic when, around 11AM I begin to feel really strange: my glucose level was almost unrecordable and my insulin level was off the chart. Nothing that couldn’t be solved with a large dollop of sugar, but it made me very sympathetic to people who get hypoglycemic from their regular treatments.

Sometimes Nature does our experiments for us: we did a lot of work on diabetes because it is associated with high rates of vascular disease. So understanding the mechanisms by which diabetes does that may help illuminate some of the cellular disturbances underlying arteriosclerosis in general. We are also interested in the few illnesses in which a single disturbed gene may lead to a definable set of signs and symptoms. There is a rare illness known as ataxia telangiectasia in which sufferers have a high risk of developing some cancers particularly lymphomas and leukemia. People with the illness are very sensitive to ionizing radiation, have a specific type of immune deficiency, degeneration of parts of the brain related to muscle function and coordination and they age prematurely. More than ten years ago it was discovered that a single gene - ataxia-telangiectasia mutated (ATM) gene – was responsible for the illness. The gene is responsible for producing a protein that recognizes damage to DNA. It now seems that ATM may also be linked to metabolic and cardiovascular diseases. It does this by inhibiting a protein called JNK, a stress kinase involved in inflammation with related effects in insulin resistance and atherosclerosis. So to everyone’s surprise a gene that can cause a rare disease can also cause insulin resistance.

In the November issue of Cell Metabolism, researchers at Washington University School of Medicine in St. Louis and St. Jude Children's Research Hospital in Memphis, Tennessee report that a small dose of chloroquine eased many symptoms of metabolic syndrome in mice, reducing blood pressure, decreasing hardening and narrowing of the arteries and improving blood sugar tolerance. The results suggest we may only need very low and perhaps infrequent doses of chloroquine to achieve similar effects in humans. Both insulin and chloroquine activate the ATM gene.

This adds to the data that some of the metabolic dysfunctions triggered by obesity may be linked to the inflammatory responses that go wrong in autoimmune disorders like arthritis and systemic lupus erythematosus.

And an older treatment for rheumatoid and lupus just happens to be chloroquine.

Chloroquine itself has some side effects, but this is important information that will help us design more effective and carefully targeted holistic treatments for both metabolic disturbances and inflammatory conditions. All in all, very good news indeed.

Multiple Sclerosis

Multiple sclerosis (MS) can be a horrible illness that does not respect age or class. Neil Cavuto, Captain Beefheart and Montel Williams are just three well-known people who have said that they have the illness. Here is a list of many other sufferers.

MS is a chronic, inflammatory disease that affects the central nervous system (CNS). MS can cause a wide variety of symptoms, including changes in sensation, visual problems, muscle weakness, depression, difficulties with coordination and speech, severe fatigue, and pain. The classic pathology is what is known as demyelination (loss of the myelin that insulates nerve cells). Since myelin is white, the lesions are typically fuond in the white matter of the CNS.

The cause remains unknown, though I shall have more to say about some of the MS theories. Amongst the candidates have been autoimmunity, slow viruses, myelinic enzymes and polio vaccination.

Most people begin to experience symptoms between 20 and 40 years old, and rarely after 50. The onset is usually insidious, though every now and then someone starts with sudden onset of a catastrophic neurological or visual problem. Symptoms are usually vague and the diagnosis is often missed in the early stages. Females are affected slightly more than males. MS seems to be a disease of temperate latitudes in both the Northern or Southern hemispheres and is rarely seen in equatorial regions. This association with latitude has fueled some of the viral theories as well as ideas to do with the impact of decreasing sunlight on vitamin D and cell membrane function.

One of the things that makes the disease such a great masquerader is that it is typically marked by apparently random exacerbations and remissions. As the disease progresses, the remissions become less complete and permanent deficit more apparent.

There is an enormous research literature on MS: over 35,000 papers at last count. But there have been some recent highlights.

There has recently been a major breakthrough in discovering the mechanism by which myelin forms. The finding from the Keck School of Medicine of the University of Southern California and the Institut de Recherches Cliniques de Montreal in Canada, could have a major impact on the treatment of multiple sclerosis and demyelination as a result of spinal cord injuries.

Jonah Chan and his colleagues showed that a protein, Par-3, is at the base of the myelination process. This protein becomes localized to one side of the myelin-forming cells that are known as Schwann cells, upon contact with the axon that is to be myelinated. Par-3 acts like a kind of molecular scaffold to set-up an "organizing centre" that brings together the key proteins essential for myelination, in particular a receptor for a molecule that is secreted by the neurons.

The researchers found that when they disrupted this organizing centre, cells could not form myelin normally. Importantly, their discovery demonstrates that Schwann cells need to become polarized so that they know which side is in contact with the axon to initiate wrapping and to bring essential molecules to this critical interface.

These studies open up some new possibilities that should help to identify other components that are recruited at the organizing center set-up by Par-3. In multiple sclerosis, or after injury, Schwann cells can re-myelinate axons of the central nervous system to some degree. Therefore, these experiments bring about the possibility that manipulating the Par-3 pathway might allow for more efficient re-myelination of damaged or diseased nerves.

In a separate study researchers from the Virginia Commonwealth University researchers have identified a unique mechanism of action of a new drug that shows great promise for the treatment of MS.

The researchers reported the unique action of FTY720, or Fingolimod, an immunosuppressant drug that was already known to affect the functioning of the immune system by preventing the egress of white blood cells from the lymph nodes into the blood. The article was published in Blood: The Journal of the American Society of Hematology, that appeared online on Sept. 28.

In this study, the research team found that FTY720 also inhibited the activity of a key enzyme called cPLA2, which is necessary for the production of inflammatory mediators, known as eicosanoids. Eicosanoids drive inflammatory disorders such as asthma and multiple sclerosis.

The inhibition of cPLA2 would shut down the entire inflammatory pathway, possibly without the side-effects caused by medications such as Vioxx, that have been withdrawn from the pharmaceutical market.

FTY720, is a drug developed by Novartis, has shown considerable therapeutic effects in a recent small, placebo-controlled clinical trial involving patients with relapsing multiple sclerosis. The study was published in the September 2006 issue of the New England Journal of Medicine by an international research team.

I could easily select a dozen more important papers published in the last year, but I am particularly interested in basic research that teaches us something new, and treatments that could fit into a comprehensive Integrated plan of treatment.

I am going to post more about the causes of this illness as well as less orthodox approaches to help the physical, psychological, social, subtle and spiritual aaspects of these illnesses.

Turmeric and Arthritis

I recently reported about some research from SIngapore that indicated that the spice turmeric might help with cognition.

Today there is a study form the University of Arizona in the journal Arthritis and Rheumatism suggesting that the spice may also be helpful in experimental rheumatoid arthritis. In line with most other studies of herbal supplements it is interesting that the maximal effect was obtained by using the natural form of turmeric, that contains three major "curcuminoids," the likely active ingredients. If one of the three is missing, the effect is a lot less.

The extracts appears to work by preventing the activation of a protein that controls when genes are switched on or off in the joint. Once the protein known as NF-KB is activated, it binds to genes and increases the production of inflammatory proteins, which in turn attack the joints.

This is not a surprise: In traditional Indian Ayurvedic medicine turmeric has been used for centuries as a treatment for inflammatory disorders including arthritis. Based on that, dietary supplements containing turmeric rhizome and turmeric extracts have been sold for years. However, there's been little direct evidence that they are helpful.

We are going to need more research before we can sy whether turmeric supplements can be recommended for medicinal pruposes, and eating more spices is unlikely to work.

These findings are opening up a new approach to treating not just rheumatoid arthritis, but perhaps also other inflammatory diseases such as inflammatory bowel disease, asthma and multiple sclerosis. Interestingly the turmeric extract also has another effect: it deactivates a biochemical pathway that leads to the resorption of bone. So it may help with osteoporosis.

Tourette’s Syndrome

No surprise here, but I was just sitting on a plane.

Again.

When I heard people sniggering.

Why? A young man in his thirties was walking along trying to find his seat. As he did so he was constantly grunting, saying partially intelligible words and jerking. As a clinician it was immediately obvious that he almost certainly had Tourette’s syndrome, a developmental disorder of the brain in which people have involuntary, stereotyped, repetitive motor and phonic tics. Some people with the disorder exclaim obscene words or socially inappropriate and derogatory remarks, which together are known as coprolalia.

The illness was originally named for Georges Albert Édouard Brutus Gilles de la Tourette, (1859–1904), a French physician and neurologist, who published an account of nine patients with the now classic clinical features in 1885.

You may not often see someone with this problem, but it is good to know what it is, and that it is an illness that can cause great distress.

We have recently made some interesting discoveries about Tourette’s syndrome.

1. It is an illness involving the dopamine systems in the basal ganglia of the brain together with some regions of the midbrain and some very specific linked regions of the cerebral cortex, cerebellum and limbic system.
2. In adults with Tourette’s syndrome, the prefrontal cortex is a little smaller than normal, and the corpus callosum linking the hemispheres is larger than expected. These findings correlate with problems in the way in which people transfer information between the hemispheres and modulate attention.
3. Very recent evidence has shown us that there are small hyper-intense lesions in the deep regions of the brain in people with Tourette’s, obsessive-compulsive disorder and attention deficit disorder. These three problems seem to have a number of biological links and two or more may co-exist in the same person. In children and adolescents with Tourette’s, the tics tend to get better over time but obsessive-compulsive disorder symptoms become more severe and persistent as they get older.
4. There is important evidence that in some people, Tourette’s is linked to a post-infectious autoimmune disorder, and many have antibodies directed against neurons in the brain.
5. There is also a link between Tourette’s and having low iron stores. Low iron stores are common in people with many chronic inflammatory illnesses. Iron is crucially important in the development of key regions of the brain. We do not have any viable evidence that giving people iron supplements will reduce the severity of Tourette’s, but it is something that needs to be examined in a formal study.

People have typically been treated with antipsychotic medicines such as risperidone that block dopamine receptors in the brain, and they can certainly help. A more recent approach is to use medicines like aripiprazole that modulate dopamine activity in the brain. A recent study done by some colleagues in the United Kingdom have confirmed that aripiprazole seems to be very helpful in about half of patients with Tourette’s, though neurological side effects do sometimes occur.

There has recently been a lot of interest in Habit Reversal Therapy: a behavioral treatment for tics. The therapy takes a lot of time and effort, but it is very interesting that behavior therapy can help with a neurological illness.

There is no published data on the use of Integrated Medicine in the treatment of people with Tourette’s, but many experts have reported that some patients have been helped with homeopathy and acupuncture.

That guy in the next seat who is cursing may not just be mean and uncouth. He may be suffering.

But maybe not for much longer.

We are getting very close. Not just to discovering the physical basis of the illness, but perhaps its meaning and purpose as well.

New discoveries are coming thick and fast, and I shall keep posting about those that will help individuals and illuminate the principles of Integrated Medicine.

Handedness and Immunity

In 1982, one of my mentors, the late Norman Geschwind, and two colleagues – Al Galaburda and Peter Behan - proposed an extraordinary hypothesis. It was that the levels of testosterone to which a baby is exposed before birth influence the development of both the cerebral and immune systems. According to this theory, high levels of testosterone result in greater incidences of left-handedness, deviations from the standard distribution of cerebral functions and increased autoimmune dysfunction. If the theory is right, then male brains should mature later than female brains, and the left hemisphere should mature later than the right.

It is certainly true that if a boy gets a head injury or infection involving the brain, he is less likely to recover than would a girl, and boys are far more likely to have some types of neurodevelopmental problems like dyslexia.

For a while it seemed as if there was also a strong association between left-handedness and certain types of allergy, and also with inflammatory bowel disease. This association with immunity also seemed to be present in mice: those who had left paw preference had more reactive immune systems, and they were thought to be more likely to produce auto-antibodies, suggesting that the central nervous system was involved in the genesis of some autoimmune diseases. Over the years the data has become less clear-cut, but the idea of an association between anomalous cerebral asymmetry and autoimmune disease never completely went away.

Recent data has again found an association between inflammatory bowel disease and laterality. And left-handers really do have more autoimmune disease.

The Geschwind-Galaburda hypothesis proposes that there should be a four-way association among neurodevelopmental disorders, special talents, non-right handedness, and immune disorders. In a huge study of 11,578 children, less than 1% had all four.

So where does this leave us?

The original theory was half right:

1. There is indeed a link between testosterone and early brain development
2. People who are left-handed or have a strong tendency toward left-handedness do seem to be at slightly increased risk of several autoimmune conditions
3. People who are left-handed or have a strong tendency toward left-handedness may have a slightly increased risk of high blood pressure, asthma and migraine
4. People who are left-handed or have mixed handedness are more likely to excel in certain disciplines: creative arts, music, computer programming and mathematics. What we don’t know is whether people with these special skills are more likely to have autoimmune diseases
5. Amongst very successful tennis players,  there are far more left-handers than would be predicted by chance. This supports the idea that support the notion that left-handed people have neurological advantages in performing certain tasks, such as visuospatial visuomotor cognitive tasks.

I was reminded of the way in which Nature seems to like to balance things out a bit: with some notable and famous exceptions, many successful athletes have not done so well academically and many academics would be unlikely to survive on the plains of Africa. Only some of these differences can be explained in terms of early direction and encouragement in school or while growing up: it seems that most of us cannot hope to become the kind of superman that Nietzsche used to dream about.

Perhaps it’s a way of stopping us from getting too full of ourselves.

Vitamin D and Interstitial Cystitis

I think that interstitial cystitis (IC) must be one of the most distressing of conditions to have, and it is certainly one of the most challenging to treat. Outside the United States, it is more often called painful bladder syndrome (PBS).

IC is a condition that results in recurring discomfort or pain in the bladder and the surrounding pelvic region. The symptoms vary from person to person and even in the same individual. It can vary from an experience of mild discomfort, pressure, tenderness, to intense pain in the bladder and pelvic area. Symptoms may include an urgent need to urinate (urgency), a frequent need to urinate (frequency), or a combination of these symptoms. Both may be severe: I’ve seen people who had to urinate every ten minutes. Pain may change in intensity as the bladder fills with urine or as it empties. Women's symptoms often get worse during menstruation, and some experience pain with vaginal intercourse. There is a good website provided as a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), that is fairly up-to-date.

Because IC varies so much in symptoms and severity, most researchers believe that it is not one, but several diseases. There are clear links between IC and fibromyalgia, irritable bowel syndrome and chronic fatigue, and probably many other illnesses.

There is good evidence that inflammation in one pelvic organ can cause pain in other organs that share some of the same nerve supply. Inflammation of the colon may make some nerves coming from the spinal cord hyper-excitable, which in turn makes nerves running to the bladder hypersensitive. Because the same nerve plexus connects with the ovaries and uterus, it is no surprise to learn that phases of the menstrual cycle impact the way in which inflammation in one pelvic organ can cause inflammation in another.

IC appears to be becoming more common, although that is always a risky comment, because it was undoubtedly not often recognized in the past. The old teaching was that it was only something that occurred in menopausal women, but it is now being diagnosed in men as well as women, and in people as young as their late teens.

The cause of IC remains unknown, though there have been many theories: infections, allergy, autoimmunity, neurological and genetic. There have been recent claims of the discovery of responsible genes, but hey would most likely be susceptibility genes, rather than causative. Otherwise why should the rates of IC genuinely seem to be increasing? What seems clear is that the normal mucus lining of the bladder wall is damaged.

Multiple types of treatment have been tried, from medication to pelvic floor exercise, to neurological implants and homeopathy and acupuncture. The report of anything new that may help is always welcome.

So I was interested to see a report from investigators in Milan on the efficacy using a molecule that has been attracting a lot of interest recently: vitamin D. The active form of vitamin D is known as calcitriol or 1,25-dihydroxycholecalciferol (1,25(OH)2D3) that is manufactured in the kidney. Its in vivo biological effects include regulation of bone metabolism, control and modulation of the proliferation of cells and some aspects of the immune response. These characteristics have already led to therapeutic applications in osteoporosis, secondary hyperparathyroidism, and psoriasis. Many reports show beneficial effects of vitamin D in animal models of diabetes, organ graft rejection, experimental allergic encephalomyelitis, lupus nephritis, and in asthma. Despite what you may have seen in some advertisements, just taking extra vitamin D does not help, and may make matters worse: they key is to have the right form of vitamin D, that can reach and affect the right areas of the body.

The Milan team used a vitamin D3 analogue (BXL628) in a mouse model of chronic cystitis. What they found was that a specific inflammatory marker in the blood went down with treatment, and at the same time histological analysis showed a decrease in edema and white blood cell (leukocyte) infiltration in the bladder wall. This and some other biochemical evidence of what is known as “mast cell degranulation,”  is very encouraging and strongly supports the potential therapeutic use of BXL628 in diseases such as human interstitial cystitis.

This is the kind of mechanism-based research that holds out enormous promise for everyone’s welfare and will help us in our goal of using science to inform the development of the next generation of treatment, health and wellness.

Women, Asthma and the Brain

There’s been a longstanding puzzle in medicine. Well actually there are lots of them, but here’s one that may be a puzzle no more.

For many years now, it’s been known that asthma is more common in women, and also that psychological stress can cause flare ups of asthma.

Many women experience “menstrual flaring:” a worsening of asthma around the time of their menstrual period. There is also a strange paradox: some women with asthma wheeze less if they take an oral contraceptive, while some non-asthmatic women begin to wheeze when they take it. In some women pregnancy makes asthma worse, and in others it affords months of relief of symptoms. Women who are obese are more likely to get asthma, presumably because their intra-abdominal fat stores are churning out inflammatory mediators.

Researchers from the University of Wisconsin have shed  some important light on this link between asthma and the brain. In research published in the Proceedings of the National Academy of Sciences. In the study, six patients with mild asthma were exposed to ragweed or dust-mite extracts. The subjects were shown three different categories of words: asthma-related (e.g., "wheeze"), non-asthma negative ("loneliness") or neutral ("curtains").

Using functional magnetic resonance imaging, they showed that activity in two regions, known as the anterior cingulate cortex and the insula showed increased activity when the asthma-related words were heard compared with the other types. What is more, this enhanced activity was specifically linked to physiologic signals from the ragweed and dust-mite extracts. So being exposed to asthma-relevant emotional stimuli is associated with markers of inflammation and airway obstruction in asthmatic people exposed to an asthma-producing antigen.

In people with asthma and other stress-related conditions, these brain regions may be hyper-responsive to disease-specific emotional and physiologic signals. Taken together, these could contribute to problems that worsen the asthma, such as inflammation.

And one of the ways of making these regions of the brain hyper-responsive? Bathe them in estrogen.

That still does not explain why pregnancy and the oral contraceptive makes some women’s asthma better, and does the opposite in others. But it may just have to do with the “set point” of the cells in these regions of the brain. In the same way that we might set the thermostat in out house. An already hyper-responsive brain might be normalized and an under-active one stimulated to be over-active.

We need to do some more experiments, but these are a great start.

If you ever wheeze, have a look to see if there are stressors or hormonal events that trigger you. Whether you are being treated with homeopathy, herbals or conventional therapy, knowing when to expect trouble gives you the power to adapt you treatment when you are entering a risky time in your life.

Another Reason to Eat Your Greens

“Health requires healthy food.”
--Roger Williams (Indian-born American Chemist who did pioneering work on the Vitamin B Complex, 1893-1988)

Earlier this year several news outlets including Time picked up a story that has been causing a great deal of discussion in medical circles.

Most of us have been extolling the virtues of fruits and vegetables for decades, but it’s always nice to have an extra piece of evidence to support what we’ve been saying. The question has been how to go from large-scale epidemiological studies proving the benefits of vegetables to the inner workings of a person’s arteries.

Investigators from Wake Forest University School of Medicine in Winston-Salem, North Carolina published an important study in the Journal of Nutrition. What they did was to study genetically altered mice, who had been bred to have a very high risk of developing rapid arteriosclerosis: the formation of fatty plaques in the arterial wall that can eventually block blood flow and lead to heart attacks and stroke.

Half the mice were fed a vegetable-free diet and half the mice were fed a diet that included broccoli, green beans, corn, peas and carrots.

After 16 weeks, the researchers measured the cholesterol content in the blood vessels and estimated that plaques in the arteries of the mice were 38% smaller. Cholesterol, and particularly the “bad” cholesterols VLDL and ILDL fell markedly in the mice on the healthy diet, but these improvements were not on their own enough to explain the improvement in the blood vessels: the anti-atherogenic effects of the vegetable diet remained largely unexplained by the variation in plasma lipoproteins or body weight.

There was a 37% reduction in serum amyloid - a marker of inflammation in mice - suggesting that consuming vegetables may inhibit inflammatory activity. This is line with data from other studies indicating that fruit and vegetables should be key components of an inflammation-lowering program. This is very important: in the last twenty years it has become very clear that arteriosclerosis is intimately associated with inflammation in the arterial wall.

Many inflammatory conditions including rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus and psoriasis, are all associated with an increased risk of developing arteriosclerosis.

Interestingly some years ago Dean Ornish presented evidence indicating that diet and exercise could reverse arteriosclerosis. I’ve always found Dean’s work interesting, well done and persuasive. It surprises me to see how many people remain unconvinced. This new research provides indirect support for his work.

The average person only eats three portions of fruit and vegetables a day: we should all be eating at least five, and they should be of as many different colors and types as possible: there is excellent evidence that combinations of fruits and vegetables are much better for your health than just eating one or two types.

As an aside, I must admit that I’m no fan of animal experiments: I don’t and won’t do them. And every time that I hear about them, I think that we need to say a sincere thank you to the animal kingdom for their sacrifice in helping us.

“God, in His infinite wisdom, neglected nothing and if we would eat our food without trying to improve, change or refine it, thereby destroying its life-giving elements, it would meet all requirements of the body.”
--Jethro Kloss (American Nutritionist and Writer 1863-1943)

“In fresh fruit and vegetables and nuts are all the vitamins and minerals and high grade proteins the human body needs to bring it to a state of physical perfection and to MAINTAIN it in that state indefinitely.”
--Herbert Shelton (English Evolutionary Philosopher, 1820-1903)

“Nothing will benefit human health and increase the chances for survival of life on earth as much as the evolution to a vegetarian diet.”
--Albert Einstein (German-born American Physicist and, in 1921, Winner of the Nobel Prize in Physics, 1879-1955)

Peripheral Neuropathy

Treating peripheral neuropathy can be one of the toughest problems facing a clinician. Peripheral neuropathy simply means disease affecting the peripheral nerves.

There are a great many cause of peripheral neuropathy. This is just a partial list to give you an idea of the things that a clinician has to think about before starting treatment:

1. Metabolic illnesses: Diabetes mellitus; porphyria; chronic renal failure; amyloidosis and disturbances in circulating proteins
2. Vitamin deficiencies: Vitamins, B1, B3, B6 and B12
3. Drugs and chemicals: Alcohol; Heavy metals like arsenic, lead and mercury; organic pesticides; several drugs used in cancer chemotherapy; isoniazid; nitrofurantoin
4. Infections: Lyme disease; Herpes zoster (shingles); Diphtheria; Brucellosis; Leprosy; Tetanus; Botulism
5. Malignant illnesses
6. Inflammatory and autoimmune illnesses: Rheumatoid arthritis; Systemic lupus erythematosus; Polyarteritis nodosa; Sarcoidosis; Guillain-Barre syndrome; Celiac disease
   
7. Physical injury: Trauma, stretching and compression of nerves, which can include things like carpal tunnel syndrome.
8. Congenital illnesses

Many causes of peripheral neuropathy, particularly diabetes, may also damage the autonomic nervous system that controls the heart, blood pressure, swallowing, intestinal and bladder function.

Neuropathic symptoms typically start in the feet, because the nerves running down there are longer and more vulnerable than the ones going to the hands.
The most common symptoms are:

1. Numbness
2. Tingling
3. Abnormal sensations called dysesthesias
4. A characteristic form of pain, called neuropathic pain or neuralgia: people usually describe it as “pins and needles,” a steady burning sensation or “electric shocks.” These pains can be difficult to describe: typically pains, like stubbing your toe or stepping on something sharp, are transmitted through pain fibers. Neuropathy also involves other neurological pathways, so that the brain receives impressions that it cannot process.

There has been a revolution in out understanding of neuropathic pain in recent years. It is now considered to be a disease rather than a symptom. Normal pain is designed to protect you: you put your foot on a hot plate and you pull it away immediately. Neuropathic pain is different: it is non-protective and it persists and therefore behaves like a disease.

Multiple different classes of medications have been shown to be effective in some people with neuropathic pain, though most are not approved for use by the Food and Drug Administration:

1. Lidocaine patches and creams
2. Capsaicin creams
3. Opioid analgesics
4. Tricyclic antidepressants
5. Serotonin-norepinephrine reuptake inhibitors (SNRIs)
6. Anticonvulsants: Carbamazepine; gabapentin; pregabalin

Earlier this week, data presented at the European Federation of IASP (International Association for the Study of Pain) Chapters (EFIC) indicated that an innovative combination of painkillers might hold the key to unlocking the severe and relatively untreatable pain of peripheral neuropathy.

Dr Magdi Hanna, Director of Pain Clinical Research Hub at King's College Hospital in London, has been studying the combination of the strong opioid oxycodone (OxyContin) with gabapentin (neurontin) in over 300 patients with severe diabetic neuropathy. This combination demonstrated a significant 33% improvement on top of the best pain relief achievable using the maximum tolerated dose of gabapentin as monotherapy. The study was part funded by one of the medicine manufacturers.

This study is good news, but even in this study there were a great many people who were not helped. In another blog item, I’m going to talk about some of the unorthodox approaches that have helped some people.

A Missing Link: Serotonin, Inflammation and Psychiatric Illness

We have previously looked at the extraordinarily high rates of inflammation in psychiatric illnesses, as well as the evidence implicating disturbances in the serotonin transporter and an array of psychiatric and physical illnesses, including fibromyalgia and irritable bowel syndrome. Disturbances in serotonin homeostasis as well inflammation-promoting (pro-inflammatory) cytokines have both been implicated as causative factors in major mental illness. So the hunt has been on to see if there’s some way of uniting these two causative pathways.

There’s an exceptional important paper out this week in the journal Neuropsychopharmacology.

Investigators from the Vanderbilt University School of Medicine in Nashville, Tennessee, have established that the pro-inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters. Using rat cells, they were able to show the precise mechanism by which these cytokines could regulate the activity of the serotonin transporter.

So why is this so important? Not only does it open up several new options for treating mental illness, but it may also explain some puzzles.

It’s recently been shown that mental illness is more common in overweight people. Large amounts of fat in the abdomen act as a kind of inflammation factory, soaking the circulation in inflammatory mediators. So here we have a link between ever expanding waistlines and the increasing rates of mental illness in the population. It’s not just stress and environmental overload; it is likely also fat causing inflammation.

Restless Legs Syndrome

Restless legs syndrome (RLS) is a common (3-15% of the population) and sometimes very unpleasant problem in which people have uncontrollable urges to move their legs. If they do not move, they will begin to feel uncomfortable, painful or odd sensations in their legs, and sometimes also in other parts of the body. The restlessness may last for minutes or even hours. Movement affords people very temporary relief. The sensations are usually between the ankle and the knees, but they can also involve the thighs. If other parts of the body are involved it always makes us question the diagnosis.

The severity of the problem is highly variable, running from a mild annoyance to an incapacitating problem. In most people the symptoms are worse when sitting or at night, and often lead to loss of sleep. Not surprisingly many people feel of exhausted and irritable during the day.

With such enormous variations in the severity of the problem, and even the parts of the legs affected, it is highly likely that RLS is a symptom of a group of illnesses.

The International Restless Legs Syndrome Study Group (IRLSSG) identified four criteria that must be present for an RLS diagnosis:

1. An urge to move, usually due to uncomfortable sensations that occur primarily in the legs.
2. Motor restlessness, expressed as activity, that relieves the urge to move.
3. Worsening of symptoms by relaxation.
4. Variability over the course of the day-night cycle, with symptoms worse in the evening and early in the night.

About 80% of the people with restless legs syndrome also suffer from a separate condition called periodic limb movements in sleep (PLMS). Periodic limb movements in sleep are involuntary jerking movements in extremities, usually the legs. You can have PLMS without having RLS, and vice versa.

RLS may start at any age, including early childhood, and is a progressive disease for a certain percentage of sufferers, although it has been known for the symptoms to disappear permanently in some sufferers. The condition runs in families; children of RLS sufferers are more likely than other people to develop RLS.

It has some similarities to a syndrome known as akathisia that occurs in people taking some medications that work in the dopamine pathways of the brain. There are some subtle ways of telling the two apart, but RLS also seems to be caused by disturbances in one of the dopamine pathways of the brain.

It has been known for many years that there is an association between RLS and iron deficiency, but this link is probably not causal: just giving iron only helps a proportion of sufferers. But because of this link, everyone with RLS should have their ferritin levels tested; ferritin levels should be at least 75 mcg for those with RLS. If it’s below this level, iron supplements may help, but they are best administered by a physician, because ferritin needs to be monitored and there are down sides to taking too much iron. In a moment I'll tell you about some very new research on iron and RLS

Caffeine and other stimulants usually make RLS worse. Restless legs syndrome frequently occurs during pregnancy. About 15% of pregnant women develop RLS symptoms during the last few months of their pregnancy. The sensations usually stop after the woman delivers the baby.

We normally divide RLS into primary and secondary. Primary RLS usually starts before age 40 and the onset is often slow. The RLS may disappear for months, or even years. But it can be progressive and get worse as the person ages.

Secondary RLS often had a sudden onset and may be daily from the very beginning. Apart from pregnancy, secondary RLS is a result of a number of medical conditions, so it is always important to rule them out. They include:

1. Iron deficiency anemia
2. Macrocytic anemia due to folate or vitamin B12 deficiency
3. Diabetes mellitus
4. Peripheral neuropathy
5. Alcohol abuse
6. Some types of cancer, particularly of the lung
7. Celiac disease
8. Renal failure
9. Inflammatory arthritis

There have been reports of associations of RLS with other illnesses, but most seem rare. Interestingly people who undergo surgery often find that RLS symptoms become worse, which may be another clue as to the cause of the problem.

An international conference entitled SLEEP 2006, the 20th Anniversary Meeting of the Associated Professional Sleep Societies took place from June 17-22, 2006 in Salt Lake City, Utah. There were a great many interesting papers this year, including several on RLS

An international group of collaborators presented the results of the first population-based pediatric RLS survey. They used the National Institutes of Health pediatric RLS diagnostic criteria and collected data from over 10,000 families. The criteria for definite RLS were met in 1.9% of 8- to 11-year-olds and in 2% of 12- to 17-year-olds. Two different papers explored the value of using a single screening question to identify possible RLS patients. Those who answered, “Yes,” then answered more detailed questions to determine whether they met the International RLS Study Group diagnostic criteria.

A single screening question can eliminate people without RLS rapidly and direct appropriate subjects to further evaluation. Two groups of researchers found a high level of sensitivity with the question, "When you try to relax in the evening or sleep at night, do you ever have unpleasant, restless feelings that can be relieved by walking or movement?"

As I mentioned, it has been known for decades that RLS may be associated with low iron, and especially with low ferritin levels. These may be present in symptomatic RLS patients during pregnancy and in people with iron-deficiency anemia and end-stage renal disease. Previous studies had suggested that supplemental iron was beneficial for RLS patients with low ferritin levels. One paper presented further evidence of the possible efficacy of supplemental iron in the treatment of selected RLS patients with a prospective, randomized, placebo-controlled, double-blind study of RLS patients with low to normal ferritin levels (15-75 mcg/L). The RLS subjects were given either placebo or iron 325 mg twice daily and were monitored with a validated RLS symptom scale. The preliminary findings showed that the iron supplementation group had significant increases in their ferritin levels and had improved quality of life compared with those on placebo; however, the interim data presented did not show a significant change in the RLS symptom score. The study is ongoing.

Treatment for RLS is based on how disruptive the symptoms are. Apart from iron, people should review their lifestyle and see what changes could be made to reduce or eliminate their RLS symptoms. These include: Finding the right level of exercise (too much worsens it, too little may trigger it)
Eliminating caffeine
Stopping smoking
Reducing alcohol intake

Several drugs have been tried for RLS: Some of the same medications used in Parkinson's disease, benzodiazepines, anticonvulsants like carbamazepine and gabapentin.

Last month saw the publication of an important paper indicating that the medicine pramipexole, another anti-Parkinsonan drug, helps many people with RLS

In the next article I shall review some of the other approaches used by Integrated Medicine.

Psychiatric Illnesses and Fibromyalgia

There’s an interesting and important article in last month’s issue of the Journal of Clinical Psychiatry, by a group of investigators from the University of Cincinnati.

They have shed important new light on fibromyalgia. We’ve recently learned how it is linked to disturbances of the serotonin transporter, as well as anti-inflammatory proteins, and that is may respond best to the kind of comprehensive multi-leveled approaches that we use in Integrated Medicine.

The new research compared people with fibromyalgia with people with rheumatoid arthritis, and it found that fibromyalgia, but not rheumatoid, may be associated with a range of psychiatric illnesses:

1. Major depressive disorder
2. Bipolar disorder
3. Comorbid anxiety disorders including panic disorder, social phobia, posttraumatic stress disorder and obsessive-compulsive disorder
4. Eating disorders and
5. Substance abuse

What was particularly important in this study was that the psychiatric problems usually preceded the onset of fibromyalgia. So it wasn’t that people were developing psychological problems because they were in chronic pain.

It’s beginning to look as if fibromyalgia is part of a larger group of disorders that all share common etiologies or causes. Family studies have indicated that fibromyalgia and mood disorders share some of the same - perhaps genetic - determinants.

The study also confirms what we have said before: fibromyalgia is not only associated with some psychiatric problems, but also with other medical disorders, several of which may also co-exist with the same psychiatric problems. They include:

1. Chronic fatigue syndrome
2. Irritable bowel syndrome
3. Interstitial cystitis
4. Multiple chemical sensitivities and
5. Migraine

Not only does this research highlight the need to check people with fibromyalgia to see if they might also be struggling with a psychiatric problem, but it is helping us home in on some of the mechanisms linking these apparently separate problems.

This particular study was done mainly in white women, and the investigators knew who had fibromyalgia, so there’s more work to be done.

But if you or a loved one is struggling with fibromyalgia, it is good news to know that we are making rapid progress in unraveling this horrible illness.

Rheumatoid Arthritis: A Neurological Disease?

For more than a century, there’s has been a puzzle in rheumatology. Why is it that so many people with inflammatory arthritis get symmetrical involvement of their joints? It is very common for people to get exactly the same joints involved in both hands or in both feet.

Sometimes joints get affected by arthritis because they have already been subjected to a lot of wear and tear: that’s thought to be one of the reasons why gout most often affects the big toe. But the symmetrical pattern of arthritis is far more difficult to understand. There has been speculation for at least 30 years that this symmetry indicates neurological involvement in the disease, and there was a stimulating paper on the topic seventeen years ago, and it has been known for some time that artificially induced arthritis in one joint produces inflammatory changes in the same joint on the other side of the body.

Now investigators from the University of California at San Diego School of Medicine have published an important discovery. Rheumatoid arthritis drugs work better, at least in arthritic rats, when delivered into the central nervous system. Rheumatoid arthritis (RA) is a disease in which there is chronic inflammation, leading to joint pain and destruction. Pain and inflammation in the joints are constantly monitored by the central nervous system, and we have known for many years that the nervous system can regulate inflammation and immune responses. It was demonstrated in the 1960s that damage to certain regions in the hypothalamus of the brain could impair the work of the immune system. The scientists from San Diego focused on a protein called p38, which is involved in a number of cellular processes critical to the development of RA. Several substances that block the action of p38 are effective in animal models of arthritis and are currently being tested in clinical trials in patients with RA.

Pain and inflammation activate p38 in the brain and spinal cord, and blocking it by introducing medicines directly into the central nervous system reduces inflammation in joints.

This is important research, because it opens up new possibilities for treating an illness that can often be very difficult to treat. It may also help explain another observation. Some patients with rheumatoid arthritis who are treated with acupuncture get a reduction in joint symptoms and sometimes even repair of some of the damage to the cartilage in their joints. Experienced acupuncturists see this in about a third of patients whom they treat, so it was a surprise to see a review claiming that acupuncture did not help RA. If we see a disconnect between clinical observation and a research study, there are two options: either clinicians are deluding themselves or there’s something wrong with the research method. Interestingly, there’s recently been a great deal of discussion about the kind of research methodology that produced this negative result, prompted by a very interesting and challenging paper.

My conclusion? Acupuncture may indeed be a valuable adjunctive treatment for RA. But whether it will work on its own remains less certain.

And the best approach of all is to address the physical, psychological, social, subtle and spiritual dimensions of a person with RA. In other words, the new form of Integrated Medicine that I describe in Healing, Meaning and Purpose.

Probiotics: Caveat Emptor

You may well have heard the advice that we all need to keep the bacetria in our intestines healthy. Countless experts have recommended that, as long as we are not lactorse intolerant, we should regularly take some live yoghurt to "re-colonize" our intestines with nice friendly bacteria.

There has just been a briefing in London to warn the public that as many as half of the "probiotic" or "friendly bacteria" products on sale in the United Kingdom could be ineffective and some may even be harmful.

The experts on the panel included Professor Glen Gibson from the University of Reading who is an expert in food microbiology, and recommended sticking to products made by major manufacturers. Too many of the other productsmight not contain the numbers of bacteria advertised, and the icrobes might not survive long enough in the intestines to do much good.

The evidence that probiotics help is still far from settled, as discussed in a recent review. But there are enough reports to think that probiotics may be helpful for irritable bowel syndrome and perhaps inflammatory bowel disease.

An even newer area or interest in the use of "prebiotics:"  short-chain carbohydrates that alter the composition, or metabolism, of the intestinal organisms in a beneficial way.

Make sure that if you are using a product, it comes from a reputable manufacturer, and that it contains at least 10 million bacteria. And as I said in my title, "Caveat Emptor," "Let the buyer beware."

Parkinson’s Disease, Allergies and Inflammation

The symptoms of Parkinson’s disease have been reported throughout history, but it was first described in the modern era by the great Scottish neurologist James Parkinson in 1817. Even after all these years, we still do not know all that much about what causes it. There’s an interesting study in the August issue of the journal Neurology, which is the official publication of the American Academy of Neurology.

Investigators from the Mayo Clinic used what is known as a case-control design (196 cases and 196 matched controls). What they found was that people who suffered from hay fever or allergic rhinitis, are 2.9 times more likely to develop Parkinson’s disease over a 20-year period.

The researchers did not find any association with autoimmune illnesses such as lupus, rheumatoid arthritis, pernicious anemia or vitiligo. They also did not find any association with asthma.

In addition, people who developed Parkinson’s disease used anti-inflammatory agents less frequently than controls, although this result was not statistically significant. The results may support the hypothesis that there is an inflammatory component in the causation of Parkinson’s disease.

You may ask, “Why on earth would anyone even look at a link like this?” The answer is that there have been previous reports of an association between the use of non-steroidal anti-inflammatories and lower rates of Parkinson’s disease in men but not in women and Alzheimer’s diseases.

This study does not suggest that hay fever causes Parkinson’s disease: it provides evidence for an association between the two. Parkinson’s is probably a group of illnesses with different causes. However, if chronic inflammation around the upper airways could produce inflammation in the brain, we might have a whole new way of preventing a degenerative brain disease.

In a future posting I’ll talk about some natural methods for reducing the burden of inflammation in your body.

How Does Fiber Help You?

Unless you’ve been living on Mars (!), you will doubtless have heard of the advantages of increasing the amount of fiber in your diet. A high-fiber diet reduces your risk of colon cancer, constipation, hemorrhoids hypercholesterolemia and insulin resistance syndrome.

We have always wanted to know how fiber does so many magical things at once, and now we may an answer. In a paper published in the open-access Public Library of Science Biology today, by a group from one our local institutions – the Medical College of Georgia in Augusta – collaborating with a researcher from Josai University, Sakado, Saitama in Japan.

The epithelial cells lining the intestine have a life span measured in 1-5 days. They spend their short life times working to process enormous amounts of food residue on its way past. It is this layer of cells that acts as the barrier between the body and items floating past on the inside of the intestine.

Long before it became the topic of some popular books are over-enthusiastic magazine articles, we became very interested in the idea of the “Leaky gut:” the concept that some illnesses are a result of breakdown of the normal integrity of this protective barrier. Over 20 years ago, a friend and colleague at Northwick Park Hospital - Ingvar Bjarnason - did some pioneering work on this important issue. Several recent studies have indicated that a breakdown of this barrier may be involved in several childhood illnesses including allergies and asthma. There is also some early information suggesting that “leaky gut” may be involved in some autoimmune processes involving the intestine. Both zinc supplementation and oats may prevent gut leakiness under certain very specific circumstances.

When the epithelial cells in the gut wall encounter indigestible fibrous foods, the outer covering of the cell ruptures, releasing a coating of cell-protecting mucus. In a matter of seconds, the cell begins to repair itself, in the process releasing yet more of the beneficial mucus. Not only does it lubricate, but also it may keep some carcinogens and allergens out of your system.

The constant buffeting of the cells causes mild damage that increases the level of lubricating mucus. Injury at the cellular level promotes the health of the gastrointestinal tract as a whole.

Here we see a basic principle of nature: many of the same things that apply in the cells of the body apply equally in the life of someone trying to achieve success. Without the buffeting, the cells of the intestine could not produce the mucus on which your life depends.

Without some occasional adversity, you will find it more difficult to grow as a human being.

“Storms make oaks take deeper root.”
-- George Herbert (English Religious Poet, 1593-1633)

“He who knows no hardships will know no hardihood. He who faces no calamity will need no courage. Mysterious though it is, the characteristics in human nature which we love best grow in a soil with a strong mixture of troubles.”
--Harry Emerson Fosdick (American Clergyman, Writer and Broadcaster, 1878-1969)

Toxoplasmosis, Behavior and Mental Illness

This title may seem odd, but this item may actually turn out to have enormous implications for all of us.

A couple of years ago I read a fascinating book: Parasites and the Behavior of Animals, in which the author – Janice Moore from Colorado State University – cataloged some of the extraordinary ways in which parasites can impact the behaviors of a vast array of animals. As difficult as it is to interpret studies of parasites in humans, I kept coming back to some odd observations about an illness with which I’ve been involved for more than 30 years: schizophrenia. I kept wondering if some of the odd observations made over the years could be explained by the parasites?

What kind of odd observations?

1. Reports of mental illness have been found throughout history, yet this strange illness that we now call schizophrenia seems to have been very rare until about 1750, when it increased dramatically throughout Western Europe. I have had the privilege of working at the Bethlem Royal Hospital from which got the word “bedlam.” I know of the incredible records kept there. Something began to change in some of the types of patients being admitted at that time. I have also had the opportunity to look at some of the records at the Philip’s Hospital in Southern Germany, which has been in existence since 1533. Again the records show the sudden appearance of many cases of something that had been quite rare until then. 1750 marked the early years of the industrial revolution in Europe and the mass migration of people from the countryside to the new and very crowded cities
2. There has been recent evidence that being born and raised in a city increases your chance of developing schizophrenia.
3. There is increasing evidence that acute episodes of psychosis, mania and depression are associated with increases in circulating inflammatory mediators. There is also intriguing new data that both psychosis and depression can be improved by giving people COX2 inhibitors.
4. There has also been the strange observation that bipolar disorder may have been becoming more common in recent years, over and above our greater ability to recognize the illness.

Several years ago the well-known psychiatrist E. Fuller Torrey first suggested that a small protozoal parasite called Toxoplasma gondii might be responsible for all of these observations. Cats can carry it, which is why pregnant mothers are advised not to pet their cats during pregnancy.

The idea that such a complex disease as schizophrenia might sometimes be caused by a parasite caught the media’s attention, but in recent years the story – but not the ongoing research – died down a bit.

There was an excellent and provocative blog item by Carl Zimmer about this almost three weeks ago, but I wanted to check everything out before responding. He gave a brief review of a new paper published in the Proceedings of the Royal Society, by Kevin Lafferty from the University of California in Santa Barbara. Lafferty has attempted to correlate the varying rates of Toxoplasma in different countries with predominant personality traits and therefore – since our societies are aggregates of all our personalities, cultural characteristics.

That may all sound far-fetched, but I don’t think that it is. And I don’t think that the Proceedings would have taken a completely half-baked proposition.

I have also found a report published in the journal the Proceedings of the Biological Society. Four eminent authors, including Torrey, revisited the while issue of Toxoplasmosis and mental illness. When the parasite gets into the nervous system it can alter behavior: Rats are normally programmed to avoid cats, but once infected they are attracted to cats. Over the last few days I’ve been plowing the world literature, and I’ve learned some very interesting things that support the idea that Toxoplasma may be playing a role in several different types of psychiatric illness.

There is strong evidence that schizophrenia, bipolar disorder and major depressive disorder lie on a spectrum. The illnesses are not the same, but people often switch from one type of clinical presentation to another. The precise type if illness would be determined by the interaction of genes, physical and Intrapsychic environment. Nobody would be sufficiently naïve to try and reduce the whole of psychiatric illness to a single bug. Mental illness is a great deal more than just a physical problem, and apart from anything else, the rates of Toxoplasma infections show remarkable variations around the globe, while the rates of major mental illness are much the same everywhere.

So what have I learned?

1. There are a remarkable numbers of studies showing that many people with schizophrenia have antibodies to Toxoplasma, including people having their first attack of the illness
2. Blood donors infected with Toxoplasma have decreased levels of novelty-seeking
3. In women who become infected, there are some marked changes in personality.
4. Toxoplasma affects the dopamine systems of the brain that we know are intimately involved in mood, cognition, movement and motivation.
5. Some drugs used to treat psychosis (haloperidol) and mood disorder (valproic acid) inhibit the replication of Toxoplasma gondii. The valproic acid already does it at concentrations lower than we normally aim for when treating humans.
6. There is some intriguing work going on into the use of antibiotics to kill Toxoplasma and reverse its behavioral effects.

In the last few years, so many illnesses have turned out to have infectious origins, from peptic ulcers to arteriosclerosis and some cancers. Perhaps some mental illnesses will be next.

Last year Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine for their pioneering work on Helicobacter. I have a strong sense that there are more prizes to come on the interaction between infectious agents, inflammation, genes, the psyche and the environment.

Perhaps the reason that some antipsychotics and mood stablizers can reverse some of the neurological damage associated with schizophrenia and bipolar disorder is becuase they are killing off the causative agents and allowing the brain to repair itself.

I shall keep you posted!

Blueberries

One of the principles of integrated medicine is that anything that’s good for you should have more than one benefit. So omega-3 fatty acids may help with cardiovascular health, mood, memory, attention deficit disorder, as well as the health of skin and bones.

Another one is the blueberry. I’ve been sufficiently impressed by the data on the health benefits of blueberries to have been a regular grower and consumer for years. They contain a number of potentially healthful compounds including polyphenols and anthocyanins, which can help modulate and balance the free radical systems of the body. Remember what I said recently about the value of keeping some free radicals in the body? The last thing that we want to do is to be rid of all of them!

There is reasonably good evidence that regularly eating blueberries can support cardiovascular health and there have been suggestions that they may reduce the risk and aggression of cancers of the prostate and colon.

There is also some evidence in animals that some of the components of blueberries may reduce inflammation and the effects of strokes – interruptions to the blood flow in the brain.

As a consumer, I’ve been carefully watching the growing evidence indicating that blueberries – or some of their constituents may have effects on animal cognition, brain aging and the normal neuroprotective mechanisms in the hippocampal region of the brain.

We do not yet have proof that these same effects occur in humans, and there are always three questions when we look at nutritional data:

1. Can we extrapolate from the animal to humans? Mice are not men
2. Are the amounts of blueberries or blueberry extracts even close to what humans could consume without spending all day eating, or getting a terribly upset intestine? There have been countless reports of the benefits of supplements that had to be taken in the most enormous doses to do any good. I’ve mentioned before the problem of L-arginine, which is sold as a “Natural Viagra.” Except that you need to take around nine grams for it to do much good, and most supplements contain less than a tenth of that. Regular readers will also remember my report concerning an article on coffee and sex. It was said that coffee would raise a woman’s libido. And indeed it does, if she drinks at least ten large cups of coffee at once. And coffee is a marvelous diuretic.
3. When extracts are used, are we sure that we are getting the correct ingredient of the fruit? Many beneficial fruits contain just the right combination of nutrients to help us, so each can be taken in a small dosage or concentration. As with so much in integrated medicine, combinations are key. Take out one extract of a fruit, and you may lose the clinical effect that you wanted.

All that being said, the evidence is becoming progressively more interesting, and there is enough suggestive evidence for me to keep packing away the blueberries.

And just to show that I leave no stone unturned when checking the literature on your behalf, I rejoiced to learn that supplementing the diet of Arctic char with various supplements - including blueberries – improved the quality of his, ahem, semen. I do not know how this information will help any of us yet. Neither do I really know why a fish would want to eat blueberries or any of the other supplements that they were tried on. Though I'm sure that people have often asked similar off the wall questions about some of my research....

Chronic Widespread Pain, Fibromyalgia and Anti-inflammatory Proteins

Chronic widespread pain is a common and distressing medical condition that can be difficult to treat and is usually associated with fatigue, poor sleep and depression. One major subgroup is fibromyalgia. A connection between fibromyalgia and cytokines – small proteins that act as messengers between cells – has been suspected for some time, since some cancer patients treated with the cytokine interleukin -2 develop fibromyalgia-like symptoms. A new study from Wurzburg in Germany, published in the August 2006 issue of Arthritis and Rheumatism examined cytokine profiles in patients with chronic widespread pain and found that they had significantly lower levels of the anti-inflammatory cytokines IL-4 and IL-10.

This is an important finding: Previous research has shown that IL-10, administered as a protein or via gene transfer, reduces sensitivity to pain. Similarly, IL-4 has been shown to dull the pain response. There is also another piece to this: genetic variations in different cytokine genes are associated with distinct diseases, such as the association between IL-4 gene variations and asthma, Crohn's disease, and chronic polyarthritis.

Although low levels of anti-inflammatory cytokines could be a consequence of chronic widespread pain and its treatment, it is much more likely that these proteins actually play a role in the causation of chronic widespread pain.

This new research raises all kinds of possibilities for the physical treatment of a particularly horrible set of illnesses.

Cranberries and the Inflammation Associated With Severe Gum Disease

There is an interesting study from a team of researchers from Quebec, Canada. The findings, published in the Journal of Antimicrobial Chemotherapy, reveal that natural compounds in cranberries may help ward off periodontitis, or severe gum disease, by serving as a powerful anti-inflammatory agent. This anti-inflammatory effect may be attributed to unique compounds in the fruit that prevent the bacterium P. gingivalis from adhering to the teeth below the gum line. Though it is early days, this new research offers promise for the estimated 67 million Americans affected by periodontitis, the primary cause of tooth loss in adults.

The reason for the study was that cranberries have what are known as "anti-adhesion" activity. This helps guard the body from certain harmful bacteria that cause urinary tract infections (UTIs), gastric ulcers and gum disease. This anti-adhesion activity is primarily due to molecules called proanthocyanidins (PACs) found naturally in cranberries and other foods. Cranberry PACs contain a unique A-type structure that is responsible for this anti-adhesion mechanism of action, while most other foods contain only the more-common B-type PACs.

Researchers discovered that cranberry compounds can reduce the growth of P. gingivalis and subsequent plaque development -- the initial step in the development of periodontitis. Periodontitis occurs when inflammation or infection of the gums is left untreated or treatment is delayed. Infection and inflammation spreads from the gums to the ligaments and bones that support the teeth and eventually leads to tooth loss.

In a paper in the Journal of Dental Research the same researchers had previously shown that cells treated with cranberry juice showed significantly less inflammation than cells that were not treated.

Not only can cranberry compounds decrease the growth of P. gingivalis, they may also prevent certain oral bacteria from directly destroying gum tissue itself -- another major factor contributing to periodontitis. This may have more widespread implications as recent studies have also linked severe gum disease with an increased likelihood for heart disease and stroke.

The study was part funded by the Ocean Spray agricultural cooperative that sells cranberry juice.

Brushing, flossing and regular professional cleaning reduces the risk of developing periodontitis by helping to prevent the onset of gingivitis, or gum infection. Cranberries may provide an interesting ingredient in the development of new therapeutic approaches for treatment of periodontitis.

Technorati tags: Cranberries Dental disease Heart disease Urinary tract infection Inflammation

Brushing Your Teeth is Good for Your Heart

This was the title of an article in Time magazine and something that I’ve been meaning to discuss for a while now.

We have known for some years now that there can be a link between periodontal bacteria and heart disease, but a new study from the Department of Health Sciences in Kristianstad University, in Sweden and published in the Journal of Periodontology.

The researchers found the presence of specific bacteria in periodontal pockets, which are those areas of tissue surrounding teeth, that might be an explanation for the relationship between periodontal disease and acute coronary syndrome (ACS). ACS is the term used to describe insufficient blood supply to the heart muscle that results in heart disease.

The investigators compared 161 subjects diagnosed with ACS with a control group of people who did not have cardiovascular disease. They found that the bacterial burden - the amount of oral bacteria –was twice as high in the ACS group for the combination for the bacteria streptococci, and three less common bacteria: P. gingivalis, T. forsythia and T. denticola. These findings suggest that this combination of bacteria is the link between periodontitis and ACS.

The periodontal bacteria cause an inflammatory response that elevates the white blood cell count and increases one of the key inflammatory markers: high sensitivity C-reactive protein levels in the blood, a factor which has been linked in past studies to heart disease.

Alveolar bone loss—atrophy of the bones that support your teeth—was also found to be significantly greater among subjects with ACS. The extent of bone loss was more severe in the ACS group than in the non-ACS group with 77%of the participants in the ACS group afflicted with periodontitis versus 42% in the control group.

The study highlights the importance of routine periodontal examinations and at-home dental care, particularly if you have a personal or family history of heart disease.

Technorati tags: Periodontal disease Heart disease Inflammation Dental hygiene

How Many Angels Can Dance on the Head of a Needle? Moving Beyond the Metabolic Syndrome

I have written a great deal both on this blog and in scholarly articles, about insulin resistance and the insulin resistance and metabolic syndromes.

You will have noticed that I’ve always used the term insulin resistance syndrome.

This is not a matter of semantics. For years now I’ve been worried about the splitting that’s been going on in the field: we currently have six sets of definitions of the metabolic syndrome. And apart from the fun of going to all those conferences in exotic parts of the world, you have to ask what’s been achieved by these ever more divisive attempts to “define” the medical consequences of insulin resistance.

The American Diabetes Association has begun to promote the concept of “cardiometabolic risk.” The Association has established a national Cardiometabolic Risk Initiative (CMRI) to stress the association between diabetes, heart disease and stroke. The idea of introducing this umbrella term is to help people better understand and manage all diabetes and cardiovascular risk factors, and to side-step some of the controversy surrounding the definition of insulin resistance or metabolic syndrome and which cluster of variables are in and out.

A new Cardiometabolic Risk (CMR) Calculator to help us evaluate an individual’s risk of diabetes or vascular disease should be available by the end of the year.
The formula already includes factors such as:
1.    Body mass index
2.    Waist circumference ratio
3.    Fasting plasma glucose
4.    HDL-cholesterol
5.    LDL-cholesterol
6.    Triglycerides
7.    Apolipoprotein B
8.    Blood pressure
9.    C-reactive protein
10.  Age
11.  Sex
12.  Race/ethnic origin
13.  Family history
14.  Tobacco use

Part of the reason for this new initiative is the discovery that pre-diabetes, or impaired fasting glucose, where plasma glucose levels are 100-125 mg/dl, is associated with a high prevalence of cardiovascular disease risk factors such as obesity, hypertension and dyslipidemias.

The person who first proposed the insulin resistance syndrome, a.k.a. syndrome X, a.k.a. metabolic syndrome, is Gerald Reaven who first recognized the syndrome in a landmark paper in 1988. He recently gave a lecture entitled; “Insulin Resistance Versus Metabolic Syndrome: Different Names, Different Concepts, Different Goals.” I am in complete agreement with his basic proposition, which is that insulin resistance explains the clustering of all of the components that make up the metabolic syndrome. So Gerry’s position is that there’s no point in trying to make a diagnosis of metabolic syndrome: everything is due to insulin resistance.

So instead of wasting time and resources in trying to diagnose metabolic syndrome, it is much better to understand the pathophysiology: what is going on at the molecular level, how these processes produce risk factors, and whether we can predict others. We should identify and treat each of the underlying processes and the complications of insulin resistance. If we are going to have a syndrome, it should be called insulin resistance syndrome.

And let’s stop these academic debates and get on with the job at hand: there is a 600% variation in peoples’ ability to have insulin transport glucose into cells. More than half the US population is destined to develop at least some degree of insulin resistance, so we need to look for better ways to identify people who have it, and to apply the principles of integrated medicine to keeping them healthy.

Technorati tags: Insulin resistance Insulin resistance syndrome Metabolic syndrome Cardiovascular disease Hypertension Inflammation Hyperlipidemia Weight gain Integrated medicine

Oxidative Stress and Insulin Resistance

As we have discussed before, insulin resistance is a cardinal feature of type 2 diabetes, and is an important factor in many other illnesses. Last year saw the publication of a study from Albert Einstein College of Medicine in New York, showing that high levels of blood glucose induced an inflammatory response in fat cells, and reactive oxygen species was a key player in the process.

Now, a very interesting paper in the journal Nature indicates that fat storage cells exposed to chemicals (dexamethasone and tumor necrosis factor-α) raise the levels of reactive oxygen species and these raise insulin resistance. If the cells are then treated to suppress this production, insulin resistance falls. We have been interested in balancing the oxidant and antioxidant systems to reduce the risk of the complications of diabetes, but now it looks as if antioxidants may also help the underlying disease process itself.

In a future blog I'm going to explain why free radicals and oxidative stress are not all bad: they are key cancer killers!

And in one of the programs coming out later this year, I shall explain how to modulate oxidative stress to keep your systems in constant dynamic balance.

Technorati tags: Oxidative stress Inflammation Insulin resistance Free radicals

Another Controller of Appetite and Weight

We recently discussed the role of cytokines in modulating appetite and energy balance. Now a study in mice has shown that animals deficient in interleukin-18 (IL-18) develop a voracious appetite, very marked obesity and insulin resistance. The insulin resistance is secondary to the obesity that was induced by increased food intake and occurred in the liver as well as muscle and fat.

When the little creatures were given recombinant IL-18 their food intake returned toward normal.

Only recently discovered, IL-18 is an important regulator of innate and acquired immune responses. The fact that a modulator or immunity and inflammation has a key role in feeding and in energy metabolism shows us once again just how closely all these systems are tied together. You lose weight when you are sick or depressed because the body is battling the illness. As you recover, the body needs to replace everything that was lost and re-establish your resilience. These systems don’t just exist in humans, they are found in all mammals and even some birds and fish. So they have evolved over millions of years and we need to be very careful about tinkering with these complex systems. Or of allowing stress or environmental toxins to compromise these protective mechanisms.

This finding may well pave the way not just for new pharmacological approaches to weight management, but also to some non-pharmacological approaches.

Technorati tags: Cytokines Weight management Insulin resistance Interleukin-18 Inflammation

Cytokines and Weight

Anyone who has ever had a sick child knows that one of the surest signs that he or she is recovering is a return of appetite. From a biological perspective, this is an attempt by the body to make up for any losses that took place during the illness. The major mediator of this effect is one set of a group of chemicals known as cytokines.

Cytokines are glycoproteins that behave like hormones and neurotransmitters, serving as chemical messengers between cells. There are many families of cytokines, including leptin, that we have met before. In recent years most of the attention of researchers has been directed not at the cytokines themselves, but at their receptors, whose activity is far more subtle.

Cytokine receptors are involved in the regulation of cell growth and repair and have important roles in immune responses. Apart from their role in feeding behavior, cytokines have roles in fatigue, fever, sleep, pain and stress. Some key cytokines: interleukin (IL)-1,  IL-6 and IL-8 are dysregulated in fibromyalgia.

At a meeting of the 6th International Congress of Neuroendocrinology in Pittsburgh last month, researchers from the Centre National de la Recherche Scientifique (CNRS) at the Pasteur Institute and the University of Lille, France, presented evidence that The cytokine interleukin-7 (IL-7) is not only involved in immune function, but also prevents obesity-prone mice from getting fat. This is the converse of those cytokines that cause weight gain. IL-7 interacts with the regions of the hypothalamus involved in appetite control. This is yet another piece of evidence indicating that the immune and neuroendocrine systems are closely inter-linked.

This is not really a surprise. One of the big problems I people with many chronic illness, particularly cancer, is that they tend to lose appetite and weight. Sometimes they lose a great deal of weight even while maintaining a decent diet. The anorexia of cancer is caused by many factors working on the signaling pathways in the hypothalamus that modulate energy homeostasis. Research has shown that cytokines are major mediators of weight and appetite loss in cancer patients, by working on two systems known as melanocortin and neuropeptide-Y. It also seems likely that the weight loss that happens with stress, depression and chronic inflammation are all mediated by specific cytokines. These same cytokines increase the risk of developing heart disease. A recent study from Ireland has shown that treatment with an SSRI antidepressant reduces measures of systemic inflammation.

It may be that this new insight into the relationship between inflammation and weight will offer up some more solutions for the problems of obesity, but we are going to need to be alert to the possibility that anything that modulates cytokines may increase the risk of vascular disease.

The more that we learn, the more that we understand about the miraculous checks and balances that keep us healthy.

Technorati tags: Cytokines Leptin Cancer cachexia Weight control Inflammation